Novel sulfonamide derivative

Abstract

The purpose of the present invention is to provide a novel compound which is useful for the suppression of TGF-β signaling, the treatment or prevention of fibrosis, obesity and diabetes, the suppression of cancer metastasis, and the enhancement of antitumor immunity.　Provided is a compound represented by formula (1) [wherein X represents an oxygen atom, a sulfur atom, or the like; Y represents a carbonyl group, a thiocarbonyl group, a sulfoxide group, or a sulfonyl group; R1 represents a lower alkyl group which may have a substituent, or the like; R2 represents a hydrogen atom, or the like; R3 represents a hydrogen atom, or the like; R4 represents a hydrogen atom, or the like; and R5 represents a hydrogen atom, or the like] or a salt thereof.

Description

Novel sulfonamide derivatives

[0001] The present invention relates to compounds that have TGF-β signaling inhibitory activity and are useful for treating or preventing fibrosis and the like, and uses thereof.

[0002] Transforming growth factor-β (TGF-β) is a cytokine with a wide range of physiological activities, including regulating cell proliferation and differentiation, repair and regeneration after tissue damage, and regulating the immune system and angiogenesis. TGF-β signaling is thought to occur via the following pathways 1) to 3). 1) After binding to type II and type I TGF-β receptors on the cell surface, TGF-β activates activin receptor-like kinase 5 (ALK5), a serine / threonine kinase domain of the type I receptor, and phosphorylates Smad2 / 3 in the cytoplasm. 2) The phosphorylated Smad2 / 3 forms a complex with Smad4 (phosphorylated Smad), translocates into the nucleus, and then binds to specific response elements on DNA, acting as a transcriptional activator. 3) As a result, physiological effects are exerted by inducing the expression of various response genes such as α-smooth muscle actin (α-SMA), collagen, tissue inhibitor of metalloprotease (TIMP), and connective tissue growth factor (CTGF) (Non-Patent Document 1). Here, nuclear localization of Smad2 / 3 is an essential process for TGF-β signaling, since TGF-β signaling is suppressed when a mutation is introduced into the nuclear localization signal of Smad3 (Non-Patent Document 2).

[0003] Abnormalities in the TGF-β signaling pathway are known to be involved in the onset and progression of various diseases, including organ fibrosis, obesity, diabetes, cancer metastasis, and suppression of antitumor immunity. Organ fibrosis is a disease in which excessive extracellular matrix accumulation in tissues due to chronic inflammation, etc., results in the replacement of normal tissue with the increased fibrous connective tissue, resulting in organ dysfunction. Progression of organ fibrosis can ultimately lead to organ failure and death. Examples of organ fibrosis include hepatic fibrosis, pulmonary fibrosis, renal fibrosis, dermal fibrosis, cardiac fibrosis, and pancreatic fibrosis. A common cause of organ fibrosis is thought to be an excessive repair response associated with chronic inflammation and tissue injury. Specifically, various physiologically active substances are secreted by immunocompetent cells mobilized to damaged tissues. TGF-β, in particular, promotes the proliferation of fibroblasts and hepatic stellate cells and their transformation into myofibroblast-like cells, as well as the production of large amounts of extracellular matrix such as collagen, resulting in the deposition of fibers. At the same time, the production of TIMPs, which are inhibitors of proteases that degrade extracellular matrix, inhibits fibrolysis, which is thought to result in the progression of fibrosis (Non-Patent Document 3).In addition, elevated TGF-β levels have been reported in patients with liver fibrosis, renal fibrosis, and pulmonary fibrosis compared to healthy individuals (Non-Patent Documents 4-6), and accelerated fibrosis has also been reported in animal models in which TGF-β was artificially overexpressed (Non-Patent Document 7).Accelerated TGF-β signaling is closely related to organ fibrosis.

[0004] Regarding the relationship between TGF-β and obesity or diabetes, it has been reported that, for example, the amount of TGF-β in serum is positively correlated with body mass index (Non-Patent Document 8), and that in high-fat diet-fed mice in which TGF-β signaling is blocked by deleting the Smad3 gene, body fat is reduced, glucose tolerance is improved, and fat accumulation in the liver is suppressed (Non-Patent Document 9).

[0005] Regarding the relationship between TGF-β and cancer metastasis, it has been reported that, for example, TGF-β acts on epithelial cancer cells and induces the expression of Snail and ZEB through the activation of Smad2 / 3, thereby causing the cells to acquire mesenchymal traits with high motility and invasiveness, promoting metastasis from the primary tumor to other organs, and at the same time enhancing resistance to anticancer drugs (Non-Patent Document 10). Regarding the relationship between TGF-β and antitumor immunity, it is known that TGF-β acts on receptors on naive T cells and induces the expression of Foxp3 through the activation of Smad2 / 3, thereby promoting differentiation into regulatory T cells (Non-Patent Document 11). It has been reported that these regulatory T cells suppress antitumor immunity mediated by cytotoxic T cells and the like in malignant tumors, promoting the progression of cancer (Non-Patent Document 12).

[0006] Therefore, it is believed that the above diseases can be prevented and treated by inhibiting the TGF-β signaling pathway, and it has been reported that TGF-β neutralizing antibodies and ALK5 inhibitors have the effect of improving fibrosis (Non-Patent Documents 13-14), that when an ALK5 inhibitor is administered to a mouse model transplanted with highly metastatic breast cancer cells, the migration and infiltration of cancer cells as well as metastasis to the lungs is suppressed (Non-Patent Document 15), and that when an immune checkpoint inhibitor and a TGF-β inhibitor antibody are administered in combination to a mouse model transplanted with malignant melanoma, urothelial cancer, or breast cancer cells, the anti-tumor immune response is enhanced and the tumors regress (Non-Patent Documents 16-17).

[0007] It has also been reported that certain sulfonamide derivatives are effective against fibrosis (Patent Documents 1 and 2) and have a TGF-β receptor binding inhibitory effect (Patent Document 3).

[0008] International Publication No. WO 2015 / 141775 International Publication No. WO 2017 / 146309 International Publication No. WO 2006 / 070984

[0009] Cell 113(6), 685-700, 2003Proc. Natl. Acad. Sci. USA97(14), 7853-7858, 2000Liver Int. 26(1), 8-22, 2006Hepatology 14, 269-273, 1991Curr. Opin. Nephrol. Hypertens.3, 446-452, 1994Arch. Bronconeumol. 42, 380-383, 2006Am. J. Physiol. 276(4), G1059-68, 1999Dis. Markers. 2009, 27, 23.Cell Metab. 2011, 14, 67.Ups. J. Med. Sci. 2012, 117, 143. J. Exp. Med. 2003, 198, 1875. Int. Immunol. 2016. 28, 401.Proc. Natl. Acad. Sci. USA 97(14), 8015-8020, 2000Br J Pharmacol. 145(2), 166-177, 2005Cancer Lett. 2014, 351, 72Cancer Immunol. Res. 2018, 6, 1459.Nature 2018, 554, 544.

[0010] The present invention relates to providing novel compounds that inhibit TGF-β signaling and are useful for treating or preventing fibrosis, obesity, and diabetes, inhibiting cancer metastasis, and enhancing anti-tumor immunity.

[0011] As a result of extensive research aimed at solving the above problems, the present inventors have found that a compound represented by the following formula (1) having a sulfonamide group at the 6-position potently inhibits TGF-β signaling by suppressing the nuclear localization of Smad2 / 3, thereby completing the present invention.

[0012] That is, the present invention relates to the following [1] to

[16] . [1] A compound represented by the following formula (1):

[0013]

[0014] [wherein X represents an oxygen atom, a sulfur atom, or a nitrogen atom which may have a substituent; Y represents a carbonyl group, a thiocarbonyl group, a sulfoxide group, or a sulfonyl group; R １ represents an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted 5- or 6-membered heteroaryl group, or an optionally substituted aralkyl group, R ２ represents a hydrogen atom, an optionally substituted lower alkyl group, a cyclo(lower alkyl) group, a heterocyclo(lower alkyl) group, an optionally substituted lower alkynyl group, an optionally substituted aralkyl group, or any of the groups shown in 1) to 5) below, 1) a group represented by the following formula (a):

[0015]

[0016] (In the formula, R a１ represents an optionally substituted lower alkyl group, a cyclo(lower alkyl) group, an optionally substituted lower alkenyl group, an optionally substituted lower alkoxy group, an optionally substituted aralkyloxy group, or an optionally substituted aryl group, and the wavy line represents the bonding site.) 2) A compound represented by the following formula (b):

[0017]

[0018] (wherein Z represents an oxygen atom or a sulfur atom, R ｂ１ and R ｂ２ may be the same or different and represent a hydrogen atom, an optionally substituted lower alkyl group, a cyclo-lower alkyl group, an optionally substituted aryl group, an optionally substituted 5- to 6-membered heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group, or R b１ and R b２ represents a 4- to 7-membered cyclic amino group which may contain a heteroatom, formed together with the adjacent nitrogen atom, and the wavy line represents the bonding site.) 3) A compound represented by the following formula (c):

[0019]

[0020] (In the formula, R ｃ１represents an optionally substituted lower alkyl group, a cyclolower alkyl group, a heterocyclolower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted aryl group, an optionally substituted 5- or 6-membered heteroaryl group, an optionally substituted aralkyl group, or an optionally substituted heteroaralkyl group, and the wavy line represents the bonding site. 4) A compound of the following formula (d):

[0021]

[0022] (In the formula, R ｄ１ and R ｄ２ may be the same or different and represent a hydrogen atom, an optionally substituted lower alkyl group, a cyclo-lower alkyl group or an optionally substituted aralkyl group, or R ｄ１ and R ｄ２ represents a cyclic amino group which may contain a 4- to 7-membered heteroatom, which is formed together with the adjacent nitrogen atom, and the wavy line represents the bonding site. ３ represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, or an aryl group; R ４ represents a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a cyclo(lower alkyl) group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxy group, an optionally substituted arylsulfoxy group, an optionally substituted lower alkoxy group, an amino group, a lower alkylamino group, a 4- to 7-membered cyclic amino group, a lower alkanoylamino group, a lower alkanoyl-lower alkylamino group, a lower alkoxycarbonylamino group, an aralkyloxycarbonylamino group, a lower alkoxycarbonyl group, a nitrile group, a carboxy group, a formyl group, an optionally substituted aryl group, an optionally substituted 5- to 6-membered heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; R ５ represents a hydrogen atom, a halogen atom or a lower alkoxy group, or a salt thereof.

[0023] [2] X is an oxygen atom, Y is a carbonyl group or a sulfonyl group, and R１ is an optionally substituted phenyl group, and R ２ is a group represented by formula (c), and R Ｃ１ is an optionally substituted phenyl group, and R ３ is a hydrogen atom, and R ４ is an optionally substituted phenyl group, and R ５ [3] The compound or salt thereof according to [1], wherein R is a hydrogen atom or a fluorine atom. １ is a phenyl group or C １－７ is a phenyl group substituted with an alkyl group, and R ２ R in formula (c) Ｃ１ is C １－７

[0023] The compound according to [2] or a salt thereof, wherein the phenyl group is substituted with an alkyl group. [4] A medicament comprising the compound according to [1] or a salt thereof, and a pharmaceutically acceptable carrier. [5] A preventive or therapeutic agent for fibrosis, comprising the compound according to [1] or a salt thereof as an active ingredient. [6] A TGF-β signaling inhibitor, comprising the compound according to [1] or a salt thereof as an active ingredient. [7] A nuclear localization inhibitor of Smad2 / 3, comprising the compound according to [1] or a salt thereof as an active ingredient. [8] Use of the compound according to [1] or a salt thereof for producing a preventive or therapeutic agent for fibrosis. [9] Use of the compound according to [1] or a salt thereof for producing a TGF-β signaling inhibitor.

[10] Use of the compound according to [1] or a salt thereof for producing a nuclear localization inhibitor of Smad2 / 3.

[11] The compound according to [1] or a salt thereof for use in preventing or treating fibrosis.

[12] The compound according to [1] or a salt thereof for use in inhibiting TGF-β signaling.

[13] The compound according to [1] or a salt thereof, which is used to inhibit the nuclear localization of Smad2 / 3.

[14] A method for preventing or treating fibrosis, which comprises administering the compound according to [1] or a salt thereof to a subject.

[15] A method for inhibiting TGF-β signaling, which comprises administering the compound according to [1] or a salt thereof to a subject.

[16] A method for inhibiting the nuclear localization of Smad2 / 3, which comprises administering the compound according to [1] or a salt thereof to a subject.

[0024] The compound of the present invention has a strong TGF-β signal inhibitory effect by suppressing the nuclear localization of Smad2 / 3, and can be used as a preventive or therapeutic drug for fibrosis in the liver, kidney, lung, skin, etc.

[0025] Smad2 / 3 nuclear localization inhibitory effect of the compound of the present invention.

[0026] The present invention will be described in detail below. In this specification, unless otherwise specified, the term "lower" means that the number of carbon atoms in the hydrocarbon portion of the group to which this term is attached is 1 to 12 if the hydrocarbon portion is linear, and 3 to 12 if the hydrocarbon portion is cyclic, and the linear hydrocarbon portion may be either a straight chain or a branched chain. In this specification, the number of carbon atoms in the hydrocarbon portion (x to y) is not limited to "C ｘ－ｙ ". Furthermore, "optionally having a substituent" means that a hydrogen atom of the target group may be substituted with another group, and the number of the substituents may be one or more, and when there are two or more substituents, the substituents may be the same or different. Furthermore, "optionally containing a heteroatom in the ring" means that one methylene chain on the target ring may be substituted with a heteroatom. The symbols used in formula (1) are explained below.

[0027] R １ Examples of the "lower alkyl group" represented by １－７ An alkyl group is preferred, and a C 1 group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a tert-butyl group is more preferred. １－４ Examples include alkyl groups, and more preferred are methyl, ethyl, isopropyl, and butyl groups.

[0028] Examples of the groups that can be substituted on the lower alkyl group include an amino group, １－３ Alkylamino group (e.g., methylamino group, ethylamino group, dimethylamino group, etc.), C １－３ Examples include alkanoylamino groups (for example, acetylamino groups, ethylcarbonylamino groups, etc.).

[0029] R １Examples of the "aryl group" represented by the formula (I) include C groups such as phenyl and naphthyl groups. ６－１０ An aryl group is exemplified, and a phenyl group is preferred. Examples of groups that can be substituted on the aryl group include a halogen atom (e.g., a fluorine atom), a hydroxy group, a C １－１２ Alkyl groups (e.g., methyl, ethyl, isopropyl, butyl, etc.), haloC １－３ Alkyl groups (e.g., difluoromethyl groups, trifluoromethyl groups, 2,2,2-trifluoroethyl groups, etc.), C １－１２ Examples include alkoxy groups (for example, methoxy, ethoxy, isopropoxy, butoxy, etc.), and nitro groups.

[0030] R １ Examples of the "5- to 6-membered heteroaryl group" represented by the formula (I) include a pyrrolyl group, a furyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, a pyrimidinyl group, a 2,4-dioxo-1,2,3,4-tetrahydromyrimidinyl group, and the like. Among these, a pyridyl group is preferred, and a (2-, 3-, 4-)pyridyl group is more preferred. Examples of groups that can be substituted on the heteroaryl group include C １－１２ Alkyl groups (e.g., methyl, ethyl, isopropyl, butyl, etc.), haloC １－３ Alkyl groups (e.g., difluoromethyl groups, trifluoromethyl groups, 2,2,2-trifluoroethyl groups, etc.), C １－１２ Alkoxy groups (e.g., methoxy, ethoxy, isopropoxy, butoxy, etc.), C １－１２ Examples include alkylamino groups (for example, methylamino, ethylamino, dimethylamino, etc.).

[0031] R １ The "aralkyl group" represented by the formula (I) includes a phenyl C group in which the aryl portion is a benzene ring and the alkyl portion is an alkyl group having 1 to 3 carbon atoms. １－３An alkyl group is preferred, and examples thereof include a benzyl group, a 1-phenylethyl group, a 2-phenylethyl group, a 1-phenylisopropyl group, and a 2-phenylisopropyl group, and more preferably a benzyl group. Examples of groups that can be substituted on the aralkyl group include groups that can be substituted on the aryl moiety of an aralkyl group, and examples thereof include a halogen atom (e.g., a fluorine atom), a C １－４ Alkyl groups (e.g., methyl, ethyl, isopropyl, butyl, etc.), haloC １－３ Examples include alkyl groups (for example, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, etc.).

[0032] R ２ Examples of the "lower alkyl group" represented by １－７ An alkyl group is preferred, and a C 1 group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a tert-butyl group is more preferred. １－４ Examples of the lower alkyl group include alkyl groups, and more preferably, methyl, ethyl, isopropyl, and butyl groups. Examples of the groups that can be substituted on the lower alkyl group include halogen atoms (e.g., fluorine atoms), hydroxy groups, C １－３ Alkoxy group (e.g., methoxy group, ethoxy group, etc.), cyclo C ３－７ Alkyl groups (e.g., cyclopropyl groups, cyclohexyl groups, etc.), amino groups, C １－３ Alkylamino group (e.g., methylamino group, ethylamino group, dimethylamino group, etc.), C １－３ Alkanoylamino groups (e.g., acetylamino groups, ethylcarbonylamino groups, etc.), 4- to 6-membered cyclic ether groups (e.g., oxetanyl groups, tetrahydrofuranyl groups, tetrahydropyranyl groups, dioxanyl groups, etc.), carboxy groups, C １－４ Examples include an alkoxycarbonyl group (for example, a methoxycarbonyl group, an ethoxycarbonyl group, etc.), a nitrile group, and the like.

[0033] R ２ The "cyclo lower alkyl group" represented by the following formula is cyclo C ３－７ An alkyl group is preferred, and a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group is more preferred.

[0034] R ２ The "heterocyclo lower alkyl group" represented by the following formula is a heterocyclo C having one or more heteroatoms such as a nitrogen atom or an oxygen atom in the ring. ２－６ Alkyl is preferred, and examples thereof include an azetidinyl group, an oxetanyl group, a pyrrolidinyl group, and a piperidinyl group, and preferred examples include a 3-azetidinyl group and a 3-oxetanyl group.

[0035] R ２ Examples of the "lower alkynyl group" represented by ２－４ An alkynyl group is preferred, and an ethynyl group is more preferred. Examples of groups that can be substituted on the lower alkynyl group include C １－７ Examples include alkyl groups (for example, methyl, ethyl, n-propyl, and n-butyl groups), alkoxycarbonyl groups (for example, methoxycarbonyl and ethoxycarbonyl groups), carboxy groups, phenyl groups, and triisopropylsilyl groups.

[0036] R ２ The "aralkyl group" represented by the formula (I) includes a phenyl C group in which the aryl portion is a benzene ring and the alkyl portion is an alkyl group having 1 to 3 carbon atoms. １－３ An alkyl group is preferred, and a benzyl group is preferred. Examples of groups that can be substituted on the aralkyl group include groups that can be substituted on the aryl moiety of an aralkyl group, such as a halogen atom (e.g., a fluorine atom), a C １－４ Alkyl groups (e.g., methyl, ethyl, isopropyl, butyl, etc.), haloC １－３ Examples include alkyl groups (for example, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, etc.).

[0037] In formula (a), R ａ１ Examples of the "lower alkyl group" represented by １－７ An alkyl group is preferred, and a C 1 group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a tert-butyl group is more preferred. １－４Examples of the lower alkyl group include alkyl groups, and more preferably methyl, ethyl, and isopropyl groups. Examples of the groups that can be substituted on the lower alkyl group include halogen atoms (e.g., fluorine atoms), hydroxy groups, C １－４ Alkoxy group (e.g., methoxy group, ethoxy group, etc.), cyclo C ３－７ Alkyl groups (e.g., cyclopropyl groups, cyclohexyl groups, etc.), amino groups, C １－４ Alkylamino group (e.g., methylamino group, ethylamino group, dimethylamino group, etc.), C １－３ Examples include alkanoylamino groups (eg, acetylamino, ethylcarbonylamino, etc.), and 4- to 6-membered cyclic ether groups (eg, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, etc.).

[0038] R ａ１ The "cyclo lower alkyl group" represented by the following formula is cyclo C ３－７ An alkyl group is preferred, and a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group is more preferred.

[0039] R ａ１ The "lower alkenyl group" represented by the formula (I) includes an aliphatic unsaturated hydrocarbon group having at least one carbon-carbon double bond, and ２－７ Alkenyl groups are preferred, and more preferred are vinyl groups, 1-propenyl groups, 2-methyl-1-propenyl groups, 1-methyl-1-propenyl groups, etc. Examples of groups that can be substituted on the lower alkenyl groups include halogen atoms (e.g., fluorine atoms, etc.), hydroxy groups, haloC １－３ Examples include alkyl groups (for example, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, etc.) and phenyl groups.

[0040] R ａ１ The "lower alkoxy group" represented by １－７ An alkyl group is preferred, and a C 1 group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a tert-butyl group is more preferred. １－４Examples of the lower alkoxy group include alkyl groups, and more preferably, methyl groups, ethyl groups, isopropyl groups, and tert-butyl groups. Examples of the group that can be substituted on the lower alkoxy group include halogen atoms (e.g., fluorine atoms), hydroxy groups, C １－３ Examples include alkoxy groups (for example, methoxy, ethoxy, and methoxymethoxy groups).

[0041] R ａ１ The "aralkyloxy group" represented by the formula: is a phenyl C group in which the aryl portion is a benzene ring and the alkyl portion is an alkoxy group having 1 to 3 carbon atoms. １－３ An alkoxy group is preferred, and a benzyloxy group is more preferred. Examples of groups that can be substituted on the aralkyloxy group include groups that can be substituted on the aryl moiety of the aralkyloxy group, such as a halogen atom (e.g., a fluorine atom), a hydroxy group, a C １－７ Examples include alkyl groups (for example, methyl, ethyl, isopropyl, and butyl groups).

[0042] R ａ１ Examples of the "aryl group" represented by the formula (I) include C groups such as phenyl and naphthyl groups. ６－１０ An aryl group is exemplified, and a phenyl group is preferred. Examples of groups that can be substituted on the aryl group include a halogen atom (e.g., a fluorine atom), a hydroxy group, a C １－７ Alkyl groups (e.g., methyl, ethyl, isopropyl, butyl, etc.), haloC １－３ Alkyl groups (e.g., difluoromethyl groups, trifluoromethyl groups, 2,2,2-trifluoroethyl groups, etc.), C １－7 Examples include alkoxy groups (for example, methoxy, ethoxy, isopropoxy, and butoxy groups).

[0043] In formula (b), R ｂ１ and R ｂ２ The "lower alkyl group" represented by R １ Examples of the group that can be substituted on the lower alkyl group include a halogen atom (e.g., a fluorine atom), C １－３ Alkoxy group (e.g., methoxy group, ethoxy group, etc.), cyclo C３－７ Alkyl groups (e.g., cyclopropyl groups, cyclohexyl groups, etc.), amino groups, C １－３ Alkylamino group (e.g., methylamino group, ethylamino group, dimethylamino group, etc.), C １－３ Alkanoylamino group (e.g., acetylamino group, ethylcarbonylamino group, etc.), carboxy group, C １－３ Examples include alkoxycarbonyl groups (for example, methoxycarbonyl groups, ethoxycarbonyl groups, etc.).

[0044] R ｂ１ and R ｂ２ The "cyclolower alkyl group" represented by R ａ１ Examples include those similar to those shown in

[0045] R ｂ１ and R ｂ２ Examples of the "optionally substituted aryl group", "optionally substituted 5- to 6-membered heteroaryl group", and "optionally substituted aralkyl group" represented by the formula １ Examples include those similar to those shown in

[0046] R ｂ１ and R ｂ２ The "heteroaralkyl group" represented by the formula (I) includes a 5- to 6-membered heteroaryl group in which the heteroaryl moiety is a 5- to 6-membered heteroaryl and the alkyl moiety is an alkyl group having 1 to 2 carbon atoms. １－２ An alkyl group is preferred, and as the 5- or 6-membered heteroaryl, a pyridyl group is preferred, and a (2-, 3-, or 4-)pyridyl group is more preferred. Examples of groups that can be substituted on the heteroaralkyl group include groups that can be substituted on the heteroaryl moiety of a heteroaralkyl group, such as C １－４ Alkyl groups (e.g., methyl, ethyl, isopropyl, butyl, etc.), haloC １－３ Examples thereof include alkyl groups.

[0047] R b１ and R b２Examples of the 4- to 7-membered cyclic amino group which may contain a heteroatom and which is formed together with the adjacent nitrogen atom include an azetidino group, a pyrrolidino group, a piperidino group, a piperazino group, and a morpholino group, and a morpholino group is preferred.

[0048] R ｂ１ and R ｂ２ represents an optionally substituted lower alkyl group, a cyclo-lower alkyl group, an optionally substituted aryl group, an optionally substituted 5- or 6-membered heteroaryl group, or R b１ and R b２ is preferably a 4- to 7-membered cyclic amino group which may contain a heteroatom, formed together with the adjacent nitrogen atom, and R b１ and R b２ Either one of them is C １－３ or an alkyl group or a phenyl group of R b１ and R b２ More preferably, together form a morpholino group.

[0049] In formula (c), R ｃ１ Examples of the "lower alkyl group" represented by １－７ An alkyl group is preferred, and a C 1 group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a tert-butyl group is more preferred. １－４ Examples of the lower alkyl group include alkyl groups, and more preferably methyl, ethyl, and isopropyl groups. Examples of the groups that can be substituted on the lower alkyl group include halogen atoms (e.g., fluorine atoms), hydroxy groups, C １－３ Alkoxy group (e.g., methoxy group, ethoxy group, etc.), cyclo C ３－７ Alkyl groups (e.g., cyclopropyl groups, cyclohexyl groups, etc.), amino groups, C １－３ Alkylamino groups (e.g., methylamino groups, ethylamino groups, dimethylamino groups, trimethylammonium groups, etc.), C １－３ Alkanoylamino groups (e.g., acetylamino groups, ethylcarbonylamino groups, etc.), 4- to 6-membered cyclic ether groups (e.g., oxetanyl groups, tetrahydrofuranyl groups, tetrahydropyranyl groups, dioxanyl groups, etc.), carboxy groups, C １－３Examples include an alkoxycarbonyl group (for example, a methoxycarbonyl group, an ethoxycarbonyl group, etc.), a 1,3-dioxoisoindolin-2-yl group, and a sulfonyl group (for example, a methanesulfonyl group, a toluenesulfonyl group, etc.).

[0050] R ｃ１ The "cyclo lower alkyl group" represented by the following formula is cyclo C ３－７ An alkyl group is preferred, and a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group is more preferred. ｃ１ The "heterocyclo lower alkyl" represented by the following formula is a heterocyclo C having one or more heteroatoms such as a nitrogen atom or an oxygen atom in the ring. ２－６ Alkyl is preferred, and examples thereof include an azetidinyl group, an oxetanyl group, a pyrrolidinyl group, and a piperidinyl group.

[0051] R ｃ１ The "lower alkenyl group" represented by C ２－７ Alkenyl groups are preferred, and more preferred are vinyl groups, 1-propenyl groups, isopropenyl groups, 2-methyl-1-propenyl groups, 1-methyl-1-propenyl groups, etc. Examples of groups that can be substituted on the lower alkenyl groups include halogen atoms (e.g., fluorine atoms, etc.), hydroxy groups, haloC １－３ Examples include alkyl groups (for example, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, etc.) and phenyl groups.

[0052] R ｃ１ Examples of the "aryl group" represented by the formula (I) include C groups such as phenyl and naphthyl groups. ６－１０ An aryl group is exemplified, and a phenyl group is preferred. Examples of groups that can be substituted on the aryl group include a halogen atom (e.g., a fluorine atom), a hydroxy group, a C １－１２ Alkyl groups (e.g., methyl, ethyl, isopropyl, butyl, etc.), haloC １－３alkyl group (for example, difluoromethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, etc.), C having as a substituent "a group selected from methylamino group, dimethylamino group, trimethylammonium group, N,O-dimethylamino group, N-methyl-N-hydroxyamino group, 1-piperidinyl group, 4-methylpiperazinyl group, 1-morpholino group, and methanesulfonyl group" １－４ Alkyl group, C as a substituent １－３ a vinyl group having an alkylsulfonyl group (e.g., a methanesulfonylethenyl group, etc.), C １－１２ Alkoxy groups (e.g., methoxy, ethoxy, isopropoxy, butoxy, butan-2-yloxy, 2-methylpropyloxy, etc.), and substituents such as amino, C １－４ Alkanoylamino group (for example, acetylamino group), 4-oxo-4-[2-(2-methoxyethoxy)ethylamino]butanoylamino group, 1 to 3 fluorine atoms, C １－４ Alkoxy group (e.g., methoxy group), 4-[2,2-dimethyl-1,3-dioxolan-4-yl] group, 1 to 3 hydroxy groups, C １－４ C having a group selected from an alkylamino group (e.g., a methylamino group), a 4-[2-(2-{5-[(3aR,6aS)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazolidin-4-yl]pentanamido}ethoxy) group, and a 4-(2-{2-[({3',6'-dihydroxy-3-oxo-3H -spiro[2-benzofuran-1,9'-xanthene]-5-yl}carbamothioyl)amino]ethoxy} group. １－３ Alkoxy group, amino group, C １－１２ Alkylamino group (for example, methylamino group, ethylamino group, dimethylamino group, etc.), N—C １－３ Alkyl-C １－５Alkoxycarbonylamino groups (e.g., N-methylmethoxycarbonylamino group, N-methyl-(2R,3R,4S,5R)-3,4,5,6-tetrahydroxyoxan-2-ylmethoxycarbonylamino group, N-methyl-(2S)-2-amino-2-carboxy-n-butoxycarbonylamino group, N-methyl-2-{[2-(2-methoxy)ethoxy]ethoxy}ethoxycarbonylamino group, N-methyl-(5-methyl-2-oxo-2H-1,3-dioxal-4-yl)methoxyamino group, etc.), N-(C １－３ alkyl)aryloxycarbonylamino group (for example, N-methyl-3-fluorophenoxycarbonyl amino group, (2S)-2-amino 2-carboxyethylphenoxycarbonylamino group, etc.), １－３ alkyl)-1-C １－３ a ureido group having an alkyl group (for example, a 3,3-diethyl-1-methylureido group), an N-(C １－３ alkyl) formylamino group (e.g., N-methylformylamino group, etc.), １－３ alkyl) groups and N-(C １－３ alkyl)-O-di(C １－３ a phosphorylamino group having a group selected from the group consisting of N-methylphosphorylamino, N-methyl-diethylphosphorylamino, and the like; １－３ Alkanoylamino group (for example, acetylamino group, ethylcarbonylamino group, etc.), nitrile group, nitro group, carboxy group, formyl group, hydroxyimino group, C as a substituent １－３ an imino group having an alkoxy group (e.g., a methoxyimino group), C １－４ Alkoxycarbonyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, etc.), １－３ alkyl) group, N-(hydroxy C １－３ alkyl) group and N,N-diC １－３ and an aminocarbonyl group having a group selected from alkyl groups (for example, a propargylaminocarbonyl group, an N,N-diethylaminocarbonyl group, a 2-hydroxyethylaminocarbonyl group, etc.), a 1-morpholinocarbonyl group, etc.

[0053] R ｃ１ Examples of the "5- to 6-membered heteroaryl group" represented by the formula (I) include a pyrrolyl group, a furyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, a pyrimidinyl group, and a 2,4-dioxo-1,2,3,4-tetrahydromyrimidinyl group. Among these, a 5- to 6-membered nitrogen-containing heteroaryl group such as a pyrazolyl group, an imidazolyl group, a pyridyl group, a pyrimidinyl group, and a 2,4-dioxo-1,2,3,4-tetrahydromyrimidinyl group is preferred, and a (3- or 4-)pyrazolyl group or a (2-, 3-, or 4-)pyridyl group is more preferred.

[0054] Examples of the groups that can be substituted on the 5- to 6-membered heteroaryl group include halogen atoms (e.g., fluorine atoms, chlorine atoms, etc.), hydroxy groups, C １－１２ Alkyl groups (e.g., methyl, ethyl, isopropyl, butyl, etc.), haloC １－３ Alkyl groups (e.g., difluoromethyl groups, trifluoromethyl groups, 2,2,2-trifluoroethyl groups, etc.), C １－１２ Alkoxy groups (e.g., methoxy groups, ethoxy groups, isopropoxy groups, butoxy groups, etc.), amino groups, C １－１２ Alkylamino group (e.g., methylamino group, ethylamino group, dimethylamino group, etc.), and substituents such as "hydroxy group, C １－３ Alkyl group and C １－４ an amino group which may have a substituent selected from "a group selected from an alkoxy group"; １－３ Alkoxy and C １－３ a 5- or 6-membered amino group (for example, a (3R)-methoxy-(4R)-dimethylaminopyrrolidinyl group, etc.) which may have a group selected from alkylamino groups, a nitrile group, a nitro group, a carboxy group, a formyl group, C １－４ Alkoxycarbonyl groups (for example, methoxycarbonyl groups, ethoxycarbonyl groups, etc.) and the like are included.

