HK1129100B

HK1129100B - Coumarin derivative having antitumor activity

Info

Publication number: HK1129100B
Application number: HK09107288.7A
Authority: HK
Inventors: 饭仓仁; 兵藤郁美; 青木纪裕; 古市纪之; 松下正行; 渡边史郎; 小泽佐和子; 堺谷政弘; 扈泌秀; 富井靖志; 高梨贤二; 原田直树
Original assignee: 中外制药株式会社; 酒井敏行
Priority date: 2006-02-09
Filing date: 2007-02-09
Publication date: 2012-05-25

Description

Coumarin derivatives with antitumor activity

Technical Field

The present invention relates to a novel coumarin derivative having an antitumor activity, and a pharmaceutical composition containing the same as an active ingredient, particularly a therapeutic agent for cell proliferative diseases.

Background

Coumarin derivatives, that is, compounds derived at various positions using a coumarin skeleton as a parent nucleus, are known to have various pharmacological actions depending on the position of chemical modification (non-patent document 31). For example, warfarin having an antithrombotic action is widely known as a drug having a coumarin skeleton (non-patent document 1). Furthermore, coumarin derivatives having antitumor activity acting on various target proteins or coumarin derivatives inhibiting proteins involved in antitumor activity are obtained by chemically modifying the parent nucleus at different positions.

In addition, coumarin derivatives that exhibit antitumor activity by inhibiting steroid sulfatase have been reported (non-patent documents 2 to 6). Clinical trials are now being conducted. The compound forms a cycloalkyl group at the 3-and 4-positions of the coumarin skeleton, and has a sulfamate group at the 7-position. It is considered to be applicable to breast cancer in terms of its pharmacological action.

Further, as coumarin derivatives exhibiting antitumor activity by binding to estrogen receptors, a group of compounds having a characteristic substituent at the 4-position has been reported. That is, a group of compounds having an arylalkyl group at the 4-position and having substituents at both the 3-position and the 7-position (patent document 1), and a group of compounds having a phenyl group directly bonded to the 4-position and having a phenoxy group at the 3-position (patent document 2) have been reported.

Further, as a coumarin derivative exhibiting Raf inhibitory activity and cell antitumor activity, a compound having a 6-pyrazinyloxy group at the 7-position has been reported (patent document 5).

In addition, some coumarin derivatives are known which, although the target protein is not clear, report an antitumor activity. These compounds include both compounds derived from natural sources (non-patent documents 7 to 12) and novel compounds obtained by chemical synthesis (non-patent documents 13 to 23 and 32 to 34). As novel compounds obtained by chemical synthesis, for example, a compound having an alkoxy group at the 5-, 6-and 7-positions of the coumarin skeleton (non-patent document 13), a compound having an alkoxy group only at the 7-position of the coumarin skeleton (non-patent document 14), a compound having an enone functional group at the 6-or 7-position of the coumarin skeleton (non-patent document 15), a compound having a methyl group at the 4-position of the coumarin skeleton and having substituents at the 7-and 8-positions (non-patent document 16), a compound having substituents at all of the 4-, 5-, 6-, 7-and 8-positions of the coumarin skeleton (non-patent document 17), a compound having an amide group, an ester group or a sulfonamide group directly bonded to the 3-position of the coumarin skeleton and having a substituent at the 6-or 8-position (non-patent documents 18 and 19), a compound having an amide group directly bonded to the 3-position of the coumarin skeleton and a substituent at the 7-position (patent document 3 and non-patent document 20), a compound having substituents at the 6-position and the 7-position of the coumarin skeleton (non-patent document 21), a compound having a hydroxyl group at the 7-position of the coumarin skeleton and a nitro group at an appropriate position among the 3-position, the 6-position, and the 8-position (non-patent documents 22 and 23), and a compound having a methoxy group or a hydroxyl group at the 7-position of the coumarin skeleton, a phenyl group at the 3-position, and a substituent at the 4-position.

Further, a compound having a substituent having a nitrogen atom at the 7-position (such as diethylamino), a cyano group at the 4-position, and a heteroaryl group at the 3-position (the 4-position may be unsubstituted) has been reported (non-patent document 32); a compound having a heteroaryl group at the 3-position and a methyl group, halogen, nitro group, or the like at the 6-, 7-, or 8-position (non-patent document 33). Further, as a ligand of a Pd compound having a cell antitumor activity, an example using a compound having a coumarin structure has also been reported (non-patent document 34).

In addition, as a report example that has no antitumor activity, compounds that may have antitumor activity and exhibit target protein inhibitory activity, coumarin derivatives that exhibit TNF α inhibitory activity (patent document 4 and non-patent documents 24 to 28), aromatase inhibitory activity (non-patent document 29), MEK inhibitory activity (non-patent document 30), and the like have been reported. In the compounds mentioned in these reports, the position of the substituent is the 3-, 4-, 6-or 7-position of the coumarin skeleton.

Thus, although some coumarin derivatives having antitumor activity are known, few compounds have been known which exhibit antitumor activity to a practical extent as anticancer agents. Therefore, there is still a great need for more practical compounds having sufficiently high antitumor activity.

Patent document 1: international publication No. 2000/039120 pamphlet

Patent document 2: international publication No. 2004/069820 pamphlet

Patent document 3: international publication No. 2003/024950 pamphlet

Patent document 4: international publication No. 2002/008217 pamphlet

Patent document 5: international publication No. 2006/067466 pamphlet

Non-patent document 1: ansell, j.; bergqvist, d.; drugs 2004, 64, 1-5

Non-patent document 2: purohit, a.; woo, l.w.l.; chander, s.k.; newman, s.p.; ireson, c.; ho, y; grasso, a.; leese, m.p.; potter, b.v.l.; reed, m.j.; J.Steroid biochem.mol.biol.2003, 86, 423-

Non-patent document 3: lloyd, m.d.; pederick, r.l.; natesh, r.; woo, l.w.l.; purohit, a.; reed, m.j.; acharya, k.r.; potter, b.v.l.; j.2005, 385, 715-720 of biochem

Non-patent document 4: purohit, a.; woo, l.w.l.; potter, b.v.l.; reed, m.j.; cancer Research 2000, 60, 3394-

Non-patent document 5: woo, l.w.l.; howarth, n.m.; purohit, a.; hejaz, a.m.; reed, m.j.; potter, b.v.l.; med chem.1998, 41, 1068-

Non-patent document 6: woo, l.w.l.; purohit, a.; reed, m.j.; potter, b.v.l.; med chem 1996, 39, 1349-

Non-patent document 7: Lopez-Perez, j.l.; olmedo, d.a.; olmo, e.d.; vasquez, y.; solis, p.n.; gupta, m.p.; felicino, a.s.; nat, prod.2005, 68, 369-

Non-patent document 8: ito, c.; itoigawa, m.; mishina, y.; filho, v.c.; enjo, f.; tokuda, h.; nishino, h.; furukawa, h.; J.nat.Prod.2003, 66, 368-one 371

Non-patent document 9: chen, Y-C.; cheng, M-J.; lee, S-J.; dixit, A-K.; ishikawa, t.; tsai, I-L.; chen, I-S.; Helv.Chim.acta 2004, 87, 2805-

Non-patent document 10: lee, K-H.; chai, H-B.; tamez, p.a.; pezzuto, j.m.; cordell, g.a.; win, k.k.; Tin-Wa, m.; phytochemistry 2003, 64, 535 541

Non-patent document 11: chaturvedula, v.s.p.; schilling, j.k.; kingston, d.g.i.; J.nat.Prod.2002, 65, 965-972-

Non-patent document 12: madari, h.; panda, d.; wilson, l.; jacobs, r.s.; cancer Research 2003, 63, 1214-

Non-patent document 13: riveiro, m.e.; shayo, c.; monczor, F.; fernandez, n.; baldi, a.; de Kimpe, n.; rossi, j.; debenedetti, s.; davio, c.; cancer Letters 2004, 210, 179-188

Non-patent document 14: baba, m.; jin, y.; mizuno, a.; suzuki, h.; okada, y.; takasuka, n.; tokuda, h.; nishino, h.; okuyama, t.; biol.pharm.Bull.2002, 25, 244-

Non-patent document 15: chen, Y-L.; wang, T-C.; tzeng, C-C; helv, Chim, acta 1999, 82, 191-one 197

Non-patent document 16: mazzei, m.; miele, m.; nieddu, e.; barbieri, f.; bruzzo, c.; alama, a.; Eur.J.Med.chem.2001, 36, 915-

Non-patent document 17: kimura, s.; ito, c.; jyoko, n.; segawa, h.; kuroda, j.; okada, m.; adachi, s.; nakahata, t.; yuasa, t.; filho, v.c.; furukawa, h.; maekawa, t.; int.j. cancer 2005, 113, 158-

Non-patent document 18: reddy, n.s.; mallereddigari, m.r.; cosenza, s.c.; gumireddy, k.; bell, s.c.; reddy, e.p.; reddy, m.v.r.; bioorg.Med.chem.Lett.2004, 14, 4093-

Non-patent document 19: reddy, n.s.; gumireddy, k.; mallereddigari, m.r.; cosenza, s.c.; venkatupura, p.; bell, s.c.; reddy, e.p.; reddy, m.v.r.; mede chem.2005, 13 3141-

Non-patent document 20: kempen, i.; papapostolouu, d.; thierry, n.; pocet, L; counerotte, s.; masereel, B.; foidart, j.m.; ravaux, m.r.; noeul, a.; pitotte, b.; Br.J. cancer 2003, 88, 1111-

Non-patent document 21: kim, h.h.; bang, s.s.; ghoi, j.s.; han, H.; kim, I-H.; cancer Letters 2005, 223, 191-201

Non-patent document 22: finn, g.j.; creaven, b.s.; egan, d.a.; cancer Letters 2004, 214, 43-54

Non-patent document 23: finn, g.j.; creaven, b.s.; egan, d.a.; Euro.J.Pharmacol.2003, 481, 159-

Non-patent document 24: cheng, j.f.; chen, m.; wallace, d.; tith, s.; arrhenius, t.; kashiwagi, h.; ono, y.; ishikawa, a.; sato, h.; kozono, t.; sato, h.; nadzan, a.m.; bioorg, med, chem, lett, 2004, 14, 2411-

Non-patent document 25: fries, w.; mazzon, e.; sturiale, s.; giofre, m.r.; lo Presti, m.a.; cuzzocrea, s.; campo, g.m.; caputi, a.p.; longo, g.; sturniolo, g.c.; life Sci.2004, 74, 2749-

Non-patent document 26: corsini, e.; lucchi, l.; binaglia, m.; viviani, b.; bevilacqua, c.; monastra, g.; marinovich, m.; gali, c.l.; Eur.J. Pharmacol.2001, 418, 231-

Non-patent document 27: cuzzocrea, s.; mazzon, e.; bevilacqua, c.; costanitino, g.; britti, d.; mazzullo, g.; de Sarro, a.; caputi, a.p.; Br.J. Pharmacol.2000, 131, 1399-

Non-patent document 28: tada, y.; shikishima, y.; takaishi, y.; shibata, h.; higuti, t.; honda, g.; ito, m.; takeda, y.; kodzhimatov, o.k.; ashurmeov, o.; ohmoto, y.; phytochemistry 2002, 59, 649-

Non-patent document 29: chen, s.; cho, m.; karlsberg, k.; zhou, d.; yuan, y.c.; chem.2004, 279, 48071-

Non-patent document 30: han, S.; zhou, v.; pan, s.; liu, y.; hornsby, m.; McMullan, d.; klock, h.e.; haugen, j.; lesley, s.a.; gray, n.; caldwell, j.; gu, X-J.; meds chem Lett.2005, 15, 5467-

Non-patent document 31: kulkarni, m.v.; kulkarni, g.m.; lin, C-H; sun, C-M; current medical Chemistry 2006, 13, 2795-

Non-patent document 32: lee, s.; sivakumar, k.; shin, W-S.; xie, f.; wang, q.; bioorganic & Medicinal Chemistry Letters 2006, 16, 4596-

Non-patent document 33: vijaya, k.p.; rajeswar, r.v.; indian journal Chemistry, Section B: organic Chemistry incorporating medicinal Chemistry 2005, 44B, 2120-

Non-patent document 34: budzisz, e.; malecka, m.; lorenz, I-P.; mayer, p.; kwieecin, r.a.; paneth, p.; krajewska, u.; rozalski, M.; inorganic chemistry 2006, 45, 9688-

Disclosure of Invention

The purpose of the present invention is to provide a compound having sufficiently high antitumor activity and being useful as a therapeutic agent for cell proliferative diseases, particularly cancer, and a medicinal composition containing the compound as an active ingredient.

The present inventors have conducted intensive studies with the object of providing a novel compound effective for the treatment of cell proliferative diseases, particularly cancer, and as a result, have found that: the coumarin derivatives having a substituent at the 3-, 4-and 7-positions of the coumarin skeleton and a substituent at the 6-position, and having a sulfonamide group or an α -amidomethylenesulfonamide group have high antitumor activity or both high antitumor activity and high exposure to an organism, and thus the present invention has been completed.

Namely, the present invention provides a compound represented by the following general formula (11) or a pharmaceutically acceptable salt thereof.

[ in the formula, G¹、G²、G³And G⁸Each independently selected from-N ═ CR ¹and-C (-G)⁹-X)＝，

G¹、G²、G³And G⁸Any one of them is-C (-G)⁹-X)＝，

X is selected from C_1-6Alkyl (the C)_1-6The alkyl radical being chosen from halogen atoms, hydroxy groups, cyano groups, -NR⁵⁶R⁵⁷Substituted with radical(s), aryl, heterocyclic radical, R³¹CS-、R³¹CO-、R³³R³⁴NCS-、R³³R³⁴NC ═ NH-and R³R⁴NCO-、R³³R³⁴NCO₂-，

G⁹Selected from single bonds, oxygen atoms, sulfur atoms, - (CR)³⁵R³⁶)_l- (wherein l represents an integer of 1 to 3) and-NR³⁷-，

Ring G⁶Selected from the group consisting of a 2-valent aryl group and a 2-valent heterocyclic group,

a is selected from a group represented by the following general formula (2) and a group represented by the following general formula (3),

G⁴selected from oxygen atoms, sulfur atoms, -NR³⁸-and-CR⁴⁰R⁴¹-，

G⁵Selected from 2 hydrogen atoms, oxygen atoms, sulfur atoms and ═ CH₂，

G⁷Selected from oxygen atoms, -CR⁴²R⁴³-、-CR⁴²R⁴³-O-、-O- CR⁴²R⁴³-、-CONR⁴⁴-、-NR⁴⁴CO-、-NR⁴⁵-、-NR⁴⁵CR⁴²R⁴³-、-CR⁴²R⁴³NR⁴⁵-、-S(＝O)_n-、-NR⁴⁴S(＝O)_n-、-S(＝O)_nNR⁴⁴- (where N represents an integer of 0 to 2), -N-CR⁴²-、-CR⁴²＝N-、-CR⁴²＝CR⁴³-、-C≡C-、-NR⁴⁴-O-、-O-NR⁴⁴-, -C (═ O) -O-and-O-C (═ O) -,

R¹selected from hydrogen atoms, halogen atoms, cyano groups, C_1-6Alkyl (the C)_1-6The alkyl group may be selected from halogen atoms, hydroxy groups and-NR⁴⁶R⁴⁷Substituted with a group of (1), C_2-7Alkenyl, carbamoyl and C_2-7Alkynyl (the C)_2-7Alkynyl may be substituted by C_1-4Acyl group substitution. ),

at G²Or G³is-CR¹＝，G⁸is-C (-G)⁹-X) ═ X is R³R⁴NCO-、R³³R³⁴NC-NH-or R³³R³⁴In case of NCS-; at G⁸is-CR¹＝，G³is-C (-G)⁹-X) ═ X is R³R⁴NCO-、R³³R³⁴NC-NH-or R³³R³⁴In case of NCS-; at G¹Or G⁸is-CR¹＝，G²is-C (-G)⁹-X) ═ X is R³R⁴NCO-、R³³R³⁴NC-NH-or R³³R³⁴In case of NCS-; or, at G²is-CR¹＝，G¹is-C (-G)⁹-X) ═ X is R ³R⁴NCO-、R³³R³⁴NC-NH-or R³³R³⁴In the case of NCS-, R¹Can be mixed with R⁴Or R³⁴Together forming a single bond or-CH₂-，

R²Represents a hydroxyl group, C_1-6Alkoxy, -NR⁴⁸R⁴⁹Or C_1-6Alkyl (the C)_1-6The alkyl group may be selected from halogen atoms, hydroxy groups, C_1-6Alkoxy, formyl, -CO2R⁵⁰and-CO 2NR⁵¹R⁵²Is substituted by the group (1). ),

R³、R⁴、R⁶、R⁷、R⁹、R¹⁰、R³¹、R⁴⁶and R⁴⁷Are each independently selected from hydrogen atoms、C_1-6Alkoxy radical, C_3-8Cycloalkyl and C_1-6Alkyl (the C)_1-6The alkyl group may be selected from cyano, halogen, hydroxy, C_1-6Alkoxy, -NR¹³R¹⁴、-CONR²⁸R²⁹And aryl group substitution. ),

R³³and R³⁴Each independently selected from hydrogen atom, C_1-6An alkyl group and an aryl group, and a pharmaceutically acceptable salt thereof,

R³and R⁴Combination of (1), R⁶And R⁷Combination of (1), R⁹And R¹⁰Combination of (1), R³³And R³⁴A combination of (2) and R⁴⁶And R⁴⁷Can form a 4-to 6-membered heterocyclic group containing at least 1 nitrogen atom (the heterocyclic group can be further condensed with a benzene ring) together with the bound nitrogen atom,

1R³⁵And 1R³⁶Each independently selected from a hydrogen atom, a halogen atom and C_1-6An alkyl group, a carboxyl group,

R⁴⁵selected from hydrogen atoms, C_1-6Alkyl and-S (═ O)_mNR⁵⁴R⁵⁵(where m represents an integer of 0 to 2.),

R¹³、R¹⁴、R⁵⁶and R⁵⁷Each independently selected from hydrogen atom, C_1-6Alkyl, -COR³²and-CO₂R³²，

R⁵、R⁸、R²⁸、R²⁹、R³²、R³⁷、R³⁸、R⁴⁰、R⁴¹、R⁴²、R⁴³、R⁴⁴、R⁴⁸、R⁴⁹、R⁵⁰、R⁵¹、R⁵²、R⁵⁴And R⁵⁵Each independently selected from hydrogen atom and C_1-6An alkyl group. Angle (c)

As G¹、G²And G³Are each independently preferably-CR¹As G ¹And G³Further, it is more preferably — CH ═ CH.

As G⁸Preferably, -C (-G)⁹-X) ═ X. As X-G⁹Examples thereof include the following groups.

At G²Or G³is-CR¹＝，G⁸is-C (-G)⁹-X) ═ X is R³R⁴NCO-、R³³R³⁴NC-NH-or R³³R³⁴In case of NCS-; at G⁸is-CR¹＝，G³is-C (-G)⁹-X) ═ X is R³R⁴NCO-、R³³R³⁴NC-NH-or R³³R³⁴In case of NCS-; at G¹Or G⁸is-CR¹＝，G²is-C (-G)⁹-X) ═ X is R³R⁴NCO-、R³³R³⁴NC-NH-or R³³R³⁴In case of NCS-; or, at G²is-CR¹＝，G¹is-C (-G)⁹-X) ═ X is R³R⁴NCO-、R³³R³⁴NC-NH-or R³³R³⁴In the case of NCS-, R¹Can be reacted with R⁴Or R³⁴Together forming a single bond or-CH₂-。

As at R¹And R⁴Part structures formed together, e.g. mayThe following partial structures are mentioned.

More specifically, for example, the following partial structures can be given.

[ in the formula, G⁹、Z⁴、R³、G¹And G³The combinations of (A) and (B) are shown in the following table. Angle (c)

G⁹	Z⁴	R³	G¹	G³
					O	O	CH₃	CH	CH
O	O	H	CH	CH
					S	O	CH₃	CH	CH

O	S	CH₃	CH	CH
					NH	O	CH₃	CH	CH
O	O	CH₃	N	CH

[ in the formula, G⁹、Z³、R³、G¹And G²The combinations of (A) and (B) are shown in the following table. Angle (c)

G⁹	Z³	R³	G¹	G²
					O	O	CH₃	CH	CH
O	O	H	CH	CH
					S	O	CH₃	CH	CCH₃
O	S	CH₃	CH	CH
					NH	O	CH₃	CH	CF
O	O	CH₃	N	CH
					O	O	CH₃	CH	N

At G⁹Is- (CR)³⁵R³⁶)_lWhen l represents an integer of 1 to 3, R is preferably used as X³³R³⁴NCO₂-。

In which X is C_1-6Alkyl (the C)_1-6The alkyl radical being chosen from halogen atoms, hydroxy groups, cyano groups, -NR⁵⁶R⁵⁷Is substituted by the group (1). ) G is⁹In the case of a single bond, as R¹Preferably a hydrogen atom, a halogen atom, a cyano group, C_2-7Alkenyl, carbamoyl or C _2-7Alkynyl (the C)_2-7Alkynyl may be substituted by C_1-4Acyl group substitution. ).

The compound represented by the general formula (11) is preferably a compound represented by the following general formula (1).

[ in the formula, X is selected from heteroaryl and R³R⁴NCO-，

Y¹And Y²Are each independently selected from-N ═ and-CR¹¹＝，

Y³And Y⁴The same or different, represent-CR¹²＝，

R¹selected from hydrogen atoms, halogen atoms, cyano groups, C_1-6Alkyl radical, C_2-7Alkenyl, carbamoyl and C_2-7Alkynyl (the C)_2-7Alkynyl may be substituted by C_1-4Acyl group substitution. ),

R²represents C which may be substituted by halogen atoms_1-6An alkyl group, a carboxyl group,

R³、R⁴、R⁶、R⁷、R⁹and R¹⁰Each independently selected from hydrogen atom, C_1-6Alkoxy radical, C_3-8Cycloalkyl and C_1-6Alkyl (the C)_1-6The alkyl group may be selected from cyano, halogen, hydroxy, C_1-6Alkoxy and-NR¹³R¹⁴Is substituted by the group (1). ),

R³and R⁴Combination of (1), R⁶And R⁷A combination of (2) and R⁹And R¹⁰Can form a 4-to 6-membered heterocyclic group containing at least 1 nitrogen atom together with the bound nitrogen atom,

R⁵、R⁸、R¹³and R¹⁴Each independently selected from hydrogen atom and C_1-6An alkyl group, a carboxyl group,

R¹¹selected from hydrogen atoms, halogen atoms, C_1-6Alkyl radical, C_1-4Acyl radical, C_1-4Acyloxy and-NR¹⁵R¹⁶，

R¹²Selected from hydrogen atoms, halogen atoms and C_1-6An alkyl group, a carboxyl group,

R¹⁵and R¹⁶Each independently selected from hydrogen atom and C_1-4An acyl group. Angle (c)

The above-mentioned compound or a pharmaceutically acceptable salt thereof has a remarkably high antitumor activity as compared with conventional compounds, or has a sufficiently high antitumor activity equivalent to conventional compounds and a higher exposure to the living body than conventional compounds, and thus has a more excellent property as an anticancer agent than conventional coumarin compounds.

The above-mentioned compound having such a characteristic or a pharmaceutically acceptable salt thereof can be used as an active ingredient of a pharmaceutical composition, that is, the present invention also provides a pharmaceutical composition containing, as an active ingredient, a compound represented by the general formula (11), preferably the general formula (1), or a pharmaceutically acceptable salt thereof.

Further, the above-mentioned compound or a pharmaceutically acceptable salt thereof can be used as an active ingredient of a therapeutic agent for cell proliferative diseases, particularly cancer. That is, the present invention further provides a therapeutic agent for a cell proliferative disease, particularly cancer, containing a compound represented by the general formula (11), preferably the general formula (1), or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention provides a compound having sufficiently high antitumor activity and useful as a therapeutic agent for cell proliferative diseases, particularly cancer, and a medicinal composition containing the compound as an active ingredient.

Detailed Description

Preferred embodiments of the present invention will be described below.

The compound of the present invention is a compound represented by the above general formula (11), preferably the above general formula (1).

In the general formula (11) and the general formula (1), the heteroaryl group means a 5 to 10-membered aromatic heterocyclic group containing 1 or more heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. Specific examples thereof include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzooxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridinyl and the like. Preferred examples of the group include thiazolyl, pyrimidinyl and pyridyl, and more preferred examples of the group include thiazol-2-yl, pyrimidin-2-yl and 2-pyridyl.

The heteroaryl group may have a halogen atom or C at an atom constituting the ring_1-6Alkyl radical, C_1-6Alkoxy, cyano, amino, carbamoyl, nitro, carboxy, C_2-7Alkenyl radical、C_2-7Alkynyl and the like, but is preferably unsubstituted.

The aryl group means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Specific examples thereof include phenyl, 1-naphthyl and 2-naphthyl. The aryl group may have a halogen atom or C on a carbon atom_1-6Alkyl radical, C_1-6Alkoxy, cyano, amino, carbamoyl, nitro, carboxy, C_2-7Alkenyl radical, C_2-7Alkynyl and the like.

The 2-valent aryl group means a group obtained by removing any one hydrogen atom from a carbon atom constituting the above-mentioned aryl group. G in 2-valent aryl⁷The substitution pattern of A is arbitrary, and for example, in the case where the 2-valent aryl group is a phenylene group, any of 1, 2-substitution, 1, 3-substitution, and 1, 4-substitution may be adopted.

The halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

C_1-6The alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 1-methylpropyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-dimethylbutyl, 2, 3-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl.

C_2-7The alkenyl group means a straight chain or branched alkenyl group having 2 to 7 carbon atoms. Specific examples thereof include vinyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, heptadienyl, and heptatrienyl.

C_2-7Alkynyl means a straight chain of 2 to 7 carbon atomsBranched and branched alkynyl groups. Specific examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, pentynyl, hexynyl, heptynyl, and heptyltrynyl.

C_1-4The acyl group means an acyl group having 1 to 4 carbon atoms. Specific examples thereof include formyl group, acetyl group, n-propionyl group, isopropionyl group, butyryl group, sec-butyryl group (isobutyryl group), and the like.

C_1-6The alkoxy group means an alkoxy group having a linear or branched alkyl group having 1 to 6 carbon atoms as an alkyl moiety. Specific examples thereof include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group and the like.

C_3-8The cycloalkyl group means a 3-to 8-membered cycloalkyl group having a total of 3 to 8 carbon atoms (the cycloalkyl group may be further substituted with a linear or branched alkyl group having 1 to 3 carbon atoms). Specific examples thereof include unsubstituted cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and substituted cycloalkyl groups such as methylcyclopropyl, ethylcyclopropyl, dimethylcyclopropyl, trimethylcyclopropyl, diethylcyclopropyl, ethylmethylcyclopropyl, dimethylethylcyclopropyl, diethylmethylcyclopropyl, methylcyclobutyl, ethylcyclobutyl, dimethylcyclobutyl, trimethylcyclobutyl, tetramethylcyclobutyl, diethylcyclobutyl, ethylmethylcyclobutyl, dimethylethylcyclobutyl, methylcyclopentyl, ethylcyclopentyl, dimethylcyclopentyl, trimethylcyclopentyl, ethylmethylcyclopentyl, methylcyclohexyl, ethylcyclohexyl, dimethylcyclohexyl and methylheptyl. Preferred examples of the group include unsubstituted cycloalkyl groups, and more preferred examples of the group include cyclopropyl groups.

