Tetrahydrobenzofuranodiazepine compounds and their pharmaceutical applications

Abstract

The present invention provides compounds having Pim-1 inhibitory activity. The present invention provides compounds of formula [I] or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, and pharmaceutical uses thereof. The symbols are as defined in the specification.

Description

Technical Field

[0001] The present invention relates to tetrahydrobenzofuranodiazepines having Pim-1 inhibitory activity A ketone compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and pharmaceutical use thereof. Background Art

[0002] Pim-1 (Proviral Integration Site for Moloney murine leukemia virus-1) is a member of the Pim family of proto-oncogene serine / threonine kinases. Pim-1 is expressed downstream of receptors for cytokines such as interleukin (IL)-2, 3, 5, 6, 7, 12, 15, and 22, the hematopoietic stimulating factor GM-CFS (granulocyte macrophage colony-stimulating factor), and the growth-derived factors VEGF (vascular endothelial growth factor) and PDGF (platelet-derived growth factor). Ligand binding to these receptors induces Pim-1 expression and constitutively activates downstream signaling through PI3K-AKT, JAK / STAT, and NF-kB signaling. It is known that Pim-1 inhibits apoptosis by phosphorylating BAD (Bcl-2-associated death promoter) and ASK1 (apoptosis signal-regulating kinase 1), and promotes cell proliferation by phosphorylating p21, p27, cdc25, and c-Myc (Non-Patent Documents 1 and 2). Therefore, Pim-1 inhibitors are expected to be effective against diseases related to apoptosis and cell proliferation.

[0003] The use of Pim-1 inhibitors will be described below.

[0004] (1) Pulmonary arterial hypertension (PAH)

[0005] It is reported that in an observational study, Pim-1 expression was increased in the plasma of PAH patients compared to healthy subjects, and the expression level was correlated with 6-minute walk distance and pulmonary vascular resistance, which are indicators of pathological conditions (non-patent literature 3). In addition, it is also reported that increased expression of Pim-1 was observed in pulmonary artery smooth muscle cells (PASMC) isolated from PAH patients, and that cell proliferation, which had increased compared to PASMC from healthy subjects, was inhibited by knocking down Pim-1. In addition, it is also reported that in a non-clinical study using a rat PAH model, knocking down Pim-1 inhibited increased pulmonary artery pressure and thickening of the medial wall of the pulmonary artery, which are characteristic pathologies of PAH (non-patent literature 4). Based on these findings, Pim-1 inhibitors are expected to inhibit medial wall thickening by inhibiting the proliferation of pulmonary artery smooth muscle cells, thereby improving the pathological conditions of PAH.

[0006] (2) Cancer

[0007] It is reported that in clinical studies, cancers that increase the expression level of Pim-1 include hematological cancers (acute lymphocytic leukemia, acute myeloid leukemia, diffuse large B-cell lymphoma, multiple myeloma) (non-patent document 5), colon cancer (non-patent document 6), pancreatic cancer (non-patent document 7), prostate cancer (non-patent document 8), bladder cancer (non-patent document 9), osteosarcoma (non-patent document 10), breast cancer (non-patent document 11), etc. Among them, acute myeloid leukemia, colon cancer, pancreatic cancer, osteosarcoma and breast cancer are reported to have a correlation between the expression level of Pim-1 and life prognosis, and cell proliferation is inhibited by knocking down Pim-1 in cell lines (non-patent documents 6, 12, 7, 10, 11, 14). Therefore, Pim-1 inhibitors are particularly expected to show therapeutic effects on the above-mentioned cancers.

[0008] It has also been reported that the Pim-1 inhibitor SMI-4a exhibits growth inhibitory and apoptosis-inducing effects on cells derived from chronic myeloid leukemia (Non-Patent Document 15), while the pan-Pim-1 inhibitor INCB053914 exhibits growth inhibitory effects on various blood cancer cells such as acute myeloid leukemia, multiple myeloma, diffuse large B-cell lymphoma, and myeloproliferative neoplasms, and also exhibits tumor growth inhibition in mouse cancer models (Non-Patent Documents 16 and 17). Therefore, Pim-1 inhibitors are also expected to exhibit therapeutic effects on the above-mentioned cancers.

[0009] (3) Psoriasis

[0010] It is known that in psoriasis, inflammatory cells infiltrate the epidermis and dermis as the dermal blood vessels are remodeled, which causes inflammation. Increased expression of Pim-1 has been observed in the dermal blood vessels of human psoriasis patients, and Pim-1 is believed to be involved in its remodeling. It is reported that in non-clinical studies, epidermal thickness and inflammatory cell infiltration observed in IL-22-induced psoriasis-like skin inflammation model animals were inhibited by knocking down Pim-1 (non-patent literature 13). According to the above findings, Pim-1 inhibitors are expected to show a therapeutic effect on psoriasis by inhibiting the remodeling of dermal blood vessels.

[0011] (4) Systemic lupus erythematosus (SLE)

[0012] Lupus nephritis (LN) is a glomerulonephritis caused by SLE. Increased expression of Pim-1 was observed in peripheral blood mononuclear cells (PBMC) of human SLE patients and in the kidneys of LN patients. In a study using human podocytes, it was found that knockdown of Pim-1 reduced inflammation-related signals NFATc1 and IL-1β. In a non-clinical study using mouse LN model animals, it was found that the Pim-1 inhibitor SMI-4a reduced glomerular damage, reduced urine albumin / creatinine ratio and improved mortality (Non-Patent Literature 18). Based on the above findings, Pim-1 inhibitors are expected to show a therapeutic effect on LN associated with SLE by inhibiting inflammation.

[0013] Reference List

[0014] Non-patent literature

[0015] [Non-patent document 1] Laurent Brault, Christelle Gasser, Franz Bracher, Kilian Huber, Stefan Knapp and Juerg Schwaller1: PIM serine / threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers. Haematologica. 2010 Jun;95(6):1004-15.

[0016] [Non-patent document 2] Patrizia Mondello, Salvatore Cuzzocrea, and Michael Mian: Pimkinases in hematological malignancies: where are we now and where are we going? J Hematol Oncol. 2014 Dec 10;7:95.

[0017] [Non-patent document 3] Se'bastien Renard, Roxane Paulin, Sandra Breuils-Bonnet, Serge Simard, Philippe Pibarot, Se'bastien Bonnet and Steeve Provencher: Pim-1: A new biomarker in pulmonary arterial hypertension. Pulm Circ. 2013 Jan;3(1):74-81.

[0018] [Non-Patent Document 4] Roxane Paulin, MSc; Audrey Courboulin, MSc; Jolyane Meloche, BSc; Vincent Mainguy, MSc; Eric Dumas de la Roque, MD; Nehme’Saksouk, PhD; JacquesCo^te’, PhD; Steeve Provencher, MD; Mark A. Sussman, PhD; Se’bastien Bonnet, PhD: Signal Transducers and Activators of Transcription-3 / Pim1 Axis Plays aCritical Role in the Pathogenesis of Human Pulmonary ArterialHypertension. Circulation. March 22, 2011; 123(11): 1205-15.

[0019] [Non-Patent Document 5] Pablo D. Garcia, John L. Langowski, Yingyun Wang, Min Chen, Joseph Castillo, Christie Fanton, Marjorie Ison, Tatiana Zavorotinskaya, Yumin Dai, Jing Lu, Xiao-Hong Niu, Stephen Basham, Julie Chan, Jianjun Yu, Michael Doyle, Paul Feucht, Robert Warne, Jamie Narberes, Tiffany Tsang, Christine Fritsch, Audrey Kauffmann, Estelle Pfister, Peter Drueckes, Joerg Trappe, Christopher Wilson, Wooseok Han, Jiong Lan, Gisele Nishiguchi, Mika Lindvall, Cornelia Bellamacina, J. Alex Aycinena, Richard Zang, Jocelyn Holash and Matthew T. Burger: Pan-PIM Kinase Inhibition Provides a Novel Therapy for Treating Hematologic Cancers. Clin Cancer Res. April 1, 2014; 20(7): 1834-45.

[0020] [Non-Patent Document 6] Yong-hai Peng, Jian-jun Li, Fang-wei Xie, Jian-fang Chen, Ying-hao Yu, Xue-nong Ouyang, Houjie Liang: Expression of pim-1 in Tumors, Tumor Stroma and Tumor-Adjacent Mucosa Co-Determines the Prognosis of Colon Cancer Patients. PLoS One. October 7, 2013; 8(10): e76693.

[0021] [Non-patent document 7] Jianwei Xu, Guangbing Xiong, Zhe Cao, Hua Huang, Tianxiao Wang, Lei You, Li Zhou, Lianfang Zheng, Ya Hu, Taiping Zhang and Yupei Zhao: PIM-1 contributes to the malignancy of pancreatic cancer and displays diagnostic and prognostic value. J Exp Clin Cancer Res. 2016 September 5; 35(1):133.

[0022] [Non-patent document 8] TL Cibull, TD Jones, L Li, JN Eble, L Ann Baldridge, SR Malott, Y Luo, L Cheng: Overexpression of Pim-1 during progression of prostatic adenocarcinoma. J Clin Pathol. 2006 Mar; 59(3): 285-8

[0023] [Non-patent document 9] Shengjie Guo, Xiaopeng Mao, Junxing Chen, Bin Huang, Chu Jin, Zhenbo Xu, Shaopeng Qiu: Overexpression of Pim-1 in bladder cancer. J Exp Clin Cancer Res. 2010 Dec 11;29:161.

[0024] [Non-patent document 10] Yunfei Liao Yong Feng Jacson Shen Yan Gao Gregory CoteEdwin Choy David Harmon Henry Mankin Francis Hornicek Zhenfeng Duan: Clinical and biological significance of PIM1 kinase in osteosarcoma. J Orthop Res. 2016 July; 34(7): 1185-94.

[0025] [Non-Patent Document 11] Horiuchi D, Camarda R, Zhou AY, Yau C, Momcilovic O, Balakrishnan S, Corella AN, Eyob H, Kessenbrock K, Lawson DA, Marsh LA, Anderton BN, Rohrberg J, Kunder R, Bazarov AV, Yaswen P, McManus MT, Werb Z, Goga A: PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression. Nat Med. November 2016; 22(11): 1321-1329.

[0026] [Non-Patent Document 12] Ulrike Weirauch, Nadine Beckmann, Maren Thomas, Arnold Grünweller, Kilian Huber, Franz Bracher, Roland K. Hartmann and Achim Aigner: Functional Role and Therapeutic Potential of the Pim-1 Kinase in Colon Carcinoma. Neoplasia. July 2013; 15(7): 783-94.

[0027] [Non-Patent Document 13] Perera GK, Ainali C, Semenova E, Hundhausen C, Barinaga G, Kassen D, Williams AE, Mirza MM, Balazs M, Wang X, Rodriguez RS, Alendar A, Barker J, Tsoka S, Ouyang W, Nestle FO: Integrative biology approach identifies cytokine targeting strategies for psoriasis. Sci Transl Med. February 12, 2014; 6(223): 223ra22.

[0028] [Non-Patent Document 14] Hui Cheng, Chongmei Huang, Xiaoqiao Xu, Xiaoxia Hu, Shenglan Gong, Gusheng Tang, Xianimn Song, Weiping Zhang, Jianmin Wang, Li Chen and Jianmin Yang: PIM-1 mRNA expression is a potential prognostic biomarker in acute myeloid leukemia. J Transl Med. 2017; 15: 179.

[0029] [Non-Patent Document 15] Rui-Fang Fan, Ying Lu, Zhi-Gang Fang, Xiao-Yan Guo, Yu-Xin Chen, Yi-Chuan Xu, Ya-Mei Lei, Ke-Fang Liu, Dong-Jun Lin, Ling-Ling Liu, Xiang-Fu Liu: PIM-1 kinase inhibitor SMI-4a exerts antitumor effects in chronic myeloid leukemia cells by enhancing the activity of glycogen synthase kinase 3β. Mol Med Rep. October 2017; 16(4): 4603-4612.

[0030] [Non-Patent Document 16] Holly Koblish, Yun-long Li, Niu Shin, Lesile Hall, Qian Wang, Kathy Wang, Maryanne Coveington, Cindy Marando, Kevin Bowman, Jason Boer, Krista Burke, Richard Wynn, Alex Margulis, Gary W. Reuther, Que T. Lambert, Varerie Dostalik Roman, Ke Zhang, Hao Feng, Chu-Biao Xue, Sharon Diamond, Greg Hollis, Swamy Yeleswaram, Wenqing Yao, Reid Huber, Kris Vaddi, Peggy Scherle: Preclinical characterization of INCB053914, a novel pan-PIM Kinase inhibitor, alone and in combination with anticancer agents, in models of hematologic malignancies. PLoS One. June 21, 2018; 13(6):e0199108.

[0031] [Non-Patent Document 17] Lucia Mazzacurati, Robert J. Collins, Garima Pandey, Que T. Lambert-Showers, Narmin E. Amin, Ling Zhang, Matthew C. Stubbs, Pearlie K. Epling-Burnette, Holly K. Koblish, Gary W. Reuther: The pan-PIM inhibitor INCB053914 displays potent synergy in combination with ruxolitinib in models of MPN. Blood Adv. November 26, 2019; 3(22):3503-3514.

[0032] [Non-patent document 18] Rong Fu MD, PhD, Yong Xia MD, PhD, Meirong Li BS, Renxiang Mao MD, Chaohuan Guo MD, Mianjing Zhou MD, Hechang Tan MD, PhD, Meiling Liu BS, Shuang Wang MD, PhD, Niansheng Yang MD, PhD, Jijun Zhao MD, PhD: Pim-1 as a Therapeutic Target in Lupus Nephritis. Arthritis Rheumatol. 2019 Aug;71(8):1308-1318. Summary of the Invention

[0033] The present invention provides a tetrahydrobenzofuranodiazepine having Pim-1 inhibitory activity Ketone compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the same, pharmaceutical uses thereof, etc. Accordingly, the present invention includes the following exemplary embodiments.

[0034] [Project 1]

[0035] A compound of formula [I] or a pharmaceutically acceptable salt thereof:

[0036]

[0037] in

[0038] Cy 1 yes

[0039] (1)C 3-7 Cycloalkyl,

[0040] (2) a 4- to 7-membered heterocycloalkyl group containing one or two heteroatoms independently selected from oxygen and sulfur atoms (the sulfur atom may be oxidized) as ring-forming atoms other than carbon atoms,

[0041] (3)C 5-8 bridged cycloalkyl,

[0042] (4) a 7- to 9-membered bridged heterocycloalkyl group containing one oxygen atom as a ring-forming atom other than a carbon atom,

[0043] (5)C 7-11 spirocycloalkyl, or

[0044] (6) 7- to 11-membered spiroheterocycloalkyl groups containing 1 to 3 oxygen atoms as ring atoms other than carbon atoms;

[0045] R of quantity m 1 Each independently

[0046] (1) Halogen,

[0047] (2) hydroxyl groups,

[0048] (3)C 1-6 Alkyl, wherein the alkyl group is optionally substituted with

[0049] (a) hydroxyl groups,

[0050] (b)C 1-4 Alkoxy,

[0051] (c) cyano,

[0052] (d)OCOR 11 , where R 11 is phenyl, or

[0053] (e)SO2R 12 , where R 12 It is C 1-4 alkyl,

[0054] (4)C 1-4 haloalkyl, wherein the haloalkyl is optionally substituted with hydroxy,

[0055] (5)C 1-4 Alkoxy, wherein the alkoxy is optionally substituted with 1 to 3 halogens,

[0056] (6)COR 13 , where R 13 yes

[0057] (a) hydroxyl, or

[0058] (b)NR 14 R 15 , where R 14 and R 15 are each independently hydrogen or C 1-4 alkyl,

[0059] (7) cyano group,

[0060] (8)SO2R 16 , where R 16 It is C 1-4 alkyl,

[0061] (9)C 3-4 cycloalkyl, wherein the cycloalkyl is optionally substituted with hydroxy, or

[0062] (10) triazole, or

[0063] Two R bonded to the same carbon atom 1 Together they form an oxygen subunit (oxo);

[0064] R of number n 2 Each independently

[0065] (1) Halogen, or

[0066] (2)C 1-4 Alkoxy, or

[0067] Two R bonded to the same carbon atom 2 Together with the carbon atoms to which they are bonded, they form C 3-4 Cycloalkanes;

[0068] R 3 and R 4 Each independently

[0069] (1) Hydrogen, or

[0070] (2)C 1-4 Alkyl, or

[0071] R 3 and R 4 Together with the carbon atoms to which they are bonded, they form C 3-4 Cycloalkanes;

[0072] R 5 is hydrogen or C 1-4 alkyl;

[0073] R 6 It is C 1-4 Haloalkyl;

[0074] R 7 is hydrogen or a halogen;

[0075] L is a straight chain C 1-4 alkylene;

[0076] m is 0, 1, 2, 3, or 4; and

[0077] n is 0, 1, 2 or 3.

[0078] [Project 2]

[0079] The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R 5 It's hydrogen.

[0080] [Item 3]

[0081] The compound according to item 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is ethylene or trimethylene.

[0082] [Item 4]

[0083] The compound according to any one of items 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 7It's hydrogen.

[0084] [Item 5]

[0085] The compound according to any one of items 1 to 4 or a pharmaceutically acceptable salt thereof, wherein the number of R is n 2 are each independently a halogen, or two R 2 Together with the carbon atoms to which they are bonded, they form C 3-4 Cycloalkane.

[0086] [Item 6]

[0087] The compound according to Item 1 or a pharmaceutically acceptable salt thereof, which is represented by formula [III]:

[0088]

[0089] in

[0090] The number of R is n1 2a are each independently halogen;

[0091] L a is ethylene or trimethylene;

[0092] n1 is 0, 1, or 2; and

[0093] Cy 1 、R 1 、R 3 、R 4 、R 6 and m are as defined in item 1.

[0094] [Item 7]

[0095] The compound according to any one of items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein

[0096] Cy 1 yes

[0097] (1)C 3-7 Cycloalkyl,

[0098] (2) a 4- to 7-membered heterocycloalkyl group containing one or two heteroatoms independently selected from oxygen and sulfur atoms (the sulfur atom may be oxidized) as ring-forming atoms other than carbon atoms,

[0099] (3)C 7-11 spirocycloalkyl, or

[0100] (4) A 7- to 11-membered spiroheterocycloalkyl group containing 1 to 3 oxygen atoms as ring-constituting atoms other than carbon atoms.

[0101] [Item 8]

[0102] The compound according to any one of items 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 6 yes

[0103] (1) monofluoromethyl,

[0104] (2) difluoromethyl, or

[0105] (3) Trifluoromethyl.

[0106] [Item 9]

[0107] The compound according to any one of items 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Each independently

[0108] (1) Hydrogen, or

[0109] (2) methyl, or

[0110] R 3 and R 4 Together with the carbon atom to which they are bonded, they form cyclopropane.

[0111] [Item 10]

[0112] The compound according to any one of items 1 to 9 or a pharmaceutically acceptable salt thereof, wherein the number of R is m 1 Each independently

[0113] (1) Halogen,

[0114] (2) hydroxyl groups,

[0115] (3)C 1-6 Alkyl, wherein the alkyl group is optionally substituted with

[0116] (a) hydroxyl groups,

[0117] (b)C 1-4 Alkoxy,

[0118] (c) cyano, or

[0119] (d)SO2R 12 , where R 12 It is C 1-4 alkyl,

[0120] (4)C 1-4 haloalkyl, wherein the haloalkyl is optionally substituted with hydroxy,

[0121] (5)C 1-4 Alkoxy, wherein the alkoxy is optionally substituted with 1 to 3 halogens,

[0122] (6)COR 13 , where R13 yes

[0123] (a) hydroxyl, or

[0124] (b)NR 14 R 15 , where R 14 and R 15 are each independently hydrogen or C 1-4 alkyl,

[0125] (7) cyano group,

[0126] (8)SO2R 16 , where R 16 It is C 1-4 Alkyl, or

[0127] (9)C 3-4 cycloalkyl, wherein the cycloalkyl is optionally substituted with hydroxy, or

[0128] Two R bonded to the same carbon atom 1 Together they form oxygen subunits.

[0129] [Item 11]

[0130] A compound selected from the group consisting of compounds of the following formula:

[0131]

[0132] or a pharmaceutically acceptable salt thereof.

[0133] [Item 12]

[0134] A pharmaceutical composition comprising the compound according to any one of items 1 to 11 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0135] [Item 13]

[0136] A Pim-1 inhibitor comprising the compound according to any one of items 1 to 11 or a pharmaceutically acceptable salt thereof.

[0137] [Item 14]

[0138] A therapeutic or preventive agent for treating or preventing a disease selected from pulmonary hypertension, cancer, psoriasis and systemic lupus erythematosus, comprising the compound according to any one of items 1 to 11 or a pharmaceutically acceptable salt thereof.

[0139] [Item 15]

[0140] A method for inhibiting Pim-1 in a mammal, comprising administering a therapeutically effective amount of a compound according to any one of items 1 to 11 or a pharmaceutically acceptable salt thereof to the mammal.

[0141] [Item 16]

[0142] A method for treating or preventing a disease selected from pulmonary hypertension, cancer, psoriasis and systemic lupus erythematosus in a mammal, comprising administering a therapeutically effective amount of a compound according to any one of items 1 to 11 or a pharmaceutically acceptable salt thereof to the mammal.

[0143] [Item 17]

[0144] Use of the compound according to any one of items 1 to 11 or a pharmaceutically acceptable salt thereof for preparing a Pim-1 inhibitor.