[0055] R ｃ１The "aralkyl group" represented by the formula (I) includes a phenyl C group in which the aryl portion is a benzene ring and the alkyl portion is an alkyl group having 1 to 3 carbon atoms. １－３ Alkyl groups are preferred, such as benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylisopropyl, and 2-phenylisopropyl groups, with benzyl groups being more preferred.

[0056] R ｃ１ The "heteroaralkyl group" represented by the formula (I) includes a 5- to 6-membered heteroaryl group in which the heteroaryl moiety is a 5- to 6-membered heteroaryl and the alkyl moiety is an alkyl group having 1 to 2 carbon atoms. １－２ An alkyl group is preferred, and as a 5- or 6-membered heteroaryl, a (2-, 3- or 4-)pyridyl group is more preferred.

[0057] Examples of the group that can be substituted on the aralkyl group or heteroaralkyl group include groups that can be substituted on the aryl moiety of the aralkyl group or heteroaralkyl group, such as a halogen atom (e.g., a fluorine atom), C １－３ Alkyl groups (e.g., methyl groups, ethyl groups, etc.), haloC １－３ Alkyl groups (e.g., difluoromethyl groups, trifluoromethyl groups, etc.), C １－３ Alkoxy groups (e.g., methoxy groups, ethoxy groups, isopropoxy groups, etc.), halo C １－３ Examples of the alkyl group include an alkoxy group (for example, a difluoromethoxy group, a trifluoromethoxy group, etc.), a hydroxyl group, a nitrile group, a nitro group, and an amino group.

[0058] R ｃ１ is preferably an optionally substituted lower alkyl group, a cyclo-lower alkyl group, or an optionally substituted aryl group, more preferably an optionally substituted phenyl group; C １－７ More preferably, it is a phenyl group substituted with an alkyl group.

[0059] In formula (d), R ｄ１ and R ｄ２ The "lower alkyl group" represented by R １Examples of the group that can be substituted on the lower alkyl group include a halogen atom (e.g., a fluorine atom), C １－３ Alkoxy group (e.g., methoxy group, ethoxy group, etc.), cyclo C ３－７ Alkyl groups (e.g., cyclopropyl groups, cyclohexyl groups, etc.), carboxy groups, C １－３ Alkoxycarbonyl groups (e.g., methoxycarbonyl groups, ethoxycarbonyl groups, etc.) are exemplified, and preferred are halogen atoms, C １－３ It is an alkoxy group.

[0060] R ｄ１ and R ｄ２ The "cyclolower alkyl group" represented by R ２ The same groups as those shown in the above can be mentioned, and a cyclopropyl group is more preferred.

[0061] R ｄ１ and R ｄ２ The "aralkyl group" represented by the formula (I) includes a phenyl C group in which the aryl portion is a benzene ring and the alkyl portion is an alkyl group having 1 to 3 carbon atoms. １－３ An alkyl group is preferred, and a 2-phenethyl group is more preferred. Examples of groups that can be substituted on the aralkyl group include groups that can be substituted on the aryl moiety of an aralkyl group, such as a halogen atom (e.g., a fluorine atom), a C １－４ Alkyl groups (e.g., methyl, ethyl, isopropyl, butyl, etc.), haloC １－３ Examples include alkyl groups (for example, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, etc.).

[0062] R ｄ１ and R ｄ２ Examples of the 4- to 7-membered cyclic amino group which may contain a heteroatom and which is formed together with the adjacent nitrogen atom include an azetidino group, a pyrrolidino group, a piperidino group, a piperazino group, and a morpholino group.

[0063] R ｄ１ and R ｄ２ is a lower alkyl group or a lower cycloalkyl group which may have a substituent, or R ｄ１ and R ｄ２is preferably a 4- to 7-membered cyclic amino group which may contain a heteroatom formed together with the adjacent nitrogen atom, and C １－３ alkyl group or R ｄ１ and R ｄ２ More preferably, together with the adjacent nitrogen atom form a morpholino group.

[0064] R ３ Examples of the "lower alkyl group" represented by １－７ An alkyl group is preferred, and a C 1 group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a tert-butyl group is more preferred. １－４ Examples include alkyl groups, and more preferably methyl groups.

[0065] R ３ The "cyclo lower alkyl group" represented by the following formula is cyclo C ３－７ An alkyl group is preferred, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, and a cyclopropyl group is more preferred.

[0066] R ３ Examples of the "aryl group" represented by the formula (I) include C groups such as phenyl and naphthyl groups. ６－１０ Examples include an aryl group, and a phenyl group is preferred.

[0067] R ３ is a hydrogen atom or C １－３ An alkyl group is preferred, and a hydrogen atom or a methyl group is more preferred.

[0068] R ４ Examples of the "halogen atom" represented by the formula include fluorine, chlorine, bromine, and iodine.

[0069] R ４ Examples of the "lower alkyl group" represented by １－７ An alkyl group is preferred, and a C 1 group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a tert-butyl group is more preferred. １－４Examples of the lower alkyl group include alkyl groups, and more preferably methyl, ethyl, and isopropyl groups. Examples of the groups that can be substituted on the lower alkyl group include halogen atoms (e.g., fluorine atoms), hydroxy groups, C １－３ Alkoxy group (e.g., methoxy group, ethoxy group, etc.), cyclo C ３－７ Alkyl groups (e.g., cyclopropyl groups, cyclohexyl groups, etc.), amino groups, C １－３ Alkylamino group (e.g., methylamino group, ethylamino group, dimethylamino group, etc.), C １－３ Examples include alkanoylamino groups (eg, acetylamino, ethylcarbonylamino, etc.), and 4- to 6-membered cyclic ether groups (eg, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, etc.).

[0070] R ４ The "cyclo lower alkyl group" represented by the following formula is cyclo C ３－７ An alkyl group is preferred, and a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group is more preferred.

[0071] R ４ The "lower alkenyl group" represented by C ２－４ Alkenyl groups are preferred, and more preferred are vinyl, allyl, and isopropenyl groups. Examples of groups that can be substituted on the lower alkenyl groups include C １－３ Examples of the alkyl group include an alkyl group (for example, a methyl group, an ethyl group, etc.), an alkoxycarbonyl group (for example, a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, etc.), a carboxy group, and a phenyl group.

[0072] R ４ Examples of the "lower alkynyl group" represented by ２－４ An alkynyl group is preferred, and an ethynyl group is more preferred. Examples of groups that can be substituted on the lower alkynyl group include C １－７Examples include alkyl groups (for example, methyl, ethyl, n-propyl, and n-butyl groups), alkoxycarbonyl groups (for example, methoxycarbonyl and ethoxycarbonyl groups), carboxy groups, phenyl groups, and triisopropylsilyl groups.

[0073] R ４ The "aryl group" of the arylsulfoxy group having the substituent represented by the formula (I) is a C group such as a phenyl group or a naphthyl group. ６－１０ An aryl group is exemplified, and a phenyl group is preferred. Groups that can be substituted on the aryl group include C １－３ Examples include alkyl groups (for example, methyl groups).

[0074] R ４ The "lower alkoxy group" represented by １－４ Examples of the lower alkoxy group include a methoxy group, an ethoxy group, an isopropoxy group, and a tert-butoxy group. Examples of the group that can be substituted on the lower alkoxy group include a halogen atom (e.g., a fluorine atom), a hydroxy group, a C １－３ Examples include alkoxy groups (for example, methoxy, ethoxy, and methoxymethoxy groups).

[0075] R ４ The "lower alkylamino group" represented by the following formula is a mono- or di-C １－３ An alkylamino group is preferred, and examples thereof include a methylamino group, a dimethylamino group, a methylethylamino group, and an isopropylamino group.

[0076] R ４ Examples of the "4- to 7-membered cyclic amino group" represented by the formula (I) include 4- to 7-membered saturated cyclic amino groups such as azetidino group, pyrrolidino group, piperidino group, hexahydroazepino group, morpholino group, and piperazino group.

[0077] R ４ The "lower alkanoylamino group" represented by C １－３ An alkanoylamino group is preferred, and an acetylamino group is more preferred.

[0078] R ４The "lower alkanoyl-lower alkylamino group" represented by the formula: N-C １－３ Alkanoyl-N-C １－３ An alkylamino group is preferred, and an N-acetyl-N-methylamino group is more preferred.

[0079] R ４ The "lower alkoxycarbonylamino group" represented by the formula: １－４ An alkoxycarbonylamino group is preferred, and a tert-butoxycarbonylamino group is more preferred.

[0080] R ４ The "aralkyloxycarbonylamino group" represented by the formula (I) is an aralkyloxycarbonylamino group having an aryl moiety of a benzene ring and an alkyl moiety of 1 to 3 carbon atoms (phenyl C １－３ Alkoxycarbonylamino group) is preferred, and a benzyloxycarbonylamino group is more preferred.

[0081] R ４ The "lower alkoxycarbonyl group" represented by the formula: １－３ An alkoxycarbonyl group is preferred, and a methoxycarbonyl group or an ethoxycarbonyl group is more preferred.

[0082] R ４ Examples of the "aryl group" represented by the formula (I) include C groups such as phenyl and naphthyl groups. ６－１０ Examples include an aryl group, and a phenyl group is preferred.

[0083] R ４ Examples of the "heteroaryl group" represented by the formula (I) include heteroaryl groups having 5 to 6 carbon atoms, such as furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and pyridyl groups, and among these, a 3-pyrazolyl group, a 2-furyl group, or a (2-, 3-, or 4-)pyridyl group is more preferred.

[0084] Examples of the groups that can be substituted on the aryl group or heteroaryl group include halogen atoms (e.g., fluorine atoms, chlorine atoms), hydroxy groups, C １－３ Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, etc.), haloC １－３Alkyl groups (e.g., difluoromethyl groups, trifluoromethyl groups, etc.), C １－３ Alkylamino C １－３ Alkyl groups (e.g., methylaminomethyl groups, dimethylaminomethyl groups, etc.), C １－４ Alkoxy groups (e.g., methoxy groups, ethoxy groups, isopropoxy groups, n-butoxy groups, etc.), and substituents such as amino groups, C 1－3 Alkanoylamino group (e.g., acetylamino group), N-methyl C 1－3 Alkanoylamino group (e.g., N-methylacetylamino group), C 1－3 alkylamino group (e.g., methylamino group), 4-oxo-4-[2-(2-methoxyethoxy)ethylamino]butanoylamino group, 1 to 3 fluorine atoms, C 1－3 C having a group selected from an alkoxy group (for example, a methoxy group), a 2,2-dimethyl-1,3-dioxolan-2-yl group, and a hydroxy group １－３ Alkoxy group (for example, 2,3-dihydroxypropyloxy group, etc.), amino group, C １－３ Alkylamino group (e.g., methylamino group, ethylamino group, dimethylamino group, etc.), C １－１８ Alkanoylamino group (for example, acetylamino group, ethylcarbonylamino group, octadecanoylamino group, etc.), N-(C １－３ alkyl)-C １－４ Alkyloxycarbonylamino group, nitrile group, nitro group, carboxy group, C １－４ Alkoxycarbonyl groups (e.g., methoxycarbonyl groups, ethoxycarbonyl groups, etc.), N,N-di(C １－３ alkyl)aminocarbonyl group (for example, N,N-diethylaminocarbonyl group, etc.), C optionally having a hydroxy group as a substituent １－３ Alkylaminocarbonyl group (for example, 2-hydroxyethylaminocarbonyl group), aminocarbonyl group, 1-morpholinocarbonyl group, C １－３ Examples include alkanoyloxy groups (such as acetoxy groups) and aralkyloxy groups (such as benzyloxy groups).

[0085] R ４ The "aralkyl group" represented by the formula (I) includes a phenyl C group in which the aryl portion is a benzene ring and the alkyl portion is an alkyl group having 1 to 3 carbon atoms. １－３ Alkyl groups are preferred, such as benzyl, 2-phenylpropan-2-yl, 1-phenylethyl, 2-phenylethyl, 1-phenylisopropyl, and 2-phenylisopropyl groups, with benzyl and 2-phenylethyl groups being more preferred.

[0086] R ４ The "heteroaralkyl group" represented by the formula (I) includes a 5- to 6-membered heteroaryl group in which the heteroaryl portion is a 5- to 6-membered heteroaryl and the alkyl portion is an alkyl group having 1 to 2 carbon atoms. １－２ An alkyl group is preferred, and a (2-, 3- or 4-)pyridyl group is more preferred.

[0087] Examples of the group that can be substituted on the aryl group or heteroaryl group include a halogen atom (e.g., a fluorine atom), C １－３ Alkyl groups (e.g., methyl groups, ethyl groups, etc.), hydroxy groups, C １－１０ Alkanoyloxy group (e.g., acetyl group, n-propanoyloxy group, n-octanoyloxy group, etc.), C having an ether bond as a substituent ３－７ Alkoxy groups (e.g., —O(CH ２ ) ２ OCH ３ , -O(CH ２ ) ２ O (CH ２ ) ２ OCH ３ , -O(CH ２ ) ２ O (CH ２ ) ２ O (CH ２ ) ２ OCH ３ , -O(CH ２ ) ３ OCH ３ , -O(CH ２ ) ３ O (CH ２ ) ３ OCH ３ , -OCH ２OCH ３ etc.) １－４ Alkanoyloxy group, C １－３ Examples include alkoxy groups (for example, methoxy, ethoxy, n-butoxy, etc.), phosphonooxymethoxy groups, and phosphonooxy groups.

[0088] R ４ represents an optionally substituted lower alkyl group, C ６－１０ An aryl group or an aralkyl group is preferred, and a phenyl group is more preferred.

[0089] R ５ The lower alkoxy group represented by the formula: １－３ Examples of the alkoxy group include a methoxy group, an ethoxy group, and an n-propoxy group.

[0090] Among the compounds represented by the formula (1) shown above, it is preferable that X is an oxygen atom, and Y is a carbonyl group or a sulfonyl group, and further, R １ is an optionally substituted phenyl group, preferably C １－７ a phenyl group optionally substituted with an alkyl group, more preferably a phenyl group, and R ２ is a group represented by formula (c), and preferably, in formula (c), R ｃ１ C which may have a substituent ６－１０ An aryl group, preferably an optionally substituted phenyl group, more preferably C １－７ is a phenyl group optionally substituted with an alkyl group, and R ３ is a hydrogen atom or a methyl group, preferably a hydrogen atom, and R ４ is an optionally substituted phenyl group, R ５ is preferably a hydrogen atom or a fluorine atom.

[0091] The compound of the present invention represented by formula (1) can form a salt with an acidic or basic compound, and these salts are also included in the compounds of the present invention.

[0092] The compound of the present invention represented by formula (1) can form a base addition salt with an acidic moiety in the compound (for example, but not limited to, a carboxylic acid). Examples of the base addition salt include (A) salts with alkali metals such as sodium and potassium, (B) salts with alkaline earth metals such as calcium and magnesium, (C) ammonium salts, (D) salts with nitrogen-containing organic bases such as triethylamine, pyridine, N-methylmorpholine, dimethylamine, 2-aminoethane-1-ol, diisopropylethylamine, and 1,1,3,3-tetramethylguanidine, and (E) salts with basic amino acids such as arginine and lysine.

[0093] The compound of the present invention represented by formula (1) can form an acid addition salt with a basic moiety in the compound (e.g., but not limited to, a pyridine or amino group). Examples of the acid addition salt include (A) salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., (B) salts with carboxylic acids such as acetic acid, citric acid, benzoic acid, etc., (C) salts with vinylic carboxylic acids such as Meldrum's acid, ascorbic acid, etc., (D) salts with sulfonic acids such as paratoluenesulfonic acid, 10-camphorsulfonic acid, trifluoromethanesulfonic acid, etc., and (E) salts with acidic amino acids such as aspartic acid, glutamic acid, etc.

[0094] The compound of formula (1) of the present invention can exist not only in an unsolvated form but also as a hydrate or solvate. Therefore, all crystalline forms and hydrates or solvates thereof are included as part of the present invention.

[0095] The compounds of the present invention represented by formula (1) may exist in their tautomeric forms (for example, keto-enol tautomers, etc.), and all tautomeric forms are encompassed within the scope of the present invention.

[0096] The compound of the present invention represented by formula (1) may exist as stereoisomers (enantiomers, diastereomers, etc.). Accordingly, all stereoisomers are included as part of the present invention. Furthermore, each stereoisomer of the sulfonamide derivative of the present invention may exist, for example, substantially pure, free from other isomers, or as a mixture, for example, a racemate.

[0097] The compound of the present invention represented by formula (1) can exist as a geometric isomer (E or Z), and both geometric isomers are encompassed in the compound of the present invention.

[0098] The compound of the present invention represented by formula (1) can basically be produced by the following methods of steps 1 to 8, and can be produced by any method suitable for the type of substituents, etc., after appropriate modification.

[0099] (Step 1)

[0100] That is, compound 1 is carbamoylated to give compound 2, which is then converted to compound 3 by Newman-Quart rearrangement, and then the aldehyde 4 can be obtained by hydrolysis.

[0101] Compound 1 is converted to compound 2 with the corresponding thiocarbonyl chloride or the like in a suitable solvent in the presence of a basic compound. The solvent used for the thiocarbamoylation may be any solvent that does not affect the reaction, including, for example, esters (e.g., ethyl acetate, butyl acetate, etc.), ethers (e.g., diethyl ether, tetrahydrofuran, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), alcohols (e.g., methanol, ethanol, etc.), water, or a mixture thereof. Examples of basic compounds used in this reaction include organic bases such as triethylamine, pyridine, N-methylpyrrolidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), etc., with DABCO and triethylamine being more preferred. The reaction is generally carried out at a temperature of from -20°C to 50°C, preferably from 0°C to 20°C, and the reaction time is generally from several minutes to 48 hours, preferably from 1 to 24 hours.

[0102] Compound 2 is converted to compound 3 by heating in a suitable solvent or in the absence of a solvent. This Newman-Quart rearrangement can be carried out with reference to J. Org. Chem. 1966, 31, 12, 3980-3984. That is, any solvent that does not affect the reaction may be used, and examples thereof include polar solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone, and aromatic hydrocarbons such as toluene and xylene. This reaction is generally carried out at 100°C to 300°C, preferably 100°C to 200°C, and the reaction time is generally 1 hour to 48 hours, preferably 12 to 24 hours.

[0103] Compound 3 is converted to compound 4 by alkaline hydrolysis in an appropriate solvent. For example, a commonly used hydrolysis reaction can be applied, and the reaction can be carried out using an inorganic base such as sodium hydroxide or potassium hydroxide in an alcoholic solution. This reaction is usually carried out at 0 to 150°C, preferably room temperature to 100°C, for a reaction time of usually 10 minutes to 48 hours.

[0104] (Step 2)

[0105] [wherein X is an oxygen atom or a sulfur atom, Y is a carbonyl group or a sulfonyl group, L is a １ represents a functional group that easily leaves, such as a halogen atom, and R ３ , R ４ , R ５ indicates the same as above.]

[0106] That is, compound 5 can be condensed with compound 6 and then subjected to cyclization conditions to give compound 8.

[0107] Alternatively, compound 5 can be reacted with compound 7 and then subjected to cyclization conditions to give compound 8.

[0108] Compound 5 can be converted to compound 8 by the method described in the following literature or a method similar thereto: 1) J. Med. Chem. 1964, 7, 446. 2) Synth. Commun. 1999, 29, 1451. 3) Journal of Chemical Research 2006, 688. 4) Tetrahedron Lett. 2007, 48, 5077. 5) Tetrahedron Lett. 2012, 53, 4422. 6) Synlett 2017, 28, 825. 7) Bioorganic and Medicinal Chemistry. 2015, 23, 12, 2895. 8) Tetrahedron, 2015, 71, 5, 863. 9) Tetrahedron, 2012, 68, 5541. 10) Chem Med Chem. 2017, 12, 1578. 11) Letters in drug design and discovery, 2013, 10, 410. 12) Bioorganic and Medicinal Chemistry. 2020, 28. 13) Journal of Medicinal Chemistry. 2015, 58, 3975.

[0109] (Step 3)

[0110] [In the formula, L １ , R １ , R ３ , R ４ indicates the same as above.]

[0111] That is, compound 8 is subjected to reduction conditions to give compound 9, which is then reacted with sulfonyl halide 10 to give compound 12 in one step. Alternatively, compound 9 can be reacted with twice the amount of sulfonyl halide 10 to give compound 11, which can then be monodesulfonylated to give compound 12.

[0112] Compound 8 is converted to compound 9 by catalytic reduction using a heterogeneous catalyst or reduction using a metal and an acid in an appropriate solvent. The solvent used in catalytic reduction using a heterogeneous catalyst may be any solvent that does not affect the reaction, including esters (e.g., ethyl acetate, butyl acetate, etc.), ethers (e.g., diethyl ether, tetrahydrofuran, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), alcohols (e.g., methanol, ethanol, etc.), and water, or a mixture thereof. Metal catalysts used include palladium, platinum, nickel, rhodium, etc., with palladium being preferred. This reaction is typically carried out at room temperature to 80°C, preferably room temperature to 50°C, and the reaction time is typically several minutes to 48 hours, preferably 1 to 24 hours. This reaction may also be carried out in the presence of an acid such as hydrochloric acid or a carboxylic acid. The solvent used in the reduction with a metal and an acid may be any solvent that does not affect the reaction, and examples thereof include ethers (e.g., diethyl ether, tetrahydrofuran, etc.), alcohols (e.g., methanol, ethanol, etc.), water, or a mixture thereof. Examples of the metal used include iron, tin, zinc, etc., with iron being preferred. Examples of the acid used include hydrochloric acid, acetic acid, ammonium chloride, etc. This reaction is usually carried out at room temperature to 100°C, preferably 50°C to 80°C, and the reaction time is usually from a few minutes to 24 hours, preferably 30 minutes to 12 hours.

[0113] The synthesis of compound 12 by monosulfonylation of compound 9 is carried out in a suitable solvent in the presence of a basic compound. Any solvent that does not interfere with the reaction may be used in this reaction, including aromatic hydrocarbons (toluene, xylene, etc.), ethers (e.g., diethyl ether, tetrahydrofuran, etc.), and halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), with halogenated hydrocarbons being preferred. Examples of basic compounds used in this reaction include organic bases such as triethylamine, pyridine, N-methylpyrrolidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO), with pyridine being more preferred. The amount of compound 10 used is preferably at least equimolar relative to compound 9, particularly about 1 to 3 times the molar amount. The reaction is generally carried out at 0 to 80°C, preferably room temperature to 50°C, and the reaction time is generally from several minutes to 48 hours, preferably from 1 to 24 hours.

[0114] The synthesis of compound 11 by sulfonylation of compound 9 is carried out in a suitable solvent in the presence of a basic compound. Any solvent that does not affect the reaction may be used, including aromatic hydrocarbons (e.g., toluene, xylene, etc.), ethers (e.g., diethyl ether, tetrahydrofuran, etc.), and halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), with halogenated hydrocarbons being preferred. Examples of basic compounds used in this reaction include organic bases such as triethylamine, pyridine, N-methylpyrrolidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO), with triethylamine being more preferred. The amount of compound 10 used is preferably at least 2 times the molar amount of compound 9, particularly about 2 to 5 times the molar amount. This reaction is usually carried out at 0 to 100°C, preferably room temperature to 80°C, for a reaction time of usually several minutes to 48 hours, preferably 1 to 24 hours. This reaction may also be carried out in the presence of an activating agent such as N,N-dimethyl-4-aminopyridine.

[0115] Monodesulfonylation of compound 11 is carried out in a suitable solvent in the presence of tetrabutylammonium fluoride according to the report by Yasuhara et al. (Chem. Pharm. Bull. 1999, 47, 809.). Any solvent that does not interfere with the reaction may be used in this reaction, including ethers (e.g., diethyl ether, tetrahydrofuran, etc.) and halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), with ethers being preferred. The amount of solvent used is not particularly limited, but may be 1 to 300 times (v / w) the amount of compound 11. This reaction is generally carried out at 0 to 80°C, preferably room temperature to 50°C, and the reaction time is generally several minutes to 24 hours, preferably 30 minutes to 12 hours.

[0116] (Step 4)

[0117] [In the formula, R １ , R ３ , R ４ indicates the same as above.]

[0118] The thiocarbonylation of compound 13 is carried out in a suitable solvent in the presence of Lawesson's reagent. The solvent used in this reaction may be any solvent that does not interfere with the reaction, including ethers (e.g., diethyl ether, tetrahydrofuran, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), benzene, and toluene, with toluene being preferred. The amount of solvent used is not particularly limited, but may be 1 to 300 times (v / w) the amount of compound 13. This reaction is generally carried out at 0 to 150°C, preferably 80 to 120°C, and the reaction time is generally several minutes to 3 days, preferably 12 hours to 1 day.

[0119] (Step 5)

[0120] [In the formula, L ２ represents a halogen atom, a mesylate group, a tosylate group, a triflate group, a lower alkoxy group, or an aryloxy group; R １ , R ２ , R３ , R ４ indicates the same as above.]

[0121] That is, compound 17 can be obtained by carrying out a substitution reaction between compound 15 and compound 16.

[0122] Here, L ２ As the "halogen atom" represented by the formula (I), a chlorine atom, a bromine atom, or an iodine atom is preferred. As the "lower alkoxy group", a tert-butoxy group is preferred. As the "aryloxy group", a pentafluorophenyloxy group is preferred.

[0123] The solvent used in this reaction may be any solvent that does not affect the reaction, and preferred are ethers (e.g., diethyl ether, tetrahydrofuran, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), and aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.).

[0124] This reaction is preferably carried out in the presence of a basic compound. Examples of basic compounds include metal hydrides such as sodium hydride and potassium hydride, inorganic bases such as sodium hydroxide and potassium carbonate, alkoxides such as sodium methoxide and potassium tert-butoxide, and organic bases such as triethylamine, pyridine, N-methylpyrrolidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO). Potassium carbonate or triethylamine is preferred. The amount of compound 16 used is preferably at least equimolar relative to compound 15, particularly about 1 to 5 times the molar amount. The amount of the basic compound used is preferably at least equimolar relative to compound 5, particularly about 1 to 10 times the molar amount. This reaction is typically carried out at 0 to 100°C, preferably room temperature to 80°C, and the reaction time is typically from several minutes to 48 hours, preferably 1 to 24 hours. This reaction may also be carried out in the presence of an activator such as N,N-dimethyl-4-aminopyridine or tetrabutylammonium iodide.

[0125] In addition, among Compound 17, R２ When is a group represented by formula (b), it can be produced by any method, but an example is as follows: (Step 6)

[0126] [wherein A represents an oxygen atom or a sulfur atom, L ３ and L ４ may be the same or different and represent a halogen atom, a halo-lower alkoxy group, an aryloxy group, or an imidazolyl group; R １ , R ３ , R ｂ１ , R ｂ２ indicates the same as above.]

[0127] That is, after preparing the reaction intermediate 20 from the compounds 18 and 19, the reaction intermediate 20 can be subjected to a substitution reaction with the compound 21 without purification or isolation to obtain the compound 22. The reaction intermediate 20 can also be purified and isolated.

[0128] Here, L ３ and L ４ The "halogen atom" represented by the formula (I) is preferably a chlorine atom. The "halo lower alkoxy group" is preferably a trichloromethyl group or a 1,1,1-trichloroethyl group. The "aryloxy group" is preferably a 4-nitrophenyloxy group.

[0129] The solvent used in this reaction may be any solvent that does not affect the reaction, and examples thereof include aromatic hydrocarbons (toluene, xylene, etc.), ethers (e.g., diethyl ether, tetrahydrofuran, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), and aprotic polar solvents (e.g., N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc.).

[0130] This reaction is preferably carried out in the presence of a basic compound. Examples of basic compounds include metal hydrides such as sodium hydride and potassium hydride, inorganic bases such as sodium hydroxide and potassium carbonate, alkoxides such as sodium methoxide and potassium tert-butoxide, and organic bases such as triethylamine, pyridine, N-methylpyrrolidine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO). Sodium hydride, potassium carbonate, triethylamine, and DBU are preferred. The amount of compound 19 used is preferably at least equimolar relative to compound 18, particularly about 1 to 5 times the molar amount. The amount of the basic compound used is preferably at least equimolar relative to compound 18, particularly about 2 to 10 times the molar amount. This reaction is typically carried out at −20 to 120° C., preferably 0 to 80° C., and the reaction time is typically from several minutes to 48 hours, preferably 1 to 24 hours.

[0131] (Step 7)

[0132] [wherein Z represents a halogen atom, L ５ represents a hydrogen atom, a halogen atom or a boryl group, preferably a boryl group; L ６ represents a halogen atom or a triflate group, and R ４ is a hydrogen atom, R 1 , R ２ , R ３ indicates the same as above.]

[0133] That is, compound 8a is halogenated to give compound 23, and compound 24 is then obtained from this in accordance with steps 3-1 and 3-3, followed by a coupling reaction with compound 25 in the presence of a transition metal catalyst to give compound 28. In a separate report, compound 24 is borylated to give compound 26, and then a coupling reaction with compound 27 in the presence of a transition metal catalyst to give compound 28.

[0134] Here, the "halogen atom" represented by Z is preferably a bromine or iodine atom. ５The "boryl group" represented by the formula (I) is preferably a dihydroxyboryl group, a pinacolboryl group, or a catecholboryl group. ６ Examples of the "halogen atom" represented by the formula (I) include a chlorine atom, a bromine atom, and an iodine atom.

[0135] The solvent used in the halogenation of compound 8a may be any solvent that does not affect the reaction, and aprotic polar solvents (e.g., N,N-dimethylformamide, acetonitrile, etc.) and halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.) are preferred.

[0136] Examples of halogenating agents include halogen molecules, a combination of N-halosuccinimide and a strong organic acid such as paratoluenesulfonic acid, and a combination of hydrohalic acid and Oxone (registered trademark of Du Pont), with a combination of hydrohalic acid and Oxone (registered trademark of Du Pont) being preferred. The amount of halogenating agent used is equimolar or more, particularly about 1 to 5 times the molar amount of compound 8a. This reaction is typically carried out at 0 to 100°C, preferably room temperature to 80°C, and the reaction time is typically several minutes to 24 hours, preferably 30 minutes to 12 hours.

[0137] Compound 23 can be converted to compound 24 by following step 3 above.

[0138] For the synthesis of compound 28 by the coupling reaction of compound 24, Suzuki-Miyaura cross-coupling reaction, Heck reaction, Sonogashira coupling reaction, Buchwald-Hartwig cross-coupling reaction, etc. may be used.

[0139] The solvent used in this reaction may be any solvent that does not affect the reaction, and examples thereof include aromatic hydrocarbons (e.g., toluene, xylene, etc.), ethers (e.g., tetrahydrofuran, 1,4-dioxane, etc.), aprotic polar solvents (e.g., N,N-dimethylformamide, acetonitrile, etc.), and water, or a mixture of these solvents.

[0140] Examples of transition metal catalysts include palladium catalysts such as palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tert-butylphosphine)palladium(0), and bis(diphenylphosphinoferrocene)dichloropalladium(II), and copper catalysts such as copper(I) iodide. These may be used alone or in combination of two or more. In the case of the Sonogashira reaction, the synthesis may be carried out in the presence of copper iodide. The amount of transition metal catalyst used may be 0.005 to 1 mole per mole of compound 24.

[0141] This reaction may be carried out by adding a phosphine compound. Examples of the phosphine compound include tri(tert-butyl)phosphine, tri(cyclohexyl)phosphine, tri(2-furyl)phosphine, and diphenylphosphinoferrocene, and preferably tri(tert-butyl)phosphine. The amount of the phosphine compound used may be 0.01 to 1 mole per mole of Compound 27.

[0142] This reaction is preferably carried out in the presence of a basic compound. Examples of basic compounds include inorganic bases such as potassium carbonate, cesium carbonate, and potassium phosphate; alkoxides such as sodium methoxide and potassium tert-butoxide; metal fluorides such as sodium fluoride and cesium fluoride; and organic bases such as triethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene. Potassium carbonate, potassium tert-butoxide, cesium fluoride, and triethylamine are preferred. The amount of basic compound used is equimolar or more relative to compound 24, particularly about 1 to 5 times the molar amount. This reaction is typically carried out at 0 to 150°C, preferably room temperature to 120°C, and the reaction time is typically several minutes to 48 hours, preferably 1 to 24 hours. This reaction is also preferably carried out under an inert gas atmosphere such as nitrogen or argon.

[0143] The solvent used in the synthesis of compound 26 by borylation of compound 24 may be any solvent that does not affect the reaction, and examples thereof include aromatic hydrocarbons (e.g., toluene, xylene, etc.), ethers (e.g., tetrahydrofuran, 1,4-dioxane, etc.), aprotic polar solvents (e.g., N,N-dimethylformamide, acetonitrile, etc.), and water, or a mixture thereof.

[0144] In this reaction, it is desirable to use tetrahydroxydiboron or a diboronic acid ester as the borylation agent. Examples of diboronic acid esters that can be used include bis(pinacolato)diboron and bis(catecholate)diboron. The amount of the borylation agent used is preferably at least equimolar, particularly about 1 to 5 times the molar amount of compound 24.

