Tetrahydrobenzofurodiazepinone compound and pharmaceutical use thereof

Abstract

The present invention provides compounds having Pim-1 inhibitory activity.SOLUTION: The present invention provides a compound of Formula [I] or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, a pharmaceutical use thereof, and the like. Wherein the symbols are the same as defined in the description SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a tetrahydrobenzofurodiazepinone compound or a pharmaceutically acceptable salt thereof having Pim-1 inhibitory activity, a pharmaceutical composition containing the same, and medical uses thereof. [Background technology]

[0002] Pim-1 (Proviral Integration site for Moloney murine leukemia virus-1) It is a member of the Pim family of proto-oncogene serine / threonine kinases. Pim-1 exists 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), the growth-derived factors VEGF (Vascular Endothelial Growth Factor), and PDGF (Platelet-Derived Growth Factor). When ligands bind to these receptors, Pim-1 expression is induced via PI3K-AKT, JAK / STAT, and NF-kB signaling, constitutively activating downstream signals. Pim-1 inhibits apoptosis through phosphorylation of BAD (Bcl-2 Associated Death Promoter) and ASK1 (Apoptosis signal-regulating kinase 1), and regulates the regulation of p21, p27, and cdc25. It is known that Pim-1 has a cell proliferation promoting effect via phosphorylation of apoptosis and c-Myc (Non-Patent Documents 1 and 2). Therefore, Pim-1 inhibitors are expected to be effective against diseases associated with apoptosis and cell proliferation.

[0003] The uses of Pim-1 inhibitors are described below. (1) Pulmonary arterial hypertension (PAH) Observational studies have shown that plasma Pim-1 expression levels are elevated in PAH patients compared with healthy subjects, and that this expression level correlates with pathological indicators such as 6-minute walking distance and pulmonary vascular resistance (Non-Patent Document 3). Furthermore, it has been reported that elevated Pim-1 expression was observed in pulmonary artery smooth muscle cells (PASMCs) isolated from PAH patients, and that the increased cell proliferation compared with PASMCs derived from healthy subjects was suppressed by Pim-1 knockdown. Furthermore, non-clinical studies using a rat PAH model have shown that Pim-1 knockdown suppresses elevated pulmonary artery pressure and medial thickening, characteristic of PAH pathology (Non-Patent Document 4). Based on these findings, Pim-1 inhibitors are expected to improve PAH pathology by inhibiting medial thickening through the suppression of pulmonary artery smooth muscle cell proliferation.

[0004] (2) Cancer Cancers in which increased Pim-1 expression has been reported in clinical studies include blood cancers (acute lymphocytic leukemia, acute myeloid leukemia, diffuse large B-cell lymphoma, and 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), and breast cancer (Non-Patent Document 11). Among these, it has been reported that Pim-1 expression levels correlate with life prognosis in acute myeloid leukemia, colon cancer, pancreatic cancer, osteosarcoma, and breast cancer, and that knocking down Pim-1 in established cell lines suppresses cell proliferation (Non-Patent Documents 6, 12, 7, 10, 11, and 14), and the therapeutic effects of Pim-1 inhibitors are particularly expected. It has been reported that the Pim-1 inhibitor SMI-4a exhibits growth-inhibitory and apoptosis-inducing effects on chronic myeloid leukemia-derived cells (Non-patent Document 15), and that the pan-Pim 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, as well as tumor growth-inhibitory effects in mouse cancer models (Non-patent Documents 16, 17). Therefore, Pim-1 inhibitors are expected to have therapeutic effects against the above-mentioned cancers as well.

[0005] (3) Psoriasis It is known that in psoriasis, inflammatory cells infiltrate the epidermis and dermis, causing inflammation, along with the remodeling of dermal blood vessels. Increased expression of Pim-1 has been observed in dermal blood vessels of human psoriasis patients, and Pim-1 is thought to be involved in this remodeling. In a non-clinical study, it was reported that the acanthosis and inflammatory cell infiltration observed in an animal model of IL-22-induced psoriasis-like skin inflammation were suppressed by knockdown of Pim-1 (Non-Patent Document 13). Based on these findings, it is expected that Pim-1 inhibitors will have a therapeutic effect on psoriasis through the suppression of dermal vascular remodeling.

[0006] (4) Systemic lupus erythematosus (SLE) Lupus nephritis (LN) is a glomerular nephritis caused by SLE. Increased expression of Pim-1 has been observed in peripheral blood mononuclear cells (PBMCs) from human SLE patients and in the kidneys of LN patients. In studies using human podocytes, knockdown of Pim-1 was shown to reduce the inflammation-related signals NFATc1 and IL-1β. Furthermore, in a nonclinical study using a mouse LN model, the Pim-1 inhibitor SMI-4a reduced glomerular damage, decreased the urinary albumin / creatinine ratio, and improved mortality (Non-Patent Document 18). Based on these findings, it is expected that Pim-1 inhibitors will have a therapeutic effect on LN associated with SLE through inflammation suppression. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Laurent Brault, Christelle Gasser, Franz Bracher, Kilian Huber, Stefan Knapp, and Juerg Schwaller1:PIM丝氨酸 / 苏氨酸激酶在血液系统恶性肿瘤和实体癌的发病机制及治疗中的作用。《血液学》。2010年6月;95(6):1004 - 15。

Non - Patent Document 2

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Non-Patent Document 5

Non-patent Document 8

Non-patent Document 9

Non-patent Document 10

Non-patent Document 11

Outdoor Tools 12

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Non-Patent Document 14

Non-Patent Document 15

Non-Patent Document 16

Non-Patent Document 17

Non-Patent Document 18

[0008] The present invention provides a tetrahydrobenzofurodiazepinone compound having Pim-1 inhibitory activity or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and medical uses thereof, etc. That is, the present invention includes the following exemplary embodiments.

[0009] [Section 1] A compound of formula [I] or a pharmaceutically acceptable salt thereof.

[0010] [ka]

[0011] [In the formula, Cy 1 teeth, (1)C 3-7 cycloalkyl, (2) a 4- to 7-membered heterocycloalkyl containing, in addition to carbon atoms as ring-constituting atoms, one or two heteroatoms independently selected from the group consisting of oxygen and sulfur atoms (the sulfur atoms may be oxidized); (3) C 5-8 bridged cycloalkyl, (4) a 7- to 9-membered bridged heterocycloalkyl containing one oxygen atom in addition to carbon atoms as ring-constituting atoms; (5) C 7-11spirocycloalkyl, or (6) 7- to 11-membered spiroheterocycloalkyl containing 1 to 3 oxygen atoms in addition to carbon atoms as ring-constituting atoms. and; m R 1 are each independently (1) halogen, (2) hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, (c) Cyano, (d)OCOR 11 (where R 11 is phenyl), or (e)SO2R 12 (where R 12 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 teeth, (a) hydroxy, 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 is C 1-4 alkyl), (9) C 3-4 cycloalkyl, wherein the cycloalkyl is optionally substituted with hydroxy; or (10) Triazolyl or two R 1 together to form oxo; n R 2 are each independently (1) Halogen, or (2) C 1-4 Alkoxy or two R 2 together with the carbon atoms to which they are attached, C 3-4 forming cycloalkanes; R 3 and R 4 are 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 attached, C 3-4 forming cycloalkanes; R 5 is hydrogen or C 1-4 is alkyl; R 6 is C 1-4 is haloalkyl; R 7 is hydrogen or halogen; L is a linear C 1-4 is alkylene; m is 0, 1, 2, 3 or 4; n is 0, 1, 2 or 3.

[0012] [Section 2] R 5 Item 2. The compound according to Item 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

[0013] [Section 3] Item 3. The compound or pharmaceutically acceptable salt thereof according to Item 1 or 2, wherein L is ethylene or trimethylene.

[0014] [Section 4] R 7Item 4. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 3, wherein is hydrogen.

[0015] [Section 5] n R 2 are each independently a halogen or two R 2 together with the carbon atoms to which they are attached, C 3-4 Item 5. The compound according to any one of Items 1 to 4, which forms a cycloalkane, or a pharmaceutically acceptable salt thereof.

[0016] [Section 6] Formula [III]:

[0017] [ka]

[0018] [In the formula, n1 R 2a are each independently a 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 are as defined in item 1. 2. The compound according to claim 1, wherein:

[0019] [Section 7] Cy 1 but, (1)C 3-7 cycloalkyl, (2) a 4- to 7-membered heterocycloalkyl containing, in addition to carbon atoms as ring-constituting atoms, one or two heteroatoms independently selected from the group consisting of oxygen and sulfur atoms (the sulfur atoms may be oxidized); (3) C 7-11 spirocycloalkyl, or (4) 7- to 11-membered spiroheterocycloalkyl containing 1 to 3 oxygen atoms in addition to carbon atoms as ring-constituting atoms. Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein:

[0020] [Section 8] R 6 but, (1) monofluoromethyl, (2) difluoromethyl, or (3) Trifluoromethyl Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof, wherein:

[0021] [Section 9] R 3 and R 4 However, each independently, (1) hydrogen, or (2) Methyl or R 3 and R 4 and R 1 and R 2 together with the carbon atom to which they are attached form a cyclopropane, or a pharmaceutically acceptable salt thereof.

[0022] [Section 10] m R 1 However, each independently, (1) halogen, (2) hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, (c) cyano, or (d)SO2R 12 (where R 12 is C 1-4 alkyl)}, (4) C 1-4 haloalkyl (wherein the haloalkyl is optionally substituted with hydroxy); (5) C 1-4alkoxy (wherein the alkoxy is optionally substituted with 1 to 3 halogens); (6) COR 13 {where R 13 teeth, (a) hydroxy, 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 is C 1-4 alkyl), or (9) C 3-4 cycloalkyl (wherein the cycloalkyl is optionally substituted with hydroxy) or two R 1 Item 10. The compound according to any one of items 1 to 9, or a pharmaceutically acceptable salt thereof, wherein:

[0023] [Section 11] The following formula:

[0024] [ka]

[0025] or a pharmaceutically acceptable salt thereof.

[0026] [Section 12] Item 12. 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.

[0027] [Section 13] Item 12. A Pim-1 inhibitor comprising the compound according to any one of items 1 to 11 or a pharmaceutically acceptable salt thereof.

[0028] [Section 14] Item 12. A therapeutic or preventive agent for a disease selected from the group consisting of pulmonary arterial 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.

[0029] [Section 15] 12. A method for inhibiting Pim-1 in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound according to any one of items 1 to 11 or a pharmaceutically acceptable salt thereof.

[0030] [Section 16] A method for treating or preventing a disease selected from the group consisting of pulmonary arterial hypertension, cancer, psoriasis, and systemic lupus erythematosus in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound according to any one of items 1 to 11 or a pharmaceutically acceptable salt thereof.

[0031] [Section 17] Item 12. Use of the compound according to any one of items 1 to 11 or a pharmaceutically acceptable salt thereof for the production of a Pim-1 inhibitor.

[0032] [Section 18] Use of the compound according to any one of items 1 to 11 or a pharmaceutically acceptable salt thereof for the manufacture of an agent for the treatment or prevention of a disease selected from the group consisting of pulmonary arterial hypertension, cancer, psoriasis, and systemic lupus erythematosus.

[0033] [Section 19] Item 12. The compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 11 for use in inhibiting Pim-1.

[0034] [Section 20] Item 12. The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 11, for use in the treatment or prevention of a disease selected from the group consisting of pulmonary arterial hypertension, cancer, psoriasis, and systemic lupus erythematosus. DETAILED DESCRIPTION OF THE INVENTION

[0035] The definitions of terms used in this specification are as follows. "Halogen" includes, for example, fluorine, chlorine, bromine, and iodine. A preferred "halogen" is fluorine.

[0036] "C 1-6 "Alkyl" means a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. 1-6 "Alkyl" includes, for example, 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" is methyl, ethyl, and isopropyl.

[0037] "C 1-4 "Alkyl" means a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. 1-4 "Alkyl" includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. 1-4 "Alkyl" is methyl, ethyl, and isopropyl.

[0038] "Linear C 1-4 "Alkylene" means a divalent group derived from a straight-chain saturated hydrocarbon having from 1 to 4 carbon atoms. 1-4 "Alkylene" includes methylene, ethylene, trimethylene, and tetramethylene. Preferred "linear C 1-4 "Alkylene" is a The following are examples of ethylene and trimethylene:

[0039] "C 1-4 "Haloalkyl" refers to the above "C" substituted with 1 to 5 halogens independently selected from the above "halogen" group. 1-4 "C" means "alkyl". 1-4Haloalkyl" includes, for example, 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" means monofluoromethyl, difluoromethyl, trifluoromethyl and 1,1-difluoroethyl.

[0040] "C 3-7 "Cycloalkyl" means a 3- to 7-membered, monocyclic saturated hydrocarbon group. 3-7 "Cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. 3-7 "Cycloalkyl" includes cyclopropyl, cyclobutyl, and cyclohexyl.

[0041] "C 3-4 "Cycloalkyl" means a 3- to 4-membered, monocyclic saturated hydrocarbon group. 3-4 "Cycloalkyl" includes cyclopropyl and cyclobutyl. 3-4 "Cycloalkyl" includes cyclopropyl and cyclobutyl.

[0042] "C 3-4 "Cycloalkane" means a 3- to 4-membered, monocyclic saturated hydrocarbon. 3-4 "Cycloalkane" includes cyclopropane and cyclobutane. 3-4 A "cycloalkane" is cyclopropane.

[0043] "C 5-8 "Bridged cycloalkyl" means a 5- to 8-membered bridged cyclic saturated hydrocarbon group. 5-8"Bridged cycloalkyl" includes, for example, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl. Preferred "C 5-8 A "bridged cycloalkyl" is bicyclo[1.1.1]pentyl.

[0044] "C 7-11 "Spirocycloalkyl" means a 7- to 11-membered, spiro-cyclic saturated hydrocarbon group. 7-11 "Spirocycloalkyl" includes, for example, spiro[3.3]heptyl, spiro[4.5]decyl, and spiro[5.5]undecyl. Preferred "C 7-11 "Spirocycloalkyl" is spiro[3.3]heptyl.

[0045] "C 1-4 "Alkoxy" refers to the above "C 1-4 "C" means a group in which "alkyl" is bonded to an oxygen atom. 1-4 Alkoxy" includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Preferred "C 1-4 "Alkoxy" is methoxy.

[0046] "4- to 7-membered heterocycloalkyl containing, in addition to carbon atoms, one or two heteroatoms independently selected from the group consisting of oxygen and sulfur atoms (which may be oxidized) as ring-constituting atoms" means a 4- to 7-membered monocyclic saturated heterocyclic group containing, in addition to carbon atoms, one or two heteroatoms independently selected from oxygen and sulfur atoms as ring-constituting atoms. Here, the sulfur atom may be oxidized. "4- to 7-membered heterocycloalkyl containing, in addition to carbon atoms, one or two heteroatoms independently selected from the group consisting of oxygen and sulfur atoms (which may be oxidized) as ring-constituting atoms" includes, for example, oxetanyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, and tetrahydrothiopyranyl. Preferred "4- to 7-membered heterocycloalkyl containing, in addition to carbon atoms as ring-constituting atoms, one or two heteroatoms independently selected from the group consisting of oxygen and sulfur atoms (the sulfur atoms may be oxidized)" are oxetanyl, tetrahydrofuryl, tetrahydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,1-dioxidetetrahydrothiopyranyl, and oxepanyl.

[0047] "7- to 9-membered bridged heterocycloalkyl containing one oxygen atom other than carbon atoms as a ring-constituting atom" refers to a 7- to 9-membered bridged saturated heterocyclic group containing one oxygen atom other than carbon atoms as a ring-constituting atom. Examples of "7- to 9-membered bridged heterocycloalkyl containing one oxygen atom other than carbon atoms as a ring-constituting 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 containing one oxygen atom other than carbon atoms as a ring-constituting atom" is 8-oxabicyclo[3.2.1]octyl.

[0048] "7- to 11-membered spiroheterocycloalkyl containing 1 to 3 oxygen atoms in addition to carbon atoms as ring-constituting atoms" refers to a 7- to 11-membered spiro-type saturated heterocyclic group containing 1 to 3 oxygen atoms in addition to carbon atoms as ring-constituting atoms. Examples of "7- to 11-membered spiroheterocycloalkyl containing 1 to 3 oxygen atoms in addition to carbon atoms as ring-constituting 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 containing 1 to 3 oxygen atoms in addition to carbon atoms as ring-constituting 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.

[0049] The expression that a substituent A is "optionally substituted" with a substituent B means that the substituent A is unsubstituted or substituted with a substituent B at any substitutable position (any hydrogen atom is replaced by a substituent B). For example, "C optionally substituted with hydroxy" means that the substituent A is unsubstituted or substituted with a substituent B at any substitutable position (any hydrogen atom is replaced by a substituent B). 1-4 "Alkyl" means C 1-4 It is meant that alkyl is unsubstituted or substituted with hydroxy at any substitutable position thereof.