[0145] [Item 18]

[0146] Use of the compound according to any one of items 1 to 11 or a pharmaceutically acceptable salt thereof for the preparation of a therapeutic or preventive agent for treating or preventing a disease selected from pulmonary hypertension, cancer, psoriasis and systemic lupus erythematosus.

[0147] [Item 19]

[0148] The compound according to any one of items 1 to 11 or a pharmaceutically acceptable salt thereof, for use in inhibiting Pim-1.

[0149] [Item 20]

[0150] The compound according to any one of items 1 to 11 or a pharmaceutically acceptable salt thereof, for use in treating or preventing a disease selected from pulmonary hypertension, cancer, psoriasis and systemic lupus erythematosus.

[0151] Embodiments of the present invention

[0152] The definitions of terms used herein are as follows.

[0153] Examples of "halogen" include fluorine, chlorine, bromine and iodine. Preferred "halogen" is fluorine.

[0154] “C 1-6 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1,1-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl. Preferred "C 1-6 "Alkyl" refers to methyl, ethyl and isopropyl.

[0155] “C 1-4 "Alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms. 1-4Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Preferred "C 1-4 "Alkyl" refers to methyl, ethyl and isopropyl.

[0156] "Straight Chain C 1-4 "Alkylene" refers to a divalent group derived from a straight-chain saturated hydrocarbon having 1 to 4 carbon atoms. "Straight-chain C 1-4 Examples of "alkylene" include methylene, ethylene, trimethylene and tetramethylene. Preferred "straight chain C 1-4 "Alkylene" refers to methylene, ethylene and trimethylene.

[0157] “C 1-4 "Haloalkyl" refers to the above-mentioned "C 1-4 Alkyl". "C 1-4 Examples of "haloalkyl" include monofluoromethyl, monochloromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1,1-difluoropropyl, 3,3,3-trifluoropropyl and 4-fluorobutyl. Preferred "C 1-4 "Haloalkyl" is monofluoromethyl, difluoromethyl, trifluoromethyl and 1,1-difluoroethyl.

[0158] “C 3-7 "Cycloalkyl" refers to a 3 to 7-membered monocyclic saturated hydrocarbon group. 3-7 Examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred "C 3-7 "Cycloalkyl" is cyclopropyl, cyclobutyl and cyclohexyl.

[0159] “C 3-4 "Cycloalkyl" refers to a 3- to 4-membered monocyclic saturated hydrocarbon group. 3-4 Examples of "cycloalkyl" include cyclopropyl and cyclobutyl. Preferred "C 3-4 "Cycloalkyl" refers to cyclopropyl and cyclobutyl.

[0160] “C 3-4 "Cycloalkane" refers to a 3- to 4-membered monocyclic saturated hydrocarbon. 3-4 Examples of "cycloalkane" include cyclopropane and cyclobutane. Preferred "C 3-4 "Cycloalkane" is cyclopropane.

[0161] “C 5-8 "Bridged cycloalkyl" refers to a 5- to 8-membered bridged saturated cyclic hydrocarbon group. 5-8 Examples of "bridged cycloalkyl" include bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl and bicyclo[2.2.2]octyl. Preferred "C 5-8"Bridged cycloalkyl" is bicyclo[1.1.1]pentyl.

[0162] “C 7-11 "Spirocycloalkyl" refers to a 7- to 11-membered spiro-type saturated cyclic hydrocarbon group. 7-11 Examples of "spirocycloalkyl" include spiro[3.3]heptyl, spiro[4.5]decyl and spiro[5.5]undecyl. Preferred "C 7-11 "Spirocycloalkyl" is spiro[3.3]heptyl.

[0163] “C 1-4 "Alkoxy" refers to the above-mentioned "C 1-4 Alkyl" is a group bonded to an oxygen atom. 1-4 Examples of "alkoxy" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. Preferred "C 1-4 "Alkoxy" is methoxy.

[0164] A “4- to 7-membered heterocycloalkyl group containing one or two heteroatoms independently selected from oxygen and sulfur atoms (the sulfur atom may be oxidized) as ring-forming atoms other than carbon atoms” refers to a 4- to 7-membered monocyclic saturated heterocyclic group containing one or two heteroatoms independently selected from oxygen and sulfur atoms (the sulfur atom may be oxidized) as ring-forming atoms other than carbon atoms. The sulfur atom may be oxidized. Examples of the “4- to 7-membered heterocycloalkyl group containing one or two heteroatoms independently selected from oxygen and sulfur atoms (the sulfur atom may be oxidized) as ring-forming atoms other than carbon atoms” include oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrahydrothiopyranyl, 1,1-dioxotetrahydrothiopyranyl, and oxepanyl. Preferred “4- to 7-membered heterocycloalkyl groups containing one or two hetero atoms independently selected from oxygen and sulfur atoms (the sulfur atom may be oxidized) as ring-constituting atoms other than carbon atoms” are oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,1-dioxotetrahydrothiopyranyl and oxepanyl groups.

[0165] A "7- to 9-membered bridged heterocycloalkyl group containing one oxygen atom as a ring-forming atom other than a carbon atom" refers to a 7- to 9-membered bridged saturated heterocyclic group containing one oxygen atom as a ring-forming atom other than a carbon atom. Examples of the "7- to 9-membered bridged heterocycloalkyl group containing one oxygen atom as a ring-forming atom other than a carbon atom" include 7-oxabicyclo[2.2.1]heptyl, 8-oxabicyclo[3.2.1]octyl, and 2-oxabicyclo[3.2.2]nonyl. A preferred "7- to 9-membered bridged heterocycloalkyl group containing one oxygen atom as a ring-forming atom other than a carbon atom" is 8-oxabicyclo[3.2.1]octyl.

[0166] A “7- to 11-membered spiroheterocycloalkyl group containing 1 to 3 oxygen atoms as ring-forming atoms other than carbon atoms” refers to a 7- to 11-membered spiro-type saturated heterocyclic group containing 1 to 3 oxygen atoms as ring-forming atoms other than carbon atoms. Examples of the “7- to 11-membered spiroheterocycloalkyl group containing 1 to 3 oxygen atoms as ring-forming atoms other than carbon atoms” include 2-oxaspiro[3.3]heptyl, 2,6-dioxaspiro[3.4]octyl, 2,7-dioxaspiro[3.5]nonyl, 1,3-dioxaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl, 1,4,8-trioxaspiro[4.5]decyl, and 3-oxaspiro[5.5]undecyl. Preferred “7- to 11-membered spiroheterocycloalkyl groups containing 1 to 3 oxygen atoms as ring-constituting atoms other than carbon atoms” are 2-oxaspiro[3.3]heptyl, 2,7-dioxaspiro[3.5]nonyl, 1,3-dioxaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl and 1,4,8-trioxaspiro[4.5]decyl.

[0167] The expression "substituent A is optionally substituted by substituent B" means that substituent A is unsubstituted or substituted by substituent B at any substitutable position (any hydrogen is replaced by substituent B). For example, "C optionally substituted by hydroxyl" 1-4 "Alkyl" means C 1-4 The alkyl group is unsubstituted or substituted with a hydroxy group at any substitutable position thereof.

[0168] The following examples illustrate specific embodiments of each group of compounds of formula [I] (hereinafter also referred to as "compound [I]"), which should not be construed as limiting. Compound [I] also includes combinations of two or more embodiments appropriately selected from the specific embodiments of each group.

[0169] Cy 1 Preferably

[0170] (1)C 3-7 Cycloalkyl,

[0171] (2) a 4- to 7-membered heterocycloalkyl group containing one or two heteroatoms independently selected from oxygen and sulfur atoms (the sulfur atom may be oxidized) as ring-forming atoms other than carbon atoms,

[0172] (3)C 7-11 spirocycloalkyl, or

[0173] (4) A 7- to 11-membered spiroheterocycloalkyl group containing 1 to 3 oxygen atoms as ring-constituting atoms other than carbon atoms.

[0174] Cy 1 More preferably

[0175] (1)C 3-7 Cycloalkyl,

[0176] (2) a 4- to 7-membered heterocycloalkyl group containing one or two heteroatoms independently selected from oxygen and sulfur atoms (the sulfur atom may be oxidized) as ring-forming atoms other than carbon atoms, or

[0177] (3) A 7- to 11-membered spiroheterocycloalkyl group containing 1 to 3 oxygen atoms as ring-constituting atoms other than carbon atoms.

[0178] Cy 1 Even more preferably

[0179] (1)C 3-7 Cycloalkyl, or

[0180] (2) A 4- to 7-membered heterocycloalkyl group containing one or two hetero atoms independently selected from oxygen and sulfur atoms (the sulfur atom may be oxidized) as ring-constituting atoms other than carbon atoms.

[0181] Cy 1 Still more preferably

[0182] (1) Cyclohexyl,

[0183] (2) tetrahydropyranyl, or

[0184] (3) 1,4-Dioxane.

[0185] As a specific embodiment, Cy 1 is a group represented by the following formula:

[0186]

[0187] The wavy line indicates the binding site with L.

[0188] R of quantity m 1 Preferably, each independently

[0189] (1) Halogen,

[0190] (2) hydroxyl groups,

[0191] (3)C 1-6 Alkyl, wherein the alkyl group is optionally substituted with

[0192] (a) hydroxyl groups,

[0193] (b)C 1-4 Alkoxy,

[0194] (c) cyano, or

[0195] (d)SO2R 12 , where R 12 It is C 1-4 alkyl,

[0196] (4)C 1-4 haloalkyl, wherein the haloalkyl is optionally substituted with hydroxy,

[0197] (5)C 1-4 Alkoxy, wherein the alkoxy is optionally substituted with 1 to 3 halogens,

[0198] (6)COR 13 , where R 13 yes

[0199] (a) hydroxyl, or

[0200] (b)NR 14 R 15 , where R 14 and R 15 are each independently hydrogen or C 1-4 alkyl,

[0201] (7) cyano group,

[0202] (8)SO2R 16 , where R 16 It is C 1-4 Alkyl, or

[0203] (9)C 3-4 Cycloalkyl, wherein the cycloalkyl is optionally substituted with hydroxy, or two R bonded to the same carbon atom 1 Together they form oxygen subunits.

[0204] R of quantity m 1 More preferably, each independently

[0205] (1) Halogen,

[0206] (2) hydroxyl groups,

[0207] (3)C 1-6 Alkyl, wherein the alkyl group is optionally substituted with

[0208] (a) hydroxyl, or

[0209] (b)SO2R 12 , where R 12 It is C 1-4 alkyl,

[0210] (4)C 1-4 haloalkyl, wherein the haloalkyl is optionally substituted with hydroxy,

[0211] (5)C 1-4 Alkoxy, wherein the alkoxy is optionally substituted with 1 to 3 halogens,

[0212] (6) cyano, or

[0213] (7)C 3-4 cycloalkyl, wherein the cycloalkyl is optionally substituted with hydroxy, or

[0214] Two R bonded to the same carbon atom 1 Together they form oxygen subunits.

[0215] R of quantity m 1 More preferably, each independently is

[0216] (1) Fluorine,

[0217] (2) hydroxyl groups,

[0218] (3)C 1-4 Alkyl, wherein the alkyl group is optionally substituted with

[0219] (a) hydroxyl, or

[0220] (b)SO2R 12 , where R 12 It's methyl.

[0221] (4)C 1-4 haloalkyl, wherein the haloalkyl is optionally substituted with hydroxy,

[0222] (5) methoxy, wherein the methoxy is optionally substituted by 1 to 3 fluorine groups,

[0223] (6) cyano, or

[0224] (7) cyclopropyl, wherein the cyclopropyl is optionally substituted with hydroxy, or

[0225] Two R bonded to the same carbon atom 1 Together they form oxygen subunits.

[0226] As a specific embodiment, the number of R is m 1 R is each independently fluoro, hydroxy, methyl, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropan-2-yl, methoxymethyl, cyanomethyl, (benzoyloxy)methyl, (methylsulfonyl)methyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1-difluoro-2-hydroxyethyl, methoxy, difluoromethoxy, carboxyl, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, cyano, methylsulfonyl, 1-hydroxycyclopropyl, or 1H-1,2,4-triazol-5-yl, or two Rs bonded to the same carbon atom 1 Together they form oxygen subunits.

[0227] R of number n 2 Preferably, each independently is halogen, or two R 2 Together with the carbon atoms to which they are bonded, they form C3-4 Cycloalkane.

[0228] R of number n 2 More preferably, each independently is halogen.

[0229] R of number n 2 Even more preferred is fluorine.

[0230] R 3 and R 4 Preferably, each independently

[0231] (1) Hydrogen, or

[0232] (2) methyl, or

[0233] R 3 and R 4 Together with the carbon atom to which they are bonded, they form cyclopropane.

[0234] R 5 Preferred is hydrogen.

[0235] R 6 Preferred is monofluoromethyl, difluoromethyl or trifluoromethyl.

[0236] R 6 More preferred is trifluoromethyl.

[0237] R 7 Preferred is hydrogen.

[0238] L is preferably an ethylene group or a trimethylene group.

[0239] L is more preferably ethylene.

[0240] m is preferably 0, 1 or 2.

[0241] n is preferably 0, 1 or 2.

[0242] One of the preferred embodiments of compound [I] is the following compound [I], wherein

[0243] Cy 1 yes

[0244] (1)C 3-7 Cycloalkyl,

[0245] (2) a 4- to 7-membered heterocycloalkyl group containing one or two heteroatoms independently selected from oxygen and sulfur atoms (the sulfur atom may be oxidized) as ring-forming atoms other than carbon atoms,

[0246] (3)C 7-11 spirocycloalkyl, or

[0247] (4) 7- to 11-membered spiroheterocycloalkyl groups containing 1 to 3 oxygen atoms as ring atoms other than carbon atoms;

[0248] R of quantity m 1 Each independently

[0249] (1) Halogen,

[0250] (2) hydroxyl groups,

[0251] (3)C 1-6 Alkyl, wherein the alkyl group is optionally substituted with

[0252] (a) hydroxyl groups,

[0253] (b)C 1-4 Alkoxy,

[0254] (c) cyano, or

[0255] (d)SO2R 12 , where R 12 It is C 1-4 alkyl,

[0256] (4)C 1-4 haloalkyl, wherein the haloalkyl is optionally substituted with hydroxy,

[0257] (5)C 1-4 Alkoxy, wherein the alkoxy is optionally substituted with 1 to 3 halogens,

[0258] (6)COR 13 , where R 13 yes

[0259] (a) hydroxyl, or

[0260] (b)NR 14 R 15 , where R 14 and R 15 are each independently hydrogen or C 1-4 alkyl,

[0261] (7) cyano group,

[0262] (8)SO2R 16 , where R 16 It is C 1-4 Alkyl, or

[0263] (9)C 3-4 cycloalkyl, wherein the cycloalkyl is optionally substituted with hydroxy, or

[0264] Two R bonded to the same carbon atom 1 Together they form oxygen subunits;

[0265] R of number n 2 are each independently a halogen, or two R 2 Together with the carbon atoms to which they are bonded, they form C 3-4 Cycloalkanes;

[0266] R 3 and R 4 Each independently

[0267] (1) Hydrogen, or

[0268] (2)C 1-4 Alkyl, or

[0269] R 3 and R 4 Together with the carbon atoms to which they are bonded, they form C 3-4 Cycloalkanes;

[0270] R 5 It is hydrogen;

[0271] R 6 It is C 1-4 Haloalkyl;

[0272] R 7 It is hydrogen;

[0273] L is ethylene or trimethylene;

[0274] m is 0, 1, 2, 3, or 4; and

[0275] n is 0, 1, 2 or 3.

[0276] Another preferred embodiment of compound [I] is a compound represented by formula [II]:

[0277]

[0278] Among them, Cy 1 、R 1 、R 2 、R 3 、R 4 、R 6 , L, m and n are as defined above.

[0279] Another preferred embodiment of compound [I] is a compound represented by formula [III]:

[0280]

[0281] in

[0282] The number of R is n1 2a are each independently halogen;

[0283] L a is ethylene or trimethylene;

[0284] n1 is 0, 1, or 2; and

[0285] Cy 1 、R 1 、R 3 、R 4 、R 6 and m are as defined above.

[0286] Another preferred embodiment of compound [I] is a compound represented by formula [IV]:

[0287]

[0288] Among them, Cy 1 、R 1 、R 2a 、R 3 、R 4 、R 6 , m and n1 are as defined above.

[0289] Another preferred embodiment of compound [I] is a compound represented by formula [V]:

[0290]

[0291] in

[0292] R 3a and R 4a are each independently hydrogen or methyl, or R 3a and R 4a Together with the carbon atom to which they are bonded, they form cyclopropane; and

[0293] Cy 1 、R 1 、R 2 、R 6 、L a , m and n are as defined above.

[0294] Another preferred embodiment of compound [I] is a compound represented by formula [VI]:

[0295]

[0296] in

[0297] Cy 1a yes

[0298] (1)C 3-7 Cycloalkyl, or

[0299] (2) a 4- to 7-membered heterocycloalkyl group containing one or two heteroatoms independently selected from oxygen and sulfur atoms (the sulfur atom may be oxidized) as ring-constituting atoms other than carbon atoms; and

[0300] R 1 、R 2 、R 3 、R 4 、R 6 , L a , m and n are as defined above.

[0301] Another preferred embodiment of compound [I] is a compound represented by formula [VII], [VIII], [IX], [X], [XI], [XII], [XIII], [XIV], [XV] or [XVI]:

[0302]

[0303] where R 1 、R 2 、R 3 、R 4 、R 6 , L a , m and n are as defined above.

[0304] Another preferred embodiment of compound [I] is a compound represented by formula [XVII], [XVIII] or [XIX]:

[0305]

[0306] in

[0307] m1 is 0 or 1; and

[0308] R 1 、R 2 、R 3 、R 4 、R 6 , L a and n are as defined above.

[0309] Another preferred embodiment of compound [I] is a compound represented by formula [XX]:

[0310]

[0311] Among them, Cy 1 、R 1 、R 2a 、R 3a 、R 4a 、R 6 , L a , m and n1 are as defined above.

[0312] Another preferred embodiment of compound [I] is a compound represented by formula [XXI]:

[0313]

[0314] Among them, Cy 1 、R 1 、R 2a 、R 3a 、R 4a 、L a , m and n1 are as defined above.

[0315] Another preferred embodiment of compound [I] is a compound represented by formula [XXII]:

[0316]

[0317] Among them, Cy 1 、R 1 、R 2a 、R 3a 、R 4a , m and n1 are as defined above.

[0318] Another preferred embodiment of compound [I] is a compound represented by formula [XXIII]:

[0319]

[0320] in

[0321] R of quantity m 1a Each independently

[0322] (1) Fluorine,

[0323] (2) hydroxyl groups,

[0324] (3)C 1-4 Alkyl, wherein the alkyl group is optionally substituted with

[0325] (a) hydroxyl, or

[0326] (b)SO2R 12 , where R 12 It's methyl.

[0327] (4)C 1-4 haloalkyl, wherein the haloalkyl is optionally substituted with hydroxy,

[0328] (5) methoxy, wherein the methoxy is optionally substituted by 1 to 3 fluorine groups,

[0329] (6) cyano, or

[0330] (7) cyclopropyl, wherein the cyclopropyl is optionally substituted with hydroxy, or

[0331] Two R bonded to the same carbon atom 1 together to form an oxygen subunit; and

[0332] Cy 1a 、R 2a 、R 3a 、R 4a , m and n1 are as defined above.

[0333] Another preferred embodiment of compound [I] is a compound represented by formula [XXIV], [XXV] or [XXVI]:

[0334]

[0335] where R 1a 、R 2a 、R 3a 、R 4a , m and n1 are as defined above.

[0336] Another preferred embodiment of compound [I] is a compound represented by formula [XXVII], [XXVIII] or [XXIX]:

[0337]

[0338] where R 1a 、R 2a 、R 3a 、R 4a , m1 and n1 are as defined above.

[0339] "Pharmaceutically acceptable salts" may be any salt known in the art, as long as they are not associated with excessive toxicity. Specific examples include salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Various forms of pharmaceutically acceptable salts are well known in the art, and they are described in the following literature.

[0340] (a) Berge et al., J. Pharm. Sci., 66, p 1–19 (1977),

[0341] (b) Stahl et al., "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002),

[0342] (c) Paulekuhn et al., J. Med. Chem., 50, p 6665–6672 (2007).

[0343] A pharmaceutically acceptable salt of the compound [I] can be obtained by reacting a compound of the formula [I] with an inorganic base, an organic base, an inorganic acid or an organic acid according to a known method.

[0344] Examples of the salt with an inorganic acid include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid. Preferred examples of the salt with an inorganic acid include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid.

[0345] Examples of salts with organic acids include salts with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glycolylparaaminophenylarsonic acid, hexylresorcinoic acid, acid), hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, teoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, and glutamic acid. Preferred examples of the salt with an organic acid include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and 2-hydroxy-1-ethanesulfonic acid.

[0346] Examples of the salt with an inorganic base include salts with ammonium, aluminum, barium, bismass, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred examples of the salt with an inorganic base include salts with sodium, potassium, calcium, magnesium and zinc.

[0347] Examples of salts with organic bases include salts with arecoline, ammonium, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, and lysine. Preferred examples of salts with organic bases include salts with tris(hydroxymethyl)methylamine, N-methylglucamine, and lysine.

[0348] Compound [I] or a pharmaceutically acceptable salt thereof may exist as a solvate.