[0145] This reaction desirably uses a transition metal catalyst. Examples of the transition metal catalyst include palladium catalysts such as palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tert-butylphosphine)palladium(0), and bis(diphenylphosphinoferrocene)dichloropalladium(II). These may be used alone or in combination of two or more. The amount of the transition metal catalyst used may be 0.005 to 1 mole per mole of compound 24.

[0146] This reaction may be carried out by adding a phosphine compound. Examples of the phosphine compound include tri(tert-butyl)phosphine, tri(cyclohexyl)phosphine, tri(2-furyl)phosphine, and diphenylphosphinoferrocene, and preferably tri(tert-butyl)phosphine. The amount of the phosphine compound used may be 0.01 to 1 mole per mole of compound 24.

[0147] This reaction is preferably carried out in the presence of a basic compound. Examples of basic compounds include inorganic bases such as potassium carbonate, cesium carbonate, and potassium phosphate; alkoxides such as sodium methoxide and potassium tert-butoxide; metal fluorides such as sodium fluoride and cesium fluoride; and organic bases such as triethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene. Potassium carbonate, potassium tert-butoxide, cesium fluoride, and triethylamine are preferred. The amount of basic compound used is equimolar or more relative to compound 24, particularly about 1 to 5 times the molar amount. This reaction is typically carried out at 0 to 150°C, preferably room temperature to 120°C, and the reaction time is typically several minutes to 48 hours, preferably 1 to 24 hours. This reaction is also preferably carried out under an inert gas atmosphere such as nitrogen or argon.

[0148] As an alternative to this borylation, compound 26 may be synthesized by reacting with a boronic acid ester or diboronic acid ester in the presence of a strong base compound.

[0149] The solvent to be used may be any solvent that does not affect the reaction, and examples thereof include hydrocarbons (e.g., hexane, etc.) and ethers (e.g., tetrahydrofuran, 1,4-dioxane, etc.), or a mixture thereof.

[0150] The strong basic compound used may be an organometallic base reagent such as a lithium species or magnesium species, and n-butyllithium or s-butyllithium is more preferred. The amount of the basic compound used is preferably equimolar or more, particularly equimolar, relative to compound 24.

[0151] Examples of the boronic acid ester or diboronic acid ester used include bis(pinacolato)diboron, bis(catecholate)diboron, isopropoxyboronic acid pinacol ester, trimethoxyborane, and the like. The amount of the boronic acid ester or diboronic acid ester used is preferably equimolar or more, particularly about 1 to 5 times the molar amount of compound 24. This reaction is typically carried out at -100°C to 50°C, preferably -78°C to 0°C, and the reaction time is typically several minutes to 48 hours, preferably 1 to 24 hours. This reaction is also preferably carried out under an inert gas atmosphere such as nitrogen or argon.

[0152] The solvent used in the synthesis of compound 28 by the reaction of compound 26 with compound 27 may be any solvent that does not affect the reaction, and examples thereof include aromatic hydrocarbons (e.g., toluene, xylene, etc.), ethers (e.g., tetrahydrofuran, 1,4-dioxane, etc.), aprotic polar solvents (e.g., N,N-dimethylformamide, acetonitrile, etc.), and water, or a mixture thereof.

[0153] This reaction uses a transition metal catalyst. Examples of the transition metal catalyst include palladium catalysts such as palladium chloride, palladium acetate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(tert-butylphosphine)palladium(0), and bis(diphenylphosphinoferrocene)dichloropalladium(II), and copper catalysts such as copper(I) iodide. These may be used alone or in combination of two or more. The amount of the transition metal catalyst used may be 0.005 to 1 mole per mole of compound 26.

[0154] This reaction may be carried out by adding a phosphine compound. Examples of the phosphine compound include tri(tert-butyl)phosphine, tri(cyclohexyl)phosphine, tri(2-furyl)phosphine, and diphenylphosphinoferrocene, and preferably tri(tert-butyl)phosphine. The amount of the phosphine compound used may be 0.01 to 1 mole per mole of Compound 26.

[0155] This reaction is preferably carried out in the presence of a basic compound. Examples of basic compounds include inorganic bases such as potassium carbonate, cesium carbonate, and potassium phosphate; alkoxides such as sodium methoxide and potassium tert-butoxide; metal fluorides such as sodium fluoride and cesium fluoride; and organic bases such as triethylamine and 1,8-diazabicyclo[5.4.0]undec-7-ene. Potassium carbonate, potassium tert-butoxide, cesium fluoride, and triethylamine are preferred. The amount of basic compound used is preferably equimolar or more, particularly about 1 to 5 times the molar amount of compound 26. This reaction is typically carried out at 0 to 150°C, preferably room temperature to 120°C, and the reaction time is typically several minutes to 48 hours, preferably 1 to 24 hours. This reaction is also preferably carried out under an inert gas atmosphere such as nitrogen or argon.

[0156] (Step 8)

[0157] [Wherein W is C １ ~C ４ represents a lower alkyl group or an aryl group, and R １ , R ４ indicates the same as above.]

[0158] That is, compound 29 is acetalized to give compound 30, which is then used to give compound 31 according to the above-mentioned step 3, followed by deprotection of the acetal to give compound 32. The obtained 32 is oxidized to give 33, from which compound 34 can be obtained according to the above-mentioned step 2.

[0159] Here, the "alkyl group" represented by W is preferably a C1 to C4 lower alkyl group such as a methyl group, an ethyl group, or a propyl group. The "aryl group" is preferably a C1 to C4 lower alkyl group such as a phenyl group or a naphthyl group. ６－１０ Examples include an aryl group, and a phenyl group is preferred.

[0160] The acetalization of compound 29 is carried out in a solvent using an acid catalyst. Any solvent that does not affect the reaction may be used for this acetalization, and aprotic polar solvents (e.g., N,N-dimethylformamide, acetonitrile, etc.) and aromatic hydrocarbons (e.g., toluene, xylene, etc.) are preferred.

[0161] Examples of the acid catalyst used in this reaction include p-toluenesulfonic acid and camphorsulfonic acid. The amount of the acid catalyst used is preferably 0.01 equivalents or more, particularly about 0.03 to 0.1 equivalents, relative to compound 29. This reaction is usually carried out at 0 to 100°C, preferably room temperature to 50°C, and the reaction time is usually several minutes to 24 hours, preferably 30 minutes to 12 hours.

[0162] Compound 30 can be converted to compound 31 by following step 3 above.

[0163] The deprotection of compound 31 is carried out using an acid catalyst in a solvent. Any solvent that does not affect the reaction may be used for this deacetalization, and protic polar solvents (e.g., water, methanol, etc.) and aromatic hydrocarbons (e.g., toluene, xylene, etc.) are preferred.

[0164] Examples of the acid catalyst used in this reaction include p-toluenesulfonic acid and camphorsulfonic acid. The amount of the acid catalyst used is preferably 0.01 equivalents or more, particularly about 0.03 to 0.1 equivalents, relative to compound 30. This reaction is usually carried out at 0 to 100°C, preferably room temperature to 50°C, and the reaction time is usually several minutes to 24 hours, preferably 30 minutes to 12 hours.

[0165] In this reaction, when the group represented by W is an aryl group, it is converted to compound 32 by catalytic reduction with a heterogeneous catalyst or reduction with a metal and an acid in an appropriate solvent.

[0166] The solvent used in the catalytic reduction using a heterogeneous catalyst may be any solvent that does not affect the reaction, and examples thereof include esters (e.g., ethyl acetate, butyl acetate, etc.), ethers (e.g., diethyl ether, tetrahydrofuran, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), alcohols (e.g., methanol, ethanol, etc.), and water, or a mixture of these solvents. Examples of metal catalysts that can be used include palladium, platinum, nickel, and rhodium, with palladium being preferred. This reaction is generally carried out at room temperature to 80°C, preferably room temperature to 50°C, and the reaction time is generally from several minutes to 48 hours, preferably 1 to 24 hours.

[0167] The oxidation of compound 32 is carried out using a suitable oxidizing agent in a solvent.

[0168] Examples of oxidizing agents that can be used to synthesize compound 33 by oxidation of compound 32 include chromium (IV)-based oxidants such as pyridinium chromate (PCC) and pyridinium dichromate (PDC), manganese (IV)-based oxidants such as manganese dioxide, ruthenium (VII)-co-oxidant based oxidants such as tetrapropylammonium perruthenate (TPAP) and N-methylmorpholine-N-oxide as a co-oxidant, hypervalent iodine-based oxidants such as Dess-Martin periodinane, and DMSO-based oxidants such as dimethyl sulfoxide (DMSO), oxalyl dichloride, and triethylamine (Swern oxidation).

[0169] Any solvent may be used as long as it does not affect the reaction, but for example, when manganese(IV) dioxide is used, aliphatic hydrocarbons (pentane, hexane, etc.), halogenated hydrocarbons (dichloromethane, chloroform, 1,2-dichloroethane, etc.), and aprotic polar solvents (N,N-dimethylformamide, acetonitrile, etc.) are preferred. The reaction is usually carried out at 0°C to 80°C, preferably room temperature to 50°C, and the reaction time is usually several minutes to 48 hours, preferably 1 to 24 hours.

[0170] Compound 33 can be converted to compound 34 by following step 2 above.

[0171] Compounds 11 to 14, Compound 17, Compound 22, Compound 28, Compound 34, or each synthetic intermediate compound can be isolated and purified as a free compound, a salt thereof, a hydrate, a solvate, or a crystalline polymorph. Compounds 11 to 14, Compound 17, Compound 22, Compound 28, Compound 34, or each synthetic intermediate compound can also be prepared by subjecting the compound to a conventional salt formation reaction. Isolation and purification can be performed using conventional chemical procedures such as extraction, fractional crystallization, various fractional chromatography techniques, evaporation, drying, filtration, and centrifugation. Various stereoisomers can be prepared by selecting appropriate starting compounds, or can be separated by utilizing differences in physicochemical properties between each isomer. For example, optical isomers can be obtained by conventional optical resolution methods for racemates (e.g., fractional crystallization leading to diastereomeric salts with optically active bases or acids, chromatography using chiral columns, etc.), or can also be prepared from appropriate optically active starting compounds.

[0172] The compound represented by formula (1) of the present invention or a salt thereof thus obtained has the effect of suppressing the nuclear localization of Smad2 / 3 in human-derived hepatic stellate cells, and has the effect of suppressing the mRNA expression of connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA), as shown in the test examples described below. SMAD2 / 3 is a major transcription factor in the TGF-β signaling pathway, and by binding to various cofactors, it is a factor involved in the regulation of the expression of a wide variety of genes, including CTGF and α-SMA. CTGF is a secretory protein that promotes the growth of fibroblasts, including hepatic stellate cells, and also acts cooperatively with TGF-β to induce their transformation into myofibroblast-like cells that produce large amounts of collagen (Lab. Invest. 2002, 82, 767; FASEB. J. 2004, 18, 469). α-SMA is a marker molecule that indicates the transformation of fibroblasts, including hepatic stellate cells, into myofibroblast-like cells that produce large amounts of collagen (Physiol. Rev. 2008, 88, 125). Specifically, the sulfonamide derivatives or salts thereof of the present invention inhibit the nuclear localization of Smad2 / 3, thereby inhibiting TGF-β signaling and enabling the prevention, treatment, or amelioration of diseases and pathological conditions induced by abnormalities in the signal transduction pathway. Examples of diseases and pathologies include fibrosis (organ fibrosis) such as hepatic fibrosis, pulmonary fibrosis, renal fibrosis, dermal fibrosis, cardiac fibrosis, and pancreatic fibrosis, as well as obesity and diabetes. Other examples include cancer metastasis and antitumor immunosuppression. Therefore, the compound represented by formula (1) of the present invention or a salt thereof can serve as a nuclear localization inhibitor of Smad2 / 3 and a TGF-β signaling inhibitor, and can also serve as a preventive or therapeutic agent for fibrosis, obesity, and diabetes, a cancer metastasis inhibitor, and an antitumor immunopotentiator. Here, "inhibition of nuclear localization of Smad2 / 3" refers to inhibiting the nuclear translocation of phosphorylated Smads, including Smad2 / 3, or degrading or transferring nuclear-translocated phosphorylated Smads, including Smad2 / 3, to the cytoplasm. "Inhibition of TGF-β signaling" refers to suppressing the nuclear localization of Smad2 / 3, thereby suppressing the expression of response genes whose transcription is induced by Smad2 / 3."Fibrosis" includes organ fibrosis such as liver fibrosis, pulmonary fibrosis, renal fibrosis, skin fibrosis, cardiac fibrosis, and pancreatic fibrosis. These fibroses are accompanied by fibrosis-related symptoms such as inflammation and atrophy, depending on the organ in which fibrosis has progressed and the degree of progression. Therefore, the present invention also encompasses treatment of symptoms associated with fibrosis.

[0173] Pulmonary fibrosis includes not only idiopathic pulmonary fibrosis but also pulmonary fibrosis symptoms including those coexisting with interstitial pneumonia. That is, pulmonary fibrosis of the present invention includes interstitial pneumonia that may be accompanied by pulmonary fibrosis.

[0174] When the compound represented by formula (1) or a salt thereof of the present invention is used as a pharmaceutical, it can be formulated as a composition (pharmaceutical composition) together with a pharmaceutically acceptable carrier for parenteral administration such as injection or rectal administration, or oral administration in solid, semi-solid, or liquid form. Examples of compositions for injection include pharmaceutically acceptable sterile aqueous solutions, non-aqueous solutions, suspensions, and emulsions. Examples of suitable non-aqueous carriers, diluents, solvents, or vehicles include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Such compositions may also contain auxiliary agents such as preservatives, wetting agents, emulsifying agents, and dispersing agents. These compositions can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use.

[0175] Solid preparations for oral administration include capsules, tablets, pills, troches, powders, granules, etc. In preparing these solid preparations, the compound of the present invention is generally mixed with at least one inert diluent such as sucrose, lactose, starch, etc. In the usual formulation, these preparations may contain additional substances other than inert diluents, such as lubricants (e.g., magnesium stearate, etc.). In the case of capsules, tablets, and pills, a buffering agent may also be contained. Tablets and pills may further be provided with an enteric coating.

[0176] Liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. containing inert diluents commonly used by those skilled in the art, such as water. In addition to such inert diluents, the compositions may also contain auxiliary substances such as wetting agents, emulsifying agents, suspending agents, sweeteners, seasonings, and flavoring agents. Preparations for rectal administration preferably contain excipients such as cocoa butter, suppository wax, etc. in addition to the compound of the present invention.

[0177] The dosage of the medicament of the present invention is determined depending on conditions such as the age, sex, weight, symptoms, and administration route of the subject to be administered, for example, a patient with or suspected of having fibrosis, but is generally in the range of 0.001 mg / kg to 1000 mg / kg, preferably 0.01 mg / kg to 100 mg / kg, and more preferably 0.1 mg / kg to 10 mg / kg, per day for an adult, as the compound represented by formula (1) or a salt thereof. The medicament of the present invention can be administered daily or at intervals.

[0178] The present invention will be explained in more detail below by way of Reference Examples and Examples, but these Examples are intended to provide a better understanding of the present invention and are not intended to limit the scope of the present invention. For the sake of convenience, compounds having tautomeric groups are shown using the structural formula of one of the tautomers.

[0179] Reference example 1 3-(2-methylphenyl)-6-nitro-2H-thiochromen-2-one

[0180] (1) 5-Nitrosalicylaldehyde (840 mg) and 1,4-diazabicyclo[2.2.2]octanetriethylenediamine (DABCO) were dissolved in dichloromethane (30 mL), and dimethylthiocarbamoyl chloride (930 mg) was added at room temperature. The mixture was stirred for 1 day. Water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (200 mL). The extract was washed with 1M aqueous HCl solution (50 mL), 1M aqueous NaOH solution (50 mL), and saturated brine (50 mL). The organic layer was dried over sodium sulfate and concentrated to give 1-(2-formyl-4-nitrophenoxy)-N,N-dimethylmethanethioamide (860 mg) as a yellow solid.

[0181] (2) 1-(2-formyl-4-nitrophenoxy)-N,N-dimethylmethanethioamide (860 mg) obtained in the previous section was dissolved in toluene (34 mL) and stirred under reflux for one day. After the reaction, the resulting precipitate was collected by filtration to obtain a crude product of 1-[(2-formyl-4-nitrophenyl)sulfanyl]-N,N-dimethylformamide.

[0182] (3) To a methanol solution (27 mL) of the crude product obtained in the previous section, 3M aqueous NaOH solution (13 mL) was added and the mixture was stirred under heating and reflux for 4 hours. The reaction mixture was acidified with 1M aqueous HCl solution and then extracted with ethyl acetate (100 mL). The extract was washed with water (30 mL) and saturated brine (30 mL). The organic layer was dried over sodium sulfate and then concentrated. The residue was purified by column chromatography (ethyl acetate / hexane = 0%-100%) to obtain 5-nitro-2-sulfanylbenzaldehyde.

[0183] (4) The 5-nitro-2-sulfanylbenzaldehyde obtained in the previous section, 2-methylphenylacetic acid (610 mg), and pyridine (0.68 mL) were dissolved in acetic anhydride (4 mL) and stirred at 135°C for 3 days. The reaction mixture was neutralized with aqueous sodium carbonate solution and then extracted with ethyl acetate (100 mL). The extract was washed with 1M aqueous HCl solution (30 mL), saturated aqueous sodium bicarbonate solution (30 mL), water (30 mL), and saturated brine (30 mL). The organic layer was dried over sodium sulfate and then concentrated. The residue was purified by column chromatography (ethyl acetate / hexane = 0%-20%) to obtain the title compound (0.310 g).

[0184] １ H NMR (500MHz, CDCl ３ ): δ8.50 (d, J=2.2Hz, 1H), 8.33 (dd, J=8.8, 2.4Hz, 1H), 7.78 (s, 1H), 7.66 (d, J=9 .0Hz, 1H), 7.37-7.33 (m, 1H), 7.31-7.27 (m, 2H), 7.22-7.19 (m, 1H), 2.25 (s, 3H)

[0185] Reference example 2 3-(4-methylphenyl)-6-nitro-2H-chromen-2-one

[0186] To a solution of triphenylphosphine (0.790 g) and iodine (0.760 g) in dichloromethane (20 mL), 5-nitrosalicylaldehyde (0.340 g), 4-methylphenylacetic acid (0.370 g), and triethylamine (1.4 mL) were added at 0°C, and the mixture was stirred at room temperature for one day. A saturated aqueous solution of sodium bicarbonate (20 mL) was added to the reaction mixture, followed by extraction with dichloromethane (100 mL). The extract was washed with water (20 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate / hexane = 66%) to obtain the title compound (0.340 g).

[0187] １ H NMR (500MHz, CDCl ３ ​​): δ8.48 (d, J=2.6Hz, 1H), 8.38 (dd, J=9.0, 2.6Hz, 1H), 7.85 (s, 1H), 7.62 ( d, J = 8.2Hz, 2H), 7.48 (d, J = 9.0Hz, 1H), 7.30 (d, J = 8.2Hz, 2H), 2.43 (s, 3H)

[0188] Reference example 3 6-nitro-3-phenyl-1,2-benzoxathiin-2,2-dioxide

[0189] (1) Triethylamine (2.8 mL) was added to a dichloromethane solution (25 mL) of 5-nitrosalicylaldehyde (840 mg), and then benzylsulfonyl chloride was added and stirred at room temperature for 3 days. Water (50 mL) was added to the reaction solution, followed by extraction with dichloromethane (100 mL x 2). The extract was dried over sodium sulfate and concentrated, and the resulting residue was purified by column chromatography (ethyl acetate / hexane = 25%) to give 2-formyl-4-nitrophenyl methanesulfonate (1.1 g).

[0190] (2) To a solution (10 mL) of the above 2-formyl-4-nitrophenyl methanesulfonate (0.300 g) in dichloromethane, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.140 mL) was added at 0°C, and the mixture was stirred for 3 hours. The reaction mixture was quenched with 1M aqueous HCl, and then extracted with a 1:1 mixture (100 mL) of diethyl ether and ethyl acetate. The extract was washed with water (30 mL). The organic layer was dried over sodium sulfate and then concentrated, and the residue was suspended in diethyl ether. The resulting solid was collected by filtration to give the title compound (130 mg) as a white solid.

[0191] １ H NMR (500MHz, CDCl ３ ): δ8.42 (d, J=2.7Hz, 1H), 8.36 (dd, J=9.0, 2.7Hz, 1H), 7.70-7.67 (m, 2H), 7.56-7.50 (m, 3H), 7.48 (d, J=9.0Hz, 1H), 7.30 (s, 1H).

[0192] Reference example 4 ​4-methyl-N-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0193] (1) A mixed solution of iron powder (140 mg) and ammonium chloride (13 mg) in ethanol / water (10 mL / 5 mL) was stirred at 70°C for 30 minutes, and then a tetrahydrofuran solution (5 mL) of 3-(4-methylphenyl)-6-nitro-2H-chromen-2-one (140 mg) obtained in Reference Example 2 or a method analogous thereto was added, followed by stirring at 70°C for 2 hours. The reaction solution was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and then concentrated to give 6-amino-3-(4-methylphenyl)-2H-chromen-2-one (126 mg) as a yellow solid.

[0194] １ H NMR (500MHz, CDCl ３ ): δ7.65 (s, 1H), 7.59 (d, J = 8.3Hz, 2H), 7.27-7.25 (m, 2H), 7.18 (d, J = 8.8Hz, 1H) , 6.86 (dd, J=8.8, 2.7Hz, 1H), 6.77 (d, J=2.7Hz, 1H), 3.72 (brs, 2H), 2.40 (s, 3H)

[0195] (2) To a dichloromethane solution (5 mL) of 6-amino-3-(4-methylphenyl)-2H-chromen-2-one (126 mg) obtained in the previous section, triethylamine (350 μL) and p-toluenesulfonyl chloride (240 mg) were added at room temperature, and the mixture was stirred at the same temperature for 2 days. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane=30%) to obtain 4-methyl-N-(4-methylbenzenesulfonyl)-N-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (120 mg) as a white solid.

[0196] １ H NMR (500MHz, CDCl ３ ​​): δ7.83-7.80 (m, 4H), 7.67 (s, 1H), 7.58 (d, J=8.2Hz, 2H), 7.38-7.34 (m, 4H), 7.30 (d, J = 8.8Hz, 1H), 7.28-7.25 (m, 3H), 7.10 (dd, J = 8.8, 2.5Hz, 1H), 2.49 (s, 6H), 2.41 (s, 3H)

[0197] (3) To a tetrahydrofuran solution (3 mL) of 4-methyl-N-(4-methylbenzenesulfonyl)-N-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (100 mg) obtained in the previous section, tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution; 240 μL) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane 33%) to obtain the title compound (41 mg) as a white solid.

[0198] １ H NMR (500MHz, CDCl ３ ): δ7.70 (s, 1H), 7.62 (d, J = 8.3Hz, 2H), 7.58 (d, J = 8.2Hz, 2H), 7.37 (d, J = 2.6Hz, 1H), 7 .27-7.21 (m, 5H), 7.08 (dd, J=8.8, 2.6Hz, 1H), 6.48 (brs, 1H), 2.40 (s, 3H), 2.39 (s, 3H)

[0199] Reference example 5 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0200] (1) 3-(2-methylphenyl)-6-nitro-2H-chromen-2-one synthesized by Reference Example 2 or a method analogous thereto was used to obtain 6-amino-3-(2-methylphenyl)-2H-chromen-2-one by the method described in Reference Example 4-(1) or a method analogous thereto.

[0201] ​(2) To a dichloromethane solution (40 mL) of the compound (950 mg) obtained above, pyridine (1.2 mL) and p-toluenesulfonyl chloride (1.1 g) were added at room temperature, and the mixture was stirred at the same temperature for 1 day. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with 1 mol / L hydrochloric acid, dried over sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 40%) to obtain the title compound (1.4 g) as a pale yellow solid.

[0202] １ H NMR (500MHz, CDCl ３ ): δ7.66-7.63 (m, 2H), 7.55 (s, 1H), 7.35-7.31 (m, 2H), 7.29-7.20 (m, 6H ), 7.11 (dd, J=8.8, 2.5Hz, 1H), 6.51 (brs, 1H), 2.40 (s, 3H), 2.28 (s, 3H)

[0203] Reference example 6 N-(3-bromo-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0204] (1) To a dichloromethane solution (20 mL) of 6-nitro-2H-chromen-2-one (1.0 g) and Oxone (registered trademark; 3.9 g), 2 mol / L hydrobromic acid (6.2 mL) was added dropwise at room temperature, and the mixture was stirred at the same temperature for 1 day. Triethylamine (4.2 mL) was added to the reaction mixture, and the mixture was further stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, water, and saturated brine, dried over sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 20%) to obtain 3-bromo-6-nitro-2H-chromen-2-one (940 mg) as a brown solid.

[0205] (2) Using 3-bromo-6-nitro-2H-chromen-2-one (935 mg) obtained in the previous section, 6-amino-3-bromo-2H-chromen-2-one (760 mg) was obtained as a brown solid by the method described in Reference Example 4-(1) or a method analogous thereto.

[0206] ​(3) Using 6-amino-3-bromo-2H-chromen-2-one (760 mg) obtained in the previous section and according to the method of Reference Example 4-(2) or a method analogous thereto, the title compound (1.7 g) was obtained as a brown solid.

[0207] １ H NMR (500MHz, CDCl ３ ): δ7.99 (s, 1H), 7.79 (d, J = 8.4Hz, 4H), 7.36 (d, J = 8.4Hz, 4H), 7.30 (d, J = 8 .8Hz, 1H), 7.18 (d, J=2.5Hz, 1H), 7.15 (dd, J=8.8, 2.5Hz, 1H), 2.49 (s, 6H)

[0208] Reference example 7 4-methyl-N-(4-methylbenzenesulfonyl)-N-[2-oxo-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-chromen-6-yl]benzene-1-sulfonamide

[0209] N-(3-bromo-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide (0.165 g) obtained by the method described in Reference Example 6, bis(pinacolato)diboron (0.114 g), potassium acetate (88 mg), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (24 mg) were suspended in 1,4-dioxane and stirred at 100°C for 2 hours under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (15 mL) was added to the reaction solution, followed by extraction with ethyl acetate (90 mL). The extract was washed with water (20 mL) and saturated brine (20 mL), dried over sodium sulfate, and concentrated to obtain the title compound.

[0210] １ H NMR (500MHz, CDCl ３ ): δ8.48 (s, 1H), 7.76 (d, J=2.6Hz, 1H), 7.71-7.68 (m, 4H), 7.50-7.48 (m, 5H), 7.38 (d, J=8.8Hz, 1H), 7.12 (dd, J=8.8, 2.6Hz, 1H), 2.46 (s, 6H), 1.30 (s, 12H).

[0211] Reference example 8​​ 5-[N,N-bis(4-methylbenzenesulfonyl)amino]salicylaldehyde

[0212] (1) Benzaldehyde dimethyl acetal (1.9 mL) and p-toluenesulfonic acid monohydrate (57 mg) were added to a solution of 2-hydroxy-5-nitrobenzyl alcohol (1.7 g) in acetonitrile (100 mL), and the mixture was stirred at room temperature for 1 day. The reaction mixture was diluted with dichloromethane (300 mL) and then washed with saturated aqueous sodium bicarbonate (100 mL x 2) and water (100 mL). The organic layer was dried over sodium sulfate and concentrated. The solid residue was collected by filtration with ethyl acetate / hexane to give 6-nitro-2-phenyl-2,4-dihydro-1,3-benzodioxine (1.2 g) as a yellow solid.

[0213] (2) Using the compound obtained above, 6-amino-2-phenyl-2,4-dihydro-1,3-benzodioxine was obtained by the method described in Reference Example 4-(1) or a method equivalent thereto, and this compound was then subjected to the method described in Reference Example 4-(2) or a method equivalent thereto to obtain 6-[bis(4-methylbenzenesulfonyl)amino]-2-phenyl-2,4-dihydro-1,3-benzodioxine (2.0 g) as a white solid.

[0214] (3) To a solution (40 mL) of the compound (2.0 g) obtained above in dichloromethane / methanol (2.4 / 1) was added (+)-camphorsulfonic acid (0.860 g) and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was neutralized with triethylamine and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 60-80%) to obtain 5-[N,N-bis(4-methylbenzenesulfonyl)amino]-2-hydroxybenzyl alcohol (1.5 g) as a white solid.

[0215] (4) To a solution (34 mL) of the compound (1.5 g) obtained above in dichloroethane, manganese dioxide (2.9 g) was added and the mixture was stirred at room temperature for 1 day. The reaction mixture was diluted with dichloromethane and ethyl acetate, filtered through Celite, and the filtrate was concentrated. The solid residue was collected by filtration with dichloromethane to give the title compound (1.3 g) as a white solid.

[0216] ​１ H NMR (500MHz, CDCl ３ ): δ11.22 (s, 1H), 9.77 (s, 1H), 7.83-7.79 (m, 4H), 7.38-7.34 (m, 4H), 7.27-7 .26 (m, 1H), 7.13 (dd, J=8.9, 2.6Hz, 1H), 6.95 (d, J=8.9Hz, 1H), 2.49 (s, 6H).

[0217] Examples 1 to 13 The compounds shown in Tables 1-1 to 1-4 were synthesized using 6-amino-3-(2-methylphenyl)-2H-chromen-2-one described in Reference Example 5-(1) and the method described in Reference Example 4-(2) or a method similar thereto.

[0218] Example 14 N-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]-1-[2-(trifluoromethyl)phenyl]-N-{[4-(trifluoromethyl)phenyl]methanesulfonyl}methanesulfonamide

[0219] The title compound was obtained by using 6-amino-3-(4-methylphenyl)-2H-chromen-2-one obtained in Reference Example 4-(1) and according to the method of Reference Example (4)-(2) or a method analogous thereto.

[0220] １ H NMR (500MHz, CDCl ３ ): δ7.77-7.68 (m, 6H), 7.58-7.51 (m, 4H), 7.37 (s, 1H), 7.29-7.26 (m, 2H), 7.07 (d, J = 8.8H z, 1H), 6.50 (dd, J=8.8, 2.5Hz, 1H), 6.42 (d, J=2.5Hz, 1H), 5.00-4.98 (m, 4H), 2.41 (s, 3H)

[0221] Example 15 N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-4-(trifluoromethyl)benzene-1-sulfonamide

[0222] ​To a dichloromethane solution (1 mL) of 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (20 mg) obtained in Reference Example 5, triethylamine (35 μL) and 4-(trifluoromethyl)benzenesulfonyl chloride (25 mg) were added at room temperature, and the mixture was stirred at the same temperature for 2 days. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane=20%) to obtain the title compound (16 mg) as a white solid.

[0223] １ H NMR (500MHz, CDCl ３ ): δ8.12 (d, J=8.3Hz, 2H), 7.86 (d, J=8.3Hz, 2H), 7.83-7.80 (m, 2H), 7.55 (s, 1H), 7.39 -7.33 (m, 4H), 7.31-7.22 (m, 4H), 7.13 (dd, J=8.8, 2.5Hz, 1H), 2.50 (s, 3H), 2.31 (s, 3H)

[0224] Examples 16 to 55 The compounds shown in Tables 2-1 to 2-10 were synthesized by the method described in Example 15 or a method similar thereto.

[0225] Example 56 6-(methylamino)-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]pyridine-3-sulfonamide

[0226] To a 1,4-dioxane solution (1 mL) of 6-chloro-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]pyridine-3-sulfonamide (40 mg) obtained in Example 50, N,N-diisopropylethylamine (24 μL) and methylamine hydrochloride (7 mg) were added at room temperature, and the mixture was stirred for 24 hours at 80° C. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane=0-60%) to obtain the title compound (4 mg) as a white solid.

[0227] １ ​​H NMR (500MHz, DMSO-d ６ ): δ8.30-8.26 (m, 1H), 8.09 (s, 1H), 7.93-7.87 (m, 1H), 7.75-7.72 (m, 2H), 7.67 (d, J = 2.6Hz, 1H), 7.62-7.56 (m, 1H), 7.52-7 .47 (m, 3H), 7.36-7.26 (m, 4H), 7.16 (dd, J = 8.7, 2.6Hz, 1H), 6.58 (d, J = 9.2Hz, 1H), 2.87 (brs, 3H), 2.45 (s, 3H), 2.23 (s, 3H)

[0228] Examples 57 to 63 The compounds shown in Tables 3-1 and 3-2 were synthesized by the method described in Example 56 or a method similar thereto.

[0229] Example 64 4-[(E)-2-methanesulfonylethenyl)-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0230] To a solution (1 mL) of 4-iodo-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (0.026 mL) obtained in Example 54 in acetonitrile, methyl vinyl sulfone (7 mg), triethylamine (24 μL), tris(p-tolyl)phosphine (5 mg), and palladium(II) acetate (3 mg) were added at room temperature, and the mixture was stirred at 90°C under a nitrogen atmosphere for 4 hours. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The extract was washed with water (10 mL) and saturated brine (10 mL). The organic layer was dried over sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0-30%) to obtain the title compound (8 mg) as a white solid.