The 4-to 6-membered heterocyclic group containing at least 1 nitrogen atom means a saturated or unsaturated heterocyclic group containing 1 or more nitrogen atoms, which may further contain 1 or more heteroatoms selected from oxygen atoms and sulfur atoms, and having 4 to 6 atoms in the ring (the heterocyclic group may be further condensed with a benzene ring. specific examples thereof include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, dihydropyrrolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, sulfapyridylalkyl, oxazolinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, pyridinyl, dihydropyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl and the like.

The 4-to 6-membered heterocyclic group containing at least 1 nitrogen atom may have a halogen atom or C on the ring-constituting atom_1-6Alkyl radical, C_1-6Alkoxy, cyano, amino, carbamoyl, nitro, carboxy, C_2-7Alkenyl radical, C_2-7Alkynyl and the like.

The heterocyclic group means a saturated or unsaturated cyclic group containing 1 or more hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, and 4 to 12-membered, preferably 5 to 7-membered. The heterocyclic ring may be a monocyclic ring or a condensed ring, and includes the above-mentioned heteroaryl group and a 4-to 6-membered heterocyclic group containing at least 1 nitrogen atom.

Specific examples of the heterocyclic group include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzooxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolizinyl, imidazopyridinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, pyrrolyl, dihydropyrrolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, sulfapyridylalkyl, oxazolinyl, oxazolidinyl, morpholinyl, and the like, Thiomorpholinyl, pyridyl, dihydropyridinyl, pyrimidinyl, pyridazinyl, tetrahydrofuryl, tetrahydrothienyl, dioxolanyl, oxathiolanyl (oxathiolanyl), dioxanyl, isobenzofuranyl, benzopyranyl, indolizinyl, indolyl, isoindolyl, indazolyl, puryl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, isobenzohydropyranyl, chromanyl, quinuclidinyl, oxepinyl, dioxacycloheptyl, thiepinyl, diazepanyl, and the like.

The heterocyclic group may have a halogen atom or C at the ring-constituting atom_1-6Alkyl radical, C_1-6Alkoxy, cyano, amino, carbamoyl, nitro, carboxy, C_2-7Alkenyl radical, C_2-7Alkynyl and the like.

The 2-valent heterocyclic group means a group obtained by removing any one hydrogen atom from the atoms constituting the heterocyclic group. In the 2-valent heterocyclic radical, G⁷The substitution pattern of A is arbitrary, and for example, in the case where the 2-valent heterocyclic group is a pyridine-diyl group, any of 2, 3-substitution, 2, 4-substitution, 2, 5-substitution, 2, 6-substitution, 3, 4-substitution, 3, 5-substitution, 3, 6-substitution, 4, 5-substitution, 4, 6-substitution, and 5, 6-substitution may be employed.

C_1-4The acyloxy group means an acyloxy group having an acyl group having 1 to 4 carbon atoms as an acyl moiety. Specific examples thereof include formyloxy, acetyloxy, n-propionyloxy, iso-propionyloxy, butyryloxy, sec-butyryloxy (iso-butyryloxy), and the like.

As C substituted by halogen atoms_1-6Specific examples of the alkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a difluoroethyl group, a trifluoroethyl group, a pentafluoroethyl group, a fluoropropyl group, a difluoropropyl group, a trifluoropropyl group, a heptafluoropropyl group, a fluorobutyl group, a difluorobutyl group, a trifluorobutyl group, a fluoropentyl group, a difluoropentyl group, a trifluoropentyl group, a tetrafluoropentyl group, a fluoroheptyl group, a difluoroheptyl group, a trifluoroheptyl group, a tetrafluoroheptyl group, a pentafluoroheptyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a chloroethyl group, a dichloroethyl group, a trichloroethyl group, a pentachloroethyl group Heptachloropropyl, chlorobutyl, dichlorobutyl, trichlorobutyl, chloropentyl, dichloropentyl, trichloropentyl, tetrachloropentyl, chloroheptyl, dichloroheptyl, trichloroheptyl, tetrachloroheptyl, pentachloroheptyl, bromomethyl, dibromomethyl, tribromomethyl, bromoethyl, dibromoethyl, tribromoethyl, pentabromoethyl, bromopropyl, dibromopropyl, tribromopropyl, heptabromopropyl, bromobutyl, tribromobutyl, bromopentyl, dibromopentyl, tribromopentyl, tetrabromopentyl, bromoheptyl, dibromoheptyl, tribromoheptyl, tetrabromoheptyl, pentabromoheptyl, iodomethyl, diiodomethyl, triiodomethyl, iodoethyl, diiodoethyl, triiodoethyl, pentaiodoethyl, iodopropyl, diiodopropyl, triiodopropyl, heptaiodopropyl, iodobutyl, diiodobutyl, triiodobutyl, iodopentyl, diiodopentyl, triiodopentyl, tetraiodopentyl, pentaiodopentyl, pentaiodoheptyl, bromoheptyl, heptaiodobutyl, pentaiodobutyl, and pentaiodopentyl, Iodoheptyl, diiodoheptyl, triiodoheptyl, tetraiodoheptyl, pentaiodoheptyl, and the like.

As R¹Preferably a hydrogen atom, a halogen atom, a cyano group, C_1-6Alkyl, carbamoyl and C_2-7Alkynyl (the C)_2-7Alkynyl may be substituted by C_1-4Acyl group substitution. ). Among them, a hydrogen atom, a halogen atom, a cyano group, a methyl group, a vinyl group and an acetylvinyl group are particularly preferable. As R ¹Further, a hydrogen atom, a halogen atom and a methyl group are preferable, and a hydrogen atom, a fluorine atom, a chlorine atom and a methyl group are particularly preferable.

As R²Preferably C which may be substituted by fluorine atoms_1-6An alkyl group. Among these, methyl, ethyl, n-propyl, fluoromethyl, 1-fluoroethyl, 2-difluoroethyl, 1-fluoro-n-propyl, 2-difluoro-n-propyl, and-CH is particularly preferred₃、-CH₂F and-CH₂CH₃。

As R³、R⁴、R⁶、R⁷、R⁹And R¹⁰Preferably each independently of the other is a hydrogen atom and C_1-6An alkyl group. Here, as C_1-6Alkyl, preferably methyl, ethyl, n-propyl and isopropyl, particularly preferably methyl, ethyl andand (3) isopropyl.

As R³And R⁴Preferably each independently is C_1-6An alkyl group. Among them, R is preferred³And R⁴All are the same C_1-6Alkyl groups, particularly preferably both methyl groups.

As R⁶And R⁷Preferably, each is independently a hydrogen atom, C_1-6Alkoxy radical, C_3-8Cycloalkyl and C_1-6Alkyl (the C)_1-6The alkyl group may be selected from cyano, halogen, hydroxy, C_1-6Alkoxy and-NR¹³R¹⁴Is substituted by the group (1). ). Here, as R⁶Or R⁷Shown as C_1-6Alkoxy, preferably methoxy and ethoxy, particularly preferably methoxy. Further, as R⁶Or R⁷Shown as C_3-8Cycloalkyl, preferably unsubstituted cycloalkyl, particularly preferably cyclopropyl. Further, as R ⁶Or R⁷Shown as C_1-6Alkyl groups, preferably methyl, ethyl and n-propyl, particularly preferably ethyl in the case of substitution and particularly preferably methyl in the case of non-substitution. Further, as being C_1-6The halogen atom selected as a substituent of the alkyl group is particularly preferably a fluorine atom. Further, as being C_1-6C selected as a substituent of an alkyl group_1-6Alkoxy, particularly preferably methoxy.

Further, as R⁶And R⁷Particularly preferred are a hydrogen atom, an unsubstituted cycloalkyl group and an unsubstituted C group, each independently_1-6An alkyl group. As R⁶And R⁷Combinations of hydrogen atoms with each other, hydrogen atoms and methyl groups, hydrogen atoms and cyclopropyl groups, methyl groups with each other, hydrogen atoms and cyanoethyl groups, hydrogen atoms and methoxyethyl groups, hydrogen atoms and aminoethyl groups, hydrogen atoms and trifluoroethyl groups, hydrogen atoms and methoxy groups, hydrogen atoms and hydroxyethyl groups, and hydrogen atoms and methylaminoethyl groups are preferred, and combinations of hydrogen atoms with each other, hydrogen atoms and cyclopropyl groups, and hydrogen atoms and methyl groups are particularly preferred.

As R⁹And R¹⁰Each independently preferably represents a hydrogen atom or C_1-6Alkyl and C_1-6An alkoxy group. Here, as C_1-6Alkyl groups, preferably methyl, ethyl, n-propyl and isopropyl groups, particularly preferably methyl, ethyl and isopropyl groups. Further, as C _1-6Alkoxy groups, preferably methoxy, ethoxy, n-propoxy and isopropoxy, particularly preferably methoxy.

Further, as R⁹And R¹⁰Preferably hydrogen atoms with each other, hydrogen atoms with methyl groups, methyl groups with each other, hydrogen atoms with ethyl groups, ethyl groups with each other, hydrogen atoms with isopropyl groups, methyl groups with isopropyl groups, ethyl groups with isopropyl groups, isopropyl groups with each other, hydrogen atoms with methoxy groups, methyl groups with methoxy groups, ethyl groups with methoxy groups, and isopropyl groups with methoxy groups. Among them, combinations of hydrogen atoms with each other, hydrogen atoms with methyl groups, methyl groups with each other, hydrogen atoms with ethyl groups, hydrogen atoms with isopropyl groups, and hydrogen atoms with methoxy groups are particularly preferable.

As R⁵And R⁸Preferably a hydrogen atom.

As R¹⁵And R¹⁶C in (1)_1-4Acyl, preferably formyl, acetyl and propionyl, particularly preferably acetyl. Further, as R¹⁵And R¹⁶The combination of (3) is preferably a combination of hydrogen atoms with each other and a combination of a hydrogen atom and an acetyl group, and particularly preferably a combination of a hydrogen atom and an acetyl group.

As R¹¹C in (1)_1-6Alkyl groups, preferably methyl, ethyl and n-propyl, particularly preferably methyl. Further, as R¹¹C in (1)_1-4Acyl, preferably formyl, acetyl and n-propionyl, particularly preferably acetyl. Further, as R ¹¹C in (1)_1-4Acyloxy groups, preferably formyloxy, acetyloxy and n-propionyloxy, particularly preferably acetyloxy. As R¹¹Hydrogen atom and halogen atom are preferable, and hydrogen atom and fluorine atom are particularly preferable.

As Y¹Preference is given to-N ═, -CH ═ CF ═ and-CCl ═ and in particularPreferred are-N ═, -CH ═ and-CF ═ and more preferred are-N ═ and-CH ═.

As Y²Of (5A) to (CR)¹¹R ═ R¹¹Preferably a hydrogen atom, a halogen atom, C_1-4Acyl and NR¹⁵R¹⁶Particularly preferred are a hydrogen atom, a fluorine atom, a chlorine atom, an acetyl group and-NHCOCH₃. As Y²Preference is given to-N ═, -CH ═ and-CF ═ with-CH ═ and-CF being particularly preferred.

As R¹²Hydrogen atom, fluorine atom and methyl group are preferable, hydrogen atom and fluorine atom are particularly preferable, and hydrogen atom is more preferable.

As R¹³And R¹⁴Hydrogen atom, methyl group and ethyl group are each independently preferred, and hydrogen atom and methyl group are particularly preferred. Further, as R¹³And R¹⁴The combination of (3) is preferably a combination of hydrogen atoms with each other and a combination of hydrogen atoms and a methyl group.

As X, thiazol-2-yl, pyrimidin-2-yl, 2-pyridyl and R are preferred³R⁴NCO- (wherein, R)³And R⁴The same as above. ). Here, R is particularly preferred³And R⁴Are all methyl.

As A, a group represented by the general formula (2) is preferable.

In the case where X is thiazol-2-yl, Y is preferably¹is-N or-CH, Y²is-CH, -CF or-CCl, R¹Is a hydrogen atom, a chlorine atom or a methyl group, R²Methyl, ethyl and fluoromethyl. And, when A is a group represented by the general formula (2), R is⁶And R⁷The combination of (3) is preferably a combination of hydrogen atoms with each other or a combination of a hydrogen atom and a methyl group, and when A is a group represented by the formula (3), R is a group⁹And R¹⁰The combination of (3) is preferably a combination of a hydrogen atom and a methyl group, and a combination of a hydrogen atom and a cyclopropyl group.

In case X is pyrimidin-2-yl, Y is preferably¹is-N or-CH, Y²is-N, -CH or-CF, R¹Is a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, R²Is methyl, ethyl or fluoromethyl, A is a group of the formula (2), R⁶And R⁷Combinations of hydrogen atoms with each other, with methyl groups, or with cyclopropyl groups.

In which X is (H)₃C)₂In the case of NCO-, Y is preferred¹is-N or-CH, Y²is-CH, -CF or-CCl, R¹Is a hydrogen atom, a fluorine atom, a chlorine atom, an iodine atom, a cyano group or a methyl group, R²Is methyl or fluoromethyl. And, when A is a group represented by the general formula (2), R is⁶And R⁷The combination of (3) is preferably a combination of hydrogen atoms with each other, a combination of hydrogen atoms with a methyl group, and a combination of methyl groups with each other, and when A is a group represented by the general formula (3), R is a group represented by ⁹And R¹⁰The combination of (3) is preferably a combination of a hydrogen atom and a methyl group, a hydrogen atom and a methoxyethyl group, and a hydrogen atom and a cyanoethyl group.

At Y¹In the case of-N ═ X is preferably thiazol-2-yl, pyrimidin-2-yl or (H)₃C)₂NCO-，Y²is-CH, -CF or-CCl, R¹Is a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, R²Is methyl or ethyl, A is a radical of the formula (2), R⁶And R⁷Combinations of hydrogen atoms with each other, with methyl groups, or with cyclopropyl groups.

At Y¹In the case of-CH ═ X is preferably thiazol-2-yl, pyrimidin-2-yl or (H)₃C)₂NCO-，Y²is-N, -CH or-CF, R¹Is a hydrogen atom, a fluorine atom, a chlorine atom, an iodine atom, a methyl group or a cyano group, R²Is methyl or fluoromethyl. And, when A is a group represented by the general formula (2), R is⁶And R⁷The combination of (3) is preferably a combination of hydrogen atoms, methyl groups and a combination of hydrogen atoms and methyl groups, and when A is a group represented by the general formula (3), R is a group represented by⁹And R¹⁰Combinations of (2), preferably hydrogen atomAnd methyl, hydrogen and methoxyethyl, and hydrogen and cyanoethyl.

At Y²In the case of-CH ═ X is preferably thiazol-2-yl, pyrimidin-2-yl or (H) ₃C)₂NCO-，Y¹is-N or-CH, R¹Is a hydrogen atom, a fluorine atom, a chlorine atom, an iodine atom, a methyl group or a cyano group, R²Is methyl, ethyl or fluoromethyl. And, when A is a group represented by the general formula (2), R is⁶And R⁷The combination of (3) is preferably a combination of hydrogen atoms, methyl groups and a combination of hydrogen atoms and methyl groups, and when A is a group represented by the general formula (3), R is a group represented by⁹And R¹⁰The combination of (3) is preferably a combination of a hydrogen atom and a methyl group, a hydrogen atom and a methoxyethyl group, and a hydrogen atom and a cyanoethyl group.

At Y²In the case of-CF ═ X is preferably thiazol-2-yl, pyrimidin-2-yl or (H)₃C)₂NCO-，Y¹is-N or-CH, R¹Is a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, R²Is methyl, ethyl or fluoromethyl, A is a group of the formula (2), R⁶And R⁷The combination of (b) is a combination of hydrogen atoms with each other, a hydrogen atom and a methyl group, or a hydrogen atom and a cyclopropyl group.

At R¹In the case of a hydrogen atom, X is preferably thiazol-2-yl, pyrimidin-2-yl or (H)₃C)₂NCO-，Y¹is-N or-CH, Y²is-N, -CH or-CF, R²Is methyl or fluoromethyl. And, when A is a group represented by the general formula (2), R is⁶And R⁷The combination of (3) is preferably a combination of hydrogen atoms and each other, and a combination of hydrogen atoms and a methyl group, and when A is a group represented by the general formula (3), R is a group ⁹And R¹⁰A combination of (3) is preferably a combination of a hydrogen atom and a methyl group.

At R¹In the case of a fluorine atom, X is preferably thiazol-2-yl, pyrimidin-2-yl or (H)₃C)₂NCO-，Y¹is-N or-CH, Y²is-N, -CH or-CF, R²Is methyl, A is a radical of the formula (2), R⁶And R⁷Combinations of hydrogen atoms with each other, methyl groups with each other, hydrogen atoms with methyl groups, hydrogen atoms with cyclopropyl groups, hydrogen atoms with methoxyethyl groups, or hydrogen atoms with cyanoethyl groups.

At R¹In the case of a chlorine atom, X is preferably thiazol-2-yl, pyrimidin-2-yl or (H)₃C)₂NCO-，Y¹is-N or-CH, Y²is-CH or-CF, R²Is methyl or trifluoromethyl. And, when A is a group represented by the general formula (2), R is⁶And R⁷The combination of (3) is preferably a combination of methyl groups and a combination of a hydrogen atom and a methyl group, and when A is a group represented by the general formula (3), R is a group represented by⁹And R¹⁰The combination of (3) is preferably a combination of a hydrogen atom and a methyl group, a hydrogen atom and a methoxyethyl group, and a hydrogen atom and a cyanoethyl group.

At R¹In the case of methyl, X is preferably thiazol-2-yl, pyrimidin-2-yl or (H)₃C)₂NCO-，Y¹is-N or-CH, Y²is-CH, -CF or-CCl, R²Is methyl, ethyl or trifluoromethyl, A is a radical of the general formula (2), R ⁶And R⁷The combination of (b) is a combination of a hydrogen atom and a methyl group.

At R²In the case of methyl, X is preferably thiazol-2-yl, pyrimidin-2-yl or (H)₃C)₂NCO-，Y¹is-N or-CH, Y²is-N ═, -CH ═, -CF ═ or-CCl ═ R¹Is hydrogen atom, fluorine atom, chlorine atom, iodine atom, methyl group or cyano group. And, when A is a group represented by the general formula (2), R is⁶And R⁷The combination of (3) is preferably a combination of hydrogen atoms with each other, methyl groups with each other, hydrogen atoms and methyl groups, and hydrogen atoms and cyclopropyl groups, and when A is a group represented by the general formula (3), R is a group represented by⁹And R¹⁰The combination of (3) is preferably a combination of a hydrogen atom and a methyl group, a hydrogen atom and a methoxyethyl group, and a hydrogen atom and a cyanoethyl group.

At R²In the case of ethyl, X is preferably thiazol-2-yl or pyrimidin-2-yl, Y¹is-N ═ Y²is-CF ═ R¹Is methyl, A is a radical of the formula (2), R⁶And R⁷The combination of (b) is a combination of a hydrogen atom and a methyl group.

At R²In the case of fluoromethyl, X is preferably thiazol-2-yl, pyrimidin-2-yl or (H)₃C)₂NCO-，Y¹is-N or-CH, Y²is-N, -CH or-CF, R¹Is a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, A is a group represented by the general formula (2), R⁶And R⁷The combination of (b) is a combination of a hydrogen atom and a methyl group.

At R⁶And R⁷In the case where the combination of (A) is a combination of hydrogen atoms with each other, X is preferably thiazol-2-yl, pyrimidin-2-yl or (H)₃C)₂NCO-，Y¹is-N or-CH, Y²is-N, -CH or-CF, R¹Is a hydrogen atom, a fluorine atom, a chlorine atom or an iodine atom, R²Is methyl, fluoromethyl or ethyl.

At R⁶And R⁷In the case where the combination of (A) is a combination of methyl groups with each other, X is preferably thiazol-2-yl, pyrimidin-2-yl or (H)₃C)₂NCO-，Y¹is-N or-CH, Y²is-N ═, -CH ═, -CF ═ or-CCl ═ R¹Is a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, R²Is methyl, fluoromethyl or ethyl.

At R⁶And R⁷In the case where the combination of (A) is a combination of a hydrogen atom and a methyl group, X is preferably thiazol-2-yl, pyrimidin-2-yl or (H)₃C)₂NCO-，Y¹is-N or-CH, Y²is-N ═, -CH ═, -CF ═ or-CCl ═ R¹Is a hydrogen atom, a fluorine atom, a chlorine atom, an iodine atom, a methyl group or a cyano group, R²Is methyl, ethyl or fluoromethyl.

At R⁹And R¹⁰In the case where the combination of (A) is a combination of a hydrogen atom and a methyl group, X is preferably thiazol-2-yl, pyrimidin-2-yl or (H)₃C)₂NCO-，Y¹is-N or-CH, Y²is-CH or-CF, R¹Is a hydrogen atom or a chlorine atom, R²Is methyl.

Suitable examples of the compound represented by general formula (11), preferably general formula (1), or a pharmaceutically acceptable salt thereof include:

3- {3- (aminosulfonyl) aminobenzyl } -4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- {3- (aminosulfonyl) aminobenzyl } -6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- {3- (aminosulfonyl) aminobenzyl } -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- (3-aminosulfonylamino-2-fluoro-benzyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- { 2-fluoro-3- (aminosulfonyl) aminobenzyl } -6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- {3- (aminosulfonyl) aminobenzyl } -6-iodo-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- {3- (aminosulfonyl) aminobenzyl } -6-methyl-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- {3- (aminosulfonyl) aminobenzyl } -6-cyano-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- {3- (aminosulfonyl) aminobenzyl } -4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- {3- (aminosulfonyl) aminobenzyl } -6-fluoro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- {3- (aminosulfonyl) aminobenzyl } -6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- (3-aminosulfonylamino-2-fluoro-benzyl) -4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- { 2-fluoro-3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -6-chloro-2-oxo-2H-1-benzopyran,

3- { 2-fluoro-3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -6-methyl-2-oxo-2H-1-benzopyran,

3- { 2-chloro-3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

4-methyl-3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

6-fluoro-4-methyl-3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- (3- (N-methylsulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- (3-methylaminosulfonylamino-2-fluoro-benzyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

6-iodo-4-methyl-3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

6-methyl-4-methyl-3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

6-cyano-4-methyl-3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

4-methyl-3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

4-methyl-3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -6-fluoro-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

4-methyl-3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -6-chloro-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

4-methyl-3- {6- (methylaminosulfonyl) aminopyridin-2-ylmethyl } -2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

4-methyl-3- {6- (methylaminosulfonyl) aminopyridin-2-ylmethyl } -6-fluoro-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

4-methyl-3- {6- (methylaminosulfonyl) aminopyridin-2-ylmethyl } -6-chloro-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- (3-methylaminosulfonylamino-2-fluoro-benzyl) -4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- (3-methylaminosulfonylaminobenzyl) -4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- (3-methylaminosulfonylaminobenzyl) -6-fluoro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

6-chloro-4-fluoromethyl-3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -6-fluoro-2-oxo-2H-1-benzopyran,

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-fluoromethyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -6-chloro-2-oxo-2H-1-benzopyran,

3- {3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -6-chloro-2-oxo-2H-1-benzopyran,

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -6-methyl-2-oxo-2H-1-benzopyran,

6-chloro-4-methyl-3- {3- (dimethylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- { 2-fluoro-3- (dimethylaminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- (3- (N- (2-cyanoethyl) sulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- (3- (N- (2-hydroxyethyl) sulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- (3- (N- (2-methoxyethyl) sulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- (3- (N- (2-aminoethyl) sulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester hydrochloride,

3- (3- (N- (N' -methyl-2-aminoethyl) methylsulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester hydrochloride,

3- (3- (N-2, 2, 2-trifluoroethyl-sulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- (3- (N-methoxysulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- (3-carbamoylmethanesulfonylamino-benzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

3- (3-methylcarbamoylmethanesulphonylamino-benzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

2- { 2-fluoro-3- [ 4-methyl-2-oxo-7- (pyrimidin-2-yloxy) -2H-1-benzopyran-3-ylmethyl ] phenylsulfamoyl } -N-methyl-acetamide,

3- (3-dimethylcarbamoylmethanesulfonylamino-benzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

2- { 2-fluoro-3- [ 4-methyl-2-oxo-7- (thiazol-2-yloxy) -2H-1-benzopyran-3-ylmethyl ] phenylsulfamoyl } -N-methyl-acetamide,

3- { 2-methyl-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (ethylamino sulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (isopropylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-fluoro-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (cyclopropylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-fluoro-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-chloro-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-ethyl-6-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (cyclopropylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (cyclopropylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-chloropyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-6-chloro-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (cyclopropylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-6-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-chloropyridin-4-ylmethyl } -4-methyl-6-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (5-fluoropyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (4-chloropyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (2, 4-dimethoxypyrimidin-6-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (benzothiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (5-bromothiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (5-fluoropyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (4-chloropyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (2, 4-dimethoxypyrimidin-6-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (benzothiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (5-bromothiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (pyrazin-2-yloxy) -2-oxo-2H-1-benzopyran, and

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (pyridin-2-yloxy) -2-oxo-2H-1-benzopyran.

Among the compounds represented by the general formula (1), the following compounds are preferred from the viewpoint of antitumor activity: x is selected from thiazol-2-yl, pyrimidin-2-yl and (H)₃C)₂NCO-，Y¹Selected from-CH and-N, Y²Selected from-CH ═, -CF ═ and-CCl ═ Y³And Y⁴is-CH ═ A is selected from-NHSO₂NR⁶⁰R⁷⁰and-NHSO₂CH₂CONCH₃R⁹⁰(Here, R is⁶⁰And R⁹⁰Each independently selected from hydrogen atom and methyl group, R ⁷⁰Selected from the group consisting of a hydrogen atom, a methyl group and an ethyl group (the ethyl group may be substituted by a substituent selected from the group consisting of a methoxy group and a cyano group). ) R is¹Selected from the group consisting of hydrogen atom, fluorine atom, chlorine atom, iodine atom, methyl group and cyano group, R²Is selected from-CH₃、-CH₂F and-CH₂CH₃。

From the viewpoint of antitumor activity, preferable compounds include, for example:

6-fluoro-4-methyl-3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate,

Dimethylcarbamic acid 3- (3-methylcarbamoylmethanesulfonylamino-benzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, and

dimethylcarbamic acid 3- (3-dimethylcarbamoylmethanesulfonylamino-benzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester.

From the viewpoint of exposure to living bodies, the following compounds are preferred: x is selected from thiazol-2-yl and pyrimidin-2-yl, Y¹Selected from-CH and-N, Y²Selected from-CH and-CF, Y³And Y⁴is-CH ═ A is selected from-NHSO₂NHR⁶⁰and-NHSO₂CH₂CONHCH₃(Here, R is⁶⁰Selected from hydrogen atoms and methyl groups. ) R is¹Selected from hydrogen atoms, fluorine atoms and methyl groups, R²Is selected from-CH₃and-CH₂F。

From the viewpoint of exposure to the living body, preferable compounds include, for example:

3- {3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -6-methyl-2-oxo-2H-1-benzopyran, and

2- { 2-fluoro-3- [ 4-methyl-2-oxo-7- (thiazol-2-yloxy) -2H-1-benzopyran-3-ylmethyl ] phenylsulfamoyl } -N-methyl-acetamide.

In addition to the compound represented by the general formula (11), there are also compounds which have sufficiently high antitumor activity as the compound represented by the general formula (11) and are useful as therapeutic agents for cell proliferative diseases, particularly cancer.