[0050] Specific examples of the substituents of the compound of formula [I] (hereinafter also referred to as "compound [I]" in this specification) are shown below, but the individual substituents of compound [I] are not limited to these specific examples, and compound [I] also includes combinations of any two or more of the specific examples of the individual substituents.

[0051] Cy 1 is preferably (1)C 3-7 cycloalkyl, (2) a 4- to 7-membered heterocycloalkyl containing, in addition to carbon atoms as ring-constituting atoms, one or two heteroatoms independently selected from the group consisting of oxygen and sulfur atoms (the sulfur atoms may be oxidized); (3) C 7-11 spirocycloalkyl, or (4) 7- to 11-membered spiroheterocycloalkyl containing 1 to 3 oxygen atoms in addition to carbon atoms as ring-constituting atoms. is.

[0052] Cy 1 is more preferably (1)C 3-7 cycloalkyl, (2) a 4- to 7-membered heterocycloalkyl containing, in addition to carbon atoms as ring-constituting atoms, one or two heteroatoms independently selected from the group consisting of oxygen and sulfur atoms (the sulfur atoms may be oxidized); or (3) 7- to 11-membered spiroheterocycloalkyl containing 1 to 3 oxygen atoms in addition to carbon atoms as ring-constituting atoms. is.

[0053] Cy 1 is more preferably (1)C 3-7 cycloalkyl, or (2) A 4- to 7-membered heterocycloalkyl containing, in addition to carbon atoms as ring-constituting atoms, one or two heteroatoms independently selected from the group consisting of oxygen and sulfur atoms (the sulfur atoms may be oxidized). is.

[0054] Cy 1 is even more preferably (1) cyclohexyl, (2) tetrahydropyranyl, or (3) 1,4-dioxanyl is.

[0055] Cy 1 In a specific embodiment, for example, the formula:

[0056] [ka]

[0057] [wherein the wavy line indicates the bonding site with L] It is a group represented by the formula:

[0058] m R 1 are preferably each independently (1) halogen, (2) hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, (c) cyano, or (d)SO2R 12 (where R 12 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 teeth, (a) hydroxy, 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 is C 1-4 alkyl), or (9) C 3-4 cycloalkyl (wherein the cycloalkyl is optionally substituted with hydroxy) or two R 1 together to form oxo.

[0059] m R 1 are more preferably each independently (1) halogen, (2) hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, or (b) SO2R 12 (where R 12 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) cyano, or (7) C 3-4 cycloalkyl (wherein the cycloalkyl is optionally substituted with hydroxy) or two R 1 together to form oxo.

[0060] m R 1 More preferably, each independently represents: (1) Fluorine, (2) hydroxy, (3) C 1-4 alkyl {wherein the alkyl is (a) hydroxy, or (b) SO2R 12 (where R 12 is methyl)}, (4) C 1-4 haloalkyl (wherein the haloalkyl is optionally substituted with hydroxy); (5) methoxy (wherein the methoxy may be substituted with 1 to 3 fluorines); (6) cyano, or (7) Cyclopropyl (wherein the cyclopropyl may be substituted with hydroxy) or two R 1 together to form oxo.

[0061] m R 1 In a specific embodiment, each of R is independently fluorine, 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, carboxy, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, cyano, methylsulfonyl, 1-hydroxycyclopropyl, or 1H-1,2,4-triazol-5-yl, or two R are bonded to the same carbon atom. 1 together to form oxo.

[0062] n R 2 are preferably each independently a halogen or two R 2 together with the carbon atoms to which they are attached, C 3-4 Forms a cycloalkane. n R 2 More preferably, each independently is halogen. n R 2 is more preferably fluorine.

[0063] R 3 and R 4 are preferably each independently (1) hydrogen, or (2) Methyl or R 3 and R 4 together with the carbon atom to which they are attached to form cyclopropane.

[0064] R 5 is preferably hydrogen. R 6 is preferably monofluoromethyl, difluoromethyl or trifluoromethyl. R 6 is more preferably trifluoromethyl. R 7 is preferably hydrogen.

[0065] L is preferably ethylene or trimethylene. L is more preferably ethylene. m is preferably 0, 1 or 2. n is preferably 0, 1 or 2.

[0066] One preferred embodiment of compound [I] is Cy 1 but, (1)C 3-7 cycloalkyl, (2) a 4- to 7-membered heterocycloalkyl containing, in addition to carbon atoms as ring-constituting atoms, one or two heteroatoms independently selected from the group consisting of oxygen and sulfur atoms (the sulfur atoms may be oxidized); (3) C 7-11 spirocycloalkyl, or (4) 7- to 11-membered spiroheterocycloalkyl containing 1 to 3 oxygen atoms in addition to carbon atoms as ring-constituting atoms. and; m R 1 However, each independently, (1) halogen, (2) hydroxy, (3) C 1-6 alkyl {wherein the alkyl is (a) hydroxy, (b)C 1-4 Alkoxy, (c) cyano, or (d)SO2R 12 (where R 12 is C1-4 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 teeth, (a) hydroxy, 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 is C 1-4 alkyl), or (9) C 3-4 cycloalkyl (wherein the cycloalkyl is optionally substituted with hydroxy) or two R 1 together to form oxo; n R 2 are each independently a halogen or two R 2 together with the carbon atoms to which they are attached, C 3-4 forming cycloalkanes; R 3 and R 4 However, 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 attached, C 3-4 forming cycloalkanes; R 5 is hydrogen; R 6 But C1-4 is haloalkyl; R 7 is hydrogen; L is ethylene or trimethylene; m is 0, 1, 2, 3, or 4; and Compound [I], wherein n is 0, 1, 2 or 3.

[0067] Another preferred embodiment of compound [I] is represented by formula [II]:

[0068] [ka]

[0069] [In the formula, Cy 1 , R 1 , R 2 , R 3 , R 4 , R 6 , L, m and n are as defined above. are synonymous] It is a compound represented by the formula:

[0070] Yet another preferred embodiment of compound [I] is represented by formula [III]:

[0071] [ka]

[0072] [In the formula, n1 R 2a are each independently a 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 are as defined above. It is a compound represented by the formula:

[0073] Yet another preferred embodiment of compound [I] is represented by formula [IV]:

[0074] [ka]

[0075] [In the formula, Cy 1 , R 1 , R 2a , R 3 , R 4 , R 6 , m and n1 are as defined above. It is a compound represented by the formula:

[0076] Another preferred embodiment of compound [I] is represented by formula [V]:

[0077] [ka]

[0078] [In the formula, R 3a and R 4a are each independently hydrogen or methyl, or R 3a and R 4a together with the carbon atoms to which they are attached to form cyclopropane; and Cy 1 , R 1 , R 2 , R 6 , L a , m and n are as defined above. It is a compound represented by the formula:

[0079] Another preferred embodiment of compound [I] is represented by formula [VI]:

[0080] [ka]

[0081] [In the formula, Cy 1a teeth, (1)C 3-7 cycloalkyl, or (2) a 4- to 7-membered heterocycloalkyl containing, in addition to carbon atoms, one or two heteroatoms independently selected from the group consisting of oxygen and sulfur atoms (which may be oxidized); and R 1 , R 2 , R 3 , R 4 , R 6 , L a , m and n are as defined above. It is a compound represented by the formula:

[0082] Yet another preferred embodiment of compound [I] is represented by formula [VII], [VIII], [IX], [X], [XI], [XII], [XIII], [XIV], [XV], or [XVI]:

[0083] [ka]

[0084] [In the formula, R 1 , R 2 , R 3 , R 4 , R 6 , L a , m and n are as defined above. It is a compound represented by the formula:

[0085] Yet another preferred embodiment of compound [I] is represented by formula [XVII], [XVIII], or [XIX]:

[0086] [ka]

[0087] [In the formula, m1 is 0 or 1; and R 1 , R2 , R 3 , R 4 , R 6 , L a and n are as defined above. It is a compound represented by the formula:

[0088] Another preferred embodiment of compound [I] is represented by formula [XX]:

[0089] [ka]

[0090] [In the formula, Cy 1 , R 1 , R 2a , R 3a , R 4a , R 6 , L a , m and n1 are as defined above. It is a compound represented by the formula:

[0091] Yet another preferred embodiment of compound [I] is represented by formula [XXI]:

[0092] [ka]

[0093] [In the formula, Cy 1 , R 1 , R 2a , R 3a , R 4a , L a , m and n1 are as defined above. It is a compound represented by the formula:

[0094] Yet another preferred embodiment of compound [I] is represented by formula [XXII]:

[0095] [ka]

[0096] [In the formula, Cy 1 , R 1 , R 2a , R 3a , R 4a , m and n1 are as defined above. It is a compound represented by the formula:

[0097] Yet another preferred embodiment of compound [I] is represented by formula [XXIII]:

[0098] [ka]

[0099] [In the formula, m R 1a are each independently (1) Fluorine, (2) hydroxy, (3) C 1-4 alkyl {wherein the alkyl is (a) hydroxy, or (b) SO2R 12 (where R 12 is methyl)}, (4) C 1-4 haloalkyl (wherein the haloalkyl is optionally substituted with hydroxy); (5) methoxy (wherein the methoxy may be substituted with 1 to 3 fluorines); (6) cyano, or (7) Cyclopropyl (wherein the cyclopropyl may be substituted with hydroxy) or two R 1 together to form oxo; and Cy 1a , R 2a , R 3a , R 4a , m and n1 are as defined above. It is a compound represented by the formula:

[0100] Yet another preferred embodiment of compound [I] is represented by formula [XXIV], [XXV], or [XXVI]:

[0101] [ka]

[0102] [In the formula, R 1a , R 2a , R 3a , R 4a , m and n1 are as defined above. It is a compound represented by the formula:

[0103] Yet another preferred embodiment of compound [I] is represented by formula [XXVII], [XXVIII], or [XXIX]:

[0104] [ka]

[0105] [In the formula, R 1a , R 2a , R 3a , R 4a , m1 and n1 are as defined above. It is a compound represented by the formula:

[0106] The term "pharmaceutically acceptable salt" refers to any salt known in the art that is not excessively toxic. Specific examples include salts with inorganic acids, organic acids, inorganic bases, and organic bases. Various forms of pharmaceutically acceptable salts are well known in the art and are described in the following references: (a)Berge et al., J.Pharm.Sci., 66, p1-19 (1977); (b)Stahl et al., "Handbook of Pharmaceutical Salt: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany,2002); (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007). According to a known method, the compound of formula [I] can be reacted with an inorganic base, an organic base, an inorganic acid, or an organic acid to obtain a pharmaceutically acceptable salt thereof.

[0107] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid. Examples of preferred salts with inorganic acids include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid.

[0108] Salts with organic acids include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylene citric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1,2- Disulfonic acid, dodecyl sulfate, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glycolylarsanilic acid, hexylresorcylic acid, hydroxy-naphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methyl sulfate, methyl nitrate, methylenebis(salicylic acid), galactaric acid, naphthalene Examples of the salts with organic acids include salts with 2-hydroxy-1-ethanesulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic 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. Examples of preferred salts with organic acids 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.

[0109] Examples of salts with inorganic bases include salts with ammonium, aluminum, barium, bismuth, calcium, lithium, magnesium, potassium, sodium, or zinc. Preferred examples of salts with inorganic bases include salts with sodium, potassium, calcium, magnesium, or zinc.

[0110] Examples of salts with organic bases include salts with arecoline, ammonium, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, or lysine. Preferred examples of salts with organic bases include salts with tris(hydroxymethyl)methylamine, N-methylglucamine, or lysine.

[0111] Compound [I] or a pharmaceutically acceptable salt thereof may exist as a solvate. A "solvate" is a compound in which solvent molecules are coordinated with compound [I] or a pharmaceutically acceptable salt thereof, and includes hydrates. The solvate is preferably a pharmaceutically acceptable solvate, and examples thereof include a hydrate, ethanol solvate, and dimethyl sulfoxide solvate of compound [I] or a pharmaceutically acceptable salt thereof. Specifically, examples of the solvates include the hemihydrate, monohydrate, dihydrate, or monoethanolate of compound [I], or the monohydrate of the sodium salt of compound [I] or the 2 / 3 ethanolate of the dihydrochloride salt, etc. These solvates can be obtained according to known methods.

[0112] Compound [I] or a pharmaceutically acceptable salt thereof may exist as a tautomer, and in that case, compound [I] or a pharmaceutically acceptable salt thereof may exist as an individual tautomer or a mixture of tautomers. Compound [I] or a pharmaceutically acceptable salt thereof may contain a carbon-carbon double bond, and in that case, compound [I] or a pharmaceutically acceptable salt thereof may exist as an E-isomer, a Z-isomer, or a mixture of E- and Z-isomers. Compound [I] or a pharmaceutically acceptable salt thereof may have stereoisomers that should be recognized as cis / trans isomers. In such cases, compound [I] or a pharmaceutically acceptable salt thereof may exist as a cis isomer, a trans isomer, or a mixture of cis and trans isomers.

[0113] Compound [I] or a pharmaceutically acceptable salt thereof may have one or more asymmetric carbon atoms, and in such cases, 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. Compound [I] or a pharmaceutically acceptable salt thereof may exist as atropisomers. In such cases, compound [I] or a pharmaceutically acceptable salt thereof may exist as an individual atropisomer or It may exist as a mixture of atropisomers. Compound [I] or a pharmaceutically acceptable salt thereof may simultaneously contain two or more structural features that give rise to the above isomers, and may contain the above isomers in any ratio.

[0114] In this specification, formulae, chemical structures, or compound names expressed without specifying stereochemistry include all of the above-mentioned possible isomers unless otherwise noted. For example, the formula:

[0115] [ka]

[0116] Unless otherwise noted, the structure shown in (1) Formula:

[0117] [ka]

[0118] A racemic mixture of two enantiomers (S and R). (2) S-enantiomer, and (3) R-enantiomer Includes all of the above.

[0119] Diastereomeric mixtures can be separated into individual diastereomers by conventional methods such as chromatography or crystallization, or individual diastereomers can be prepared by synthetic methods using stereochemically pure starting materials or stereoselective reactions.

[0120] Separation of individual enantiomers from a mixture of enantiomers can be accomplished by methods well known in the art. For example, enriched or substantially pure single diastereomers can be separated from a mixture of enantiomers and diastereomers formed by reacting a substantially pure enantiomer with a compound known as a chiral auxiliary by standard methods such as fractional crystallization or chromatography. The separated diastereomers can be converted to the desired enantiomer by cleavage and removal of the added chiral auxiliary. Alternatively, a mixture of enantiomers can be directly separated by chromatographic methods using chiral stationary phases, well known in the art. Alternatively, one enantiomer can be stereoselectively synthesized (asymmetric induction) using substantially pure optically active starting materials or prochiral intermediates with chiral auxiliaries or asymmetric catalysts. It can also be obtained by

[0121] Absolute configuration may be determined by X-ray crystallography of crystalline products or intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known configuration.

[0122] Compound [I] or a pharmaceutically acceptable salt thereof may contain isotopes ( 2 H, 3 H, 14 C. 35It may be labeled with (e.g., S).

[0123] Compound [I] or a pharmaceutically acceptable salt thereof is preferably a substantially pure compound [I] or a pharmaceutically acceptable salt thereof, more preferably a compound [I] or a pharmaceutically acceptable salt thereof having a purity of 80% or more.

[0124] In this specification, the pharmaceutical composition may be prepared by appropriately mixing compound [I] or a pharmaceutically acceptable salt thereof with at least one or more pharmaceutically acceptable carriers, etc. in appropriate amounts, according to a method known in the field of pharmaceutical formulation. The content of compound [I] or a pharmaceutically acceptable salt thereof in the pharmaceutical composition varies depending on the dosage form, dosage, etc., but is, for example, 0.1 to 100% by weight of the total composition.

[0125] Dosage forms of compound [I] or a pharmaceutically acceptable salt thereof include oral preparations such as tablets, capsules, granules, powders, troches, syrups, emulsions, and suspensions, and parenteral preparations such as topical preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations.

[0126] Examples of "pharmaceutically acceptable carriers" include various organic or inorganic carrier substances commonly used as formulation materials, such as excipients, disintegrants, binders, fluidizing agents, lubricants, etc. in solid preparations, solvents, solubilizing agents, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid preparations, and bases, emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH adjusters, absorption enhancers, gelling agents, preservatives, fillers, solubilizers, solubilizing agents, suspending agents, etc. in semi-solid preparations. Furthermore, additives such as preservatives, antioxidants, colorants, sweeteners, etc. may also be used, if necessary.

[0127] Examples of "excipients" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and gum arabic. Examples of the "disintegrant" include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and crystalline cellulose. Examples of "binders" include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic, and the like. Examples of the "fluidizing agent" include light anhydrous silicic acid, magnesium stearate, and the like. "Lubricants" include magnesium stearate, calcium stearate, talc, and the like. Examples of "solvents" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, etc. Examples of "solubilizing agents" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, and the like. "Suspending agents" include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methylcellulose, and glycerin monostearate. Serine and the like. Examples of "isotonicity agents" include glucose, D-sorbitol, sodium chloride, D-mannitol, and the like. Examples of "buffers" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, and the like. "Soothing agents" include benzyl alcohol and the like. Examples of "bases" 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, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, purified lanolin, absorbent ointment, hydrous 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, polyvinylpyrrolidone, etc.), propylene glycol, macrogols (macrogol 200 to 600, etc.), and combinations of two or more thereof. Examples of the "preservative" include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like. "Antioxidants" include sodium sulfite, ascorbic acid, and the like. Examples of "coloring agents" include food dyes (such as food red No. 2 or No. 3, food yellow No. 4 or No. 5, etc.), β-carotene, and the like. "Sweetening agents" include saccharin sodium, dipotassium glycyrrhizinate, aspartame, etc.