[0231] １ H NMR (500MHz, DMSO-d ６ ​): δ8.08 (s, 1H), 8.04-8.02 (m, 2H), 7.90-7.88 (m, 2H), 7.77 (d, J = 15.5Hz, 1H), 7.75-7.73 (m, 2H), 7.67 (d, J = 2.6Hz, 1H), 7.6 4 (d, J = 15.5Hz, 1H), 7.52-7.50 (m, 3H), 7.36-7.28 (m, 4H), 7.16 (dd, J = 8.7, 2.6Hz, 1H), 3.15 (s, 3H), 2.46 (s, 6H), 2.23 (s, 3H)

[0232] Example 65 4-(2-methanesulfonylethyl)-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0233] To a methanol solution (3 mL) of 4-[(E)-2-methanesulfonylethenyl)-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (6 mg) obtained in Example 64, 10% palladium on carbon (40 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 day. The reaction solution was filtered through a membrane filter, and the filtrate was concentrated to give the title compound (2 mg).

[0234] １ H NMR (500MHz, DMSO-d ６ ): δ8.07 (s, 1H), 7.79-7.77 (m, 2H), 7.71-7.69 (m, 2H), 7.66-7.62 (m, 3H), 7.50-7.49 (m, 3H), 7.36-7.25 (m, 4 H), 7.11 (dd, J=8.8, 2.6Hz, 1H), 3.56-3.50 (m, 2H), 3.20-3.16 (m, 2H), 3.01 (s, 3H), 2.46 (s, 6H), 2.23 (s, 3H)

[0235] Example 66 4-Hydroxy-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0236] ​To a dichloromethane solution (2.0 mL) of 4-methoxy-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (90 mg) obtained in Example 17, 1 M boron tribromide dichloromethane solution (0.470 mL) was added at −20° C., and the mixture was stirred at room temperature for 1 day. Methanol (1 mL) was added to the reaction solution, followed by ethyl acetate (50 mL). This solution was washed with water (10 mL) and saturated brine (10 mL). The organic layer was dried over sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane=45%) to obtain the title compound (20 mg) as a white solid.

[0237] １ H NMR (500MHz: CDCl ３ ): δ7.85-7.81 (m, 4H), 7.54 (s, 1H), 7.38-7.32 (m, 4H), 7.31-7.21 (m, 4H), 7.12 (dd, J=8.8, 2.5Hz, 1H), 6.97-6.94 (m, 2H), 5.91 (brs, 1H), 2.48 (s, 3H), 2.30 (s, 3H)

[0238] Example 67 4-amino-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0239] Using N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-4-nitrobenzene-1-sulfonamide obtained in Example 19, the title compound (1.3 g) was obtained as a pale yellow solid according to the method described in Reference Example 4-(1) or a method analogous thereto.

[0240] １ H NMR (500MHz, DMSO-d ６ ​​): δ8.08 (s, 1H), 7.73-7.69 (m, 2H), 7.62 (d, J = 2.6Hz, 1H), 7.49-7.46 (m, 3H), 7.37-7.25 (m, 6H), 7.06 (dd, J=8.8, 2.6Hz, 1H), 6.63-6.60 (m, 2H), 6.44 (brs, 2H), 2.45 (s, 3H), 2.23 (s, 3H)

[0241] Example 68 4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]benzoic acid

[0242] To a solution (0.5 mL) of methyl 4-({N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-4-methylbenzenesulfonamido}sulfonyl)benzoate (50 mg) obtained in Example 21 in acetic acid, 6 M hydrochloric acid solution (0.500 mL) was added, and the mixture was stirred at 100° C. for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was suspended in water, and the precipitated solid was collected by filtration to obtain the title compound (43 mg) as a white solid.

[0243] １ H NMR (500MHz, CDCl ３ ): δ8.30-8.26 (m, 2H), 8.10-8.06 (m, 2H), 7.84-7.81 (m, 2H), 7.54 (s, 1H), 7.40-7. 33 (m, 4H), 7.31-7.22 (m, 4H), 7.13 (dd, J=8.8, 2.5Hz, 1H), 2.50 (s, 3H), 2.31 (s, 3H)

[0244] Example 69 4-(2-aminoethoxy)-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0245] ​(1) To a tetrahydrofuran solution (1.5 mL) of 4-hydroxy-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (76 mg) obtained in Example 66, tert-butyl N-(2-hydroxyethyl)carbamate (45 mg), and triphenylphosphine (110 mg), di-tert-butyl azodicarboxylate (65 mg) was added at 0°C, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane=25%) to obtain tert-butyl N-{2-[4-({N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-4-methylbenzenesulfonamido}sulfonyl)phenoxy]ethyl}carbamate as a white solid.

[0246] １ H NMR (500MHz, CDCl ３ ): δ7.90-7.86 (m, 2H), 7.85-7.81 (m, 2H), 7.54 (s, 1H), 7.38-7.32 (m, 5H), 7.31-7.21 (m, 3H), 7.12 (dd, J = 8.8, 2.5Hz, 1 H), 7.03-6.99 (m, 2H), 4.96 (brs, 1H), 4.13 (t, J = 5.2Hz, 2H), 3.61-3.59 (m, 2H), 2.49 (s, 3H), 2.30 (s, 3H), 1.46 (s, 9H)

[0247] (2) Trifluoroacetic acid (1 mL) was added at room temperature to a dichloromethane solution (2 mL) of tert-butyl N-{2-[4-({N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-4-methylbenzenesulfonamido}sulfonyl)phenoxy]ethyl}carbamate (63 mg) obtained in the previous section, and the mixture was stirred at the same temperature for 4 hours. The reaction solution was concentrated, neutralized with saturated sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated. The residue was dispersed in a hexane / dichloromethane (5:1) solution and collected by filtration to obtain the title compound (37 mg) as a white solid.​

[0248] １ H NMR (500MHz, DMSO-d ６ ): δ8.08 (s, 1H), 7.74-7.71 (m, 4H), 7.64 (d, J = 2.6Hz, 1H), 7.51-7.48 (m, 3H), 7.37-7.25 (m, 4H), 7.20-7.17 (m, 2H), 7.11 (dd, J=8.8, 2.6Hz, 1H), 4.06 (t, J=5.7Hz, 2H), 2.92 (t, J=5.7Hz, 2H), 2.46 (s, 3H), 2.23 (s, 3H)

[0249] Example 70 N-(2-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenoxy}ethyl)acetamide

[0250] To a dichloromethane solution (500 μL) of 4-(2-aminoethoxy)-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (12 mg) obtained in Example 69, triethylamine (8 μL) and acetyl chloride (2 μL) were added at room temperature, and the mixture was stirred at the same temperature for 5 days. Water was added to the reaction solution, and the resulting solid was collected by filtration to obtain the title compound (9 mg) as a white solid.

[0251] １ H NMR (500MHz, CDCl ３ ): δ7.91-7.87 (m, 2H), 7.85-7.81 (m, 2H), 7.54 (s, 1H), 7.38-7.32 (m, 4H), 7.31-7.22 (m, 4H), 7.12 (dd, J=8.8, 2.5Hz, 1H), 7. 03-7.00 (m, 2H), 5.92-5.86 (m, 1H), 4.15 (t, J = 5.2Hz, 2H), 3.69 (dt, J = 5.2, 5.2Hz, 2H), 2.49 (s, 3H), 2.30 (s, 3H), 2.04 (s, 3H)

[0252] Example 71 ​​N-[2-(2-methoxyethoxy)ethyl]-N'-(2-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenoxy}ethyl)butanediamide

[0253] The title compound was obtained using 4-hydroxy-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Example 66 and according to the method described in Example 69-(1) or a method analogous thereto.

[0254] １ H NMR (500MHz, CDCl ３ ): δ7.89-7.85 (m, 2H), 7.84-7.81 (m, 2H), 7.55 (s, 1H), 7.38-7.32 (m, 4H), 7.31-7.22 (m, 4H), 7.12 (dd, J=8.8, 2.5Hz, 1H), 7.03-7.00 (m, 2H), 6.62 (t, J=6.0Hz, 1H), 6.27-6 .. 22 (brs, 1H), 4.14 (t, J = 5.2Hz, 2H), 3.69 (q, J = 5.2Hz, 2H), 3.62-3.59 (m, 2H), 3.56-3 .52 (m, 4H), 3.43 (q, J=5.2Hz, 2H), 3.39 (s, 3H), 2.54 (s, 4H), 2.49 (s, 3H), 2.30 (s, 3H)

[0255] Example 72 4-(2-hydroxyethoxy)-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0256] ​(1) To a solution (1 mL) of 4-hydroxy-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (56 mg) obtained in Example 66 in N,N-dimethylformamide, potassium carbonate (69 mg) and O-trityloxyethyl bromide (73 mg) were added, and the mixture was stirred at room temperature for one day. A saturated aqueous solution of ammonium chloride (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed with water (20 mL x 3 times) and saturated brine (20 mL), dried over sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane=0-50%) to give 4-(2-trityloxyethoxy)-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (20 mg) as a white solid.

[0257] (2) The compound obtained in the previous section was treated as in Example 69-(2) or a method equivalent thereto to give the title compound (3 mg) as a white solid.

[0258] １ H NMR (500MHz, CDCl ３ ): δ7.93-7.89 (m, 2H), 7.84-7.81 (m, 2H), 7.54 (s, 1H), 7.37-7.32 (m, 4H), 7.30-7.22 (m, 4H), 7.11 (dd, J = 8.7 , 2.5Hz, 1H), 7.04-7.02 (m, 2H), 4.76-4.74 (m, 2H), 4.39-4,37 (m, 2H), 3.50 (s, 1H), 2.48 (s, 3H), 2.30 (s, 3H)

[0259] Example 73 4-[2-(methylamino)ethoxy]-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide hydrochloride

[0260] ​(1) Using 4-hydroxy-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Example 66, 4-[2-(N-methyl)-(N-tert-butoxycarbonyl)aminoethoxy]-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (37 mg) was obtained according to the method described in Example 69-(1) or a method equivalent thereto.

[0261] (2) The target compound (30 mg) was obtained as a white solid by the method described in Example 69-(2) or a method equivalent thereto.

[0262] １ H NMR (500MHz: DMSO-d ６ ): δ8.80 (brs, 2H), 8.08 (s, 1H), 7.84-7.80 (m, 2H), 7.75-7.71 (m, 2H), 7.62 (d, J = 2.6Hz, 1H), 7.53-7.49 (m, 3H), 7.38-7.23 (m, 6H) ), 7.10 (dd, J=8.8, 2.6Hz, 1H), 4.39 (dd, J=4.9, 4.9Hz, 2H), 3.42-3.37 (m, 2H), 2.65 (t, J=5.3Hz, 3H), 2.46 (s, 3H), 2.23 (s, 3H)

[0263] Example 74 5-[(3aS,4S,6aS)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazolidin-4-yl]-N-[2-(2-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenoxy}ethoxy)ethyl]pentanamide

[0264] ​(1) Using 4-hydroxy-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Example 66, N-(4-{N'-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-N'-(4-methylbenzenesulfonyl)aminosulfonyl}phenoxyethoxyethyl)carbamic acid tert-butyl ester was obtained according to the method described in Example 69-(1) or a method equivalent thereto.

[0265] (2) Using the compound obtained in the previous section, 4-[2-aminoethylethoxy]-N-(4-methylbenzenesulfonyl)-N-[3-(2methylphenyl)-2-oxo-2H-chromen-6-yl]benzenesulfonamide hydrochloride (30 mg) was obtained as a white solid according to the method described in Example 69-(2) or a method equivalent thereto.

[0266] (3) To a solution (1 mL) of the compound obtained above in N,N-dimethylformamide, triethylamine (0.024 mL) and biotin N-succinimide ester (30 mg) were added and stirred at room temperature for 3 days. The reaction solution was diluted with ethyl acetate (50 mL) and then washed with water (10 mL x 4). The organic layer was dried over sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 2-8%) to obtain the title compound (31 mg) as an orange solid.

[0267] １ H NMR (500MHz, DMSO-d ６ ​): δ8.08 (s, 1H), 7.86 (t, J = 5.7Hz, 1H), 7.75-7.71 (m, 4H), 7.64 (d, J = 2.6Hz, 1H), 7.52-7.48 (m, 3H), 7.37-7.25 (m, 4H), 7 .22-7.18 (m, 2H), 7.10 (dd, J=8.8, 2.6Hz, 1H), 6.41 (brs, 1H), 6.35 (brs, 1H), 4.31-4.27 (m, 1H), 4.26-4.22 (m, 2H), 4.13- 4.09 (m, 1H), 3.79-3.75 (m, 2H), 3.48 (t, J = 5.9Hz, 2H), 3.22 (dd, J = 11.7, 5.9Hz, 2H), 3.11-3.05 (m, 1H), 2.80 (dd, J = 12.4, 5.1Hz, 1H), 2.57 (d, J = 12.4Hz, 1H), 2.46 (s, 3H), 2.23 (s, 3H), 2.06 (t, J = 7.4Hz, 1H), 1.69-1.40 (m, 5H), 1.36-1.26 (m, 1H)

[0268] Example 75 3-{3',6'-dihydroxy-3-oxo-3H-spiro[2-benzofuran-1,9'-xanthen]-5-yl}-1-[2-(2-{4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenoxy}ethoxy)ethyl]thiourea

[0269] (1) To a dichloromethane / methanol (2 / 1) solution (1.5 mL) of 4-[2-(methylamino)ethoxy]-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide hydrochloride (60 mg) obtained in Example 74-(2), fluorescein isothiocyanate (34 mg) was added, followed by triethylamine (0.024 mL) and stirring at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (methanol / dichloromethane=2-8%) to obtain the title compound (31 mg) as an orange solid.

[0270] １ H NMR (500MHz, DMSO-d ６ ​): δ10.11 (s, 2H), 10.02 (brs, 1H), 8.26 (s, 1H), 8.13 (brs, 1H), 8.08 (s, 1H), 7.74-7.70 (m, 5H), 7.63 (d, J = 2.6Hz, 1H), 7.51-7.48 (m, 3H), 7.36-7.25 (m, 4H), 7.23-7.19 (m, 2H), 7.18 (d, J = 8.4H z, 1H), 7.10 (dd, J = 8.8, 2.6Hz, 1H), 6.67 (d, J = 2.3Hz, 1H), 7.59 (d, J = 8.7Hz, 1H), 6.55 (dd, J = 8. 7, 2.3Hz, 1H), 4.32-4.28 (m, 2H), 3.88-3.84 (m2H), 3.77-3.68 (m, 4H), 2.45 (s, 3H), 2.23 (s, 3H)

[0271] Examples 76 to 80 Using 4-hydroxy-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Example 66, the compounds shown in Tables 4-1 and 4-2 were obtained according to Example 69-(1) or a method analogous thereto.

[0272] Example 81 4-(Dihydroxypropyl)-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0273] To a solution (5 mL) of 4-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (25 mg) obtained in Example 77 in dichloromethane / methanol (5 / 1), (+)-camphorsulfonic acid (5 mg) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was neutralized with triethylamine and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane=25%) to obtain the title compound (17 mg) as a white solid.

[0274] １ H NMR (500MHz, CDCl ３ ​): δ7.91-7.87 (m, 2H), 7.85-7.81 (m, 2H), 7.54 (s, 1H), 7.38-7.32 (m, 4H), 7.31-7.22 (m, 4H), 7.12 (dd, J=8.8, 2.4Hz, 1H), 7.06-7.03 (m, 2H), 4.21-4.14 (m, 3H), 3.91-3.86 (m, 1H), 3.81-3.76 (m, 1H) ), 2.50 (d, J = 4.4Hz, 1H), 3.49 (s, 3H), 2.49 (s, 3H), 2.30 (s, 3H), 1.89 (d, J = 5.9Hz, 1H)

[0275] Example 82 4-butylamino-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0276] To a solution (1 mL) of 4-amino-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (56 mg) obtained in Example 67 in 1,2-dichloroethane, n-butylaldehyde (12 μL) was added, followed by sodium triacetoxyborohydride (55 mg), and the mixture was stirred at 60°C for 24 hours. Water (10 mL) was added to the reaction mixture, which was then extracted with dichloromethane (30 mL). The organic layer was dried over sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane=80%) to obtain the title compound (5 mg) as a white solid.

[0277] １ H NMR (500MHz, DMSO-d ６ ): δ8.07 (s, 1H), 7.71-7.69 (m, 2H), 7.60 (d, J = 2.6Hz, 1H), 7.48-7.46 (m , 3H), 7.40-7.38 (m, 2H), 7.33-7.28 (m, 4H), 7.07 (dd, J=8.8, 2.6Hz, 1H) , 6.98-6.96 (m, 1H), 6.64-6.63 (m, 2H), 3.12-3.08 (m, 2H), 2.45 (s, 3H), 2.23 (s, 3H), 1.58-1.50 (m, 2H), 1.42-1.36 (m, 2H), 0.91 (t, J = 7.4Hz, 3H)​

[0278] Example 83 4-butylamino-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0279] To a dichloromethane solution (0.1 mL) of 4-amino-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (10 mg) obtained in Example 67, diisopropylethylamine (6 μL) was added, followed by trimethyloxonium tetrafluoroborate (3 mg), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane=0-50%) to obtain the title compound (5 mg) as a white solid.

[0280] １ H NMR (500MHz, DMSO-d ６ ): δ8.07 (s, 1H), 7.72-7.70 (m, 2H), 7.49-7.45 (m, 2H), 7.36-7.25 (m, 4H), 7.06 (dd, J = 8.8, 2.6Hz, 1H), 7.06 (d d, J = 8.8, 2.6Hz, 1H), 7.02 (d, J = 4.9Hz, 1H), 6.64-6.59 (m, 2H), 2.77 (d, J = 4.8Hz, 3H), 2.45 (s, 3H), 2.23 (s, 3H)

[0281] Example 84 4-(dimethylamino)-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0282] ​To a dichloromethane solution (9 mL) of 4-amino-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (0.30 g) obtained in Example 67, diisopropylethylamine (0.2 mL) was added, followed by trimethyloxonium tetrafluoroborate (87 mg), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane=0-50%) to obtain the title compound (43 mg) as a white solid.

[0283] １ H NMR (500MHz, DMSO-d ６ ): δ8.08 (s, 1H), 7.72-7.70 (m, 2H), 7.62 (d, J=2.6Hz, 1H), 7.51-7.46 (m, 5H), 7.36-7.25 (m, 4H), 7.06 (dd, J=8.8, 2.6Hz, 1H), 6.80-6.78 (m, 2H), 3.06 (s, 6H), 2.45 (s, 3H), 2.23 (s, 3H).

[0284] Example 85 N-methyl-N-[4-{N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]4-methylbenzenesulfonamido}sulfonyl]phenyl]formamide

[0285] (1) To a dichloromethane solution (1 mL) of 4-(methylamino)-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (57 mg) obtained in Example 83, triphosgene (45 mg) was added, and then triethylamine (0.025 mL) was added at 0° C., followed by stirring at room temperature for 24 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane=0-50%) to give N-methyl-N-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl}carbamoyl chloride (51 mg) as a white solid.

[0286] ​(2) To a solution (1 mL) of the acid chloride (51 mg) obtained above in dichloromethane, 2,3,4,6-tetra-O-benzyl-β-D-glucose (48 mg) was added, followed by triethylamine (0.022 mL), and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0-50%) to give N-methyl-N-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl}carbamic acid [3,4,5,6-tetrakis(benzyloxy)oxan-2-yl]methyl ester (51 mg) as a white solid.

[0287] (3) To a solution (10 mL) of the compound (58 mg) obtained above in ethyl acetate, 10% Pd—C (40 mg) was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 24 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain the title compound (14 mg) as a white solid.

[0288] １ H NMR (500MHz, DMSO-d ６ ): δ8.89 (s, 1H), 8.08 (s, 1H), 7.84-7.83 (m, 2H), 7.74-7.72 (m, 2H), 7.67-7.63 (m, 3H), 7.52-7. 50 (m, 3H), 7.34-7.27 (m, 6H), 7.16 (dd, J=8.8, 2.6Hz, 1H), 3.29 (s, 3H), 2.46 (s, 3H), 2.23 (s, 3H)

[0289] Example 86 N-methyl-N-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl]carbamic acid methyl ester

[0290] ​N-methyl-N-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl}carbamoyl chloride (20 mg) obtained in Example 85-(1) was dissolved in methanol (0.5 mL) and stirred for 24 hours at 50° C. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane=0-50%) to give N-methyl-N-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl}carbamoyl chloride (8 mg) as a white solid.

[0291] １ H NMR (500MHz, DMSO-d ６ ): δ8.06 (s, 1H), 7.83-7.79 (m, 2H), 7.72-7.68 (m, 2H), 7.68-7.65 (m, 2H), 7.64 (dd, J=2.6Hz, 1H), 7.52-7.4 7 (m, 3H), 7.37-7.25 (m, 4H), 7.15 (dd, J = 8.8, 2.6Hz, 1H), 3.70 (s, 3H), 3.34 (s, 3H), 2.45 (s, 3H), 2.23 (s, 3H)

[0292] Example 87 3,3-diethyl-1-methyl-1-[4-({N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-N-(4-methylbenzenesulfonyl)amino}sulfonyl)phenyl]urea

[0293] ​To a dichloromethane solution (0.5 mL) of N-methyl-N-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl}carbamoyl chloride (20 mg) obtained in Example 85-(1), 1,2:3,4-di-O-isopropylidene-α-D-galactopyranoses (13 mg) and triethylamine (0.014 mL) were added, and the mixture was stirred at room temperature for 20 hours and at 40°C for 24 hours. Further, 1,2-dichloroethane (0.5 mL) was added, and the mixture was stirred at 70°C for 24 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0-35%) to give the title compound (8 mg).

[0294] １ H NMR (500MHz, CDCl ３ ): δ7.84-7.82 (m, 2H), 7.82-7.81 (m, 2H), 7.54 (s, 1H), 7.38-7.32 (m, 4H), 7.30-7.24 (m, 3H), 7.12 (dd, J=8.7, 2.5Hz, 1H), 7.04-7.02 (m, 2H), 3.28 (q, J = 7.2Hz, 4H), 3.24 (s, 3), 2.48 (s, 3H), 2.30 (s, 3H), 1.14 (t, J = 7.2Hz, 6H)

[0295] Example 88 N-methyl-N-(4-{(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl}phenyl)carbamic acid [(3R,4S,5R,6R)-3,4,5,6-tetrahydroxyoxan-2-yl]methyl ester

[0296] ​To a solution (0.5 mL) of 1,2:3,4-di-O-isopropylidene-α-D-galactopyranoses (25 mg) in N,N-dimethylformamide was added 60% sodium hydride (3.3 mg) at 0°C. Then, a solution (0.5 mL) of N-methyl-N-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl}carbamoyl chloride (40 mg) obtained in Example 85-(1) in N,N-dimethylformamide was added at 0°C. The mixture was stirred at 0°C for 30 minutes. Water (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL). The extract was washed with water (10 mL) and saturated brine (10 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane=50%). The resulting solid was dissolved in dichloromethane (0.2 mL), and water (0.2 mL) and trifluoroacetic acid (0.8 mL) were added at 0°C, followed by stirring at room temperature for 7 hours. The reaction solution was concentrated, and the residue was suspended in water. The precipitate was collected by filtration to obtain the title compound (15 mg) as a white solid.

[0297] １ H NMR (500MHz, MeCN-d ３ ): δ7.81-7.78 (m, 0.8H), 7.73-7.70 (m, 1.2H), 7.60-7.58 (m, 0.8H), 7.44-7.43 (m, 0.8H), 7.40 (d , J=8.8Hz, 0.4H), 7.36-7.30(m, 1.2H), 7.28-7.27(m, 0.8H), 7.20(dd, J=8.8, 2.6Hz, 0.4H), 5.10( d, J = 3.7Hz, 0.4H), 4.25-4.23 (m, 0.4H), 4.16-4.12 (m, 0.4H), 3.80 (d, J = 3.4Hz, 0.4H), 3.65 (dd, J =9.8, 3.2Hz, 0.4H), 3.58 (dd, J=9.8, 3.6Hz, 0.4H), 3.36 (s, 1.2H), 2.47 (s, 1.2H), 2.26 (s, 1.2H).

[0298] Example 89 ​(2S)-2-Amino-5-{[methyl({4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl})carbamoyl]oxy}pentanoic acid hydrochloride

[0299] (1) Using N-methyl-N-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl}carbamoyl chloride obtained in Example 85-(1), and in a manner analogous thereto, (2S)-2-{[(tert-butoxy)carbonyl]amino}-5-{[methyl({4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl})carbamoyl]oxy}pentanoic acid tert-butyl ester (34 mg) was obtained.

[0300] (2) The compound obtained above was treated as in Example 69-(2) or a method analogous thereto to give the title compound (6 mg).

[0301] １ H NMR (500MHz, DMSO-d ６ ): δ8.10 (s, 1H), 7.83-7.79 (m, 2H), 7.73-7.66 (m, 5H), 7.52 (d, J = 8.6Hz, 1H), 7.50-7.48 (m, 2H), 7.36-7.26 (m, 4H), 7.15 (dd, J = 8. 7, 2.6Hz, 1H), 4.12-4.09 (m, 2H), 3.38-3.37 (m, 1H), 3.35 (s, 3H), 3.10-2.91 (m, 2H), 2.45 (s, 3H), 2.23 (s, 3H), 1.74-1.70 (m, 2H).

[0302] Example 90 N-methyl-N-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl}carbamic acid 2-[2-(2-methoxyethoxy)ethoxy]ethyl ester

[0303] ​The title compound (15 mg) was obtained using N-methyl-N-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl}carbamoyl chloride obtained in Example 85-(1) and according to a method similar thereto.

[0304] １ H NMR (500MHz, DMSO-d ６ ): δ8.07 (s, 1H), 7.82-7.79 (m, 2H), 7.73-7.66 (m, 4H), 7.64 (d, J = 2.5Hz, 1H), 7.53-7.48 (m, 3H), 7.37-7.26 (m, 4H), 7.14 (dd, J = 8.7, 2.6 Hz, 1H), 4.23-4.22 (m, 2H), 3.66-3.63 (m, 2H), 3.54-3.47 (m, 6H), 3.39-3.38 (m, 2H), 3.35 (s, 3H), 3.19 (s, 3H), 2.46 (s, 3H), 2.23 (s, 3H)

[0305] Example 91 (2S)-2-Amino-3(4-{[N-methyl({4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl})carbamoyl]oxy}phenyl)propionic acid hydrochloride

[0306] The title compound (23 mg) was obtained using N-methyl-N-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl}carbamoyl chloride obtained in Example 85-(1) and according to a method similar thereto.

[0307] １ H NMR (500MHz, DMSO-d ６ ​​): δ8.29 (brs, 4H), 8.07 (s, 1H), 7.90-7.88 (m, 2H), 7.82-7.79 (m, 2H), 7.69-7.68 (m, 2H), 7.66 (d, J = 2.6Hz, 1H), 7.51-7.47 (m, 3H), 7. 35-7.27 (m, 6H), 7.22-7.20 (m, 2H), 7.15 (dd, J=8.6, 2.6Hz, 1H), 4.42-4.40 (m, 1H), 3.56 (s, 3H), 3.47 (s, 2H), 2.44 (s, 3H), 2.23 (s, 3H)

[0308] Example 92 N-methyl-N-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl}carbamic acid 3-fluorophenyl ester

[0309] The title compound (10 mg) was obtained in Example 86 or a method similar thereto using N-methyl-N-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl}carbamoyl chloride obtained in Example 85-(1).

[0310] １ H NMR (500MHz, DMSO-d ６ ): δ8.06 (s, 1H), 7.89-7.87 (m, 2H), 7.82-7.80 (m, 2H), 7.68-7.66 (m, 3H), 7.51 (d, J = 9.0Hz, 1H), 7.48-7.46 (m, 2H), 7.3 6-7.27 (m, 5H), 7.25-7.23 (m, 1H), 7.15 (dd, J=8.7, 2.6Hz, 1H), 7.14-7.10 (m, 2H), 3.48 (s, 3H), 2.43 (s, 3H), 2.22 (s, 3H)

[0311] Example 93 N-methyl-N-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl}carbamic acid (5-methyl-2-oxo-2H-1,3-dioxal-4-yl)methyl ester

[0312] ​The title compound (1.4 mg) was obtained using N-methyl-N-{4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl}carbamoyl chloride obtained in Example 85-(1) and according to a method similar thereto.

[0313] １ H NMR (500MHz, DMSO-d ６ ): δ8.07 (s, 1H), 7.84-7.82 (m, 2H), 7.70-7.65 (m, 5H), 7.52-7.48 (m, 3H), 7.38-7.26 ( m, 4H), 7.16 (dd, J=8.7, 2.6Hz, 1H), 5.04 (s, 2H), 2.45 (s, 3H), 2.23 (s, 3H), 2.17 (s, 3H)

[0314] Example 94 4-[N-(diethylphosphoryl)-N-(methyl)amino]-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0315] To a solution (2.6 mL) of 4-(methylamino)-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (0.150 g) obtained in Example 83, diethylphosphoryl chloride (0.076 mL) and a 1 M THF solution (0.52 mL) of potassium hexamethyldisilazide were added at 0°C, and the mixture was stirred for 2 hours and then at room temperature for 4 hours. Water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0-50%) to obtain the title compound (36 mg) as a white solid.

[0316] １ H NMR (500MHz, DMSO-d ６ ​​): δ8.05 (s, 1H), 7.76-7.74 (m, 2H), 7.72-7.69 (m, 2H), 7.63 (d, J = 2.5Hz, 1H), 7.55-7.48 (m, 5H), 7.37-7.25 (m, 4H), 7.13 (dd, J = 8.8, 2.6Hz, 1H), 4.10-3.98 (m, 4H), 3.22 (d, J=8.2Hz, 3H), 2.46 (s, 3H), 2.23 (s, 3H), 1.26-1.20 (m, 6H)

[0317] Example 95 4-[N-(phosphono)-N-(methyl)amino]-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0318] Trimethylsilyl bromide (0.015 mL) was added to an acetonitrile solution (0.66 mL) of 4-[N-(diethylphosphoryl)-N-(methyl)amino]-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (10 mg) obtained in Example 94 at 0° C., and the mixture was stirred for 50 hours at 50° C. The reaction solution was purified by preparative thin-layer chromatography (methanol / ethyl acetate=25%) to obtain the title compound (2.5 mg).

[0319] １ H NMR (500MHz, DMSO-d ６ ): δ8.06 (s, 1H), 7.73-7.70 (m, 4H), 7.68-7.67 (m, 1H), 7.51-7.49 (m, 3H), 7.47-7. 44 (m, 2H), 7.35-7.29 (m, 4H), 7.16 (dd, J=8.6, 2.6Hz, 1H), 2.45 (s, 3H), 2.23 (s, 3H)

[0320] Example 96 4-({N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-4-methylbenzenesulfonamide}sulfonyl)-N-(prop-2-yn-1-yl)benzamide

[0321] ​To a dichloromethane solution (500 μL) of 4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]benzoic acid (15 mg) obtained in Example 68, prop-2-yn-1-amine (2 μL), 1-hydroxybenzotriazole (5 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2 mg) were added at room temperature, and the mixture was stirred at the same temperature for 1 day. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water, and saturated brine, dried over sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane=33%) to obtain the title compound (9 mg) as a white solid.

[0322] １ H NMR (500MHz, CDCl ３ ): δ8.07-8.04 (m, 2H), 7.98-7.95 (m, 2H), 7.83-7.80 (m, 2H), 7.54 (s, 1H), 7.39-7.32 (m, 4H), 7.31-7.22 (m, 4H), 7. 11 (dd.

[0323] Examples 97 to 99 The compounds shown in Table 5 were synthesized by the method described in Example 96 or a method similar thereto.

[0324] Example 100 4-[(methylamino)methyl]-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0325] ​(1) Using 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Reference Example 5, 4-formyl-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide was obtained in accordance with Example 15 or a method equivalent thereto.

[0326] (2) The compound obtained above was treated in the same manner as in Example 82 to obtain the title compound.

[0327] １ H NMR (500MHz, CDCl ３ ): δ8.07-8.04 (m, 2H), 7.98-7.95 (m, 2H), 7.83-7.80 (m, 2H), 7.54 (s, 1H), 7.39-7.32 (m, 4H), 7.31-7.22 (m, 4H), 7. 11 (dd.

[0328] Example 101 4-[(dimethylamino)methyl]-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0329] To a solution (1 mL) of 4-[(methylamino)methyl]-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (26 mg) obtained in Example 100 in N,N-dimethylformamide, potassium carbonate (18 mg) and methyl iodide (4 μL) were added and stirred at room temperature for 3 hours. Water (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (30 mL). The extract was washed with water (10 mL x 2), dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 0-100%, methanol / ethyl acetate = 100%) to obtain the title compound (24 mg) as a white solid. ​

[0330] １ H NMR (500MHz, DMSO-d ６ ): δ8.05 (s, 1H), 7.78-7.76 (m, 2H), 7.71-7.69 (m, 2H), 7.63 (d, J = 2.6Hz, 1H), 7.60-7.58 (m, 2H), 7.51-7.48 (m, 3H), 7.36-7.29 (m, 4H), 7.13 (dd, J=8.8, 2.6Hz, 1H), 3.53 (s, 2H), 2.45 (s, 3H), 2.22 (s, 3H), 2.18 (s, 6H)

[0331] Example 102 Trimethyl({4-[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]sulfamoyl]phenyl}methyl)ammonium iodide

[0332] The title compound was obtained using 4-[(dimethylamino)methyl]-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Example 101 and according to a method analogous thereto.