Examples of such compounds include, in addition to their partial structures:

a compound having the same structure as general formula (11) except that it has the following structure instead.

For example, there can be mentioned, in addition to the partial structure:

Further, for example, there can be also mentioned, in addition to the partial structure:

[ in the formula, G⁹、Z⁷、Z⁸、G¹And G³The combinations of (A) and (B) are shown in the following table. Angle (c)

G⁹	Z⁷	Z⁸	G¹	G³
					O	N(CH₃)₂	N	CH	CH
S	N(CH₃)₂	N	CH	CH
					NH	N(CH₃)₂	N	CH	CH
O	N(CH₃)₂	CH	CH	CH

[ in the formula, G⁹、Z⁵、Z⁶、G¹And G²The combinations of (A) and (B) are shown in the following table. Angle (c)

G⁹	Z⁵	Z⁶	G¹	G²
					O	N(CH₃)₂	N	CH	CCH₃
S	N(CH₃)₂	N	CH	CH
					NH	N(CH₃)₂	N	CH	CF
O	N(CH₃)₂	CH	CH	CH
					O	N(CH₃)₂	N	CH	N
S	N(CH₃)₂	N	N	CH

[ in the formula, G⁹、Z¹¹、Z¹²、G¹And G³The combinations of (A) and (B) are shown in the following table. Angle (c)

G⁹	Z¹¹	Z¹²	G¹	G³
					O	N(CH₃)₂	N	CH	CH
S	N(CH₃)₂	N	CH	CH
					O	N(CH₃)₂	CH	CH	CH
NH	N(CH₃)₂	N	CH	CH

[ in the formula, G⁹、Z⁹、Z¹⁰、G¹And G²The combinations of (A) and (B) are shown in the following table. Angle (c)

G⁹	Z⁹	Z¹⁰	G¹	G²
					O	N(CH₃)₂	N	CH	CH
S	N(CH₃)₂	N	CH	CH
					O	N(CH₃)₂	CH	CH	CH
NH	N(CH₃)₂	N	CH	CH

A may be selected from the group represented by the following formulae in addition to the group represented by the above general formula (2) or (3).

[ in the formula, the symbol is represented by the formula⁶The location of the bond. Angle (c)

When A is a group represented by the general formula (2), R ⁷And form a ring G⁶May together form a ring. Specific examples of the partial structure formed in this case include a partial structure represented by the following formula.

[ in the formula, the symbol is represented by the formula⁷The location of the bond. Angle (c)

More specifically, for example, the following partial structures can be given.

[ in the formula, the symbol is represented by the formula⁷Position of binding, Y¹、Y³、Y⁴And Z²The combinations of (A) and (B) are shown in the following table. Angle (c)

Y¹	Y³	Y²	Z²
				CH	CH	CH	NH
CF	CH	CH	NCH₃
				CH	CH	CH	CH₂
CF	CH	CH	N(CH₃)CH₂
				CH	CH	CH	N(CH₃)CH₂CH₂
CH	CH	CH	CH₂CH₂
				CH	CH	CH	CH₂CH₂CH₂
CF	CH	CH	NH
				CH	CH	N	NCH₃

[ in the formula, the symbol is represented by the formula⁷Position of binding, Y¹、Y³、Y⁴And Z¹The combinations of (A) and (B) are shown in the following table. Angle (c)

Y¹	Y³	Y⁴	Z¹
				CH	CH	CH	NH
N	CH	CH	NCH₃
				CH	CH	CH	CH₂
N	CH	CH	N(CH₃)CH₂
				CH	CH	CH	N(CH₃)CH₂CH₂
CH	CH	CH	CH₂CH₂
				CH	CH	CH	CH₂CH₂CH₂
N	CH	CH	NH
				N	CH	N	NCH₃

Specific examples of the compound represented by the general formula (11) include compounds represented by the following formulae.

[ in the formula, G⁹、Y¹、Y²、Y³、Y⁴、G¹、G²、G³、NR⁶R⁷、G⁷And R²The combinations of (A) and (B) are shown in the following table. Angle (c)

X

G⁹

Y¹

Y²

Y³

Y⁴

G¹

G²

G³

NR⁶R⁷

G⁷

R²

(CH₃)₂NCO

O

N

CF

CH

N

CH

N(CH₃)₂

GH₂

CH₃

(CH₃)₂NCO

O

CH

CF

CH

N

CH

NH₂

CH₂

CH₃

2-N-methyl-imidazolyl

O

CH

CF

CH

N

CH

NH₂

CH₂

CH₃

(CH₃)₂NCO

O

CH

CF

N

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

CF

CH

N

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

N

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

CF

CH

N

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

CF

CH

N

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

N

CF

CH

N

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

NH

N

CF

CH

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

CH

N

CH

CCH₃

CH

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

N

CF

CH

N

CH

NHCH₃

CH₂

CH₂CH₃

2-pyrimidinyl radicals

O

CH

CF

CH

N

CH

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

N

CH

N

CH

NHCH₃

CH₂

CH₂F

2-pyrimidinyl radicals

CH₂

CH

CF

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

O

N

CF

CH

N

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

O

CH

CF

CH

N

NHCH₃

CH₂

CH₃

2-thiazolyl group

O

CH

N

CH

CF

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

O

N

CF

CH

NHCH₃

SO

CH₃

2-thiazolyl group

CF₂

N

CF

CH

N

CH

NHCH₃

SO

CH₃

2-N-methyl-imidazolyl

O

CH

CF

CH

NHCH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

N

CF

CH

NHCH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

CH

CF

CH

CCH₃

CH

NHCH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

CH

CF

CH

CI

CH

NHCH₃

CH₂

CH₃

Or

[ in the formula, G⁹、Z¹³、Z¹⁴、Z¹⁵、G¹、G²、G³、NR⁶R⁷、G⁷And R²The combinations of (A) and (B) are shown in the following table. Angle (c)

X

G⁹

Z¹³

Z¹⁴

Z¹⁵

G¹

G²

G³

NR⁵R⁷

G⁷

R²

(CH₃)₂NCO

O

S

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

S

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

S

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

NH

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

NH

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

NH

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

O

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

O

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

S

NH

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

N

CH

NH

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

S

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

CH₂

S

CH

N

CH

NHCH₃

S

CH₃

(CH₃)₂NCO

CF₂

CH

S

CH

N

CH

NHCH₃

SO

CH₃

2-pyrimidinyl radicals

O

S

CH

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

CH

S

CH

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

CH

S

CH

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

S

CH

N

CH

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

CH

S

CH

CCH₃

CH

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

CH

S

N

CH

NHCH₃

CH₂

2-pyrimidinyl radicals

O

S

CH

NHCH₃

O

CH₃

2-pyrimidinyl radicals

O

CH

S

CH

NHCH₃

S

CH₃

2-pyrimidinyl radicals

O

CH

S

CH

NHCH₃

NH

CH₃

2-thiazolyl group

O

S

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

O

CH

S

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

O

CH

S

CH

NHCH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

S

CH

NHCH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

CH

S

CH

CCH₃

CH

NHCH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

N

S

CH

CCH₃

CH

NHCH₃

S

CH₃

Next, an example of a method for producing the compound or salt of the present invention will be described. In each of the manufacturing methods described below, the order of the steps can be changed as necessary. Further, when a reaction substance in some steps is subjected to an undesired chemical change under the reaction conditions in the step, the production method can be carried out by, for example, protecting and deprotecting a functional group. As for the selection of the protecting Groups, and the selection of the protecting and deprotecting methods, for example, reference may be made to t.w.greene, p.g.m.wuts, Protective Groups in Organic Synthesis, Second Edition, John Wiley & Sons, inc.

In addition, X, Y¹、Y²、Y³、Y⁴、R¹、R⁵、R⁶、R⁷、R⁸、R⁹And R¹⁰In the same sense as above, Hal represents a halogen atom, R^aIs represented by C_1-6Alkyl (the C)_1-6The alkyl groups may be selected from fluorine atoms, maySubstituted with a substituent of protected hydroxy, oxo which may be protected, and carboxy which may be protected. ) R is ^bRepresents a leaving group (halogen atom, 2-oxazolidin-3-yl group, etc.), R^cA protecting group (C) representing a carboxyl group_1-4Alkyl, etc.), R^dAnd R^eMay be the same or different and each independently or collectively represent a protecting group for an amino group, R^fIs represented by C_1-4Alkyl radical, R^gRepresents a hydroxyl group or a halogen atom, R^hRepresents methyl or R^cOCO-，RⁱRepresents a hydrogen atom or C_1-5Alkyl, B represents nitro or-NR^dR^e。

(general preparation method-1)

General Process-1 is an example of a particularly preferred production process for the following compounds: the compound is a compound represented by the general formula (1), R²Is R^a，Y¹And Y²Same or different is-CR¹¹A compound of (i).

Step 1-1:

compound 1c can be obtained by condensing the apoplast obtained by reacting compound 1b with a base with compound 1 a.

Examples of the base include sodium hydride, potassium hydride, and lithium hexamethyldisilazane (referred to as "LiHMDS" in the present specification), and sodium hydride is preferable.

Examples of the reaction solvent include ether solvents such as tetrahydrofuran (referred to as "THF" in the present specification) and diethyl ether; and halogen-based solvents such as methylene chloride, preferably THF.

The reaction temperature can be appropriately selected depending on the kind of the reaction solvent, etc., and when the compound 1b is reacted with a base, it is usually from-20 ℃ to 25 ℃, preferably from 0 ℃ to 10 ℃; when the apoplast is condensed with the compound 1a, it is usually 0 to 60 ℃ and preferably 15 to 35 ℃.

The reaction time can be appropriately selected depending on the reaction temperature and the like, and when the compound 1b is reacted with a base, it is usually 10 minutes to 3 hours, preferably 20 minutes to 1 hour; when the apoplast is condensed with the compound 1a, it is usually from 2 to 20 hours, preferably from 5 to 15 hours.

As a method of supplying the deprotonated body and the compound 1a to the reaction, a method of dropwise adding a solution containing the deprotonated body to a solution containing the compound 1a is preferable.

Step 1-2:

compound 1e can be obtained by reacting compound 1c with compound 1d in the presence of an acid.

Examples of the acid include Lewis acids such as zirconium chloride, samarium (II) chloride and aluminum chloride; inorganic acids such as sulfuric acid; an acidic resin such as zeolite, etc., and sulfuric acid is preferred. The solvent may be an inert solvent used in the reaction, but preferably no solvent is used. In the case of using sulfuric acid, the number of equivalents for the compound 1d is usually 1 to 5, preferably 1 to 3.

The reaction temperature is usually from-20 ℃ to 50 ℃ and preferably from-10 ℃ to 30 ℃.

The reaction time can be appropriately selected depending on the reaction temperature, and is usually 2 to 20 hours, preferably 5 to 16 hours.

Step 1 to step 3:

compound 1e and compound 1f are reacted in the presence of a base, whereby compound 1g can be obtained.

Examples of the base include weakly basic inorganic salts such as sodium carbonate, potassium carbonate, and cesium carbonate; and metal hydrides such as sodium hydride and potassium hydride, and potassium carbonate, cesium carbonate and sodium hydride are preferable.

Examples of the reaction solvent include ether solvents such as tetrahydrofuran and diethyl ether; n, N-dimethylformamide and the like are preferable, and tetrahydrofuran and N, N-dimethylformamide are preferable.

The reaction temperature can be appropriately selected depending on the kind of the reaction solvent, and is usually 60 to 150 ℃ and preferably 70 to 100 ℃ in the case where X is an electron-deficient heteroaryl group such as a pyridyl group or a pyrimidyl group, 90 to 200 ℃ and preferably 100 to 120 ℃ in the case where X is an electron-deficient heteroaryl group such as a thiazolyl group, and R is R³R⁴In the case of the group represented by NCO-, the range is usually from 0 ℃ to 50 ℃ and preferably from 0 ℃ to 30 ℃.

The reaction time can be appropriately selected depending on the reaction temperature and the like, and is usually 30 minutes to 5 hours, preferably 40 minutes to 2 hours.

When X is an electron-rich heteroaryl group such as thiazolyl group, copper (I) iodide or CuPF is preferable₆And 1-valent copper salts such as Cu (I) OTf (copper (I) trifluoromethanesulfonate), preferably in the presence of copper (I) iodide, and the like, and the reaction is carried out while irradiating with microwaves.

Step 1 to step 4:

by reducing compound 1g, compound 1h can be obtained.

Examples of the reducing agent include tin (II) chloride and zinc, and tin (II) chloride is preferable.

Examples of the reaction solvent include alcohol solvents such as methanol and ethanol; acetic acid esters such as ethyl acetate, n-propyl acetate, n-butyl acetate and the like; and a mixed solvent thereof, preferably ethyl acetate, and a mixed solvent of ethanol and ethyl acetate.

The reaction temperature is usually from 50 ℃ to 150 ℃, preferably from 60 ℃ to 90 ℃.

The reaction time is usually 30 minutes to 5 hours, preferably 1 hour to 3 hours.

The compound 1h can be obtained by subjecting the compound 1a to the steps 1 to 4, 1 to 1, 1 to 2, and 1 to 3 in this order, or the compound 1c to the steps 1 to 4, 1 to 2, and 1 to 3 in this order.

Further, referring to bioorg.med.chem.lett., 2004, 14, 2411-2415, the compound 1h can be obtained from compounds other than the compound 1g by catalytic hydrogenation using palladium carbon or the like as a catalyst.

Step 1 to step 5:

compound 1j can be obtained by reacting compound 1h with compound 1 i.

Examples of the reaction solvent include dichloromethane, acetonitrile, N-dimethylformamide, and the like, and acetonitrile, N-dimethylformamide, and the like are preferable from the viewpoint of solubility of the compound for 1 hour.

The reaction temperature is usually from 15 ℃ to 120 ℃ and preferably from 20 ℃ to 85 ℃.

The reaction time is usually 1 hour to 2 days, preferably 2 hours to 24 hours.

In addition, it is preferable to allow the base to coexist in the reaction. As the base, organic amines such as pyridine, triethylamine, diisopropylethylamine and the like are preferable.

Step 1 to step 6:

compound 1h is reacted with compound 1l in the presence of a base, followed by deprotection to convert Rc to a hydrogen atom, whereby compound 1m can be obtained.

In the reaction with the compound 1l, examples of the base include organic amines such as pyridine, triethylamine and diisopropylethylamine, and diisopropylethylamine is preferable.

The reaction solvent includes ether solvents such as diethyl ether, THF, and dioxane, and THF is preferable.

The reaction temperature is usually from 10 ℃ to 50 ℃ and preferably from 15 ℃ to 40 ℃.

The reaction time is usually 20 minutes to 2 hours, preferably 30 minutes to 1 hour.

As the deprotection method, a method of performing hydrolysis in the presence of a base is preferable.

Examples of the base include metal hydroxides such as sodium hydroxide and potassium hydroxide, and sodium hydroxide is preferable.

Examples of the reaction solvent include alcohol solvents such as methanol, ethanol, and n-propanol; water; and a mixed solvent thereof, preferably a mixed solvent of water and methanol.

The reaction temperature and reaction time were the same as those of compound 1 l.

Step 1 to step 8:

compound 1o can be obtained by condensing compound 1m with compound 1 n.

Examples of the condensing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide is preferable. Further, it is preferable that an active esterifying agent such as N-hydroxysuccinimide, N-hydroxybenzotriazole, 3-hydroxy-3, 4-dihydro-4-oxo-1, 2, 3-benzotriazole (preferably 3-hydroxy-3, 4-dihydro-4-oxo-1, 2, 3-benzotriazole) is allowed to coexist.

Examples of the reaction solvent include ether solvents such as diethyl ether, THF, and dimethoxyethane; halogen solvents such as methylene chloride, chloroform and carbon tetrachloride; n, N-dimethylformamide; acetonitrile, etc., preferably N, N-dimethylformamide.

The reaction time is usually 5 to 40 hours, preferably 10 to 25 hours.

Step 1 to 7 and step 1 to 9:

if necessary, subjecting Compound 1j and Compound 1o to C_1-6Alkylation, whereby Compound 1k and Compound 1 can be obtained p。

C_1-6Alkylation can be carried out, for example, by referring to the methods described in Bioorganic Medicinal Chemistry 2005, 13, 1393-.

Further, compound 1k can be obtained by subjecting compound 1h to steps 1 to 7 and steps 1 to 5 in this order. Further, compound 1p can be obtained by subjecting compound 1h to steps 1 to 9, steps 1 to 6, and steps 1 to 8 in this order.

The compound 1b can be obtained as a commercially available product, and can be produced, for example, by a method described in general textbooks on organic Chemistry (Jerry March, WILEY INTERSCIENCE advanced organic Chemistry 4th edition). The compound 1d is commercially available, and can be produced by the methods described in Journal of fluorine Chemistry 2003, 120, 173-32183, Journal of Organic Chemistry 1986, 51, 3242-3244, and the like.

(general preparation method-2)

General Process-2 is an example of a process for producing compound 1a of general Process-1.

Step 2-1:

compound 1a can be obtained by halogenating, preferably brominating, compound 2 a.

Examples of the halogenating agent include N-bromosuccinimide, N-chlorosuccinimide, and N-iodosuccinimide, and N-bromosuccinimide is preferable.

The reaction solvent is preferably a nonpolar inert solvent such as carbon tetrachloride.

The reaction temperature is usually from 20 ℃ to 100 ℃ and preferably from 50 ℃ to 90 ℃.

The reaction time is usually 30 minutes to 10 hours, preferably 1 hour to 7 hours.

Step 2-2:

compound 2c can be obtained by reducing compound 2 b.

Examples of the reducing agent include lithium aluminum hydride and diisobutylaluminum hydride (hereinafter referred to as "DIBAH"), with DIBAH being preferred.

Examples of the reaction solvent include ether solvents such as diethyl ether and THF; and benzene solvents such as benzene, toluene, and xylene, and when DIBAH is used as the reducing agent, toluene and the like are preferable.

The reaction temperature is usually from-100 ℃ to 10 ℃ and preferably from-85 ℃ to 0 ℃.

The reaction time is usually 10 minutes to 3 hours, preferably 30 minutes to 2 hours.

Furthermore, by reacting R of compound 2b^cCompound 2c can also be obtained by subjecting the compound obtained by OCO-conversion into a formyl group to step 2-2.

Step 2-3:

compound 1a can be obtained by converting the hydroxyl group of compound 2c to a halogen atom, preferably to a bromine atom.

Examples of the halogenating agent include diethylaminosulfur trifluoride (also referred to as "DAST" in the present specification), thionyl chloride, phosphorus tribromide, a combination of triphenylphosphine and iodine, a combination of p-toluenesulfonic acid chloride and sodium iodide, and the like, and phosphorus tribromide is preferable.

The reaction solvent includes ether solvents such as diethyl ether, THF, and dioxane, and diethyl ether is preferred.

The reaction temperature is usually from-10 ℃ to 10 ℃ and preferably from-5 ℃ to 5 ℃.

The reaction time is usually 10 minutes to 1 hour, preferably 20 minutes to 40 minutes.

The compounds 2a and 2b are commercially available, and can be produced, for example, by a method described in general textbooks on organic Chemistry (Jerry March, WILEY INTERSCIENCE advanced organic Chemistry 4th edition). Furthermore, the compound 2b can also be reacted, for example, with the corresponding halogenated aryl compound (in the compound 2b, -COOR^cA compound obtained by substitution with a halogen atom) is produced by performing any one of the following operations: (i) converting a halogen atom to a carboxyl group; (ii) reaction with copper (I) cyanide in sulfuric acid (Journal of Antibiotics1994, 47, 1456-; and (iii) insertion of carbon monoxide at the position of the halogen atom bonded using a palladium catalyst (Journal of organic chemistry 1999, 64, 6921-6923).

(general preparation method-3)

General Process for preparation of 3 is the general Process for preparation of 2, Compound 2a or Y in Compound 2b²An example of a particularly preferred production method of a compound which is-CF ═ is.

Step 3-1:

compound 3b can be obtained by reacting compound 3a (Hal is preferably a chlorine atom) with a fluorinating agent (preferably cesium fluoride) such as sodium fluoride, potassium fluoride, cesium fluoride or the like. In addition, quaternary ammonium salts such as tetramethylammonium chloride may be added as necessary.

As the reaction solvent, dimethyl sulfoxide, sulfolane, N-dimethylformamide and the like are preferable.

The reaction temperature is usually from 100 ℃ to 200 ℃ and preferably from 120 ℃ to 160 ℃.

Reaction time at R^hIn the case of a methyl group, it is usually 5 to 20 hours, preferably 7 to 15 hours, in R^hIs R^cIn the case of OCO-, the reaction time is usually 20 minutes to 2 hours, preferably 30 minutes to 1 hour.

Compounds 3b, especially Y¹、Y³And Y⁴Compounds in which any one of the above-mentioned groups is-CH ═ are novel compounds and are useful as synthesis intermediates of the compounds represented by general formula (1).

The compound 3a is commercially available, and can be produced by a method described in, for example, Yakugaku Zasshi 1955, 75, 292-.

(general preparation method-4)

General Process-4 is another method for producing Compound 1 h.

Step 4-1:

compound 4a can be synthesized by reducing compound 1 e. This step can be performed in the same manner as steps 1 to 4.

Step 4-2:

compound 4a can be reacted with compound 1f in the presence of a base to give compound 1 h. This step can be performed in the same manner as in steps 1 to 3.

(general preparation method-5)

General Process-5 is another method for producing Compound 1 h. Y can be produced by this method¹And Y²Are each independently-N ═ or-CR¹¹Compound 1 h.

Step 5-1:

by protecting the amino group of compound 5a, preferably by reacting R^dAnd R^eIs tert-butoxycarbonyl, to obtain compound 5 b.

Boc is preferred as a protecting agent₂O (di-tert-butyl dicarbonate), and the like.

The reaction solvent includes ether solvents such as diethyl ether and THF, and THF is preferable.

The reaction temperature can be appropriately selected depending on the kind of the reaction solvent, and is usually 0 to 90 ℃, preferably 20 to 70 ℃.

The reaction time is usually 2 hours to 2 days, preferably 3 hours to 20 hours.

Further, it is preferable to coexist a reaction accelerator such as N, N-dimethylaminopyridine.

Step 5-2:

compound 5c can be obtained by halogenating, preferably brominating, compound 5 b.

Examples of the halogenating agent include chlorine molecule, bromine molecule, iodine molecule, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide and the like, and N-bromosuccinimide is preferable. Further, it is preferable to coexist a radical initiator such as azoisobutyronitrile or benzoyl peroxide (preferably benzoyl peroxide).

Examples of the reaction solvent include halogen-based solvents such as carbon tetrachloride and chloroform; and hydrocarbon nonpolar solvents such as cyclohexane and hexane, and carbon tetrachloride is preferred.

The reaction temperature is usually from 50 ℃ to 100 ℃ and preferably from 70 ℃ to 90 ℃.

The reaction time is usually 1 to 8 hours, preferably 2 to 6 hours.

Step 5-3:

compound 5t can be obtained by reacting compound 5c with compound 1b in the presence of a base.

Examples of the base include metal hydrides such as sodium hydride, potassium hydride, and LiHMDS, and sodium hydride is preferable.

Examples of the reaction solvent include ether solvents such as THF and diethyl ether; and a chlorine-based solvent such as methylene chloride, preferably THF.

The reaction temperature is usually from-20 ℃ to 25 ℃ and preferably from 0 ℃ to 10 ℃.

The reaction time is usually 2 to 24 hours, preferably 6 to 15 hours.

Further, the compound 5t can be obtained by the condensation reaction described in WO2002/08217 and subsequent catalytic hydrogenation.

Step 5-4:

deprotection of the amino group is carried out simultaneously with the condensation reaction of compound 5t and compound 1d in the presence of an acid, whereby compound 5d can be obtained.

Examples of the acid include Lewis acids such as zirconium chloride, samarium (II) chloride and aluminum chloride; inorganic acids such as sulfuric acid; an acidic resin such as zeolite, etc., and sulfuric acid is preferred. The reaction solvent may be an inert solvent used in the reaction, but it is preferable not to use a solvent. In the case of using sulfuric acid, the number of equivalents for the compound 1d is usually 1 to 5, preferably 1 to 3.

Step 5-5:

compound 1h can be obtained by reacting compound 5d with compound 1f in the presence of a base. This step can be performed in the same manner as in steps 1 to 3.

Compound 5a is commercially available, and can be referred to, for example, European journal of Medicinal Chemistry 1999, 34, 1003-1008, Bioorganic & Medicinal Chemistry Letters 2004，16，1411-1416、Bioorganic & MedicinalChemistry Letters 2002，12，2109-2112、Chemical &Pharmaceutical bulletin 2004, 52, 818-829 and the like. Further, compound 5a and compound 5b can also be produced, for example, by: for the corresponding halogenated aryl compound (in compounds 5a or 5b, amino or-NR)^dR^eA compound obtained by substitution with a halogen atom), a nitrogen atom is introduced at the position to which the halogen atom is bonded using a palladium catalyst (Organic Letters2002, 4, 4689-4692).

Furthermore, in the general preparation methods-1, -4, -5 and-8, with respect to R^aIs C_1-6Alkyl (the C)_1-6The alkyl group is substituted with a substituent selected from the group consisting of a hydroxyl group which may be protected, an oxo group which may be protected, and a carboxyl group which may be protected. ) The compound of (1), wherein R is a group represented by the formula²Is C substituted by halogen atoms_1-6Alkyl compounds. The conversion to a fluorine atom can be carried out at an appropriate stage in the general production methods-1, -4, -5 and-8 with reference to Synthesis 2002, 17, 2561, 2578 and the like using DAST or the like as a fluorinating agent. Conversion to chlorine and bromine atoms thionyl chloride, PBr, can be prepared by reference to Comprehensive Organic Transformations by Larock et al ₃And the like as a halogenating agent using compound 1j, compound 1o, and the like.

(general preparation method-6)

General Process for producing-6A compound represented by the formula (1)In, R²Is C substituted by fluorine atoms_1-6An example of a preferable production method of the alkyl compound is.

Step 6-1:

compound 6b can be obtained by introducing a halogen atom, preferably a bromine atom, into compound 6 a.

Examples of the halogenating agent include N-chlorosuccinimide, N-bromosuccinimide, and N-iodosuccinimide, and N-bromosuccinimide is preferable.

The reaction solvent includes carbon tetrachloride, diethyl ether, THF, and the like, and THF and the like are preferable.

The reaction temperature is usually from-50 ℃ to 10 ℃ and preferably from-20 ℃ to 5 ℃.

Step 6-2:

compound 6c can be obtained by further substituting the halogen atom of compound 6b with a fluorine atom.

Examples of the fluorinating agent include metal fluorides such as potassium fluoride and sodium fluoride, and potassium fluoride is preferable. Further, it is preferable to coexist crown ethers corresponding to the metals in the metal fluorides used, such as 18-crown compound-6.

As the reaction solvent, for example, acetonitrile is preferable.

The reaction temperature is usually from 20 ℃ to 100 ℃ and preferably from 20 ℃ to 80 ℃.

The reaction time is usually 1 to 6 hours, preferably 1.5 to 5 hours.

Will obtainCompound 6c can be obtained by deprotecting, if necessary, and then subjecting the compound to the steps 1 to 4, 1 to 5, or 1 to 6 and thereafter of general production Process-1, thereby obtaining a compound represented by general formula (1) wherein R is²Is C substituted by fluorine atoms_1-6Alkyl compounds.

(general preparation method-7)

General Process for producing the compound represented by the formula (1), wherein R is²Is C substituted by halogen atoms_1-6An example of a preferable production method of the alkyl compound is.