[0128] In this specification, the pharmaceutical composition can be administered orally or parenterally (topically, rectally, intravenously, intramuscularly, subcutaneously, etc.) to mammals other than humans (mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.) and humans. The dosage (hereinafter also referred to as "therapeutically effective amount" in this specification) varies depending on the subject, disease, symptoms, dosage form, administration route, etc., but for example, the dosage when administered orally to an adult patient is usually in the range of about 0.01 mg to 1 g per day of Compound [I], the active ingredient. These amounts can be administered once or in divided doses.

[0129] Compound [I] or a pharmaceutically acceptable salt thereof has Pim-1 inhibitory activity and is therefore useful as a Pim-1 inhibitor. "Having Pim-1 inhibitory activity" or "inhibiting Pim-1" means inhibiting the function of Pim-1 and eliminating or weakening its activity, for example, means inhibiting the function of Pim-1 based on the conditions of Test Example 1 described below. "Pim-1" preferably refers to "human Pim-1."

[0130] Since compound [I] or a pharmaceutically acceptable salt thereof has Pim-1 inhibitory activity, compound [I] or a pharmaceutically acceptable salt thereof can be used as an active ingredient of a therapeutic or preventive agent for the following diseases: (a) Pulmonary arterial hypertension; (b) cancers such as hematological cancers (acute lymphocytic 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, and breast cancer; (c) psoriasis; and (d) Systemic lupus erythematosus. As used herein, "treatment" refers to the improvement of symptoms, prevention of aggravation, maintenance of remission, and prevention of recurrence. , and even prevention of recurrence. As used herein, "prevention" means suppressing the onset of symptoms.

[0131] In this specification, the therapeutically effective amount may be varied appropriately depending on the subject of administration, the administration route, the target disease, symptoms, the severity of the disease, and a combination thereof. When compound [I] or a pharmaceutically acceptable salt thereof is orally administered to a human (body weight 60 kg), the lower limit of the therapeutically effective amount may be, 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 may be, 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. As used herein, the frequency of administration of a Pim-1 inhibitor includes once, twice, three or more times per day.

[0132] In certain embodiments, the Pim-1 inhibitor or pharmaceutical composition may be provided in the form of a kit (e.g., an administration, treatment, and / or prevention kit), a package (e.g., a wrapping), or a pharmaceutical set (and / or container) containing the Pim-1 inhibitor or pharmaceutical composition together with written material indicating that the Pim-1 inhibitor or pharmaceutical composition can or should be used in the treatment and / or prevention of the disease. Such kits, packages, and pharmaceutical sets may include one or more containers filled with the Pim-1 inhibitor and / or other pharmaceutical or drug (or ingredient). Examples of such kits, packages, and pharmaceutical sets include commercial kits, commercial packages, and commercial pharmaceutical sets suitable for the treatment and / or prevention of the disease. The written material included in such kits, packages, and pharmaceutical sets may include notices or inserts in the form required by a governmental agency regulating the manufacture, use, or sale of pharmaceutical or biological products, indicating the agency's approval of the product for manufacture, use, or sale for human administration. The above kits, packages, and pharmaceutical sets include packaged products, and may also include structures configured for appropriate administration steps, or structures configured to achieve more desirable medical treatment and / or prevention, including treatment and / or prevention of a target disease. In this specification, the presentation of preferred aspects and options of the compounds, methods, uses and compositions of the present invention also includes the presentation of combinations of such preferred aspects and options, provided that these are combinable and not inconsistent.

[0133] General methods for producing compound [I] or a pharmaceutically acceptable salt thereof are described below. However, the methods for producing compound [I] or a pharmaceutically acceptable salt thereof are not limited to these methods. Furthermore, the salts of each compound in the general methods can be appropriately selected from the above-mentioned "pharmaceutically acceptable salts" unless otherwise specified. The compounds obtained in each step can be isolated or purified by known methods such as distillation, recrystallization, column chromatography, etc., as necessary, but in some cases, they may be used to proceed to the next step without isolation or purification. In this specification, room temperature refers to a temperature in an uncontrolled state, and in one embodiment, it is 1°C to 40°C.

[0134] Production method A1: Production method of compound [I] or a salt thereof Compound [I] or a salt thereof can be produced, for example, by the following Production Method A1.

[0135] [ka]

[0136] [In the formula, Cy 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L, m, and n are as defined above; P 1 is a protecting group for carboxy (e.g., methyl and ethyl), P 2 is an amino protecting group (e.g., 9-fluorenylmethyloxycarbonyl and benzyloxycarbonyl).

[0137] (Process A1-1) Compound [A1-4] or a salt thereof can be produced by subjecting compound [A1-1] or a salt thereof and compound [A1-2] or a salt thereof to a dehydration condensation reaction in a solvent, and then reacting the resulting product with compound [A1-3] or a salt thereof in the presence of a base. Examples of the solvent include N,N-dimethylformamide and N,N-dimethylacetamide. The preferred solvent is N,N-dimethylformamide. Examples of bases include potassium carbonate and tripotassium phosphate. A preferred base is potassium carbonate. The reaction temperature is, for example, 0°C to 30°C, preferably 10°C to 20°C. The compound [A1-1] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method. The compound [A1-2] or a salt thereof is commercially available or may be prepared from a commercially available product by a known method. The compound [A1-2] or a salt thereof can also be prepared by, for example, the below-described preparation method M1 or M2. The compound [A1-3] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0138] (Process A1-2) 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. The acid may be, for example, trifluoroacetic acid. The preferred acid is trifluoroacetic acid. The reducing agent may be, for example, triethylsilane, and the preferred reducing agent is triethylsilane. Solvents include, for example, toluene and dichloromethane, with toluene being the preferred solvent. The reaction temperature is, for example, 0°C to 30°C, preferably 10°C to 20°C. The compound [A1-5] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0139] (Process A1-3) Compound [I] or a salt thereof is P of compound [A1-6] or a salt thereof 2 The deprotection reaction can be carried out by removing P 2 The process may be carried out under suitable conditions depending on the type of material. For example, P 2When is 9-fluorenylmethyloxycarbonyl, 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, followed by cyclization. The base may be, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene. A preferred base is 1,8-diazabicyclo[5.4.0]undec-7-ene. Solvents include, for example, methanol and tetrahydrofuran, with methanol being the preferred solvent. The reaction temperature in the deprotection reaction is, for example, 0°C to 60°C, preferably 20°C to 60°C. is. The reaction temperature in the cyclization reaction is, for example, 20°C to 60°C, preferably 50°C to 60°C. In place of the compound [A1-2] or a salt thereof, R 1 a functional group or a protected functional group that can be converted into 1 The compound or a salt thereof shown above is used in the present production method to obtain a compound or a salt thereof corresponding to compound [I], and then the functional group is converted to R 1 Compound [I] or a salt thereof may be prepared by converting the compound [I] into the following compound [I]:

[0140] Production method A2: Production method of compound [IA] or a salt thereof R in compound [I] 5 The compound [IA] or a salt thereof, wherein is hydrogen, can also be prepared, for example, by the following Preparation Method A2.

[0141] [ka]

[0142] [In the formula, Cy 1 , R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , L, m, n, and P 1is as defined above, P 3 is an amino protecting group (e.g., p-methoxybenzyl and benzyl), Z 1 is a leaving group (e.g., methanesulfonyloxy, bromine, and p-toluenesulfonyloxy).

[0143] (Process A2-1) The compound [A2-1] or a salt thereof is P of the compound [A1-4] or a salt thereof. 1 The deprotection reaction can be carried out by removing P 1 The process may be carried out under suitable conditions depending on the type of material. For example, P 1 C 1-4 In the case of alkyl, the compound [A2-1] or a salt thereof can be produced by alkaline hydrolysis of the compound [A1-4] or a salt thereof in a solvent. Examples of alkalis include lithium hydroxide monohydrate, sodium hydroxide, and potassium hydroxide. A preferred alkali is lithium hydroxide monohydrate. Examples of the solvent include methanol, tetrahydrofuran, water, and a mixture thereof. A preferred solvent is a mixture of methanol, tetrahydrofuran, and water. The reaction temperature is, for example, 20 to 50°C, preferably 40 to 50°C.

[0144] (Process A2-2) 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. An example of a condensing agent is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate. The combination drug is 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate. Examples of the base include N,N-diisopropylethylamine and triethylamine. A preferred base is N,N-diisopropylethylamine. Examples of the solvent include N,N-dimethylformamide and N,N-dimethylacetamide. The preferred solvent is N,N-dimethylformamide. The reaction temperature is, for example, 0°C to 20°C, preferably 10°C to 20°C. The compound [A2-2] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0145] (Process A2-3) The compound [A2-4] or a salt thereof can be prepared by converting the hydroxy of the compound [A2-3] or a salt thereof into Z. 1 It can be produced by converting it into Z 1 The process may be carried out under conditions appropriate for the type of material. For example, Z 1 When is methanesulfonyloxy, the compound [A2-4] or a salt thereof can be produced by methanesulfonylation of the compound [A2-3] or a salt thereof in a solvent in the presence of a base. Examples of methanesulfonylating agents include methanesulfonic anhydride and methanesulfonyl chloride. A preferred methanesulfonylating agent is methanesulfonic anhydride. Examples of bases include triethylamine and pyridine. A preferred base is triethylamine. Examples of solvents include dichloromethane and tetrahydrofuran. A preferred solvent is dichloromethane. The reaction temperature is, for example, 0°C to 20°C, preferably 0°C to 10°C.

[0146] (Process A2-4) 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. Examples of bases include cesium carbonate and potassium carbonate. A preferred base is cesium carbonate. Examples of the solvent include N,N-dimethylformamide and N,N-dimethylacetamide. The preferred solvent is N,N-dimethylformamide. The reaction temperature is, for example, 0°C to 30°C, preferably 10°C to 30°C.

[0147] (Process A2-5) The compound [IA] or a salt thereof is P of the compound [A2-5] or a salt thereof. 3 The deprotection reaction can be carried out by removing P 3 The process may be carried out under suitable conditions depending on the type of material. For example, P 3 When is p-methoxybenzyl, the compound [IA] or a salt thereof can be prepared by reacting the compound [A2-5] or a salt thereof in a solvent in the presence of an acid. Acids include, for example, trifluoroacetic acid and hydrochloric acid. A preferred acid is trifluoroacetic acid. The solvent may be, for example, anisole, and the preferred solvent is anisole. The reaction temperature is, for example, 50 to 90°C, preferably 70 to 90°C. In place of the compound [A1-4] or a salt thereof, R 1 can be converted into A functional group or a protected functional group is attached to the ring Cy 1 The compound or a salt thereof shown above is used in the present production method to obtain a compound or a salt thereof corresponding to compound [IA], and then the functional group is converted to R 1 Compound [IA] or a salt thereof may be prepared by converting the compound [IA] into the following compound.

[0148] Preparation method A3: Alternative method for preparing compound [IA] or a salt thereof R in compound [I] 5 The compound [IA] or a salt thereof, wherein is hydrogen, can also be prepared by, for example, the following Preparation Method A3.

[0149] [ka]

[0150] [In the formula, Cy 1 , R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , L, m, n, and P 1 is as defined above, P 4 is an amino protecting group (e.g., tert-butoxycarbonyl), P 5 is a protecting group for hydroxy (e.g., C such as methyl, ethyl, etc.) 1-4 alkyl), and Z 2 is a leaving group (e.g., p-toluenesulfonyloxy, bromine, and methanesulfonyloxy).

[0151] (Process A3-1) Compound [A3-2] or a salt thereof can be produced by reacting compound [A1-1] or a salt thereof, compound [A3-1] or a salt thereof, and compound [A1-3] or a salt thereof according to step A1-1. The compound [A3-1] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0152] (Process A3-2) The compound [A3-3] or a salt thereof is P of the compound [A3-2] or a salt thereof. 4 The deprotection reaction can be carried out by removing P 4 The process may be carried out under suitable conditions depending on the type of material. For example, P 4is tert-butoxycarbonyl, the compound [A3-3] or a salt thereof can be produced 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. Acids include, for example, trifluoroacetic acid and hydrochloric acid. A preferred acid is trifluoroacetic acid. Examples of the solvent include trifluoroacetic acid and chloroform. The preferred solvent is trifluoroacetic acid. The reaction temperature is, for example, 0°C to 20°C, preferably 10°C to 20°C.

[0153] (Process A3-3) 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. Examples of bases include sodium methoxide and sodium ethoxide. A preferred base is sodium methoxide. Examples of the solvent include methanol and ethanol, and the preferred solvent is methanol. The reaction temperature is, for example, 0°C to 60°C, preferably 20°C to 60°C.

[0154] (Process A3-4) Compound [A3-5] or a salt thereof is a compound [A3-4] or a salt thereof, wherein P is a lactam. 5 It can be produced by introducing P 5 The introduction of the above may be carried out under conditions appropriate for the type of the substance. For example, P 5 C 1-4 In the case of alkyl, 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. Alkylating agents include trimethyloxonium tetrafluoroborate and triethyloxonium tetrafluoroborate. A preferred alkylating agent is trimethyloxonium tetrafluoroborate. Examples of the base include cesium carbonate and potassium carbonate. A preferred base is cesium carbonate. Examples of solvents include ethyl acetate and 1,2-dimethoxyethane. A preferred solvent is ethyl acetate. The reaction temperature is, for example, 0°C to 30°C, preferably 20°C to 30°C.

[0155] (Process A3-5) 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. Examples of the base include sodium bistrimethylsilylamide and potassium tert- butoxide. A preferred base is sodium bistrimethylsilylamide. Examples of the solvent include tetrahydrofuran and N,N-dimethylformamide. The preferred solvent is tetrahydrofuran. The reaction temperature is, for example, 0°C to 30°C, preferably 20°C to 30°C. The compound [A3-6] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method. The compound [A3-6] or a salt thereof can be prepared, for example, by the preparation method M1 or M2 described below. It can also be manufactured by

[0156] (Process A3-6) Compound [IA] or a salt thereof is P of compound [A3-7] or a salt thereof 5 The deprotection reaction can be carried out by removing P 5 The process may be carried out under suitable conditions depending on the type of material. For example, P 5 C 1-4In the case of alkyl, the compound [IA] or a salt thereof can be prepared by dealkylating the compound [A3-7] or a salt thereof in a solvent. Dealkylating agents include, for example, hydrochloric acid and acetic acid. A preferred dealkylating agent is hydrochloric acid. Examples of solvents include 1,2-dimethoxyethane and acetic acid. A preferred solvent is 1,2-dimethoxyethane. The reaction temperature is, for example, 60 to 90°C, preferably 80 to 90°C. In place of the compound [A3-6] or a salt thereof, R 1 a functional group or a protected functional group that can be converted into 1 The compound or a salt thereof shown above is used in the present production method to obtain a compound or a salt thereof corresponding to compound [IA], and then the functional group is converted to R 1 Compound [IA] or a salt thereof may be prepared by converting the compound [IA] into the following compound.

[0157] Production method A4: Production method of compound [IB] or a salt thereof R in compound [I] 3 , R 4 and R 5 The compound [IB] or a salt thereof, wherein is hydrogen, can also be prepared, for example, by the following Preparation Method A4.

[0158] [ka]

[0159] [In the formula, Cy 1 , R 1 , R 2 , R 6 , R 7 , L, m, n, and P 1 is as defined above, Z 3 is a leaving group (e.g., chlorine), Z 4 is a leaving group (e.g., chlorine)]

[0160] (Process A4-1) 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. The base may be, for example, N,N-dimethylaniline, and the preferred base is N,N-dimethylaniline. Examples of solvents include dichloromethane and chloroform, with dichloromethane being the preferred solvent. The reaction temperature is, for example, 0°C to 20°C, preferably 10°C to 20°C. The compound [A4-1] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0161] (Process A4-2) The compound [A4-3] or a salt thereof can be produced by reducing the compound [A4-2] or a salt thereof in a solvent. The reducing agent may be, for example, a borane-tetrahydrofuran complex. A preferred reducing agent is a borane-tetrahydrofuran complex. The solvent may be, for example, tetrahydrofuran, and the preferred solvent is tetrahydrofuran. The reaction temperature is, for example, 0°C to 30°C, preferably 10°C to 20°C.

[0162] (Process A4-3) The compound [A4-4] or a salt thereof can be produced by azidating the compound [A4-3] or a salt thereof in a solvent in the presence of a catalyst. The azidating agent includes, for example, potassium azide, and the preferred azidating agent is potassium azide. Catalysts include, for example, sodium iodide and potassium iodide, with sodium iodide being the preferred catalyst. Examples of the solvent include N,N-dimethylformamide and N,N-dimethylacetamide. The preferred solvent is N,N-dimethylformamide. The reaction temperature is, for example, 20 to 80°C, preferably 60 to 80°C.