[0349] "Solvate" refers to a solvate in which a solvent molecule is coordinated with Compound [I] or a pharmaceutically acceptable salt thereof, and also includes hydrates. The solvate is preferably a pharmaceutically acceptable solvate, and examples thereof include hydrates, ethanolates, and dimethyl sulfoxidates of Compound [I] or a pharmaceutically acceptable salt thereof.

[0350] Specific examples include hemihydrate, monohydrate, dihydrate and monoethanolate of compound [I], monohydrate of sodium salt of compound [I] and 2 / 3 ethanolate of dihydrochloride of compound [I]. These solvates can be obtained according to known methods.

[0351] Compound [I] or a pharmaceutically acceptable salt thereof may exist as tautomers. In this case, compound [I] or a pharmaceutically acceptable salt thereof may be a single tautomer or a mixture thereof.

[0352] Compound [I] or a pharmaceutically acceptable salt thereof may have a carbon-carbon double bond. In this case, compound [I] or a pharmaceutically acceptable salt thereof may exist as E form, Z form or a mixture thereof.

[0353] Compound [I] or a pharmaceutically acceptable salt thereof may contain stereoisomers, which should be identified as cis / trans isomers. In this case, Compound [I] or a pharmaceutically acceptable salt thereof may exist as a cis form, a trans form, or a mixture thereof.

[0354] Compound [I] or a pharmaceutically acceptable salt thereof may contain one or more asymmetric carbon atoms. In this case, compound [I] or a pharmaceutically acceptable salt thereof may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers.

[0355] Compound [I] or a pharmaceutically acceptable salt thereof may exist as an atropisomer. In this case, compound [I] or a pharmaceutically acceptable salt thereof may exist as a single atropisomer or a mixture thereof.

[0356] Compound [I] or a pharmaceutically acceptable salt thereof may contain multiple structural features that give rise to the above-mentioned isomers. In addition, compound [I] or a pharmaceutically acceptable salt thereof may contain the above-mentioned isomers in any ratio.

[0357] Unless otherwise stated, the formulas, chemical structures and compound names indicated herein include all possible isomers without specifying their stereochemistry. For example, the structure represented by the following formula:

[0358]

[0359] Includes all of the following

[0360] (1) A racemate of two enantiomers (S-form and R-form) represented by the following formula:

[0361]

[0362] (2) the S-enantiomer, and

[0363] (3) R-enantiomer,

[0364] Unless otherwise stated.

[0365] Diastereomeric mixtures can be separated into the individual diastereomers by conventional methods such as chromatography and crystallization. Alternatively, individual diastereomers can be produced by using stereochemically unique starting materials or by synthetic methods employing stereoselective reactions.

[0366] Enantiomeric mixtures can be separated into individual single enantiomers by methods well known in the art. For example, first, diastereomeric mixtures can be prepared by reacting a mixture of enantiomers with a substantially pure enantiomeric compound known as a chiral auxiliary. Then, the resulting diastereomeric mixture can be separated into a single diastereomer or a substantially pure single diastereomer with a high isomer ratio by conventional methods such as fractional crystallization and chromatography. Finally, the added chiral auxiliary can be removed by cracking to convert the separated diastereomer into the desired enantiomer. In addition, enantiomeric mixtures can also be directly separated by chromatography using a chiral solid phase well known in the art. Alternatively, one of the enantiomers can be obtained by using substantially pure optically active starting materials or by using a chiral auxiliary and an asymmetric catalyst stereoselective synthesis (asymmetric induction) of a prochiral intermediate.

[0367] The absolute spatial configuration can be determined by X-ray crystallography of crystalline products or intermediates. In this case, if necessary, crystalline products or intermediates derivatized with a reagent having an asymmetric center in known spatial configuration can be used.

[0368] Compound [I] or a pharmaceutically acceptable salt thereof may be modified with isotopes (e.g. 2 H. 3 H. 14 C and 35 S) mark.

[0369] Compound [I] or a pharmaceutically acceptable salt thereof is preferably substantially pure, more preferably has a purity of 80% or more.

[0370] As used herein, the pharmaceutical composition can be prepared according to methods known per se in the art of pharmaceutical preparations by appropriately mixing compound [I] or a pharmaceutically acceptable salt thereof with an appropriate amount of at least one pharmaceutically acceptable carrier, etc. The content of compound [I] or a pharmaceutically acceptable salt thereof in the pharmaceutical composition varies depending on the dosage form, dosage, etc., and is, for example, 0.1 to 100% by weight of the entire composition.

[0371] Examples of dosage forms of compound [I] or a pharmaceutically acceptable salt thereof include oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions and suspensions; and parenteral preparations such as external preparations, suppositories, injections, eye drops, nasal preparations and pulmonary preparations.

[0372] Examples of "pharmaceutically acceptable carriers" include various organic or inorganic carrier substances conventionally used as formulation materials, and specifically include excipients, disintegrants, binders, glidants, lubricants, etc. for solid preparations; solvents, solubilizers, suspending agents, isotonic agents, buffers, soothing agents, etc. for liquid preparations; and bases, emulsifiers, humectants, stabilizers, stabilizing agents, dispersants, plasticizers, pH adjusters, absorption promoters, gelling agents, preservatives, fillers, solvents, solubilizers, suspending agents, etc. for semisolid preparations. Additives such as preservatives, antioxidants, colorants, sweeteners, etc. may be used as necessary.

[0373] Examples of the "excipient" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, gum arabic and the like.

[0374] Examples of the "disintegrant" include carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethyl starch sodium, cross-linked carboxymethylcellulose sodium, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose and the like.

[0375] Examples of the "binder" include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, sodium carboxymethyl cellulose, gum arabic and the like.

[0376] Examples of the "glidant" include light anhydrous silicic acid, magnesium stearate and the like.

[0377] Examples of the "lubricant" include magnesium stearate, calcium stearate, talc and the like.

[0378] Examples of the "solvent" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.

[0379] Examples of the "solubilizer" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like.

[0380] Examples of the "suspending agent" include benzalkonium chloride, carboxymethylcellulose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glyceryl monostearate and the like.

[0381] Examples of the "isotonic agent" include glucose, D-sorbitol, sodium chloride, D-mannitol and the like.

[0382] Examples of the "buffer" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the like.

[0383] Examples of the "soothing agent" include benzyl alcohol and the like.

[0384] Examples of the “base” include water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, purified lanolin, water-absorbing ointment, aqueous lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, etc.), propylene glycol, polyethylene glycol (Macrogol 200 to 600), and combinations of two or more thereof.

[0385] Examples of the "preservative" include ethyl paraben, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like.

[0386] Examples of the "antioxidant" include sodium sulfite, ascorbic acid and the like.

[0387] Examples of the "colorant" include food coloring (such as Food Color Red No. 2 or 3, and Food Color Yellow No. 4 or 5, etc.), β-carotene, and the like.

[0388] Examples of the "sweetener" include saccharin sodium, dipotassium glycyrrhizate, aspartame and the like.

[0389] As used herein, pharmaceutical compositions can be administered orally or parenterally (topically, rectally, intravenously, intramuscularly, and subcutaneously, etc.) to humans and mammals other than humans (mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cattle, horses, sheep, monkeys, etc.). The dosage (hereinafter also referred to as "therapeutically effective amount") varies depending on the subject of administration, disease, symptoms, dosage form, route of administration, etc. For example, based on the active ingredient (i.e., compound [I]), the daily oral dosage for adult patients is generally in the range of about 0.01 mg to 1 gram. This amount can be administered in one or several doses.

[0390] Since compound [I] or a pharmaceutically acceptable salt thereof has Pim-1 inhibitory activity, it is useful as a Pim-1 inhibitor.

[0391] The expression "having Pim-1 inhibitory activity" or "inhibiting Pim-1" means eliminating or weakening Pim-1 activity by inhibiting Pim-1 function. For example, it means inhibiting Pim-1 function under the following conditions of Experimental Example 1.

[0392] "Pim-1" is preferably "human Pim-1".

[0393] Since compound [I] or a pharmaceutically acceptable salt thereof has Pim-1 inhibitory activity, it can be used as an active ingredient for treating or preventing the following diseases, etc.:

[0394] (a) Pulmonary hypertension;

[0395] (b) Cancer, such as hematologic cancers (acute lymphoblastic leukemia, acute myeloid leukemia, multiple myeloma, chronic myeloid leukemia, diffuse large B-cell lymphoma, myeloproliferative neoplasms, etc.), colorectal cancer, pancreatic cancer, prostate cancer, bladder cancer, osteosarcoma, breast cancer, etc.;

[0396] (c) psoriasis; and

[0397] (d) Systemic lupus erythematosus.

[0398] As used herein, "treating" includes ameliorating symptoms, preventing worsening of symptoms, maintaining remission of symptoms, preventing worsening of symptoms, and preventing recurrence of symptoms.

[0399] As used herein, "preventing" or "preventing" refers to inhibiting the onset of symptoms.

[0400] As used herein, the therapeutically effective amount can be appropriately selected depending on the subject of administration, route of administration, target disease, symptoms, severity of the disease, combinations thereof, etc. When compound [I] or a pharmaceutically acceptable salt thereof is orally administered to a human (weighing 60 kg), the lower limit of the therapeutically effective amount is, for example, about 0.01 mg, about 0.1 mg, about 0.5 mg, about 1 mg, about 10 mg, about 20 mg, or about 50 mg per day, and the upper limit of the therapeutically effective amount is, for example, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 500 mg, or about 1000 mg per day.

[0401] As used herein, the frequency of administration of Compound [I] or a pharmaceutically acceptable salt thereof is once, twice, three times or more per day.

[0402] In some embodiments, a Pim-1 inhibitor or pharmaceutical composition may be provided in the form of a kit (such as an administration, treatment, and / or prevention kit), packaging (such as a packaged product), or a medicine set (and / or container) accompanied by written material indicating that it can or should be used to prevent or treat the aforementioned diseases. Such kits, packaging, and medicine sets may include one or more containers containing a Pim-1 inhibitor and / or other drugs or pharmaceuticals (or components). Examples of such kits, packaging, and medicine sets include commercial kits, commercial packaging, and commercial pharmaceuticals, which are appropriately targeted for the treatment and / or prevention of the target disease. Examples of written material included therein include instructions or package inserts, which are in a format specified by a governmental organization regulating the manufacture, use, or sale of drugs or biological products, indicating that the governmental organization has approved the manufacture, use, or sale of the product for human administration. The above-mentioned kits, packaging, and medicine sets may also include packaged products, structures configured for appropriate administration procedures, and structures configured to achieve more preferred medical treatments and / or preventions (including the treatment and / or prevention of the target disease).

[0403] As used herein, presentation of preferred embodiments and options of the compounds, methods, uses and compositions of the invention also encompasses presentation of combinations of such preferred embodiments and options, provided they are combinable and compatible.

[0404] The following explains the preparation method of compound [I] or its pharmaceutically acceptable salt, which should not be construed as limitative. Unless otherwise mentioned, the salt of each compound in the general preparation method can be appropriately selected from the above-mentioned "pharmaceutically acceptable salt".

[0405] The compound obtained in each step can be isolated or purified, if necessary, according to a method known per se, such as distillation, recrystallization and column chromatography, or directly used in the next step without isolation or purification.

[0406] As used herein, room temperature refers to a temperature in a state where the temperature is not controlled, and one embodiment includes 1°C to 40°C.

[0407] Preparation method A1: Preparation method of compound [I] or its salt

[0408] Compound [I] or a salt thereof can be produced, for example, according to the following Production Method A1.

[0409]

[0410] in

[0411] Cy 1 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 , L, m and n are as defined above,

[0412] P 1 is a carboxyl-protecting group (such as methyl and ethyl), and

[0413] P 2 is an amino-protecting group (such as 9-fluorenylmethoxycarbonyl and benzyloxycarbonyl).

[0414] (Step A1-1)

[0415] Compound [A1-4] or a salt thereof can be produced by subjecting compound [A1-1] or a salt thereof to a dehydration condensation reaction with compound [A1-2] or a salt thereof in a solvent and reacting the resulting product with compound [A1-3] or a salt thereof in the presence of a base.

[0416] Examples of the solvent include N,N-dimethylformamide and N,N-dimethylacetamide. A preferred solvent is N,N-dimethylformamide.

[0417] Examples of the base include potassium carbonate and tripotassium phosphate. A preferred base is potassium carbonate.

[0418] The reaction temperature is, for example, 0°C to 30°C, preferably 10°C to 20°C.

[0419] The compound [A1-1] or a salt thereof may be a commercially available product, or can be produced from a commercially available product by a known method.

[0420] Compound [A1-2] or a salt thereof may be a commercially available product, or may be prepared from a commercially available product by a known method. Compound [A1-2] or a salt thereof may also be prepared, for example, according to the following Preparation Method M1 or M2.

[0421] The compound [A1-3] or a salt thereof may be a commercially available product, or can be produced from a commercially available product by a known method.

[0422] (Step A1-2)

[0423] The compound [A1-6] or a salt thereof can be produced by reacting the compound [A1-4] or a salt thereof with the compound [A1-5] or a salt thereof in a solvent in the presence of an acid and a reducing agent.

[0424] Examples of the acid include trifluoroacetic acid. A preferred acid is trifluoroacetic acid.

[0425] Examples of reducing agents include triethylsilane. A preferred reducing agent is triethylsilane.

[0426] Examples of the solvent include toluene and dichloromethane. A preferred solvent is toluene.

[0427] The reaction temperature is, for example, 0°C to 30°C, preferably 10°C to 20°C.

[0428] The compound [A1-5] or a salt thereof may be a commercially available product, or can be produced from a commercially available product by a known method.

[0429] (Steps A1-3)

[0430] Compound [I] or a salt thereof can be prepared by subjecting compound [A1-6] or a salt thereof to P 2 The deprotection reaction can be carried out in a suitable P 2 It is carried out under the conditions of the type.

[0431] For example, when P 2 In the case of 9-fluorenylmethoxycarbonyl, compound [I] or a salt thereof can be produced by reacting compound [A1-6] or a salt thereof in a solvent in the presence of a base, and then subjecting the resulting compound to a cyclization reaction.

[0432] Examples of the base include 1,8-diazabicyclo[5.4.0]undec-7-ene. A preferred base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0433] Examples of the solvent include methanol and tetrahydrofuran. A preferred solvent is methanol.

[0434] The reaction temperature for the deprotection reaction is, for example, 0°C to 60°C, preferably 20°C to 60°C.

[0435] The reaction temperature for the cyclization reaction is, for example, 20°C to 60°C, preferably 50°C to 60°C.

[0436] Alternatively, compound [I] or a salt thereof can also be prepared by using a 1 The above has a known reaction to convert into R 1 This preparation method is carried out by replacing compound [A1-2] or its salt with a compound having a functional group or a protected functional group thereof, and then converting the functional group of the obtained compound corresponding to compound [I] or its salt into R 1 And prepared.

[0437] Preparation method A2: Preparation method of compound [IA] or its salt

[0438] Compound [IA] - wherein R 5 Compound [I] which is hydrogen or a salt thereof can also be produced, for example, according to the following production method A2.

[0439]

[0440] in

[0441] Cy 1 、R 1 、R 2 、R 3 、R 4 、R 6 、R 7 , L, m, n and P 1 As defined above,

[0442] P 3 is an amino-protecting group (such as p-methoxybenzyl and benzyl), and

[0443] Z 1 is a leaving group (e.g., methanesulfonyloxy, bromo, and p-toluenesulfonyloxy).

[0444] (Step A2-1)

[0445] Compound [A2-1] or a salt thereof can be prepared by removing P of compound [A1-4] or a salt thereof by a deprotection reaction. 1 The deprotection reaction can be carried out in a suitable 1 It is carried out under the conditions of the type.

[0446] For example, when P 1 It is C 1-4 In the case of an alkyl group, the compound [A2-1] or a salt thereof can be produced by subjecting the compound [A1-4] or a salt thereof to alkaline hydrolysis in a solvent.

[0447] Examples of the base include lithium hydroxide monohydrate, sodium hydroxide and potassium hydroxide. A preferred base is lithium hydroxide monohydrate.

[0448] Examples of the solvent include methanol, tetrahydrofuran, water, and mixed solvents thereof. A preferred solvent is a mixed solvent of methanol, tetrahydrofuran, and water.

[0449] The reaction temperature is, for example, 20°C to 50°C, preferably 40°C to 50°C.

[0450] (Step A2-2)

[0451] The compound [A2-3] or a salt thereof can be produced by reacting the compound [A2-1] or a salt thereof with the compound [A2-2] or a salt thereof in a solvent in the presence of a condensing agent and a base.

[0452] Examples of the condensing agent include 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate. A preferred condensing agent is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate.

[0453] Examples of the base include N,N-diisopropylethylamine and triethylamine. A preferred base is N,N-diisopropylethylamine.

[0454] Examples of the solvent include N,N-dimethylformamide and N,N-dimethylacetamide. A preferred solvent is N,N-dimethylformamide.

[0455] The reaction temperature is, for example, 0°C to 20°C, preferably 10°C to 20°C.

[0456] The compound [A2-2] or a salt thereof may be a commercially available product, or can be produced from a commercially available product by a known method.

[0457] (Step A2-3)

[0458] Compound [A2-4] or a salt thereof can be prepared by converting the hydroxyl group of compound [A2-3] or a salt thereof into Z 1 This transformation can be carried out in a suitable Z 1 It is carried out under the conditions of the type.

[0459] For example, when Z 1 In the case of a methanesulfonyloxy group, the compound [A2-4] or a salt thereof can be produced by subjecting the compound [A2-3] or a salt thereof to mesylation in a solvent in the presence of a base.

[0460] Examples of the mesylation agent include methanesulfonic anhydride and methanesulfonyl chloride. A preferred mesylation agent is methanesulfonic anhydride.

[0461] Examples of the base include triethylamine and pyridine. A preferred base is triethylamine.

[0462] Examples of the solvent include dichloromethane and tetrahydrofuran. A preferred solvent is dichloromethane.

[0463] The reaction temperature is, for example, 0°C to 20°C, preferably 0°C to 10°C.

[0464] (Step A2-4)

[0465] The compound [A2-5] or a salt thereof can be produced by subjecting the compound [A2-4] or a salt thereof to a cyclization reaction in a solvent in the presence of a base.

[0466] Examples of the base include cesium carbonate and potassium carbonate. A preferred base is cesium carbonate.

[0467] Examples of the solvent include N,N-dimethylformamide and N,N-dimethylacetamide. A preferred solvent is N,N-dimethylformamide.

[0468] The reaction temperature is, for example, 0°C to 30°C, preferably 10°C to 30°C.

[0469] (Step A2-5)

[0470] Compound [IA] or a salt thereof can be prepared by subjecting compound [A2-5] or a salt thereof to P 3 The deprotection reaction can be prepared by a deprotection reaction suitable for P 3 It is carried out under the conditions of the type.

[0471] For example, when P 3 In the case of p-methoxybenzyl group, compound [IA] or a salt thereof can be produced by reacting compound [A2-5] or a salt thereof in a solvent in the presence of an acid.

[0472] Examples of the acid include trifluoroacetic acid and hydrochloric acid. A preferred acid is trifluoroacetic acid.

[0473] Examples of the solvent include anisole. A preferred solvent is anisole.

[0474] The reaction temperature is, for example, 50°C to 90°C, preferably 70°C to 90°C.

[0475] Alternatively, compound [IA] or a salt thereof can also be prepared by using a 1 The above has a known reaction to convert into R 1 This preparation method is carried out by replacing compound [A1-4] or its salt with a compound having a functional group or a protected functional group thereof, and then converting the functional group of the obtained compound corresponding to compound [IA] or its salt into R 1 And prepared.

[0476] Preparation method A3: Another preparation method of compound [IA] or its salt

[0477] Compound [IA] - wherein R 5 Compound [I] which is hydrogen or a salt thereof can also be produced, for example, according to the following production method A3.

[0478]

[0479] in

[0480] Cy 1 、R 1 、R 2 、R 3 、R 4 、R 6 、R 7 , L, m, n and P 1 As defined above,

[0481] P 4 is an amino-protecting group (e.g., tert-butoxycarbonyl),

[0482] P 5 is a hydroxy-protecting group (e.g. C 1-4 alkyl groups, such as methyl, ethyl, etc.), and

[0483] Z 2 is a leaving group (eg, p-toluenesulfonyloxy, bromo, and methanesulfonyloxy).

[0484] (Step A3-1)

[0485] The compound [A3-2] or a salt thereof can be produced by reacting the compound [A1-1] or a salt thereof, the compound [A3-1] or a salt thereof, and the compound [A1-3] or a salt thereof according to step A1-1.

[0486] The compound [A3-1] or a salt thereof may be a commercially available product, or can be produced from a commercially available product by a known method.

[0487] (Step A3-2)

[0488] Compound [A3-3] or a salt thereof can be prepared by removing P of compound [A3-2] or a salt thereof by a deprotection reaction. 4 The deprotection reaction can be carried out in a suitable 4 It is carried out under the conditions of the type.

[0489] For example, when P 4 When it is a tert-butoxycarbonyl group, the compound [A3-3] or a salt thereof can be prepared by reacting the compound [A3-2] or a salt thereof in a solvent in the presence of an acid. The acid and the solvent may be the same.

[0490] Examples of the acid include trifluoroacetic acid and hydrochloric acid. A preferred acid is trifluoroacetic acid.

[0491] Examples of the solvent include trifluoroacetic acid and chloroform. A preferred solvent is trifluoroacetic acid.