Step 7-1:

compound 7c can be obtained by reacting compound 7b with a deplasmin obtained by reacting compound 1g with a base.

Examples of the base include sodium hydride, potassium hydride, and LiHMDS is preferable.

The reaction temperature can be appropriately selected depending on the kind of the reaction solvent, etc., and when 1g of the compound is reacted with a base, it is usually from-100 ℃ to 10 ℃, preferably from-85 ℃ to 5 ℃, and when the apoplast is reacted with the compound 7b, it is usually from-5 ℃ to 40 ℃, preferably from 0 ℃ to 30 ℃.

The reaction time can be suitably selected depending on the reaction temperature and the like, and is usually from 20 minutes to 3 hours, preferably from 30 minutes to 1.5 hours, when the compound 1g is reacted with the base, and from 20 minutes to 20 hours, preferably from 30 minutes to 15 hours, when the apoplast is reacted with the compound 7 b.

Step 7-3:

compound 7f can be obtained by reacting compound 7e with a deplasmin obtained by reacting compound 1g with a base. This step can be performed in the same manner as step 7-1.

Step 7-2 and step 7-4:

by reducing compound 7c and compound 7f, compound 7d and compound 7g can be obtained, respectively. This step can be performed in the same manner as steps 1 to 4.

By converting compound 7d or compound 7g in the same manner as in general Process-1, R in the compound represented by the general formula (1)²Is C substituted by halogen atoms_1-6Alkyl compounds.

And as R²Is C substituted by fluorine atoms_1-6The alkyl compound can also be produced by converting the hydroxyl group or oxo group of the introduced compound 7c or 7f into a fluorine atom and then performing the steps after step 1-4 of the general production method-1. Here, the conversion of a hydroxyl group or an oxo group into a fluorine atom can be carried out by referring to Synthesis 2002, 17, 2561, 2578 and the like using DAST or the like as a fluorinating agent.

(general preparation method-8)

General Process-8 is another method for producing Compound 5t, wherein Y is in the compound represented by the formula (1)¹An example of a particularly preferred production method of the compound represented by the formula-N ═ is.

[ in the formula, R^jRepresents a halogen atom, C_1-4Alkoxy, di (C)_1-4Alkyl) amino group, or hydrogen atom, R^kRepresents a leaving group such as an acetoxy group, a trifluoroacetoxy group, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, or a halogen atom. Angle (c)

Step 8-1:

apopores obtained by reacting compound 8a with a strong base are reacted with a compound of formula (la): r^jCHO (hereinafter also referred to simply as "R^jCHO ". ) The reaction can yield compound 8 b.

Examples of the strong base include metal amides such as lithium hexamethyldisilazide and lithium diisopropylamide; alkyl metals such as butyl lithium and ethyl lithium; alkyl magnesium halide, etc., preferably hexamethyldisilazane lithium amide, diisopropylamide lithium, etc. As R^jCHO includes formic acid derivatives such as formic acid chloride and formic acid esters; n, N-dimethylformamide (also referred to as "DMF" in the present specification), formamide such as N, N-diethylformamide, etc., and DMF is preferable. Furthermore, by using formaldehyde as R^jCHO, compound 8c can also be obtained directly from compound 8a without compound 8 b.

Examples of the reaction solvent include ether solvents such as THF and diethyl ether; and chlorine-based solvents such as methylene chloride and carbon tetrachloride, preferably THF.

The reaction temperature can be appropriately selected depending on the kind of the reaction solvent, etc., and when the compound 8a is reacted with a strong base, it is usually from-100 ℃ to 25 ℃, preferably from-95 ℃ to-65 ℃, when the apoplast and R are reacted with each other^jThe CHO reaction is carried out at a temperature of usually-100 ℃ to 35 ℃ and preferably-30 ℃ to 10 ℃.

The reaction time can be appropriately selected depending on the reaction temperature and the like, and when the compound 8a is reacted with a strong base, it is usually 10 minutes to 10 hours, preferably 20 minutes to 5 hours, when the proton-removing agent and R are reacted^jThe CHO reaction time is usually 30 minutes to 40 hours, preferably 30 minutes to 4 hours.

Step 8-2:

compound 8c can be obtained by reacting compound 8b with a reducing agent.

Examples of the reducing agent include: the metal hydrogen complex (for example, sodium borohydride, sodium sulfide borohydride, sodium cyanoborohydride, sodium trimethoxyborohydride, lithium borohydride, lithium cyanoborohydride, lithium triethylborohydride, lithium tri-sec-butylborohydride, lithium tri-tert-butylborohydride, calcium borohydride, potassium triisopropoxyborohydride, potassium tri-sec-butylborohydride, zinc borohydride, sodium triacetoxyborohydride, and other boron hydrides, and lithium aluminum hydride, lithium trimethoxyaluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium aluminum hydride/aluminum trichloride, lithium aluminum hydride/boron trifluoride, magnesium aluminum hydride chloride, aluminum magnesium hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium bis (methoxyethoxy) aluminum hydride, and other aluminum hydrides), preferably sodium borohydride, such as sodium borohydride.

Examples of the reaction solvent include ether solvents such as THF and diethyl ether; chlorine solvents such as methylene chloride and carbon tetrachloride; and an alcohol solvent such as methanol or ethanol, preferably THF.

The reaction temperature can be appropriately selected depending on the kind of the reaction solvent, and is usually-100 to 100 ℃ and preferably-10 to 50 ℃.

The reaction time can be appropriately selected depending on the reaction temperature and the like, and is usually 10 minutes to 30 hours, preferably 1 hour to 8 hours.

Step 8-3:

compound 8d can be obtained by reacting compound 8c with an amination agent.

Examples of the amination agent include ammonia; ammonia water; ammonium salts such as ammonium chloride and ammonium acetate; metal amides such as lithium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hexamethyldisilazide, lithium amide, sodium amide, potassium amide, and the like; and silazane such as hexamethyldisilazane, preferably ammonia, and metal amide such as lithium hexamethyldisilazide.

When ammonia is used as the aminating agent, an organic amine such as triethylamine and a base such as sodium hydroxide may be allowed to coexist in the reaction. In addition, in the case of using a metal amide such as lithium hexamethyldisilazane as the aminating agent, the palladium catalyst and the phosphine ligand, which are the same as those used in the step 8 to 5, can be coexisted in the reaction.

Examples of the reaction solvent include hydrocarbon solvents such as toluene and benzene; ether solvents such as THF, diethyl ether, and dioxane; chlorine solvents such as methylene chloride; aprotic polar solvents such as DMF, and the like, and toluene, DMF and dioxane are particularly preferable.

The reaction temperature may be appropriately selected depending on the kind of the reaction solvent, and is usually 0 to 200 ℃, preferably 30 to 150 ℃.

The reaction time may be appropriately selected depending on the reaction temperature, and is usually 1 to 30 hours, preferably 2 to 10 hours.

Compound 8d can also be obtained by pre-protecting the hydroxyl group of compound 8c, then performing this step, and then deprotecting the hydroxyl group.

As for the selection of the protecting Groups and the selection of the method for protection and deprotection, for example, reference can be made to t.w.greene, p.g.m.wuts, Protective Groups in organic synthesis, Second Edition, John Wiley & Sons, inc. Preferred protecting groups include trisubstituted silyl groups such as trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, dimethylisopropylsilyl group, diethylisopropylsilyl group, dimethyl (2, 3-dimethyl-2-butyl) silyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, tribenzylsilyl group, tri-p-xylylsilyl group, triphenylsilyl group, benzhydrylsilyl group, and tert-butylmethoxyphenylsilyl group; and substituted benzyl groups such as benzyl, triphenylmethyl, 2, 4, 6-trimethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-methoxybenzyl, 2, 6-dimethoxybenzyl, etc., among which tert-butyldimethylsilyl (also referred to as "TBS group" in the present specification) is preferable.

In the case where the protecting group is a tri-substituted silyl group, protection of the hydroxyl group can be carried out by reacting the compound 8c with a tri-substituted silyl halide in the presence of a base.

Examples of the base include amines such as triethylamine, pyridine, imidazole, triazole, benzimidazole, and benzotriazole, and imidazole is preferable.

The halide includes chloride, bromide and iodide, and preferably chloride.

The reaction solvent includes amide solvents such as N, N-dimethylacetamide, N-dimethylimidazolidinone (also referred to as "DMI" in the present specification), and DMF is preferred.

The reaction temperature can be appropriately selected depending on the kind of the reaction solvent, and is usually 0 to 150 ℃, preferably 15 to 65 ℃.

The reaction time can be appropriately selected depending on the reaction temperature and the like, and is usually 30 minutes to 30 hours, preferably 1 hour to 5 hours.

When the protecting group is a trisubstituted silyl group, deprotection of the hydroxyl group of the protected compound 8d can be performed by, for example, reacting an acid with a fluorine-based reagent.

Examples of the acid include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid; and organic acids such as trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, citric acid, and the like, and acidic ion exchange resins can also be cited.

Examples of the fluorine-based reagent include tetrabutylammonium fluoride, hydrogen fluoride/pyridine, hydrogen fluoride/triethylamine, hydrofluoric acid, lithium fluoride, sodium fluoride, potassium fluoride, and cesium fluoride, and tetrabutylammonium fluoride is preferable.

The reaction solvent can be appropriately selected, and for example, an alcohol solvent; ether solvents such as THF and diethyl ether; ester solvents such as ethyl acetate and methyl acetate; nitrile solvents such as acetonitrile, benzonitrile, and phenylacetonitrile; amide solvents such as N, N-dimethylacetamide, DMI, and DMF, and ether solvents such as THF are preferred.

The reaction time can be appropriately selected depending on the reaction temperature, and is usually 5 minutes to 30 hours, preferably 10 minutes to 3 hours.

Step 8-4:

compound 8e can be obtained by protecting the amino group of compound 8 d.

Examples of the method for protecting an amino group include a method using various protecting groups which can be generally used in organic chemistry, and a method of forming a carbamate salt using tert-butoxycarbonyl or the like is preferable; a method of forming an imine from a phenylmethylene, diphenylmethylene, or the like; a method of forming an amide by acetylation, trifluoroacetylation, or the like, and particularly a method of forming a carbamate by t-butoxycarbonyl or the like, and a method of forming an imine by diphenylmethine or the like are preferable.

The carbamate can be formed in the same manner as in step 5-1.

The imine formation method can be carried out by heating the compound 8d together with an aldehyde such as benzaldehyde or a ketone such as benzophenone.

The reaction solvent is preferably an alcohol solvent such as methanol, ethanol, n-propanol, or isopropanol, and particularly preferably methanol.

The reaction temperature can be appropriately selected depending on the kind of the reaction solvent, and is usually 10 to 120 ℃ and preferably 40 to 90 ℃.

The reaction time can be appropriately selected depending on the reaction temperature, and is usually 30 minutes to 20 hours, preferably 1 hour to 5 hours.

Step 8-5:

compound 8e can be prepared by reacting compound 8c with a compound of formula (la): HNR^dR^eThe compound shown (hereinafter also referred to as "HNR" for short)^dR^e". ) And (3) reacting to obtain the compound.

As HNR^dR^eExamples thereof include acetamides such as acetamide and bis (trimethylsilyl) acetamide; imines such as diphenylimine; aralkyl amines such as benzyl amine, etc., preferably acetamide, bis (trimethylsilyl) acetamide and diphenylimine.

At the time of the reaction, it is preferable to co-exist a palladium catalyst and a phosphine ligand in order to promote the reaction.

Examples of the palladium catalyst include palladium acetate, palladium trifluoroacetate, palladium chloride, palladium carbon, allylpalladium chloride dimer, tetrakis (triphenylphosphine) palladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium-chloroform complex, dichlorobis (triphenylphosphine) palladium, bis (acetonitrile) palladium dichloride and the like, and bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium and the like are preferable.

Examples of the phosphine ligand include triphenylphosphine, tri-o-tolylphosphine, tris (2-furyl) phosphine, tri-tert-butylphosphine, tricyclohexylphosphine, tri-n-butylphosphine, 1, 2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, 1, 4-bis (diphenylphosphino) butane, 1 '-bis (diphenylphosphino) ferrocene, 2' -bis (diphenylphosphino) -1, 1 '-binaphthyl, dicyclohexyl [ 2', 4 ', 6' -tris (1-methylethyl) -1, 1 '-biphenyl-2-yl ] phosphine (X-Phos), etc., with 2, 2' -bis (diphenylphosphino) -1, 1 '-binaphthyl and dicyclohexyl [ 2', 4 ', 6' -tris (1-methylethyl) -1 being preferred, 1' -Biphenyl-2-yl ] phosphine (X-Phos).

Examples of the reaction solvent include hydrocarbon solvents such as hexane, heptane, octane, toluene, benzene, xylene, and the like; ether solvents such as THF, diethyl ether, and dioxane; aprotic polar solvents such as DMF and N, N-dimethylacetamide, and aromatic hydrocarbon solvents such as toluene and benzene are preferred.

The reaction temperature can be appropriately selected depending on the kind of the reaction solvent, and is usually 20 to 140 ℃ and preferably 45 to 80 ℃.

The reaction time can be appropriately selected depending on the reaction temperature, and is usually 1 to 30 hours, preferably 5 to 20 hours.

The compound 8e can also be obtained by pre-protecting the hydroxyl group of the compound 8c, then performing this step, and then deprotecting the hydroxyl group. This can be performed in the same manner as in the case where compound 8d is obtained by pre-protecting the hydroxyl group of compound 8c, then performing step 8-3, and then deprotecting the hydroxyl group.

Step 8-6:

the compound 8f can be obtained by converting the hydroxyl group of the compound 8e into a leaving group, for example, by esterifying the hydroxyl group (e.g., acetylating, mesylating, tosylating, etc.) or by substituting the hydroxyl group with a halogen atom, preferably by sulfonating the hydroxyl group (e.g., mesylating, tosylating, etc.).

The sulfoesterification of the compound 8e can be performed by reacting the compound 8e with methanesulfonyl chloride, p-toluenesulfonyl chloride, or the like in the presence of a base.

Examples of the base include metal hydrides such as sodium hydride, potassium hydride, and lithium hydride; and metal alkoxides such as potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium tert-pentoxide, sodium tert-pentoxide, and lithium tert-pentoxide, and preferably metal alkoxides such as lithium tert-butoxide.

The reaction solvent is preferably an ether solvent such as THF, diethyl ether, dioxane or the like, and THF is particularly preferred.

The reaction temperature can be appropriately selected depending on the kind of the reaction solvent, etc., and is usually-90 to 30 ℃ and preferably-50 to 10 ℃.

The reaction time can be appropriately selected depending on the reaction temperature, and is usually 5 minutes to 10 hours, preferably 15 minutes to 2 hours.

The acetic acid esterification (acetylation, trifluoroacetylation, etc.) of the compound 8e can be easily performed by a method generally used in organic chemistry. For example, the reaction of the compound 8e with a corresponding acid halide (acetyl chloride, trifluoroacetyl chloride, etc.) or acid anhydride (acetic anhydride, trifluoroacetic anhydride, etc.) is carried out in the presence of a base.

Halogenation of the compound 8e can be carried out in the same manner as in the step 2-3. Further, it can be carried out by an exchange reaction of the sulfonic acid ester obtained by the above-mentioned sulfonic acid esterification with a halogen anion.

Step 8-7:

compound 5t can be obtained by reacting compound 8f with compound 1b in the presence of a base. This step can be performed in the same manner as step 5-3.

The compound 8a can be obtained as a commercially available product, and can be produced, for example, by a method described in general textbooks on Organic Chemistry (Jerry March, wide interactive Organic Chemistry 4th edition). Hal in the compound 8a is preferably a chlorine atom. Further, some of the compounds 8b and 8c are known compounds and can be easily obtained.

According to the general production methods-1 to-8 and the examples described later, or by referring to them, for example, the following compounds can also be synthesized:

3- {2- (aminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-chloro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-chloro-3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-methyl-3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-6-fluoro-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (aminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-6-fluoro-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (aminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-6-chloro-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (aminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-6-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (aminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-fluoro-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (aminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-fluoro-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-chloro-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (aminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-chloro-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (aminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-chloro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-methyl-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-methyl-3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-6-fluoro-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (aminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-6-fluoro-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-6-chloro-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (aminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-6-chloro-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (aminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-6-methyl-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (aminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-fluoro-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (aminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-fluoro-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-chloro-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (aminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-chloro-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-methyl-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- {2- (aminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-methyl-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-chloro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-chloro-3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-methyl-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-methyl-3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran,

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran, and

3- { 2-fluoro-3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (N-methylimidazol-2-yloxy) -2-oxo-2H-1-benzopyran.

The invention includes pharmaceutically acceptable salts of the compounds represented by the general formula (11), preferably the general formula (1). These salts can be produced by bringing the compound into contact with an acid or a base which can be used for the production of a pharmaceutical. Among the salts, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and the like are included; sulfonates such as methanesulfonate, benzenesulfonate and toluenesulfonate; carboxylates such as formate, acetate, oxalate, maleate, fumarate, citrate, malate, succinate, malonate, gluconate, mandelate, benzoate, salicylate, fluoroacetate, trifluoroacetate, tartrate, propionate, and glutarate; alkali metal salts such as lithium salt, sodium salt, potassium salt, cesium salt, rubidium salt and the like; alkaline earth metal salts such as magnesium salts and calcium salts; ammonium salts such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts and tetraalkylammonium salts. Among them, alkali metal salts such as lithium salt, sodium salt, potassium salt, cesium salt, rubidium salt and the like are preferable, and sodium salt and potassium salt are particularly preferable.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, can be used in the treatment of cell proliferative disorders, particularly cancer, by administering to a patient, either directly or in the form of a pharmaceutical composition, a pharmaceutically effective amount thereof, according to an appropriate method of administration. The administration method may be any of systemic administration such as oral administration, rectal administration, intravenous administration, intramuscular administration, subcutaneous administration, intracisternal administration, intravaginal administration, intraperitoneal administration, intravesical administration, and inhalation administration, and topical administration by ointment, gel, cream, and the like.

When the compound of the present invention or a pharmaceutically acceptable salt thereof is used in the form of a pharmaceutical composition, it is usually used in a predetermined formulation (dosage form). Examples of such preparations include tablets, capsules, granules, powders, fine granules, pills, and aqueous or nonaqueous solutions and suspensions. The compound or salt can be used in the form of various controlled release preparations, and examples of such controlled release preparations include preparations used by embedding in the body, and preparations suitable for oral mucosa or nasal mucosa. In addition, the solution and the suspension can be stored in containers suitable for being divided into small portions according to the individual dose.

The above-mentioned various preparations can be produced by mixing the compound or salt with pharmaceutically acceptable additives by a known method. Examples of such additives include excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, bases, dispersants, diluents, surfactants, and emulsifiers.

Examples of the excipient include starch (starch, potato starch, corn starch, etc.), lactose, crystalline cellulose, and calcium phosphate.

As the lubricant (coating agent), for example, ethyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax and paraffin wax can be cited.

Examples of the binder include polyvinylpyrrolidone and polyethylene glycol, and other than these, the same compounds as those of the above vehicle can be used.

Examples of the disintegrating agent include chemically modified starches such as croscarmellose sodium, sodium carboxymethyl starch and crospovidone, and other similar compounds to the above excipients.

Examples of the stabilizer include parabens such as methyl paraben and propyl paraben; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.

Examples of the taste and smell correcting agent include commonly used sweeteners, souring agents, and flavors.

Examples of the base include fats such as lard; vegetable oils such as olive oil and sesame oil; higher alcohols such as stearyl alcohol and cetyl alcohol; animal oil; lanolin acids; vaseline; paraffin wax; bentonite; glycerol; and glycerol.

Examples of the dispersing agent include cellulose derivatives (gum arabic, tragacanth gum, methylcellulose, etc.), polyesters of stearic acid, Sorbitan Sesquioleate (sodium Sesquioleate), aluminum monostearate, sodium alginate, polysorbates (polysorbates), and Sorbitan fatty acid esters.

Examples of the solvent or diluent in the liquid agent include phenol, chlorocresol, purified water and distilled water.

As the surfactant or emulsifier, for example, polysorbate 80, Polyoxyl (40) Stearate (Polyoxyl 40 Stearate), and lauromacrogol may be cited.

The preferable content of the compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation varies depending on the dosage form, but is generally 0.01 to 100% by weight.

When the compound of the present invention or a pharmaceutically acceptable salt thereof is used as a therapeutic agent for cell proliferative diseases, the dosage thereof can be appropriately determined depending on the severity of symptoms, age, body weight, relative health status, whether drugs are used in combination, administration method, and the like. For example, in the case where the subject to be administered is a warm-blooded animal, particularly a human, the amount administered per 1kg body weight per 1 day is, in general, preferably 0.00001 to 5000mg, more preferably 0.0001 to 10mg in the case of oral administration. In addition, when the medicine is not orally taken, the medicine is preferably 0.00001-5000 mg, and more preferably 0.0001-10 mg. The dose may be administered 1 time within 1 day to 3 weeks, or may be administered 2 to 4 times per 1 day.

As described above, the compound of the present invention or a pharmaceutically acceptable salt thereof and the pharmaceutical composition of the present invention can be used as a therapeutic agent for cell proliferative diseases, particularly cancer. Here, examples of the cancer include blood and lymph cancer such as leukemia (acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and the like), malignant lymphoma (hodgkin's disease, non-hodgkin's lymphoma, and the like), multiple myeloma, myelodysplastic syndrome, and the like; and solid cancers such as brain tumor, nerve tumor, head and neck cancer (pharyngeal cancer, laryngeal cancer, tongue cancer, etc.), esophageal cancer, gastric cancer, large intestine cancer, lung cancer (small cell cancer, non-small cell cancer, etc.), thyroid cancer, breast cancer, gallbladder cancer, pancreatic cancer, liver cancer, prostate cancer, ovarian cancer, uterine cancer, testis cancer, renal cell cancer, bladder cancer, renal pelvis-ureter cancer, malignant melanoma, skin cancer, etc.

In addition, as the compound of the present invention or a pharmaceutically acceptable salt thereof, a compound represented by the following formula or a pharmaceutically acceptable salt thereof can be mentioned.

[ in the formula, G⁹、Y¹、Y²、Y³、Y⁴、G¹、G²、G³、Z¹⁹、G⁷And R²The combinations of (A) and (B) are shown in the following table. Angle (c)

X

G⁹

Y¹

Y²

Y³

Y⁴

G¹

G²

G³

Z¹⁹

G¹

R²

(CH₃)₂NCO

O

N

CH

CH₂CH₂CH₃

CH₂

CH₃

(CH₃)₂NCO

O

N

CH

CH₂CH₃

CH₂

CH₃

(CH₃)₂NCO

O

N

CF

CH

N

CH

CH₂CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

N

CF

CH

CH₂CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

N

CF

CH

CF

CH

CH₂CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

N

CF

CH

CCH₃

CH

CH₂CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

CH

CF

CH

N

CCH₃

CH

CH₂CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

CH

CF

CH

N

CH

CH₂CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

CH

CF

CH

N

CH₂CH₃

CH₂

CH₃

2-pyrimidinyl radicals

S

N

CH

CH₂CH₃

CH₂

CH₃

2-pyrimidinyl radicals

NH

N

CH

CH₂CH₃

CH₂

CH₃

2-pyrimidinyl radicals

CF₂

N

CH

CH₂CH₃

CH₂

CH₃

2-thiazolyl group

O

N

CF

CH

CCH₃

CH

CH₂CH₃

CH₂

CH₃

2-thiazolyl group

O

N

CH

CCH₃

CH

CH₂CH₃

CH₂

CH₃

2-thiazolyl group

O

CH

CF

CH

N

CH

CH₂CH₃

CH₂

CH₃

2-thiazolyl group

O

CH

N

CH

CCH₃

CH

CH₂CH₃

CH₂

CH₃

2-thiazolyl group

O

CH

CF

CH

N

CH

CCH₃

CH

CH₂CH₃

CH₂

CH₃

2-thiazolyl group

O

N

CF

CH

CH₂CH₃

S

CH₃

2-N-methyl-imidazolyl

O

CH

CF

CH

N

CH

CH₂CH₃

CH₂

CH₃

(CH₃)₂NCO

O

N

CF

CH

CCH₃

CH

CH₂CONHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

N

CF

CH

CCH₃

CH

CH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

CF

CH

N

CH

CCH₃

CH

CH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

CF

CH

N

CH

CH₃

CH₂

CH₂CH₃

(CH₃)₂NCO

O

CH

CF

CH

N

CH

CH₃

CH₂

CH₃

(CH₃)₂NCO

S

N

CF

CH

CH₃

CH₂

CH₃

(CH₃)₂NCO

S

N

CF

CH

CH₃

S

CH₃

(CH₃)₂NCO

NH

CH

CF

CH

CH₃

O

CH₃

2-thiazolyl group

S

N

CF

CH

CH₃

NH

CH₃

2-N-methyl-imidazolyl

O

N

CF

CH

CH₃

CH₂

CH₃

Or

[ in the formula, G⁹、Y¹、Y²、Y³、Y⁴、Z¹⁶、Z¹⁷、Z¹⁸、G⁷And R²The combinations of (A) and (B) are shown in the following table. Angle (c)

X

G⁹

Y¹

Y²

Y³

Y⁴

Z¹⁶

Z¹⁷

Z¹⁸

G⁷

R²

2-pyrimidinyl radicals

O

CH

S

CH₂CH₃

CH₂

CH₃

2-thiazolyl group

O

CH

S

CH₂CH₃

CH₂

CH₃

2-thiazolyl group

O

N

CF

CH

S

CH₂CH₃

CH₂

CH₃

2-thiazolyl group

O

N

CH

S

CH₂CH₃

CH₂

CH₃

(CH₃)₂NCO

O

N

CF

CH

S

CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

CH

CF

CH

S

CH

CH₃

CH₂

CH₃

2-thiazolyl group

O

CH

S

CH

CH₃

CH₂

CH₃

2-thiazolyl group

O

N

CF

CH

S

CH

CH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

CH

CF

CH

NH

CH

CH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

N

CF

N

CH

O

CH₃

CH₂

CH₂CH₃

Or

[ in the formula, G⁹、Z¹³、Z¹⁴、Z¹⁵、G¹、G²、G³、Z¹⁶、G⁷And R²The combinations of (a) and (b) are performed as follows. Angle (c)

X

G⁹

Z¹³

Z¹⁴

Z¹⁵

G¹

G²

G³

Z¹⁶

G⁷

R²

(CH₃)₂NCO

O

CH

S

CH

CH₂CH₃

CH₂

CH₃

(CH₃)₂NCO

O

N

CH

NH

CH

CH₂CH₃

CH₂

CH₃

2-thiazolyl group

O

CH

S

CH

CH₂CH₃

O

CH₃

2-thiazolyl group

O

CH

S

CH

N

CH

CH₂CH₃

CH₂

CH₃

(CH₃)₂NCO

O

S

CH

N

CH

CH₃

CH₂

CH₃

(CH₃)₂NCO

NH

CH

S

CH

N

CH

CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

S

CH

CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

CH

O

CH

CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

CH

NH

CH

CH₃

CH₂

CH₃

2-thiazolyl group

O

S

CH

CH₃

CH₂

CH₂CH₃

2-thiazolyl group

O

CH

S

CH

CH₃

CH₂

CH₃

2-thiazolyl group

O

S

CH

N

CH

CH₃

S

CH₂CH₃

2-N-methyl-imidazolyl

O

CH

S

CH

N

CH

CH₃

CH₂

CH₃

Or

[ in the formula, G⁹、Y¹、Y²、Y³、Y⁴、Z¹⁶、Z¹⁷、NR⁶R⁷、G⁷And R²The combinations of (a) and (b) are performed as follows. Angle (c)