[0163] (Process A4-4) The compound [IB] or a salt thereof can be produced by subjecting the compound [A4-4] or a salt thereof to reduction and cyclization in a solvent. The reducing agent may be, for example, triphenylphosphine, and the preferred reducing agent is triphenylphosphine. Examples of the solvent include 1,2-dimethoxyethane, tetrahydrofuran, and a mixture of these with water. A preferred solvent is a mixture of 1,2-dimethoxyethane and water. The reaction temperature is, for example, 20 to 90°C, preferably 80 to 90°C. In place of the compound [A1-4] or a salt thereof, R 1 a functional group or a protected functional group that can be converted into 1 The compound or a salt thereof shown above is used in the present production method to obtain a compound or a salt thereof corresponding to compound [IB], and then the functional group is converted to R 1 Compound [IB] or a salt thereof may be prepared by converting the compound [IB] into the following compound.

[0164] Production method M1: A method for producing compound [M1-8] and compound [M1-6] or salts thereof (1) R in the compound [A1-2] or a salt thereof used in the production method A1 2 is a halogen, L is ethylene, and n is 2, in the compound [M1-8] or a salt thereof, and (2) the compound [A3-6] or a salt thereof used in the production method A3, in which R 2 Hello The compound [M1-6] or a salt thereof in which N is aryl, L is ethylene, and n is 2 can be produced, for example, by the following production method M1.

[0165] [ka]

[0166] [In the formula, Cy 1 , R 1 , m, and P 1 is as defined above, R 21 is a halogen, P 6 is a protecting group for hydroxy (e.g., methyl and ethyl), Z 5 is a leaving group (e.g., trifluoromethanesulfonyloxy)]

[0167] (Process M1-1) Compound [M1-3] or a salt thereof can be produced by subjecting compound [M1-1] or a salt thereof and compound [M1-2] or a salt thereof to Horner-Wadsworth-Emmons reaction in a solvent in the presence of a base, followed by catalytic hydrogenation of the resulting product in a solvent in the presence of a palladium catalyst. The base in the Horner-Wadsworth-Emmons reaction includes, for example, potassium carbonate and sodium hydride. The preferred base is potassium carbonate. Examples of solvents used in the Horner-Wadsworth-Emmons reaction include N,N-dimethylformamide and tetrahydrofuran. The preferred solvent is N,N-dimethylformamide. The reaction temperature for the Horner-Wadsworth-Emmons reaction is, for example, 0°C to 80°C. , preferably 30°C to 80°C. Examples of the palladium catalyst in catalytic hydrogenation include palladium on carbon and palladium hydroxide on carbon. A preferred palladium catalyst is palladium on carbon. Examples of solvents used in catalytic hydrogenation include tetrahydrofuran and ethyl acetate. The preferred solvent is tetrahydrofuran. The reaction temperature in catalytic hydrogenation is, for example, 0°C to 20°C, preferably 10°C to 20°C. is. The compound [M1-1] or a salt thereof is commercially available or can be prepared from a commercially available product by a known method. Good too. The compound [M1-2] or a salt thereof is commercially available, or may be prepared from a commercially available product by a known method.

[0168] (Process M1-2) The compound [M1-4] or a salt thereof can be produced by halogenating the compound [M1-3] or a salt thereof. The halogenation can be carried out under conditions appropriate for the type of halogen. For example, R 21 When 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. The fluorinating agent may be, for example, N-fluorobenzenesulfonimide. A preferred fluorinating agent is N-fluorobenzenesulfonimide. Examples of the base include sodium bistrimethylsilylamide and lithium bistrimethylsilylamide. A preferred base is sodium bistrimethylsilylamide. Examples of the solvent include tetrahydrofuran, toluene, and a mixture thereof. A preferred solvent is a mixture of tetrahydrofuran and toluene. The reaction temperature is, for example, from -78°C to 20°C, preferably from -78°C to -20°C.

[0169] (Process M1-3) The compound [M1-5] or a salt thereof can be produced by reducing the compound [M1-4] or a salt thereof in a solvent. Examples of reducing agents include lithium aluminum hydride and sodium borohydride. A preferred reducing agent is lithium aluminum hydride. The solvent may be, for example, tetrahydrofuran, and the preferred solvent is tetrahydrofuran. The reaction temperature is, for example, 0°C to 20°C, preferably 0°C to 10°C.

[0170] (Process M1-4) The compound [M1-6] or a salt thereof can be prepared by converting the hydroxy of the compound [M1-5] or a salt thereof into Z 5 It can be produced by converting it into Z 5 The process may be carried out under conditions appropriate for the type of material. For example, Z 5 When is trifluoromethanesulfonyloxy, compound [M1-6] or a salt thereof can be produced by trifluoromethanesulfonylation of compound [M1-5] or a salt thereof in a solvent in the presence of a base, which may be the same as the solvent. Examples of trifluoromethanesulfonylating agents include trifluoromethanesulfonic anhydride and trifluoromethanesulfonic acid chloride. A preferred trifluoromethanesulfonylating agent is trifluoromethanesulfonic anhydride. Examples of bases include pyridine and triethylamine. A preferred base is pyridine. Solvents include, for example, pyridine and dichloromethane, with pyridine being the preferred solvent. The reaction temperature is, for example, 0°C to 30°C, preferably 0°C to 10°C.

[0171] (Process M1-5) 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. Examples of the solvent include N,N-dimethylformamide and N,N-dimethylacetamide. A preferred solvent is N,N-dimethylformamide. The reaction temperature is, for example, 0°C to 30°C, preferably 20°C to 30°C.

[0172] (Process M1-6) Compound [M1-8] or a salt thereof can be produced by removing the phthaloyl group from compound [M1-7] or a salt thereof. The phthaloyl group can be removed by a known method. For example, compound [M1-8] or a salt thereof can be produced by reacting compound [M1-7] or a salt thereof with hydrazine monohydrate in a solvent. Examples of the solvent include tetrahydrofuran, ethanol, methanol, and mixtures thereof. A preferred solvent is a mixture of tetrahydrofuran and ethanol. The reaction temperature is, for example, 20 to 60°C, preferably 50 to 60°C.

[0173] Production method M2: A method for producing compound [M2-4] and compound [M2-2] or salts thereof (1) Compound [A1-2] or a salt thereof used in Production Method A1, in which L is ethylene and n is 0, or a salt thereof, and (2) Compound [A3-6] or a salt thereof used in Production Method A3, in which L is ethylene and n is 0, or a salt thereof, can also be produced by, for example, Production Method M2 shown below.

[0174] [ka]

[0175] [In the formula, Cy 1 , R 1 , m, P 1 , and Z 1 are as defined above]

[0176] (Process M2-1) 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.

[0177] (Process M2-2) 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.

[0178] (Process M2-3) 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.

[0179] (Process M2-4) The compound [M2-4] or a salt thereof can be prepared by reacting the compound [M2-3] or a salt thereof according to step M1-6. [Example]

[0180] Next, the method for producing compound [I] or a pharmaceutically acceptable salt thereof will be specifically explained by way of Preparation Examples, but the method for producing compound [I] or a pharmaceutically acceptable salt thereof is not limited to these Preparation Examples.

[0181] [Production Example 1]: cis isomer (racemic form, Example 12) and trans isomer (racemic form, Example 11) of 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]diazepin-5-one Synthesis of racemic form) and each optically active form (Examples 58, 59, 66, 67)

[0182] [ka]

[0183] (1) Ethyl (E)-3-(but-3-en-1-yloxy)acrylate

[0184] [ka]

[0185] Under ice cooling, 3-buten-1-ol (68.4 mL, 806 mmol), 4-methylmorpholine (89 mL, 806 mmol) Ethyl propiolate (82 mL, 806 mmol) was added dropwise to a solution of the above in cyclopentyl methyl ether (540 mL). The 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) and water (1162 mL) was added dropwise to the reaction mixture. The layers were separated. The aqueous layer was re-extracted with hexane / ethyl acetate = 3 / 1 (400 mL). The combined organic layers were 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 give the title compound (151.4 g, purity 91%, yield 100%). 1 H-NMR (DMSO-D6) δ: 1.18 (3H, t, J = 7.1 Hz), 2.36-2.42 (2H, m), 3.98 (2H, t, J = 6.6 Hz), 4.07 (2H, q, J = 7.1 Hz), 5.05-5.09 (1H, m), 5.13 (1H, dq, J = 17.2, 1.7 Hz), 5.26 (1H, d, J = 12.6 Hz), 5.74-5.85 (1H, m), 7.58 (1H, d, J = 12.6 Hz).

[0186] (2) Ethyl 2-(4-hydroxytetrahydro-2H-pyran-2-yl)acetate

[0187] [ka]

[0188] Under ice-cooling, trifluoroacetic acid (186 mL, 2418 mmol) was added dropwise to a solution of ethyl (E)-3-(but-3-en-1-yloxy)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, and the mixture was extracted with chloroform. The aqueous layer was re-extracted with chloroform. The organic layer was The combined extracts were washed with water and saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure using ethanol as an azeotrope. Ethanol (1616 mL) and potassium carbonate (9.82 g, 71.1 mmol) were added to the resulting residue, which was then stirred at room temperature for 2 hours. Insoluble matter was removed by filtration using Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 9 / 1). The title compound (106 g, purity 93%, yield 74%) was obtained by purifying the crude product using a solvent-free solvent (from 0 / 100 to 0 / 100). 1 H-NMR (DMSO-D6) δ: 1.00-1.09 (0.78H, m), 1.17 (2.34H, t, J = 7.2 Hz), 1.18 (0.66H, t, J = 7.2 Hz), 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, 1.7 Hz), 3.95-4.00 (0.22H, m), 4.00-4.09 (2.22H, m), 4.62 (0.22H, d, J = 2.9 Hz), 4.75 (0.78H, d, J = 4.6 Hz).

[0189] (3) Ethyl 2-(4-oxotetrahydro-2H-pyran-2-yl)acetate

[0190] [ka]

[0191] Under cooling with water, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one To a solution of ethyl 2-(4-hydroxytetrahydro-2H-pyran-2-yl)acetate (126 g, 296 mmol) in chloroform (400 mL), a solution of ethyl 2-(4-hydroxytetrahydro-2H-pyran-2-yl)acetate (50 g, 93% purity, 247 mmol) obtained in (2) in chloroform (65 mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. 1,1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one (31.4 g, 74.0 mmol) was added, and the mixture was stirred for an additional 30 minutes. Hexane (465 mL) was added to the solution, and the mixture was stirred at room temperature for 30 minutes. Insoluble matter was removed by filtration, and the filtrate was Add 1000 mL of 10% sodium bicarbonate solution and 100 mL of 10% sodium thiosulfate solution. The mixture was stirred for 1 hour. Insoluble matter was removed by filtration, and the filtrate was separated into layers. The organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain the title compound (62.5 g, purity 77%, yield 105%). 1 H-NMR (DMSO-D6) δ: 1.18 (3H, t, J = 7.1 Hz), 2.12-2.20 (1H, m), 2.28-2.34 (1H, m), 2.39 (1H, ddd, J = 14.6, 10.8, 0.9 Hz), 2.48-2.63 (3H, m), 3.58-3.65 (1H, m), 3.94-4.01 (1H, m), 4.07 (2H, q, J = 7.1 Hz), 4.14 (1H, ddd, J = 11.4, 7.5, 1.4 Hz).

[0192] (4) Ethyl 2-(1,4,8-trioxaspiro[4,5]decan-7-yl)acetate

[0193] [ka]

[0194] Under an argon atmosphere, ethyl 2-(4-oxotetrahydro-2H- A solution of pyran-2-yl acetate (60 g, 322 mmol) in toluene (600 mL) was added to ethylene glycol. Pyridinium p-toluenesulfonate (4.86 g, 19.33 mmol) was added to the mixture, and the dehydration reaction was carried out at 140°C for 3 hours using a Dean-Stark apparatus. After cooling to room temperature, saturated aqueous sodium bicarbonate solution (200 mL) and water (200 mL) were added to the reaction mixture, and the layers were separated. The aqueous layer was extracted three times with hexane / ethyl acetate = 1 / 1. The organic layers were combined and washed with water and saturated brine. The organic layers were separated using sulfuric acid. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 90 / 10 to 0 / 100) to obtain the title compound (67.8 g, purity 90%, yield 82%). 1 H-NMR (DMSO-D6) δ: 1.17 (3H, t, J = 7.2 Hz), 1.41 (1H, dd, J = 12.9, 11.7 Hz), 1.53-1.64 (2H, m), 1.70 (1H, dt, J = 12.9, 2.1 Hz), 2.39 (1H, dd, J = 15.5, 8.3 Hz), 2.44-2.50 (1H, m), 3.39-3.47 (1H, m), 3.76-3.93 (6H, m), 4.05 (2H, q, J = 7.2 Hz).

[0195] (5) Ethyl 2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]decan-7-yl)acetate

[0196] [ka]

[0197] A solution of ethyl 2-(1,4,8-trioxaspiro[4,5]decan-7-yl)acetate (17.0 g, 66.4 mmol) obtained in (4) in a mixture of toluene (230 mL) and tetrahydrofuran (765 mL) was added to N-fluoroisopropyl methylcellulose. Dibenzosulfonimide (84.0 g, 266 mmol) was added and the mixture was cooled to -78°C. Trimethylsilylamide-tetrahydrofuran solution (233 mL, 233 mmol) was added dropwise, and the mixture was stirred for 1 hour. The temperature was raised to 0°C over a period of time, and the mixture was stirred for a further 2 hours under ice cooling. Triethylamine (74.1 mL, 532 mmol) was added dropwise to the reaction mixture. Water (1000 mL) and hexane (330 mL) were added to the reaction mixture, and the layers were 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 filtered off using Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate). The title compound (15.1 g, 85% yield) was obtained by purifying the mixture with a solvent (from 94 / 6 to 50 / 50). 1 H-NMR (DMSO-D6) δ: 1.26 (3H, t, J = 7.2 Hz), 1.58-1.82 (4H, m), 3.48-3.56 (1H, m), 3.89-4.03 (6H, m), 4.32 (2H, q, J = 7.1 Hz).

[0198] (6) 2,2-Difluoro-2-(1,4,8-trioxaspiro[4,5]decan-7-yl)ethan-1-ol

[0199] [ka]

[0200] Under argon atmosphere and ice cooling, lithium aluminum hydride (2.82 g, 74.4 mmol) was dissolved in tetrahydrofuran. To a suspension of tetrahydrofuran (90 mL), a solution of ethyl 2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]decan-7-yl)acetate (18.0 g, 67.6 mmol) obtained in the same reaction as in (5) in tetrahydrofuran (36 mL) was added dropwise, and the mixture was stirred for 1 hour. The reaction mixture was diluted with water (2.8 mL), 4N aqueous sodium hydroxide, and the mixture was stirred for 1 hour. The solution (2.8 mL) and water (8.4 mL) were added dropwise, and the mixture was stirred at room temperature for 2 hours. Insoluble matter was filtered off using 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%). 1 H-NMR (DMSO-D6) δ: 1.54-1.79 (4H, m), 3.46-4.01 (9H, m), 5.45 (1H, t, J = 6.4 Hz).

[0201] (7) 2,2-Difluoro-2-(1,4,8-trioxaspiro[4,5]decan-7-yl)ethyl trifluoromethanesulfonate

[0202] [ka]

[0203] Under ice cooling, 2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]decane-7-yl) Trifluoromethanesulfonyl chloride (8 mL, 71.2 mmol) was added dropwise to a solution of (14.0 g, 62.4 mmol)ethan-1-ol and triethylamine (11.3 mL, 81 mmol) in dichloromethane (140 mL), 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, and the mixture was stirred for an additional 2 hours. Triethylamine (0.85 mL, To the reaction mixture was added trifluoromethanesulfonyl chloride (0.7 mL, 6.2 mmol), and the mixture was stirred for another 30 minutes. Water was added to the reaction mixture, and the layers were separated. The organic layer was washed with water and saturated brine. The layers were dried over sodium sulfate and then concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and the layers were separated. The organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain the title compound (23.4 g, yield 100%). 1 H-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).

[0204] (8) 2-(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]decan-7-yl)ethyl)isopropyl Endolin-1,3-dione

[0205] [ka]

[0206] 2,2-Difluoro-2-(1,4,8-trioxaspiro[4,5]decan-7-yl)ethyl trifluoromethanesulfonate (22.2 g, 62.4 mmol) obtained in (7) in N,N-dimethylformamide (133 mL) Potassium phthalimide (15.0 g, 81 mmol) was added to the solution, and the mixture was stirred at room temperature for 15 hours. Water (150 mL) was added, 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 collected solid, and the mixture was stirred for an additional 1 hour. The precipitated solid was filtered and dried under reduced pressure to give the title compound (16.4 g, yield 74%). 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, 5.5 Hz), 4.13-4.32 (2H, m), 7.72-7.77 (2H, m), 7.87-7.92 (2H, m).