[0333] １ H NMR (500MHz, DMSO-d ６ ): δ8.05 (s, 1H), 7.98-7.96 (m, 2H), 7.84-7.83 (m, 2H), 7.77-7.76 (m, 2H), 7.66 (d, J = 2.6Hz, 1H), 7.53-7.50 (m, 3H), 7.38-7.28 (m, 4H), 7.20 (dd, J=8.8, 2.6Hz, 1H), 4.67 (s, 2H), 3.08 (s, 9H), 2.47 (s, 3H), 2.23 (s, 3H)

[0334] Examples 103-109 Using 4-formyl-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Example 100-(1), the compounds shown in Tables 6-1 and 6-2 were obtained according to the method of Example 82 or a method analogous thereto.

[0335] Example 110 ​​4-Octyl-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0336] A 1.56M n-butyllithium hexane solution (0.12 mL) was added to a THF suspension (1 mL) of n-heptylphosphonium bromide (88 mg) at 0°C, and the mixture was stirred for 30 minutes. A THF solution (0.5 mL) of 4-formyl-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (57 mg) obtained in Example 100-(1) was added to the reaction mixture at 0°C, and the mixture was stirred for 1 hour. A saturated aqueous ammonium chloride solution (15 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (40 mL). The extract was washed with water (10 mL) and saturated brine (10 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0-50%). The obtained compound was treated according to the method of Example 65 or a method equivalent thereto to give the title compound (34 mg) as a white solid.

[0337] １ H NMR (500MHz, DMSO-d ６ ): δ8.05 (s, 1H), 7.73-7.71 (m, 2H), 7.70-7.68 (m, 2H), 7.62 (d, J = 2.6Hz, 1H), 7.51-7.47 (m, 5H), 7.37-7.26 (m, 4H), 7.11 (dd, J =8.7, 2.6Hz, 1H), 2.71 (t, J = 7.8Hz, 2H), 2.45 (s, 3H), 2.23 (s, 3H), 1.64-1.58 (m, 2H), 1.32-1.20 (m, 10H), 0.85 (t, J = 7.1Hz, 3H)

[0338] Example 111 3-({N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-4-methylbenzenesulfonamide}sulfonyl)propionic acid

[0339] ​(1) 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Reference Example 5 was treated in Example 15 or a method analogous thereto to give 3-({N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]methylbenzenesulfonamide}sulfonyl)propionic acid methyl ester.

[0340] (2) To a solution of the compound (15 mg) obtained above in acetic acid / 1,4-dioxane (1 / 1), 6 M hydrochloric acid (0.5 mL) was added and the mixture was stirred for 2 hours at 100° C. The reaction solution was concentrated to obtain the title compound (5.2 mg) as a pale brown solid.

[0341] １ H NMR (500MHz, CDCl ３ ): δ7.75-7.70 (m, 2H), 7.57 (s, 1H), 7.38-7.17 (m, 9H), 4.07 (t, J = 7.4Hz, 2H), 3.06 (d, J = 7.6Hz, 2H), 2.47 (s, 3H), 2.29 (s, 3H)

[0342] Example 112 N-(2-hydroxyethylsulfonyl)-4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0343] (1) 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Reference Example 5 was treated in Example 15 or a method analogous thereto to give N-(2-benzyloxyethylsulfonyl)-4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide.

[0344] (2) The compound obtained above was treated in the same manner as in Example 65 or a method equivalent thereto to give the title compound (8 mg) as a white solid.

[0345] １ H NMR (500MHz, CDCl ３ ​​): δ7.77-7.74 (m, 2H), 7.57 (s, 1H), 7.41 (d, J = 2.5Hz, 1H), 7.38-7.32 (m, 4H), 7.31-7.28 (m, 1H), 7.2 7-7.21 (m, 3H), 4.28-4.23 (m, 2H), 3.96-3.91 (m, 2H), 2.48 (s, 3H), 2.44 (t, J = 6.7Hz, 1H), 2.30 (s, 3H)

[0346] Example 113 N,4-dimethyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0347] Using 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (40 mg) obtained in Reference Example 5 and according to the method of Example 101 or a method equivalent thereto, the title compound (41 mg) was obtained as a white solid.

[0348] １ H NMR (500MHz, CDCl3): δ7.58 (s, 1H), 7.46 (d, J = 8.3Hz, 2H), 7.39 (d, J = 2.6Hz, 1H), 7.33 (ddd, J = 7.7, 6.9, 1.9Hz, 1H) , 7.29-7.24 (m, 5H), 7.23 (dd, J = 7.7, 1.8Hz, 1H), 7.14 (dd, J = 8.9, 2.6Hz, 1H), 3.19 (s, 3H), 2.44 (s, 3H), 2.30 (s, 3H)

[0349] Examples 114 to 122 The compounds shown in Tables 7-1 to 7-3 were synthesized according to the method of Example 113.

[0350] Example 123 N-cyclohexyl-4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-8-yl]benzene-1-sulfonamide

[0351] ​To a dichloromethane solution (2 mL) of 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (80 mg) obtained in Reference Example 5, cyclohexene (0.08 mL), potassium carbonate (16 mg), and boron trifluoride diethyl ether complex (0.150 mL) were added, and the mixture was stirred at 80°C for 22 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with water (20 mL) and saturated brine (20 mL), dried over sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 17%) to obtain the title compound (8 mg) as a yellow solid.

[0352] １ H NMR (500MHz, CDCl ３ ): δ7.63 (d, J=8.3Hz, 2H), 7.57 (s, 1H), 7.35-7.28 (m, 5H), 7.24-7.23 (m, 1H), 7.09 (dd, J=8.7, 2.4Hz, 1H), 4.18 (tt, J=12.0, 3.6Hz, 1H), 2.43 (s, 3H), 2.30 ( s, 3H), 1.87-1.85 (m, 2H), 1.74-1.72 (m, 2H), 1.57-1.46 (m, 1H), 1.43-1.32 (m , 2H), 1.05 (dddd, J=12.5, 12.5, 12.5, 3.5Hz, 2H), 0.81 (tt, J=13.2, 3.6Hz, 1H)

[0353] Example 124 N-(2-hydroxyethyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-4-methylbenzenesulfonamide

[0354] ​Using 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Reference Example 5, N-(2-methoxymethoxyethyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-4-methylbenzenesulfonamide was obtained in Example 101 or a method analogous thereto. A 10% solution of hydrogen chloride in methanol (1 mL) was added to a solution of the obtained compound in dichloromethane (1 mL), and the mixture was stirred at room temperature for one day. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 40%) to obtain the title compound (11 mg) as a white solid.

[0355] １ H NMR (500MHz, CDCl ３ ): δ7.59 (s, 1H), 7.56-7.53 (m, 2H), 7.44 (d, J=2.5Hz, 1H), 7.37-7.33 (m, 1H), 7.33-7.29 (m, 4H), 7.28-7. 23 (m, 2H), 7.09 (dd, J = 8.8, 2.5Hz, 1H), 3.76-3.68 (m, 4H), 2.46 (s, 3H), 2.31 (s, 3H), 1.93 (t, J = 5.2Hz, 1H)

[0356] Example 125 2-{N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]}-N-(4-methylbenzenesulfonyl)aminoacetic acid

[0357] (1) Using 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Reference Example 5, 2-{N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]}-N-(4-methylbenzenesulfonyl)aminoacetic acid tert-butyl ester was obtained in accordance with Example 101 or a method analogous thereto.

[0358] ​(2) The 2-{N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]}-N-(4-methylbenzenesulfonyl)aminoacetic acid tert-butyl ester obtained above was treated by the method of Example 69-(2) or a method analogous thereto to give the title compound (13 mg).

[0359] １ H NMR (500MHz, CDCl ３ ): δ7.59-7.54 (m, 4H), 7.36-7.32 (m, 1H), 7.31-7.19 (m, 7H), 4.46 (s, 2H), 2.44 (s, 3H), 2.29 (s, 3H)

[0360] Example 126 N-(azetidin-3-yl)-4-methyl-N-[(3-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide hydrochloride

[0361] (1) N-(1-benzhydrylazetidin-3-yl)-4-methyl-N-[(3-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide was obtained in Example 101 or a method analogous thereto using 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Reference Example 5. 4M HCl / AcOEt (1 mL) was added to the obtained compound, and the mixture was stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration and converted into the hydrochloride salt.

[0362] (2) The compound obtained above was treated in the same manner as in Example 65 or a method equivalent thereto to give the title compound (13 mg) as a pale brown solid.

[0363] １ H NMR (500MHz: DMSO-d ６ ​​): δ 9.01 (brs, 1H), 8.67 (brs, 1H), 8.02 (s, 1H), 7.57 (d, J = 2.6Hz, 1H), 7.46 (d, J = 8.8Hz, 1H), 7.44 (s, 4H), 7.38-7.25 (m , 4H), 7.08 (dd, J=8.8, 2.6Hz, 1H), 4.79-4.72 (m, 1H), 4.14-4.06 (m, 2H), 3.90-3.81 (m, 2H), 2.42 (s, 3H), 2.22 (s, 3H)

[0364] Example 127 N-(4-aminobutyl)-4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0365] (1) Using 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Reference Example 5, N-[4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)butyl]-4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide was obtained in Example 101 or a method analogous thereto.

[0366] (2) To a solution of the compound obtained above (35 mg) in dichloromethane / methanol (1 / 1, 1 mL) was added hydrazine monohydrate (0.014 mL) and the mixture was stirred at room temperature for two days. After concentrating the reaction mixture, the residue was diluted with dichloromethane and insoluble materials were removed by filtration. The filtrate was concentrated to obtain the title compound (27 mg).

[0367] １ H NMR (500MHz, CDCl ３ ): δ7.59 (s, 1H), 7.51-7.48 (m, 2H), 7.38 (d, J=2.5Hz, 1H), 7.37-7.31 (m, 1H), 7.32-7.23 (m, 6H), 7.06 (dd, J =8.8, 2.5Hz, 1H), 3.59-3.55 (m, 2H), 2.70-2.66 (m, 2H), 2.45 (s, 3H), 2.32 (s, 3H), 1.52-1.47 (m, 4H)

[0368] Example 128 ​N-(4-{N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]4-methylbenzenesulfonamido}butyl)acetamide

[0369] Using N-(4-aminobutyl)-4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Example 127 and according to the procedure of Example 70 or a method analogous thereto, the title compound (30 mg) was obtained.

[0370] １ H NMR (500MHz, CDCl ３ ): δ7.59 (s, 1H), 7.49-7.46 (m, 2H), 7.36-7.32 (m, 2H), 7.31-7.23 (m, 6H), 7.06 (dd, J=8.8, 2.5Hz, 1H), 5.55-5.50 (m, 1H), 3. 57 (t, J=6.9Hz, 2H), 3.23 (td, J=7.1, 6.1Hz, 2H), 2.44 (s, 3H), 2.31 (s, 3H), 1.95 (s, 3H), 1.63-1.55 (m, 2H), 1.51-1.44 (m, 2H)

[0371] Example 129 4-methyl-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzamide

[0372] Triethylamine (21 μL), N,N-dimethyl-4-aminopyridine (1 mg), and 4-methylbenzoic acid chloride (20 μL) were added to a dichloromethane solution (1 mL) of 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (40 mg) obtained in Reference Example 5, at 0° C., and the mixture was stirred at room temperature for 1 day. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane=20%) to obtain the title compound (47 mg) as a white solid.

[0373] １ H NMR (500MHz, CDCl ３ ​​): δ7.82 (d, J=8.4Hz, 2H), 7.55 (s, 1H), 7.45 (d, J=2.5Hz, 1H), 7.39 (d, J=8.4Hz, 2H), 7.35-7.31 (m, 3H), 7. 29-7.21 (m, 4H), 7.18 (dd, J = 8.8, 2.5Hz, 1H), 7.02 (d, J = 8.0Hz, 2H), 2.45 (s, 3H), 2.29 (s, 3H), 2.27 (s, 3H)

[0374] Examples 130 to 145 The compounds shown in Tables 8-1 to 8-4 were synthesized according to Example 129 or a method similar thereto.

[0375] Example 146 6-amino-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]hexanamide hydrochloride

[0376] (1) To a dichloromethane solution (1 mL) of 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (40 mg) obtained in Reference Example 5, triethylamine (0.069 mL), tert-butoxycarbonylaminohexanoic acid, and HATU (57 mg) were added, and the mixture was stirred at room temperature for 2 days. A saturated aqueous solution of sodium bicarbonate (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL). The organic layer was washed with water (20 mL) and saturated brine (20 mL), dried over sodium sulfate, and then concentrated. The residue was purified by silica gel chromatography (ethyl acetate / hexane=20%) to give N-(6-{N′-(4-methylbenzenesulfonyl)-N′-[3-(2-methylphenyl-2-oxo-2H-chromen-6-yl)]amino}-6-oxohexyl)carbamic acid tert-butyl ester.

[0377] (2) Using the compound obtained above, the title compound (30 mg) was obtained according to Example 69-(2) or a method analogous thereto.

[0378] １ H NMR (500MHz: DMSO-d ６ ​): δ 8.08 (s, 1H), 7.91-7.88 (m, 3H), 7.72-7.58 (m, 3H), 7.69 (dd, J=8.8, 2.5Hz, 1H), 7.63 (d, J=8.8Hz, 1H), 7.50-7.47 (m, 2H), 7.39-7.27 (m, 4H), 7.27-6.62 (m, 2H), 2.44 (s, 3H), 2.45 (s, 3H), 2.09 (d, J=7.2Hz, 2H), 1.42-1.33 (m, 2H), 1.31-1.24 (m, 2H), 1.15-1.09 (m, 2H)

[0379] Example 147 2-Hydroxy-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]acetamide

[0380] (1) Using 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Reference Example 5, 2-benzyloxy-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]acetamide was obtained in accordance with Example 146-(1) or a method analogous thereto.

[0381] (2) Using the compound obtained above, the title compound (7 mg) was obtained according to the method of Example 65 or a method equivalent thereto.

[0382] １ H NMR (500MHz, CDCl ３ ): δ7.93-7.90 (m, 2H), 7.63 (s, 1H), 7.48 (d, J = 8.6Hz, 1H), 7.47 (d, J = 2.4Hz, 1H), 7.42-7.34 (m , 3H), 7.32-7.24 (m, 4H), 3.98 (d, J = 5.1Hz, 2H), 2.85 (t, J = 5.1Hz, 1H), 2.49 (s, 3H), 2.32 (s, 3H)

[0383] Example 148 3-ethyl-1-(4-methylbenzenesulfonyl)-1-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]urea

[0384] ​Triethylamine (0.14 mL) and ethyl isocyanate (0.080 mL) were added to a dichloromethane solution (1 mL) of 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (40 mg) obtained in Reference Example 5, and the mixture was stirred at room temperature for 3.5 hours. Water (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (20 mL x 2). The extract was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 20%) to obtain the title compound (31 mg) as a white solid.

[0385] １ H NMR (500MHz, DMSO-d ６ ): δ8.13 (s, 1H), 7.78-7.76 (m, 3H), 7.54 (d, J = 8.7Hz, 1H), 7.44-7.40 (m, 3H), 7.37-7.26 (m, 4 H), 6.87 (t, J = 5.6 Hz, 1H), 2.97-2.92 (m, 2H), 2.42 (s, 3H), 2.22 (s, 3H), 0.90 (t, J = 7.1Hz, 3H)

[0386] Examples 149 to 151 The compounds shown in Table 9 were synthesized according to the method of Example 148 or a method analogous thereto.

[0387] Example 152 2-{[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]carbamoyl]amino}acetic acid

[0388] The compound obtained in Example 150 was treated in the manner described in Example 111-(2) or a similar method to give the title compound.

[0389] １ H NMR (500MHz, DMSO-d ６ ): δ12.54 (brs, 1H), 8.15 (s, 1H), 7.81-7.79 (m, 3H), 7.57 (d, J = 8.8Hz, 1H), 7.44-7.40 (m, 3H) ), 7.37-7.27 (m, 4H), 7.06 (t, J = 5.8Hz, 1H), 3.57 (d, J = 5.8Hz, 2H), 2.42 (s, 3H), 2.22 (s, 3H) ​​

[0390] Example 153 N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]morpholine-4-carboxamide

[0391] (1) To a dichloromethane solution (2 mL) of triphosgene (0.24 g), 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (0.160 g) obtained in Reference Example 5 and triethylamine (0.10 mL) were added at 0°C, and the mixture was stirred at room temperature for 16 hours. Water (15 mL) was added to the reaction mixture, followed by extraction with dichloromethane (30 mL × 2). The extract was dried over sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 25%) to obtain N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]carbamoyl chloride (0.140 g) as a white solid.

[0392] (2) To a solution (1 mL) of the compound (19 mg) obtained above in dichloromethane, triethylamine (0.011 mL) and morpholine (4 μL) were added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 30%) to obtain the title compound (0.010 g) as a white solid.

[0393] １ H NMR (500MHz, CDCl ３ ): δ7.57 (d, J=8.4Hz, 2H), 7.54 (s, 1H), 7.49 (d, J=2.5Hz, 1H), 7.40 (m, 1H), 7.3 6-7.23 (m, 7H), 3.67-3.64 (m, 4H), 3.61-3.59 (m, 4H), 2.41 (s, 3H), 2.29 (s, 3H)

[0394] Examples 154 to 164 The compounds shown in Tables 10-1 to 10-3 were synthesized according to the methods of Example 153-(1) and (2) or methods equivalent thereto.

[0395] Example 165 ​3-methyl-3-[2-(methylamino)ethyl]-1-(4-methylbenzenesulfonyl)-1-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]urea hydrochloride

[0396] (1) Using N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]carbamoyl chloride obtained in Example 153-(1), and according to a method similar thereto, N-methyl-N-(2-{methyl[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]carbamoyl]amino}ethyl)carbamic acid tert-butyl ester was obtained.

[0397] (2) Using the compound obtained above (35 mg), the title compound (29 mg) was obtained according to Example 69-(2) or a method analogous thereto.

[0398] １ H NMR (500MHz, CDCl ３ ): δ9.75 (brs, 2H), 7.60 (s, 1H), 7.52 (d, J=8.0Hz, 2H), 7.36-7.31 (m, 2H), 7.30-7.26 (m, 5H), 7.25 -7.21 (m, 2H), 3.84 (brs, 2H), 3.29 (brs, 2H), 3.10 (s, 3H), 2.80 (s, 3H), 2.42 (s, 3H), 2.29 (s, 3H).

[0399] Example 166 N-methyl-N-(2-{methyl[(4-methylbenzenesulfonyl)[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]carbamoyl]amino}ethyl)acetamide

[0400] Using 3-methyl-3-[2-(methylamino)ethyl]-1-(4-methylbenzenesulfonyl)-1-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]urea hydrochloride obtained in Example 165-(2), and according to a method similar to that of Example 70, the title compound (12 mg) was obtained.

[0401] １ ​​H NMR (500MHz, CDCl ３ (contains rotamers in a 4:1 ratio): δ7.58-7.52 (m, 4H), 7.40-7.27 (m, 5H), 7.25-7.22 (m, 3H), 3.58-3.54 (m, 2H), 3.51-3.49 (m, 2H), 3.09 (brs, 2.4H), 3.07 (brs, 0.6H), 3.05 (brs, 2.4H), 2.94 (brs, 0.6H), 2.42 (brs, 0.6H), 2.41 (brs, 2.4H), 2.30 (s, 3H), 2.05 (s, 3H).

[0402] Example 167 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-N-(ethynyl)benzene-1-sulfonamide

[0403] (1) To a 1,4-dioxane suspension of 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (40 mg) obtained in Reference Example 5, copper(II) sulfate pentahydrate (2.5 mg), 1,10-phenanthroline (36 mg), potassium carbonate (28 mg), and trimethylsilylbromoacetylene (19 μL) were added and the mixture was stirred for 6 hours at 100° C. After the reaction solution was filtered through Celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane=25%) to give 4-methyl-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-N-(trimethylsilylethynyl)benzene-1-sulfonamide (12 mg).

[0404] (2) To a solution (1 mL) of the compound (43 mg) obtained above in methanol, potassium carbonate (35 mg) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 20%) to obtain the title compound (25 mg).

[0405] １ H NMR (500MHz, CDCl ３ ​): δ7.62 (d, J = 8.4Hz, 2H), 7.59 (s, 1H), 7.51 (d, J = 2.0Hz, 1H), 7.34-7.31 (m, 5H ), 7.30-7.28 (m, 2H), 7.25-7.23 (m, 1H), 2.89 (s, 1H), 2.46 (s, 3H), 2.29 (s, 3H)

[0406] Example 168 N-[3-(4-methoxyphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0407] A DMF / water mixed solution (500 μL / 50 μL) of N-(3-bromo-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide (30 mg) obtained in Reference Example 6, (4-methoxyphenyl)boronic acid (13 mg), potassium carbonate (15 mg), and bis(diphenylphosphinoferrocene)dichloropalladium(II) dichloromethane adduct (2 mg) was stirred at 70°C for 1 hour under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25) to obtain the title compound (21 mg) as a white solid.

[0408] １ H NMR (500MHz, CDCl ３ ): δ7.81 (d, J=8.4Hz, 4H), 7.66 (d, J=9.0Hz, 2H), 7.63 (s, 1H), 7.35 (d, J=8.4Hz, 4H), 7.30 (d, J=8.8Hz, 1H), 7.26 (d, J = 2.5Hz, 1H), 7.08 (dd, J = 8.8, 2.5Hz, 1H), 6.98 (d, J = 9.0Hz, 2H), 3.86 (s, 3H), 2.48 (s, 6H)

[0409] Examples 169 to 198 The compounds shown in Tables 11-1 to 11-8 were synthesized according to Example 168 or a method similar thereto.

[0410] Example 199 ​N-[3-(4-aminophenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0411] The title compound was obtained using tert-butyl N-(4-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenyl)carbamate obtained in Example 175 and according to Example 69-(2) or a method analogous thereto.

[0412] １ H NMR (500MHz, CDCl ３ ): δ7.81 (d, J = 8.4Hz, 4H), 7.59 (s, 1H), 7.53 (d, J = 8.6Hz, 2H), 7.35 (d, J = 8.4Hz, 4H), 7.28 (d, J = 8.8Hz, 1H) ), 7.23 (d, J=2.4Hz, 1H), 7.05 (dd, J=8.8, 2.4Hz, 1H), 6.72 (d, J=8.6Hz, 2H), 3.89 (br-s, 2H), 2.48 (s, 6H)

[0413] Example 200 N-(4-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenyl)octadecanamide

[0414] The title compound was obtained using N-[3-(4-aminophenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 199 and according to the method of Example 146 or an analogous method.

[0415] １ H NMR (500MHz, CDCl ３ ​​): δ7.81 (d, J = 8.1 Hz, 4H), 7.66 (s, 1H), 7.66 (d, J = 8.5Hz, 2H), 7.61 (d, J = 8.5Hz, 2H), 7.36 (d, J = 8.1Hz, 4H), 7.30 (d, J = 8.8Hz, 1H), 7.27 (d, J = 2. 5Hz, 1H), 7.10 (dd, J = 8.8, 2.5Hz, 1H), 2.48 (s, 6H), 2.38 (t, J = 7.7Hz, 2H ), 1.74 (tt, J=7.7, 7.7Hz, 2H), 1.42-1.20 (m, 28H), 0.88 (t, J=7.1Hz, 3H)

[0416] Example 201 N-(4-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenyl)acetamide

[0417] The title compound was obtained using N-[3-(4-aminophenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 199 and according to the method of Example 70 or an analogous method.

[0418] １ H NMR (500MHz, CDCl ３ ): δ7.81 (d, J=8.4Hz, 4H), 7.67 (d, J=8.5Hz, 2H), 7.67 (s, 1H), 7.59 (d, J=8.5Hz, 2H), 7.36 (d, J=8.4Hz, 4H), 7.3 2 (br-s, 1H), 7.30 (d, J = 8.8Hz, 1H), 7.27 (d, J = 2.4Hz, 1H), 7.10 (dd, J = 8.8, 2.4Hz, 1H), 2.48 (s, 6H), 2.21 (s, 3H)

[0419] Example 202 4-methyl-N-{3-[4-(methylamino)phenyl]-2-oxo-2H-chromen-6-yl}-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0420] ​(1) Using tert-butyl N-(4-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenyl)carbamate obtained in Example 175, tert-butyl N-methyl-N-[N'-(4-{6-[N'-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenyl)]carbamate was obtained in accordance with Example 101 or a method analogous thereto.

[0421] (2) The title compound was obtained using the above-obtained tert-butyl N-methyl-N-[N'-(4-{6-[N'-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenyl)]carbamate according to Example 69-(2) or a method analogous thereto.

[0422] １ H NMR (500MHz, DMSO-d ６ ): δ8.12 (s, 1H), 7.71-7.70 (m, 4H), 7.58-7.56 (m, 2H), 7.55 (d, J = 2.6Hz, 1H), 7.52-7.48 (m, 4H), 7.42 (d, J = 8. 7Hz, 1H), 7.03 (dd, J = 8.7, 2.6Hz, 1H), 6.62-6.59 (m, 2H), 6.08-6.05 (m, 1H), 2.73 (d, J = 5.0Hz, 3H), 2.46 (s, 6H)

[0423] Example 203 N-{3-[4-(dimethylamino)phenyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0424] The compound obtained in Example 202 was treated in the same manner as in Example 101 or a method analogous thereto to give the title compound.

[0425] １ H NMR (500MHz, DMSO-d ６ ​​): δ8.17 (s, 1H), 7.72-7.70 (m, 4H), 7.66-7.64 (m, 2H), 7.57 (d, J = 2.6Hz, 1H), 7.50-7.49 (m, 4H) , 7.43 (d, J=8.7Hz, 1H), 7.04 (dd, J=8.8, 2.7Hz, 1H), 6.79-6.78 (m, 2H), 2.97 (s, 6H), 2.46 (s, 6H)

[0426] Example 204 N-methyl-N-(4-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenyl)carbamic acid (5-methyl-2-oxo-2H-1,3-dioxal-4-yl)methyl ester

[0427] (1) The compound obtained in Example 202 was treated in Example 85-(1) or a method analogous thereto to give N-methyl-N-(4-{6-[4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenyl)carbamic acid chloride.

[0428] (2) The compound obtained above was treated in the same manner as in Example 86 to obtain the title compound.

[0429] １ H NMR (500MHz, DMSO-d ６ ): δ8.31 (s, 1H), 7.74-7.70 (m, 6H), 7.61 (d, J = 2.6Hz, 1H), 7.51-7.47 (m, 6H), 7.44 (d, J = 8 .8Hz, 1H), 7.12 (dd, J=8.8, 2.6Hz, 1H), 4.98 (s, 2H), 2.46 (s, 6H), 2.16 (s, 3H), 2.10 (s, 3H)

[0430] Example 205 4-methyl-N-(4-methylbenzenesulfonyl)-N-(2-oxo-3-{4-[(2-propenyl)amino]phenyl}-2H-chromen-6-yl)benzene-1-sulfonamide

[0431] ​(1) Using tert-butyl N-(4-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenyl)carbamate obtained in Example 175, tert-butyl N-(2-propenyl)-N-[N'-(4-{6-[N'-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenyl)]carbamate was obtained in accordance with Example 101 or a method analogous thereto.

[0432] (2) The compound obtained above was treated in Example 69-(2) or a method analogous thereto to give the title compound.

[0433] １ H NMR (500MHz, DMSO-d ６ ): δ8.11 (s, 1H), 7.72-7.70 (m, 4H), 7.55-7.53 (m, 3H), 7.50-7.49 (m, 4H), 7.42 (d, J = 8.8Hz, 1H), 7.03 (dd, J = 8.8, 2.5Hz, 1H), 6.65-6.63 (m, 2H), 6.30-6.25 (m, 1H), 5.95-5.86 (m, 1H), 5.26-5.11 (m, 1H), 5.13-5.10 (m, 1H), 3.78-3.74 (m, 2H), 2.46 (s, 6H)

[0434] Example 206 4-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}benzoic acid

[0435] The title compound was obtained using methyl 4-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}benzoate obtained in Example 170 and according to the method of Example 111 or an analogous method.

[0436] １ H NMR (500MHz, DMSO-d ６ ​​): δ8.38 (s, 1H), 7.79 (d, J = 8.5Hz, 2H), 7.71 (d, J = 8.4Hz, 4H), 7.64 (d, J = 2.6Hz, 1H), 7.51-7.48 (m, 5H), 7.4 5 (d, J=8.5Hz, 2H), 7.13 (dd, J=8.8, 2.6Hz, 1H), 3.45 (brs, 2H), 3.22 (brs, 2H), 1.16 (brs, 3H), 1.08 (brs, 3H)

[0437] Example 207 N,N-Diethyl-4-{6-[N'-(4-methylbenzenesulfonyl)-N'-(4-methylbenzenesulfonylamino)]-2-oxo-2H-chromen-3-yl}benzoic acid carboxamide

[0438] Using 4-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}benzoic acid obtained in Example 206 and according to the method of Example 146 or an analogous method, the title compound was obtained.

[0439] １ H NMR (500MHz, DMSO-d ６ ): δ13.09 (brs, 1H), 8.42 (s, 1H), 8.04 (d, J=8.7Hz, 2H), 7.86 (d, J=8.7Hz, 2H), 7.71 (d, J=8. 4Hz, 4H), 7.66 (d, J = 2.6Hz, 1H), 7.51-7.49 (m, 5H), 7.14 (dd, J = 8.8, 2.6Hz, 1H), 2.46 (s, 6H)

[0440] Example 208 4-methyl-N-(4-methylbenzenesulfonyl)-N-{3-[4-(morpholine-4-carbonyl)phenyl]-2-oxo-2H-chromen-6-yl}benzene-1-sulfonamide

[0441] Using 4-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}benzoic acid obtained in Example 206 and according to the method of Example 146 or an analogous method, the title compound was obtained.

[0442] １H NMR (500MHz, DMSO-d ６ ): δ8.37 (s, 1H), 7.80 (d, J = 8.5Hz, 2H), 7.71 (d, J = 8.3Hz, 4H), 7.64 (d, J = 2.6Hz, 1 H), 7.53-7.48 (m, 7H), 7.14 (dd, J=8.8, 2.5Hz, 1H), 3.68-3.54 (m, 8H), 2.46 (s, 6H)

[0443] Example 209 N-(2-hydroxyethyl)-4-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}benzamide

[0444] Using 4-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}benzoic acid obtained in Example 206 and according to the method of Example 146 or an analogous method, the title compound was obtained.

[0445] １ H NMR (500MHz, CDCl ３ ): δ7.88 (d, J = 8.4Hz, 2H), 7.82-7.77 (m, 7H), 7.37-7.32 (m, 6H), 7.13 (dd, J = 9.0, 2.7Hz, 1H ), 6.62-6.60 (m, 1H), 3.89-3.86 (m, 2H), 3.70-3.66 (m, 2H), 2.49 (s, 6H), 2.38-2.35 (m, 1H)

[0446] Example 210 4-(2-aminoethoxy)-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0447] (1) Using N-[3-(4-hydroxyphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 174, N-[2-(4-{6-[N',N'-bis(methylbenzenesulfonyl)amino]}-2-oxo-2H-chromen-3-ylphenoxy)ethyl]carbamic acid tert-butyl ester was obtained in accordance with Example 69-(1) or a method analogous thereto.

[0448] (2) The compound obtained above was treated with 69-(2) or a method analogous thereto to give the title compound.

[0449] １ H NMR (500MHz, CDCl ３ ): δ8.26 (s, 1H), 7.99 (br-s, 2H), 7.73 (d, J = 8.9Hz, 2H), 7.71 (d, J = 8.4Hz, 4H), 7.63 (d, J = 2.6Hz, 1H), 7.50 ( d, J = 8.4Hz, 4H), 7.47 (d, J = 8.9Hz, 1H), 7.11-7.08 (m, 3H), 4.23 (t, J = 5.1Hz, 2H), 3.27 (brs, 2H), 2.46 (s, 6H)

[0450] Example 211 N-[2-(2-methoxyethoxy)ethyl]-N'-[2-(4-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenoxy)ethyl]butanediamide

[0451] The title compound was obtained using 4-(2-aminoethoxy)-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Example 210 and according to the method of Example 146 or an analogous method.