X

G⁹

Y¹

Y²

Y³

Y⁴

Z¹⁶

Z¹⁷

NR⁶R⁷

G⁷

R²

2-thiazolyl group

O

CH

S

CH

N(CH₃)₂

CH₂

CH₃

2-thiazolyl group

O

CH

S

NH₂

CH₂

CH₃

(CH₃)₂NCO

O

CH

S

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

S

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

N

CF

CH

S

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

N

CH

NH

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

NH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

O

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

N

CF

CH

O

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

S

CH

S

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

S

CH

S

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

NH

CH

S

CH

NHCH₃

CH₂

CH₂CH₃

(CH₃)₂NCO

NH

CH

CF

CH

S

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

S

N

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

N

S

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

N

NHCH₃

CH₂

CH₂CH₃

(CH₃)₂NCO

O

CH

N

NHCH₃

CH₂

CH₃

2-pyrimidinyl

O

CH

CF

CH

S

CH

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

CH

S

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

CH

S

CH

NHCH₃

O

CH₃

2-pyrimidinyl radicals

O

CH

S

NHCH₃

S

CH₃

2-pyrimidinyl radicals

O

N

CH

S

CH

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

N

CF

CH

S

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

S

CH

NCH₃

CH

NHCH₃

CH₂

CH₂CH₃

2-pyrimidinyl radicals

NH

CH

NCH₃

NHCH₃

CH₂

CH₃

2-thiazolyl group

O

N

CF

CH

O

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

O

N

CH

O

NHCH₃

CH₂

CH₂CH₃

2-thiazolyl group

O

N

CH

S

NHCH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

N

CF

CH

S

NHCH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

N

CF

CH

S

NHCH₃

O

CH₃

OrOr

Or

[ in the formula, G⁹、Z²³、Z²⁴、Z²⁵、Z²¹、Z²²、Z²⁵、G⁷And R²The combinations of (A) and (B) are shown in the following table. Angle (c)

X

G⁹

Z²³

Z²⁴

Z²⁵

Z²¹

Z²²

Z²⁶

G⁷

R²

(CH₃)₂NCO

O

S

CH

S

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

S

CH

S

CH

CH₂CONHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

S

CH

S

CH

CH₂CH₃

CH₂

CH₃

(CH₃)₂NCO

O

S

CH

S

CH

CH₂CH₂OH

CH₂

CH₃

(CH₃)₂NCO

O

S

CH

S

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

S

CH

S

CH

NHCH₃

CH₂

CH₃

(CH₃)₂XNCO

O

CH

S

CH

S

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

S

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

S

CH

S

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

NH

CH

S

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

NH

CH

S

CH

CH₂CONHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

NCH₃

CH

S

CH

CH₂CH₃

CH₂

CH₃

(CH₃)₂NCO

O

NH

CH

S

CH

CH₂CH₂OH

CH₂

CH₃

(CH₃)₂NCO

O

NH

CH

S

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

NH

CH

S

CH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

NH

CH

S

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

NH

CH

S

CH

CH₂CH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

NH

CH

S

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

NH

CH

S

CH₂CONHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

NH

S

CH

NHCH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

NH

S

CH

CH₂CH₃

CH₂

CH₃

(CH₃)₂NCO

O

CH

NH

CH

S

NHCH₃

CH₂

CH₃

X

G⁹

Z²³

Z²⁴

Z²⁵

Z²¹

Z²²

Z²⁶

G⁷

R²

2-pyrimidinyl radicals

O

S

CH

S

CH

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

S

CH

S

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

S

NH

CH

S

CH

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

S

NH

CH

S

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

S

CH

S

N

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

S

CH

N

S

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

NH

S

CH

S

CH

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

NH

S

CH

S

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

N

CH

NH

S

CH

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

N

CH

NCH₃

CH

S

NHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

S

CH

S

CH

CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

S

CH

S

CH₂CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

S

NH

CH

S

CH

CH₂CH₂OH

CH₂

CH₃

2-pyrimidinyl radicals

O

S

NH

CH

S

CH₂CONHCH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

S

CH

S

N

CH₂CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

S

CH

N

S

CH₂CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

NH

S

CH

S

CH

CH₂CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

NH

S

CH

S

CH₂CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

N

CH

NH

S

CH

CH₂CH₃

CH₂

CH₃

2-pyrimidinyl radicals

O

N

CH

NCH₃

CH

S

CH₂CH₃

CH₂

CH₃

X

G⁹

Z²³

Z²⁴

Z²⁵

Z²¹

Z²²

Z²⁶

G⁷

R²

2-thiazolyl group

O

CH

O

CH

S

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

O

CH

O

CH

S

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

O

NH

O

CH

S

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

O

NH

O

CH

S

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

O

N

CH

NH

S

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

O

N

CH

NH

S

CH

NHCH₃

CH₂

CH₃

2-thiazolesBase of

O

CH

O

CH

NH

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

O

CH

O

CH

NCH₃

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

S

CH

O

CH

S

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

NH

CH

O

CH

S

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

CH₂

NH

O

CH

S

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

CF₂

NH

O

CH

S

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

S

N

CH

NH

S

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

S

N

CH

NH

S

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

NH

CH

O

CH

NH

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

SO

CH

O

CH

NCH₃

CH

NHCH₃

CH₂

CH₃

2-thiazolyl group

O

CH

O

CH

S

CH

NHCH₃

S

CH₃

2-thiazolyl group

O

CH

O

CH

S

CH

NHCH₃

NH

CH₃

2-thiazolyl group

O

NH

O

CH

S

CH

NHCH₃

O

CH₃

2-thiazolyl group

O

NH

O

CH

S

CH

CH₃

CH₂

CH₃

2-thiazolyl group

O

N

CH

NH

S

CH

CH₂CH₃

CH₂

CH₃

2-thiazolyl group

O

N

CH

NH

S

CH

CH₂CH₂OH

CH₂

CH₃

2-thiazolyl group

O

CH

O

CH

NH

CH

CH₂CONHCH₃

CH₂

CH₃

2-thiazolyl group

O

CH

O

CH

NCH₃

CH

CH₂CH₃

CH₂

CH₃

X

G⁹

Z²³

Z²⁴

Z²⁵

Z²¹

Z²²

Z²⁶

G⁷

R²

2-N-methyl-imidazolyl

O

NH

CH

S

NHCH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

S

CH

NH

NHCH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

CH

S

CH

NH

NHCH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

CH

S

CH

NH

NHCH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

S

CH

N

NH

NHCH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

CH

S

CH

N

NH

NHCH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

CH

S

N

NH

NHCH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

NH

CH

S

CH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

S

CH

NH

CH₂CH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

CH

S

CH

NH

CH₂CH₂OH

CH₂

CH₃

2-N-methyl-imidazolyl

O

CH

S

CH

NH

CH₂CONHCH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

S

CH

N

NH

CH₂CH₃

CH₂

CH₃

2-N-methyl-imidazolyl

O

N

S

CH

N

NH

NHCH₃

CH₂

CH₃

Hereinafter, the mode of the present invention will be described more specifically based on examples (production examples and experimental examples).

[ production example ]

In the following production examples (synthesis examples), NMR analysis was carried out using JNM-EX270(270MHz) manufactured by JEOL, JNM-GSX400(400MHz) manufactured by JEOL, or ARX-300(300MHz) manufactured by Bruka, and NMR data were shown in ppm (parts permillion, delta) with reference to the deuterium lock signal from the sample solvent.

The mass spectrum data was obtained using JMS-DX303 manufactured by JEOL, JMS-SX/SX102A manufactured by JEOL, or using a micro mass spectrometer (Navigator manufactured by Finningan) equipped with Agilent1100 gradient HPLC manufactured by Agilent Technologies.

When a commercially available reagent is used, it is used in the reaction without pretreatment such as distillation or recrystallization. As the reaction solvent, in the case of using a commercially available solvent, an anhydrous solvent is used.

In addition, all chemical reactions were carried out under a nitrogen atmosphere.

Further, "removal of the solvent" means that the solvent is distilled under reduced pressure using a rotary evaporator.

In addition, in the case where a sufficiently high purity compound cannot be obtained by standard synthetic means, a sufficiently high purity compound can be obtained by separation and purification by silica gel chromatography, alumina gel chromatography or the like, as necessary.

(general preparation method-1)

First, a production example related to the above general production method-1 will be described.

Compound 1 c-2:

2- (2-fluoro-3-nitro-compoundBenzyl) -3-Butyronic acid ethyl ester

Ethylacetoacetate (37.4mL, 294mmol) was added at 0 deg.C to a suspension of sodium hydride (65%, 10.8g) in THF (600mL) and stirred at 0 deg.C for 30 min. This was added dropwise to a solution of 1-bromomethyl-2-fluoro-3-nitrobenzene (compound 1a-1) (68.7g, 294mmol) in THF (400mL) at 0 deg.C, and the reaction mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was poured into 0.5N hydrochloric acid, and extracted with ethyl acetate. The organic extract was washed with saturated brine and dried over magnesium sulfate. Subsequently, the crude product was obtained by concentration under reduced pressure, which was purified by column chromatography (ethyl acetate: hexane ═ 1: 3) to give the title compound (52.2g, 63%) as a yellow oil.

¹H NMR(DMSO-d₆270MHz) (ketone body) δ (ppm): 8.01(td, J ═ 7.6, 1.9Hz, 1H), 7.72(td, J ═ 7.2, 1.9Hz, 1H), 7.37(td, J ═ 7.5, 1.1Hz, 1H), 4.11(m, 1H), 4.07(qd, J ═ 7.0, 1.0Hz, 2H), 3.16(t, J ═ 7.3Hz, 2H), 2.23(s, 3H), 1.10(t, J ═ 7.0Hz, 3H).

ESIMS m/z：284(M+H).

Compound 1 c-1:

2- (3-nitrobenzyl) -3-butanoic acid ethyl ester

The title compound was synthesized under the same conditions as in the preparation example of compound 1c-2, except that 1-bromomethyl-3-nitrobenzene was used instead of 1-bromomethyl-2-fluoro-3-nitrobenzene.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：1.08(3H，t，J＝6.8Hz)， 2.25(3H，s)，3.17(2H，m)，4.05(2H，qd，J＝6.8Hz，2.7Hz)，4.16(1H，m)，7.58(1H，dd，J＝8.1Hz)，7.71(1H，d，J＝8.1Hz)，8.08(1H，d，J＝8.1Hz)，8.14(1H，s).

ESI (LC/MS positive mode) m/z: 266(M + H).

Compound 1 c-3:

2- (2-methyl-3-nitrobenzyl) -3-butanoic acid ethyl ester

The title compound was synthesized under the same conditions as in the preparation of compound 1c-2 except that 1-chloromethyl-2-methyl-3-nitrobenzene was used instead of 1-bromomethyl-2-fluoro-3-nitrobenzene.

¹H NMR(Bruker，300MHz，CDCl₃)δ(ppm)：7.62(1H，d，J＝8.0Hz)，7.37(1H，d，J＝7.2Hz)，7.23(1H，m)，4.16(2H，q)，3.73(1H，t，J＝7.4Hz)，3.28(2H，m)，2.43(3H，s)，2.24(3H，s)，1.21(3H，t，J＝7.1Hz).

Compound 1 c-46:

2- (4-nitrobenzyl) -3-butanoic acid ethyl ester

The title compound was synthesized under the same conditions as in the preparation example of compound 1c-2, except that 1-bromomethyl-4-nitrobenzene was used instead of 1-bromomethyl-2-fluoro-3-nitrobenzene.

1H-NMR(Bruker，300MHz，CDCl₃).δ(ppm)：8.14(2H，d，J＝8.7Hz)，7.36(2H，d，J＝8.7Hz)，4.17(2H，m)，3.79(1H，t，J＝7.6Hz)，3.25(2H，m)，2.24(3H，s)，1.22(3H，m)

Compound 1 c-45:

2- (2-nitrobenzyl) -3-butanoic acid ethyl ester

The title compound was synthesized under the same conditions as in the preparation example of compound 1c-2, except that 1-bromomethyl-2-nitrobenzene was used instead of 1-bromomethyl-2-fluoro-3-nitrobenzene.

1H-NMR(Bruker，300MHz， )δ(ppm)：8.00(1H，d，J＝8.4Hz)，7.52-7.42(3H，m)，4.22-4.09(2H，m)，4.01(1H，q)，3.54-3.32(2H，m)，2.28(3H，s)，1.20(3H，t，J＝7.1Hz)

Compound 1 c-36:

2- (4-fluoro-3-nitrobenzyl) -3-butanoic acid ethyl ester

The title compound was synthesized by the same method as the method for producing the compound 1c-2, using 1-bromomethyl-3-nitro-4-fluorobenzene instead of 1-bromomethyl-2-fluoro-3-nitrobenzene.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.07(dd，1H，J＝7.1，2.2Hz)，7.67(m，1H)，7.52(dd，1H，J＝10.7，8.6Hz)，4.11(m，1H)，4.07(q，2H，J＝7.0Hz)，3.20(m，2H)，2.21(s，3H)，1.13(t，3H，J＝7.0Hz).

ESIMS m/z：284(M+H).

Compound 1c-51 a:

3- (Methoxycarbonylhydrazonylidene) -2- (3-nitrophenylamino) butanoic acid ethyl ester

3-nitroaniline (2.92g, 21.27mmol) was added to a solution of ethyl 3-carbomethoxyazocrotonate (4.2g, 21, 13mmol), known in the literature, in THF (40mL) and stirred at 70 ℃ overnight. After the reaction mixture was cooled to room temperature, hexane was added, and the precipitated precipitate was collected by filtration to obtain the title compound (5.08g, 71%).

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：10.10(s，1H)，7.55(s，1H)，7.46-7.31(m，2H)，7.11(d，1H，J＝8.1Hz)，6.96(d，1H，J＝7.4Hz)，4.94(d，1H，J＝7.7Hz)，4.18(q，2H，J＝7.1Hz)，3.67(s，3H)，1.83(s，3H)，1.21(t，3H，J＝7.1Hz).

ESIMS m/z：339(M+H).

Compound 1 c-51:

2- (3-Nitrophenylamino) -3-butanoic acid ethyl ester

To a solution of ethyl 3- (methoxycarbonylhydrazono) -2- (3-nitrophenylamino) butyrate (compound 1c-51a) (5.0g, 14.78mmol) in acetone (50mL) was added titanium trichloride (10% solution in 20-30% HCl), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate, and the organic extract was washed with water and saturated brine. After drying over magnesium sulfate, the crude product was obtained by concentration under reduced pressure, which was purified by column chromatography to obtain the title compound (3.75g, 95%) as a yellow oil.

¹H NMR(270MHz，DMSO-d₆) (2: 1 mixture of ketone type and enol type) delta (ppm): 12.37(s, 1/3H), 7.53(t, 2/3H, J ═ 2.2Hz), 7.47-7.37(m, 10/3H), 7.27(t, 1/3H, J ═ 2.2Hz), 7.13(m, 2/3H), 7.05(d, 2/3H, J ═ 8.6Hz), 6.92(d, 1/3H, J ═ 9.1Hz), 5.35(d, 2/3H, J ═ 8.6Hz), 4.25-4.11(m, 6/3H), 2.31(s, 6/3H), 1.99(s, 3/3H), 1.21(t, 6/3H, J ═ 7.1Hz), 1.08(t, 3/3H, J ═ 397.1 Hz).

ESIMS m/z：267(M+H).

Compound 1 c-59:

2- (2-nitrobenzoylamino) -3-butanoic acid ethyl ester (known Compound)

To a solution of Ethyl diazoacetoacetate (Ethyl diazoacetoacetate) (1.0g, 6.32mmol) and 2-nitrobenzamide (1.05g, 6.32mmol) in dichloromethane (15mL) was added Rh₂(OAc)₄(30mg, 0.063mmol), and stirred at 40 ℃ overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate, and the organic extract was washed with water and saturated brine. After drying over magnesium sulfate, the crude product was obtained by concentration under reduced pressure, and the crude product was purified by column chromatography to obtain the title compound (1.42g, 77%) as a yellow oil.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：9.58(d，1H，J＝7.4Hz)，8.09 (d，1H，J＝7.9Hz)，7.84(td，1H，J＝7.5，0.5Hz)，7.73(td，1H，J＝7.8，1.2Hz)，7.63(dd，1H，J＝7.4，1.5Hz)，5.39(d，1H，J＝7.6Hz)，4.21(m，2H)，2.30(s，3H)，1.24(t，3H，J＝7.3Hz).

ESIMS m/z：295(M+H).

Compound 1 c-73:

2- (5-Nitro-thiophen-2-ylmethyl) -3-butanoic acid ethyl ester

To a mixture of sodium iodide (379mg, 2.53mmol) in tetrahydrofuran was added ethyl acetoacetate (0.64mL, 5.06 mmol). A1M solution of LiOtBu in THF (3.03mL, 3.03mmol) was added at 4 deg.C and stirred for 30 min. A solution of compound 1a-73(600mg, 2.53mmol) in tetrahydrofuran (2.0mL) was added at 4 deg.C, warmed to room temperature and stirred for 22 hours. Water (20mL) was added and the organic layer was extracted with ethyl acetate. Purification by silica gel chromatography (hexane: ethyl acetate 6: 1) gave the title compound (623mg, 91%).

¹H-NMR(Bruker(ARX300)，300MHz，CDCl₃)δ(ppm)：7.79(1H，d，J＝4.20Hz)，6.85(1H，d，J＝4.20Hz)，4.27(2H，q)，3.84(1H，t，J＝6.87Hz)，3.41(2H，dd，J＝6.87Hz，J＝7.25Hz)，2.34(3H，s)，1.32(3H，t，d＝6.87Hz)

Compound 1 e-0-4:

3- (2-fluoro-3-nitrobenzyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

Concentrated sulfuric acid (21.5mL) was added to a mixture of resorcinol (14.8g, 135mmol) and ethyl 2- (2-fluoro-3-nitrobenzyl) -3-butanoate (38.2g, 135mmol) at 0 deg.C, and the reaction mixture was stirred at room temperature overnight. After that, the reaction mixture was poured into water, and the solid was filtered and washed with water and methanol to give the title compound (28.3g, 64%) as a pale yellow powder.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：7.98(td，J＝8.9，1.6Hz，1H)，7.69(d，J＝8.9Hz，1H)，7.58(td，J＝6.2，4.3Hz，1H)，7.32(td，J＝8.9，1.1Hz，1H)，6.83(dd，J＝8.9，2.4Hz，1H)，6.72(d，J＝2.4Hz，1H)，4.02(s，2H)，2.43(s，3H).

ESIMS m/z：330(M+H).

Compound 1 e-0-1:

3- (3-nitrobenzyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from resorcinol and compound 1c-1 using the same conditions as in the preparation of compound 1 e-0-4.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.44(3H，s)，4.08(2H，s)，6.72(1H，d，J＝1.9Hz)，6.82(1H，dd，J＝1.9，8.6Hz)，7.58(1H，dd，J＝7.8，7.8Hz)，7.66-7.72(2H，m)，8.05-8.08(2H，m).

ESI (LC/MS positive mode) m/z: 312(M + H).

Compound 1 e-0-2:

3- (3-nitrobenzyl) -7-hydroxy-4-methyl-6-fluoro-2-oxo-2H-1-benzopyran

The title compound was synthesized from 4-fluororesorcinol and compound 1c-1 using the same conditions as in the preparation of compound 1 e-0-4.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.43(3H，s)，4.13(2H，s)，6.71(2H，d.J＝7.6Hz)，7.55-7.71(3H，m)，8.05-8.07(2H，m)，10.51(1H，s).

ESI (LC/MS positive mode) m/z: 330(M + H).

Compound 1 e-0-3:

3- (3-nitrobenzyl) -7-hydroxy-4-methyl-6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized from 4-chlororesorcinol and compound 1c-1 using the same conditions as in the preparation of compound 1 e-0-4.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.48(3H，s)，4.09(2H，s)，6.90(1H，s)，7.55(1H，t，J＝7.7Hz)，7.70(1H，d，J＝7.7Hz)，7.81(1H，s)，8.05(1H，d，J＝7.7Hz)，8.06(1H，s).

ESI (LC/MS positive mode) m/z: 346(M + H).

Compound 1 e-0-5:

3- (2-fluoro-3-nitrobenzyl) -7-hydroxy-4-methyl-6-fluoro-2-oxo-2H-1-benzopyran

The title compound was synthesized from 4-fluororesorcinol and compound 1c-2 under the same conditions as in the preparation of compound 1 e-0-4.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.42(3H，s)，4.03(2H，s)，6.92(1H，d，J＝7.6Hz)，7.32(1H，dd，J＝7.7，8.6Hz)，7.57(1H，dd，J＝7.7，6.3Hz)，7.69(1H，d，J＝12.0Hz)，7.99(1H，dd，J＝6.9，8.6Hz)，11.07(1H，brs).

ESI (LC/MS positive mode) m/z: 347(M + H).

Compound 1 e-0-6:

3- (2-methyl-3-nitrobenzyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from resorcinol and compound 1c-3 under the same conditions as in the preparation of compound 1 e-0-4.

¹H NMR(Bruker，300MHz，DMSO-d6)δ(ppm)：10.51(1H，s)，7.69(1H，d，J＝8.8Hz)，7.65(1H，d，J＝8.0Hz)，7.27(1H，t，J＝8.0Hz)，7.12(1H，d，J＝7.6Hz)，6.84(1H，dd，J＝2.3，8.8Hz)，6.74(1H，d，J＝2.3Hz)，3.95(2H，s)，2.42(3H，s)，2.33(3H，s).

Compound 1 e-0-7:

3- (3-nitrobenzyl) -7-hydroxy-4-methyl-6-iodo-2-oxo-2H-1-benzopyran

The title compound was synthesized from 4-iodoresorcinol and compound 1c-1 using the same conditions as in the preparation of compound 1 e-0-4.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.44(3H，s)，4.07(2H，s)，6.82(1H，s)，7.57(1H，dd，J＝5.4，5.4Hz)，7.69(1H，d，J＝2.7Hz)，8.05-8.10(3H，m)，11.39(1H，s).

ESI (LC/MS positive mode) m/z: 437(M + H).

Compound 1 e-0-8:

3- (3-nitrobenzyl) -7-hydroxy-4-methyl-6-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from 4-methylresorcinol and compound 1c-1 using the same conditions as in the preparation of compound 1 e-0-4.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.19(3H，s)，2.44(3H，s)，4.07(2H，s)，6.74(1H，s)，7.53-7.61(2H，m)，7.69(1H，d，J＝7.9Hz)，8.02-8.09(2H，m)，10.50(1H，s).

ESI (LC/MS positive mode) m/z: 326(M + H).

Compound 1 e-0-36:

3- (4-fluoro-3-nitrobenzyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized by the same method as that for the production of compound 1e-0-4, except that compound 1c-36 was used instead of compound 1 c-2.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：7.98(dd，1H，J＝7.1，2.2Hz)，7.69-7.61(m，2H)，7.49(dd，1H，J＝10.7，8.6Hz)，6.82(dd，1H，J＝8.9，2.4Hz)，6.72(d，1H，J＝2.4Hz)，4.07(s，2H)，2.38(s，3H).

ESIMS m/z：371(M+H).

Compound 1 e-0-46:

3- (4-nitrobenzyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from resorcinol and compounds 1c-46 using the same conditions as for the preparation of compound 1 e-0-4.

¹H-NMR(Bruker，300MHz，DMSO- )δ(ppm)：10.48(1H，s)，8.13(2H，d，J＝8.4Hz)，7.66(1H，d，J＝8.8Hz)，7.50(2H，d，J＝8.4Hz)，6.82(1H，dd，J＝2.3Hz，8.8Hz)，6.72(1H，d，J＝2.3Hz)，4.06(2H，s)，2.41(3H，s)

Compound 1 e-0-45:

3- (2-nitrobenzyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from resorcinol and compounds 1c-45 using the same conditions as in the preparation of compound 1 e-0-4.

¹H-NMR(Bruker，300MHz，DMSO-d₆)δ(ppm)：10.55(1H，s)，7.97(1H，d，J＝8.0Hz)，7.69(1H，d，J＝8.8Hz)，7.56(1H，d，J＝7.6Hz)，7.46(1H，t，J＝7.6Hz)，7.20(1H，d，J＝7.6Hz)，6.83(1H，dd，J＝2.3Hz，8.8Hz)，6.72(1H，d，J＝2.3Hz)，4.17(2H，s)，2.37(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：311.76(M+H)

Compound 1 e-0-47:

4, 7-dihydroxy-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran

To a mixture of triethylamine (1.57mL, 11.23 mmol) and formic acid (1.07mL, 28.07mmol) were added 4, 7-dihydroxy-2-oxo-2H-1-benzopyran (500mg, 2.81mmol) and 3-nitrobenzaldehyde (424mg, 2.81mmol), and the mixture was stirred at 100 ℃ for 2 hours. Thereafter, 5 equivalents of aqueous hydrochloric acid solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (300mg, 34%) as a pale yellow solid.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：10.52(s，1H)，8.09-8.04(m，2H)，7.83(d，1H，J＝8.7Hz)，7.71(d，1H，J＝7.6Hz)，7.57(t，1H，J＝7.7Hz)，6.80(dd，1H，J＝9.0，2.4Hz)，6.69(d，1H，J＝2.0Hz)，3.95(s，2H).

ESIMS m/z：314(M+H).

Compound 1 e-0-51:

7-hydroxy-4-methyl-3- (3-nitrophenylamino) -2-oxo-2H-1-benzopyran

The title compound was synthesized by the same method as that for the production of compound 1e-0-4, using ethyl 2- (3-nitrophenylamino) -3-butanoate (compound 1c-51) instead of compound 1 c-2.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：10.50(s，1H)，8.13(s，1H)，7.65(d，1H，J＝8.7Hz)，7.51(d，1H，J＝9.1Hz)，7.42-7.34(m，2H)，7.01(d，1H，J＝7.3Hz)，6.86(dd，1H，J＝8.7，2.3Hz)，6.77(d，1H，J＝2.3Hz)，2.29(s，3H).

ESIMS m/z：313(M+H).

Compound 1 e-0-59:

2-nitro-N- (7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran-3-yl) benzamide

The title compound was synthesized by the same method as that for the production of compound 1e-0-4, except that compound 1c-59 was used instead of compound 1 c-2.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：10.68(s，1H)，10.26(s，1H)，8.12(d，1H，J＝7.7Hz)，7.89(t，1H，J＝6.3Hz)，7.80-7.74(m，3H)，7.71(d，1H，J＝8.7Hz)，6.88(dd，1H，J＝8.4，2.3Hz)，6.77(d，1H，J＝2.3Hz)，2.40(s，3H).

ESIMS m/z：341(M+H).

Compound 1 e-0-72:

7-hydroxy-4-methyl-3- (3-nitrobenzyl) -pyran [2, 3-b]Pyridin-2-ones

To a suspension of pyridine-2, 6-diol (204mg, 1.84mmol) and ethyl 2- (3-nitrobenzyl) -3-oxobutanoate (488mg, 1.84mmol) in methanol (10mL) was added Zn (OTf)₂(669mg, 1.84mmol), stirring at 75 ℃ for 30 hours. After that, the reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with saturated brine and dried over magnesium sulfate. Subsequently, the crude product was obtained by concentration under reduced pressure and purified by column chromatography to obtain the title compound (330mg, 57%).