[0207] (9) 2,2-Difluoro-2-(1,4,8-trioxaspiro[4,5]decan-7-yl)ethan-1-amine

[0208] [ka]

[0209] 2-(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]decan-7-yl) ethylenediamine obtained in (8) To a mixed solution of (ethyl)isoindoline-1,3-dione (16.4 g, 46.4 mmol) in ethanol (115 mL) and tetrahydrofuran (115 mL), hydrazine monohydrate (4.51 mL, 93 mmol) was added and stirred at 60°C for 2 hours. Hydrazine monohydrate (2.5 mL, 51.7 mmol) was added, and the mixture was stirred at 60°C for an additional 1 hour. After cooling the reaction mixture in an ice bath, the insoluble matter was filtered off and washed twice with ethanol (115 mL). The filtrate was concentrated, and ethanol (60 mL) was added to the precipitated solid, which was then filtered off. The filtrate was concentrated under reduced pressure to give the title compound (10.6 g, 92% yield). 1H-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, 3.1 Hz), 3.82-3.99 (6H, m).

[0210] (10) Methyl 3-((2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]decan-7-yl)ethyl) (trifluoromethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate

[0211] [ka]

[0212] To a solution of 2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]decan-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. The mixture was stirred at room temperature for 15 hours. Water (180 mL) was added to the reaction mixture under ice cooling, and the precipitated solid was collected by filtration. The solid was washed with water (90 mL). To the obtained solid, hexane / ethyl acetate = 2 / 1 (120 mL) was added and stirred for 30 minutes. The solid was collected by filtration and washed with hexane / ethyl acetate = 2 / 1 (60 mL). The product was dried at room temperature under reduced pressure to give the title compound (13.7 g, 63% yield). 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 = 7.4 Hz), 7.54 (1H, d, J = 8.8 Hz), 7.68 (1H, dd , J = 8.8, 1.6 Hz), 8.26 (1H, br s).

[0213] (11) Methyl 3-(2-chloro-N-(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]decan-7-yl)ethyl)acetamido)-5-(trifluoromethyl)benzofuran-2-carboxylate

[0214] [ka]

[0215] Under ice cooling, chloroacetyl chloride (7.02 mL, 88 mmol) was added dropwise to a solution of methyl 3-((2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]decan-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), 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. The mixture was stirred for another 6 hours. 10% citric acid water was added and the layers were separated. The organic layer was separated with 10% citric acid water, The mixture was washed with saturated aqueous sodium bicarbonate and saturated saline. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / The mixture was purified with ethyl acetate (6 / 1 to 3 / 2) and dissolved in ethyl acetate (20 mL). Hexane (40 mL) was added and the mixture was stirred for 1 hour. The precipitated solid was filtered and dried under reduced pressure to give the title compound (14.3 g). The product was obtained in a yield of 90%. 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, 0.8 Hz), 4.44-4.80 (1H, m), 7.89-7.97 (1H, m), 8.01-8.08 (1H, m), 8.20 (1H, d, J = 8.6 Hz).

[0216] (12) Methyl 3-((2-chloroethyl)(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]de) (7-Iron-7-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate

[0217] [ka]

[0218] Under ice cooling, a solution of methyl 3-(2-chloro-N-(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]decan-7-yl)ethyl)acetamido)-5-(trifluoromethyl)benzofuran-2-carboxylate (12.3 g, 22.7 mmol) obtained in (11) in tetrahydrofuran (148 mL) was added to 0.91 M aqueous solution of benzofuran-2-carboxylate (12.3 g, 22.7 mmol). Lanthanide-tetrahydrofuran complex (54.9 mL, 49.9 mmol) was added dropwise, and the mixture was stirred at room temperature for 7 hours. Under cooling, 20% aqueous citric acid was added to the reaction mixture, which was then stirred for 10 minutes, followed by extraction with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were washed with saturated brine. After drying over sodium hydroxide, the mixture was concentrated under reduced pressure, and 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%). 1 H-NMR (DMSO-D6) δ: 1.45-1.68 (4H, m), 3.10 (1H, td, J = 11.8, 2.5 Hz), 3.62-4.10 (15H, m), 7.87 (1H, dd, J = 9.0, 1.6 Hz), 7.91 (1H, d, J = 9.0 Hz), 8.20 (1H, br s).

[0219] (13) Methyl 3-((2-azidoethyl)(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]de) (7-Iron-7-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate

[0220] [ka]

[0221] Methyl 3-((2-chloroethyl)(2,2-difluoro-2-(1,4,8- To a solution of (trioxaspiro[4,5]decan-7-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (8.5 g, 16.10 mmol) in N,N-dimethylformamide (85 mL), potassium azide (2.61 g, 32.2 mmol) and sodium iodide (0.483 g, 3.22 mmol) were added and the mixture was stirred at 80°C for 4 hours. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (8.6 g, 100% yield). 1H-NMR (DMSO-D6) δ: 1.45-1.67 (4H, m), 3.09 (1H, td, J = 11.8, 2.6 Hz), 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, 1.7 Hz), 7.91 (1H, d, J = 8.9 Hz), 8.19 (1H, br s).

[0222] (14) 1-(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]decan-7-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine-5-ol hmm

[0223] [ka]

[0224] Methyl 3-((2-azidoethyl)(2,2-difluoro-2-(1,4,8-trioxazosyl)methyl)-2-(azidoethyl)-2- ... Pyrro[4,5]decan-7-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carbohydrate To a solution of the carboxylate (8.60 g, 16.1 mmol) 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 mixture was concentrated under reduced pressure. To the resulting residue was added hexane / ethyl acetate = 1 / 1 (34 mL), and the mixture was stirred for 1 hour, and the resulting solid was collected by filtration. Ethyl acetate (34 mL) was added to the resulting solid, and the mixture was stirred for another 1 hour. The precipitated solid The residue was filtered and dried under reduced pressure to give the title compound (4.5 g, yield 53%). 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 = 5.0 Hz), 8.32 (1H, br s).

[0225] (15) 1-(2,2-difluoro-2-(4-oxotetrahydro-2H-pyran-2-yl)ethyl)-9-(trifluoromethyl)- Fluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepin-5-one

[0226] [ka]

[0227] 1-(2,2-difluoro-2-(1,4,8-trioxaspiro[4,5]decan-7-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazonium monoxide (14) A solution of zepin-5-one (0.452 g, 0.949 mmol) in acetic acid (3.6 mL) was added with 2 N hydrochloric acid (0.904 mL, 1.808 mmol). The mixture was added and stirred at 80°C for 3 hours. After cooling to room temperature, ethyl acetate and water were added to dilute the mixture, and 10% aqueous sodium carbonate solution was slowly added dropwise. The layers were separated, and the aqueous layer was re-extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. Ethanol (4 mL) was added to the residue, and the mixture was stirred for 1 hour. The precipitated solid was filtered and dried under reduced pressure to obtain the title compound (0.304 g, yield 74%). 1H-NMR (DMSO-D6) δ: 2.27 (1H, d, J = 15.3 Hz), 2.38 (1H, d, J = 14.3 Hz), 2.60-2.73 (2H, m), 3.28-3.62 (4H, m), 3.78 (1H, td, J = 11.7, 2.8 Hz), 4.07-4.39 (4H, m), 7.75-7.84 (2H, m), 8.11 (1H, t, J = 5.0 Hz), 8.34 (1H, br s).

[0228] (16) 1-(2,2-difluoro-2-(4-hydroxy-4-methyltetrahydro-2H-pyran-2-yl)ethoxylate (ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazo Zepin-5-one

[0229] [ka]

[0230] Under argon atmosphere and ice cooling, 1-(2,2-difluoro-2-(4-oxo-2-methyl-2-methyl-4-oxo ... (isotetrahydro-2H-pyran-2-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro Tetrahydro-5H-benzofuro[3,2-e][1,4]diazepin-5-one (0.925g, 1.879mmol) To the suspension in furan (37 mL), 3.0 M methylmagnesium chloride-tetrahydrofuran solution (2.25 mL, 6.76 mmol) was added dropwise, and the mixture was stirred for 2 hours. Under ice-cooling, 10% aqueous ammonium chloride solution (50 mL) was added dropwise, and the mixture was extracted three times with ethyl acetate. The organic layers were combined, and then saturated aqueous sodium bicarbonate solution was added. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform / methanol = 9 / 1) and The product was purified by preparative thin-layer chromatography (developing solvent: chloroform / methanol = 9 / 1). The residue obtained by concentrating under reduced pressure was purified by reversed-phase liquid chromatography (column: XTERRA PrepMS C18 OBD TM 5μm, 30x50mm Column, Mobile phase: Water (0.1% trifluoroacetic acid) / By purifying with acetonitrile (0.1% trifluoroacetic acid), a racemic mixture in which the relative configuration of the substituents on the tetrahydropyran ring is cis (0.205 g, yield 24%, the compound of Example 12) and a racemic mixture in which the relative configuration of the substituents on the tetrahydropyran ring is trans (0.272 g, yield 32%, the compound of Example 12) were obtained. The compound of Example 11 was obtained. The relative configuration of the substituents on the tetrahydropyran ring was cis. The racemate (0.205 g) was optically resolved using supercritical fluid chromatography (apparatus: Waters SFC Prep15 System, column: Daicel CHIRALPAK IG / SFC, 10 mm (ID) x 250 mm (L), 5 μm, column temperature: 40°C, column back pressure: 120 bar, mobile phase flow rate: 15 mL / min, mobile phase mixture ratio: isocratic, carbon dioxide / methanol = 85 / 15, fraction trigger: UV 214 nm). The compound of Example 58 (0.086 g) was obtained as the first peak fraction (10.0-11.9 min), and the compound of Example 59 (0.085 g) was obtained as the second peak fraction (12.3-14.8 min). The racemate (0.136 g) in which the relative configuration of the substituents on the tetrahydropyran ring was trans was purified by supercritical fluid chromatography (instrument name: Optical resolution was performed using a Waters SFC Prep15 System, column: Daicel CHIRALPAK IF / SFC, 10 mm (ID) x 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), fraction trigger: UV 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). (Examples 12, 58, and 59) 1 H-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, 4.3 Hz), 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 = 5.0 Hz), 8.34 (1H, br s). (Examples 11, 66, and 67) 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 = 5.0 Hz), 8.34 (1H, br s).

[0231] [Production Example 2]: Synthesis of 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]diazepin-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]diazepin-5-one (Example 77)

[0232] [ka]

[0233] (1) Methyl (S)-3,4-dihydroxybutanoate

[0234] [ka]

[0235] Under ice cooling, dimethyl (S)-2-hydroxysuccinate (35 g, 216 mmol) was added to tetrahydrofuran. Borane-dimethyl sulfide complex (26.6 mL, 281 mol) was added dropwise to a solution of borane (350 mL) and stirred for 1 hour. Sodium borohydride (0.204 g, 5.40 mmol) was added and stirred for 2 hours. Sodium uronide (0.204 g, 5.40 mmol) was added and the mixture was stirred for another 30 minutes. Methanol (140 mL) was added dropwise to the reaction mixture and the mixture was stirred for 15 minutes. The mixture was concentrated under reduced pressure under azeotropic conditions with toluene and methanol. The title compound (29.9 g, 103% yield) was obtained. 1H-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, 3.3 Hz), 4.63 (1H, t, J = 5.8 Hz), 4.78 (1H, d, J = 5.3 Hz).

[0236] (2) Methyl (S)-4-((tert-butyldiphenylsilyl)oxy)-3-hydroxybutanoate

[0237] [ka]

[0238] Under ice cooling, tert-butyldiphenylchlorosilane (58.6 mL, 228 mmol) was added dropwise to a solution of methyl (S)-3,4-dihydroxybutanoate (29.6 g, 207 mmol) obtained in (1) and imidazole (31.1 g, 456 mmol) in N,N-dimethylformamide (223 mL), and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, which was then extracted with hexane / ethyl acetate = 1 / 3. The organic layer was washed with water and saturated brine. The organic layer was 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%). 1H-NMR (DMSO-D6) δ: 0.99 (9H, s), 2.35 (1H, dd, J = 15.0, 8.3 Hz), 2.64 (1H, dd, J = 15.0, 4.6 Hz), 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 = 5.5 Hz), 7.44-7.47 (6H, m), 7.62-7.63 (4H, m).

[0239] (3) Methyl (S)-3-(allyloxy)-4-((tert-butyldiphenylsilyl)oxy)butanoate Route

[0240] [ka]

[0241] To a solution of methyl (S)-4-((tert-butyldiphenylsilyl)oxy)-3-hydroxybutanoate (65.6 g, 176 mmol) obtained in (2) and allyl 2,2,2-trichloroacetimidate (37.2 mL, 247 mmol) in cyclohexane (328 mL), trifluoromethanesulfonic acid (1.24 mL, 14.1 mmol) was added and stirred at room temperature for 3 days. Hexane was added to the reaction solution, and insoluble matter was removed by filtration. The filtrate was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate). The mixture was purified using a solvent mixture (from 97 / 3 to 70 / 30) to obtain the title compound (61.1 g, yield 84%). 1H-NMR (DMSO-D6) δ: 0.99 (9H, s), 2.53 (1H, dd, J = 15.5, 7.6 Hz), 2.64 (1H, dd, J = 15.5, 5.3 Hz), 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, 1.6 Hz), 5.19 (1H, dq, J = 17.2, 1.8 Hz), 5.76-5.86 (1H, m), 7.41-7.50 (6H, m), 7.60-7.65 (4H, m).

[0242] (4) Methyl (S)-3-(allyloxy)-4-hydroxybutanoate

[0243] [ka]

[0244] Under ice cooling, 1 M tetrabutylammonium fluoride-tetrahydrofuran solution (20.1 mL, 20.1 mmol) was added to a mixed solution of methyl (S)-3-(allyloxy)-4-((tert-butyldiphenylsilyl)oxy)butanoate (6.9 g, 16.7 mmol) obtained in the same reaction as in (3) in acetic acid (0.956 mL, 16.7 mmol) and tetrahydrofuran (35 mL), and the mixture was stirred for 4 hours. The same procedure was carried out using methyl (S)-3-(allyloxy)-4-((tert-butyldiphenylsilyl)oxy)butanoate (61.1 g, 148 mmol) obtained in (3), and these reaction solutions were combined. Water (400 mL) was added to the reaction solution, which was then extracted with ethyl acetate (400 mL). The aqueous layer was re-extracted with ethyl acetate (200 mL). The combined organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 82 / 18 to 20 / 80) to obtain the title compound (24.6 g, yield 86%). 1H-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 (1H, m), 3.59 (3H, s), 3.69-3.72 (1H, m), 3.96 (1H, ddt, J = 13.2, 5.3, 1.8 Hz), 4.02-4.08 (1H, m), 4.71-4.74 (1H, br m), 5.09 (1H, dq, J = 10.4, 1.6 Hz), 5.21 (1H, dq, J = 17.2, 1.8 Hz), 5.78-5.88 (1H, m).

[0245] (5) Methyl 2-((2S)-5-(iodomethyl)-1,4-dioxan-2-yl)acetate

[0246] [ka]

[0247] Under ice cooling, N-iodosuccinimide (47.7 g, 212 mmol) was added to a solution of methyl (S)-3-(allyloxy)-4-hydroxybutanoate (24.6 g, 141 mmol) obtained in (4) in acetonitrile (738 mL), and the mixture was stirred at room temperature for 2 days. An aqueous solution (400 mL) of sodium hydrogen sulfite (14.7 g, 141 mmol) was added to the reaction mixture, and the mixture was stirred for 30 minutes. Water (400 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (800 mL). The organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 95 / 5). The resulting mixture was purified from hexane / ethyl acetate / methanol (60 / 40 / 2) to give the title compound (16.0 g, yield 42%). 1H-NMR (DMSO-D6) δ: 2.34 (0.33H, td, J = 14.1, 7.5 Hz), 2.46-2.49 (0.33H, m), 2.58-2.65 (1.34H, m), 3.10 (0.33H, dd, J = 10.6, 6.9 Hz), 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).

[0248] (6) ((5S)-5-(2-Methoxy-2-oxoethyl)-1,4-dioxan-2-yl)methyl 4-nitrobenzyl Nzoate

[0249] [ka]

[0250] To a solution of methyl 2-((2S)-5-(iodomethyl)-1,4-dioxan-2-yl)acetate (16.0 g, 53.3 mmol) obtained in (5) in dimethyl sulfoxide (112 mL), potassium 4-nitrobenzoate (32.8 g, 160 mmol) and 18-crown-6 (1.41 g, 5.33 mmol) were added and the mixture was stirred at 90°C for 3 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed with water, saturated aqueous sodium bicarbonate, and saturated brine. The organic layers were dried over sodium sulfate and then concentrated under reduced pressure to obtain the title compound (18.9 g, 104% yield). 1 H-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, dd, J = 6.8, 2.7 Hz), 3.34-3.36 (0.5H, m), 3.49 (0.5H, dd, J = 11.2, 10.5 Hz), 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, 7.5 Hz), 8.19-8.22 (2H, m), 8.35-8.37 (2H, m).