[0492] The reaction temperature is, for example, 0°C to 20°C, preferably 10°C to 20°C.

[0493] (Step A3-3)

[0494] The compound [A3-4] or a salt thereof can be produced by reacting the compound [A3-3] or a salt thereof in a solvent in the presence of a base.

[0495] Examples of the base include sodium methoxide and sodium ethoxide. A preferred base is sodium methoxide.

[0496] Examples of the solvent include methanol and ethanol. A preferred solvent is methanol.

[0497] The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 60°C.

[0498] (Step A3-4)

[0499] Compound [A3-5] or a salt thereof can be prepared by 5 Prepared by introducing lactam of compound [A3-4] or its salt. 5 The introduction can be carried out under conditions appropriate to the species.

[0500] For example, when P 5 It is C 1-4 In the case of an alkyl group, the compound [A3-5] or a salt thereof can be produced by alkylating the compound [A3-4] or a salt thereof in a solvent in the presence of a base.

[0501] Examples of the alkylating agent include trimethyloxonium tetrafluoroborate and triethyloxonium tetrafluoroborate. A preferred alkylating agent is trimethyloxonium tetrafluoroborate.

[0502] Examples of the base include cesium carbonate and potassium carbonate. A preferred base is cesium carbonate.

[0503] Examples of the solvent include ethyl acetate and 1,2-dimethoxyethane. A preferred solvent is ethyl acetate.

[0504] The reaction temperature is, for example, 0°C to 30°C, preferably 20°C to 30°C.

[0505] (Steps A3-5)

[0506] The compound [A3-7] or a salt thereof can be produced by reacting the compound [A3-5] or a salt thereof with the compound [A3-6] or a salt thereof in a solvent in the presence of a base.

[0507] Examples of the base include sodium bis(trimethylsilyl)amide and potassium tert-butoxide. A preferred base is sodium bis(trimethylsilyl)amide.

[0508] Examples of the solvent include tetrahydrofuran and N,N-dimethylformamide. A preferred solvent is tetrahydrofuran.

[0509] The reaction temperature is, for example, 0°C to 30°C, preferably 20°C to 30°C.

[0510] Compound [A3-6] or a salt thereof may be a commercially available product, or may be prepared from a commercially available product by a known method. Compound [A3-6] or a salt thereof may also be prepared, for example, according to the following Preparation Method M1 or M2.

[0511] (Step A3-6)

[0512] Compound [IA] or a salt thereof can be prepared by removing P of compound [A3-7] or a salt thereof by a deprotection reaction. 5 The deprotection reaction can be carried out in a suitable 5 It is carried out under the conditions of the type.

[0513] For example, when P 5 It is C 1-4 In the case of an alkyl group, compound [IA] or a salt thereof can be produced by dealkylating compound [A3-7] or a salt thereof in a solvent.

[0514] Examples of the dealkylating agent include hydrochloric acid and acetic acid. A preferred dealkylating agent is hydrochloric acid.

[0515] Examples of the solvent include 1,2-dimethoxyethane and acetic acid. A preferred solvent is 1,2-dimethoxyethane.

[0516] The reaction temperature is, for example, 60 to 90°C, preferably 80 to 90°C.

[0517] Alternatively, compound [IA] or a salt thereof can also be prepared by using a 1 The above has a known reaction to convert into R 1 This preparation method is carried out by replacing compound [A3-6] or its salt with a compound having a functional group or a protected functional group thereof, and then converting the functional group of the obtained compound corresponding to compound [IA] or its salt into R 1 And prepared.

[0518] Preparation method A4: Preparation method of compound [IB] or its salt

[0519] Compound [IB] - wherein R 3 、R 4 and R 5Compound [I] which is hydrogen or a salt thereof can also be produced, for example, according to the following production method A4.

[0520]

[0521] Among them, Cy 1 、R 1 、R 2 、R 6 、R 7 , L, m, n and P 1 As defined above,

[0522] Z 3 is a leaving group (e.g., chlorine), and

[0523] Z 4 is a leaving group (e.g. chlorine).

[0524] (Step A4-1)

[0525] The compound [A4-2] or a salt thereof can be produced by reacting the compound [A1-4] or a salt thereof with the compound [A4-1] or a salt thereof in a solvent in the presence of a base.

[0526] Examples of the base include N,N-dimethylaniline. A preferred base is N,N-dimethylaniline.

[0527] Examples of the solvent include dichloromethane and chloroform. A preferred solvent is dichloromethane.

[0528] The reaction temperature is, for example, 0°C to 20°C, preferably 10°C to 20°C.

[0529] The compound [A4-1] or a salt thereof may be a commercially available product, or can be produced from a commercially available product by a known method.

[0530] (Step A4-2)

[0531] Compound [A4-3] or a salt thereof can be produced by reducing compound [A4-2] or a salt thereof in a solvent.

[0532] Examples of the reducing agent include borane-tetrahydrofuran complex. A preferred reducing agent is borane-tetrahydrofuran complex.

[0533] Examples of the solvent include tetrahydrofuran. A preferred solvent is tetrahydrofuran.

[0534] The reaction temperature is, for example, 0°C to 30°C, preferably 10°C to 20°C.

[0535] (Step A4-3)

[0536] The compound [A4-4] or a salt thereof can be produced by subjecting the compound [A4-3] or a salt thereof to azidation in a solvent in the presence of a catalyst.

[0537] Examples of the azidating agent include potassium azide. A preferred azidating agent is potassium azide.

[0538] Examples of catalysts include sodium iodide and potassium iodide. A preferred catalyst is sodium iodide.

[0539] Examples of the solvent include N,N-dimethylformamide and N,N-dimethylacetamide. A preferred solvent is N,N-dimethylformamide.

[0540] The reaction temperature is, for example, 20°C to 80°C, preferably 60°C to 80°C.

[0541] (Step A4-4)

[0542] Compound [IB] or a salt thereof can be produced by subjecting compound [A4-4] or a salt thereof to reduction and cyclization reactions in a solvent.

[0543] Examples of the reducing agent include triphenylphosphine. A preferred reducing agent is triphenylphosphine.

[0544] Examples of the solvent include 1,2-dimethoxyethane, tetrahydrofuran, and a mixed solvent thereof with water. A preferred solvent is a mixed solvent of 1,2-dimethoxyethane and water.

[0545] The reaction temperature is, for example, 20°C to 90°C, preferably 80°C to 90°C.

[0546] Alternatively, compound [IB] or a salt thereof can also be prepared by using a 1 The above has a known reaction to convert into R 1 This preparation method is carried out by replacing compound [A1-4] or its salt with a compound having a functional group or a protected functional group thereof, and then converting the functional group of the obtained compound corresponding to compound [IB] or its salt into R 1 And prepared.

[0547] Preparation method M1: Preparation method of compound [M1-8] and compound [M1-6] or their salts

[0548] The following compounds:

[0549] (1) With respect to the compound [A1-2] or a salt thereof used in the production method A1, the compound [M1-8] wherein R 2 is a halogen, L is ethylene and n is 2 [A1-2] - or a salt thereof, and

[0550] (2) With respect to the compound [A3-6] or a salt thereof used in the production method A3, the compound [M1-6] is a compound wherein R 2 is a halogen, L is ethylene and n is 2 [A3-6] - or a salt thereof,

[0551] It can be prepared, for example, according to the following Preparation Method M1.

[0552]

[0553] in

[0554] Cy 1 、R 1 , m and P 1 As defined above,

[0555] R 21 It is halogen,

[0556] P 6 is a hydroxy-protecting group (such as methyl and ethyl), and

[0557] Z 5 is a leaving group (e.g., trifluoromethanesulfonyloxy).

[0558] (Step M1-1)

[0559] Compound [M1-3] or a salt thereof can be prepared by subjecting compound [M1-1] or a salt thereof to a Horner-Wadsworth-Emmons reaction with compound [M1-2] or a salt thereof in a solvent in the presence of a base, and then subjecting the resulting product to catalytic hydrogenation in the presence of a palladium catalyst in a solvent.

[0560] Examples of the base used in the Horner-Wadsworth-Emmons reaction include potassium carbonate and sodium hydride. A preferred base is potassium carbonate.

[0561] Examples of the solvent used in the Horner-Wadsworth-Emmons reaction include N,N-dimethylformamide and tetrahydrofuran. A preferred solvent is N,N-dimethylformamide.

[0562] The reaction temperature for the Horner-Wadsworth-Emmons reaction is, for example, 0°C to 80°C, preferably 30°C to 80°C.

[0563] Examples of the palladium catalyst used in the catalytic hydrogenation include palladium on carbon and palladium hydroxide on carbon. A preferred palladium catalyst is palladium on carbon.

[0564] Examples of the solvent used in the catalytic hydrogenation include tetrahydrofuran and ethyl acetate. A preferred solvent is tetrahydrofuran.

[0565] The reaction temperature for the catalytic hydrogenation is, for example, 0°C to 20°C, preferably 10°C to 20°C.

[0566] The compound [M1-1] or a salt thereof may be a commercially available product, or can be produced from a commercially available product by a known method.

[0567] The compound [M1-2] or a salt thereof may be a commercially available product, or can be produced from a commercially available product by a known method.

[0568] (Step M1-2)

[0569] Compound [M1-4] or a salt thereof can be prepared by halogenating compound [M1-3] or a salt thereof. The halogenation can be carried out under conditions suitable for the type of halogen.

[0570] For example, when R 21 When it is fluorine, the compound [M1-4] or a salt thereof can be produced by fluorinating the compound [M1-3] or a salt thereof in a solvent in the presence of a base.

[0571] Examples of the fluorinating agent include N-fluorobenzenesulfonimide. A preferred fluorinating agent is N-fluorobenzenesulfonimide.

[0572] Examples of the base include sodium bis(trimethylsilyl)amide and lithium bis(trimethylsilyl)amide. A preferred base is sodium bis(trimethylsilyl)amide.

[0573] Examples of the solvent include tetrahydrofuran, toluene, and mixed solvents thereof. A preferred solvent is a mixed solvent of tetrahydrofuran and toluene.

[0574] The reaction temperature is, for example, -78°C to 20°C, preferably -78°C to -20°C.

[0575] (Step M1-3)

[0576] Compound [M1-5] or a salt thereof can be produced by reducing compound [M1-4] or a salt thereof in a solvent.

[0577] Examples of reducing agents include lithium aluminum hydride and sodium borohydride. A preferred reducing agent is lithium aluminum hydride.

[0578] Examples of the solvent include tetrahydrofuran. A preferred solvent is tetrahydrofuran.

[0579] The reaction temperature is, for example, 0°C to 20°C, preferably 0°C to 10°C.

[0580] (Steps M1-4)

[0581] Compound [M1-6] or a salt thereof can be prepared by converting the hydroxyl group of compound [M1-5] or a salt thereof into Z 5 This transformation can be carried out in a suitable Z5 It is carried out under the conditions of the type.

[0582] For example, when Z 5 When it is a trifluoromethanesulfonyloxy group, compound [M1-6] or a salt thereof can be prepared by triflation of compound [M1-5] or a salt thereof in a solvent in the presence of a base. The base and the solvent may be the same.

[0583] Examples of the trifluoromethanesulfonylating agent include trifluoromethanesulfonic anhydride and trifluoromethanesulfonyl chloride. A preferred trifluoromethanesulfonylating agent is trifluoromethanesulfonic anhydride.

[0584] Examples of the base include pyridine and triethylamine. A preferred base is pyridine.

[0585] Examples of the solvent include pyridine and dichloromethane. A preferred solvent is pyridine.

[0586] The reaction temperature is, for example, 0°C to 30°C, preferably 0°C to 10°C.

[0587] (Steps M1-5)

[0588] The compound [M1-7] or a salt thereof can be produced by reacting the compound [M1-6] or a salt thereof with potassium phthalimide in a solvent.

[0589] Examples of the solvent include N,N-dimethylformamide and N,N-dimethylacetamide. A preferred solvent is N,N-dimethylformamide.

[0590] The reaction temperature is, for example, 0°C to 30°C, preferably 20°C to 30°C.

[0591] (Steps M1-6)

[0592] Compound [M1-8] or a salt thereof can be prepared by removing the phthaloyl group of compound [M1-7] or a salt thereof. A known method can be used as a method for removing the phthaloyl group. For example, compound [M1-8] or a salt thereof can be prepared by reacting compound [M1-7] or a salt thereof with hydrazine monohydrate in a solvent.

[0593] Examples of the solvent include tetrahydrofuran, ethanol, methanol and mixed solvents thereof. A preferred solvent is a mixed solvent of tetrahydrofuran and ethanol.

[0594] The reaction temperature is, for example, 20°C to 60°C, preferably 50°C to 60°C.

[0595] Preparation method M2: Preparation method of compound [M2-4] and compound [M2-2] or their salts The following compounds:

[0596] (1) With respect to the compound [A1-2] or a salt thereof used in the production method A1, the compound [M2-4] which is the compound [A1-2] wherein L is ethylene and n is 0 or a salt thereof, and

[0597] (2) With respect to the compound [A3-6] or a salt thereof used in the production method A3, the compound [M2-2], which is the compound [A3-6] wherein L is ethylene and n is 0, or a salt thereof,

[0598] It can also be prepared, for example, according to the following Preparation Method M2.

[0599]

[0600] Among them, Cy 1 、R 1 ,m,P 1 and Z 1 As defined above.

[0601] (Step M2-1)

[0602] The compound [M2-1] or a salt thereof can be produced by reacting the compound [M1-3] or a salt thereof according to step M1-3.

[0603] (Step M2-2)

[0604] The compound [M2-2] or a salt thereof can be produced by reacting the compound [M2-1] or a salt thereof according to step A2-3.

[0605] (Step M2-3)

[0606] The compound [M2-3] or a salt thereof can be produced by reacting the compound [M2-2] or a salt thereof according to step M1-5.

[0607] (Step M2-4)

[0608] The compound [M2-4] or a salt thereof can be produced by reacting the compound [M2-3] or a salt thereof according to step M1-6. Example

[0609] Next, the preparation method of compound [I] or a pharmaceutically acceptable salt thereof is specifically explained by referring to the preparation examples, which should not be construed as limitative.

[0610] [Preparation Example 1]: 1-(2,2-difluoro-2-(4-hydroxy-4-methyltetrahydro-2H-pyran-2-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine Synthesis of the cis-isomer (Example 12 racemate), trans-isomer (Example 11 racemate) and various optically active forms (Examples 58, 59, 66 and 67) of -5-ketone

[0611]

[0612] (1) Ethyl (E)-3-(but-3-en-1-yloxy)acrylate

[0613]

[0614] Under ice cooling, ethyl propiolate (82 mL, 806 mmol) was added dropwise to a solution of 3-butene-1-ol (68.4 mL, 806 mmol) and 4-methylmorpholine (89 mL, 806 mmol) in cyclopentyl methyl ether (540 mL). The used dropping funnel was washed with cyclopentyl methyl ether (41 mL), and the mixture was stirred at room temperature for 17 hours. Under ice cooling, a mixture of acetic acid (55.4 mL, 967 mmol)-water (1162 mL) was added dropwise to the reaction solution and separated. The aqueous layer was re-extracted with hexane / ethyl acetate = 3 / 1 (400 mL). The organic layers were combined, washed twice with water (300 mL) and once with saturated brine (200 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (151.4 g, purity 91%, yield 100%).

[0615] 1 H-NMR (DMSO-D6) δ: 1.18 (3H, t, J = 7.1Hz), 2.36-2.42 (2H, m), 3.98 (2H, t, J = 6.6Hz), 4.07 (2H, q, J = 7.1Hz), 5.05 -5.09(1H,m),5.13(1H,dq,J=17.2,1.7Hz),5.26(1H,d,J=12.6Hz),5.74-5.85(1H,m),7.58(1H,d,J=12.6Hz).

[0616] (2) ethyl 2-(4-hydroxytetrahydro-2H-pyran-2-yl)acetate

[0617]

[0618] Under ice cooling, trifluoroacetic acid (186 mL, 2418 mmol) was added dropwise to a solution of (E)-3-(but-3-ene-1-yloxy) ethyl acrylate (151.4 g, purity 91%, 806 mmol) obtained in (1) in chloroform (686 mL), and the mixture was stirred at room temperature for 7 hours. Under ice cooling, an aqueous solution (1235 mL) of tripotassium phosphate (257 g, 1209 mmol) was added dropwise thereto, and the mixture was extracted with chloroform. The aqueous layer was re-extracted with chloroform. The organic layers were combined and washed with water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure with ethanol and azeotropic reaction. Ethanol (1616 mL) and potassium carbonate (9.82 g, 71.1 mmol) were added to the resulting residue, and the mixture was stirred at room temperature for 2 hours. Insoluble matter was removed by filtration through diatomaceous earth (Celite), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 9 / 1 to 0 / 100) to give the title compound (106 g, purity 93%, yield 74%).

[0619] 1 H-NMR (DMSO-D6) δ: 1.00-1.09 (0.78H, m), 1.17 (2.34H, t, J = 7.2Hz), 1.18 (0.66H, t, J = 7.2Hz), 1.20-1 .30(0.78H,m),1.34-1.44(0.44H,m),1.52-1.65(0.44H,m),1.65-1.73(0.78H,m),1.79-1.87(0.78H ,m),2.27-2.48(2H,m),3.23-3.31(0.78H,m),3.51-3.74(2H,m),3.81(0.78H,ddd,J=11.6,4.8,1.7H z), 3.95-4.00 (0.22H, m), 4.00-4.09 (2.22H, m), 4.62 (0.22H, d, J = 2.9Hz), 4.75 (0.78H, d, J = 4.6Hz).

[0620] (3) ethyl 2-(4-oxotetrahydro-2H-pyran-2-yl)acetate

[0621]

[0622] To a solution of 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (126 g, 296 mmol) in chloroform (400 mL) was added dropwise a solution of ethyl 2-(4-hydroxytetrahydro-2H-pyran-2-yl)acetate (50 g, purity 93%, 247 mmol) obtained in (2) in chloroform (65 mL) under water cooling, and the mixture was stirred at room temperature for 3 hours. 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (31.4 g, 74.0 mmol) was added thereto, and the mixture was stirred for another 30 minutes. Hexane (465 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and a saturated aqueous sodium bicarbonate solution (1000 mL) and a 10% aqueous sodium thiosulfate solution (100 mL) were added to the filtrate at room temperature, and the mixture was stirred for 1 hour. The insoluble material was removed by filtration, and the filtrate was separated. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (62.5 g, purity 77%, yield 105%).

[0623] 1 H-NMR (DMSO-D6) δ: 1.18 (3H, t, J = 7.1Hz), 2.12-2.20 (1H, m), 2.28-2.34 (1H, m), 2.39 (1H, ddd, J = 14.6, 10.8, 0.9Hz) ,2.48-2.63(3H,m),3.58-3.65(1H,m),3.94-4.01(1H,m),4.07(2H,q,J=7.1Hz),4.14(1H,ddd,J=11.4,7.5,1.4Hz).

[0624] (4) ethyl 2-(1,4,8-trioxaspiro[4,5]dec-7-yl)acetate

[0625]

[0626] Under an argon atmosphere, ethylene glycol (25.2 mL, 451 mmol) and pyridinium p-toluenesulfonate (4.86 g, 19.33 mmol) were added to a solution of ethyl 2-(4-oxotetrahydro-2H-pyran-2-yl)acetate (60 g, 322 mmol) in toluene (600 mL) obtained by the same reaction as (3), and the mixture was subjected to a dehydration reaction at 140° C. for 3 hours using a Dean-Stark apparatus. The reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate solution (200 mL) and water (200 mL) were added thereto, and the mixture was separated. The aqueous layer was extracted three times with hexane / ethyl acetate = 1 / 1. The organic layers were combined, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 90 / 10 to 0 / 100) to give the title compound (67.8 g, purity 90%, yield 82%).

[0627] 1 H-NMR (DMSO-D6) δ: 1.17 (3H, t, J = 7.2Hz), 1.41 (1H, dd, J = 12.9, 11.7Hz), 1.53-1.64 (2H, m), 1.70 (1H, dt, J = 12.9, 2. 1Hz), 2.39 (1H, dd, J = 15.5, 8.3Hz), 2.44-2.50 (1H, m), 3.39-3.47 (1H, m), 3.76-3.93 (6H, m), 4.05 (2H, q, J = 7.2Hz).

[0628] (5) ethyl 2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)acetate

[0629]

[0630] To a mixed solution of ethyl 2-(1,4,8-trioxaspiro[4,5]dec-7-yl)acetate (17.0 g, 66.4 mmol) obtained in (4) in toluene (230 mL)-tetrahydrofuran (765 mL) was added N-fluorobenzenesulfonimide (84.0 g, 266 mmol), and the mixture was cooled to -78°C. 1M sodium bis(trimethylsilyl)amide-tetrahydrofuran solution (233 mL, 233 mmol) was added dropwise thereto, and the mixture was warmed to 0°C over 1 hour and stirred under ice cooling for another 2 hours. Triethylamine (74.1 mL, 532 mmol) was added dropwise to the reaction solution. Water (1000 mL) was added to the reaction solution, followed by hexane (330 mL), and the mixture was separated. The aqueous layer was extracted twice with hexane / ethyl acetate = 1 / 1 (600 mL). The organic layers were combined and washed three times with water (400 mL), 5% aqueous sodium sulfite solution (580 mL) and saturated brine (340 mL). Sodium sulfate and silica gel were added to the organic layer and the mixture was stirred. Insoluble matter was removed by filtration through diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 94 / 6 to 50 / 50) to obtain the title compound (15.1 g, yield 85%).