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.44(3H，s)，4.07(2H，s)，6.67(1H，d，J＝8.6Hz)，7.57(1H，dd，J＝7.7，7.9Hz)，7.71(1H，d，J＝7.7Hz)，8.05-8.14(3H，m)

ESI (LC/MS positive mode) M/z 313(M + H)

Compound 1 e-0-73:

3- (5-Nitro-thiophen-2-ylmethyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from compound 1c-73 under the same conditions as in the preparation of compound 1 e-0-4.

¹H-NMR(Bruker(ARX-300)，300MHz，DMSO- )δ(ppm)：10.58(1H，s)，7.98(1H，d，J＝4.20)，7.68(1H，d，J＝8.77Hz)，7.11(1H，d，J＝4.20Hz)，6.82(1H，dd，J＝8.77Hz)，J＝1.91Hz)，6.72(1H，d，J＝2.29Hz)，4.17(2H，s)，2.47(3H，s)

MS(Micromass，Quttromicro，ESI-)m/z：315.83(M-1)

Compound 1 g-1-5:

dimethylcarbamic acid 2-oxo-2H-3- (2-fluoro-3-nitrobenzyl) -4-methyl-6-fluoro-1-benzopyran-7-yl ester

To a solution of compound 1e-0-5(364.9mg, 1.05mmol) in THF (4mL) was added sodium hydride (60%, 46.2mg, 1.16mmol), and the mixture was stirred at room temperature for 5 minutes. N, N-dimethylcarbamoyl chloride (116. mu.L, 1.26mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour. Thereafter, a saturated aqueous ammonium chloride solution (2mL) was added to the reaction mixture, and the precipitated precipitate was collected. Subsequently, washing with water gave the title compound (407.8mg, 93%) as a white solid.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.42(3H，s)，2.94(3H，s)，3.09(3H，s)，4.07(2H，s)，7.31-7.34(1H，m)，7.49(1H，d，J＝6.8Hz)，7.59-7.63(1H，m)，7.89(1H，d，J＝11.4Hz)，7.99(1H，dd，J＝6.9，8.24Hz).

ESI (LC/MS positive mode) m/z: 419(M + H).

Compound 1 g-1-1:

dimethyl carbamic acid 4-methyl-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1g-1-5 except that Compound 1e-0-1 was used instead of Compound 1 e-0-5.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：8.12(s，1H)，8.07(d，J＝8.2Hz，1H)，7.86(d，J＝8.7Hz，1H)，7.72(d，J＝7.7Hz，1H)，7.58(t，J＝7.9Hz，1H)，7.26(d，J＝2.3Hz，1H)，7.19(dd，J＝8.7，2.5Hz，1H)，4.14(s，2H)，3.07(s，3H)，2.93(s，3H)，2.51(s，3H).

ESIMS m/z：383(M+H).

Compound 1 g-1-2:

dimethylcarbamic acid 2-oxo-2H-3- (3-nitrobenzyl) -4-methyl-6-fluoro-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1g-1-5 except that Compound 1e-0-2 was used in place of Compound 1 e-0-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.50(3H，s)，2.94(3H，s)，3.08(3H，s)，4.14(2H，s)，7.49(1H，d，J＝6.8Hz)，7.58(1H，dd，J＝7.9，7.9Hz)，7.72(1H，d，J＝7.9Hz)，7.86(1H，d，J＝11.1Hz)，8.08(1H，m)，8.12(1H，s).

ESI (LC/MS positive mode) m/z: 419(M + H).

Compound 1 g-1-3:

dimethylcarbamic acid 2-oxo-2H-3- (3-nitrobenzyl) -4-methyl-6-chloro-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1g-1-5 except that Compound 1e-0-3 was used in place of Compound 1 e-0-5.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：8.12(s，1H)，8.08(d，J＝8.2Hz，1H)，8.02(s，1H)，7.72(d，J＝8.2Hz，1H)，7.58(t，J＝8.2Hz，1H)，7.50(s，1H)，4.14(s，2H)，3.11(s，3H)，2.95(s，3H)，2.51(s，3H).

ESIMS m/z：417(M+H).

Compound 1 g-1-4:

dimethylcarbamic acid 2-oxo-2H-3- (2-fluoro-3-nitrobenzyl) -4-methyl-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1g-1-5 except that Compound 1e-0-4 was used in place of Compound 1 e-0-5.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.93(3H，s)，3.07(3H，s)，4.08(2H，s)，7.20(1H，dd，J＝8.7，2.3Hz)，7.26(1H，d，J＝2.3Hz)，7.31(1H，td，J＝8.3，2.3Hz)，7.60(1H，ddd，J＝8.3，6.5，1.8Hz)，7.88(1H，d，J＝8.7Hz)，7.99(1H，ddd，J＝8.3，6.5，1.8Hz).

ESI (LC-MS positive mode) m/z: 401(M +1H).

Compounds 1 g-1-7:

dimethylcarbamic acid 2-oxo-2H-3- (3-nitrobenzyl) -4-methyl-6-iodo-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1g-1-5 except that Compound 1e-0-7 was used in place of Compound 1 e-0-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.96(3H，s)，3.13(3H，s)，4.13(2H，s)，7.38(1H，s)，7.57(1H，dd，J＝7.7，8.1Hz)，7.71(1H，d，J＝7.7Hz)，8.08(1H，d，J＝8.1Hz)，8.11(1H，s)，8.24(1H，s).

CH₃Overlaps with the peak of DMSO.

ESI (LC/MS positive mode) m/z: 509(M + H).

Compound 1 g-1-8:

dimethylcarbamic acid 2-oxo-2H-3- (3-nitrobenzyl) -4-methyl-6-methyl-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1g-1-5 except that Compound 1e-0-8 was used instead of Compound 1 e-0-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.23(3H，s)，2.94(3H，s)，3.09(3H，s)，4.13(2H，s)，7.22(1H，s)，7.57(1H，dd，J＝7.4，8.1Hz)，7.71(1H，d，J＝7.4Hz)，7.76(1H，s)，8.08(1H，d，J＝8.1Hz)，8.10(1H，s).

CH₃Overlaps with the peak of DMSO.

ESI (LC/MS positive mode) m/z: 397(M + H).

Compound 1 g-1-9:

dimethylcarbamic acid 2-oxo-2H-3- (3-nitrobenzyl) -4-methyl-6-cyano-1-Benzopyran-7-yl esters

The title compound was synthesized under the same conditions as in the preparation of Compound 1g-1-5 except that Compound 1e-0-9 was used instead of Compound 1 e-0-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.99(3H，s)，3.14(3H，s)，4.12(2H，s)，7.38(1H，s)，7.57(1H，dd，J＝7.7，8.1Hz)，7.71(1H，d，J＝7.7Hz)，8.08(1H，d，J＝8.1Hz)，8.11(1H，s)，8.24(1H，s).

CH₃Overlaps with the peak of DMSO.

ESI (LC/MS positive mode) m/z: 408(M + H).

Compound 1 g-1-38:

dimethylcarbamic acid 6-carbamoyl-4-methyl-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

To compound 1g-1-9(1.2g, 2.95mmol) were added acetic acid (5mL) and concentrated sulfuric acid (5mL), and the mixture was stirred at room temperature for 1.5 hours. Thereafter, the reaction mixture was poured into an aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic extract was washed with saturated brine and dried over magnesium sulfate. Subsequently, the crude product was obtained by concentration under reduced pressure, which was purified by column chromatography to obtain the title compound (1.1g, 90%).

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.90(3H，s)，3.06(3H，s)，4.15(2H，s)，7.29(1H，s)，7.50(1H，brs)，7.55-7.61(2H，m)，7.70-7.73(2H，m)，7.80(1H，brs)，8.01(1H，s)

One peak of methyl overlaps with the peak of DMSO.

ESI (LC/MS positive mode) M/z 426(M + H)

Compound 1 g-1-39:

3- (3-nitrobenzyl) -4-methyl-2-oxo-6-trimethylsilylethynyl-2H-1-benzopyran-7-yl dimethylcarbamate

Compound 1g-1-7(1.45g, 2.85mmol), bis (triphenylphosphine) palladium (II) dichloride (100mg, 0.143mmol), copper (I) iodide (55mg, 0.29mmol), trimethylsilyl (silanyl) acetylene (1.4g, 14.3mmol), diisopropylethylamine (550. mu.L, 3.2mmol) and 10mL of anhydrous tetrahydrofuran were mixed, and the mixture was heated and stirred at 45 to 55 ℃ for 10 hours. Purification by silica gel chromatography (eluting with methylene chloride) gave 1.06g of the title compound.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：0.21(9H，s)，2.94(3H，s)，3.08(3H，s)，4.13(2H，s)，7.39(1H，s)，7.57(1H，t，J＝8.0Hz)，7.70(1H，d，J＝8.0Hz)，7.94(1H，s)，8.06(1H，d，J＝8.0Hz)，8.12(1H，s)

One peak of methyl overlaps with the peak of DMSO. .

ESI (LC/MS positive mode) M/z 449(M + H)

Compound 1 g-1-59:

dimethylcarbamic acid 3- (2-nitrobenzoylamino) -4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by the same method as that for the production of compound 1g-1-5, except that compound 1e-0-59 was used instead of compound 1 e-0-5.

¹H NMR(270MHz，DMSO-d₆)δ(PPM)：10.44(s，1H)，8.13(d，1H，J＝7.7Hz)，7.92-7.88(m，2H)，7.80-7.76(m，2H)，7.33(d，1H，J＝2.1Hz)，7.25(dd，1H，J＝8.7，2.3Hz)，3.08(s，3H)，2.92(s，3H)，2.46(s，3H).

ESIMS m/z：412(M+H).

Compound 1 g-1-72:

dimethyl carbamic acid 4-methyl-3- (3-nitrobenzyl) -2-oxo-2H-pyrano [2, 3-b]Pyridin-7-yl esters

The title compound was synthesized under the same conditions as in the preparation of Compound 1g-1-5 except that Compound 1e-0-72 was used in place of Compound 1 e-0-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.95(3H，s)，3.07(3H，s)，4.14(2H，s)，7.28(1H，d，J＝8.4Hz)，7.58(1H，dd，J＝7.7，8.1Hz)，7.73(1H，d，J＝7.7Hz)，8.05-8.14(2H，m)，8.43(1H，d，J＝8.4Hz).

CH₃The peak of (a) overlaps with the peak of DMSO.

ESI (LC/MS positive mode) M/z 384(M + H)

Compound 1g-1 b-1:

7-isobutoxy-4-methyl-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the compound 1e-0-1 in place of the compound 1e-0-4 and isopropyl bromide in place of bromopyrimidine, under the same conditions as in the preparation of the compound 1 g-2-4.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：0.98(3H，s)，1.00(3H，s)，1.95-2.11(1H，m)，2.47(3H，s)，3.86(2H，d，J＝6.5Hz)，4.10(2H，s)，6.93-7.06(2H，m)，7.58(1H，dd，J＝8.1、7.8Hz)，7.64-7.79(2H，m)，8.00-8.11(2H，m).

ESI (LC-MS positive mode) m/z: 368(M + H).

2-fluoroethyl p-toluenesulfonate

1g (15.6mmol) of 2-fluoroethanol was dissolved in pyridine (15ml), and 6.5g (34.1mmol) of p-toluenesulfonic acid was added thereto for 30 minutes while stirring under ice cooling, and the mixture was stirred under a nitrogen stream at 0 ℃ for 3 hours. To the reaction solution was added 35ml of ice water, followed by extraction with 30ml of ethyl acetate. The organic layer was washed with 30ml of 1N hydrochloric acid 3 times, and then washed with an aqueous sodium carbonate solution and a saturated saline solution. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, whereby 3.19g (94%) of the title compound was obtained as a colorless oily substance.

¹H-NMR(270MHz，CDCl₃)δ(ppm)：2.46(3H，s)，4.14-4.25(1H，m)，4.25-4.36(1H，m)，4.43-4.36(1H，m)，4.61-4.71(1H，m)，7.36(2H，d，J＝8.1Hz)，7.81(2H，d，J＝8.1Hz).

Compound 1g-1 c-1:

7- (2-Fluoroethoxy) -4-methyl-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1g-2-4, except that Compound 1e-0-1 was used instead of Compound 1e-0-4 and p-toluenesulfonic acid 2-fluoroethyl ester was used instead of bromopyrimidine.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.43(3H，s)，4.10(2H，s)，4.29-4.36(1H，m)，4.39-4.46(1H，m)，4.64-4.71(1H，m)，4.82-4.89(1H，m)，6.96-7.07(2H，m)，7.58(1H，dd，J＝8.1、7.6Hz)，7.71(1H，d，J＝8.1Hz)，7.78(1H，d，J＝8.6Hz)，8.01-8.11(2H，m).

Compound 1g-1 c-3:

6-chloro-7- (2-fluoroethoxy) -4-methyl-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1g-2-4, except that Compound 1e-0-3 was used instead of Compound 1e-0-4 and p-toluenesulfonic acid 2-fluoroethyl ester was used instead of bromopyrimidine.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.43(3H，s)，4.11(2H，s)，4.36-4.43(1H，m)，4.46-4.54(1H，m)，4.68-4.73(1H，m)，4.86-4.91(1H，m)，7.30(1H，s)，7.58(1H，dd，J＝8.1、7.8Hz)，7.71(1H，d，J＝8.1Hz)，7.93(1H，s)，8.04-8.11(2 H，m).

Compound 1g-1 d-1:

pyrrolidine-1-carboxylic acid 4-methyl-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of 1g-1-5 using 1e-0-1 instead of 1e-0-5 and pyrrolidine chloride-1-carbonyl instead of N, N-carbamic acid chloride.

¹H-NMR(CDC1₃，270MHz)δ(PPM)：1.93-2.02(4H，m)，2.49(3H，s)，3.50(2H，t，J＝6.6Hz)，3.59(2H，t，J＝6.6Hz)，4.15(2H，s)，7.14-7.19(2H，m)，7.45(1H，t，J＝7.8Hz)，7.61-7.65(2H，m)，8.06-8.10(2H，m)

ESI (LC/MS positive mode) M/z 409(M + H)

Compound 1 g-2-4:

4-methyl-3- (2-fluoro-3-nitrobenzyl) -7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

Compound 1e-0-4(15g, 45.6mmol) and 2-bromopyrimidine (72.4g, 455mmol) were dissolved in N, N-dimethylformamide (300mL), potassium carbonate (12.6g, 91.2mmol) was added, and the mixture was stirred at 80 ℃ for 1 hour under a nitrogen atmosphere. Then, ethyl acetate was added to the reaction solution, and the mixture was washed with an aqueous sodium hydrogencarbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 2) to obtain the title compound (10.57g, 57%) as a pale yellow powder.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.52(3H，s)，4.10(2H，s)，7.28(1H，dd，J＝8.8、2.4Hz)，7.30-7.36(2H，m)，7.38(1H，d，J＝2.4Hz)，7.59-7.64(1H，m)，7.93(1H，d，J＝8.8Hz)，7.97-8.03(1H，m)，8.69(2H，d，J＝4.4Hz).

ESI (LC-MS positive mode) m/z: 408(M + H).

Compound 1 g-2-1:

4-methyl-3- (3-nitrobenzyl) -7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of compound 1g-2-4 except that compound 1e-0-1 was used instead of compound 1 e-0-4.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.52(3H，s)，4.17(2H，s)，7.12(1H，t，J＝4.8Hz)，7.20(1H，dd，J＝2.1，8.7Hz)，7.20-7.40(1H，m)，7.46(1H，dd，J＝7.7，7.7Hz)，7.64(1H，d，J＝7.7Hz)，7.72(1H，d，J＝8.7Hz)，8.07-8.10(2H，m)，8.59(2H，d，J＝4.8Hz).

ESI (LC/MS positive mode) m/z: 390(M + H).

Compound 1 g-2-3:

4-methyl-3- (3-nitrobenzyl) -7- (pyrimidin-2-yloxy) -6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of compound 1g-2-4 except that compound 1e-0-3 was used instead of compound 1 e-0-4.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.51(3H，s)，4.16(2H，s)， 7.13(1H，t，J＝4.8Hz)，7.29(1H，s)，7.45(1H，t，J＝7.7Hz)，7.62(1H，d，J＝7.7Hz)，7.75(1H，s)，8.06(1H，d，J＝7.7Hz)，8.07(1H，brs)，8.60(2H，d，J＝4.8Hz).

ESI (LC/MS positive mode) m/z: 424(M + H).

Compound 1 g-2-47:

4-hydroxy-3- (3-nitrobenzyl) -7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1g-2-4 except that Compound 1e-0-47 was used instead of Compound 1 e-0-4.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.69(d，2H，J＝4.8Hz)，8.12(m，1H)，8.09-8.03(dx2，2H)，7.73(d，1H，J＝7.7Hz)，7.57(t，1H，J＝7.9Hz)，7.35-7.32(m，2H)，7.25(dd，1H，J＝9.0，2.2Hz)，4.00(s，2H).

ESIMS m/z：392(M+H).

Compound 1 g-3-3:

4-methyl-3- (3-nitrobenzyl) -7- (thiazol-2-yloxy) -6-chloro-2-oxo-2H-1-benzopyran

Compound 1e-0-3(2.0g, 5.78mmol) was dissolved in N, N-dimethylformamide (10mL), 2-bromothiazole (2.1mL, 23.1mmol), cesium carbonate (3.8g, 11.6mmol) and copper (I) iodide (220mg, 1.16mmol) were added, and the mixture was stirred at 110 ℃ for 1 hour while irradiating with a microwave (100W). Then, ethyl acetate was added to the reaction solution, which was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol 20: 1) to give the title compound (496mg, 20%) as a pale yellow powder.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.50(3H，s)，4.15(2H，s)，6.94(1H，d，J＝3.8Hz)，7.23(1H，d，J＝3.8Hz)，7.44-7.50(2H，m)，7.60-7.63(1H，m)，7.75(1H，s)，8.07-8.10(2H，m).

ESI (LC/MS positive mode) m/z: 429(M + H).

Compound 1 g-3-1:

4-methyl-3- (3-nitrobenzyl) -7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of compound 1g-3-3, except that compound 1e-0-1 was used instead of compound 1 e-0-3.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.50(3H，s)，4.15(2H，s)，6.93(1H，d，J＝3.8Hz)，7.26-7.34(3H，m)，7.43-7.50(1H，m)，7.61-7.66(1H，m)，7.68(1H，d，J＝8.8Hz)，8.05-8.10(2H，m).

ESI (LC/MS positive mode) m/z: 395(M + H).

Compound 1 g-3-8:

4-methyl-3- (3-nitrobenzyl) -7- (thiazol-2-yloxy) -6-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of compound 1g-3-3, except that compound 1e-0-8 was used instead of compound 1 e-0-3.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.28(3H，s)，4.14(2H，s)，7.29(2H，s)，7.45(1H，s)，7.58(1H，dd，J＝7.4，8.2Hz)，7.72(1H，d，J＝7.4Hz)，7.87(1H，s)，8.08(1H，d，J＝8.2Hz)，8.11(1H，s).

CH₃Overlaps with the peak of DMSO.

ESI (LC/MS positive mode) m/z: 409(M + H).

Compound 1 g-11-3:

4-methyl-3- (3-nitrobenzyl) -7- (thiophen-3-yl) -6-chloro-2-oxo-2H-1-benzopyran

Using the same conditions as in the preparation example of Compound 1g-1-5, compound 1e-0-3 was used instead of Compound 1e-0-5 and trifluorosulfonic anhydride was used instead of dimethylcarbamoyl chloride, to give 2-oxo-2H-3- (3-nitrobenzyl) -4-methyl-6-chloro-1-benzopyran-7-yl trifluorosulfonate (Compound 1g-1 e-3).

Compound 1g-1e-3(200mg, 0.419mmole) was added to tetrahydrofuran (6mL), thiophene-3-boronic acid (160mg, 1.25mmole), tetrakis (triphenylphosphine) palladium (72mg, 0.084mmole), K ₃PO₄(412mg, 2.51mmole) ofAnd stirred at 80 ℃ for 12 hours. Purification by silica gel chromatography (hexane: ethyl acetate 4: 1) gave the title compound (121 mg).

¹H-NMR(Bruker(ARX-300)，300MHz，CDCl₃)δ(PPM)：8.10(1H，s)，8.08(1H，d，J＝6.49Hz)，7.73(1H，s)，7.65(1H，d，J＝8.01Hz)，7.59(1H，dd，J＝3.05Hz，J＝1.53Hz))，7.50-7.42(3H，m)，7.36(1H，dd，J＝5.34Hz，J＝1.53Hz)，4.17(2H，s)，2.51(3H，s)

Compound 1 g-12-1:

4-methyl-3- (3-nitrobenzyl) -7- (pyridin-4-yl) -2-oxo-2H-1-benzopyran

Using the same conditions as in the preparation example of Compound 1g-1-5, compound 1e-0-1 was used instead of Compound 1e-0-5 and trifluoroacetic anhydride instead of dimethylcarbamoyl chloride, to give 2-oxo-2H-3- (3-nitrobenzyl) -4-methyl-6-chloro-1-benzopyran-7-yl trifluorosulfonate (Compound 1g-1 e-1).

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1g-11-3, but using the compound 1g-1e-1 instead of the compound 1g-1e-3 and pyridine-4-boronic acid instead of thiophene-3-boronic acid.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(PPM)：8.73(2H，d，J＝6.49Hz)，8.10(1H，s)，8.08(1H，d，J＝9.16Hz)，7.78(1H，d，J＝9.16Hz)，7.71-7.44(6H，m)，4.19(2H，s)，2.56(3H，s)

Compound 1 g-13-1:

4-methyl-3- (3-nitrobenzyl) -7- (diphenylmethylene)2-oxo-2H-1-benzopyran

Compound 1g-1e-1(88mg, 0.2mmol), BINAP (11mg, 0.02mmol), palladium (II) acetate (3mg, 0.013mmol), cesium carbonate (164mg, 0.5mmol), benzophenone imine (154mg, 0.24mmol) were mixed and heated under reflux for 3.5 hours under a nitrogen atmosphere. Purification by silica gel chromatography (ethyl acetate: hexane ═ 8: 1 to 4: 1) gave the title compound (49mg, 52%).

¹H-NMR(Bruker(ARX-300)，300MHz，CDCl₃)δ(PPM)：8.08(1H，d，J＝1.91Hz)，8.06(1H，d，J＝9.54Hz)，7.76(2H，d，J＝7.25Hz)，7.64(1H，d，J＝7.63Hz)，7.55-7.41(5H，m)，7.29(3H，m)，7.13(2H，d，J＝4.96Hz)，6.70(1H，dd，J＝8.39Hz，J＝2.29Hz)，6.67(1H，d，J＝1.91Hz)，4.10(2H，s)，2.42(3H，s)

Compound 1 g-14-1:

4-methyl-3- (3-nitrobenzyl) -7-amino-2-oxo-2H-1-benzopyran

2.5mL of 2N hydrochloric acid was added to a mixture of compound 1g-13-1(6.2g) in THF (50mL), and the mixture was stirred at room temperature for 20 minutes. After adding a 1N aqueous solution of sodium hydroxide, the mixture was extracted with dichloromethane. After removal of the solvent, the mixture was solidified with a 2: 1 hexane: ethyl acetate solution (3.9g, 96%).

¹H-NMR(Bruker(ARX-300)，300MHz，DMSO- )δ(PPM)：8.05(1H，s)，8.04(1H，d，J＝6.49Hz)，7.68(1H，d，J＝7.63Hz)，7.56(1H，t，J＝7.63Hz)，7.47(1H，d，J＝8.78Hz)，6.58(1H，d，J＝8.39Hz)，6.42(1H，s)，6.06(2H，s)，4.02(2H，s)，2.36(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：311.35(M+1)

Compound 1 g-15-1:

4-methyl-3- (3-nitrobenzyl) -7-iodo-2-oxo-2H-1-benzopyran

NaNO was added to 1g-14-1(620mg, 0.064mmol), 0.013mL of concentrated sulfuric acid, and 0.13mL of water at 0 ℃ over 1h₂(4.6mg, 0.068mmol) in water (0.013 mL). An aqueous solution (0.09mL) of potassium iodide (32mg, 0.192mmol) was added dropwise over 30 minutes at 0 deg.C and stirred at room temperature for 1 hour. Purification by silica gel chromatography (hexane: ethyl acetate 2: 1) gave the title compound (25mg, 92%).

¹H-NMR(Bruker(ARX-300)，300MHz，CDCl₃)δ(PPM)：8.08(1H，s)，8.07(1H，d，J＝6.49Hz)，7.72(1H，d，J＝.53Hz)，7.65(2H，dd，J＝8.39Hz，J＝1.91Hz)，7.46(1H，t，J＝7.63Hz)，7.35(1H，d，J＝8.39Hz)，4.14(2H，s)，2.48(3H，s)

MS(Micromass，Quttromicro，ESI-)m/z：420.43(M-1)

5-tributyltin thiazole

5-bromothiazole at-78 ℃ for 30 minutes under a nitrogen atmosphereTo a solution of n-BuLi in anhydrous tetrahydrofuran (0.46mL, 5.0mmol) was added dropwise a solution of n-BuLi in hexane (4.14mL, 10mmol), and the mixture was stirred for 1 hour. n-Bu was added dropwise at-78 ℃ over 30 minutes₃After a solution of SnCl (1.41mL, 5.0mmol) in THF, it was stirred for 2 hours, then it was further warmed to room temperature and stirred for 1 hour. 3 drops of 1N HCl solution were added and the organic layer was extracted 2 times from the aqueous layer with 10mL of diethyl ether. The solvent was distilled off to obtain the objective compound (650mg, 35 mL).

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：9.09(1H，s)，7.88(1H，s)，1.61-0.87(27H，m)

MS(Micromass，Quttromicro，ESI+)m/z：376.07(M+1)

Compound 1 g-16-1:

4-methyl-3- (3-nitrobenzyl) -7- (thiazol-5-yl) -2-oxo-2H-1-benzopyran

The compounds 1g-15-1(150mg, 0.36mmol), 5-tributyltin thiazole (173mg, 0.46mmol), bis (triphenylphosphine) palladium dichloride (6.5mg, 0.009mmol), tris (2-furyl) phosphine (4.3mg, 0.02mmol), acetonitrile (4.5mL) were mixed and heated under argon atmosphere to reflux overnight. Purification by silica gel chromatography (hexane: ethyl acetate: 2: 1-dichloromethane: hexane: ethyl acetate: 1) gave the title compound (126mg, 70%).

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(PPM)：8.84(1H，s)，8.20(1H，s)，8.10(1H，s)，8.09(1H，d，J＝8.39Hz)，7.68(2H，t，J＝6.87Hz)，7.54(2H，m)，7.47(1H，t，J＝7.63Hz)，4.17(2H，s)，2.53Hz(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：397.04(M+1)

2-tributyltin thiazole

To a mixture of 2-bromothiazole (4.6mL, 50mmol) and dehydrated ether (50mL) was added dropwise n-BuLi in hexane (22mL, 55mmol) under a nitrogen atmosphere at-70 ℃ and stirred for 30 minutes. At-70 ℃ add nBu₃A solution of SnCl (14mL, 50mmol) in diethyl ether (20mL) was stirred for a further 4 hours, then warmed to room temperature and stirred for 1 hour. Water (50mL) was added, and the organic layer was extracted 3 times with diethyl ether (50mL), and then the solvent was distilled off. Purification by silica gel chromatography (hexane: ethyl acetate 20: 1) gave the title compound (17g, 90%).