[0251] (7) Methyl 2-((2S)-5-(hydroxymethyl)-1,4-dioxan-2-yl)acetate

[0252] [ka]

[0253] To a solution of ((5S)-5-(2-methoxy-2-oxoethyl)-1,4-dioxan-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 mixture, 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, and the organic layers were combined again, dried over sodium sulfate, and concentrated under reduced pressure. Concentration under reduced pressure gave the title compound (5.4 g, yield 51%). 1 H-NMR (DMSO-D6) δ: 2.32 (0.5H, dd, J = 15.7, 7.9 Hz), 2.45-2.48 (0.5H, m), 2.60-2.64 (1H, m), 3.22-3.30 (2H, 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).

[0254] (8) Methyl 2-((2S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxa (2-phenyl) acetate

[0255] [ka]

[0256] To a solution of methyl 2-((2S)-5-(hydroxymethyl)-1,4-dioxan-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-butyldiphenylchlorosilane (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-butyldiphenylchlorosilane (0.73 mL, 2.8 mmol) were added, and the mixture was stirred for an additional 2 hours. Water was added to the reaction solution, which was then extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 97 / 3 to 75 / 25) to obtain the title compound (5.8 g, yield 48%). 1 H-NMR (DMSO-D6) δ: 0.99-1.00 (9H, m), 2.33 (0.6H, dd, J = 15.8, 8.0 Hz), 2.45-2.47 (0.6H, m), 2.58-2.62 (0.8H, m), 3.27 (0.6H, t, J = 11.6 Hz), 3.39 (0.6H, t, J = 11.3 Hz), 3.47 (0.4H, dd, J = 11.8, 5.3 Hz), 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).

[0257] (9) Methyl 2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxane-2- (yl)-2,2-difluoroacetate (trans and cis isomers)

[0258] [ka]

[0259] Toluene was added to methyl 2-((2S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxan-2-yl)acetate (5.82 g, 13.6 mmol) obtained in (8), and the mixture was concentrated under reduced pressure. To the residue, a mixed solvent of toluene (29 mL) and tetrahydrofuran (116 mL) was added, and the mixture was cooled with ice. N-Fluorobenzenesulfonimide (17.1 g, 54.3 mmol) was added and the mixture was cooled to -78°C. 1 M sodium bistrimethylsilylamide-tetrahydrofuran solution (47.5 mL, 47.5 mmol) was added dropwise, and the temperature was gradually raised over 30 minutes. Triethylamine (15.1 mL, 109 mmol) was added dropwise to the reaction mixture at -10°C. Water was added to the reaction mixture, 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 aqueous sodium bicarbonate and saturated brine. Sodium sulfate and silica gel were added to the organic layer and the mixture was stirred. Insoluble matter was filtered off using Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane / acetic acid). The mixture was purified with ethyl acetate (97 / 3 to 80 / 20) to give the trans isomer of the title compound (3.2 g, 51% yield) and the cis isomer of the title compound (1.8 g, 29% yield). Trans isomer: 1H-NMR (DMSO-D6) δ: 0.98 (9H, s), 3.49 (1H, dd, J = 11.1, 9.9 Hz), 3.56-3.66 (4H, m), 3.86 (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). Cis isomer: 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).

[0260] (10) 2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxan-2-yl)-2,2-difluoroethan-1-ol (trans isomer)

[0261] [ka]

[0262] Under ice cooling, a suspension of lithium aluminum hydride (0.288 g, 7.58 mmol) in tetrahydrofuran (16 mL) was added to the trans isomer of methyl 2-(5-(((tert-butyldiphenylsilyl)methyl) obtained in (9). A solution of (1,4-dioxan-2-yl)oxymethyl-2,2-difluoroacetate (3.2 g, 6.89 mmol) in tetrahydrofuran (4.8 mL) was added dropwise and stirred for 30 minutes. A 4N aqueous solution of sodium hydroxide (0.288 mL) and water (0.864 mL) were added dropwise in that order, and the mixture was stirred for 2.5 hours. The insoluble matter was removed by filtration using a light, and the filtrate was concentrated under reduced pressure to give the title compound (3.1 g, yield 103%). The relative configuration of the compound was determined by NOESY measurement of a compound synthesized in the same manner. 1 H-NMR (DMSO-D6) δ: 1.00 (9H, s), 3.48 (1H, t, J = 10.6 Hz), 3.55-3.70 (6H, m), 3.84-3.88 (1H, m), 3.93 (2H, t, J = 11.3 Hz), 5.55 (1H, t, J = 6.4 Hz), 7.42-7.50 (6H, m), 7.62-7.63 (4H, m).

[0263] (11) 2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxan-2-yl)-2,2-difluoroethyl trifluoromethanesulfonate (trans isomer)

[0264] [ka]

[0265] Under ice cooling, 2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4- A solution of (dioxan-2-yl)-2,2-difluoroethan-1-ol (3.1 g, 7.03 mmol) and triethylamine (1.47 mL, 10.55 mmol) in dichloromethane (31 mL) was added with trifluoromethanesulfonyl chloride. Chloride (1.12 mL, 10.55 mmol) was added dropwise and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (4.14 g, yield 104%). 1 H-NMR (DMSO-D6) δ: 1.00 (9H, s), 3.52 (1H, t, J = 10.5 Hz), 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).

[0266] (12) ((5-(2-azido-1,1-difluoroethyl)-1,4-dioxan-2-yl)methoxy)(tert-butyl)diphenylsilane (trans isomer)

[0267] [ka]

[0268] 2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxa (2-phenyl-2-yl)-2,2-difluoroethyl trifluoromethanesulfonate (4.14g, 7.28mmol) To a solution of the above in N,N-dimethylformamide (33 mL) was added potassium azide (0.886 g, 10.92 mmol), The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, saturated The organic layer was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (3.27 g, yield 97%). 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).

[0269] (13) 2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxan-2-yl)-2,2-difluoroethan-1-amine (trans isomer)

[0270] [ka]

[0271] ((5-(2-azido-1,1-difluoroethyl)-1,4-dioxan-2-yl)methoxy)(tert-butyl)diphenylsilane (3.27 g, 7.08 mmol) obtained in (12) in tetrahydrofuran (16.4 mL), To a mixture of methanol (16.4 mL) and 10% palladium on carbon (0.654 g) was added, and the mixture was heated at room temperature under atmospheric hydrogen pressure. The mixture was stirred at rt for 3 hours. After filtering off the insoluble matter using Celite, the filtrate was concentrated under reduced pressure to give the title compound. The compound (2.9 g, yield 95%) was obtained. 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).

[0272] (14) Methyl 3-((2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxa (2-phenyl-2,2-difluoroethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate Carboxylate (trans isomer)

[0273] [ka]

[0274] 2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxa N,N-dimethylformamide 2-Hydroxy-5-(trifluoromethyl)benzaldehyde (1.21 g, 6.38 mmol) was added to a solution of 2,2-dichloromethane (29 mL) and stirred at room temperature for 1.5 hours. Methyl acetate (0.794 mL, 7.66 mmol) was added, and the mixture was stirred at room temperature for 17 hours. After adding water to the reaction mixture, The organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. Hexane / ethyl acetate = 5 / 1 was added to the residue and stirred for 1 hour. The precipitated solid was filtered and dried under reduced pressure to obtain the title compound (1.35 g, yield 31%). The filtrate was The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate). The title compound (1.0 g, yield 23%) was also obtained by purifying with ethyl acetate (95 / 5 to 75 / 25). 1 H-NMR (DMSO-D6) δ: 0.98 (9H, s), 3.42 (1H, t, J = 10.8 Hz), 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 = 7.3 Hz), 7.41-7.50 (6H, m), 7.59-7.61 (4H, m), 7.78 (1H, d, J = 8.8 Hz), 7.86 (1H, dd, J = 9.0, 1.6 Hz), 8.48 (1H, s).

[0275] (15) Methyl 3-(N-(2-(-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxan-2-yl)-2,2-difluoroethyl)-2-chloroacetamido)-5-(trifluoromethyl) Benzofuran-2-carboxylate (trans isomer)

[0276] [ka]

[0277] 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 chloroacetyl chloride (0.833 mL, 10.4 mmol) dropwise and the mixture was stirred at room temperature for 16 hours. To the reaction mixture were added additional N,N-dimethylaniline (0.85 mL, 6.94 mmol) and chloroacetyl chloride (0.4 mL, 5.2 mmol), and the mixture was stirred at room temperature for an additional 4 hours. Chloroacetyl Chloride (0.2 mL, 2.6 mmol) was added and the mixture was stirred at room temperature for another hour. 10% aqueous citric acid was added to the reaction mixture, which was then extracted with chloroform. The organic layer was washed with 10% aqueous citric acid and saturated saline. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, and 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, yield 85%). 1 H-NMR (DMSO-D6) δ: 0.98 (9H, s), 3.40 (1H, dd, J = 20.7, 10.5 Hz), 3.49-3.67 (4H, m), 3.87-3.96 (6H, m), 4.06-4.12 (1H, m), 4.22 (1H, dd. dd, J = 9.0, 1.8 Hz), 8.05 (1H, d, J = 8.8 Hz), 8.23 ​​(1H, s).

[0278] (16) Methyl 3-((2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxa (2-chloroethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (trans isomer)

[0279] [ka]

[0280] Under ice cooling, methyl 3-(N-(2-(-5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxan-2-yl)-2,2-difluoroethyl)-2-chloroacetamido)-5-( (trifluoromethyl)benzofuran-2-carboxylate (2.22g, 2.94mmol) tetrahydro To a solution of tetrahydrofuran (27 mL), 0.91 M borane-tetrahydrofuran complex (9.7 mL, 8.83 mmol) was added dropwise and stirred at room temperature for 18 hours. Under ice cooling, 10% aqueous citric acid was added to the reaction mixture and stirred for 5 minutes. Ethyl acetate was added and extracted. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layer was washed with saturated brine. The organic layer was 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%). 1 H-NMR (DMSO-D6) δ: 0.96 (9H, s), 3.20 (1H, t, J = 10.2 Hz), 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).

[0281] (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)

[0282] [ka]

[0283] The methyl 3-((2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxan-2-yl)-2,2-difluoroethyl)(2-chloroethyl)amino)-5-(trifluoromethyl)- Potassium azide (0.239 g, 2.95 mmol) and sodium iodide (0.044 g, 0.295 mmol) were added to a solution of (trimethyl)benzofuran-2-carboxylate (1.09 g, 1.473 mmol) in N,N-dimethylformamide (10.9 mL), and the mixture was stirred at 80°C for 1 hour. Water was added to the reaction mixture 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 obtain the title compound (1.24 g, yield 113%). 1 H-NMR (DMSO-D6) δ: 0.96 (9H, s), 3.18 (1H, t, J = 10.5 Hz), 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).

[0284] (18) 1-(2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4-dioxan-2-yl)-2,2-difluoroethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzo[b] b[3,2-e][1,4]diazepin-5-one (trans isomer)

[0285] [ka]

[0286] Methyl 3-((2-azidoethyl)(2-(5-(((tert-butyldiphenylsilyl) To a mixture of (oxy)methyl)-1,4-dioxan-2-yl)-2,2-difluoroethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (1.12 g, 1.500 mmol), water (1.12 mL), and 1,2-dimethoxyethane (11.2 mL) was added triphenylphosphine (0.472 g, 1.800 mmol). The mixture was stirred at 80°C for 1 hour, and then at 100°C for another 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was Ethyl acetate was added to the mixture and stirred for 1 hour. The precipitated solid was filtered and dried under reduced pressure to give the title compound. The compound was obtained (0.458 g, yield 44%). 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).

[0287] (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- On (trans isomer)

[0288] [ka]

[0289] To a solution of 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]diazepin-5-one (0.380 g, 0.552 mmol) obtained in (18) in tetrahydrofuran (3.8 mL) was added 1 M 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 mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was 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 filtered and dried under reduced pressure. The title compound (0.193 g, yield 78%) was obtained by concentrating the filtrate, and the residue was purified by reversed-phase column chromatography (column: ODS, developing solvent: water / acetonitrile = 85 / 15). The title compound (0.02 g, yield 8%) was also obtained by purifying the residue with HCl (0 / 100). 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 = 11.1 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 = 4.8 Hz), 8.32 (1H, s).

[0290] (20) 1-(2,2-difluoro-2-((2R,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)ethoxybenzoate (ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazo Zepin-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-benzyl Benzofuro[3,2-e][1,4]diazepin-5-one (Example 77)

[0291] [ka]

[0292] 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]diazepin-5-one (0.210 g, 0.466 mmol) obtained by the same reaction as in (19) was purified by supercritical fluid chromatography (apparatus: Waters SFC Prep15 System, column: Daicel CHIRALPAK IA / SFC, 10 mm (ID) x 250 mm (L), 5 μm, column temperature: 40 °C, column back pressure: 120 bar, mobile phase flow rate: 15 mL / min, mobile phase mixture ratio: isocratic, carbon dioxide / (methanol / acetonitrile = 20 / 80) = 70 / 30, fraction trihydrate). The compound of Example 95 (0.149 g, yield 71%) was obtained as the first peak fraction (10.7-13.7 min), and the compound of Example 77 (0.030 g, yield 14%) was obtained as the second peak fraction (14.4-17.0 min). The absolute configuration on the dioxane ring of the compound of Example 95 is This was determined by X-ray crystal structure analysis. (Compound of Example 95) 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 = 4.8 Hz), 8.32 (1H, s). (Compound of Example 77) 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 = 11.1 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 = 4.8 Hz), 8.32 (1H, s).

[0293] [Production Example 3]: 1-(2-((1s,4s)-4-hydroxy-4-(hydroxymethyl)cyclohexyl)ethyl (trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine Synthesis of pin-5-one (Example 90)

[0294] [ka]

[0295] (1) Ethyl 2-(1,4-dioxaspiro[4,5]decan-8-ylidene)acetate

[0296] [ka]

[0297] Under an argon atmosphere, 1,4-dioxaspiro[4,5]decan-8-one (15.0 g, 96 mmol), phosphodiester A solution of 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, and the mixture was stirred at 80°C for an additional 21 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was 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, 86% yield). 1 H-NMR (CDCl3) δ: 1.28 (3H, t, J = 7.2 Hz), 1.77 (4H, dt, J = 12.5, 4.5 Hz), 2.38 (2H, t, J = 6.6 Hz), 3.00 (2H, t, J = 6.6 Hz), 3.98 (4H, s), 4.15 (2H, q, J = 7.2 Hz), 5.67 (1H, s).

[0298] (2) Ethyl 2-(1,4-dioxaspiro[4,5]decan-8-yl)acetate

[0299] [ka]

[0300] To a solution of ethyl 2-(1,4-dioxaspiro[4,5]decan-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 hydrogen pressure for 24 hours. After filtering off insoluble matter using Celite, the filtrate was concentrated under reduced pressure with toluene azeotropy to give the title compound (18.6 g, yield 99%). 1H-NMR (CDCl3) δ: 1.26 (3H, t, J = 7.2 Hz), 1.27-1.36 (2H, m), 1.53-1.64 (2H, m), 1.70-1.78 (4H, m), 1.79-1.88 (1H, m), 2.22 (2H, d, J = 7.2 Hz), 3.94 (4H, s), 4.13 (2H, q, J = 7.2 Hz).

[0301] (3) 2-(1,4-dioxaspiro[4,5]decan-8-yl)ethan-1-ol

[0302] [ka]

[0303] Under argon atmosphere and ice cooling, lithium aluminum hydride (6.2 g, 163 mmol) was added to the tetrahydrofuran. In a suspension of 1,4-dioxaspiro[4,5]decane-8-ol (93 mL), A solution of 18.6 g (82 mmol) of methyltrimethylsilyl acetate in 93 mL of tetrahydrofuran was added dropwise and stirred for 1 hour. Water (6.2 mL), 4N aqueous sodium hydroxide solution (6.2 mL), and water (18.6 mL) were added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 15 minutes. After filtering off insoluble matter using Celite, the filtrate was concentrated under reduced pressure in a toluene azeotropic solution to give the title compound (13.3 g, 88% yield). 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).

[0304] (4) 2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl 4-methylbenzenesulfonate

[0305] [ka]

[0306] Under ice cooling, a solution of 2-(1,4-dioxaspiro[4,5]decan-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 to 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 solution of sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was 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%). 1 H-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), 2.45 (3H, s), 3.88-3.95 (4H, m), 4.06 (2H, t, J = 6.5 Hz), 7.35 (2H, d, J = 8.1 Hz), 7.79 (2H, d, J = 8.1 Hz).