[0631] 1 H-NMR (DMSO-D6) δ: 1.26 (3H, t, J = 7.2Hz), 1.58-1.82 (4H, m), 3.48-3.56 (1H, m), 3.89-4.03 (6H, m), 4.32 (2H, q, J = 7.1Hz).

[0632] (6) 2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethan-1-ol

[0633]

[0634] Under an argon atmosphere and ice cooling, a solution of ethyl 2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)acetate (18.0 g, 67.6 mmol) in tetrahydrofuran (36 mL) obtained by the same reaction as (5) was added dropwise to a suspension of lithium aluminum hydride (2.82 g, 74.4 mmol) in tetrahydrofuran (90 mL), and the mixture was stirred for 1 hour. Water (2.8 mL), 4N aqueous sodium hydroxide solution (2.8 mL) and water (8.4 mL) were successively added dropwise to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Insoluble matter was removed by filtration through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 88 / 12 to 0 / 100) to give the title compound (14.5 g, yield 94%).

[0635] 1 H-NMR (DMSO-D6) δ: 1.54-1.79 (4H, m), 3.46-4.01 (9H, m), 5.45 (1H, t, J = 6.4Hz).

[0636] (7) 2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethyl trifluoromethanesulfonate

[0637]

[0638] Under ice cooling, trifluoromethanesulfonyl chloride (8 mL, 71.2 mmol) was added dropwise to a solution of 2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethan-1-ol (14.0 g, 62.4 mmol) and triethylamine (11.3 mL, 81 mmol) obtained in (6) in dichloromethane (140 mL) under ice cooling, and the mixture was stirred for 2.5 hours. Triethylamine (1.7 mL, 12.5 mmol) and trifluoromethanesulfonyl chloride (1.4 mL, 12.5 mmol) were added again, and the mixture was stirred for another 2 hours. Triethylamine (0.85 mL, 6.2 mmol) and trifluoromethanesulfonyl chloride (0.7 mL, 6.2 mmol) were added again, and the mixture was stirred for another 30 minutes. Water was added to the reaction solution, and the mixture was separated. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. To the residue were added ethyl acetate and water, and the mixture was separated. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (23.4 g, yield 100%).

[0639] 1H-NMR(CDCl3)δ: 1.61-1.67(1H,m), 1.75-1.92(3H,m), 3.64-3.73(1H,m), 3.84-4.09(6H,m), 4.60-4.78(2H,m).

[0640] (8) 2-(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethyl)isoindoline-1,3-dione

[0641]

[0642] To a solution of 2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethyl trifluoromethanesulfonate (22.2 g, 62.4 mmol) obtained in (7) in N,N-dimethylformamide (133 mL) was added potassium phthalimide (15.0 g, 81 mmol), and the mixture was stirred at room temperature for 15 hours. Water (150 mL) was added to the reaction solution, the mixture was stirred for 30 minutes, and the precipitated solid was collected by filtration. Hexane / ethyl acetate = 3 / 1 (80 mL) was added to the obtained solid, and the mixture was stirred for another hour. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (16.4 g, yield 74%).

[0643] 1 H-NMR(CDCl3)δ: 1.60-1.66(1H,m),1.76-1.95(3H,m),3.65-3.73(1H,m),3.79-3.89(1H,m),3.93- 4.03(4H,m),4.08(1H,dd,J=11.6,5.5Hz),4.13-4.32(2H,m),7.72-7.77(2H,m),7.87-7.92(2H,m).

[0644] (9) 2,2-Difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethan-1-amine

[0645]

[0646] To a mixed solution of 2-(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethyl)isoindoline-1,3-dione (16.4 g, 46.4 mmol) obtained in (8) in ethanol (115 mL) and tetrahydrofuran (115 mL) was added hydrazine monohydrate (4.51 mL, 93 mmol), and the mixture was stirred at 60° C. for 2 hours. Hydrazine monohydrate (2.5 mL, 51.7 mmol) was added thereto again, and the mixture was stirred at 60° C. for another 1 hour. The reaction solution was cooled in an ice bath, insoluble matter was removed by filtration, and washed twice with ethanol (115 mL). The filtrate was concentrated, ethanol (60 mL) was added to the precipitated solid, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure to obtain the title compound (10.6 g, yield 92%).

[0647] 1 H-NMR (DMSO-D6) δ: 1.53-1.77 (4H, m), 1.91 (2H, br s), 2.81-3.02 (2H, m), 3.54 (1H, td, J = 11.8, 3.1Hz), 3.82-3.99 (6H, m).

[0648] (10) Methyl 3-((2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate

[0649]

[0650] To a solution of 2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethan-1-amine (10.4 g, 46.4 mmol) obtained in (9) in N,N-dimethylformamide (88 mL) was added 2-hydroxy-5-(trifluoromethyl)benzaldehyde (8.82 g, 46.4 mmol), and the mixture was stirred at room temperature for 30 minutes. Potassium carbonate (19.24 g, 139 mmol) and methyl 2,2-dichloroacetate (5.77 mL, 55.7 mmol) were added thereto, and the mixture was stirred at room temperature for 15 hours. Under ice cooling, water (180 mL) was added to the reaction solution, and the precipitated solid was collected by filtration and washed with water (90 mL). Hexane / ethyl acetate = 2 / 1 (120 mL) was added to the obtained solid, and the mixture was stirred for 30 minutes. The solid was collected by filtration, washed with hexane / ethyl acetate = 2 / 1 (60 mL), and dried under reduced pressure at room temperature to give the title compound (13.7 g, yield 63%).

[0651] 1H-NMR(CDCl3)δ: 1.58-1.65(1H,m),1.78-1.94(3H,m),3.52-3.61(1H,m),3.85-4.23(11H ,m),6.39(1H,t,J=7.4Hz),7.54(1H,d,J=8.8Hz),7.68(1H,dd,J=8.8,1.6Hz),8.26(1H,br s).

[0652] (11) 3-(2-chloro-N-(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethyl)acetylamino)-5-(trifluoromethyl)benzofuran-2-carboxylic acid methyl ester

[0653]

[0654] To a solution of methyl 3-((2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (13.6 g, 29.2 mmol) obtained in (10) and N,N-dimethylaniline (14.8 mL, 117 mmol) in dichloromethane (340 mL) was added dropwise chloroacetyl chloride (7.02 mL, 88 mmol) under ice cooling, and the mixture was stirred at room temperature for 16 hours. N,N-dimethylaniline (3.7 mL, 29.2 mmol) and chloroacetyl chloride (2.3 mL, 28.8 mmol) were added again thereto, and the mixture was stirred for another 6 hours. A 10% aqueous citric acid solution was added thereto, and the mixture was separated. The organic layer was washed with a 10% aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution, and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate=6 / 1 to 3 / 2) and dissolved in ethyl acetate (20 mL). Hexane (40 mL) was added thereto and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (14.3 g, 90% yield).

[0655] 1 H-NMR(DMSO-D6)δ: 1.47-1.77(4H,m),3.33-3.44(1H,m),3.67-3.80(1H,m),3.82-3.98(8H,m),4.03-4.28(2H,m ),4.32(1H,dd,J=14.4,0.8Hz),4.44-4.80(1H,m),7.89-7.97(1H,m),8.01-8.08(1H,m),8.20(1H,d,J=8.6Hz).

[0656] (12) Methyl 3-((2-chloroethyl)(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate

[0657]

[0658] To a solution of methyl 3-(2-chloro-N-(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethyl)acetylamino)-5-(trifluoromethyl)benzofuran-2-carboxylate (12.3 g, 22.7 mmol) obtained in (11) in tetrahydrofuran (148 mL) was added dropwise 0.91 M borane-tetrahydrofuran complex (54.9 mL, 49.9 mmol) under ice cooling, and the mixture was stirred at room temperature for 7 hours. Under ice cooling, a 20% aqueous citric acid solution was added to the reaction solution, the mixture was stirred for 10 minutes, and extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 6 / 1 to 3 / 2) to give the title compound (7.2 g, yield 54%).

[0659] 1 H-NMR (DMSO-D6) δ: 1.45-1.68 (4H, m), 3.10 (1H, td, J = 11.8, 2.5Hz), 3.62-4 .10(15H,m),7.87(1H,dd,J=9.0,1.6Hz),7.91(1H,d,J=9.0Hz),8.20(1H,br s).

[0660] (13) Methyl 3-((2-azidoethyl)(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate

[0661]

[0662] To a solution of methyl 3-((2-chloroethyl)(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (8.5 g, 16.10 mmol) obtained by the same reaction as (12) in N,N-dimethylformamide (85 mL) were added potassium azide (2.61 g, 32.2 mmol) and sodium iodide (0.483 g, 3.22 mmol), and the mixture was stirred at 80° C. for 4 hours. The reaction solution was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (8.6 g, yield 100%).

[0663] 1 H-NMR(DMSO-D6)δ: 1.45-1.67(4H,m),3.09(1H,td,J=11.8,2.6Hz),3.40-3.52(2H,m),3.57-3 .70(3H,m),3.78-4.09(10H,m),7.87(1H,dd,J=8.9,1.7Hz),7.91(1H,d,J=8.9Hz),8.19(1H,br s).

[0664] (14) 1-(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine -5-Keto

[0665]

[0666] To a solution of methyl 3-((2-azidoethyl)(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (8.60 g, 16.1 mmol) obtained in (13) in water (8.6 mL) and 1,2-dimethoxyethane (86 mL) was added triphenylphosphine (5.07 g, 19.32 mmol), and the mixture was stirred at 80° C. for 8 hours. The reaction solution was concentrated under reduced pressure, and to the obtained residue was added hexane / ethyl acetate = 1 / 1 (34 mL). The mixture was stirred for 1 hour, and the obtained solid was collected by filtration. Ethyl acetate (34 mL) was added to the obtained solid, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (4.5 g, yield 53%).

[0667] 1H-NMR(DMSO-D6)δ: 1.61-1.85(4H,m),3.29-3.41(2H,m),3.47-3.61(3H,m ),3.81-4.33(8H,m),7.76-7.79(2H,m),8.08(1H,t,J=5.0Hz),8.32(1H,br s).

[0668] (15) 1-(2,2-difluoro-2-(4-oxotetrahydro-2H-pyran-2-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofurano[3,2-e][1,4]diazepine -5-Keto

[0669]

[0670] 1-(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine obtained in (14) was added to the 1-(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]dec-7-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine To a solution of -5-ketone (0.452 g, 0.949 mmol) in acetic acid (3.6 mL) was added 2N hydrochloric acid (0.904 mL, 1.808 mmol), and the mixture was stirred at 80 ° C for 3 hours. The mixture was cooled to room temperature and slowly diluted with ethyl acetate and water, to which a 10% aqueous sodium carbonate solution was slowly added dropwise. The mixture was separated and the aqueous layer was re-extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Ethanol (4 mL) was added to the residue, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (0.304 g, yield 74%).

[0671] 1 H-NMR (DMSO-D6) δ: 2.27 (1H, d, J = 15.3Hz), 2.38 (1H, d, J = 14.3Hz), 2.60-2.73 (2H, m), 3.28-3.62 (4H, m) ,3.78(1H,td,J=11.7,2.8Hz),4.07-4.39(4H,m),7.75-7.84(2H,m),8.11(1H,t,J=5.0Hz),8.34(1H,br s).

[0672] (16) 1-(2,2-difluoro-2-(4-hydroxy-4-methyltetrahydro-2H-pyran-2-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine -5-Keto

[0673]

[0674] Under argon atmosphere and ice cooling, 1-(2,2-difluoro-2-(4-oxotetrahydro-2H-pyran-2-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine obtained by the same reaction as (15) was added to the reaction mixture. To a suspension of -5-ketone (0.925 g, 1.879 mmol) in tetrahydrofuran (37 mL) was added dropwise 3.0 M methylmagnesium chloride-tetrahydrofuran solution (2.25 mL, 6.76 mmol), and the mixture was stirred for 2 hours. Under ice cooling, 10% aqueous ammonium chloride solution (50 mL) was added dropwise to the reaction solution, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 9 / 1) and then by preparative thin layer chromatography (eluent: chloroform / methanol = 9 / 1). The fraction was concentrated under reduced pressure, and the resulting residue was purified by reverse phase liquid chromatography (column: XTERRA PrepMS C18 OBD TMThe mixture was purified by HPLC-MS / MS using a 5 μm, 30×50 mm Column, mobile phase: water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid) to obtain a racemate (0.205 g, yield 24%, the compound of Example 12) in which the relative configuration of the substituents on the tetrahydropyran ring is cis-configuration, and a racemate (0.272 g, yield 32%, the compound of Example 11) in which the relative configuration of the substituents on the tetrahydropyran ring is trans-configuration. The racemate (0.205 g) in which the relative configuration of the substituents on the tetrahydropyran ring is cis-configuration was optically resolved by supercritical fluid chromatography (apparatus: Waters SFC Prep15 System, column: Daicel CHIRALPAK IG / SFC, 10 mm (ID) × 250 mm (L), 5 μm, column temperature: 40°C, column back pressure: 120 bar, mobile phase flow rate: 15 mL / min, mobile phase mixing ratio: isocratic, carbon dioxide / methanol = 85 / 15, fraction trigger: UV 214 nm) to obtain the compound of Example 58 (0.086 g) as the first peak fraction (10.0-11.9 min) and the compound of Example 59 (0.085 g) as the second peak fraction (12.3-14.8 min). The chromatographic analysis was performed using supercritical fluid chromatography (apparatus: Waters SFC Prep 15 System, column: Daicel CHIRALPAK IF / SFC, 10 mm (ID) × 250 mm (L), 5 μm, column temperature: 40° C., column back pressure: 120 bar, mobile phase flow rate: 15 mL / min, mobile phase mixing ratio: gradient, carbon dioxide / (methanol / acetonitrile = 10 / 90) = 60 / 40 (0 min) - 60 / 40 (10 min) - 50 / 50 (10.5 min) - 50 / 50 (15 min), component trigger: UV The racemate (0.136 g) in which the relative configuration of the substituents on the tetrahydropyran ring was trans-configuration was subjected to optical resolution at 400 nm (254 nm) to obtain the compound of Example 66 (0.043 g) as the first peak fraction (7.9-10.4 min), and the compound of Example 67 (0.043 g) as the second peak fraction (11.0-13.7 min).

[0675] (Example 12, Example 58 and Example 59)

[0676] 1H-NMR(DMSO-D6)δ: 1.23(3H,s),1.47-1.68(4H,m),3.30-3.43(2H,m),3.45-3.60(3H,m),3.73 -3.85(1H,m),3.91(1H,dd,J=11.6,4.3Hz),3.97-4.13(1H,m),4.16-4.32(1H,m),4.78(1H,br s),7.76-7.79(2H,m),8.08(1H,t,J=5.0Hz),8.34(1H,br s).

[0677] (Example 11, Example 66 and Example 67)

[0678] 1 H-NMR(DMSO-D6)δ: 1.19(3H,s),1.38-1.66(4H,m),3.27-3.41(2H,m),3.45- 3.61(2H,m),3.66-3.80(2H,m),3.93-4.31(3H,m),4.53(1H,s),7.78(2H,br s), 8.07 (1H, t, J = 5.0Hz), 8.34 (1H, br s).

[0679] [Preparation Example 2]: 1-(2,2-difluoro-2-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine -5-one (Example 95), and 1-(2,2-difluoro-2-((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine Synthesis of -5-ketone (Example 77)

[0680]

[0681] (1) (S)-3,4-dihydroxybutyric acid methyl ester

[0682]

[0683] Under ice cooling, to a solution of (S)-2-hydroxysuccinic acid dimethyl ester (35 g, 216 mmol) in tetrahydrofuran (350 mL) was added dropwise borane-dimethyl sulfide complex (26.6 mL, 281 mol), and the mixture was stirred for 1 hour. Sodium borohydride (0.204 g, 5.40 mmol) was added thereto, and the mixture was stirred for 2 hours. Sodium borohydride (0.204 g, 5.40 mmol) was added thereto, and the mixture was stirred for another 30 minutes. Methanol (140 mL) was added dropwise to the reaction solution, and the mixture was stirred for 15 minutes, azeotroped with toluene and methanol and concentrated under reduced pressure to give the title compound (29.9 g, yield 103%).

[0684] 1 H-NMR (DMSO-D6) δ: 2.22 (1H, dd, J = 15.0, 8.8 Hz), 2.52 (1H, dd, J = 14.9, 4.0 Hz), 3.18-3.23 (1H, m), 3.31-3 .37(1H,m),3.58(3H,s),3.83(1H,ddd,J=9.7,5.1,3.3Hz),4.63(1H,t,J=5.8Hz),4.78(1H,d,J=5.3Hz).

[0685] (2) (S)-4-((tert-Butyldiphenylsilyl)oxy)-3-hydroxybutyric acid methyl ester

[0686]

[0687] Under ice cooling, to a solution of (S)-3,4-dihydroxybutyric acid methyl ester (29.6 g, 207 mmol) and imidazole (31.1 g, 456 mmol) obtained in (1) in N,N-dimethylformamide (223 mL) was added dropwise tert-butyldiphenylchlorosilane (58.6 mL, 228 mmol), and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, and the mixture was extracted with hexane / ethyl acetate = 1 / 3. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 96 / 4 to 60 / 40) to obtain the title compound (65.6 g, yield 85%).

[0688] 1H-NMR(DMSO-D6)δ: 0.99(9H,s),2.35(1H,dd,J=15.0,8.3Hz), 2.64(1H,dd,J=15.0,4.6Hz), 3.48(1H,dd,J=9.9,6.5 Hz),3.59(3H,s),3.60-3.61(1H,m),3.99-4.02(1H,m),4.99(1H,d,J=5.5Hz),7.44-7.47(6H,m),7.62-7.63(4H,m).

[0689] (3) Methyl (S)-3-(allyloxy)-4-((tert-butyldiphenylsilyl)oxy)butanoate

[0690]

[0691] To a solution of (S)-4-((tert-butyldiphenylsilyl)oxy)-3-hydroxybutyric acid methyl ester (65.6 g, 176 mmol) obtained in (2) and allyl 2,2,2-trichloroacetimidate (37.2 mL, 247 mmol) in cyclohexane (328 mL) was added trifluoromethanesulfonic acid (1.24 mL, 14.1 mmol), and the mixture was stirred at room temperature for 3 days. Hexane was added to the reaction solution, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 97 / 3 to 70 / 30) to obtain the title compound (61.1 g, yield 84%).

[0692] 1 H-NMR(DMSO-D6)δ: 0.99(9H,s),2.53(1H,dd,J=15.5,7.6Hz),2.64(1H,dd,J=15.5,5.3Hz),3.59(3H,s),3.66-3.67(2H,m),3.84-3.86(1H, m),3.92-4.06(2H,m),5.09(1H,dq,J=10.4,1.6Hz),5.19(1H,dq,J=17.2,1.8Hz),5.76-5.86(1H,m),7.41-7.50(6H,m),7.60-7.65(4H,m).

[0693] (4) (S)-3-(Allyloxy)-4-hydroxybutyric acid methyl ester

[0694]

[0695] Under ice cooling, to a mixed solution of (S)-3-(allyloxy)-4-((tert-butyldiphenylsilyl)oxy)butanoic acid methyl ester (6.9 g, 16.7 mmol) obtained by the same reaction as (3) in acetic acid (0.956 mL, 16.7 mmol) and tetrahydrofuran (35 mL) was added 1 M tetrabutylammonium fluoride-tetrahydrofuran solution (20.1 mL, 20.1 mmol), and the mixture was stirred for 4 hours. The same operation was performed using (S)-3-(allyloxy)-4-((tert-butyldiphenylsilyl)oxy)butanoic acid methyl ester (61.1 g, 148 mmol) obtained in (3), and these reaction solutions were combined. Water (400 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (400 mL). The aqueous layer was re-extracted with ethyl acetate (200 mL). The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 82 / 18 to 20 / 80) to give the title compound (24.6 g, yield 86%).

[0696] 1 H-NMR (DMSO-D6) δ: 2.40 (1H, dd, J = 15.5, 8.1 Hz), 2.56 (1H, dd, J = 15.5, 4.6 Hz), 3.36-3.38 (1H, m), 3.44-3.47 (1 H,m),3.59(3H,s),3.69-3.72(1H,m),3.96(1H,ddt,J=13.2,5.3,1.8Hz),4.02-4.08(1H,m),4.71-4.74(1H,br m),5.09(1H,dq,J=10.4,1.6Hz),5.21(1H,dq,J=17.2,1.8Hz),5.78-5.88(1H,m).

[0697] (5) Methyl 2-((2S)-5-(iodomethyl)-1,4-dioxane-2-yl)acetate

[0698]

[0699] To a solution of (S)-3-(allyloxy)-4-hydroxybutyric acid methyl ester (24.6 g, 141 mmol) obtained in (4) in acetonitrile (738 mL) was added N-iodosuccinimide (47.7 g, 212 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 days. An aqueous solution (400 mL) of sodium bisulfite (14.7 g, 141 mmol) was added to the reaction solution, and the mixture was stirred for 30 minutes. Water (400 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (800 mL). The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 95 / 5 to hexane / ethyl acetate / methanol = 60 / 40 / 2) to obtain the title compound (16.0 g, yield 42%).