[0452] １ H NMR (500MHz, CDCl ３ ​​): δ7.82 (d, J = 8.4Hz, 4H), 7.65 (d, J = 8.9Hz, 2H), 7.65 (s, 1H), 7.36 (d, J = 8.4Hz, 4H), 7.31 (d, J = 8.8Hz, 1H) ), 7.27 (d, J=2.5Hz, 1H), 7.10 (dd, J=8.8, 2.5Hz, 1H), 6.98 (d, J=8.9Hz, 2H), 6.51 (br-s, 1H), 6.27 (br-s, 1H), 4.09 (t, J = 5.2Hz, 2H), 3.69 (t, J = 5.3Hz, 2H), 3.62 (t, J = 6.3Hz, 2H), 3.55 (t, J = 6.3Hz, 2H), 3.55 (t, J =5.2Hz, 2H), 3.45 (t, J = 5.3Hz, 2H), 3.40 (s, 3H), 2.55 (t, J = 2.1Hz, 2H), 2.55 (t, J = 2.1Hz, 2H), 2.49 (s, 6H)

[0453] Example 212 N-[2-(4-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenoxy)ethyl]acetamide

[0454] The title compound was obtained using 4-(2-aminoethoxy)-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Example 210 and according to the method of Example 70 or an analogous method.

[0455] １ H NMR (500MHz, CDCl ３ ): δ7.81 (d, J=8.4Hz, 4H), 7.65 (d, J=9.0Hz, 2H), 7.65 (s, 1H), 7.36 ( d, J = 8.4Hz, 4H), 7.30 (d, J = 8.8Hz, 1H), 7.27 (d, J = 2.5Hz, 1H), 7.09 (d d, J = 8.8, 2.5Hz, 1H), 6.98 (d, J = 9.0Hz, 2H), 5.91 (br-s, 1H), 4.10 (t , J=5.0Hz, 2H), 3.69 (dt, J=5.0, 5.0Hz, 2H), 2.48 (s, 6H), 2.03 (s, 3H)

[0456] Example 213 ​N-methyl-N-[2-(4-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenoxy)ethyl]acetamide

[0457] (1) Using N-[3-(4-hydroxyphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 174, N-methyl-N-[2-(4-{6-[N',N'-bis(methylbenzenesulfonyl)amino]}-2-oxo-2H-chromen-3-ylphenoxy)ethyl]carbamic acid tert-butyl ester was obtained in accordance with Example 69-(1) or a method analogous thereto.

[0458] (2) The compound obtained above was treated with 69-(2) or a method analogous thereto to give 4-methyl-N-(3-{4-[2-(methylamino)ethoxy]phenyl}-2-oxo-2H-chromen-6-yl)-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide.

[0459] (3) The compound obtained above was treated in the same manner as in Example 70 to obtain the title compound. １ H NMR (500MHz, CDCl ３ ), (70:30 Rotamer mixture): δ7.81 (d, J = 8.4Hz, 4H), 7.67-7.64 (m, 3H), 7.35 (d, J = 8.4Hz, 4H), 7.30 (d , J=8.8Hz, 1H), 7.27 (d, J=2.5Hz, 1H), 7.08 (dd, J=8.8, 2.5Hz, 1H), 6.98-6.94 (m, 2H) , 4.19 (t, J=5.3Hz, 1.4H), 4.15 (t, J=5.3Hz, 0.6H), 3.77 (t, J=5.3, 1.4H), 3.74 (t, J= 5.3, 0.6H), 3.17 (s, 2.1H), 3.02 (s, 0.9H), 2.49 (s, 6H), 2.21 (s, 0.9H), 2.11 (s, 2.1H)

[0460] Example 214 4-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenyl acetate

[0461] To a dichloromethane solution (0.5 mL) of N-[3-(4-hydroxyphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide (14 mg) obtained in Example 174, 4-dimethylaminopyridine (1 mg), triethylamine (7 μL), and acetic anhydride (5 μL) were added and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25) to obtain the title compound (4 mg) as a white solid.

[0462] １ H NMR (500MHz, CDCl ３ ): δ7.81 (d, J=8.4Hz, 4H), 7.71 (d, J=8.9Hz, 2H), 7.68 (s, 1H), 7.36 (d, J=8.4Hz, 4H), 7.32 (d, J=8.8Hz, 1H), 7.26 (d, J = 2.5Hz, 1H), 7.19 (d, J = 8.9Hz, 2H), 7.13 (dd, J = 8.8, 2.5Hz, 1H), 2.49 (s, 6H), 2.33 (s, 3H)

[0463] Example 215 N-[3-(2-hydroxyphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0464] The title compound was obtained in Example 65 or a method analogous thereto using N-{3-[2-(benzyloxy)phenyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 186.

[0465] １ H NMR (500MHz, DMSO-d ６ ​​): δ9.63 (s, 1H), 8.07 (s, 1H), 7.72-7.70 (m, 4H), 7.63 (d, J = 2.6Hz, 1H), 7.51-7.46 (m, 4H), 7.46 (d, J = 8.8Hz, 1H), 7 .28-7.23 (m, 2H), 7.08 (dd, J=8.8, 2.6Hz, 1H), 6.91 (dd, J=8.3, 1.0Hz, 1H), 6.88 (td, J=7.4, 1.1Hz, 1H), 2.46 (s, 6H)

[0466] Example 216 N-[3-(2-butoxyphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0467] The title compound was obtained using N-[3-(2-hydroxyphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 215 and according to the method described in Example 69-(1) or a method analogous thereto.

[0468] １ H NMR (500MHz, DMSO-d ６ ): δ8.07 (s, 1H), 7.73-7.70 (m, 4H), 7.60 (d, J = 2.6Hz, 1H), 7.52-7.46 (m, 5H), 7.44-7.39 (m, 1H), 7.35 (dd, J = 7.5, 1.8Hz, 1H), 7.1 2-7.08 (m, 2H), 7.04-7.00 (m, 1H), 3.99 (t, J = 6.4Hz, 2H), 2.46 (s, 6H), 1.63-1.58 (m, 2H), 1.36-1.32 (m, 2H), 0.84 (t, J = 7.5Hz, 3H)

[0469] Example 217 1,2-dimethyl-5-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl]}-1H-pyrazole-2-ium iodide

[0470] ​The title compound was obtained using 4-methyl-N-[3-(1-methyl-1H-pyrazol-5-yl)-2-oxo-2H-chromen-6-yl]-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 185 and according to the method of Example 101 or a method analogous thereto.

[0471] １ H NMR (500MHz, DMSO-d ６ ): δ8.59 (d, J=2.9Hz, 1H), 8.49 (s, 1H), 7.81 (d, J=2.6Hz, 1H), 7.72-7.69 (m, 4H), 7.57 (d, J=8.9Hz, 1H), 7. 52-7.50 (m, 4H), 7.25 (dd, J = 8.8, 2.6Hz, 1H), 7.06 (d, J = 2.9Hz, 1H), 4.22 (s, 3H), 4.06 (s, 3H), 2.47 (s, 6H)

[0472] Example 218 N-{3-[(E)-2-(2-hydroxyphenyl)ethynyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0473] ​(1) N-(3-bromo-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide (0.10 g) obtained in Reference Example 6, 2-methoxystyrene (37 mg), N,N-diisopropylethylamine (0.048 mL), silver acetate (2 mg), tris(4-methylphenyl)phosphine (4 mg), and tris(dibenzylideneacetone)dipalladium(0) (8 mg) were suspended in 1,4-dioxane and stirred at 90°C for 18 hours under a nitrogen atmosphere. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (60 mL). The extract was washed with water (10 mL) and saturated brine (10 mL) and then dried over anhydrous sodium sulfate. The filtrate was concentrated, and the residue was purified by silica gel chromatography (ethyl acetate / hexane=0 to 50%) to give N-{3-[(E)-2-(2-methoxyphenyl)ethynyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide (60 mg) as a pale yellow solid.

[0474] (2) The compound obtained above was treated in the same manner as in Example 66 to obtain the title compound.

[0475] １ H NMR (500MHz, DMSO-d ６ ): δ9.96 (s, 1H), 8.30 (s, 1H), 7.83 (d, J = 16.6Hz, 1H), 7.73-7.70 (m, 4 H), 7.57 (d, J=2.6Hz, 1H), 7.56-7.54 (m, 1H), 7.52-7.49 (m, 1H), 7.45 (d, J=8.7Hz, 1H), 7.20 (d, J=16.6Hz, 1H), 7.17-7.13 (m, 1H), 7.07 (dd , J=8.7, 2.6Hz, 1H), 6.91-6.89 (m, 1H), 6.87-6.83 (m, 1H), 2.46 (s, 6H)

[0476] Example 219 N-{3-[2-(2-hydroxyphenyl)ethyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide ​

[0477] The compound obtained in Example 218 was treated in the same manner as in Example 65 or a method analogous thereto to give the title compound.

[0478] １ H NMR (500MHz, DMSO-d ６ ): δ9.31 (s, 1H), 7.78 (s, 1H), 7.70-7.67 (m, 4H), 7.50-7.46 (m, 4H), 7.43-7.40 (m, 2H), 7.08-7.0 0 (m, 3H), 6.78-6.76 (m, 1H), 6.73-6.70 (m, 1H), 2.85-2.82 (m, 2H), 2.73-2.70 (m, 2H), 2.46 (s, 6H)

[0479] Example 220 N-{3-[(E)-2-(2-butoxyphenyl)ethenyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0480] The compound obtained in Example 218 was treated in the manner described in Example 69-(1) or a method analogous thereto to give the title compound.

[0481] １ H NMR (500MHz, DMSO-d ６ ): δ8.25 (s, 1H), 7.89 (d, J = 16.3Hz, 1H), 7.74-7.70 (m, 4H), 7.63-7.60 (m , 1H), 7.56 (d, J = 2.6Hz, 1H), 7.52-7.49 (m, 1H), 7.45 (d, J = 8.7Hz, 1H), 7.3 2-7.29 (m, 1H), 7.25 (d, J=16.6Hz, 1H), 7.09-7.06 (m, 2H), 7.02-6.97 (m, 1H), 4.07 (t, J=6.4Hz, 2H), 2.46 (s, 3H), 1.82-1.77 (m, 2H), 1.58-1.50 (m, 2H), 0.98 (t, J=7.5Hz, 3H)

[0482] Example 221 N-{3-[2-(2-butoxyphenyl)ethyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0483] ​​The compound obtained in Example 220 was treated in the same manner as in Example 65 or a method analogous thereto to give the title compound.

[0484] １ H NMR (500MHz, DMSO-d ６ ): δ7.70-7.64 (m, 5H), 7.51-7.46 (m, 4H), 7.42 (d, J = 8.8Hz, 1H), 7.38 (d, J = 2.5Hz , 1H), 7.20-7.14 (m, 1H), 7.05 (dd, J=8.7, 2.5Hz, 1H), 6.91 (dd, J=8.0, 0.8Hz, 1H) , 6.87 (td, J=7.5, 0.9Hz, 1H), 3.85 (t, J=6.5Hz, 2H), 2.90-2.85 (m, 2H), 2.75-2.7 0 (m, 2H), 2.46 (s, 6H), 1.70-1.60 (m, 2H), 1.48-1.39 (m, 2H), 0.98 (t, J = 7.5Hz, 3H)

[0485] Example 222 4-methyl-N-(4-methylbenzenesulfonyl)-N-[2-oxo-3-(2-phenylethynyl)2H-chromen-6-yl]benzene-1-sulfonamide

[0486] N-(3-bromo-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide (0.10 g) obtained in Reference Example 6, phenylacetylene (5 μL), N,N-diisopropylethylamine (7 μL), triphenylphosphine (0.5 mg), bis(triphenylphosphine)palladium(II) chloride (1.3 mg), and copper iodide (0.3 mg) were suspended in 1,4-dioxane (0.5 mL) and stirred for 20 hours at 50° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (ethyl acetate / hexane=25-50%) to give the title compound (11 mg) as a pale yellow solid.

[0487] １ H NMR (500MHz, CDCl ３ ​​): δ7.82 (s, 1H), 7.81 (d, J=8.3Hz, 4H), 7.60-7.58 (m, 2H), 7.39-7.36 (m, 7H), 7.3 1 (d, J=8.8Hz, 1H), 7.20 (d, J=2.5Hz, 1H), 7.13 (dd, J=8.8, 2.5Hz, 1H), 2.50 (s, 6H)

[0488] Example 223 4-methyl-N-(4-methylbenzenesulfonyl)-N-[2-oxo-3-(2-phenylethynyl)2H-chromen-6-yl]benzene-1-sulfonamide

[0489] Using N-(3-bromo-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Reference Example 6 and according to the method of Example 222 or a method analogous thereto, the title compound was obtained.

[0490] １ H NMR (500MHz, CDCl ３ ): δ7.80 (d, J = 8.3Hz, 4H), 7.66 (s, 1H), 7.36 (d, J = 8.3Hz, 4H), 7.27 (d, J = 8.8Hz, 1H), 7.15 (d, J = 2.5Hz, 1H), 7.09 (dd, J = 8.8, 2 .5Hz, 1H), 2.49 (s, 6H), 2.48 (t, J=7.3Hz, 2H), 1.62 (tt, J=7.6 , 7.3Hz, 2H), 1.49 (tq, J = 7.6, 7.4Hz, 2H), 0.96 (t, J = 7.4Hz, 2H)

[0491] Example 224 4-methyl-N-(4-methylbenzenesulfonyl)-N-{2-oxo-3-[2-(trimethylsilyl)ethynyl]-2H-chromen-6-yl}benzene-1-sulfonamide

[0492] Using N-(3-bromo-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Reference Example 6 and according to the method of Example 222 or a method analogous thereto, the title compound was obtained.

[0493] １ ​​H NMR (500MHz, CDCl ３ ): δ7.79 (d, J=8.2Hz, 4H), 7.76 (s, 1H), 7.35 (d, J=8.2Hz, 4H), 7.27 (d, J=8.8Hz, 1H), 7.16 (d, J = 2.2Hz, 1H), 7.11 (dd, J = 8.8, 2.2Hz, 1H), 2.48 (s, 6H), 0.27 (s, 9H)

[0494] Example 225 N-(3-ethynyl-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0495] To a solution (1 mL) of 4-methyl-N-(4-methylbenzenesulfonyl)-N-{2-oxo-3-[2-(trimethylsilyl)ethynyl]-2H-chromen-6-yl}benzene-1-sulfonamide (15 mg) obtained in Example 224 in a 1 / 1 methanol / tetrahydrofuran mixture, 3 μL of acetic acid was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography (ethyl acetate / hexane = 25-50%) to obtain the title compound (7 mg) as a dark yellow solid.

[0496] １ H NMR (500MHz, CDCl ３ ): δ7.83 (s, 1H), 7.80 (d, J = 8.4Hz, 4H), 7.36 (d, J = 8.4Hz, 4H), 7.30 (d, J = 8.9Hz, 1H), 7.20 (d, J = 2.4Hz, 1H), 7.15 (dd, J = 8.9, 2.4 Hz, 1H), 3.43 (s, 1H), 2.49 (s, 6H)

[0497] Example 226 N-[3-(4-methoxyphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0498] ​(1) Using N-(3-bromo-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Reference Example 6, and according to Example 168 or a method analogous thereto, N-[3-(4-formylphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide was obtained.

[0499] (2) The compound obtained above was treated in the same manner as in Example 82 to obtain the title compound.

[0500] １ H NMR (500MHz, DMSO-d ６ ): δ8.31 (s, 1H), 7.72-7.69 (m, 6H), 7.62 (d, J=2.6Hz, 1H), 7.51-7.47 (m, 5H), 7.4 0-7.38 (m, 2H), 7.11 (dd, J=8.8, 2.6Hz, 1H), 3.49 (s, 2H), 2.46 (s, 6H), 2.17 (s, 6H)

[0501] Example 227 N-[3-(4-methoxyphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0502] The title compound was obtained using N-[3-(4-formylphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 226-(1) and according to the method of Example 82 or a method analogous thereto.

[0503] １ H NMR (500MHz, DMSO-d ６ ): δ8.87-8.73 (brs, 1H), 8.35 (s, 1H), 7.80-7.78 (m, 2H), 7.71-7.69 (m, 4H), 7.66 (d, J=2.6Hz, 1H), 7. 59-7.57 (m, 2H), 7.52-7.48 (m, 5H), 7.13 (dd, J=8.8, 2.6Hz, 1H), 4.18 (s, 2H), 2.60 (s, 3H), 2.46 (s, 6H) ​​

[0504] Example 228 4-methyl-N-(4-methylbenzenesulfonyl)-N-[3-(morpholin-4-yl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0505] N-(3-bromo-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide (30 mg) obtained in Reference Example 6, morpholine (9.5 μL), bis[tri(tert-butyl)phosphine]palladium(0) (8.4 mg), and potassium tert-butoxide (12 mg) were suspended in toluene (0.55 mL) and stirred at 110° C. for 19 hours under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (3 mL) was added to the reaction solution, followed by extraction with ethyl acetate (3 mL × 2). The extract was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (ethyl acetate / hexane = 0 to 35%) to obtain the title compound (1.1 mg) as a pale yellow solid.

[0506] １ H NMR (500MHz, CDCl ３ ): δ7.80 (d, J=8.3Hz, 4H), 7.14 (d, J=8.3Hz, 4H), 7.21 (d, J=8.7Hz, 1H), 7.16 (d, J=2.5Hz, 1H), 6. 90 (dd, J=8.7, 2.5Hz, 1H), 6.68 (s, 1H), 3.89 (t, J=4.6Hz, 4H), 3.22 (t, J=4.6Hz, 4H), 2.49 (s, 6H)

[0507] Example 229 N-{3-[2-fluoro-4-(trifluoromethyl)phenyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0508] ​A suspension (1.1 mL) of 4-methyl-N-(4-methylbenzenesulfonyl)-N-[2-oxo-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-chromen-6-yl]benzene-1-sulfonamide (30 mg), 2-fluoro-4-trifluoromethylbromobenzene (7 μL), potassium phosphate (21 mg), and bis[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium-dichloromethane complex (II) (4 mg) in N,N-dimethylformamide / water (10 / 1) was stirred at 50 °C for 1 hour. A saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL). The extract was dried over sodium sulfate and concentrated, and the residue was purified by silica gel chromatography (ethyl acetate / hexane = 0 to 50%) to obtain the title compound (7 mg) as a white solid.

[0509] １ H NMR (500MHz, DMSO-d ６ ): δ8.36 (s, 1H), 7.88-7.80 (m, 2H), 7.75-7.73 (m, 1H), 7.72-7.70 (m, 4H), 7.68 (d, J = 2.5H z, 1H), 7.53 (d, J = 8.8Hz, 1H), 7.50-7.49 (m, 4H), 7.17 (dd, J = 8.8, 2.6Hz, 1H), 2.46 (s, 6H)

[0510] Examples 230 to 232 The compounds shown in Table 12 were synthesized according to the method of Example 229 or a method analogous thereto.

[0511] Example 233 4-methyl-N-(4-methylbenzenesulfonyl)-N-[3-(3-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0512] (1) 3-(3-methylphenyl)-6-nitro-2H-chromen-2-one was obtained from 5-nitrosalicylaldehyde according to the method described in Reference Example 2 or a method analogous thereto.

[0513] ​(2) The compound obtained above was treated in the manner described in Reference Example 4-(1) or a method analogous thereto to give 6-amino-3-(4-methylphenyl)-2H-chromen-2-one.

[0514] (3) The compound obtained above was treated according to Reference Example 4-(2) or a method analogous thereto to give the title compound.

[0515] １ H NMR (500MHz, CDCl ３ ): δ7.83-7.80 (m, 4H), 7.68 (s, 1H), 7.49-7.45 (m, 2H), 7.37-7.30 (m, 6H) , 7.28-7.24 (m, 2H), 7.11 (dd, J=8.8, 2.5Hz, 1H), 2.49 (s, 6H), 2.43 (s, 3H)

[0516] Examples 234 to 253 The compounds shown in Tables 13-1 to 13-5 were synthesized according to Example 233 or a method equivalent thereto.

[0517] Example 254 N-[3-(3-methoxyphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0518] (1) The compound obtained in Example 234 was treated in the same manner as in Example 68 or a method analogous thereto to give N-[3-(3-hydroxyphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide.

[0519] (2) The compound obtained above was treated in the same manner as in Example 101 to obtain the title compound.

[0520] １ H NMR (500MHz, CDCl ３ ​​): δ7.81 (d, J=8.4Hz, 4H), 7.70 (s, 1H), 7.37 (dd, J=8.1, 8.1Hz, 1H), 7.36 (d, J=8.4Hz, 4H), 7.32 (d, J=8.8Hz, 1H), 7.27 (d, J = 2.5Hz, 1H), 7.26-7.23 (m, 2H), 7.11 (dd, J = 8.8, 2.4Hz, 1H), 6.97 (ddd, J = 8.8, 2.5, 1.1Hz, 1H), 3.68 (s, 3H), 2.48 (s, 6H)

[0521] Example 255 4-methyl-N-(3-{3-[2-(methylamino)ethoxy]phenyl}-2-oxo-2H-chromen-6-yl)-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0522] (1) The compound obtained in Example 254-(1) was treated in Example 69-(1) or a method analogous thereto to give N-methyl-N-(2-{3-[6-N',N'-bis(4-methylbenzenesulfonyl)amino-2-oxo-2H-chromen-3-yl]phenoxy}ethyl)carbamic acid tert-butyl ester.

[0523] (2) The compound obtained above was treated with 69-(2) or a method analogous thereto to give the title compound.

[0524] １ H NMR (500MHz, CDCl ３ ): δ7.80 (d, J=8.4Hz, 4H), 7.72 (s, 1H), 7.35 (d, J=8.4Hz, 4H), 7.33-7.28 (m, 3H), 7.25-7.23 (m, 2H), 7.09 (dd, J=8.8, 2.5Hz, 1H), 7.01 (ddd, J=8.1, 2.6, 0.9Hz, 1H), 4.37 (t, J=4.9Hz, 2H), 3.30 (t, J=4.9Hz, 2H), 2.75 (s, 3H), 2.47 (s, 6H)

[0525] Example 256 N-methyl-N-[2-(3-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenoxy)ethyl]acetamide ​

[0526] The compound obtained in Example 255 was treated in the same manner as in Example 70 to obtain the title compound.

[0527] １ H NMR (500MHz, CDCl ３ ), (66:34 mixture of rotamers): δ7.81 (d, J = 8.3Hz, 4H), 7.72 (s, 0.34H), 7.71 (s, 0.66H), 7.38-7.35 ( m, 5H), 7.33-7.22 (m, 5H), 7.13-7.10 (m, 1H), 6.97-6.93 (m, 1H), 6.98-6.94 (m, 2H ), 4.19 (t, J = 5.3 Hz, 1.4 H), 4.16 (t, J = 5.3 Hz, 0.6 H), 3.78 (t, J = 5.3, 1.4 H), 3.74 ( t, J = 5.3, 0.6H), 3.18 (s, 2H), 3.03 (s, 1H), 2.48 (s, 6H), 2.22 (s, 1H), 2.11 (s, 2H)

[0528] Example 257 N-{3-[3-(2-methoxyethoxy)phenyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0529] The compound obtained in Example 254-(1) was treated in Example 69-(1) or a method analogous thereto to give the title compound.

[0530] １ H NMR (500MHz, CDCl ３ ): δ7.84-7.80 (m, 4H), 7.69 (s, 1H), 7.39-7.35 (m, 5H), 7.32 (d, J = 8.8Hz, 1H), 7.28-7.25 (m, 3H), 7.12 (d d, J = 8.7, 2.4Hz, 1H), 7.02-6.99 (m, 1H), 4.20-4.17 (m, 2H), 3.80-3.77 (m, 2H), 3.47 (s, 3H), 2.49 (s, 6H)

[0531] Example 258 ​​N-{3-[3-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)phenyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0532] The compound obtained in Example 254-(1) was treated in Example 69-(1) or a method analogous thereto to give the title compound.

[0533] １ H NMR (500MHz, CDCl ３ ): δ7.84-7.81 (m, 4H), 7.71 (s, 1H), 7.40-7.35 (m, 5H), 7.33 (d, J = 8.8Hz, 1H), 7 .29-7.26 (m, 3H), 7.13 (dd, J=8.8, 2.5Hz, 1H), 7.02-6.99 (m, 1H), 4.55-4.49 (m , 1H), 4.20 (dd, J=8.5, 6.5Hz, 1H), 4.12 (dd, J=9.4, 5.6Hz, 1H), 4.02 (dd, J=9.4 , 5.9Hz, 1H), 3.94 (dd, J=8.5, 5.9Hz, 1H) 2.50 (s, 6H), 1.49 (s, 3H), 1.43 (s, 3H)

[0534] Example 259 N-{3-[3-(2,3-dihydroxypropoxy)phenyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0535] The compound obtained in Example 258 was treated in the same manner as in Example 81 to obtain the title compound.

[0536] １ H NMR (500MHz, CDCl ３ ​​): δ7.85-7.80 (m, 4H), 7.72 (s, 1H), 7.41-7.35 (m, 5H), 7.33 (d, J = 8.8Hz, 1H), 7.30-7.26 (m, 3H), 7.13 (dd, J = 8.8, 2.5Hz, 1H), 7.0 2-6.99 (m, 1H), 4.19-4.08 (m, 3H), 3.91-3.85 (m, 1H), 3.82-3.76 (m, 1H), 2.57 (d, J = 4.5Hz, 1H), 2.50 (s, 6H), 1.96 (t, J = 6.0Hz, 1H)

[0537] Example 260 6-[N,N-bis(4-methylbenzenesulfonyl)amino]-2-oxo-2H-chromene-3-carboxylic acid

[0538] (1) Meldrum's acid (0.173 g) and iron(III) chloride were added to a benzyl alcohol solution (3 mL) of 5-nitrosalicylaldehyde (0.170 g), and the mixture was stirred at 70° C. for one day. The reaction mixture was diluted with ethyl acetate, and the precipitate was collected by filtration to obtain 6-nitro-2-oxo-2H-chromene-3-carboxylic acid benzyl ester (0.168 g) as a white solid.

[0539] (2) The compound obtained above was treated in the manner described in Reference Example 4-(1) or a method analogous thereto to give 6-amino-2-oxo-2H-chromene-3-carboxylic acid benzyl ester.

[0540] (3) The compound obtained above was treated in the manner described in Reference Example 4-(2) or a method analogous thereto to give 6-[N,N-bis(4-methylbenzenesulfonyl)amino]-2-oxo-2H-chromene-3-carboxylic acid benzyl ester.

[0541] (4) The compound obtained above was treated in accordance with the procedure of Reference Example 65 or a method analogous thereto to give the title compound.

[0542] １ H NMR (500MHz, CDCl ３ ): δ12.01 (brs, 1H), 8.81 (s, 1H), 7.82-7.78 (m, 4H), 7.47 (d, J = 8.9Hz, 1H), 7.42-7.36 (m, 6H), 2.51 (s, 6H)

[0543] Example 261​ N-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}carbamic acid tert-butyl ester

[0544] To a solution of 6-[N,N-bis(4-methylbenzenesulfonyl)amino]-2-oxo-2H-chromene-3-carboxylic acid (26 mg) obtained in Example 260 in tert-butanol (0.3 mL) were added triethylamine (0.010 mL) and diphenylphosphoryl azide (0.016 mL), and the mixture was stirred at 80°C for 30 minutes. The reaction solution was diluted with ethyl acetate (30 mL) and washed with 1 M hydrochloric acid (10 mL), saturated aqueous sodium bicarbonate solution (10 mL), water (10 mL), and saturated brine (10 mL). The organic layer was dried over sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane 20%) to obtain the title compound (3 mg) as a white solid.

[0545] １ H NMR (500MHz, DMSO-d ６ ): δ8.66 (s, 1H), 8.21 (s, 1H), 7.72-7.68 (m, 4H), 7.58 (d, J = 2.6Hz, 1H), 7.51-7.47 ( m, 4H), 7.42 (d, J = 8.8Hz, 1H), 6.97 (dd, J = 8.8, 2.6Hz, 1H), 2.46 (s, 6H), 1.49 (s, 9H)

[0546] Example 262 N-{6-[N,N-bis(4-methylbenzenesulfonyl)amino]-2-oxo-2H-chromen-6-yl}carbamic acid benzyl ester

[0547] Using 6-[N,N-bis(4-methylbenzenesulfonyl)amino]-2-oxo-2H-chromene-3-carboxylic acid obtained in Example 260 and according to the method of Example 261 or an analogous method, the title compound was obtained.

[0548] １ H NMR (500MHz: DMSO-d ６ ​​): δ9.43 (s, 1H), 8.26 (s, 1H), 7.72-7.68 (m, 4H), 7.59 (d, J = 2.6Hz, 1H), 7 .51-7.33 (m, 10H), 6.97 (dd, J=8.8, 2.6Hz, 1H), 5.22 (s, 2H), 2.46 (s, 6H)

[0549] Example 263 N-(3-amino-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0550] The compound obtained in Example 261 was used to obtain the title compound according to Example 69-(2) or a method analogous thereto.

[0551] １ H NMR (500MHz: DMSO-d ６ ): δ7.72-7.68 (m, 4H), 7.51-7.47 (m, 4H), 7.30 (d, J=8.7Hz, 1H), 7.16 (d, J=2.5Hz, 1H), 6.71 (dd, J=8.7, 2.5 Hz, 1H), 6.65 (s, 1H), 5.93 (brs, 2H), 2.46 (s, 6H)

[0552] Example 264 N-[3-(aminomethyl)-2-oxo-2H-chromen-3-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide hydrochloride

[0553] (1) To a solution of 5-nitrosalicylaldehyde (89 mg) in acetic anhydride (0.53 mL), 3-[(tert-butoxycarbonyl)amino]propionic acid (0.100 g) and triethylamine (0.19 mL) were added and stirred at 140°C for 18 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL). The extract was washed with saturated aqueous ammonium chloride solution (20 mL) and saturated brine (20 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane 0-50%) to obtain 3-[3-N,N-bis(acetyl)aminomethyl]-6-nitro-2H-chromen-2-one (25 mg) as a yellow solid. ​

[0554] (2) The compound obtained above was treated in the manner described in Reference Example 4-(1) or a method analogous thereto to give 6-amino-3-[3-N,N-bis(acetyl)aminomethyl]-2H-chromen-2-one.

[0555] (3) The compound obtained above was treated in the manner described in Reference Example 4-(2) or a method analogous thereto to give N-acetyl-N-({6-[N',N'-bis(4-methylbenzenesulfonyl)amino]-2-oxo-2H-chromen-3-yl}methyl)acetamide.

[0556] (4) The compound obtained above was treated in the same manner as in Reference Example 111 to obtain the title compound.

[0557] １ H NMR (500MHz, DMSO-d ６ ): δ8.16 (s, 1H), 8.10 (brs, 1H), 7.70 (d, J = 8.4Hz, 4H), 7.64 (d, J = 2.6Hz, 1H), 7.53 (d, J = 8.9Hz, 1H), 7.50 (d, J = 8.1Hz, 4H), 7.18 (d, J = 8.9, 2.6Hz, 1H), 3.91 (s, 2H), 2.46 (s, 6H)

[0558] Example 265 1-methyl-2-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}-pyridinium iodide

[0559] The title compound was obtained using 4-methyl-N-(4-methylbenzenesulfonyl)-N-[2-oxo-3-(pyridin-2-yl)-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Example 235 and according to the method of Example 101 or an analogous method.

[0560] １ H NMR (500MHz, DMSO-d ６ ​​): δ9.19 (d, J = 6.0 Hz, 1H), 8.76-8.72 (m, 1H), 8.52 (s, 1H), 8.27-8.24 (m, 2H), 7.83 (d, J = 2.6Hz, 1H), 7.73-7 .70 (m, 4H), 7.62 (d, J=8.9Hz, 1H), 7.52-7.49 (m, 4H), 7.26 (dd, J=8.8, 2.6Hz, 1H), 4.31 (s, 3H), 2.46 (s, 6H)

[0561] Example 266 N-methyl-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}acetamide

[0562] Using N-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}acetamide obtained in Example 241 and according to the method of Example 101 or an analogous method, the title compound was obtained.

[0563] １ H NMR (500MHz, CDCl ３ ): δ7.81 (d, J=8.5Hz, 4H), 7.76 (s, 1H), 7.74 (d, J=8.5Hz, 4H), 7.33 (d, J=9.0Hz), 7. 27 (d, J=2.5Hz), 7.13 (dd, J=2.5Hz, 9.0Hz), 3.24 (s, 3H), 2.49 (6H, s), 2.10 (brs, 3H)

[0564] Example 267 4-methyl-N-(4-methylbenzenesulfonyl)-N-[2-oxo-3-(hydroxymethyl)-2H-chromen-6-yl]benzene-1-sulfonamide

[0565] ​Palladium(II) chloride (33 mg) and sodium acetate (30 mg) were added to a solution of 4-methyl-N-(4-methylbenzenesulfonyl)-N-{2-oxo-3-[(prop-2-en-1-yloxy)methyl]-2H-chromen-6-yl}benzene-1-sulfonamide (50 mg) obtained in Example 242 in a 10 / 1 mixed solvent of acetic acid and water (1.1 mL), and the mixture was stirred at 75°C for 30 minutes. The reaction mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water (50 mL), aqueous sodium bicarbonate solution (50 mL), and saturated brine (50 mL). The organic layer was dried over sodium sulfate and concentrated. The solid residue was collected by filtration with ethyl acetate / hexane to give the title compound (36 mg) as a pale brown solid.