[0307] (5) Methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate

[0308] [ka]

[0309] 2-Hydroxy-5-(trifluoromethyl)benzaldehyde (3.0 g, 15.8 mmol) in methanol To a solution of 15 mL of ethanol, a solution of tert-butyl (2-aminoethyl)carbamate (2.5 g, 15.8 mmol) in methanol (15 mL) was added dropwise, and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure under azeotropic toluene, and the resulting residue was dissolved in N,N-dimethylformamide (52 mL), to which methyl 2,2-dichloroacetate (2.0 mL, 18.9 mmol) and potassium carbonate (6.5 g, 47.3 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture. After addition, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain the title compound (5.6 g, yield 88%). 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 = 6.6 Hz), 7.03 (1H, t, J = 5.4 Hz), 7.76 (1H, d, J = 8.8 Hz), 7.84 (1H, dd, J = 8.8, 1.4 Hz), 8.47 (1H, s).

[0310] (6) 9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diaze Pin-5-on

[0311] [ka]

[0312] Methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5-( To (trifluoromethyl)benzofuran-2-carboxylate (5.6 g, 13.9 mmol), 2 M hydrochloric acid-methanol solution (62.6 mL, 125 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Methanol (112 mL) was added to the residue, and the resulting mixture was cooled with water and cooled with 5M sodium methoxide. A ethanol solution (9.7 mL, 48.7 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 hours. After adding ethyl acetate, the mixture was extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. Ethyl acetate (28 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration and dried under reduced pressure. The title compound was obtained (2.9 g, 77% yield). 1 H-NMR (DMSO-D6) δ: 3.29-3.36 (2H, m), 3.42-3.45 (2H, m), 7.26 (1H, t, J = 3.6 Hz), 7.70-7.72 (2H, m), 7.76 (1H, dd, J = 8.8, 1.8 Hz), 8.32 (1H, s).

[0313] (7) 5-Methoxy-9-(trifluoromethyl)-2,3-dihydro-1H-benzofuro[3,2-e][1,4]diazonium Zepin

[0314] [ka]

[0315] A solution of 9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepin-5-one (2.9 g, 10.8 mmol) obtained in (6) in ethyl acetate (44 mL) was added to the Sodium tetrafluoroborate (1.9 g, 12.9 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. A solution (44 mL) of sodium carbonate (3.4 g, 32.3 mmol) was added dropwise to the reaction mixture, and the mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane / acetic acid). The title compound (2.7 g, yield 87%) was obtained by purifying the crude product with ethyl acetate (2 / 1 to 1 / 2). 1 H-NMR (DMSO-D6) δ: 3.34 (2H, br, s), 3.72 (3H, s), 3.75 (2H, br, s), 7.17 (1H, t, J = 4.3 Hz), 7.70 (1H, d, J = 8.8 Hz), 7.77 (1H, dd, J = 8.8, 1.8 Hz), 8.26 (1H, s).

[0316] (8) 1-(2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl)-5-methoxy-9-(trifluoromethyl)- (trimethyl)-2,3-dihydro-1H-benzofuro[3,2-e][1,4]diazepine

[0317] [ka]

[0318] 5-Methoxy-9-(trifluoromethyl)-2,3-dihydro-1H-benzyl ether obtained by the same reaction as (7) To a solution of benzofuro[3,2-e][1,4]diazepine (1.5 g, 5.28 mmol) and 2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl 4-methylbenzenesulfonate (4.5 g, 13.2 mmol) obtained in (4) in tetrahydrofuran (23 mL), 1 M sodium bistrimethylsilylamide-tetrahydrofuran solution (13.2 mL, 13.2 mmol) was added dropwise and stirred at room temperature for 19 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. 10% aqueous citric acid and saturated saline were added to the aqueous layer, and the mixture was reconstituted with ethyl acetate. The organic layers were combined and washed with saturated saline. The organic layers were dried over sodium sulfate and then concentrated under reduced pressure. A mixed solvent of hexane / ethyl acetate (1 / 1) was added to the resulting residue and stirred at room temperature. The precipitated solid was collected by filtration and dried under reduced pressure to give the title compound (1.2 g, 51% yield). The filtrate was concentrated, and the 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, 39% yield). 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 (2H, 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).

[0319] (9) 1-(2-(4-oxocyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepin-5-one

[0320] [ka]

[0321] To a solution of 1-(2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl)-5-methoxy-9-(trifluoromethyl)-2,3-dihydro-1H-benzofuro[3,2-e][1,4]diazepine (2.2 g, 4.80 mmol) obtained in (8) 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. Ethyl acetate and an aqueous solution of potassium phosphate were added to the reaction mixture under ice cooling. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (1.1 g, yield 58%). The organic layer of the filtrate was washed with saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. Ethyl acetate was 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. The title compound (0.459 g, yield 25%) was obtained. 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, 5.8 Hz), 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 = 4.8 Hz), 8.07 (1H, s).

[0322] (10) Methyl 1-((tert-butyldimethylsilyl)oxy)-4-(2-(5-oxo-9-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzofuro[3,2-e][1,4]diazepin-1-yl)ethyl) Cyclohexane-1-carboxylate

[0323] [ka]

[0324] Under ice cooling, 1-(2-(4-oxocyclohexyl)ethyl)-9-(trifluoromethyl) (tert-butyldimethylsilyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepin-5-one (600 mg, 1.52 mmol), 2-((tert-butyldimethylsilyl)oxy)malononitrile (448 mg, 2.28 mmol) Methanol (0.308 mL, 7.61 mmol) and 4-dimethylaminopyridine (0.372 g, 3.04 mmol) were added to the tetrahydrofuran (9 mL) solution, and the mixture was stirred for 2 hours. The temperature was raised to room temperature, and the mixture was stirred for another 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate. The organic layers were combined and washed with saturated brine. The organic layers were dried over sodium sulfate and then 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 obtain the title compound (0.373 g, 43% yield). Got it. 1 H-NMR (DMSO-D6) δ: 0.03 (6H, s), 0.85 (9H, s), 1.38-1.44 (3H, m), 1.63-1.68 (6 H, 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 = 4.8 Hz), 8.03 (1H, s).

[0325] (11) 1-(2-(4-((tert-butyldimethylsilyl)oxy)-4-(hydroxymethyl)cyclohexane (Ci)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepin-5-one

[0326] [ka]

[0327] Under ice cooling, the methyl 1-((tert-butyldimethylsilyl)oxy)-4-(2-(5-hydroxypropyl)methylsilyl)-4-(2-methyl-1-methyl-2 ... Tetrahydro-9-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzofuro[3,2-e][1,4]diazepin-1-yl)ethyl)cyclohexane-1-carboxylate (0.373 g, 0.656 mmol) A 1M lithium borohydride-tetrahydrofuran solution (1.31 mL, 1.31 mmol) was added dropwise to the tetrahydrofuran solution (3.7 mL), and the mixture was stirred at room temperature for 24 hours. After addition, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate and then 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%). 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 = 5.3 Hz), 3.30-3.32 (2H, m), 3.39-3.41 (2H, m), 3.53-3.57 (2H, m), 4.75 (1H, t, J = 5.3 Hz), 7.79-7.80 (2H, m), 8.00 (1H, t, J = 4.7 Hz), 8.04 (1H, s).

[0328] (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-ol hmm

[0329] [ka]

[0330] A solution of 1-(2-(4-((tert-butyldimethylsilyl)oxy)-4-(hydroxymethyl)cyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepin-5-one (90 mg, 0.166 mmol) obtained in (11) in tetrahydrofuran (0.9 mL) was added to a 1 M tetrabutylammonium fluoride-tetrahydrofuran solution (0.333 mL, 0.333 mmol). The mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by reversed-phase liquid chromatography (apparatus: Waters Prep System, column: XTERRA PrepMS C18 OBD TM The title compound (0.021 g, 30% yield) was obtained by purifying the 5 μm, 30x50 mm column using a gradient mixture of water (0.1% trifluoroacetic acid) and acetonitrile (0.1% trifluoroacetic acid) at room temperature, a flow rate of 40 mL / min, and a ratio of 90 / 10 (0 min) to 50 / 50 (8 min) to 0 / 100 (8.05 min). The relative configuration on the cyclohexane ring was determined by X-ray crystal structure analysis. 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 = 5.9 Hz), 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 = 5.9 Hz), 7.77-7.82 (2H, m), 8.00 (1H, t, J = 4.9 Hz), 8.06 (1H, br s). 1-(2-((1s,4s)-4-hydroxy-4-(hydroxymethyl)cyclohexane)-4-hydroxy-4-methylcyclohexane obtained by the same reaction as above (2,3-Dimethylhexyl)ethyl-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepin-5-one (50 mg) in a 2:1 mixture of toluene and N,N-dimethylformamide. The solvent (500 μL) was added and the mixture was stirred at room temperature for 1 week. A portion of the suspension was filtered and the resulting solid was dried. Drying the solution affords 1-(2-((1s,4s)-4-hydroxy-4-(hydroxymethyl)cyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazonium. Crystals of zepin-5-one were obtained.

[0331] [Production 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- Synthesis of 1-(2,2-difluoro-2-(4-hydroxycyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepin-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]diazepin-5-one (Example 107)

[0332] [ka]

[0333] (1) Ethyl 2-fluoro-2-(1,4-dioxaspiro[4,5]decan-8-ylidene)acetate

[0334] [ka]

[0335] Under ice cooling and argon atmosphere, N,N-dimethyl sodium hydride (60%) (0.141 g, 3.52 mmol) was added to To a solution of 1,4-dioxaspiro[4,5]decan-8-one (0.5 g, 3.20 mmol) in formamide (2.5 mL), 2-fluoro-2-phosphonoacetate triethyl (0.651 mL, 3.20 mmol) was added dropwise and stirred for 15 minutes. A solution of this in N,N-dimethylformamide (2.5 mL) was added dropwise and stirred for 1 hour. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were washed with water and saturated brine. The organic layer was 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%). 1 H-NMR (DMSO-D6) δ: 1.24 (3H, t, J = 7.1 Hz), 1.66-1.69 (4H, m), 2.43 (2H, td, J = 6.6, 2.4 Hz), 2.82 (2H, td, J = 6.5, 1.3 Hz), 3.90 (4H, s), 4.21 (2H, q, J = 7.1 Hz).

[0336] (2) Ethyl 2-fluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)acetate

[0337] [ka]

[0338] Ethyl 2-fluoro-2-(1,4-dioxaspiro[4,5]decan-8-ylidene)acetate obtained in (1) To a solution of acetate (0.569 g, 2.33 mmol) in ethyl acetate (5.7 mL) was added 10% palladium carbon (0.057 g), and the mixture was stirred at room temperature under normal hydrogen pressure for 6 hours. Insoluble matter was removed by filtration using Celite, and the filtrate was then diluted with toluene. The mixture was concentrated under reduced pressure under azeotropic ene distillation to give the title compound (0.583 g, yield 102%). 1H-NMR (DMSO-D6) δ: 1.22 (3H, t, J = 7.2 Hz), 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 = 7.1 Hz), 4.96 (1H, dd, J = 48.3, 4.2 Hz).

[0339] (3) Ethyl 2,2-difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)acetate

[0340] [ka]

[0341] Under an argon atmosphere, a solution of ethyl 2-fluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)acetate (0.574 g, 2.33 mmol) obtained in (2) in tetrahydrofuran (5.7 mL) and toluene (1.7 mL) was added to a 1 M sodium bistrimethylsilylamide-tetrahydrofuran solution at -78°C. The reaction mixture was stirred for 15 minutes. N-fluorobenzenesulfonimide (0.882 g, 2.80 mmol) was added and stirred for 2 hours. Triethylamine (0.65 mL, The solution was extracted with water and a mixed solvent of hexane / ethyl acetate (3 / 1). The extract was re-extracted with a mixed solvent of hexane / ethyl acetate = 3 / 1, and the combined organic layers were washed with saturated sodium bicarbonate. The extract was washed with aqueous sodium chloride and saturated brine. The organic layer was dried over sodium sulfate and then 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%). 1H-NMR (DMSO-D6) δ: 1.26 (3H, t, J = 7.1 Hz), 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 = 7.1 Hz).

[0342] (4) 2,2-Difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethan-1-ol

[0343] [ka]

[0344] Under argon flow and ice cooling, a solution of ethyl 2,2-difluoro-2-(1,4-dioxaspiro[4,5]decan-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 mixture, and the mixture was stirred at room temperature for 30 minutes. After filtering off the insoluble matter using Celite, The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 3 / 1 to 2 / 3) to obtain the title compound (0.236 g, yield 70%). 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, 6.0 Hz), 3.85 (4H, s), 5.42 (1H, t, J = 6.1 Hz).

[0345] (5) 2,2-Difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl trifluoromethanesulfonate

[0346] [ka]

[0347] Under ice cooling, trifluoromethanesulfonic anhydride (0.359 mL, 2.12 mmol) was added dropwise to a pyridine (1.9 mL) solution of 2,2-difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethan-1-ol (0.236 g, 1.06 mmol) obtained in (4), and the mixture was stirred for 30 minutes. Water was added to the reaction mixture, and then acetic acid was added. The organic layer was extracted with ethyl acetate, 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%). 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 = 14.2 Hz).

[0348] (6) 2-(2,2-difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl)isoindo Phosphorus-1,3-dione

[0349] [ka]

[0350] 2,2-Difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl acetate obtained in (5) Potassium phthalimide (0.212 g, 1.15 mmol) was added to a solution of trifluoromethanesulfonate (0.338 g, 0.954 mmol) in N,N-dimethylformamide (3.4 mL), and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane / ethyl acetate = 4 / 1 to 1 / 1) to obtain the title compound (0.270 g). The yield was 81%. 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 = 15.5 Hz), 7.87-7.94 (4H, m).

[0351] (7) 2,2-Difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethan-1-amine

[0352] [ka]

[0353] 2-(2,2-difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl)isoindoline-1,3-dione (0.270 g, 0.768 mmol) obtained in (6) was dissolved in ethanol (1.9 mL), tetrahydrofuran (1.2 mL), and 2-(2,2-difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl)isoindoline-1,3-dione (0.270 g, 0.768 mmol). To the mixture of ran (1.9 mL), hydrazine monohydrate (0.112 mL, 2.31 mmol) was added, and the mixture was heated at 60°C for 2 hours. Toluene (3.8 mL) was added, and the mixture was further stirred for 2 hours at 60° C. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure to obtain the title compound (0.180 g, yield 106%). 1H-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 = 15.3 Hz), 3.85 (4H, s).

[0354] (8) Methyl 3-((2,2-difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl)a (amino)-5-(trifluoromethyl)benzofuran-2-carboxylate

[0355] [ka]

[0356] 2,2-Difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethane-1- obtained in (7) To a solution of the amine (0.170 g, 0.768 mmol) in N,N-dimethylformamide (1.5 mL), 2-hydroxy-5-(trifluoromethyl)benzaldehyde (0.146 g, 0.768 mmol) was added and 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 and stirred at room temperature for 16 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layer was washed with water and saturated brine. The organic layer was 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, 76% yield). 1H-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, 7.1 Hz), 6.70 (1H, t, J = 6.9 Hz), 7.77 (1H, d, J = 8.8 Hz), 7.85 (1H, dd, J = 8.8, 1.6 Hz), 8.40 (1H, s).

[0357] (9) Methyl 3-(2-chloro-N-(2,2-difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl)acetamido)-5-(trifluoromethyl)benzofuran-2-carboxylate

[0358] [ka]

[0359] Under ice cooling, methyl 3-((2,2-difluoro-2-(1,4-dioxaspiro[4,5]deca) To a solution of (benzo-8-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (0.272 g, 0.587 mmol) and N,N-dimethylaniline (0.297 mL, 2.35 mmol) in dichloromethane (2.7 mL), chloroacetyl chloride (0.141 mL, 1.77 mmol) was added dropwise and stirred at room temperature for 16 hours. The mixture was extracted with 10% aqueous citric acid and hexane / ethyl acetate (1 / 1). The aqueous layer was re-extracted with hexane / ethyl acetate (1 / 1). The combined organic layer was washed with 10% aqueous citric acid, water, and saturated brine. The organic layer was 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, 93% yield). 1H-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 = 14.4 Hz), 4.33 (1H, d, J = 14.4 Hz), 4.45-4.57 (1H, m), 7.94 (1H, dd, J = 8.9, 1.7 Hz), 8.04 (1H, d, J = 8.8 Hz), 8.24 (1H, s).

[0360] (10) Methyl 3-((2-chloroethyl)(2,2-difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate

[0361] [ka]

[0362] Under argon atmosphere and ice cooling, methyl 3-(2-chloro-N-(2,2-difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl)acetamido)-5-(trifluoromethyl)acetamido obtained in (9) was Benzofuran-2-carboxylate (0.296 g, 0.548 mmol) dissolved in tetrahydrofuran (3.0 mL) To the solution, 0.91M borane-tetrahydrofuran complex (1.5mL, 1.37mmol) was added dropwise and stirred for 16 hours. Under ice cooling, 10% aqueous citric acid was added and stirred for 5 minutes. Ethyl acetate was added and extracted. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layer was washed with 10% aqueous sodium carbonate, water, and saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 4 / 1 to 3 / 2) to obtain the title compound (0.148 g, yield 51%). 1H-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 = 14.4 Hz), 7.86-7.92 (2H, m), 8.23 ​​(1H, s).