[0700] 1 H-NMR (DMSO-D6) δ: 2.34 (0.33H, td, J = 14.1, 7.5Hz), 2.46-2.49 (0.33H, m), 2.58-2.65 (1.34H, m), 3.10 (0.33H, dd, J = 10.6, 6.9Hz) ,3.23-3.26(0.66H,m),3.40-3.43(1.67H,m),3.56-3.61(5.01H,m),3.65-3.84(2H,m),3.86-3.95(1H,m),4.00-4.06(0.33H,m).

[0701] (6) ((5S)-5-(2-methoxy-2-oxoethyl)-1,4-dioxane-2-yl)methyl 4-nitrobenzoate

[0702]

[0703] To a solution of methyl 2-((2S)-5-(iodomethyl)-1,4-dioxane-2-yl)acetate (16.0 g, 53.3 mmol) obtained in (5) in dimethyl sulfoxide (112 mL) were added potassium 4-nitrobenzoate (32.8 g, 160 mmol) and 18-crown-6 (1.41 g, 5.33 mmol), and the mixture was stirred at 90° C. for 3 hours. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The organic layers were combined, washed with water, a saturated aqueous sodium bicarbonate solution, and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (18.9 g, yield 104%).

[0704] 1H-NMR (DMSO-D6) δ: 2.35 (0.5H, dd, J = 15.8, 8.0 Hz), 2.52-2.54 (0.5H, m), 2.62 (1H, d d,J=6.8,2.7Hz),3.34-3.36(0.5H,m),3.49(0.5H,dd,J=11.2,10.5Hz),3.60-3.61 (3.5H,m),3.65-3.88(2.5H,m),3.92-3.95(1.5H,m),3.99-4.25(0.5H,m),4.27-4. 42(1.5H,m),4.66(0.5H,dd,J=11.7,7.5Hz),8.19-8.22(2H,m),8.35-8.37(2H,m).

[0705] (7) Methyl 2-((2S)-5-(hydroxymethyl)-1,4-dioxane-2-yl)acetate

[0706]

[0707] To a solution of ((5S)-5-(2-methoxy-2-oxoethyl)-1,4-dioxane-2-yl)methyl 4-nitrobenzoate (18.9 g, 55.7 mmol) obtained in (6) in methanol (189 mL) was added potassium carbonate (30.8 g, 223 mmol), and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was extracted twice with ethyl acetate, the organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (5.4 g, yield 51%).

[0708] 1 H-NMR (DMSO-D6) δ: 2.32 (0.5H, dd, J = 15.7, 7.9Hz), 2.45-2.48 (0.5H, m), 2.60-2.64 (1H, m), 3.22-3.30 (2 H,m),3.37-3.55(2H,m),3.58-3.60(4H,m),3.75-3.79(2.5H,m),3.90-3.91(0.5H,m),4.69-4.71(1H,m).

[0709] (8) Methyl 2-((2S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxane-2-yl)acetate

[0710]

[0711] To a solution of methyl 2-((2S)-5-(hydroxymethyl)-1,4-dioxane-2-yl)acetate (5.38 g, 28.3 mmol) obtained in (7) and imidazole (4.24 g, 62.2 mmol) in N,N-dimethylformamide (43 mL) was added dropwise tert-butyldiphenylsilyl chloride (8.0 mL, 31.1 mmol) under ice cooling, and the mixture was stirred at room temperature for 18 hours. Imidazole (0.4 g, 5.9 mmol) and tert-butyldiphenylsilyl chloride (0.73 mL, 2.8 mmol) were added again thereto, and the mixture was stirred for another 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 97 / 3 to 75 / 25) to give the title compound (5.8 g, yield 48%).

[0712] 1 H-NMR (DMSO-D6) δ: 0.99-1.00 (9H, m), 2.33 (0.6H, dd, J = 15.8, 8.0Hz), 2.45 -2.47(0.6H,m),2.58-2.62(0.8H,m),3.27(0.6H,t,J=11.6Hz),3.39(0.6H ,t,J=11.3Hz),3.47(0.4H,dd,J=11.8,5.3Hz),3.54-3.66(5.8H,m),3.74- 3.84(3.2H,m),3.90-3.93(0.4H,m),7.39-7.51(6H,m),7.58-7.66(4H,m).

[0713] (9) Methyl 2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxan-2-yl)-2,2-difluoroacetate (trans isomer and cis isomer)

[0714]

[0715] To methyl 2-((2S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxane-2-yl)acetate (5.82 g, 13.6 mmol) obtained in (8) was added toluene, and the mixture was concentrated under reduced pressure. A mixed solvent of toluene (29 mL)-tetrahydrofuran (116 mL) was added to the residue, N-fluorobenzenesulfonimide (17.1 g, 54.3 mmol) was added thereto under ice cooling, and the mixture was cooled to -78°C. 1M sodium bis(trimethylsilyl)amide-tetrahydrofuran solution (47.5 mL, 47.5 mmol) was added dropwise thereto, and the mixture was gradually heated over 30 minutes. Triethylamine (15.1 mL, 109 mmol) was added dropwise to the reaction solution at -10°C. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The organic layers were combined and washed with saturated sodium bicarbonate aqueous solution and saturated brine. Sodium sulfate and silica gel were added to the organic layer, and the mixture was stirred. Insoluble matter was removed by filtration through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate=97 / 3 to 80 / 20) to obtain the title compound (3.2g, yield 51%) as a trans isomer and the title compound (1.8g, yield 29%) as a cis isomer.

[0716] Trans isomer:

[0717] 1 H-NMR (DMSO-D6) δ: 0.98 (9H, s), 3.49 (1H, dd, J = 11.1, 9.9Hz), 3.56-3.66 (4H, m), 3.8 6(3H,s),3.93-4.01(2H,m),4.02-4.09(1H,m),7.40-7.48(6H,m),7.60-7.61(4H,m).

[0718] Cis isomer:

[0719] 1 H-NMR(DMSO-D6)δ: 1.00(9H,s),3.72-3.77(5H,m),3.80-3.92(5H,m),4.06-4.15(1H,m),7.42-7.50(6H,m),7.62-7.63(4H,m).

[0720] (10) 2-(5-(((tert-Butyldiphenylsilyl)oxy)methyl)-1,4-dioxane-2-yl)-2,2-difluoroethan-1-ol (trans isomer)

[0721]

[0722] Under ice cooling, to a suspension of lithium aluminum hydride (0.288 g, 7.58 mmol) in tetrahydrofuran (16 mL) was added dropwise a solution of the trans isomer of methyl 2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxane-2-yl)-2,2-difluoroacetate (3.2 g, 6.89 mmol) obtained in (9) in tetrahydrofuran (4.8 mL), and the mixture was stirred for 30 minutes. Water (0.288 mL), 4N aqueous sodium hydroxide solution (0.288 mL) and water (0.864 mL) were successively added dropwise to the reaction solution, and the mixture was stirred for 2.5 hours. The insoluble matter was removed by filtration through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain the title compound (3.1 g, yield 103%). The relative configuration of the compound was determined by NOESY measurement of the compound synthesized by the same method.

[0723] 1 H-NMR (DMSO-D6) δ: 1.00 (9H, s), 3.48 (1H, t, J = 10.6Hz), 3.55-3.70 (6H, m), 3.84-3.88 (1H ,m),3.93(2H,t,J=11.3Hz),5.55(1H,t,J=6.4Hz),7.42-7.50(6H,m),7.62-7.63(4H,m).

[0724] (11) 2-(5-(((tert-Butyldiphenylsilyl)oxy)methyl)-1,4-dioxane-2-yl)-2,2-difluoroethyl trifluoromethanesulfonate (trans isomer)

[0725]

[0726] To a solution of 2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxane-2-yl)-2,2-difluoroethane-1-ol (3.1 g, 7.03 mmol) obtained in (10) and triethylamine (1.47 mL, 10.55 mmol) in dichloromethane (31 mL) was added dropwise trifluoromethanesulfonyl chloride (1.12 mL, 10.55 mmol) under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (4.14 g, yield 104%).

[0727] 1H-NMR (DMSO-D6) δ: 1.00 (9H, s), 3.52 (1H, t, J = 10.5Hz), 3.63-3.66 (4H, m), 3.97-4.03(3H,m),5.13-5.18(2H,m),7.43-7.48(6H,m),7.61-7.62(4H,m).

[0728] (12)((5-(2-azido-1,1-difluoroethyl)-1,4-dioxan-2-yl)methoxy)(tert-butyl)diphenylsilane (trans isomer)

[0729]

[0730] To a solution of 2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxane-2-yl)-2,2-difluoroethyl trifluoromethanesulfonate (4.14 g, 7.28 mmol) obtained in (11) in N,N-dimethylformamide (33 mL) was added potassium azide (0.886 g, 10.92 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (3.27 g, yield 97%).

[0731] 1 H-NMR(DMSO-D6)δ: 0.99(9H,s),3.49-3.54(1H,m),3.58-3.68(4H,m),3.80-3.97(5H,m),7.44-7.47(6H,m),7.61-7.63(4H,m).

[0732] (13) 2-(5-(((tert-Butyldiphenylsilyl)oxy)methyl)-1,4-dioxane-2-yl)-2,2-difluoroethan-1-amine (trans isomer)

[0733]

[0734] To a mixed solution of ((5-(2-azido-1,1-difluoroethyl)-1,4-dioxane-2-yl)methoxy)(tert-butyl)diphenylsilane (3.27 g, 7.08 mmol) obtained in (12) in tetrahydrofuran (16.4 mL) and methanol (16.4 mL) was added 10% palladium on carbon (0.654 g), and the mixture was stirred at room temperature under normal pressure of hydrogen for 3 hours. Insoluble matter was removed by filtration through celite, and the filtrate was concentrated under reduced pressure to give the title compound (2.9 g, yield 95%).

[0735] 1 H-NMR(DMSO-D6)δ: 1.00(9H,s),2.18(2H,br s),2.90-2.96(2H,m),3.47-3.67(5H,m),3.91-3.96(3H,m),7.42-7.50(6H,m),7.61-7.63(4H,m).

[0736] (14) Methyl 3-((2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxan-2-yl)-2,2-difluoroethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (trans isomer)

[0737]

[0738] To a solution of 2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxane-2-yl)-2,2-difluoroethan-1-amine (2.92 g, 6.70 mmol) obtained in (13) in N,N-dimethylformamide (29 mL) was added 2-hydroxy-5-(trifluoromethyl)benzaldehyde (1.21 g, 6.38 mmol), and the mixture was stirred at room temperature for 1.5 hours. Potassium carbonate (2.65 g, 19.15 mmol) and methyl 2,2-dichloroacetate (0.794 mL, 7.66 mmol) were added thereto, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Hexane / ethyl acetate = 5 / 1 was added to the residue, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (1.35 g, 31% yield). In addition, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate=95 / 5 to 75 / 25) to obtain the title compound (1.0 g, 23% yield).

[0739] 1 H-NMR(DMSO-D6)δ: 0.98(9H,s),3.42(1H,t,J=10.8Hz),3.57-3.68(4H,m),3.86(3H,s),3.91-3.94(3H,m),4.22-4.24(2H,m) ,6.73(1H,t,J=7.3Hz),7.41-7.50(6H,m),7.59-7.61(4H,m),7.78(1H,d,J=8.8Hz),7.86(1H,dd,J=9.0,1.6Hz),8.48(1H,s).

[0740] (15) Methyl 3-(N-(2-(5-((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxan-2-yl)-2,2-difluoroethyl)-2-chloroacetylamino)-5-(trifluoromethyl)benzofuran-2-carboxylate (trans isomer)

[0741]

[0742] To a solution of methyl 3-((2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxan-2-yl)-2,2-difluoroethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (2.35 g, 3.47 mmol) obtained in (14) and N,N-dimethylaniline (1.76 mL, 13.87 mmol) in dichloromethane (24 mL) was added dropwise chloroacetyl chloride (0.833 mL, 10.4 mmol), and the mixture was stirred at room temperature for 16 hours. N,N-dimethylaniline (0.85 mL, 6.94 mmol) and chloroacetyl chloride (0.4 mL, 5.2 mmol) were added to the reaction solution again, and the mixture was stirred at room temperature for another 4 hours. Chloroacetyl chloride (0.2 mL, 2.6 mmol) was added thereto again, and the mixture was stirred at room temperature for another 1 hour. To the reaction solution was added a 10% aqueous citric acid solution, and the mixture was extracted with chloroform. The organic layer was washed with 10% citric acid, water, and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 95 / 5 to 65 / 35) to give the title compound (2.22 g, 85% yield).

[0743] 1 H-NMR (DMSO-D6) δ: 0.98 (9H, s), 3.40 (1H, dd, J = 20.7, 10.5Hz), 3.49-3.67 (4H ,m),3.87-3.96(6H,m),4.06-4.12(1H,m),4.22(1H,dd,J=14.3,1.4Hz),4.33 (1H,dd,J=14.3,0.9Hz),4.50-4.67(1H,m),7.41-7.49(6H,m),7.60(4H,dt,J =7.8,1.5Hz),7.94(1H,dd,J=9.0,1.8Hz),8.05(1H,d,J=8.8Hz),8.23(1H,s).

[0744] (16) Methyl 3-((2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxan-2-yl)-2,2-difluoroethyl)(2-chloroethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (trans isomer)

[0745]

[0746] To a solution of methyl 3-(N-(2-(-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxane-2-yl)-2,2-difluoroethyl)-2-chloroacetylamino)-5-(trifluoromethyl)benzofuran-2-carboxylate (2.22 g, 2.94 mmol) obtained in (15) in tetrahydrofuran (27 mL) was added dropwise 0.91 M borane-tetrahydrofuran complex (9.7 mL, 8.83 mmol) under ice cooling, and the mixture was stirred at room temperature for 18 hours. To the reaction solution was added 10% aqueous citric acid solution under ice cooling, the mixture was stirred for 5 minutes and extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 95 / 5 to 60 / 40) to give the title compound (1.09 g, yield 50%).

[0747] 1 H-NMR (DMSO-D6) δ: 0.96 (9H, s), 3.20 (1H, t, J = 10.2Hz), 3.49-3.61 (4H, m), 3.69-3.76 (5H, m ),3.92-3.98(7H,m),7.41-7.49(6H,m),7.57-7.59(4H,m),7.89-7.89(2H,m),8.24(1H,s).

[0748] (17) Methyl 3-((2-azidoethyl)(2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxan-2-yl)-2,2-difluoroethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (trans isomer)

[0749]

[0750] To a solution of methyl 3-((2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxane-2-yl)-2,2-difluoroethyl)(2-chloroethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (1.09 g, 1.473 mmol) obtained in (16) in N,N-dimethylformamide (10.9 mL) were added potassium azide (0.239 g, 2.95 mmol) and sodium iodide (0.044 g, 0.295 mmol), and the mixture was stirred at 80° C. for 1 hour. Water was added to the reaction solution at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (1.24 g, yield 113%).

[0751] 1 H-NMR (DMSO-D6) δ: 0.96 (9H, s), 3.18 (1H, t, J = 10.5Hz), 3.44-3.73 (10H, m), 3.86-3.89 (5H, m),3.96-3.98(1H,m),7.41-7.49(6H,m),7.57-7.59(4H,m),7.89-7.89(2H,m),8.24(1H,s).

[0752] (18) 1-(2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxane-2-yl)-2,2-difluoroethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine -5-Keto(trans isomer)

[0753]

[0754] To a mixed solution of methyl 3-((2-azidoethyl)(2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxan-2-yl)-2,2-difluoroethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (1.12 g, 1.500 mmol) obtained in (17) in water (1.12 mL) and 1,2-dimethoxyethane (11.2 mL) was added triphenylphosphine (0.472 g, 1.800 mmol), and the mixture was stirred at 80° C. for 1 hour and then at 100° C. for another 1 hour. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (0.458 g, yield 44%).

[0755] 1 H-NMR(DMSO-D6)δ: 0.98(9H,s),3.33-3.35(2H,m),3.45-3.53(3H,m),3.56-3.61(1H,m),3.64-3.70(3H,m),3. 96-3.99(3H,m),4.14-4.21(2H,m),7.43-7.46(6H,m),7.59-7.61(4H,m),7.77-7.78(2H,m),8.09(1H,t,J=4.9 Hz),8.35(1H,s).

[0756] (19) 1-(2,2-difluoro-2-(5-(hydroxymethyl)-1,4-dioxan-2-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine -5-Keto(trans isomer)

[0757]

[0758] To the 1-(2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxan-2-yl)-2,2-difluoroethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine obtained in (18) To a solution of -5-ketone (0.380 g, 0.552 mmol) in tetrahydrofuran (3.8 mL) was added 1M tetrabutylammonium fluoride-tetrahydrofuran solution (1.10 mL, 1.10 mmol), and the mixture was stirred at room temperature for 1 hour. 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 sodium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (0.193 g, yield 78%). In addition, the filtrate was concentrated, and the resulting residue was purified by reverse phase column chromatography (column: ODS, eluent: water / acetonitrile = 85 / 15 to 0 / 100) to obtain the title compound (0.02 g, yield 8%).

[0759] 1H-NMR(DMSO-D6)δ: 3.34-3.35(3H,m),3.39-3.45(2H,m),3.50-3.55(3H,m),3.64(1H,t,J=11.1 Hz),3.90-3.95(3H,m),4.11-4.23(2H,m),4.79(1H,t,J=5.4 Hz),7.79-7.79(2H,m),8.10(1H,t,J=4.8Hz),8.32(1H,s).

[0760] (20) 1-(2,2-difluoro-2-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine -5-one (Example 95), and 1-(2,2-difluoro-2-((2S,5S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine -5-ketone (Example 77)

[0761]

[0762] 1-(2,2-difluoro-2-(5-(hydroxymethyl)-1,4-dioxan-2-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine obtained by the same reaction as (19) was subjected to supercritical fluid chromatography (apparatus: Waters SFC Prep15 System, column: Daicel CHIRALPAKIA / SFC, 10 mm (ID) × 250 mm (L), 5 μm, column temperature: 40°C, column back pressure: 120 bar, mobile phase flow rate: 15 mL / min, mobile phase mixing ratio: isocratic, carbon dioxide / (methanol / acetonitrile=20 / 80)=70 / 30, component trigger: UV 214 nm). -5-ketone (0.210 g, 0.466 mmol) was subjected to optical resolution to obtain the compound of Example 95 (0.149 g, 71% yield) as the first peak fraction (10.7-13.7 min) and the compound of Example 77 (0.030 g, 14% yield) as the second peak fraction (14.4-17.0 min). The absolute configuration of the dioxane ring of the compound of Example 95 was determined by X-ray crystallography.

[0763] (Compound of Example 95)

[0764] 1 H-NMR(DMSO-D6)δ: 3.34-3.35(3H,m),3.39-3.45(2H,m),3.50-3.55(3H,m),3.64(1H,t,J=11.1Hz),3.90-3 .95(3H,m),4.11-4.23(2H,m),4.79(1H,t,J=5.4Hz),7.79-7.79(2H,m),8.10(1H,t,J=4.8Hz),8.32(1H,s).

[0765] (Compound of Example 77)

[0766] 1 H-NMR(DMSO-D6)δ: 3.34-3.35(3H,m),3.39-3.45(2H,m),3.50-3.55(3H,m),3.64(1H,t,J=11.1Hz),3.90-3 .95(3H,m),4.11-4.23(2H,m),4.79(1H,t,J=5.4Hz),7.79-7.79(2H,m),8.10(1H,t,J=4.8Hz),8.32(1H,s).

[0767] [Preparation Example 3]: 1-(2-((1s,4s)-4-hydroxy-4-(hydroxymethyl)cyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine Synthesis of -5-ketone (Example 90)

[0768]

[0769] (1) ethyl 2-(1,4-dioxaspiro[4,5]dec-8-ylidene)acetate

[0770]

[0771] Under an argon atmosphere, a solution of 1,4-dioxaspiro[4,5]decan-8-one (15.0 g, 96 mmol), triethyl phosphonoacetate (32.7 mL, 163 mmol), and potassium carbonate (13.3 g, 96 mmol) in N,N-dimethylformamide (120 mL) was stirred at 80°C for 21 hours. Triethyl phosphonoacetate (9 mL, 45 mmol) was added again, and the mixture was stirred at 80°C for another 21 hours. 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 sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 10 / 1 to 3 / 1) to give the title compound (18.7 g, yield 86%).

[0772] 1 H-NMR(CDCl3)δ: 1.28(3H,t,J=7.2Hz), 1.77(4H,dt,J=12.5,4.5Hz), 2.38(2H,t, J=6.6Hz), 3.00(2H,t,J=6.6Hz), 3.98(4H,s), 4.15(2H,q,J=7.2Hz), 5.67(1H,s).

[0773] (2) ethyl 2-(1,4-dioxaspiro[4,5]dec-8-yl)acetate

[0774]

[0775] To a solution of ethyl 2-(1,4-dioxaspiro[4,5]dec-8-ylidene)acetate (18.7 g, 83 mmol) obtained in (1) in tetrahydrofuran (187 mL) was added 10% palladium on carbon (3.8 g), and the mixture was stirred at room temperature under normal pressure of hydrogen for 24 hours. Insoluble matter was removed by filtration through celite, and the filtrate was concentrated under azeotropy with toluene and under reduced pressure to give the title compound (18.6 g, yield 99%).

[0776] 1 H-NMR (CDCl3) δ: 1.26 (3H, t, J = 7.2Hz), 1.27-1.36 (2H, m), 1.53-1.64 (2H, m), 1.70-1.7 8(4H,m),1.79-1.88(1H,m),2.22(2H,d,J=7.2Hz),3.94(4H,s),4.13(2H,q,J=7.2Hz).