[0566] １ H NMR (500MHz, CDCl ３ ): δ7.80 (d, J=8.4Hz, 4H), 7.67 (s, 1H), 7.36 (d, J=8.4Hz, 4H), 7.31 (d, J=9.0Hz, 1H), 7.22 (d, J=2 .5Hz, 1H), 7.13 (dd, J=9.0, 2.5Hz, 1H), 4.64 (d, J=6.2Hz, 2H), 2.49 (s, 6H), 2.36 (t, J=1.7Hz, 2H)

[0567] Example 268 N-(3-formyl-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0568] Manganese dioxide (600 mg) was added to a dichloroethane solution (2 mL) of 4-methyl-N-(4-methylbenzenesulfonyl)-N-[2-oxo-3-(hydroxymethyl)-2H-chromen-6-yl]benzene-1-sulfonamide (100 mg) obtained in Example 267, and the mixture was stirred at room temperature for 95 hours. The reaction mixture was diluted with dichloromethane and filtered through Celite. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane 0-25%) to give the title compound (45 mg) as a white solid.

[0569] １ H NMR (500MHz, CDCl ３ ​​): δ10.23 (s, 1H), 8.28 (s, 1H), 7.79 (d, J = 8.4Hz, 4H), 7.37-7.35 (m, 6H), 7.28 (dd, J = 8.9, 2.5Hz, 1H), 2.49 (s, 6H)

[0570] Example 269

[0571] (2E)-3-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}prop-2-enoic acid tert-butyl ester

[0572] To a tetrahydrofuran solution (0.5 mL) of diethylphosphonoacetic acid tert-butyl ester (0.026 mL) was added 60% sodium hydride (4.1 mg) at 0°C, and the mixture was stirred at room temperature for 30 minutes. A tetrahydrofuran solution (1 mL) of N-(3-formyl-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide (37 mg) obtained in Example 268 was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL). The extract was washed with water (50 mL) and saturated brine (50 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane 0-25%) to obtain the title compound (25 mg) as a white solid.

[0573] １ H NMR (500MHz, CDCl ３ ): δ7.81 (d, J = 8.4Hz, 4H), 7.71 (s, 1H), 7.43 (d, J = 15.9Hz, 1H), 7.36 (d, J = 8.4Hz, 4H), 7.30 (d, J = 8.8H) z, 1H), 7.24 (d, J = 2.5Hz, 1H), 7.16 (dd, J = 8.8, 2.5Hz, 1H), 7.01 (d, J = 15.9Hz, 1H), 2.50 (s, 6H), 1.54 (s 9H)

[0574] Example 270 ​(2E)-3-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}prop-2-enecarboxylic acid

[0575] The title compound was obtained using (2E)-3-{6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}prop-2-enoic acid tert-butyl ester obtained in Example 269 and according to a method analogous thereto.

[0576] １ H NMR (500MHz, CDCl ３ ): δ7.80 (d, J=8.4Hz, 4H), 7.78 (s, 1H), 7.61 (d, J=15.5Hz, 1H), 7.36 (d, J=8.4Hz, 4H), 7.31 (d, J=8 .6Hz, 1H), 7.28 (d, J=2.3Hz, 1H), 7.18 (dd, J=8.6, 2.3Hz, 1H), 7.13 (d, J=15.5Hz, 1H), 2.49 (s, 6H)

[0577] Example 271 N-{3-[(2-hydroxyphenyl)methyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0578] The title compound was obtained using N-{3-[(2-methoxyphenyl)methyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 245 and according to the method of Example 66 or an analogous method.

[0579] １ H NMR (500MHz, DMSO-d ６ ​​): δ9.47 (s, 1H), 7.67 (d, J = 8.4Hz, 4H), 7.60 (brs, 1H), 7.59 (d, J = 2.6Hz, 1H), 7.46 (d, J = 7.7Hz, 4H), 7.40 (d, J = 8.8Hz, 1H), 7.14 (dd, J = 7.5, 1.7Hz , 1H), 7.10 (td, J=7.9, 1.6Hz, 1H), 6.98 (dd, J=8.8, 2.4Hz, 1H), 6.85 (dd, J=8.1, 1.1Hz, 1H), 6.77 (td, J=7.3, 1.1Hz, 1H), 3.72 (s, 2H), 2.44 (s, 6H)

[0580] Example 272 Propionic acid 2-({6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}methyl)phenyl ester

[0581] To a solution of N-{3-[(2-hydroxyphenyl)methyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide (57 mg) obtained in Example 271 in N,N-dimethylformamide (1 mL), 1-hydroxybenzotriazole (HOBt) monohydrate (18 mg), propionic acid (7.4 μL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) (29 mg), and triethylamine (0.028 mL) were added and stirred at room temperature for 24 hours. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30 mL x 2). The extract was washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL), and saturated brine (30 mL), then dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane 0-50%) to obtain the title compound (27 mg) as a white solid.

[0582] １ H NMR (500MHz, DMSO-d ６ ​): δ7.75 (s, 1H), 7.69-7.66 (m, 4H), 7.54 (d, J=2.6Hz, 1H), 7.49-7.46 ( m, 4H), 7.44-7.40 (m, 2H), 7.33 (td, J = 7.8, 1.9Hz, 1H), 7.25 (td, J = 7.5 , 1.2Hz, 1H), 7.11 (dd, J=8.0, 1.2Hz, 1H), 7.02 (dd, J=8.7, 2.6Hz, 1H), 3.74 (s, 2H), 2.58 (q, J = 7.5Hz, 2H), 2.45 (s, 6H), 1.04 (t, J = 7.5Hz, 3H)

[0583] Example 273 2-({6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}methyl)phenyl octanate

[0584] The title compound was obtained in the same manner as in Example 272 using N-{3-[(2-hydroxyphenyl)methyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 271.

[0585] １ H NMR (500MHz, DMSO-d ６ ): δ7.68-7.66 (m, 4H), 7.63 (s, 1H), 7.50 (d, J=2.5Hz, 1H), 7.48-7.45 (m, 4H), 7. 43-7.39 (m, 2H), 7.35 (td, J = 7.8, 1.7Hz, 1H), 7.26 (td, J = 7.5, 1.3Hz, 1H), 7.12 ( dd, J=8.0, 1.1Hz, 1H), 7.05 (dd, J=8.8, 2.6Hz, 1H), 3.73 (s, 2H), 2.54 (t, J=7.3H z, 2H), 2.45 (s, 6H), 1.56-1.50 (m, 2H), 1.28-1.14 (m, 8H), 0.83 (t, J = 6.8Hz, 3H)

[0586] Example 274 [2-({6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}methyl)phenoxy]phosphate

[0587] ​The title compound was obtained in Example 94 and Example 95 or a method analogous thereto using N-{3-[(2-hydroxyphenyl)methyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 271.

[0588] １ H NMR (500MHz, DMSO-d ６ ): δ7.68-7.67 (m, 4H), 7.58 (s, 1H), 7.48-7.46 (m, 5H), 7.42 (d, J = 8.6Hz, 1H), 7.35-7.32 (m, 1H ), 7.31-7.27 (m, 2H), 7.14-7.11 (m, 1H), 7.02 (dd, J=8.7, 2.5Hz, 1H), 3.85 (s, 2H), 2.45 (s, 6H)

[0589] Example 275 [2-({6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}methyl)phenoxymethoxy]phosphate

[0590] (1) To a solution of N-{3-[(2-hydroxyphenyl)methyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide (0.114 mg) obtained in Example 271 in N,N-dimethylformamide (2 mL), potassium carbonate (41 mg) and chloromethyl phosphate dibenzyl ester (0.19 mL) were added at 0°C, and the mixture was stirred at room temperature for 3 hours. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30 mL x 2). The extract was washed with water (30 mL), saturated brine (20 mL x 3), and saturated brine (20 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane 0-50%) to give [2-({6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}methyl)phenoxymethoxy]phosphate dibenzyl ester (84 mg) as a white amorphous solid.

[0591] ​(2) The compound obtained above was treated in the same manner as in Example 65 to obtain the title compound.

[0592] １ H NMR (500MHz, DMSO-d ６ ): δ7.69-7.66 (m, 4H), 7.58 (s, 1H), 7.48-7.39 (m, 6H), 7.35-7.33 (m, 1H), 7.30-7.27 (m, 2 H), 7.14-7.12 (m, 1H), 7.01 (dd, J = 8.6, 2.6Hz, 1H), 3.85 (s, 2H), 2.45 (s, 6H), 2.40 (s, 2H)

[0593] Example 276 2,5,8,11-Tetraoxatetradecane-14-carboxylic acid 2-({6-[N-(4-methylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}methyl)phenyl ester

[0594] (1) The title compound was obtained in Example 272 or a method analogous thereto using N-{3-[(2-hydroxyphenyl)methyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 271.

[0595] １ H NMR (500MHz, DMSO-d ６ ): δ7.73 (s, 1H), 7.69-7.67 (m, 4H), 7.51 (d, J = 2.6Hz, 1H), 7.48-7.46 (m, 4H), 7 42 (d, J=8.8Hz, 1H), 7.40-7.38 (m, 1H), 7.35-7.31 (m, 1H), 7.27-7.23 (m, 1H), 7.12-7.10 (m, 1H), 7.04 (dd, J=8.8, 2.6Hz, 1H), 3.73 (s, 2H), 3.71 (t, J=6.2Hz, 2H), 3.52-3.43 (m, 10H), 3.38-3.36 (m, 2H), 2.82 (t, J=6.1Hz, 2H), 2.45 (s, 6H)

[0596] Example 277 ​​N-{3-[(2-butoxyphenyl)methyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0597] (1) The title compound was obtained using N-{3-[(2-hydroxyphenyl)methyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 271 and according to the method described in Example 69-(1) or a method analogous thereto.

[0598] １ H NMR (500MHz, DMSO-d ６ ): δ7.70-7.65 (m, 4H), 7.57 (s, 1H), 7.52 (d, J=2.5Hz, 1H), 7.48-7.4 4 (m, 4H), 7.42 (d, J = 8.8Hz, 1H), 7.27-7.22 (m, 2H), 7.02-6.98 (m, 2H) , 6.91 (td, J=7.5, 0.9Hz, 1H), 3.96 (t, J=6.1Hz, 2H), 3.76 (s, 2H), 2.4 4 (s, 6H), 1.66-1.60 (m, 2H), 1.34-1.28 (m, 2H), 0.79 (t, J = 7.4Hz, 3H)

[0599] Example 278 4-butyl-N-[3-(4-chlorophenyl)-2-oxo-2H-chromen-6-yl]-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0600] (1) Using N-[3-(4-chlorophenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 193, N-[3-(4-chlorophenyl)-2-oxo-2H-chromen-6-yl]-4-methylbenzenesulfonamide was obtained according to Reference Example 4-(3) or a method analogous thereto.

[0601] (2) Using the compound obtained above, the title compound was obtained according to the method of Reference Example 4-(2) or a method analogous thereto.

[0602] １ ​​H NMR (500MHz, DMSO-d ６ ): δ8.33 (s, 1H), 7.76-7.74 (m, 2H), 7.73-7.71 (m, 2H), 7.70-7.68 (m, 2H), 7.60 (d, J = 2.6Hz, 1H), 7.57-7.55 (m, 2H), 7.52-7.4 7 (m, 5H), 7.13 (dd, J = 8.8, 2.6Hz, 1H), 2.73 (t, J = 7.7Hz, 2H), 2.46 (s, 3H), 1.64-1.56 (m, 2H), 1.36-1.28 (m, 2H), 0.90 (t, J7.4) Hz, 3H)

[0603] Example 279 N-(3-hydroxy-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0604] (1) Using 5-[N,N-bis(4-methylbenzenesulfonyl)amino]salicylaldehyde obtained in Reference Example 8, N-(3-benzyloxy-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide was obtained according to the method of Reference Example 2 or a similar method.

[0605] (2) Using the compound obtained above, the title compound was obtained according to the method of Example 65 or a method analogous thereto.

[0606] ESI-MS [M+Na] ＋ : 486.0

[0607] Example 280 4-methyl-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylpyridin-3-yl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0608] Using 5-[N,N-bis(4-methylbenzenesulfonyl)amino]salicylaldehyde obtained in Reference Example 8 and according to the method of Reference Example 2 or a method analogous thereto, the title compound was obtained.

[0609] １ H NMR (500MHz, CDCl ３ ​): δ8.59 (dd, J=4.9, 1.7Hz, 1H), 7.84-7.81 (m, 4H), 7.58-7.56 (m, 2H), 7.38-7.34 (m, 5H), 7.27-7.25 (m, 1H) ), 7.29 (d, J=2.4Hz, 1H), 7.23 (dd, J=7.7, 4.9Hz, 1H), 7.15 (d, J=8.8, 2.4Hz, 1H), 2.55 (s, 3H), 2.49 (s, 6H)

[0610] Example 281 4-methyl-N-(4-methylbenzenesulfonyl)-N-(2-oxo-2H-chromen-6-yl)benzene-1-sulfonamide

[0611] The title compound was obtained using 6-amino-2H-chromen-2-one according to Reference Example 4-(2) or a method analogous thereto.

[0612] １ H NMR (500MHz, CDCl ３ ): δ7.82-7.79 (m, 4H), 7.61 (d, J = 9.6Hz, 1H), 7.38-7.35 (m, 4H), 7.29 (d, J = 8.8Hz, 1H) , 7.22 (d, J=2.5Hz, 1H), 7.13 (dd, J=8.8, 2.5Hz, 1H), 6.47 (d, J=9.6Hz, 1H), 2.49 (s, 6H)

[0613] Example 282 4-Methoxy-N-(4-methylbenzenesulfonyl)-N-[2-oxo-3-(pyridin-2-yl)-2H-chromen-6-yl]benzene-1-sulfonamide

[0614] (1) Using 4-methyl-N-(4-methylbenzenesulfonyl)-N-[2-oxo-3-(pyridin-2-yl)-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Example 235, 4-methyl-N-[3-(pyridin-2-yl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide was obtained in accordance with Reference Example 4-(3) or a method analogous thereto.

[0615] (2) Using the compound obtained above, the title compound was obtained according to the method of Reference Example 4-(2) or a method analogous thereto. ​

[0616] １ H NMR (500MHz, CDCl ３ ): δ8.70-8.67 (m, 1H), 8.67 (s, 1H), 8.40 (d, J = 8.0Hz, 1H), 7.88-7.85 (m, 2H), 7.83-7.79 (m, 3H) ), 7.38-7.31 (m, 5H), 7.17 (dd, J=8.8, 2.5Hz, 1H), 7.03-7.00 (m, 2H), 3.93 (s, 3H), 2.49 (s, 3H)

[0617] Example 283 4-Hydroxy-N-(4-methylbenzenesulfonyl)-N-[2-oxo-3-(pyridin-2-yl)-2H-chromen-6-yl]benzene-1-sulfonamide

[0618] The title compound was obtained using 4-methoxy-N-(4-methylbenzenesulfonyl)-N-[2-oxo-3-(pyridin-2-yl)-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Example 282 and according to the method of Example 66 or an analogous method.

[0619] １ H NMR (500MHz, CDCl ３ ): δ8.69 (ddd, J=5.0, 1.8, 1.0Hz, 1H), 8.64 (s, 1H), 8.39 (dt, J=8.0, 1.0Hz, 1H), 7.84-7. 80 (m, 5H), 7.38-7.33 (m, 5H), 7.18 (dd, J=8.8, 2.5Hz, 1H), 6.97-6.94 (m, 2H), 2.49 (s, 3H)

[0620] Example 284 4-(2-aminoethoxy)-N-(4-methylbenzenesulfonyl)-N-[2-oxo-3-(pyridin-2-yl)-2H-chromen-6-yl]benzene-1-sulfonamide

[0621] ​​(1) N-{N'-(4-methylbenzenesulfonyl)-N'-[2-oxo-3-(pyridin-2-yl)-2H-chromen-6-ylaminosulfonyl]phenoxyethylcarbamic acid tert-butyl ester was obtained in accordance with Example 69-(1) or a method analogous thereto, using 4-hydroxy-N-(4-methylbenzenesulfonyl)-N-[2-oxo-3-(pyridin-2-yl)-2H-chromen-6-yl]benzene-1-sulfonamide obtained in Example 283. (2) The title compound was obtained in accordance with Example 69-(2) using the compound obtained above.

[0622] １ H NMR (500MHz, CDCl ３ ): δ8.68-8.66 (m, 1H), 8.60 (s, 1H), 8.34-8.31 (m, 1H), 7.84-7.84 (m, 5H), 7.47 (d, J = 2.0Hz, 1H), 7.34-7.2 7 (m, 4H), 7.12 (dd, J = 8.8, 2.5Hz, 1H), 7.09-7.05 (m, 2H), 4.41-4.36 (m, 1H), 3.49-3.44 (m, 1H), 2.46 (s, 3H)

[0623] Example 285 2-amino-N-methyl-N-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]ethane-1-sulfonamide

[0624] (1) Using 6-amino-3-(4-methylphenyl)-2H-chromen-2-one obtained in Reference Example 4-(1), 2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]ethane-1-sulfonamide was obtained in accordance with Reference Example 5-(2) or a method analogous thereto.

[0625] (2) Using the compound obtained above, the title compound 2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-methyl-N-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]ethane-1-sulfonamide was obtained according to Example 101 or a method analogous thereto. ​

[0626] (3) Using the compound obtained above, the title compound was obtained according to Example 127-(2) or a method analogous thereto.

[0627] １ H NMR (500MHz, CDCl ３ ): δ 12.29 (brs, 1H), 7.75 (s, 1H), 7.72-7.69 (m, 6H), 7.54-7.48 (m, 8H), 7.10 (d, J =8.8Hz, 1H), 6.95 (dd, J=8.8, 2.6Hz, 1H), 2.45 (s, 6H), 7.77 (s, 1H), 7.62 -7.58 (m, 3H), 7.51 (dd, J=8.9, 2.6Hz, 1H), 7.37 (d, J=8.9, 1H), 7.29-7.2 5 (m, 2H), 3.39 (s, 3H), 3.24-3.20 (m, 2H), 3.17-3.13 (m, 2H), 2.41 (s, 3H)

[0628] Example 286 N-(2-{N'-methyl-N'-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]amino}sulfonyl)acetamide

[0629] Using 2-amino-N-methyl-N-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]ethane-1-sulfonamide obtained in Example 285 and according to the method of Example 70 or an analogous method, the title compound was obtained.

[0630] １ H NMR (500MHz, CDCl3): δ7.75 (s, 1H), 7.71-7.67 (m, 2H), 7.64-7.60 (m, 2H), 7.47-7.44 (m, 3H), 7.36 (d, J = 8.9Hz, 1H), 7.30-7.27 (m, 2H), 7.19 (dd, J = 8.9, 2.6Hz, 1H), 6.42 (brs, 1H), 4.40 (s, 2H), 2.42 (s, 3H)

[0631] Example 287 N-methyl-2-(methylamino)-N-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]ethane-1-sulfonamide

[0632] ​​(1) 2-amino-N-methyl-N-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]ethane-1-sulfonamide (50 mg) obtained in Example 285 was dissolved in a tetrahydrofuran / dichloroethane (2 / 1) mixed solvent (1.5 mL) with triethylamine (0.054 mL) and di-tert-butyl dicarbonate (Boc ２ The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane 0-35%) to give N-(2-{N'-methyl-N'-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]amino}sulfonyl)ethylcarbamic acid tert-butyl ester (20 mg) as a white amorphous solid.

[0633] (2) Using the compound obtained above, N-methyl-N-(2-{N'-methyl-N'-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]amino}sulfonyl)ethylcarbamic acid tert-butyl ester was obtained according to Example 101 or a method analogous thereto. (3) Using the compound obtained above, the title compound was obtained according to 69-(2) or a method analogous thereto.

[0634] ESI-MS[M+H] ＋ : 387.1

[0635] Example 288 Methyl 3-[methyl({N-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]4-methylbenzenesulfonamido}sulfonyl)amino]propionate

[0636] (1) Using 6-amino-3-(4-methylphenyl)-2H-chromen-2-one obtained in Reference Example 4-(1), 3-{N-methyl,N-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-ylaminosulfonyl]amino}propionic acid methyl ester was obtained according to the method described in Reference Example 5-(2) or a method analogous thereto.

[0637] (2) Using the compound obtained above, the title compound was obtained according to the method of Reference Example 4-(2) or a method analogous thereto.

[0638] １ H NMR (500MHz, CDCl ３ ): δ7.72-7.69 (m, 3H), 7.61-7.58 (m, 2H), 7.40 (d, J = 2.5Hz, 1H), 7.33-7.28 (m, 4H), 7.28-7.25 (m, 1H), 7.22 (dd, J = 8.8, 2.5Hz, 1H), 3.71 (s, 3H), 3.69-3.64 (m, 2H), 3.06 (s, 3H), 2.68 (t, J = 7.1Hz, 1H), 2.47 (s, 3H), 2.42 (s, 3H)

[0639] Example 289 3-[methyl({N-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]4-methylbenzenesulfonamido}sulfonyl)amino]propionic acid

[0640] The title compound was obtained using methyl 3-[methyl({N-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]4-methylbenzenesulfonamido}sulfonyl)amino]propionate obtained in Example 288 and according to a method analogous thereto.

[0641] ESI-MS[MH] － : 569.0

[0642] Example 290 4-methyl-N-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]-N-(pyrimidin-2-yl)benzene-1-sulfonamide

[0643] ​(1) To a solution of 6-amino-3-(4-methylphenyl)-2H-chromen-2-one (0.163 g) obtained in Reference Example 4-(1) in a 1,4-dioxane / water (1 / 1) mixed solvent (9.6 mL), 2-bromopyrimidine (0.127 g) and concentrated hydrochloric acid (0.96 mL) were added, and the mixture was stirred at 100°C for 2 days. A saturated aqueous solution of sodium bicarbonate (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL). The extract was washed with water (30 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 45-70%) to give 3-(4-methylphenyl)-6-(pyrimidin-2-ylamino)-2H-chromen-2-one (4 mg) as a white solid.

[0644] (2) Using the compound obtained above, the title compound was obtained according to the method of Reference Example 4-(2) or a method analogous thereto.

[0645] ESI-MS[M+Na] ＋ : 484.3

[0646] Example 291 4-butyl-N-[3-(2-chlorophenyl)-2-oxo-2H-chromen-6-yl]-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0647] (1) Using N-[3-(2-chlorophenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 189, 4-methyl-N-[3-(2-chlorophenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide was obtained in accordance with Reference Example 4-(3) or a method analogous thereto.

[0648] (2) Using the compound obtained above, the title compound was obtained according to the method of Reference Example 4-(2) or a method analogous thereto.

[0649] １ H NMR (500MHz, DMSO-d ６ ​): δ8.16 (s, 1H), 7.73-7.72 (m, 2H), 7.71-7.69 (m, 2H), 7.65 (d, J = 2.6Hz, 1H), 7.61-7.59 (m, 1H), 7.55-7.47 (m, 8H), 7.1 5 (dd.

[0650] Example 292 4-butyl-N-[3-(4-propylphenyl)-2-oxo-2H-chromen-6-yl]-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0651] (1) Using N-[3-(4-propylphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 195, 4-methyl-N-[3-(4-n-propylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide was obtained in accordance with Reference Example 4-(3) or a method analogous thereto.

[0652] (2) Using the compound obtained above, the title compound was obtained according to the method of Reference Example 4-(2) or a method analogous thereto.

[0653] １ H NMR (500MHz, DMSO-d ６ ): δ8.33 (s, 1H), 7.76-7.74 (m, 2H), 7.73-7.71 (m, 2H), 7.70-7.68 (m, 2H), 7.60 (d, J = 2.6Hz, 1H), 7.57-7.55 (m, 2H), 7.52-7.47 (m , 5H), 7.13 (dd, J = 8.8, 2.6Hz, 1H), 2.73 (t, J = 7.7Hz, 2H), 2.46 (s, 3H), 1.64-1.56 (m, 2H), 1.36-1.28 (m, 2H), 0.90 (t, J = 7.4Hz, 3H)

[0654] Example 293 ​4-butyl-N-{3-[4-(methylamino)phenyl]-2-oxo-2H-chromen-6-yl}-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0655] (1) Using N-(3-bromo-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Reference Example 6, and according to the method of Example 168 or an analogous method thereto, N-{3-[4-(tert-butoxycarbonyl)aminophenyl]-2-oxo-2H-chromen-6-yl}-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide was obtained.

[0656] (2) Using the compound obtained above, N-(3-{4-[N'-(tert-butoxycarbonyl)]-N'-methylaminophenyl}-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide was obtained according to Example 101 or a method analogous thereto.

[0657] (3) Using the compound obtained above, N-(3-{4-[N'-(tert-butoxycarbonyl)]-N'-methylaminophenyl}-2-oxo-2H-chromen-6-yl)-4-methylbenzene-1-sulfonamide was obtained according to Reference Example 4-(3) or a method analogous thereto.

[0658] (4) Using the compound obtained above, N-(3-{4-[N'-(tert-butoxycarbonyl)]-N'-methylaminophenyl}-2-oxo-2H-chromen-6-yl)-4-butyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide was obtained according to Reference Example 4-(2) or a method analogous thereto.

[0659] (5) Using the compound obtained above, the title compound was obtained according to Example 69-(2) or a method analogous thereto.

[0660] １ H NMR (500MHz, DMSO-d ６ ​): δ8.10 (s, 1H), 7.73-7.71 (m, 2H), 7.70-7.68 (m, 2H), 7.57-7.56 (m, 2H), 7.52-7.48 (m, 5H), 7.42 (d, J = 8.8Hz, 1H), 7.04 (dd, J = 8.8, 2.6Hz , 1H), 6.61-6.59 (m, 2H), 6.08 (q, J=5.1Hz, 1H), 2.74-2.72 (m, 5H), 2. 46 (s, 6H), 1.64-1.58 (m, 2H), 1.36-1.30 (m, 2H), 0.91 (t, J = 7.4Hz, 3H)

[0661] Example 294 4-butyl-N-{3-[4-(dimethylamino)phenyl]-2-oxo-2H-chromen-6-yl}-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0662] The title compound was obtained using 4-butyl-N-{3-[4-(methylamino)phenyl]-2-oxo-2H-chromen-6-yl}-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 293 and according to the method of Example 101 or a method analogous thereto.

[0663] １ H NMR (500MHz, DMSO-d ６ ): δ8.15 (s, 1H), 7.73-7.71 (m, 2H), 7.70-7.68 (m, 2H), 7.66-7.64 (m, 2H) , 7.54 (d, J = 2.6 Hz, 1H), 7.51-7.48 (m, 4H), 7.42 (d, J = 8.8 Hz, 1H), 7.05 (d d, J=8.8, 2.6Hz, 1H), 6.79-6.77 (m, 2H), 2.97 (s, 6H), 2.74-2.72 (m, 2H), 2.46 (s, 6H), 1.65-1.58 (m, 2H), 1.35-1.28 (m, 2H), 0.91 (t, J=7.4Hz, 3H)

[0664] Example 295 N-methyl-N-(4-{6-[4-butylbenzenesulfonyl)4-methylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenyl)carbamic acid 5-methyl-2-oxo-2H-1,3-dioxal-4-ylmethyl ester​

[0665] (1) Using 4-butyl-N-{3-[4-(methylamino)phenyl]-2-oxo-2H-chromen-6-yl}-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 293, and according to a method equivalent thereto, N-methyl-N-(4-{6-[4-methylbenzenesulfonyl)4-n-butylbenzenesulfonamido]-2-oxo-2H-chromen-3-yl}phenyl)carbamic acid chloride was obtained.

[0666] (2) Using the compound obtained above, the title compound was obtained according to the method of Example 86 or a method analogous thereto.

[0667] １ H NMR (500MHz, DMSO-d ６ ): δ7.99 (s, 1H), 7.72-7.68 (m, 4H), 7.63 (d, J=2.5Hz, 1H), 7.51-7.48 (m, 4H), 7.45 (d, J=8.8Hz, 1H), 7. 11-7.04 (m, 2H), 7.01-6.99 (m, 1H), 6.70-6.66 (m, 1H), 6.59-6.55 (m, 2H), 5.09 (brs, 2H), 2.46 (s, 3H).

[0668] Example 296 N-[8-methoxy-3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0669] (1) 3-Methoxy-5-nitrosalicylaldehyde was used in the manner described in Reference Example 2 or a method analogous thereto to obtain 3-(3-methylphenyl)-8-methoxy-6-nitro-2H-chromen-2-one.

[0670] (2) The compound obtained above was treated in the manner described in Reference Example 4-(1) or a method analogous thereto to give 6-amino-3-(3-methylphenyl)-8-methoxy-2H-chromen-2-one.

[0671] (3) The compound obtained above was treated according to Reference Example 4-(2) or a method analogous thereto to give the title compound.

[0672] ​​１ H NMR (500MHz, CDCl ３ ): δ7.87-7.84(m, 4H), 7.50 (s, 1H), 7.39-7.35 (m, 4H), 7.35-7.31 (m, 1H), 7.29-7.21 (m, 3H), 6.8 4 (d, J = 2.2Hz, 1H), 6.58 (d, J = 2.2Hz, 1H), 3.78 (s, 3H), 2.49 (s, 6H), 2.29 (s, 3H)

[0673] Example 297 N-[8-hydroxy-3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0674] (1) The title compound was obtained using N-[8-methoxy-3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 296 and according to the method of Example 66 or a method analogous thereto.

[0675] １ H NMR (500MHz, CDCl ３ ): δ7.86-7.83 (m, 4H), 7.54 (s, 1H), 7.38-7.33 (m, 5H), 7.31-7.21 (m, 3H), 6.82 (d, J=2.3Hz, 1H), 680 (d, J=2.3Hz, 1H), 6.18 (brs, 1H), 2.48 (s, 6H), 2.30 (s, 3H)

[0676] Example 298 N-[8-fluoro-3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0677] The title compound was obtained using 3-fluoro-5-nitrosalicylaldehyde according to the procedure described in Example 296 or a method analogous thereto.

[0678] １ H NMR (500MHz, CDCl ３ ​​): δ7.85-7.81 (m, 4H), 7.53 (d, J=1.0Hz, 1H), 7.40-7.33 (m, 5H), 7.31-7.25 (m, 2H), 7.2 4-7.21 (m, 1H), 7.05-7.03 (m, 1H), 6.95 (dd, J=9.9, 2.3Hz, 1H), 2.49 (m, 6H), 2.30 (m, 3H)

[0679] Example 299 4-methyl-N-[4-methyl-3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0680] (1) A solution of 2-hydroxy-5-nitroacetophenone (0.180 g) in n-butyl acetate (1 mL) was added to 2-methylphenylacetic acid (0.165 g), 1.7 M propylphosphonic anhydride (T3P (R) A solution of 2-(2-methylphenyl)-4-methyl-6-nitro-2H-chromen-2-one (110 mg) was obtained as a white solid.

[0681] (2) The compound obtained above was treated in the manner described in Reference Example 4-(1) or a method analogous thereto to give 6-amino-3-(2-methylphenyl)-4-methyl-2H-chromen-2-one.

[0682] (3) The compound obtained above was treated according to Reference Example 4-(2) or a method analogous thereto to give the title compound.

[0683] １ H NMR (500MHz, CDCl ３ ​): δ7.88-7.82 (m, 4H), 7.39-7.32 (m, 7H), 7.30-7.28 (m, 2H), 7.16 (dd, J= 8.8, 2.5Hz, 1H), 7.12-7.09 (m, 1H), 2.49 (s, 6H), 2.19 (s, 3H), 2.02 (s, 3H)

[0684] Example 300 N-[4-cyclopropyl-3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0685] (1) To a dichloromethane solution (7 mL) of 5-[N,N-bis(4-methylbenzenesulfonyl)amino]salicylaldehyde (0.450 g) obtained in Reference Example 8, a 0.7 M THF solution (2.9 mL) of cyclopropylmagnesium bromide was added, and the mixture was stirred under reflux for 30 minutes. A saturated aqueous solution of ammonium chloride (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (100 mL). The extract was washed with water (30 mL), dried over sodium sulfate, and concentrated. Ethyl acetate was added to the residue to crystallize it, which was then filtered to give N-[3-(1-cyclopropyl-1-hydroxy)methyl-4-hydroxyphenyl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide (0.370 g) as a white solid.

[0686] (2) The compound obtained above was treated in the manner described in Reference Example 8-(4) or a method analogous thereto to give N-[3-(1-cyclopropyl-1-oxo)methyl-4-hydroxyphenyl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide.

[0687] (3) The compound obtained above was treated according to Reference Example 1-(4) or a method analogous thereto to give the title compound.