[0363] (11) Methyl 3-((2-azidoethyl)(2,2-difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate

[0364] [ka]

[0365] To a solution of methyl 3-((2-chloroethyl)(2,2-difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl)amino)-5-(trifluoromethyl)benzofuran-2-carboxylate (0.148 g, 0.281 mmol) obtained in (10) 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. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound (0.128 g, 85% yield). 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 = 5.8 Hz), 3.72 (2H, t, J = 5.8 Hz), 3.82-3.93 (6H, m), 4.00 (3H, s), 7.62 (1H, d, J = 8.8 Hz), 7.72 (1H, dd, J = 8.8, 1.6 Hz), 8.03 (1H, s).

[0366] (12) 1-(2,2-difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepin-5-one

[0367] [ka]

[0368] To a solution of methyl 3-((2-azidoethyl)(2,2-difluoro-2-(1,4-dioxaspiro[4,5]decan-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. The mixture was cooled, concentrated under reduced pressure using toluene as an azeotrope, and ethanol was added to the residue, followed by stirring for 1 hour. The solid was collected by filtration and dried under reduced pressure to obtain the title compound (0.070 g, yield 61%). 1H-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 = 16.8 Hz), 7.79-7.80 (2H, m), 8.09 (1H, t, J = 5.0 Hz), 8.14 (1H, s).

[0369] (13) 1-(2,2-difluoro-2-(4-oxocyclohexyl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepin-5-one

[0370] [ka]

[0371] 1-(2,2-difluoro-2-(1,4-dioxaspiro[4,5]decan-8-yl)ethyl)-9-(trifluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepine obtained in (12) A solution of 1-methyl-5-one (0.07 g, 0.148 mol) in acetic acid (0.56 mL) was added to 2N hydrochloric acid (0.14 mL) and heated at 80°C for 4 hours. The mixture was stirred at room temperature, and a 10% aqueous solution of dipotassium hydrogen phosphate was added, followed by extraction with ethyl acetate. The extract was re-extracted twice with ethyl acetate, and the combined organic layers were washed with saturated brine. After drying over sodium, the extract was concentrated under reduced pressure to give the title compound (0.056 g, yield 88%). 1H-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 = 16.8 Hz), 7.79-7.80 (2H, m), 8.10 (1H, t, J = 4.9 Hz), 8.16 (1H, s).

[0372] (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]diazepin-5-one ( Example 106), and 1-(2,2-difluoro-2-(4-hydroxycyclohexyl)ethyl)-9-(trifluoromethyl)- (fluoromethyl)-1,2,3,4-tetrahydro-5H-benzofuro[3,2-e][1,4]diazepin-5-one ( Example 107)

[0373] [ka]

[0374] 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-5- Sodium borohydride (0.009 g, 0.260 mmol) was added to a mixed solution of 1,2-dione (0.056 g, 0.130 mmol) in methanol (0.45 mL) and tetrahydrofuran (0.45 mL), and the mixture was stirred for 3 hours. Under ice-cooling, 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was analyzed by reversed-phase liquid chromatography (apparatus: Waters Prep System, column: XTERRA PrepMS C18 OBD TM The compound of Example 106 (0.028 g) was purified using a 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)). The compound of Example 106 (0.003 g, yield 50%) and the compound of Example 107 (0.003 g, yield 6%) were obtained. The relative configuration on the hexane ring was determined by two-dimensional NMR. =4 / 1 mixture.

[0375] (Compound of Example 106) 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 = 16.6 Hz), 4.61 (1H, d, J = 4.4 Hz), 7.77-7.80 (2H, m), 8.08 (1H, t, J = 4.3 Hz), 8.14 (1H, br s). (Compound of Example 107) 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 = 16.6 Hz), 4.38 (0.8H, d, J = 2.8 Hz), 4.61 (0.2H, d, J = 4.4 Hz), 7.77-7.80 (2H, m), 8.09 (1H, t, J = 4.7 Hz), 8.14-8.16 (1H, m).

[0376] The compounds of other Examples were obtained by the same methods as those in the above-mentioned Production Examples or Production Examples, or by using known methods as necessary. The structural formulas 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.

[0377] Test Example 1: Evaluation of human Pim-1 inhibitory activity The human Pim-1 inhibitory activity of the test compounds was evaluated as follows. (1) Purification of human Pim-1 Human Pim-1 gene inserted plasmid DNA (Kazusa DNA Research Institute, product number FXC11400) was prepared by PCR (polymerase chain reaction). A DNA fragment with a His-Tag sequence and translation termination sequence added to the 3' end of the human Pim-1 translation sequence was amplified using pGEx-6P-1 (GE Healthcare Japan, product number 27-4597-01) as a template. The amplified DNA fragment was fused with pGEx-6P-1 (GE Healthcare Japan, product number 27-4597-01) digested with BamHI and EcoRI using the In-Fusion HD Cloning Kit (Takara Bio Inc., product number 639649). Human Pim-1 expression plasmid DNA was isolated from Escherichia coli DH5α (TOYOBO, product number DNA-903) transformed with the resulting In-Fusion reaction product. The nucleotide sequence of Pim-1 cloned into the vector was determined by the dye terminator method using the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, product number 4337456). The determined sequence was compared with the human Pim-1 (Accession No. 10 ... n number NM_002648.3) This sequence had a His-Tag sequence and a translation termination sequence introduced at the 3' end of the translation region. Human Pim-1 expression plasmid E. coli BL21(DE3) (Merck KGaA, Cat. No. 6944 9-4) using 2xYT medium (Becton Dickinson, product number 244020). The cells were cultured 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 bD-1-thiogalactopyranoside. After incubation, the cells were harvested and suspended in homogenate buffer (50 mmol / L Tris-HCl (pH 7.5), 500 mmol / L NaCl, 1% Tween 20, cOmplete, EDTA-free (Roche, model number 1873580)). The cells were then disrupted using a Microfluidizer M-110H (Mizuho Industries Co., Ltd.). The precipitate was removed by centrifugation (10,100 × g, 10 minutes, 4°C), and the supernatant was filtered through a MILLEX-HV filter (0.45 μm) (Millipore, SLHV033RS) to remove cell debris. The filtrate was purified with Complete His-Tag Purification Resin (Roche Diagnostics, product number 05 893 682 0 0 1) was added to Equilibration Buffer-1 (50 mmol / L Tris-HCl (pH 7.5), 500 mmol / L NaCl, 1% Tween 20) containing 5 mmol / L imidazole, followed by 50 mmol / L After washing the column with Equilibration Buffer-1 containing imidazole, the column was washed with Equilibration Buffer-2 containing 150 mmol / L imidazole. GST-tagged human Pim-1 derived from pGEx-6P-1 was eluted with Buffer-1. Glutathione Sepharose 4B (GE Healthcare Japan, product number 17-0756-05) was added to the eluate, and the resulting solution was equilibrated. ation Buffer-2 (50 mmol / L Tris-HCl (pH7.5), 500 mmol / L NaCl, 0.05% Tween20, 0.5 mmol / L After washing the column with 20 units / mL PreScission Protease (GE Healthcare, model no. 27- The column was suspended in Equilibration Buffer-2 containing 0843-01. The column was stirred overnight at 4°C to carry out the protease reaction, and human Pim-1 from which the GST-Tag sequence had been cleaved was eluted. The eluate was applied to a gel filtration column (Superdex-2 00 30 / 100 GL (GE Healthcare, Model No. 17-5175-01)) and added to Equilibration Buffer-3 (50 mmol / L Tris-HCl (pH 7.5), 500 mmol / L NaCl, 0.05% Tween 20, 0.5 mmol / L EDTA, 2 mmol / L DTT, 10% Glycerol The eluate was used as a purified human Pim-1 fraction. Protein concentrations of purified human Pim-1 fractions were determined using a Pierce 660nm Protein The purified fraction was rapidly frozen using liquid nitrogen and then stored at -80°C. His-tagged human Pim-1 was detected by Western blotting using a mouse anti-His monoclonal antibody (WAKO, product number 011-23091). was detected.

[0378] (2) Evaluation of human Pim-1 inhibitory activity The Pim-1 inhibitory activity of the compound was calculated using the following solutions and ADP-Glo ​​Kinase. Protocol attached to the ase Assay (cat. V9102, Promega) The human Pim-1 purified enzyme used was prepared as described above.

[0379] (i) Preparation of solutions Kinase buffer (50 mmol / L HEPES (pH 7.5), 5 mmol / L MgCl2, 1 mmol / L DTT, 0.05% BSA) was prepared from HEPES (Jena Biosciences) The solution was prepared by dissolving ence), MgCl2 (Sigma-Aldrich), DTT (Sigma-Aldrich), and BSA (Sigma-Aldrich) in purified water. ATP solution (288 μmol / L) was prepared by dissolving 100 mmol / L ATP (Promega) in kinase buffer. Enzyme / substrate solution (0.2nmol / L Pim-1,30μmol / L Pim2tid e) was prepared by dissolving Pim-1 (described above) and Pim2tide (custom synthesized by GenScript USA, the same product as Millipore's PIM2tide cat. 12-542) in kinase buffer. A test compound solution (containing 12.5% ​​DMSO) was prepared by dissolving a DMSO solution of the test compound in kinase buffer. Vehicle solution (containing 12.5% ​​DMSO) was prepared by dissolving DMSO in kinase buffer.

[0380] (ii) Method Test compound solution or vehicle solution (control) was added to each well of a 384-well assay plate (Corning, 4513) at 1 μL / well, enzyme / substrate solution or kinase buffer solution (blank) at 2 μL / well, and ATP solution at 2 μL / well. After the enzyme reaction was carried out at room temperature for 45 minutes, 5 μL / well of ADP-Glo ​​Reagent (Promega) was added and mixed. After the reaction was carried out at room temperature for 60 minutes, 10 μL / well of Kinase Detection Reagent (Promega) was added and mixed. After the reaction was carried out at room temperature for 30 minutes, the luminescence intensity of each well was measured for 10 msec using the EnVidion multilabel plate reader (PerkinElmer).

[0381] (iii) Aggregation The luminescence intensity of each well was subtracted by the luminescence intensity of the blank well to obtain the data. The Pim-1 inhibition rate for each concentration of test compound was calculated using [Equation 1]. The IC50 (50% inhibitory concentration) of the test compound was calculated by fitting the inhibition rate for each concentration of test compound to a logistic curve. This was then converted to a Ki value using [Equation 2].

[0382]

number

[0383] A: Measurement value of vehicle solution (control) B: Measurement value of test compound

[0384]

number

[0385] E: Enzyme concentration S:ATP concentration Km: Michaelis-Menten constant

[0386] The results are shown in Tables 1-1 to 1-25.

[0387] [Table 1-1]

[0388] [Table 1-2]

[0389] [Table 1-3]

[0390] [Table 1-4]

[0391] Table 1-5

[0392] Table 1-6

[0393] Table 1-7

[0394] Table 1-8

[0395] Table 1-9

[0396] Table 1-10

[0397] Table 1-11

[0398] Table 1-12

[0399] Table 1-13

[0400] Table 1-14

[0401] Table 1-15

[0402] Table 1-16

[0403] Table 1-17

[0404] Table 1-18

[0405] Table 1-19

[0406] Table 1-20

[0407] Table 1-21

[0408] Table 1-22

[0409] Table 1-23

[0410] Table 1-24

[0411] Table 1-25

[0412] Examples of the formulation of the present invention include the following formulations: However, the present invention is not limited to these formulation examples.

[0413] Formulation Example 1: Capsule production 1) 30 mg of the compound of Example 1 2) Microcrystalline cellulose 10mg 3) Lactose 19mg 4) Magnesium stearate 1mg 1), 2), 3) and 4) are mixed and filled into a gelatin capsule.

[0414] Formulation Example 2: Tablet production 1) 10 g of the compound of Example 1 2) Lactose 50g 3) 15g corn starch 4) Carmellose calcium 44g 5) Magnesium stearate 1g The total amount of 1), 2), and 3) and 30 g of 4) are mixed with water, vacuum dried, and then sized. 14 g of 4) and 1 g of 5) are mixed with this sized powder and compressed into tablets using a tablet press. 1,000 tablets containing 10 mg of the compound of Example 1 per tablet are thus obtained. [Industrial Applicability]

[0415] The compound of formula [I] or a pharmaceutically acceptable salt thereof has Pim-1 inhibitory activity and may therefore be useful in the treatment or prevention of a disease selected from the group consisting of pulmonary arterial hypertension, cancer, psoriasis, and systemic lupus erythematosus.

Claims

1. A compound of formula [I] or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 [In the formula, Cy １ teeth, (1) C ３－７ cycloalkyl, (2) a 4- to 7-membered heterocycloalkyl containing, in addition to carbon atoms as ring-constituting atoms, one or two heteroatoms independently selected from the group consisting of oxygen and sulfur atoms (the sulfur atoms may be oxidized); (3) C ５－８ bridged cycloalkyl, (4) a 7- to 9-membered bridged heterocycloalkyl containing one oxygen atom in addition to carbon atoms as ring-constituting atoms; (5) C ７－１１ spirocycloalkyl, or (6) 7- to 11-membered spiroheterocycloalkyl containing 1 to 3 oxygen atoms in addition to carbon atoms as ring-constituting atoms. and m R １ are each independently (1) halogen, (2) hydroxy, (3) C １－６ alkyl {wherein the alkyl is (a) hydroxy, (b) C １－４ Alkoxy, (c) cyano, (d) OCOR １１ (where R １１ is phenyl), or (e) SO ２ R １２ (where R １２ 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 teeth, (a) hydroxy, or (b) NR １４ R １５ (where R １４ and R １５ are each independently hydrogen or C １－４ alkyl)}, (7) cyano, (8) Special Officer ２ R １６ (where R １６ is C １－４ alkyl), (9) C ３－４ cycloalkyl, wherein the cycloalkyl is optionally substituted with hydroxy; or (10) triazolyl or two R １ together to form oxo; n R ２ are each independently (1) halogen, or (2) C １－４ Alkoxy or two R ２ together with the carbon atoms to which they are attached, C ３－４ forming a cycloalkane; R ３ and R ４ are 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 attached, C ３－４ forming a cycloalkane; R ５ is hydrogen or C １－４ is alkyl; R ６ is C １－４ haloalkyl; R ７ is hydrogen or halogen; L is a linear C １－４ alkylene; m is 0, 1, 2, 3 or 4; n is 0, 1, 2 or 3.

2. R ５ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

3. 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is ethylene or trimethylene.

4. R ７ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

5. n R ２ are each independently a halogen or two R ２ together with the carbon atoms to which they are attached, C ３－４ 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, which forms a cycloalkane.

6. Formula [III]: 【Chemistry 2】 [In the formula, n1 R ２ａ are each independently a 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 are as defined in claim 1.

2. The compound of claim 1, wherein:

7. Cy １ but, (1) C ３－７ cycloalkyl, (2) a 4- to 7-membered heterocycloalkyl containing, in addition to carbon atoms as ring-constituting atoms, one or two heteroatoms independently selected from the group consisting of oxygen and sulfur atoms (the sulfur atoms may be oxidized); (3) C ７－１１ spirocycloalkyl, or (4) 7- to 11-membered spiroheterocycloalkyl containing 1 to 3 oxygen atoms in addition to carbon atoms as ring-constituting atoms.

7. The compound according to any one of claims 1 to 6, wherein:

8. R ６ but, (1) monofluoromethyl, (2) difluoromethyl, or (3) Trifluoromethyl 8. The compound according to any one of claims 1 to 7, wherein:

9. R ３ and R ４ However, each independently, (1) hydrogen, or (2) Methyl or R ３ and R ４ or a pharmaceutically acceptable salt thereof, of the compound of any one of claims 1 to 8, wherein: together with the carbon atom to which they are attached form a cyclopropane.

10. m R １ However, each independently, (1) halogen, (2) hydroxy, (3) C １－６ alkyl {wherein the alkyl is (a) hydroxy, (b) C １－４ Alkoxy, (c) cyano, or (d) SO ２ R １２ (where R １２ 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 teeth, (a) hydroxy, or (b) NR １４ R １５ (where R １４ and R １５ are each independently hydrogen or C １－４ alkyl)}, (7) cyano, (8) Special Officer ２ R １６ (where R １６ is C １－４ alkyl), or (9) C ３－４ cycloalkyl (wherein the cycloalkyl is optionally substituted with hydroxy); or two R １ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

11. The following formula: 【Transformation 3】 or a pharmaceutically acceptable salt thereof.

12. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

13. A Pim-1 inhibitor comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

14. A therapeutic or preventive agent for a disease selected from the group consisting of pulmonary arterial hypertension, cancer, psoriasis, and systemic lupus erythematosus, comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

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

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

17. Use of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for the manufacture of a Pim-1 inhibitor.

18. Use of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for the manufacture of an agent for the treatment or prevention of a disease selected from the group consisting of pulmonary arterial hypertension, cancer, psoriasis, and systemic lupus erythematosus.

19. 12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use in inhibiting Pim-1.

20. 12. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease selected from the group consisting of pulmonary arterial hypertension, cancer, psoriasis, and systemic lupus erythematosus.

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