[0777] (3) 2-(1,4-dioxaspiro[4,5]dec-8-yl)ethan-1-ol

[0778]

[0779] Under argon atmosphere and ice cooling, to a suspension of lithium aluminum hydride (6.2 g, 163 mmol) in tetrahydrofuran (93 mL) was added dropwise a solution of ethyl 2-(1,4-dioxaspiro[4,5]dec-8-yl)acetate (18.6 g, 82 mmol) obtained in (2) in tetrahydrofuran (93 mL), and the mixture was stirred for 1 hour. Water (6.2 mL), 4N aqueous sodium hydroxide solution (6.2 mL) and water (18.6 mL) were successively added dropwise to the reaction solution, and the mixture was stirred at room temperature for 15 minutes. Insoluble matter was removed by filtration through celite, and the filtrate was concentrated under azeotropy with toluene and under reduced pressure to obtain the title compound (13.3 g, yield 88%).

[0780] 1 H-NMR(CDCl3)δ: 1.19-1.32(3H,m),1.45-1.57(5H,m),1.72-1.77(4H,m),3.67-3.72(2H,m),3.94(4H,s).

[0781] (4) 2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl 4-methylbenzenesulfonate

[0782]

[0783] Under ice cooling, to a solution of 2-(1,4-dioxaspiro[4,5]dec-8-yl)ethan-1-ol (13.3 g, 71.4 mmol) obtained in (3), triethylamine (14.9 mL, 107 mmol) and 1-methyl-1H-imidazole (8.5 mL, 107 mmol) in tetrahydrofuran (67 mL) was added dropwise a solution of 4-methylbenzenesulfonyl chloride (20.4 g, 107 mmol) in tetrahydrofuran (67 mL), and the mixture was stirred at room temperature for 4 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 6 / 1 to 2 / 3) to obtain the title compound (21.4 g, yield 88%).

[0784] 1H-NMR(CDCl3)δ: 1.12-1.22(2H,m),1.35-1.50(3H,m),1.54-1.61(4H,m),1.64-1.70(2H,m),2.4 5(3H,s),3.88-3.95(4H,m),4.06(2H,t,J=6.5Hz),7.35(2H,d,J=8.1Hz),7.79(2H,d,J=8.1Hz).

[0785] (5) Methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate

[0786]

[0787] To a solution of 2-hydroxy-5-(trifluoromethyl)benzaldehyde (3.0 g, 15.8 mmol) in methanol (15 mL) was added dropwise a solution of tert-butyl (2-aminoethyl)carbamate (2.5 g, 15.8 mmol) in methanol (15 mL), and the mixture was stirred at room temperature for 16 hours and concentrated under azeotropy with toluene and under reduced pressure. The resulting residue was dissolved in N, N-dimethylformamide (52 mL), methyl 2,2-dichloroacetate (2.0 mL, 18.9 mmol) and potassium carbonate (6.5 g, 47.3 mmol) were added thereto, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (5.6 g, yield 88%).

[0788] 1 H-NMR(DMSO-D6)δ: 1.34(9H,s),3.16-3.21(2H,m),3.65-3.70(2H,m),3.83(3H,s),6.55(1H,t,J =6.6Hz), 7.03(1H,t,J=5.4Hz), 7.76(1H,d,J=8.8Hz), 7.84(1H,dd,J=8.8,1.4Hz), 8.47(1H,s).

[0789] (6) 9-(Trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofurano[3,2-e][1,4]diazepine -5-Keto

[0790]

[0791] To methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (5.6 g, 13.9 mmol) obtained in (5) was added 2 M hydrochloric acid-methanol solution (62.6 mL, 125 mmol), and the mixture was stirred at room temperature for 16 hours, and concentrated under azeotropy with toluene and under reduced pressure. Methanol (112 mL) was added to the obtained residue, and 5 M sodium methoxide-methanol solution (9.7 mL, 48.7 mmol) was added dropwise thereto under water cooling, and the mixture was stirred at room temperature for 16 hours. Under ice cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Ethyl acetate (28 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (2.9 g, yield 77%).

[0792] 1 H-NMR (DMSO-D6) δ: 3.29-3.36(2H,m), 3.42-3.45(2H,m), 7.26(1H,t,J=3.6Hz), 7.70-7.72(2H,m), 7.76(1H,dd,J=8.8,1.8Hz), 8.32(1H,s).

[0793] (7) 5-methoxy-9-(trifluoromethyl)-2,3-dihydro-1H-benzofurano[3,2-e][1,4]diazepine

[0794]

[0795] To the 9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofurano[3,2-e][1,4]diazepine obtained in (6) To a solution of -5-ketone (2.9 g, 10.8 mmol) in ethyl acetate (44 mL) was added trimethyloxonium tetrafluoroborate (1.9 g, 12.9 mmol), and the mixture was stirred at room temperature for 16 hours. To the reaction solution was added dropwise an aqueous solution (44 mL) of sodium carbonate (3.4 g, 32.3 mmol), the mixture was stirred for 10 minutes, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 2 / 1 to 1 / 2) to give the title compound (2.7 g, yield 87%).

[0796] 1H-NMR(DMSO-D6)δ: 3.34(2H,br,s),3.72(3H,s),3.75(2H,br,s),7.17(1H,t ,J=4.3Hz),7.70(1H,d,J=8.8Hz),7.77(1H,dd,J=8.8,1.8Hz),8.26(1H,s).

[0797] (8) 1-(2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl)-5-methoxy-9-(trifluoromethyl)-2,3-dihydro-1H-benzofurano[3,2-e][1,4]diazepine

[0798]

[0799] 5-Methoxy-9-(trifluoromethyl)-2,3-dihydro-1H-benzofuro[3,2-e][1,4]diazepine obtained by the same reaction as (7) was added. To a solution of 4-methylbenzenesulfonic acid 2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl ester (4.5 g, 13.2 mmol) obtained in tetrahydrofuran (23 mL) was added dropwise 1 M sodium bis(trimethylsilyl)amide-tetrahydrofuran solution (13.2 mL, 13.2 mmol), and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. 10% aqueous citric acid solution and saturated brine were added to the aqueous layer, and the mixture was re-extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. A mixed solvent of hexane / ethyl acetate = 1 / 1 was added to the obtained residue, and the mixture was stirred at room temperature. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (1.2 g, yield 51%). Furthermore, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3 / 1 to 1 / 4) to give the title compound (0.94 g, yield 39%).

[0800] 1 H-NMR(DMSO-D6)δ: 1.21-1.31(2H,m),1.36-1.48(3H,m),1.65-1.67(4H,m),1.72-1.76(2H,m),3.17(2 H,br,s),3.42-3.46(2H,m),3.68(2H,br,s),3.74(3H,s),3.84(4H,s),7.80-7.81(2H,m),7.99(1H,s).

[0801] (9) 1-(2-(4-oxocyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofurano[3,2-e][1,4]diazepine -5-Keto

[0802]

[0803] 1-(2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl)-5-methoxy-9-(trifluoromethyl)-2,3-dihydro-1H-benzofuro[3,2-e][1,4]diazepine obtained in (8) was added to the 1-(2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl)-5-methoxy-9-(trifluoromethyl)-2,3-dihydro-1H-benzofuro[3,2-e][1,4]diazepine To a solution of (2.2 g, 4.80 mmol) in 1,2-dimethoxyethane (22 mL) was added 6N hydrochloric acid (8.0 mL, 48.0 mmol), and the mixture was stirred at 90 ° C for 3 hours. Under ice cooling, ethyl acetate and potassium phosphate tribasic aqueous solution were added to the reaction solution. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (1.1 g, yield 58%). In addition, the organic layer of the filtrate was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (0.459 g, yield 25%).

[0804] 1 H-NMR(DMSO-D6)δ: 1.39-1.49(2H,m),1.69-1.75(2H,m),1.80-1.87(1H,m),2.02-2.06(2H,m),2.18-2.22(2H,m),2.39(2H,td, J=13.6,5.8Hz),3.30-3.34(2H,m),3.42-3.44(2H,m),3.57-3.61(2H,m),7.79-7.80(2H,m),8.02(1H,t,J=4.8Hz),8.07(1H,s).

[0805] (10) 1-((tert-butyldimethylsilyl)oxy)-4-(2-(5-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzofurano[3,2-e][1,4]diazepine -1-yl)ethyl)cyclohexane-1-carboxylic acid methyl ester

[0806]

[0807] Under ice cooling, 1-(2-(4-oxocyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine obtained in (9) was added to the To a solution of -5-ketone (600 mg, 1.52 mmol) and 2-((tert-butyldimethylsilyl)oxy)malononitrile (448 mg, 2.28 mmol) in tetrahydrofuran (9 mL) were added methanol (0.308 mL, 7.61 mmol) and 4-dimethylaminopyridine (0.372 g, 3.04 mmol), and the mixture was stirred for 2 hours. The mixture was warmed to room temperature and stirred for another 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1 / 4 to ethyl acetate / methanol = 3 / 1) to give the title compound (0.373 g, yield 43%).

[0808] 1 H-NMR(DMSO-D6)δ: 0.03(6H,s),0.85(9H,s),1.38-1.44(3H,m),1.63-1.68(6H,m),1.76-1.80(2H,m),3.28-3.32 (2H,m),3.39-3.41(2H,m),3.52-3.57(2H,m),3.66(3H,s),7.79-7.80(2H,m),8.01(1H,t,J=4.8Hz),8.03(1H,s).

[0809] (11) 1-(2-(4-((tert-butyldimethylsilyl)oxy)-4-(hydroxymethyl)cyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofurano[3,2-e][1,4]diazepine -5-Keto

[0810]

[0811] Under ice cooling, 1-((tert-butyldimethylsilyl)oxy)-4-(2-(5-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzofuro[3,2-e][1,4]diazepine obtained in (10) was added to the To a solution of methyl)cyclohexane-1-formate (0.373 g, 0.656 mmol) in tetrahydrofuran (3.7 mL) was added dropwise 1 M lithium borohydride-tetrahydrofuran solution (1.31 mL, 1.31 mmol), and the mixture was stirred at room temperature for 24 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Ethyl acetate and methanol were added to the resulting residue, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (0.232 g, yield 65%).

[0812] 1 H-NMR(DMSO-D6)δ: 0.07(6H,s),0.83(9H,s),1.24-1.45(5H,m),1.50-1.63(6H,m),3.25(2H,d,J=5.3Hz),3.30-3.32(2H ,m),3.39-3.41(2H,m),3.53-3.57(2H,m),4.75(1H,t,J=5.3Hz),7.79-7.80(2H,m),8.00(1H,t,J=4.7Hz),8.04(1H,s).

[0813] (12) 1-(2-((1s,4s)-4-hydroxy-4-(hydroxymethyl)cyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine -5-Keto

[0814]

[0815] To the 1-(2-(4-((tert-butyldimethylsilyl)oxy)-4-(hydroxymethyl)cyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine obtained in (11) To a solution of -5-ketone (90 mg, 0.166 mmol) in tetrahydrofuran (0.9 mL) was added 1 M tetrabutylammonium fluoride-tetrahydrofuran solution (0.333 mL, 0.333 mmol), and the mixture was stirred at room temperature for 1 hour. 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 sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase liquid chromatography (apparatus: Waters Prep System, column: XTERRA PrepMS C18 OBD TMA 5 μm, 30×50 mm column was used. Column temperature: room temperature, mobile phase flow rate: 40 mL / min, mobile phase mixture ratio: gradient: water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid) = 90 / 10 (0 min) - 50 / 50 (8 min) - 0 / 100 (8.05 min) to obtain the title compound (0.021 g, 30% yield). The relative configuration of the cyclohexane ring was determined by X-ray crystallography.

[0816] 1 H-NMR(DMSO-D6)δ: 1.18-1.45(7H,m),1.49-1.56(2H,m),1.57-1.65(2H,m),3.12(2H,d,J=5.9Hz),3.28-3.34(2H,m),3.38 -3.42(2H,m),3.51-3.57(2H,m),3.80(1H,s),4.44(1H,t,J=5.9Hz),7.77-7.82(2H,m),8.00(1H,t,J=4.9Hz),8.06(1H,br s).

[0817] To the 1-(2-((1s,4s)-4-hydroxy-4-(hydroxymethyl)cyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine obtained by the same reaction as above was added. A mixed solvent of toluene / N,N-dimethylformamide = 2 / 1 (500 μL) was added to 1-(2-((1s,4s)-4-hydroxy-4-(hydroxymethyl)cyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofurano[3,2-e][1,4]diazepine (50 mg), and the mixture was stirred at room temperature for one week. A portion of the suspension was filtered, and the resulting solid was dried to give 1-(2-((1s,4s)-4-hydroxy-4-(hydroxymethyl)cyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofurano[3,2-e][1,4]diazepine -5-ketone crystals.

[0818] [Preparation Example 4]: 1-(2,2-difluoro-2-((1r,4r)-4-hydroxycyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine -5-one (Example 106) and 1-(2,2-difluoro-2-(4-hydroxycyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine Synthesis of -5-ketone (Example 107)

[0819]

[0820] (1) Ethyl 2-fluoro-2-(1,4-dioxaspiro[4,5]dec-8-ylidene)acetate

[0821]

[0822] Under an argon atmosphere and ice cooling, 2-fluoro-2-phosphonoacetic acid triethyl ester (0.651 mL, 3.20 mmol) was added dropwise to a solution of sodium hydride (60%) (0.141 g, 3.52 mmol) in N, N-dimethylformamide (2.5 mL), and the mixture was stirred for 15 minutes. A solution of 1,4-dioxaspiro[4,5]dec-8-one (0.5 g, 3.20 mmol) in N, N-dimethylformamide (2.5 mL) was added dropwise, and the mixture was stirred for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate, the organic layers were combined, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 7 / 1 to 4 / 1) to give the title compound (0.569 g, yield 73%).

[0823] 1 H-NMR (DMSO-D6) δ: 1.24 (3H, t, J = 7.1Hz), 1.66-1.69 (4H, m), 2.43 (2H, td, J = 6.6, 2.4Hz), 2.82 (2H, td, J = 6.5, 1.3Hz), 3.90 (4H, s), 4.21 (2H, q, J = 7.1Hz).

[0824] (2) Ethyl 2-fluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)acetate

[0825]

[0826] To a solution of ethyl 2-fluoro-2-(1,4-dioxaspiro[4,5]dec-8-ylidene)acetate (0.569 g, 2.33 mmol) obtained in (1) in ethyl acetate (5.7 mL) was added 10% palladium on carbon (0.057 g), and the mixture was stirred at room temperature under normal pressure of hydrogen for 6 hours. Insoluble matter was removed by filtration through celite, and the filtrate was concentrated under azeotropy with toluene and under reduced pressure to give the title compound (0.583 g, yield 102%).

[0827] 1H-NMR (DMSO-D6) δ: 1.22 (3H, t, J = 7.2Hz), 1.38-1.53 ​​(5H, m), 1.65-1.72 (3H, m), 1. 81-1.95(1H,m),3.84(4H,s),4.19(2H,q,J=7.1Hz),4.96(1H,dd,J=48.3,4.2Hz).

[0828] (3) ethyl 2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)acetate

[0829]

[0830] To a mixed solution of ethyl 2-fluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)acetate (0.574 g, 2.33 mmol) obtained in (2) in tetrahydrofuran (5.7 mL) and toluene (1.7 mL) was added dropwise a 1 M sodium bis(trimethylsilyl)amide-tetrahydrofuran solution (3.0 mL, 3.03 mmol) under an argon stream at -78°C, and the mixture was stirred for 15 minutes. N-Fluorobenzenesulfonimide (0.882 g, 2.80 mmol) was added thereto, and the mixture was stirred for 2 hours. Triethylamine (0.65 mL, 4.66 mmol) was added dropwise to the reaction solution under ice cooling, and a mixed solvent of water and hexane / ethyl acetate = 3 / 1 was added thereto, and the mixture was subjected to extraction. The aqueous layer was re-extracted with a mixed solvent of hexane / ethyl acetate = 3 / 1, and the organic layers were combined, washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 7 / 1 to 3 / 1) to give the title compound (0.403 g, yield 65%).

[0831] 1 H-NMR (DMSO-D6) δ: 1.26 (3H, t, J = 7.1Hz), 1.33-1.44 (2H, m), 1.47-1.55 (2H, m),1.67-1.72(4H,m),2.10-2.25(1H,m),3.85(4H,s),4.31(2H,q,J=7.1Hz).

[0832] (4) 2,2-Difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethan-1-ol

[0833]

[0834] Under an argon stream and under ice cooling, a solution of ethyl 2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)acetate (0.403 g, 1.53 mmol) obtained in (3) in tetrahydrofuran (2.0 mL) was added dropwise to a suspension of lithium aluminum hydride (0.087 g, 2.29 mmol) in tetrahydrofuran (2.0 mL), and the mixture was stirred for 30 minutes. Water (0.087 mL), 4N aqueous sodium hydroxide solution (0.087 mL) and water (0.261 mL) were added dropwise to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. Insoluble matter was removed by filtration through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 3 / 1 to 2 / 3) to give the title compound (0.236 g, yield 70%).

[0835] 1 H-NMR(DMSO-D6)δ: 1.35-1.50(4H,m),1.69-1.77(4H,m),1.91-2.02(1H,m),3.59(2H,td,J=14.1,6.0Hz),3.85(4H,s),5.42(1H,t,J=6.1Hz).

[0836] (5) 2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl trifluoromethanesulfonate

[0837]

[0838] Under ice cooling, trifluoromethanesulfonic anhydride (0.359 mL, 2.12 mmol) was added dropwise to a solution of 2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethan-1-ol (0.236 g, 1.06 mmol) obtained in (4) in pyridine (1.9 mL) under ice cooling, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (0.338 g, yield 90%).

[0839] 1 H-NMR(DMSO-D6)δ: 1.36-1.51(4H,m),1.70-1.79(4H,m),2.03-2.11(1H,m),3.85(4H,s),5.12(2H,t,J=14.2Hz).

[0840] (6) 2-(2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl)isoindoline-1,3-dione

[0841]

[0842] To a solution of 2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl trifluoromethanesulfonate (0.338 g, 0.954 mmol) obtained in (5) in N,N-dimethylformamide (3.4 mL) was added potassium phthalimide (0.212 g, 1.15 mmol), and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4 / 1 to 1 / 1) to give the title compound (0.270 g, yield 81%).

[0843] 1 H-NMR(DMSO-D6)δ: 1.42-1.52(4H,m),1.72-1.75(2H,m),1.89-1.91(2H,m) ,1.94-2.10(1H,m),3.86(4H,s),4.04(2H,t,J=15.5Hz),7.87-7.94(4H,m).

[0844] (7) 2,2-Difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethan-1-amine

[0845]

[0846] To a mixed solution of 2-(2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl)isoindoline-1,3-dione (0.270 g, 0.768 mmol) obtained in (6) in ethanol (1.9 mL) and tetrahydrofuran (1.9 mL) was added hydrazine monohydrate (0.112 mL, 2.31 mmol), and the mixture was stirred at 60° C. for 2 hours. Toluene (3.8 mL) was added thereto, and the mixture was stirred at 60° C. for another 2 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.180 g, yield 106%).

[0847] 1 H-NMR (DMSO-D6) δ: 1.32-1.50(4H,m), 1.59(2H,br,s), 1.68-1.76(4H,m), 1.95-2.10(1H,m), 2.84(2H,t,J=15.3Hz), 3.85(4H,s).

[0848] (8) Methyl 3-((2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate

[0849]

[0850] To a solution of 2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethan-1-amine (0.170 g, 0.768 mmol) obtained in (7) in N,N-dimethylformamide (1.5 mL) was added 2-hydroxy-5-(trifluoromethyl)benzaldehyde (0.146 g, 0.768 mmol), and the mixture was stirred at room temperature for 2 hours. Potassium carbonate (0.318 g, 2.30 mmol) and methyl 2,2-dichloroacetate (0.095 mL, 0.922 mmol) were added thereto, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate, and the organic layers were combined, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4 / 1 to 1 / 1) to give the title compound (0.272 g, yield 76%).

[0851] 1 H-NMR(DMSO-D6)δ: 1.44-1.53(4H,m),1.69-1.76(2H,m),1.84-1.86(2H,m),1.94-2.08(1H,m),3.85(3H,s),3.86(4H,s ), 4.20(2H,td,J=15.8,7.1Hz), 6.70(1H,t,J=6.9Hz), 7.77(1H,d,J=8.8Hz), 7.85(1H,dd,J=8.8,1.6Hz), 8.40(1H,s).

[0852] (9) 3-(2-chloro-N-(2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl)acetylamino)-5-(trifluoromethyl)benzofuran-2-carboxylic acid methyl ester

[0853]

[0854] To a solution of methyl 3-((2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (0.272 g, 0.587 mmol) obtained in (8) and N,N-dimethylaniline (0.297 mL, 2.35 mmol) in dichloromethane (2.7 mL) was added dropwise chloroacetyl chloride (0.141 mL, 1.77 mmol) under ice cooling, and the mixture was stirred at room temperature for 16 hours. A 10% aqueous citric acid solution and hexane / ethyl acetate = 1 / 1 were added thereto, and the mixture was subjected to extraction. The aqueous layer was re-extracted with hexane / ethyl acetate = 1 / 1, and the organic layers were combined, washed with a 10% aqueous citric acid solution, water, and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 7 / 1 to 1 / 1) to give the title compound (0.296 g, yield 93%).