[0688] ESI-MS[M+Na] ＋ : 600.3

[0689] Example 301 4-methyl-N-(4-methylbenzenesulfonyl)-N-(2-oxo-4-phenyl-2H-chromen-6-yl)benzene-1-sulfonamide

[0690] (1) To a toluene solution (40 mL) of 4-hydroxycoumarin (1.6 g), tetra-n-butylammonium bromide (9.6 g) was added over 15 minutes, and the mixture was stirred at 100°C for 10 minutes. Next, phosphorus pentoxide (2.8 g) was added over 10 minutes, and the mixture was stirred at 100°C for 1 hour. The reaction mixture was cooled to 0°C, and saturated sodium bicarbonate solution (50 mL) was added. The bilayer mixture was extracted with ethyl acetate (100 mL x 2), and the extract was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 0-50%) to obtain 4-bromocoumarin (1.4 g).

[0691] (2) To a solution of the compound obtained above (1.4 g) in concentrated sulfuric acid (49 mL), concentrated nitric acid (7 mL) was added at -10°C, and the mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature and then added to crushed ice. The precipitated solid was collected by filtration, and the obtained solid was washed with water (50 mL x 2). The obtained solid was purified by silica gel column chromatography (ethyl acetate / hexane = 0-50%) to give 4-bromo-6-nitrocoumarin (0.9 g).

[0692] (3) Using the compound obtained above, 6-amino-4-bromo-coumarin was obtained according to the method described in Reference Example 4-(1) or a method equivalent thereto.

[0693] (4) Using the compound obtained above, N-(4-bromo-2-oxo-2H-chromen-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide was obtained according to Reference Example 4-(2) or a method analogous thereto.

[0694] (5) Using the compound obtained above, the title compound was obtained according to the method of Example 168 or a method analogous thereto.

[0695] １ H NMR (500MHz, DMSO-d ６ ​): δ7.64 (d, J=8.4Hz, 4H), 7.61 (d, J = 8.8Hz, 1H), 7.58-7.55 (m, 1H), 7.51-7.48 (m, 2H), 7.45 (d, J = 8.0Hz, 4H), 7.40 (dd, J = 8.8, 2.5Hz, 1H), 7.30-7.28 (m, 2H), 6.76 (d, J = 2.5Hz, 1H), 6.52 (s, 1H), 2.46 (s, 6H).

[0696] Example 302 N-(2,2-dioxo-3-phenyl-1,2-benzoxathiin-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0697] (1) A mixed solution (4.5 mL) of iron powder (120 mg) and ammonium chloride (11 mg) in ethanol / water (2 / 1) was stirred at 70°C for 30 minutes, and then a tetrahydrofuran solution (5 mL) of 6-nitro-3-phenyl-1,2-benzoxathiin-2,2-dioxide (0.130 g) obtained in Reference Example 3 was added, followed by stirring at 70°C for 2 hours. The reaction solution was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water (30 mL) and saturated brine (30 mL), dried over sodium sulfate, and concentrated to obtain crude 6-amino-3-phenyl-1,2-benzoxathiin-2,2-dioxide.

[0698] (2) To a dichloromethane solution (4 mL) of the compound obtained above, triethylamine (0.3 mL) and p-toluenesulfonyl chloride (0.210 g) were added and stirred at room temperature for 1 day. Water (10 mL) was added to the reaction mixture, which was then extracted with dichloromethane (50 mL). The organic layer was dried over sodium sulfate and concentrated, and the residue was purified by column chromatography (ethyl acetate / hexane = 0-30%) to obtain the title compound (0.130 g).

[0699] １ H NMR (500 MHz, CDCl ３ ​): δ7.84-7.79 (m, 4H), 7.68-7.63 (m, 2H), 7.52-7.47 (m, 3H), 7.38-7.34 (m, 4H), 7.26-7. 24 (m, 1H), 7.22 (d, J = 2.7Hz, 1H), 7.11 (s, 1H), 7.05 (dd, J = 9.0, 2.7Hz, 1H), 2.49 (s, 6H)

[0700] Example 303 N-(2,2-dioxo-3-phenyl-1,2-benzoxathiin-6-yl)-N-(benzenesulfonyl)benzene-1-sulfonamide

[0701] Using 6-nitro-3-phenyl-1,2-benzoxathiin-2,2-dioxide obtained in Reference Example 3, the title compound was obtained according to the method of Example 302 or a method analogous thereto.

[0702] １ H NMR (500MHz, CDCl ３ ): δ7.97-7.93 (m, 4H), 7.74-7.70 (m, 2H), 7.67-7.64 (m, 2H), 7.61-7.57 (m, 4H), 7.52-7.48 (m, 3H), 7.27 (d, J=8.7Hz, 1H), 7.20 (d, J=2.6Hz, 1H), 7.10 (s, 1H), 7.06 (dd, J=8.7, 2.6Hz, 1H), 2.49 (s, 6H)

[0703] Example 304 N-(2,2-dioxo-3-phenyl-1,2-benzoxathiin-6-yl)-N-(4-methoxybenzenesulfonyl)-4-methylbenzenesulfonamide

[0704] (1) Using 6-amino-3-phenyl-1,2-benzoxathiin-2,2-dioxide obtained in Example 302-(1), N-(2,2-dioxo-3-phenyl-1,2-benzoxathiin-6-yl)-4-methylbenzenesulfonamide was obtained according to Reference Example 5-(2) or a method analogous thereto.

[0705] (2) The compound obtained above was used to obtain the title compound according to the method of Example 15 or a method equivalent thereto.

[0706] １ ​​H NMR (500MHz, CDCl ３ ): δ7.69-7.61 (m, 4H), 7.54-7.46 (m, 3H), 7.33 (d, J = 2.5Hz, 1H), 7.28 (s, 1H), 7.17 (d , J=8.8Hz, 1H), 7.15 (s, 1H), 7.02 (dd, J=8.7, 2.5Hz, 1H), 6.57 (brs, 1H), 2.40 (s, 3H).

[0707] Example 305 N-(2,2-dioxo-3-phenyl-1,2-benzoxathiin-6-yl)-N-(4-hydroxybenzenesulfonyl)-4-methylbenzenesulfonamide

[0708] To a dichloromethane solution (0.5 mL) of N-(2,2-dioxo-3-phenyl-1,2-benzoxathiin-6-yl)-N-(4-methoxybenzenesulfonyl)-4-methylbenzenesulfonamide (30 mg) obtained in Example 304, 2-methyl-2-butene (0.016 mL) and 1 M boron tribromide dichloromethane solution (0.15 mL) were added at -20°C, and the mixture was stirred in the dark for 18 hours. Methanol (1 mL) was added to the reaction solution at 0°C, and after warming to room temperature, the reaction solution was poured into water (10 mL), and the organic and aqueous layers were separated. The organic layer was washed with saturated brine (5 mL), dried over sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane 0-50%) to obtain the title compound (48 mg) as a pale brown oil.

[0709] １ H NMR (500MHz, CDCl ３ ): δ7.84-7.77 (m, 4H), 7.68-7.61 (m, 2H), 7.52-7.46 (m, 3H), 7.36 (d, J = 8.5Hz, 2H), 7.28-7.24 (m, 1H), 7.23 (d, J=2.4Hz, 1H), 7.16-7.11 (m, 1H), 7.06 (dd, J=8.7, 2.5Hz, 1H), 6.94 (d, J=8.8Hz, 2H), 6.58 (s, 1H), 2.48 (s, 3H).

[0710] Example 306 ​N-{2-[2-(4-{[N-(2,2-dioxo-3-phenyl-1,2-benzoxathiin-6-yl)-4-methylbenzenesulfonylamino]sulfonyl}phenoxy)ethoxy]ethyl}carbamic acid tert-butyl ester

[0711] The title compound was obtained using N-(2,2-dioxo-3-phenyl-1,2-benzoxathiin-6-yl)-N-(4-hydroxybenzenesulfonyl)-4-methylbenzenesulfonamide obtained in Example 305 and according to the method described in Example 69-(1) or a method analogous thereto.

[0712] １ H NMR (500MHz, CDCl ３ ): δ7.86 (d, J=9.1Hz, 2H), 7.82 (d, J=8.4Hz, 2H), 7.69-7.63 (m, 2H), 7.53-7.46 (m, 3 H), 7.36 (d, J = 8.1Hz, 2H), 7.26 (d, J = 8.7Hz, 1H), 7.22 (d, J = 2.5Hz, 1H), 7.13 (s, 1H), 7.08-7.01 (m, 3H), 4.92 (brs, 1H), 4.21 (dd, J=4.5, 4.5Hz, 2H), 3.86 (dd, J=4.6, 4.6H z, 2H), 3.62 (t, J = 5.2Hz, 2H), 3.36 (dt, J = 5.1, 5.1Hz, 2H), 2.48 (s, 3H), 1.45 (s, 9H).

[0713] Example 307 N-{4-[2-(2-aminoethoxy)ethoxy]benzenesulfonyl}-N-(2,2-dioxo-3-phenyl-1,2-benzoxathiin-6-yl)-4-methylbenzenesulfonamide hydrochloride

[0714] The title compound was obtained using N-{2-[2-(4-{[N-(2,2-dioxo-3-phenyl-1,2-benzoxathiin-6-yl)-4-methylbenzenesulfonylamino]sulfonyl}phenoxy)ethoxy]ethyl}carbamic acid tert-butyl ester obtained in Example 306 and according to Example 69-(2) or a method analogous thereto.

[0715] １ H NMR (500MHz, DMSO-d​​６ ): δ8.00 (s, 1H), 7.81-7.66 (m, 9H), 7.61-7.56 (m, 4H), 7.52 (d, J = 8.0Hz, 2H), 7.22 (d, J = 9.1Hz, 2H), 7.10 (dd, J = 8.7, 2.6Hz, 2H), 4.29 (dd, J = 4.1, 4.1Hz, 1H), 3.84 (d, J = 4.3, 4.3Hz, 1H), 3.67 (t, J = 5.1Hz, 2H), 3.02 (d, J = 5.7, 5.0Hz, 2H), 2.49 (s, 3H).

[0716] Example 308 5-[(3aR,4R,6aS)-2-oxohexahydro-1H-thieno[3,4-d]imidazolidin-4-yl]-N-{2-[2-(4-{[N-(2,2-dioxo-3-phenyl-1,2-benzoxathiin-6-yl)-4-methylbenzenesulfonylamino]sulfonyl}phenoxy)ethoxy]ethyl}pentanamide

[0717] The title compound was obtained using N-{4-[2-(2-aminoethoxy)ethoxy]benzenesulfonyl}-N-(2,2-dioxo-3-phenyl-1,2-benzoxathiin-6-yl)-4-methylbenzenesulfonamide hydrochloride obtained in Example 307 and according to a method similar to that of Example 74-(3).

[0718] １ H NMR (500MHz, CDCl ３ ​): δ7.88 (d, J=8.9Hz, 2H), 7.81 (d, J=8.3Hz, 2H), 7.72-7.60 (m, 2H), 7.54-7.45 (m, 3H), 7.36 (d, J=8.5Hz, 2H), 7.26 (d, J=8. 5Hz, 1H), 7.17 (s, 1H), 7.05 (d, J = 8.9Hz, 1H), 6.29 (brs, 1H), 5.89 (brs, 1H), 5.03 (brs, 1H), 4.43 (dd, J = 4.9, 4.9Hz, 1H), 4.3 4-4.17 (m, 3H), 3.87 (dd, J = 4.4, 4.4Hz, 2H), 3.64 (t, J = 5.1Hz, 2H), 3.54-3.39 (m, 3H), 3.11 (dt, J = 7.4, 4.4Hz, 1H), 2.87 (1d , J=12.8, 4.9Hz, H), 2.68 (d, J=12.8Hz, 1H), 2.48 (s, 3H), 2.26-2.11 (m, 2H), 1.77-1.64 (m, 4H), 1.42 (tt, J=7.7, 7.7Hz, 2H),

[0719] Example 309 N-[2,2-dioxo-3-(3-methoxyphenyl)-1,2-benzoxathiin-6-yl]-4-methoxy-N-(4-methoxybenzenesulfonyl)benzene-1-sulfonamide

[0720] (1) Using 5-nitrosalicylaldehyde, 6-nitro-3-(3-methoxyphenyl)-1,2-benzoxathiin-2,2-dioxide was obtained according to the method described in Reference Example 3 or a method analogous thereto.

[0721] (2) Using the compound obtained above, the title compound was obtained according to the method of Example 302 or a method analogous thereto.

[0722] １ H NMR (500MHz, CDCl ３ ): δ7.88-7.84 (m, 4H), 7.40 (t, J=8.0Hz, 1H), 7.27-7.22 (m, 2H), 7.22 (d, J=2.5Hz, 1H), 7.17-7. 16 (m, 1H), 7.12 (s, 1H), 7.06 (dd, J=8.7, 2.5Hz, 1H), 7.05-7.00 (m, 5H), 3.92 (s, 6H), 3.87 (s, 3H)

[0723] Example 310​ N-(2,2-dioxo-3-phenyl-1,2-benzoxathiin-6-yl)-4-methoxy-N-(4-methoxybenzenesulfonyl)benzene-1-sulfonamide

[0724] Using 6-nitro-3-phenyl-1,2-benzoxathiin-2,2-dioxide obtained in Reference Example 3, the title compound was obtained according to the method of Example 302 or a method analogous thereto.

[0725] １ H NMR (500MHz, CDCl ３ ): δ7.88-7.84 (m, 4H), 7.67-7.64 (m, 2H), 7.51-7.48 (m, 2H), 7.26 (d, J = 8.8Hz, 1H), 7.22 ( d, J=2.5Hz, 1H), 7.12 (s, 1H), 7.06 (dd, J=8.8, 2.5Hz, 1H), 7.04-7.00 (m, 4H), 3.92 (s, 6H)

[0726] Example 311 N-[2,2-dioxo-3-(2-methylphenyl)-1,2-benzoxathiin-6-yl]-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0727] (1) Using 5-nitrosalicylaldehyde, 6-nitro-3-(2-methylphenyl)-1,2-benzoxathiin-2,2-dioxide was obtained according to the method described in Reference Example 3 or a method analogous thereto.

[0728] (2) Using the compound obtained above, the title compound was obtained according to the method of Example 302 or a method analogous thereto.

[0729] １ H NMR (500MHz, CDCl ３ ): δ7.82 (d, J=8.5Hz, 4H), 7.44-7.42 (m, 1H), 7.40-7.32 (m, 6H), 7.29-7.26 (m, 2H), 7. 16 (d, J=2.5Hz, 1H), 7.05 (dd, J=8.8, 2.5Hz, 1H), 6.91 (s, 1H), 2.48 (s, 6H), 2.44 (s, 3H)

[0730] Example 312 ​​4-butyl-N-(2,2-dioxo-3-phenyl-1,2-benzoxazin-6-yl)-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0731] (1) Using N-(2,2-dioxo-3-phenyl-1,2-benzoxazin-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide obtained in Example 302, N-(2,2-dioxo-3-phenyl-1,2-benzoxazin-6-yl)4-methylbenzenesulfonamide was obtained according to Reference Example 4-(3) or a method analogous thereto.

[0732] (2) The compound obtained above was treated in the same manner as in Example 15 to obtain the title compound.

[0733] １ H NMR (500MHz, DMSO-d ６ ): δ7.98 (s, 1H), 7.76-7.70 (m, 6H), 7.65 (d, J = 2.6Hz, 1H), 7.60-7.57 (m, 4H), 7.52-7.49 (m, 4H), 7.13 (dd, J = 8.8, 2.6Hz, 1H), 2.75-2.71 (m, 2H), 2.46 (s, 3H), 1.64-1.56 (m, 2H), 1.36-1.29 (m, 2H), 0.90 (t, J = 7.4Hz, 3H)

[0734] Example 313 4-methyl-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-sulfanylidene-2H-chromen-6-yl]benzene-1-sulfonamide

[0735] ​(1) A toluene solution (10 mL) of 4-methyl-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide (0.170 g) obtained in Example 1 was stirred with Lawesson's reagent (80 mg) under reflux for 1 day under a nitrogen atmosphere. The reaction solution was passed through a short column of silica gel using a solvent of ethyl acetate / hexane = 2 / 1, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane 20%) to obtain the title compound (54 mg) as an orange solid.

[0736] １ H NMR (500MHz, CDCl ３ ): δ7.86-7.80 (m, 4H), 7.45 (d, J = 8.9Hz, 1H), 7.38-7.32 (m, 6H), 7.29-7.25 (m, 3H), 7.16-7.13 (m, 2H), 2.49 (s, 6H), 2.26 (s, 3H)

[0737] Example 314 4-methyl-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-thiochromen-6-yl]benzene-1-sulfonamide

[0738] (1) Using 3-(2-methylphenyl)-6-nitro-2H-thiochromen-2-one obtained in Reference Example 1, 6-amino-3-(2-methylphenyl)-2H-thiochromen-2-one was obtained according to the method described in Reference Example 4-(1) or a method analogous thereto.

[0739] (2) The compound obtained above was treated in the manner described in Reference Example 4-(2) or a method analogous thereto to give the title compound.

[0740] １ H NMR (500MHz, CDCl3): δ7.85-7.81 (m, 4H), 7.55 (s, 1H), 7.46 (d, J = 8.5Hz, 1H), 7.38-7.30 (m, 6H) ), 7.29-7.24 (m, 2H), 7.20-7.17 (m, 1H), 7.09 (dd, J=8.5, 2.2Hz, 1H), 2.48 (s, 6H), 2.25 (s, 3H) ​​

[0741] Example 315 4-methyl-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-sulfanylidene-2H-thiochromen-6-yl]benzene-1-sulfonamide

[0742] The title compound was obtained using 4-methyl-N-(4-methylbenzenesulfonyl)-N-[3-(2-methylphenyl)-2-oxo-2H-thiochromen-6-yl]benzene-1-sulfonamide obtained in Example 314 and according to the procedure of Example 313 or a method analogous thereto.

[0743] １ H NMR (500MHz, CDCl ３ ): δ7.85-7.81 (m, 4H), 7.41 (d, J=8.5Hz, 1H), 7.39 (s, 1H), 7.38-7.31 ( m, 6H), 7.28-7.24 (m, 2H), 7.13-7.09 (m, 2H), 2.48 (s, 6H), 2.21 (s, 3H)

[0744] Example 316 N-(2,2-dioxo-3-phenyl-1H-2,1-benzothiazin-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0745] (1) Imidazole (0.510 g) and tert-butyldimethylchlorosilane (0.497 g) were added to a solution of 2-amino-5-nitrobenzyl alcohol (0.50 g) in N,N-dimethylformamide (10 mL), and the mixture was stirred at room temperature for 3 hours. Water (20 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (40 mL x 2). The extract was washed with water (50 mL x 2) and saturated brine (50 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane 0-40%) to obtain 2-[(tert-butyldimethylsilyl)oxymethyl]-4-nitroaniline (0.812 g) as a yellow oil.

[0746] ​(2) To a solution (10 mL) of the compound (0.812 g) obtained above in tetrahydrofuran, sodium bicarbonate (0.480 g) and benzyloxycarbonyl chloride (0.44 mL) were added at 0°C, and the mixture was stirred at room temperature for 3 days. Water (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL x 2). The extract was washed with water (50 mL) and saturated brine (50 mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane 0-40%) to obtain 2-[(tert-butyldimethylsilyl)oxymethyl]-4-nitrophenylcarbamic acid benzyl ester (0.953 g) as a white solid.

[0747] (3) Using the compound obtained above, 4-amino-2-[(tert-butyldimethylsilyl)oxymethyl]-phenylcarbamic acid benzyl ester was obtained according to the method of Reference Example 4-(1) or a method analogous thereto.

[0748] (4) Using the compound obtained above, 2-[(tert-butyldimethylsilyl)oxymethyl]-4-[bis(4-methylbenzenesulfonyl)amino]phenylcarbamic acid benzyl ester was obtained according to Reference Example 4-(2) or a method analogous thereto.

[0749] (5) Using the compound obtained above, 2-hydroxymethyl-4-[bis(4-methylbenzenesulfonyl)amino]phenylcarbamic acid benzyl ester was obtained according to the method described in Reference Example 8-(3) or a method analogous thereto.

[0750] (6) Using the compound obtained above, 2-(benzyloxycarbonylamino)-5-[bis(4-methylbenzenesulfonyl)amino]benzaldehyde was obtained according to Reference Example 8-(4) or a method analogous thereto.

[0751] (7) To a solution of the compound obtained above (0.175 g) in N,N-dimethylformamide (3 mL) was added 60% sodium hydride (24 mg) at 0°C, and the mixture was stirred for 30 minutes. After that, benzylsulfonyl chloride (86 mg) was added at 0°C, and the mixture was stirred at room temperature for 17 hours. Water (10 mL) was added to the reaction mixture, and then the mixture was extracted with ethyl acetate (30 mL). The extract was washed with water (40 mL x 2) and saturated brine (40 mL), dried over sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane 0-40%) to obtain a compound containing 4-hydroxy-6-[N-bis(4-methylbenzenesulfonyl)amino]-2,2-dioxo-3-phenyl-3,4-dihydro-1H-2,1-benzothiazine-1-carboxylic acid benzyl ester.

[0752] (8) DBU (0.010 mL) was added to a dichloromethane solution (1 mL) of the compound obtained above at 0°C, and the mixture was stirred for 1 hour and then at room temperature for 4 hours. 3 M hydrochloric acid was added to the reaction mixture to make it acidic, and then the mixture was extracted with ethyl acetate (15 mL × 2). The extract was washed with water (20 mL), dried over sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane 0-50%) to obtain the title compound (15 mg) as a white solid.

[0753] １ H NMR (500MHz, DMSO-d ６ ): δ12.29 (brs, 1H), 7.75 (s, 1H), 7.72-7.69 (m, 6H), 7.54-7.48 (m, 8H), 7.10 (d, J = 8.8Hz, 1H), 6.95 (dd, J = 8.8, 2.6Hz, 1H), 2.45 (s, 6H)

[0754] Example 317 N-(2,2-dioxo-3-phenyl-1-methyl-1H-2,1-benzothiazin-6-yl)-4-methyl-N-(4-methylbenzenesulfonyl)benzene-1-sulfonamide

[0755] The compound obtained in Example 316 was treated in the same manner as in Example 101 to obtain the title compound.

[0756] ​​１ H NMR (500MHz, CDCl3): δ7.83 (d, J = 8.4Hz, 4H), 7.66-7.64 (m, 2H), 7.48-7.46 (m, 3H), 7.35 (d, J = 8.0Hz, 4H), 7. 20 (d, J = 2.3Hz, 1H), 7.17 (s, 1H), 7.12 (d, J = 8.9Hz, 1H), 7.09 (dd, J = 8.8, 2.3Hz, 1H), 3.58 (s, 3H), 2.48 (s, 6H)

[0757] Example 318 4-methyl-N-(4-methylbenzenesulfonyl)-N-[3-(4-methylphenyl)-2-oxo-2H-chromen-6-yl]benzene-1-sulfonamide

[0758] Triethylamine (350 μL) and p-toluenesulfonyl chloride (240 mg) were added to a dichloromethane solution (5 mL) of 6-amino-3-(4-methylphenyl)-2H-chromen-2-one (126 mg) obtained in Reference Example 4-(1), and the mixture was stirred at the same temperature for 2 days. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / hexane=30%) to obtain the title compound (120 mg) as a white solid.

[0759] １ H NMR (500MHz, CDCl ３ ): δ7.83-7.80 (m, 4H), 7.67 (s, 1H), 7.58 (d, J=8.2Hz, 2H), 7.38-7.34 (m, 4H), 7.30 (d, J = 8.8Hz, 1H), 7.28-7.25 (m, 3H), 7.10 (dd, J = 8.8, 2.5Hz, 1H), 2.49 (s, 6H), 2.41 (s, 3H)

[0760]

[0761]

[0762]

[0763]

[0764] ​

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

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[0806] Test Example 1: Smad2 / 3 Nuclear Localization Inhibitory Effect TWNT-4 human-derived hepatic stellate cell line was suspended in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS) and plated at 1 x 10 cells per well in a 96-well plate. ３ After seeding at a density of 100 cells / well, the cells were incubated in 5% CO ２The cells were cultured for 24 hours at 37°C in the presence of 1% paraformaldehyde. The compounds of the present invention were dissolved in dimethyl sulfoxide to a concentration of 1 mM, and then further diluted with dimethyl sulfoxide and 5% FBS-DMEM to final concentrations of 5000, 1667, 556, 185, 62, 21, 7, and 2 nM, respectively. The TWNT-4 cell medium was removed, and 0.1 mL of each solution was added to each well along with 1 ng / mL TGF-β1 (Peprotech), followed by culture for 24 hours. The medium was then removed, and the cells were fixed with 4% paraformaldehyde and replaced with phosphate buffered saline (PBS). Blocking was performed for 30 minutes with PBS containing 2% bovine serum albumin and 0.1% Triton X-100, and then anti-Smad2 / 3 antibody (Cell Signaling Technology) diluted 1 / 4000 in the same blocking solution was incubated overnight at 4°C. After incubation, the cells were washed three times with PBS containing Tween-20 (PBS-T), and then Alexa Fluor 647-fluorescently labeled anti-rabbit immunoglobulin antibody (Thermo Fisher Scientific) and nuclear stain Hoechst 33342 (Dojindo Chemical Industries) were each diluted 1 / 4000 in the blocking solution and incubated at room temperature for 1 hour. After the reaction was completed, the cells were washed three times with PBS-T and replaced with PBS. Stained images were then obtained using a fluorescence microscope (CellinSight CX5, manufactured by Thermo Fisher Scientific). From the obtained stained images, the nuclear Smad2 / 3 fluorescence intensity and the cytoplasmic Smad2 / 3 fluorescence intensity were quantified using analysis software (HCS Studio, manufactured by Thermo Fisher Scientific), and the nuclear localization ratio of Smad2 / 3 was calculated from the ratio. The nuclear localization rate of Smad2 / 3 was calculated by the least squares method, with the TGF-β-treated group without compound treatment being set to 100% and the TGF-β-treated group with 10 μM of the ALK5 inhibitor SB431542 (Sigma) being set to 0%. ５０ (nM)) was calculated. The results are shown in Table 14.

[0807]

[0808] The results in Table 14 demonstrate that the compounds of the present invention significantly inhibit the nuclear localization of Smad2 / 3 induced by TGF-β stimulation.

[0809] Test Example 2: Inhibitory effect on CTGF and α-SMA mRNA expression (anti-fibrotic effect) TWNT-4 cells were suspended in 10% FBS-DMEM and plated at 2 × 10 ４ After seeding at a density of 100 cells / well, the cells were incubated in 5% CO ２ The cells were cultured for 24 hours at 37°C in the presence of 1% FBS-DMEM. The compound of the present invention was dissolved in dimethyl sulfoxide to a concentration of 1 mM, and then further diluted with dimethyl sulfoxide and 1% FBS-DMEM so that the final concentrations of the compound of the present invention were 10, 1, 0.1, and 0.3 μM, respectively. After removing the TWNT-4 cell medium, 1 mL of each solution was added to each well along with 2 ng / mL TGF-β1 (Peprotech), and the cells were cultured for 24 hours. Thereafter, RNA was extracted using TRIzol reagent (Thermo Fisher Scientific), and the absorbance at 260 nm was measured using a spectrophotometer (Nano Drop, manufactured by Thermo Fisher Scientific), and the RNA concentration was determined. Using this RNA as a template, a reverse transcription reaction was performed using the ReverTra Ace qPCR RT Kit (TOYOBO) according to the package insert to synthesize cDNA. Furthermore, using this cDNA as a template, real-time PCR was performed according to the package insert using THUNDERBIRD SYBR qPCR Mix (TOYOBO) and primers for CTGF (connective tissue growth factor), α-SMA (α-smooth muscle actin), or GAPDH as an internal standard gene. After measuring the threshold cycle (Ct) value of each gene, the relative mRNA expression level was calculated using the ΔΔCt method. The results are shown in Figure 1. From the results shown in FIG. 1, it was found that the compound of the present invention significantly suppressed the mRNA expression levels of CTGF and α-SMA induced by TGF-β stimulation.

Claims

1. The following formula (1): [wherein X represents an oxygen atom, a sulfur atom or a nitrogen atom which may have a substituent; Y represents a carbonyl group, a thiocarbonyl group, a sulfoxide group or a sulfonyl group; R １ represents an optionally substituted lower alkyl group, an optionally substituted aryl group, an optionally substituted 5- to 6-membered heteroaryl group, or an optionally substituted aralkyl group; R ２ represents a hydrogen atom, an optionally substituted lower alkyl group, a cyclo(lower alkyl) group, a heterocyclo(lower alkyl) group, an optionally substituted lower alkynyl group, an optionally substituted aralkyl group, or any of the groups shown in 1) to 5) below, 1) a group represented by the following formula (a): (In the formula, R a１ represents an optionally substituted lower alkyl group, a cyclo(lower alkyl) group, an optionally substituted lower alkenyl group, an optionally substituted lower alkoxy group, an optionally substituted aralkyloxy group or an optionally substituted aryl group, and a wavy line represents a bonding site. 2) A compound represented by the following formula (b): (wherein Z represents an oxygen atom or a sulfur atom; R b１ and R b２ may be the same or different and represent a hydrogen atom, an optionally substituted lower alkyl group, a cyclo-lower alkyl group, an optionally substituted aryl group, an optionally substituted 5- to 6-membered heteroaryl group, an optionally substituted aralkyl group, or an optionally substituted heteroaralkyl group, or R b１ and R b２ represents a 4- to 7-membered cyclic amino group which may contain a heteroatom, which is formed together with the adjacent nitrogen atom, and the wavy line represents the bonding site.) 3) A compound represented by the following formula (c): (In the formula, R ｃ１ represents an optionally substituted lower alkyl group, a cyclo(lower alkyl) group, a heterocyclo(lower alkyl) group, an optionally substituted lower alkenyl group, an optionally substituted aryl group, an optionally substituted 5- to 6-membered heteroaryl group, an optionally substituted aralkyl group, or an optionally substituted heteroaralkyl group, and the wavy line represents the bonding site. 4) The following formula (d): (In the formula, R ｄ１ and R ｄ２ may be the same or different and represent a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower cycloalkyl group, or an optionally substituted aralkyl group, or R ｄ１ and R ｄ２ represents a 4- to 7-membered cyclic amino group which may contain a heteroatom, which is formed together with the adjacent nitrogen atom, and the wavy line represents the bonding site. ３ represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, or an aryl group; R ４ represents a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group, a cyclo-lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxy group, an optionally substituted arylsulfoxy group, an optionally substituted lower alkoxy group, an amino group, a lower alkylamino group, a 4- to 7-membered cyclic amino group, a lower alkanoylamino group, a lower alkanoyl-lower alkylamino group, a lower alkoxycarbonylamino group, an aralkyloxycarbonylamino group, a lower alkoxycarbonyl group, a nitrile group, a carboxy group, a formyl group, an optionally substituted aryl group, an optionally substituted 5- to 6-membered heteroaryl group, an optionally substituted aralkyl group or an optionally substituted heteroaralkyl group; R ５ represents a hydrogen atom, a halogen atom or a lower alkoxy group, or a salt thereof.

2. X is an oxygen atom, Y is a carbonyl group or a sulfonyl group, and R １ is an optionally substituted phenyl group, R ２ is a group represented by formula (c), and R Ｃ１ is an optionally substituted phenyl group, R ３ is a hydrogen atom, R ４ is an optionally substituted phenyl group, R ５ The compound or salt thereof according to claim 1 , wherein is a hydrogen atom or a fluorine atom.

3. R １ is a phenyl group or C １－７ is a phenyl group substituted with an alkyl group; R ２ R in formula (c) Ｃ１ C １－７ The compound or salt thereof according to claim 2, which is a phenyl group substituted with an alkyl group.

4. A medicine comprising the compound according to claim 1 or a salt thereof and a pharma- ceutically acceptable carrier.

5. A preventive or therapeutic agent for fibrosis, comprising the compound or salt thereof according to claim 1 as an active ingredient.

6. A TGF-β signal inhibitor comprising the compound according to claim 1 or a salt thereof as an active ingredient.

7. A nuclear localization inhibitor of Smad2 / 3, comprising the compound according to claim 1 or a salt thereof as an active ingredient.

8. Use of the compound or salt thereof according to claim 1 for the manufacture of an agent for the prevention or treatment of fibrosis.

9. Use of the compound or a salt thereof according to claim 1 for the production of a TGF-β signal inhibitor.

10. Use of the compound according to claim 1 or a salt thereof for the production of an inhibitor of nuclear localization of Smad2 / 3.

11. The compound or salt thereof according to claim 1, which is used for preventing or treating fibrosis.

12. The compound or salt thereof according to claim 1, which is used for inhibiting TGF-β signaling.

13. The compound or salt thereof according to claim 1, which is used for inhibiting the nuclear localization of Smad2 / 3.

14. A method for preventing or treating fibrosis, which comprises administering the compound or salt thereof according to claim 1 to a subject.

15. A method for inhibiting TGF-β signaling, which comprises administering the compound or salt thereof according to claim 1 to a subject.

16. A method for inhibiting nuclear localization of Smad2 / 3, comprising administering the compound or salt thereof according to claim 1 to a subject.

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