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(PPM)：8.17(1H，d，J＝3.05Hz)，7.54(1H，d，J＝3.05Hz)，1.65-1.55(6H，m)，1.38-1.19(12H，m)，0.89(9H，t，J＝7.25Hz)

Compound 1 g-17-1:

4-methyl-3- (3-nitrobenzyl) -7- (thiazol-2-yl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of 1g-16-1 using 2-tributyltin thiazole instead of 5-tributyltin thiazole.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(PPM)：8.12(1H，s)，8.08(1H，d，J＝8.01Hz)，7.94(3H，m)，7.72(1H，d，J＝8.01Hz)，7.67(1H，d，J＝7.63Hz)，7.48(1H，d，J＝8.01Hz)，7.44(1H，d，J＝3.43Hz)，4.18(2H，s)，2.54(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：397.04(M+1)

Compound 1 g-18-1:

4-methyl-3- (3-nitrobenzyl) -7- (pyridin-3-yl) -2-oxo-2H-1-benzopyran

Using the same conditions as in the preparation example of Compound 1g-1-5, compound 1e-0-1 was used instead of Compound 1e-0-5 and trifluorosulfonic anhydride was used instead of dimethylcarbamoyl chloride, to give 2-oxo-2H-3- (3-nitrobenzyl) -4-methyl-1-benzopyran-7-yl trifluorosulfonate (Compound 1g-1 e-1).

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1g-11-3, but using the compound 1g-1e-1 instead of the compound 1g-1e-3 and pyridine-3-boronic acid instead of thiophene-3-boronic acid.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(PPM)：8.91(1H，d，J＝1.91Hz)，8.67(1H，dd，J＝4.58Hz，J＝1.53Hz)，8.11(1H，s)，8.08(1H，dd，J＝8.77Hz，J＝1.91Hz)，7.92(1H，dt，J＝8.01Hz，J＝2.29Hz)，7.78-7.42(6H，m)，4.19(2H，s)，2.56(3H，s)

Compound 1 g-19-3:

4-methyl-3- (3-nitrobenzyl) -6-chloro-7- (3-methoxyphenyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of 1g-11-3 using 3-phenoxyboronic acid instead of thiophene-3-boronic acid.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(PPM)：8.09(1H，s)，8.08(1H，d，J＝6.49Hz)，7.74(1H，s)，7.65(1H，d，J＝7.63Hz)，7.49(1H，t，J＝8.01Hz)，7.39(1H，t，J＝8.77Hz)，7.35(1H，s)，7.03(1H，dd，J＝7.63Hz，J＝1.14Hz)，6.99-6.97(2H，m)，4.18(2H，s)，3.86(3H，s)，2.52(3H，s)

1-methyl-2-tributyltin-1H-imidazole

n-BuLi (7.6mL, 18.9mmol) was added dropwise to a solution of 1-methyl-1H-imidazole (1.6mL, 18.8mmol) in anhydrous tetrahydrofuran (20mL) at-10 ℃ for 30 minutes under a nitrogen atmosphere, and then stirred for 2.5 hours. Bu was added dropwise at-78 ℃ over 1 hour ₃After a solution of SnCl (5.1mL, 18.8mmol) in tetrahydrofuran (12mL), it was warmed to room temperature and stirred overnight. The objective compound (5.48g, 79%) was obtained by distillation under reduced pressure (140 ℃ C., 142 ℃ C., 0.5 mmHg).

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：7.20(1H，s)，7.01(1H，s)，3.68(3H，s)，1.56(6H，m)，1.37-1.15(12H，m)，0.88(9H，t，J＝7.2Hz)

Compound 1 g-20-1:

4-methyl-3- (3-nitrobenzyl) -7- (1-methyl-1H-imidazol-2-yl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of 1g-16-1 using 1-methyl-2-tributyltin-1H-imidazole instead of 5-tributyltin thiazole.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(PPM)：8.10(1H，s)，8.08(1H，d，J＝8.01Hz)，7.74(2H，s)，7.67(1H，d，J＝7.25Hz)，7.58(1H，s)，7.47(1H，t，J＝7.63Hz)，7.18(1H，d，J＝1.14Hz)，7.04(1H，d，J＝0.76Hz)，4.19(2H，s)，3.85(3H，s)，2.55(3H，s)

Compound 1 g-21-3:

4-methyl-3- (3-nitrobenzyl) -6-chloro-7- (5-acetylthiophen-2-yl) -2-oxo-2H-1-benzopyran

The title compound was synthesized using 5-acetylthiophene-2-boronic acid instead of thiophene-3-boronic acid under the same conditions as in the preparation example of compound 1 g-11-3.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(PPM)：8.15～8.05(3H，m)，8.02(1H，d，J＝4.19Hz)，7.83(1H，s)，7.72(2H，dd，)，7.60(1H，t)，4.16(2H，s)，2.60(3H，s)，2.54(3H，s)

Compound 1 g-22-1:

4-methyl-3- (3-nitrobenzyl) -7- (3-acetyl-phenyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1g-11-3, but using the compound 1g-1e-1 instead of the compound 1g-1e-3 and 3-acetylphenylboronic acid instead of thiophene-3-boronic acid.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(PPM)：8.23(1H，t)，8.05(2H，m)，7.88(1H，d，J＝7.63Hz)，7.82(1H，d，J＝7.63Hz)，7.75(1H，d＝1.49Hz)，7.73(1H，d，J＝8.01Hz)，7.61(3H，m)，7.45(1H，t)，4.22(2H，s)，2.65(3H，s)，2.46(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：414.08(M+1)

Compound 1 g-23-1:

4-methyl-3- (3-nitrobenzyl) -7- (4-acetyl-phenyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1g-11-3, but using the compound 1g-1e-1 instead of the compound 1g-1e-3 and 4-acetylphenylboronic acid instead of thiophene-3-boronic acid.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：8.01(4H，m)，7.85(1H，d，J＝8.77Hz)，7.64(4H，m)，7.45(1H，t)，6.85(1H，d，J＝8.39Hz)，4.22(2H，s)，2.65(3H，s)，2.46(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：414.08(M+1)

Compound 1 g-28-1:

4-methyl-3- (3-nitrobenzyl) -7- (4-N, N-dimethylaminophenyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1g-11-3, but using the compound 1g-1e-1 instead of the compound 1g-1e-3 and 4-N, N-dimethylaminophenylboronic acid instead of the thiophene-3-boronic acid.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(PPM)：8.11(2H，t，d，J＝8.77Hz)，7.53(7H，m)，6.78(2H，d，J＝8.77Hz)，4.22(2H，s)，3.10(6H，s)，2.52(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：415.25(M+1)

1-methyl-5-tributyltin-1H-imidazole

A mixture of n-BuLi (18mL, 45mmol) and TMEDA (6.7mL, 44.6mmol) was added dropwise to a solution of 1-methylimidazole (1.6mL, 18.8mmol) in dehydrated tetrahydrofuran (10mL) at-20 deg.C under a nitrogen atmosphere. After stirring directly for 30 minutes, the temperature was raised to room temperature and stirred for 1 hour. Cooling to-20 deg.C again, and dropping n-Bu₃A solution of SnCl (12.5mL, 46.4mmol) in tetrahydrofuran (10mL) was warmed to room temperature and stirred for 17 h. After the reaction was stopped with water (15mL), it was extracted 2 times with ethyl acetate (20 mL). Purification by silica gel chromatography (ethyl acetate: methanol 96: 4) gave the title compound (2.2g, 32%).

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(PPM)：7.61(1H，s)，7.02(1H，s)，3.67(3H，s)，1.48-1.56(6H，m)，1.29-1.37(6H，m)，1.09(6H，t，J＝8.4Hz)，0.89(9H，t，J＝7.2Hz)

MS(Micromass，Quttromicro，ESI+)m/z：372.99(M+2)

Compound 1 g-32-1:

4-methyl-3- (3-nitrobenzyl) -7- (3-methyl-3H-imidazol-4-yl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of 1g-16-1 using 1-methyl-5-tributyltin-1H-imidazole instead of 5-tributyltin thiazole.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：8.08(2H，d，J＝6.9Hz)，7.70(2H，m)，7.58(1H，s)，7.47(1H，t，J＝7.8Hz)，7.38(2H，m)，7.26(1H，d，J＝3.9Hz)，4.18(2H，s)，3.76(3H，s)，2.53(3H，s)

Compound 1 h-1-5:

dimethylcarbamic acid 2-oxo-2H-3- (2-fluoro-3-aminobenzyl) -4-methyl-6-fluoro-1-benzopyran-7-yl ester

To a solution of compound 1g-1-5(342.5mg, 0.819mmol) in ethanol-ethyl acetate (volume ratio 1: 1, 50mL) was added tin (II) chloride dihydrate (923mg, 4.09mmol), and the mixture was stirred at 80 ℃ for 3 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with a sodium carbonate aqueous solution and a saturated saline solution and dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off under reduced pressure to obtain the title compound (311.3mg, 98%) as a white solid.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.41(3H，s)，2.95(3H，s)，3.09(3H，s)，4.08(2H，s)，6.21-6.26(1H，m)，6.58-6.75(2H，m)，7.47(1H，d，J＝6.8Hz)，7.83(1H，d，J＝11.2Hz).

ESI (LC/MS positive mode) m/z: 389(M + H).

Compound 1 h-1-1:

dimethylcarbamic acid 2-oxo-2H-3- (3-aminobenzyl) -4-methyl-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-1-1 was used in place of Compound 1 g-1-5.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.42(3H，s)，3.03(3H，s)，3.13(3H，s)，3.60(2H，brs)，3.97(2H，s)，6.51(1H，dd，J＝2.0，7.7Hz)，6.58(1H，s)，6.64(1H，d，J＝7.7Hz)，7.02-7.12(3H，m)，7.59(1H，d，J＝8.9Hz).

ESI (LC/MS positive mode) m/z: 352(M + H).

Compound 1 h-1-2:

dimethylcarbamic acid 2-oxo-2H-3- (3-aminobenzyl) -4-methyl-6-fluoro-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-1-2 was used in place of Compound 1 g-1-5.

¹H-NMR(CD₃OD，270MHz)δ(PPM)：2.44(3H，s)，3.02(3H，s)，3.15(3H，s)，3.95(2H，s)，6.54-6.60(2H，m)，7.00(1H，dd，J＝7.6，7.6Hz)，7.29(1H，d，J＝6.6Hz)，7.64(1H，d，J＝11.1Hz).

ESI (LC/MS positive mode) m/z: 371(M + H).

Compound 1 h-1-3:

dimethylcarbamic acid 2-oxo-2H-3- (3-aminobenzyl) -4-methyl-6-chloro-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-1-3 was used in place of Compound 1 g-1-5.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.40(3H，s)，3.04(3H，s)，3.15(3H，s)，3.96(2H，s)，6.45-6.65(3H，m)，7.05(1H，dd，J＝7.7Hz)，7.25(1H，s)，7.64(1H，s).

ESI (LC/MS positive mode) m/z: 387(M + H).

Compound 1 h-1-4:

dimethylcarbamic acid 2-oxo-2H-3- (2-fluoro-3-aminobenzyl) -4-methyl-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-1-4 was used in place of Compound 1 g-1-5.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.93(3H，s)，3.06(3H，s)，3.91(2H，s)，5.07(2H，brs)，6.22(1H，brt，J＝7.3Hz)，6.55-6.75(2H，m)，7.17(1H，dd，J＝8.7，2.3Hz)，7.24(1H，d，J＝2.3Hz)，7.83(1H，d，J＝8.7Hz).

ESI (LC-MS positive mode) m/z: 371(M +1H).

Compounds 1 h-1-7:

dimethylcarbamic acid 2-oxo-2H-3- (3-aminobenzyl) -4-methyl-6-iodo-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-1-7 was used in place of Compound 1 g-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.43(3H，s)，2.96(3H，s)， 3.13(3H，s)，3.83(2H，s)，4.96(2H，brs)，6.35-6.38(3H，m)，6.89(1H，dd，J＝7.8，7.8Hz)，7.37(1H，s)，8.22(1H，s).

ESI (LC/MS positive mode) m/z: 479(M + H).

Compound 1 h-1-8:

dimethylcarbamic acid 2-oxo-2H-3- (3-aminobenzyl) -4-methyl-6-methyl-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-1-8 was used in place of Compound 1 g-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.22(3H，s)，2.43(3H，s)，2.94(3H，s)，3.10(3H，s)，3.83(2H，s)，4.96(2H，brs)，6.35-6.38(3H，m)，6.90(1H，dd，J＝8.1，8.1Hz)，7.21(1H，s)，7.73(1H，s).

ESI (LC/MS positive mode) m/z: 367(M + H).

Compound 1 h-1-9:

dimethylcarbamic acid 2-oxo-2H-3- (3-aminobenzyl) -4-methyl-6-cyano-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-1-9 was used in place of Compound 1 g-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.46(3H，s)，2.97(3H，s)，3.12(3H，s)，3.84(2H，s)，4.96(2H，brs)，6.36-6.38(3H，m)，6.90(1H，dd，J＝7.9，7.9Hz)，7.59(1H，s)，8.44(1H，s).

ESI (LC/MS positive mode) m/z: 378(M + H).

Compound 1 h-1-10:

dimethylcarbamic acid 2-oxo-2H-3- (2-aminopyridin-4-ylmethyl) -4-methyl-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1g-1-5, except that Compound 5d-0-10 was used instead of Compound 1 e-0-5.

¹H-NMR(300MHz)(DMSO-d₆)δ(ppm)：2.42(3H，s)，2.93(3H，s)，3.06(3H，s)，3.82(2H，s)，5.75(2H，brs)，6.19(1H，s)，6.37(1H，dd，J＝1.52，5.34Hz)，7.18(1H，dd，J＝2.28，8.77Hz)，7.25(1H，d，J＝2.28Hz)，7.76(1H，d，J＝5.34Hz)，7.84(1H，d，J＝8.77Hz).

Compounds 1 h-1-11:

dimethylcarbamic acid 2-oxo-2H-3- (2-aminopyridin-4-ylmethyl) -4-methyl-6-fluoro-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1g-1-5, except that Compound 5d-0-11 was used instead of Compound 1 e-0-5.

¹H-NMR(300MHz)(DMSO-d₆)δ(ppm)：2.41(3H，s)，2.94(3H，s)，3.08(3H，s)，3.82(2H，s)，5.75(2H，brs)，6.19(1H，s)，6.37(1H，d，J＝4.95Hz)，7.48(1H，d，J＝7.24Hz)，7.76(1H，d，J＝5.72Hz)，7.85(1H，d，J＝9.53Hz).

Compound 1 h-1-13:

3- (6-Aminopyridin-2-ylmethyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation of Compound 1g-1-5 except that Compound 5d-0-13 was used instead of Compound 1 e-0-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.42(3H，s)，2.93(3H，s)，3.07(2H，d)，3.88(2H，s)，5.79(2H，brs)，6.23(1H，d，J＝8.1Hz)，6.30(1H，d，J＝8.1Hz)，7.15-7.26(3H，m)，7.83(1H，d，J＝10.8Hz).

ESI (LC/MS positive mode) m/z: 354(M + H).

Compound 1 h-1-14:

3- (6-Aminopyridin-2-ylmethyl) -6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation of Compound 1g-1-5, except that Compound 5d-0-14 was used instead of Compound 1 e-0-5.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.45(3H，s)，3.04(3H，s)，3.09(3H，s)，4.04(2H，s)，6.31(1H，d，J＝7.8Hz)，6.54(1H，d，J＝7.8Hz)，7.15-7.40(3H，m).

ESI (LC/MS positive mode) m/z: 372(M + H).

Compound 1 h-1-15:

3- (6-Aminopyridin-2-ylmethyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation of Compound 1g-1-5, except that Compound 5d-0-15 was used instead of Compound 1 e-0-5.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.46(3H，s)，3.05(3H，s)，3.17(3H，s)，4.04(2H，s)，6.31(1H，d，J＝7.8Hz)，6.55(1H，d，J＝7.8Hz)，7.20-7.35(2H，m)，7.66(1H，s).

ESI (LC/MS positive mode) m/z: 388(M + H).

Compounds 1 h-1-4F:

dimethylcarbamic acid 3- (3-amino-2-fluoro-benzyl) -4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester

To 4-fluoromethyl-3- (2-fluoro-3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate (20.5mg) (6c-1-4) was added ethyl acetate (2.0mL) to give a suspension, and then tin (II) chloride dihydrate (60mg) was added thereto at room temperature with stirring, followed by heating and refluxing for 1.5 hours. After the reaction solution was cooled to room temperature, saturated sodium hydrogencarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off under reduced pressure to give the title compound (19.5 mg).

¹H-NMR(270MHz，CDCl₃)δ(ppm)：3.03(3H，s)，3.13(3H，s)，4.09(2H，s)，5.66(2H，d，J＝46.8Hz)，6.62(1H，brt，7.9Hz)，6.65(1H，td，J＝7.9，1.0Hz)，6.83(1H，dd，J＝7.9，1.0Hz)，7.12(1H，dd，J＝8.2，2.3Hz)，7.15(1H，d，J＝2.3Hz)，7.76(1H，dd，J＝8.2，2.3Hz).

ESI (LC-MS positive mode) m/z: 389(M + H).

Compound 1 h-1-1F:

dimethylcarbamic acid 3- (3-aminobenzyl) -4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-4F, except that Compound 6c-1-1 was used instead of Compound 6 c-1-4.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.93(3H，s)，3.07(3H，s)，3.91(2H，s)，4.98(2H，brs)，5.81(2H，d，J＝46.3Hz)，6.29-6.43(3H，m)，6.91(1H，t，J＝8.2Hz)，7.21(1H，dd，J＝8.7，2.3Hz)，7.30(1H，d，J＝2.3Hz)，7.89(1H，d，J＝8.7，2.3Hz).

ESI (LC-MS positive mode) m/z: 371(M + H).

Compound 1 h-1-2F:

3- (3-aminobenzyl) 6-fluoro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-4F, except that Compound 6c-1-2 was used instead of Compound 6 c-1-4.

¹H-NMR(270MHz，CDCl₃)δ(ppm)：3.04(3H，s)，3.15(3H，s)，4.03(2H，brs)，5.59(2H，d，J＝47.0Hz)，6.50-6.60(3H，m)，7.01-7.10(1H，m)，7.20-7.30(1H，m)，7.54(2H，1H，dd，J＝10.5，1.8Hz).

ESI (LC-MS positive mode) m/z: 389(M + H).

Compounds 1 h-1-3F:

dimethylcarbamic acid 6-chloro-4-fluoromethyl-3- (3-aminobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-4F, except that Compound 6c-1-3 was used instead of Compound 6 c-1-4.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：8.04(s，1H)，7.54(s，1H)，6.90(t，J＝7.8Hz，1H)，6.36(m，3H)，5.84(d，J＝46.0Hz，2H)，3.92(s，2H)，3.11(s，3H)，2.95(s，3H).

ESIMS m/z：405(M+H).

Compound 1 h-1-38:

3- (3-aminobenzyl) -6-carbamoyl-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-1-38 was used in place of Compound 1 g-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.47(3H，s)，2.90(3H，s)，3.05(3H，s)，3.85(2H，s)，4.97(2H，s)，6.35-6.38(3H，m)，6.90(1H，t，J＝7.8Hz)，7.28(1H，s)，7.50(1H，s)，7.80(1H，s)，7.98(1H，s)

ESI (LC/MS positive mode) M/z 396(M + H)

Compound 1h-1-39

3- (3-aminobenzyl) -4-methyl-2-oxo-6-trimethylsilylethynyl-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-1-39 was used in place of Compound 1 g-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：0.23(9H，s)，2.44(3H，s)，2.94(3H，s)，3.11(3H，s)，3.82(2H，s)，4.96(2H，s)，6.12-6.15(3H，m)，6.66(1H，t，J＝8.1Hz)，7.14(1H，s)，7.68(1H，s)

ESI (LC/MS positive mode) M/z 449(M + H)

Compound 1 h-1-40:

3- (3-aminobenzyl) -6-ethynyl-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

TBAF (0.245mL in THF, 1.0M) was added to a solution of compound 1g-1-39(100mg, 0.223mmol) in THF (2mL), and the mixture was stirred at room temperature for 1 hour. After that, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the title compound (77mg, 92%).

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.44(3H，s)，2.94(3H，s)，3.09(3H，s)，3.83(2H，s)，4.45(1H，s)，4.97(1H，brs)，6.35-6.38(3H，m)，6.96(1H，t，J＝8.0Hz)，7.38(1H，s)，7.97(1H，s)

ESI (LC/MS positive mode) M/z 377(M + H)

Compound 1 h-1-59:

dimethylcarbamic acid 3- (2-aminobenzamidoyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by the same method as that for the preparation of compound 1h-1-5, except that compound 1g-1-59 was used instead of compound 1 g-1-5.

¹H NMR(270MHz，DMSO-d₆)δ(PPM)：9.63(s，1H)，7.86(d，1H，J＝8.7Hz)，7.76(d，1H，J＝6.6Hz)，7.31(d，1H，J＝2.3Hz)，7.25-7.20(m，2H)，6.75(d，1H.J＝8.2Hz)，6.58(t，1H，J＝7.3Hz)，6.50(s，2H)，3.08(s，3H)，2.94(s，3H)，2.36(s，3H).

ESIMS m/z：382(M+H).

Compound 1h-1 d-1:

pyrrolidine-1-carboxylic acid 3- (3-aminobenzyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-1d-1 was used in place of Compound 1 g-1-5.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：1.90-2.04(4H，m)，2.42(3H，s)，3.50(2H，t，J＝6.6Hz)，3.56-3.61(4H，m)，3.97(2H，s)，6.49-6.66(3H，m)，7.05(1H，t，J＝7.8Hz)，7.09-7.17(2H，m)，7.59(1H，d，J＝7.4Hz)

ESI (LC/MS positive mode) M/z 379(M + H)

Compound 1h-2-1

4-methyl-3- (3-aminobenzyl) -7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-2-1 was used in place of Compound 1 g-1-5.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.45(3H，s)，3.60(1H，brs)，3.99(2H，s)，6.52(1H，dd，J＝2.0，7.6Hz)，6.57(1H，s)，6.64(1H，d，J＝7.6Hz)，7.06(1H，dd，J＝7.6，7.6Hz)，7.11(1H，t，J＝4.8Hz)，7.16(1H，dd，J＝2.3，8.7Hz)，7.23(1H，d，J＝2.3Hz)，7.68(1H，d，J＝8.7Hz)，8.59(2H，d，J＝4.8Hz).

ESI (LC/MS positive mode) m/z: 360(M + H).

Compound 1 h-2-3:

4-methyl-3- (3-aminobenzyl) -7- (pyrimidin-2-yloxy) -6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-2-3 was used in place of Compound 1 g-1-5.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.42(3H，s)，4.00(2H，s)，6.52(1H，d，J＝7.7Hz)，6.55(1H，brs)，6.63(1H，d，J＝7.7Hz)，7.04(1H，t，J＝7.7Hz)，7.10(1H，t，J＝4.8Hz)，7.26(1H，s)，7.72(1H，s)，8.60(2H，d，J＝4.8Hz).

ESI (LC/MS positive mode) m/z: 394(M + H).

Compound 1 h-2-4:

4-methyl-3- (2-fluoro-3-aminobenzyl) -7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

(Synthesis method 1)

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-2-4 was used in place of Compound 1 g-1-5.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.45(3H，s)，3.93(2H，s)，5.08(2H，br.s)，6.25(1H，ddd，J＝7.2、1.7Hz、J_HF＝7.2Hz)，6.61(1H，ddd，J＝8.2、1.7Hz、J_HF＝8.2Hz)，6.73(1H，dd，J＝8.2、7.2Hz)，7.26(1H，dd，J＝8.8、2.4Hz)，7.34(1H，t，J＝4.8Hz)，7.37(1H，d，J＝2.4Hz)，7.89(1H，d，J＝8.8Hz)，8.68(2H，d，J＝4.8Hz).

ESI (LC-MS positive mode) m/z: 378(M + H).

Compound 1h-2-4S 2:

3- { 2-fluoro-3-aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzothiopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 5d-0-4S2 was used in place of Compound 4 a-0-4.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：4.02(2H，s)，5.09(2H，s)，6.11(1H，dd，J＝7.0、Hz、J_HF＝7.0Hz)，6.60(1H，dd，J＝8.5、Hz、J_HF＝8.5Hz)，6.71(1H，dd，J＝7.7、7.7Hz)，7.28(1H，dd，J＝8.9，2.3Hz)，7.31-7.42(2H，m)，7.61-7.64(1H，m)，8.67-8.71(2H，m).

CH₃The peak of (a) overlaps with the peak of DMSO.

ESI (LC-MS positive mode) M/z 394(M + H).

Compound 1 h-2-5:

2-oxo-2H-3- (2-fluoro-3-aminobenzyl) -4-methyl-6-fluoro-7- (pyrimidin-2-yloxy) -1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of compound 1g-2-4 except that compound 4a-0-5 was used instead of compound 1 e-0-4.

¹H-NMR(CD₃OD，270MHz)δ(PPM)：2.39(3H，s)，4.03(2H，s)，6.29-6.43(1H，m)，6.69-6.78(2H，m)，7.28-7.39(3H，m)，7.68-7.72(1H，m)，7.98(1H，m).

ESI (LC/MS positive mode) m/z: 396(M + H).

Compound 1 h-2-6:

4-methyl-3- (2-methyl-3-aminobenzyl) -7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 4a-0-6 was used instead of Compound 4 a-0-4.

¹H NMR(Bruker，300MHz，CDCl₃)δ(ppm)：8.61(2H，d，J＝5.0Hz)，7.70(1H，d，J＝8.8Hz)，7.26(1H，d，J＝3.1Hz)，7.18(1H，dd，J＝2.7，8.8Hz)，7.12(1H，t，J＝4.8Hz)，6.88(1H，t，J＝7.8Hz)，6.59(1H，d，J＝7.6Hz)，6.32(1H，d，J＝7.6Hz)，4.02(2H，s)，3.73-3.63(2H，br)，2.35(3H，s)，2.22(3H，s).

MS(Micromass，Quttromicro，ESI+)m/z：373.97(M+H).

Compound 1 h-2-10:

4-methyl-3- (2-aminopyridin-4-ylmethyl) -7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1g-2-4, except that Compound 5d-0-10 was used instead of Compound 1 e-0-4.

¹H-NMR(CD₃OD，270MHz)δ(PPM)：2.36(3H，s)，3.85(2H，s)，6.32(1H，brs)，6.42(1H，d，J＝5.7Hz)，7.10-7.20(3H，m)，7.66(1H，d，J＝4.9Hz)，7.75(1H，d，J＝8.6Hz)，8.52(2H，d，J＝4.9Hz).

ESI (LC/MS positive mode) m/z: 361(M + H).

Compound 1 h-2-12:

4-methyl-3- (2-aminopyridin-4-ylmethyl) -7- (pyrimidin-2-yloxy) -6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1g-2-4, except that Compound 5d-0-12 was used instead of Compound 1 e-0-4.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.42(3H，s)，3.96(2H，s)，6.35(1H，brs)，6.53(1H，d，J＝6.5Hz)，7.13(1H，dd，J＝4.9Hz)，7.31(1H，s)，7.74(1H，s)，7.96(1H，d，J＝6.5Hz)，8.59(2H，d，J＝4.9Hz).

ESI (LC/MS positive mode) m/z: 395(M + H).