[0855] 1 H-NMR(DMSO-D6)δ: 1.33-1.47(4H,m),1.68-1.81(4H,m),1.99-2.08(1H,m),3.84(4H,s),3.90(3H,s),4.00-4.06(1H,m),4.22 (1H,d,J=14.4Hz),4.33(1H,d,J=14.4Hz),4.45-4.57(1H,m),7.94(1H,dd,J=8.9,1.7Hz),8.04(1H,d,J=8.8Hz),8.24(1H,s).

[0856] (10) Methyl 3-((2-chloroethyl)(2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate

[0857]

[0858] To a solution of methyl 3-(2-chloro-N-(2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl)acetylamino)-5-(trifluoromethyl)benzofuran-2-carboxylate (0.296 g, 0.548 mmol) obtained in (9) in tetrahydrofuran (3.0 mL) was added dropwise 0.91 M borane-tetrahydrofuran complex (1.5 mL, 1.37 mmol) under an argon stream and ice cooling, and the mixture was stirred for 16 hours. Under ice cooling, a 10% aqueous citric acid solution was added thereto, and the mixture was stirred for 5 minutes and extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate, and the organic layers were combined, washed with a 10% aqueous sodium carbonate solution, water, and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4 / 1 to 3 / 2) to give the title compound (0.148 g, yield 51%).

[0859] 1 H-NMR(DMSO-D6)δ: 1.25-1.37(4H,m),1.60-1.64(4H,m),2.04-2.15(1H,m),3.68-3.77( 4H,m),3.81(4H,s),3.91(3H,s),3.93(2H,t,J=14.4Hz),7.86-7.92(2H,m),8.23(1H,s).

[0860] (11) Methyl 3-((2-azidoethyl)(2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate

[0861]

[0862] To the 3-((2-chloroethyl)(2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-

[0863] To a solution of methyl (5-(trifluoromethyl)benzofuran-2-carboxylate (0.148 g, 0.281 mmol) in N,N-dimethylformamide (1.5 mL) were added potassium azide (0.041 g, 0.507 mmol) and sodium iodide (0.008 g, 0.056 mmol), and the mixture was stirred at 80° C. for 16 hours. The reaction solution was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (0.128 g, yield 85%).

[0864] 1H-NMR(CDCl3)δ: 1.36-1.46(2H,m),1.46-1.55(2H,m),1.68-1.75(4H,m),1.86-2.00(1H,m),3.39(2H,t,J=5.8Hz),3 .72(2H,t,J=5.8Hz),3.82-3.93(6H,m),4.00(3H,s),7.62(1H,d,J=8.8Hz),7.72(1H,dd,J=8.8,1.6Hz),8.03(1H,s).

[0865] (12) 1-(2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine -5-Keto

[0866]

[0867] To a mixed solution of methyl 3-((2-azidoethyl)(2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (0.128 g, 0.240 mmol) obtained in (11) in 1,2-dimethoxyethane (2.6 mL) and water (0.26 mL) was added triphenylphosphine (0.076 g, 0.288 mmol), and the mixture was stirred at 100° C. for 5 hours. The mixture was cooled to room temperature and concentrated under azeotropy with toluene and under reduced pressure. Ethanol was added to the residue, and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (0.070 g, yield 61%).

[0868] 1 H-NMR(DMSO-D6)δ: 1.44-1.55(4H,m),1.70-1.75(2H,m),1.87-1.88(2H,m),1.96-2.10(1H,m),3.32-3.35(2H,m ),3.51-3.53(2H,m),3.87(4H,s),4.10(2H,t,J=16.8Hz),7.79-7.80(2H,m),8.09(1H,t,J=5.0Hz),8.14(1H,s).

[0869] (13) 1-(2,2-difluoro-2-(4-oxocyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofurano[3,2-e][1,4]diazepine -5-Keto

[0870]

[0871] 1-(2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine obtained in (12) was added to the 1-(2,2-difluoro-2-(1,4-dioxaspiro[4,5]dec-8-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine To a solution of -5-ketone (0.07 g, 0.148 mol) in acetic acid (0.56 mL) was added 2N hydrochloric acid (0.14 mL), and the mixture was stirred at 80°C for 4 hours. A 10% aqueous solution of dipotassium hydrogen phosphate was added at room temperature, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted twice more with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (0.056 g, 88% yield).

[0872] 1 H-NMR(DMSO-D6)δ: 1.67-1.76(2H,m),2.16-2.18(2H,m),2.24-2.28(2H,m),2.45-2.55(3H,m),3.32-3.37 (2H,m),3.54-3.56(2H,m),4.17(2H,t,J=16.8Hz),7.79-7.80(2H,m),8.10(1H,t,J=4.9Hz),8.16(1H,s).

[0873] (14) 1-(2,2-difluoro-2-((1r,4r)-4-hydroxycyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine -5-one (Example 106) and 1-(2,2-difluoro-2-(4-hydroxycyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine -5-ketone (Example 107)

[0874]

[0875] Under ice cooling, 1-(2,2-difluoro-2-(4-oxocyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine obtained in (13) was added. To a mixed solution of -5-ketone (0.056 g, 0.130 mmol) in methanol (0.45 mL) and tetrahydrofuran (0.45 mL) was added sodium borohydride (0.009 g, 0.260 mmol), and the mixture was stirred for 3 hours. A 5% aqueous potassium hydrogen sulfate solution was added thereto under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse phase liquid chromatography (apparatus: Waters Prep System, column: XTERRA PrepMS C18 OBD TM 5 μm, 30×50 mm column, column temperature: room temperature, mobile phase flow rate: 40 mL / min, mobile phase mixing ratio: gradient, water (0.1% trifluoroacetic acid) / acetonitrile (0.1% trifluoroacetic acid) = 90 / 10 (0 min) - 50 / 50 (8 min) - 0 / 100 (8.05 min)) to obtain the compound of Example 106 (0.028 g, 50% yield) and the compound of Example 107 (0.003 g, 6% yield). The relative configuration of the cyclohexane ring of the compound of Example 106 was determined by two-dimensional NMR. The compound of Example 107 was obtained as a cis / trans = 4 / 1 mixture.

[0876] (Compound of Example 106)

[0877] 1 H-NMR(DMSO-D6)δ: 1.08-1.37(4H,m),1.82-1.94(5H,m),3.27-3.41(3H,m),3.49-3.55(2H,m),4. 09(2H,t,J=16.6Hz),4.61(1H,d,J=4.4Hz),7.77-7.80(2H,m),8.08(1H,t,J=4.3Hz),8.14(1H,br s).

[0878] (Compound of Example 107)

[0879] 1H-NMR(DMSO-D6)δ: 1.08-1.37(0.8H,m),1.40-1.46(1.6H,m),1.57-1.78(4 .8H,m),1.82-1.97(1.8H,m),3.27-3.41(2.2H,m),3.49-3.55(2H,m),3.83 -3.87(0.8H,m),4.09(2H,t,J=16.6Hz),4.38(0.8H,d,J=2.8Hz),4.61(0.2 H,d,J=4.4Hz),7.77-7.80(2H,m),8.09(1H,t,J=4.7Hz),8.14-8.16(1H,m).

[0880] The compounds of other examples were obtained by the same methods as the above-mentioned preparation methods or preparation examples, and if necessary, known methods were used. The structures and physical property data of the compounds of Examples 1 to 167 and 2-01 to 2-07 are shown in Tables 1-1 to 1-25.

[0881] Experimental Example 1: Evaluation of human Pim-1 inhibitory activity

[0882] The human Pim-1 inhibitory activity of the test compounds was evaluated as follows.

[0883] (1) Purification of human Pim-1

[0884] Using the plasmid DNA (Kazusa DNA Laboratory, model FXC11400) inserted by the human Pim-1 gene as a template, a DNA fragment in which the His-Tag sequence and translation termination sequence are added to the 3'-end of the human Pim-1 translation sequence is amplified by PCR (polymerase chain reaction). The amplified DNA fragment is fused with pGEx-6P-1 (GE Healthcare Japan, model 27-4597-1) digested with BamHI and EcoRI using In-Fusion HD cloning kit (Takara Bio, model 639649). Human Pim-1 expression plasmid DNA is isolated from Escherichia coli DH5α (TOYOBO, model DNA-903) transformed with the obtained In-Fusion reaction product. The base sequence of the Pim-1 cloned into the vector is determined by the Dye Terminator method using BigDye Terminator v3.1 cycle sequencing kit (Applied Biosystems, model 4337456). The sequence determined is a sequence in which a His-Tag sequence and a translation termination sequence were introduced at the 3'-end of the sequence of the translation region of human Pim-1 registered in the NCBI reference database (accession number NM_002648.3). Escherichia coli BL21 (DE3) (Merck KGaA, model 69449-4) transformed with human Pim-1 expression plasmid DNA was cultured in 2×YT medium (Becton Dickinson, model 2404020) at 30°C until the optical density at 620 nm (OD620) reached 0.6, and then cultured overnight at 20°C in the presence of 0.5 mmol / L isopropyl b-D-1-thiogalactopyranoside. After the culture was completed, the cells were collected and suspended in a homogenization buffer (50 mmol / L Tris-HCl (pH 7.5), 500 mmol / L NaCl, 1% Tween 20, cOmplete, EDTA-free (Roche, Model 1873580)), and the suspended cells were lysed by passing through a microfluidizer M-110H (Mizuho Kogyo Co., Ltd.). The lysate was centrifuged at 10,100 × g and 4° C. for 10 minutes, and the supernatant was filtered through a MILLEX-HV filter (0.45 μm) (Millipore, SLHV033RS) to remove cell residues. The filtrate was loaded onto cOmplete His-Tag Purification Resin (Roche Diagnostics, Model 05 893 6820.01).The column was washed with equilibration buffer-1 (50 mmol / L Tris-HCl (pH 7.5), 500 mmol / L NaCl, 1% Tween 20) containing 5 mmol / L imidazole, and then with equilibration buffer-1 containing 50 mmol / L imidazole. Human Pim-1, to which the GST-Tag derived from pGEx-6P-1 was attached, was eluted with equilibration buffer-1 containing 150 mmol / L imidazole. Glutathione Sepharose 4B (GE Healthcare Japan, model 17-0756-05) was added to the eluate, and the column was washed with equilibration buffer-2 (50 mmol / L Tris-HCl (pH 7.5), 500 mmol / L NaCl, 0.05% Tween 20, 0.5 mmol / L ETA, 2 mmol / L DTT), and then suspended in equilibration buffer-2 containing 20 units / ml of PreScission protease (GE Healthcare, model 27-0843-01). The protease reaction was carried out by stirring overnight at 4°C, and the human Pim-1 in which the GST-Tag sequence was cleaved was eluted. The eluate was loaded onto a gel filtration column (Superdex-20030 / 100GL (GE Healthcare, model 17-5175-01)) equilibrated with equilibration buffer-3 (50 mmol / L Tris-HCl (pH 7.5), 500 mmol / L NaCl, 0.05% Tween 20, 0.5 mmol / L E-TTA, 2 mmol / L DTT, 10% glycerol) and eluted. The eluate was used as a human Pim-1 purification fraction.

[0885] The protein concentration of the purified human Pim-1 fraction was measured using the Pierce 660 nm protein assay reagent (Thermo Fisher Scientific, Model 22660). The purified fraction was quickly frozen in liquid nitrogen and then stored at -80°C. Human Pim-1 with His-Tag added was detected by Western blotting using a mouse anti-His monoclonal antibody (WAKO, Model 011-23091).

[0886] (2) Evaluation of human Pim-1 inhibitory activity

[0887] The Pim-1 inhibitory activity of the compound was calculated using the following solution according to the protocol attached to the ADP-Glo ​​Kinase Assay (cat. V9102, Promega): The purified human Pim-1 enzyme described above was used.

[0888] (i) Solution preparation

[0889] Kinase buffer solution (50 mmol / L HEPES (pH 7.5), 5 mmol / L MgCl2, 1 mmol / L DTT, 0.05% BSA) was prepared by dissolving HEPES (Jena Bioscience), MgCl2 (Sigma-Aldrich), DTT (Sigma-Aldrich), and BSA (Sigma-Aldrich) in purified water.

[0890] ATP solution (288 μmol / L) was prepared by dissolving 100 mmol / L ATP (Promega) in kinase buffer solution.

[0891] An enzyme / substrate solution (0.2 nmol / L Pim-1, 30 μmol / L Pim2tide) was prepared by dissolving Pim-1 (described above) and Pim2tide (custom synthesized product from GenScript USA, the same product as PIM2tide cat. 12-542 from Millipore) in kinase buffer solution.

[0892] Test compound solution (containing 12.5% ​​DMSO) was prepared by dissolving the DMSO solution of the test compound in kinase buffer solution.

[0893] Vehicle solution (containing 12.5% ​​DMSO) was prepared by dissolving DMSO in kinase buffer solution.

[0894] (ii) Methods

[0895] To a 384-well assay plate (Corning, 4513), 1 μL / well of the test compound solution or vehicle solution (control) was added, 2 μL / well of enzyme / substrate solution or kinase buffer solution (blank) was added, and 2 μL / well of ATP solution was added and mixed. After 45 minutes of enzymatic reaction at room temperature, ADP-Glo ​​reagent (Promega) was added at 5 μL / well and mixed. After 60 minutes of reaction at room temperature, kinase detection reagent (Promega) was added at 10 μL / well and mixed. After 30 minutes of reaction at room temperature, the luminescence of each well was measured for 10 milliseconds using a multi-label plate reader EnVision (PerkinElmer).

[0896] (iii) Aggregate Computing

[0897] The value obtained by subtracting the luminescence of the blank well from the luminescence of each well was used as the data. The Pim-1 inhibition rate at each concentration of the test compound was calculated using [Equation 1]. The IC value of the test compound was calculated by applying the inhibition rate of the test compound at each concentration to the logarithmic curve.50 (50% inhibitory concentration) Furthermore, it was converted into a Ki value using [Equation 2].

[0898] Equation 1

[0899]

[0900] A: Measured value of vehicle solution (control)

[0901] B: Measured value of the test compound

[0902] Equation 2

[0903]

[0904] E: enzyme concentration

[0905] S: ATP concentration

[0906] Km: Michaelis-Menten constant. The results are shown in Tables 1-1 to 1-25.

[0907] Table 1-1

[0908]

[0909] Table 1-2

[0910]

[0911] Table 1-3

[0912]

[0913] Table 1-4

[0914]

[0915] Table 1-5

[0916]

[0917] Table 1-6

[0918]

[0919] Table 1-7

[0920]

[0921] Table 1-8

[0922]

[0923] Table 1-9

[0924]

[0925] Table 1-10

[0926]

[0927] Table 1-11

[0928]

[0929] Table 1-12

[0930]

[0931] Table 1-13

[0932]

[0933] Table 1-14

[0934]

[0935] Table 1-15

[0936]

[0937] Table 1-16

[0938]

[0939] Table 1-17

[0940]

[0941] Table 1-18

[0942]

[0943] Table 1-19

[0944]

[0945] Table 1-20

[0946]

[0947] Table 1-21

[0948]

[0949] Table 1-22

[0950]

[0951] Table 1-23

[0952]

[0953] Table 1-24

[0954]

[0955] Table 1-25

[0956]

[0957] The formulation examples of the present invention include the following formulations. However, the present invention is not limited to these formulation examples.

[0958] Preparation Example 1 (Preparation of Capsules)

[0959]

[0960] 1), 2), 3) and 4) are mixed and filled in gelatin capsules.

[0961] Preparation Example 2 (Preparation of Tablets)

[0962]

[0963] The total amount of 1), 2), and 3) and 30 g of 4) were kneaded with water, vacuum-dried, and then granulated. The granulated powder was mixed with 14 g of 4) and 1 g of 5), and the mixture was compressed using a tablet press. In this manner, 1000 tablets were obtained, each containing 10 mg of the compound of Example 1.

[0964] Industrial Applicability

[0965] Since the compound of formula [I] or a pharmaceutically acceptable salt thereof has Pim-1 inhibitory activity, it can be used to treat or prevent a disease selected from pulmonary hypertension, cancer, psoriasis and systemic lupus erythematosus.

Claims

1. A compound of formula [I] or a pharmaceutically acceptable salt thereof: in Cy 1 yes (1)C 3-7 Cycloalkyl, (2) a 4- to 7-membered heterocycloalkyl group containing one or two heteroatoms independently selected from oxygen and sulfur atoms as ring-forming atoms other than carbon atoms, wherein the sulfur atom may be oxidized, (3)C 5-8 bridged cycloalkyl, (4) a 7- to 9-membered bridged heterocycloalkyl group containing one oxygen atom as a ring-forming atom other than a carbon atom, (5)C 7-11 spirocycloalkyl, or (6) 7- to 11-membered spiroheterocycloalkyl groups containing 1 to 3 oxygen atoms as ring atoms other than carbon atoms; R of quantity m 1 Each independently (1) Halogen, (2) hydroxyl groups, (3)C 1-6 Alkyl, wherein the alkyl group is optionally substituted with (a) hydroxyl groups, (b)C 1-4 Alkoxy, (c) cyano, (d)OCOR 11 , where R 11 is phenyl, or (e)SO2R 12 , where R 12 It is C 1-4 alkyl, (4)C 1-4 haloalkyl, wherein the haloalkyl is optionally substituted with hydroxy, (5)C 1-4 Alkoxy, wherein the alkoxy is optionally substituted with 1 to 3 halogens, (6)COR 13 , where R 13 yes (a) hydroxyl, or (b)NR 14 R 15 , where R 14 and R 15 are each independently hydrogen or C 1-4 alkyl, (7) cyano group, (8)SO2R 16 , where R 16 It is C 1-4 alkyl, (9)C 3-4 cycloalkyl, wherein the cycloalkyl is optionally substituted with hydroxy, or (10) triazole, or Two R bonded to the same carbon atom 1 Together they form oxygen subunits; R of number n 2 Each independently (1) Halogen, or (2)C 1-4 Alkoxy, or Two R bonded to the same carbon atom 2 Together with the carbon atoms to which they are bonded, they form C 3-4 Cycloalkanes; R 3 and R 4 Each independently (1) Hydrogen, or (2)C 1-4 Alkyl, or R 3 and R 4 Together with the carbon atoms to which they are bonded, they form C 3-4 Cycloalkanes; R 5 is hydrogen or C 1-4 alkyl; R 6 It is C 1-4 Haloalkyl; R 7 is hydrogen or a halogen; L is a straight chain C 1-4 alkylene; m is 0, 1, 2, 3, or 4; and n is 0, 1, 2 or 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 It's hydrogen.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L is ethylene or trimethylene.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 It's hydrogen.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the number of R is n 2 are each independently a halogen, or two R 2 Together with the carbon atoms to which they are bonded, they form C 3-4 Cycloalkane.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is represented by formula [III]: in The number of R is n1 2a are each independently halogen; L a is ethylene or trimethylene; n1 is 0, 1, or 2; and Cy 1 、R 1 、R 3 、R 4 、R 6 and m as defined in claim 1.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Cy 1 yes (1)C 3-7 Cycloalkyl, (2) a 4- to 7-membered heterocycloalkyl group containing one or two heteroatoms independently selected from oxygen and sulfur atoms as ring-forming atoms other than carbon atoms, wherein the sulfur atom may be oxidized, (3)C 7-11 spirocycloalkyl, or (4) A 7- to 11-membered spiroheterocycloalkyl group containing 1 to 3 oxygen atoms as ring-constituting atoms other than carbon atoms.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 yes (1) monofluoromethyl, (2) difluoromethyl, or (3) Trifluoromethyl.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Each independently (1) Hydrogen, or (2) methyl, or R 3 and R 4 Together with the carbon atom to which they are bonded, they form cyclopropane.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the number of R is m 1 Each independently (1) Halogen, (2) hydroxyl groups, (3)C 1-6 Alkyl, wherein the alkyl group is optionally substituted with (a) hydroxyl groups, (b)C 1-4 Alkoxy, (c) cyano, or (d)SO2R 12 , where R 12 It is C 1-4 alkyl, (4)C 1-4 haloalkyl, wherein the haloalkyl is optionally substituted with hydroxy, (5)C 1-4 Alkoxy, wherein the alkoxy is optionally substituted by 1 to 3 halogens, (6) COR 13 , where R 13 yes (a) hydroxyl, or (b)NR 14 R 15 , where R 14 and R 15 are each independently hydrogen or C 1-4 Alkyl, (7) cyano, (8)SO2R 16 , where R 16 It is C 1-4 Alkyl, or (9)C 3-4 Cycloalkyl, wherein the cycloalkyl is optionally substituted with hydroxy, or two R bonded to the same carbon atom 1 Together they form oxygen subunits.

11. A compound selected from the group consisting of compounds of the following formula: or a pharmaceutically acceptable salt thereof.

12. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

13. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

14. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

15. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

16. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

17. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

18. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

19. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

20. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

21. Compounds of the formula: or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23. A Pim-1 inhibitor comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

24. A therapeutic or preventive agent for treating or preventing a disease selected from pulmonary hypertension, cancer, psoriasis and systemic lupus erythematosus, comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

25. Use of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof for preparing a Pim-1 inhibitor.

26. Use of the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof for the preparation of a therapeutic or preventive agent for treating or preventing a disease selected from pulmonary hypertension, cancer, psoriasis and systemic lupus erythematosus.

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