Compound 1 h-2-4F:

3- (3-amino-2-fluorobenzyl) -4-fluoromethyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 6c-2-4 was used instead of Compound 1 g-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：8.68(d，J＝4.9Hz，2H)，7.94(dd，J＝8.9，2.4Hz，1H)，7.41(d，J＝2.2Hz，1H)，7.33(t，J＝4.6Hz，1H)，7.29(dd，J＝8.7，2.2Hz，1H)，6.72(t，J＝7.6Hz，1H)，6.60(td，J＝8.1，1.6Hz，1H)，6.24(t，J＝6.2Hz，1H)，5.83(d，J＝46.2Hz，2H)，5.08(s，2H)，4.00(s，2H).

ESIMS m/z：396(M+H).

Compound 1 h-2-16:

3- { 3-fluoro-2-aminopyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 5d-0-16 was used instead of Compound 4 a-0-4.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.45-2.55(3H，m)，3.94(2H，s)，6.12(2H，brs)，6.28(1H，dd，J＝4.7Hz)，7.27(1H，dd，J＝8.6Hz，J＝2.1Hz)，7.34(1H，dd，J＝4.9Hz)，7.38(1H，d，J＝2.1Hz)，7.58(1H，d，J＝4.7Hz)，7.91(1H，d，J＝8.6Hz)，8.68(2H，d，J＝4.7Hz).

ESI (LC/MS positive mode) m/z: 479(M + H).

Compound 1 h-2-17:

3- (2-amino-3-fluoropyridin-4-ylmethyl) -6-fluoro-4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 5d-0-17 was used instead of Compound 4 a-0-4.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.45(3H，s)，3.94(2H，s)，6.13(2H，s)，6.28(1H，t，J＝5.1Hz)，7.38(1H，t，J＝4.8Hz)，7.59(1H，d，J＝5.1Hz)，7.65(1H，d，J＝6.8Hz)，7.92(1H，d，J＝11.5Hz)，7.91(1H，d，J＝11.5Hz)，8.70(2H，d，J＝4.8Hz).

ESI (LC/MS positive mode) m/z: 397(M + H).

Compound 1 h-2-19:

3- { 3-fluoro-2-aminopyridin-4-ylmethyl } -4-methyl-6-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 5d-0-19 was used instead of Compound 4 a-0-4.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.15(3H，s)，2.46(3H，s)，3.93(2H，s)，6.10(2H，brs)，6.27(1H，dd，J＝5.1Hz)，7.31(1H，t，J＝4.7Hz)，7.58(1H，d，J＝5.1Hz)，7.82(1H，s)，8.66(2H，d，J＝8.66Hz).

ESI (LC/MS positive mode) m/z: 393(M + H).

Compound 1h-2-19 Me:

3- (2-amino-3-fluoropyridin-4-ylmethyl) -4-ethyl-6-methyl-7- (pyrimidin-2-yloxy) -2-oxo substituted-2H-1-benzopyrans

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 5d-0-19Me was used instead of Compound 4 a-0-4.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：1.06(3H，brt，J＝7.4Hz)，2.16(3H，s)，2.89(2H，brq，J＝7.4Hz)，3.91(2H，s)，6.12(2H，s)，6.26(1H，t，J＝5.1Hz)，7.28-7.37(3H，m)，7.58(1H，d，J＝5.1Hz)，7.83(1H，s)，8.67(2H，d，J＝4.8Hz).

ESI (LC/MS positive mode) m/z: 407(M + H).

Compound 1 h-2-45:

4-methyl-3- (2-aminobenzyl) -7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 4a-0-45 was used instead of Compound 4 a-0-4.

¹H-NMR(Bruker，300MHz， )δ(ppm)：8.59(2H，d，J＝4.6Hz)，7.69(1H，d，J＝8.8Hz)，7.24(1H，d，J＝2.3Hz)，7.18(1H，dd，J＝2.3Hz，8.8Hz)，7.11(1H，t，J＝4.8Hz)，7.03(1H，t，J＝7.4Hz)，6.97(1H，d，J＝7.2Hz)，6.69(2H，d，J＝7.2Hz)，3.92(2H，s)，2.49(3H，s)

Compound 1 h-2-46:

4-methyl-3- (4-aminobenzyl) -7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 4a-0-46 was used instead of Compound 4 a-0-4.

1H-NMR(Bruker，300MHz， )δ(ppm)：8.59(2H，d，J＝5.0Hz)，7.67(1H，d，J＝8.8Hz)，7.22(1H，d，J＝2.3Hz)，7.15(1H，dd，J＝2.3Hz，8.8Hz)，7.10(1H，t，J＝5.0Hz)，7.05(2H，d，J＝8.4Hz)，6.61(2H，d，J＝8.4Hz)，5.30(2H，s)，3.95(2H，s)，2.45(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：359.99(M+H)

Compound 1 h-2-47:

3- (3-aminobenzyl) -4-hydroxy-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized by the same method as that for the preparation of compound 1h-1-5, except that compound 1g-2-47 was used instead of compound 1 g-1-5.

¹H NMR(270MHz，CD₃OD)δ(ppm)：8.54(d，2H，J＝4.9Hz)，7.94(d，1H，J＝8.4Hz)，7.32-7.25(m，2H)，7.20-7.10(m，4H)，7.02(m，1H)，3.89(s，2H).

ESIMS m/z：362(M+H).

Compound 1 h-2-51:

3- (3-aminophenylamino) -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 4a-0-51 was used instead of Compound 4 a-0-4.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.69(d，2H，J＝4.8Hz)，7.81(d，1H，J＝8.6Hz)，7.38(d，1H，J＝2.1Hz)，7.33(t，1H，J＝4.8Hz)，7.29-7.24(m，2H)，6.80(t，1H，J＝7.7Hz)，6.00(m，2H)，5.86(s，1H)，4.86(s，2H)，2.26(s，3H).

ESIMS m/z：361(M+H).

Compound 1 h-2-52:

3- (3-aminophenoxy) -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 5d-0-52 was used instead of Compound 4 a-0-4.

¹H-NMR(300MHz， )δ(ppm)：8.61(1H，d，J＝5.0Hz)，7.68(1H，d，J＝8.4Hz)，7.28(1H，d，J＝2.3Hz)，7.24(1H，dd，J＝2.3Hz，J＝8.4Hz)，7.12(1H，m)，7.06(1H，m)，6.38(1H，m)，6.33(2H，m)，3.69(2H，s)，2.40(3H，s)

MS(ESI+)m/z：361.99(M+H)

Compound 1 h-2-53:

3- (3-aminophenylthio) -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 5d-0-53 was used instead of Compound 4 a-0-4.

¹H-NMR(300MHz，CDCl₃)δ(ppm)：8.61(2H，d，J＝4.6Hz)，7.75(1H，d，J＝8.8Hz)，7.26(1H，m)，7.21(1H，dd，J＝2.3Hz，J＝8.8Hz)，7.13(1H，m)，7.04(1H，m)，6.64(1H，m)，6.57(1H，m)，6.50(1H，m)，3.66(2H，bs)，2.76(3H，s)

MS(ESI+)m/z：377.98(M+H)

Compound 1 h-2-74:

3- (2-amino-thiazol-4-ylmethyl) -7- (pyrimidin-2-yloxy) -4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from compound 5d-0-74 under the same conditions as in the preparation of Compound 1h-2-4 (Synthesis method 2).

¹H-NMR(Bruker(ARX-300)，DMSO- )δ(ppm)：8.68(2H，d，J＝4.5Hz)，7.88(1H，d，J＝8.4Hz)，7.35～7.31(2H，m)，7.24(1H，dd，J＝9.0Hz，J＝2.4Hz)，6.83(2H，s)，6.10(1H，s)，3.79(2H，s)，2.47(3H，s)

Compound 1 h-3-1:

4-methyl-3- (3-aminobenzyl) -7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-3-1 was used in place of Compound 1 g-1-5.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.46(3H，s)，4.00(2H，s)，6.50-6.67(3H，m)，6.92(1H，d，J＝3.8Hz)，7.05(1H，dd，J＝7.8，7.8Hz)，7.21-7.33(3H，m)，7.64(1H，d，J＝8.9Hz).

ESI (LC/MS positive mode) m/z: 365(M + H).

Compound 1 h-3-3:

4-methyl-3- (3-aminobenzyl) -7- (thiazol-2-yloxy) -6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-3-3 was used in place of Compound 1 g-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.45(3H，s)，3.83(2H，s)，4.96(2H，brs)，6.35-6.37(3H，m)，6.86-6.92(1H，m)，7.28(1H，d，J＝3.6Hz)，7.32(1H，d，J＝3.6Hz)，7.73(1H，s)，8.09(1H，s).

ESI (LC/MS positive mode) m/z: 399(M + H).

Compound 1 h-3-4:

4-methyl-3- (2-fluoro-3-aminobenzyl) -7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

(Synthesis method 1)

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-3-4 was used in place of Compound 1 g-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.44(3H，s)，3.92(2H，s)，6.24(1H，ddd，J＝1.5，7.0Hz，J_HF＝7.0Hz)，6.61(1H，ddd，J＝1.5，8.3Hz，J_HF＝8.3Hz)，6.72(1H，dd，J＝7.0，8.3Hz)，7.34-7.38(4H，m)，7.49(1H，d，J＝2.5Hz)，7.92(1H，d，J＝8.9Hz).

ESI (LC/MS positive mode) m/z: 383(M + H).

Compound 1 h-3-8:

4-methyl-3- (3-aminobenzyl) -7- (thiazol-2-yloxy) -6-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-3-8 was used in place of Compound 1 g-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.27(3H，s)，2.45(3H，s)，3.84(2H，s)，4.97(2H，s)，6.33-6.40(3H，m)，6.90(1H，dd，J＝8.2，8.2Hz)，7.27-7.31(2H，m)，7.44(1H，s)，7.84(1H，s).

ESI (LC/MS positive mode) m/z: 379(M + H).

Compound 1 h-3-19:

3- (2-amino-3-fluoropyridin-4-ylmethyl) -4, 6-dimethyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

¹H NMR(CDCl₃，270MHz)δ(ppm)：7.87(1H，s)，7.58(1H，d，J＝4.8Hz)，7.45(1H，s)，7.35-7.25(2H，m)，6.27(1H，dd，J＝4.8Hz)，6.10(2H，brs)，3.93(2H，s)，2.46(3H，s)，2.28(3H，s).

ESI (LC/MS positive mode) m/z: 398(M + H).

Compound 1h-2 a-4:

3- { 2-fluoro-3-aminobenzyl } -4-methyl-7- (5-fluoropyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized using 2-chloro-5-fluoropyrimidine instead of 2-bromopyrimidine under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2).

¹H-NMR(Bruker，300MHz，CDCl₃)δ(ppm)：8.44(2H，s)，7.69(1H，d，J＝8.8Hz)，7.21(1H，d，J＝2.7Hz)，7.14(1H，dd，J＝2.3Hz，8.8Hz)，6.81(1H，m)，6.63(1H，m)，6.55(1H，m)，4.06(2H，s)，3.70(2H，s)，2.44(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：395.85(M+H)

Compound 1h-2 b-4:

3- { 2-fluoro-3-aminobenzyl } -4-methyl-7- (4-chloropyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-2-4 (Synthesis method 2) except that 2, 4-dichloropyrimidine was used instead of 2-bromopyrimidine.

¹H-NMR(Bruker，300MHz， )δ(ppm)：8.51(1H，d，J＝5.7Hz)，7.69(1H，d，J＝8.8Hz)，7.18(1H，d，J＝2.7Hz)，7.13(1H，dd，J＝2.3Hz，8.8Hz)，6.92(1H，d，J＝5.7Hz)，6.82(1H，m)，6.64(1H，m)，6.57(1H，m)，4.07(2H，s)，3.71(2H，s)，2.46(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：411.75(M)，413.80(M+2)

Compound 1 h-5-4:

3- { 2-fluoro-3-aminobenzyl } -4-methyl-7- (2, 4-dimethoxypyrimidin-6-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that 6-chloro-2, 4-dimethoxypyrimidine was used instead of 2-bromopyrimidine.

¹H-NMR(Bruker，300MHz， )δ(ppm)：7.64(1H，d，J＝8.8Hz)，7.15(1H，d，J＝2.7Hz)，7.09(1H，dd，J＝2.3Hz，J＝8.8Hz)，6.81(1H，m)，6.64(1H，m)，6.57(1H，m)，5.86(1H，s)，4.05(2H，s)，3.97(3H，s)，3.89(3H，s)，3.70(2H，brs)，2.44(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：438.06(M+H)

Compound 1h-3 a-4:

3- { 2-fluoro-3-aminobenzyl } -4-methyl-7- (benzothiazol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-3-4 (Synthesis method 2) except that 2-chlorobenzothiazole was used instead of 2-bromothiazole.

¹H NMR(Bruker，300MHz，CDCl₃)δ(ppm)：7.72(3H，m)，7.47(1H，d，J＝2.7Hz)，7.42(1H，m)，7.32(2H，m)，6.82(1H，m)，6.64(1H，m)，6.57(1H，m)，4.07(2H，s)，3.70(2H，s)，2.45(3H，s).

MS(Micromass，Quttromicro，ESI+)m/z：433.00(M+H).

Compound 1h-1 a-4:

dimethylthiocarbamic acid 4-methyl-3- (2-fluoro-3-aminobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized using dimethylthiocarbamoyl chloride instead of 2-bromothiazole under the same conditions as in the preparation example (synthesis method 2) of the compound 1 h-3-4.

¹H-NMR(Bruker，300MHz，CDCl₃)δ(ppm)：7.64(1H，d，J＝9.5Hz)，7.06(1H，s)，7.04(1H，dd，J＝2.3Hz，J＝8.0Hz)，6.81(1H，m)，6.63(1H，m)，6.55(1H，m)，4.05(2H，s)，3.70(2H，s)，3.47(3H，s)，3.38(3H，s)，2.43(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：387.04(M+H)

Compound 1h-3 b-4:

3- (2-fluoro-3-aminobenzyl) -4-methyl-7- (5-bromothiazol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-3-4 (Synthesis method 2) except that 2, 5-dibromothiazole was used instead of 2-bromothiazole.

¹H-NMR(Bruker，300MHz， )δ(ppm)：7.66(1H，d，J＝8.8Hz)，7.29(1H，d，J＝2.7Hz)，7.21(1H，dd，J＝2.7Hz，J＝9.7Hz)，7.19(1H，s)，6.81(1H，m)，6.63(1H，m)，6.55(1H，m)，4.05(2H，s)，3.70(2H，s)，2.43(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：460.67(M)，462.75(M+2)

Compound 1h-2 a-16:

4-methyl-3- (3-fluoro-2-aminopyridin-4-ylmethyl) -7- (5-fluoropyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 5d-0-16 was used instead of Compound 4a-0-4 and 2-chloro-5-fluoropyrimidine was used instead of 2-bromopyrimidine.

¹H-NMR(Bruker，300MHz， )δ(ppm)：8.44(2H，s)，7.71(1H，d， J＝5.3Hz)，7.69(1H，d，J＝8.4Hz)，7.22(1H，d，J＝1.9Hz)，7.16(1H，dd，J＝1.9Hz，J＝8.4Hz)，6.50(1H，m)，4.55(2H，brs)，4.05(2H，s)，2.43(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：396.98(M+H)

Compound 1h-2 b-16:

4-methyl-3- (3-fluoro-2-aminopyridin-4-ylmethyl) -7- (4-chloropyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 5d-0-16 was used in place of Compound 4a-0-4 and 2, 4-dichloropyrimidine was used in place of 2-bromopyrimidine.

¹H-NMR(Bruker，300MHz， )δ(ppm)：8.52(1H，d，J＝5.3Hz)，7.73(1H，d，J＝1.9Hz)，7.71(1H，d，J＝5.3Hz)，7.21(1H，d，J＝2.7Hz)，7.15(1H，dd，J＝1.9Hz，J＝8.4Hz)，6.93(1H，d，J＝5.7Hz)，6.53(1H，m)，4.57(2H，brs)，4.06(2H，s)，2.46(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：412.98(M)，414.95(M+2)

Compound 1 h-5-16:

4-methyl-3- (3-fluoro-2-aminopyridin-4-ylmethyl) -7- (2, 4-dimethoxypyrimidin-6-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the compound 5d-0-16 in place of the compound 4a-0-4 and 2, 4-dimethoxy-6-chloropyrimidine in place of 2-bromopyrimidine under the same conditions as in the preparation example of the compound 1h-2-4 (Synthesis method 2).

¹H-NMR(Bruker，300MHz， )δ(ppm)：7.72(1H，d，J＝5.3Hz)，7.65(1H，d，J＝8.8Hz)，7.17(1H，d，J＝2.3Hz)，7.12(1H，dd，J＝2.3Hz，J＝8.8Hz)，6.52(1H，m)，5.87(1H，s)，4.57(2H，brs)，4.04(2H，s)，3.98(3H， s)，3.89(3H，s)，2.44(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：439.02(M+H)

Compound 1h-3 a-16:

4-methyl-3- (3-fluoro-2-aminopyridin-4-ylmethyl) -7- (benzothiazol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 5d-0-16 was used in place of Compound 4a-0-4 and 2-chlorobenzothiazole was used in place of 2-bromopyrimidine.

¹H NMR(Bruker，300MHz，CDCl₃)δ(ppm)：7.73(4H，m)，7.50(1H，d，J＝2.3Hz)，7.43(1H，m)，7.36(1H，dd，J＝2.7，8.8Hz)，7.33(1H，m)，6.51(1H，m)，4.58(2H，bs)，4.05(2H，s)，2.46(3H，s).

MS(Micromass，Quttromicro，ESI+)m/z：433.96(M+H).

Compound 1h-3 b-16:

4-methyl-3- (3-fluoro-2-aminopyridin-4-ylmethyl) -7- (5-bromothiazol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 5d-0-16 was used instead of Compound 4a-0-4 and 2, 5-dibromothiazole was used instead of 2-bromopyrimidine.

¹H-NMR(Bruker，300MHz， )δ(ppm)：7.71(1H，d，J＝5.3Hz)，7.68(1H，d，J＝8.8Hz)，7.31(1H，d，J＝2.3Hz)，7.24(1H，dd，J＝2.7Hz，J＝8.8Hz)，7.20(1H，s)，6.50(1H，m)，4.56(2H，s)，4.04(2H，s)，2.44(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：461.90(M)，463.90(M+2)

Compound 1h-1 a-16:

dimethylthiocarbamic acid 2-oxo-2H-3- (2-amino-3-fluoropyridin-4-ylmethyl) -4-methyl-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 5d-0-16 was used in place of Compound 4a-0-4 and dimethylthiocarbamoyl chloride was used in place of 2-bromopyrimidine.

¹H-NMR(Bruker，300MHz， )δ(ppm)：7.71(1H，d，J＝5.3Hz)，7.65(1H，d，J＝9.2Hz)，7.08(1H，s)，7.06(1H，d，J＝4.6Hz)，6.50(1H，m)，4.55(2H，brs)，4.04(2H，s)，3.47(3H，s)，3.38(3H，s)，2.43(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：388.00(M+H)

Compound 1h-1 b-1:

3- (3-aminobenzyl) -7-isobutoxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-1b-1 was used in place of Compound 1 g-1-5.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：0.98(3H，s)，1.00(3H，s)，1.95-2.12(1H，m)，2.39(3H，s)，3.79(2H，s)，3.86(2H，d，J＝6.5Hz)，4.96(2H，br.s)，6.32-6.41(3H，m)，6.82-7.00(3H，m)，7.72(1H，d，J＝9.5Hz).

ESI (LC-MS positive mode) m/z: 338(M + H).

Compound 1h-1 c-1:

3- (3-aminobenzyl) -7- (2-fluoroethoxy) -4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-1c-1 was used in place of Compound 1 g-1-5.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.40(3H，s)，3.80(2H，s)，4.27-4.32(1H，m)，4.37-4.45(1H，m)，4.66-4.71(1H，m)，4.84-4.89(1H，m)，4.96(2H，br.s)，6.32-6.39(3H，m)，6.90(1H，dd，J＝8.6、7.3Hz)，6.96-7.07(2H，m)，7.75(1H，d，J＝8.6Hz).

ESI (LC-MS positive mode) m/z: 328(M + H).

Compound 1h-1 c-3:

3- (3-aminobenzyl) -6-chloro-7- (2-fluoroethoxy) -4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-1c-3 was used in place of Compound 1 g-1-5.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.41(3H，s)，3.80(2H，s)，4.36-4.43(1H，m)，4.46-4.54(1H，m)，4.68-4.75(1H，m)，4.86-4.93(1H，m)，4.96(2H，br.s)，6.32-6.39(3H，m)，6.90(1H，dd，J＝8.6、7.0Hz)，7.29(1H，s)，7.90(1H，s).

ESI (LC-MS positive mode) m/z: 362(M + H).

Compound 1 h-11-3:

4-methyl-3- (3-aminobenzyl) -7- (thiophen-3-yl) -6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-11-3 was used in place of Compound 1 g-1-5.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：7.68(1H，s)，7.57((1H，dd，J＝3.05Hz，J＝1.14Hz)，7.34-7.39(2H，m)，7.35(1H，dd，J＝3.82hz，J＝1.14Hz)，7.06(1H，t，J＝8.01Hz)，6.64(1H，d，J＝8.01Hz)，6.60(1H，s)，6.53(1H，dd，J＝7.63Hz，J＝1.53Hz)，3.99(2H，s)，2.44(3H，s)，2.27(2H，br)

Compound 1 h-12-1:

4-methyl-3- (3-aminobenzyl) -7- (pyridin-4-yl) -2-oxo-2H-1-benzopyran

To compound 1g-12-1(23mg, 0.062mmol) was added MeOH: H₂2mL of a 9: 1 solution of O, metallic zinc (81mg, 1.2mmol) and ammonium chloride (20mg, 1.6mmol) was stirred at room temperature for 2 days. Purification by silica gel chromatography (dichloromethane: methanol 30: 1) gave the title compound (15mg, 73%).

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：8.72(2H，d，J＝6.10Hz)，7.73(1H，d，J＝8.01Hz)，7.59-7.53(4H，m)，7.06(1H，t，J＝7.63Hz)，6.66(1H，d，J＝7.63Hz)，6.62(1H，s)，6.53(1H，dd，J＝7.63Hz，J＝2.29Hz)，4.01(2H，s)，2.49(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：343.40(M+1)

Compound 1 h-16-1:

4-methyl-3- (3-aminobenzyl) -7- (thiazol-5-yl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-16-1 was used in place of Compound 1 g-1-5.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：8.82(1H，s)，8.18(1H，s)，7.64(1H，d，J＝8.01Hz)，7.52(1H，s)，7.50(1H，d，J＝8.39Hz)，7.09(1H，t，J＝7.63Hz)，6.66(1H，d，J＝7.63Hz)，6.62(1H，s)，6.53(1H，d，J＝7.63Hz)，3.99(2H，s)，2.46(3H，s)

Compound 1 h-17-1:

4-methyl-3- (3-aminobenzyl) -7- (thiazol-2-yl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-17-1 was used in place of Compound 1 g-1-5.

¹H-NMR(Bruker(ARX-300)，300MHz，DMSO- )δ(ppm)：8.02(1H，d，J＝3.05Hz)，7.94(2H，s)，7.91(1H，d，J＝3.43Hz)，7.90(1H，s)，6.91(1H，t，J＝8.01Hz)，6.40-6.36(3H，m)，4.95(2H，s)，3.86(2H，s)，2.47(3H，s)

Compound 1 h-18-1:

4-methyl-3- (3-aminobenzyl) -7- (pyridin-3-yl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-12-1, except that Compound 1g-18-1 was used instead of Compound 1 g-12-1.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：8.89(1H，d，J＝1.91Hz)，8.66(1H，dd，J＝4.96Hz，J＝1.53Hz)，7.92(1H，dt，J＝8.01Hz，J＝1.91Hz)，7.72(1H，d，J＝8.01Hz)，7.54-7.51(2H，m)，7.42(1H，dd，J＝7.63Hz，J＝0.30Hz)，7.06(1H，t，J＝8.01Hz)，6.66(1H，d，J＝8.01Hz)，6.62(1H，s)，6.52(1H，dd，J＝8.01Hz，J＝1.91Hz)，4.01(2H，s)，2.49(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：343.27(M+1)

Compound 1 h-19-3:

4-methyl-3- (3-aminobenzyl) -6-chloro-7- (3-methoxyphenyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-19-3 was used in place of Compound 1 g-1-5.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：7.69(1H，s)，7.38(1H，t，J＝7.63Hz)，7.32(1H，s)，7.09-6.96(4H，m)，6.64(1H，d，J＝7.25Hz)，6.60(1H，s)，6.52(1H，dd，J＝8.01Hz，J＝2.29Hz)，3.99(2H，s)，3.87(3H，s)，3.62(2H，bs)，2.46(3H，s)

Compound 1 h-21-3:

4-methyl-3- (3-aminobenzyl) -6-chloro-7- (5-acetylthiophen-2-yl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 1g-21-3 was used in place of Compound 1 g-1-5.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：8.79(2H，d，J＝4.96Hz)，8.17(1H，s)，7.73(1H，s)，7.46(1H，t)，7.13(2H，m)，6.96(1H，d，J＝7.63Hz)，4.06(2H，s)，2.60(3H，s)，2.41(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：424.09(M+H)

Compound 1 h-22-1:

4-methyl-3- (3-aminobenzyl) -7- (3-acetyl-phenyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-12-1, except that Compound 1g-22-1 was used instead of Compound 1 g-12-1.

¹H-NMR(Bruker(ARX-300)，300MHz，DMSO- )δ(ppm)：8.23(1H，t)，8.05(1H，d，J＝8.01Hz)，7.95(1H，d，J＝8.39Hz)，7.84(1H，d，J＝1.53Hz)，7.78(1H，dd，J＝8.01Hz)，7.65(2H，t)，6.91(1H，t)，6.43(3H，m)，4.98(2H，s)，3.85(2H，s)，2.71(3H，s)，2.50(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：384.35(M+1)

Compound 1 h-23-1:

4-methyl-3- (3-aminobenzyl) -7- (4-acetyl-phenyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-12-1, except that Compound 1g-23-1 was used instead of Compound 1 g-12-1.

MS(Micromass，Quttromicro，ESI+)m/z：413.27(M+Na)

Compound 1h-1 e-1:

trifluoromethanesulfonic acid 4-methyl-3- (3-aminobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-12-1, except that Compound 1g-1e-1 was used instead of Compound 1 g-12-1.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：7.67(1H，d，J＝8.77Hz)，7.22(2H，m)，7.05(1H，t)，6.59(3H，t，d，J＝8.39Hz)，5.29(1H，s)，4.02(2H，s)，2.46(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：414.10(M+1)

Compound 1 g-28-1:

4-methyl-3- (3-aminobenzyl) -7- (4-N, N-dimethylaminophenyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-12-1, except that Compound 1g-28-1 was used instead of Compound 1 g-12-1.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：7.65(5H，m)，6.63(2H，d，J＝8.77Hz)，6.65(2H，s，d，J＝8.39Hz)，6.53(2H，dd，J＝8.6Hz)，4.02(2H，s)，3.64(2H，bs)，3.15(6H，s)，2.43(3H，s)

Compound 1 j-1-5-1:

3- { 2-fluoro-3- (aminosulfonyl) aminobenzyl } -6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

Formic acid (754. mu.L, 10.0mmol) was added to chlorosulfonyl isocyanate (1.74mL, 20.0mmol) at 0 ℃ and stirred at room temperature for 1 hour. Methylene chloride (10mL) was added thereto, and the mixture was stirred for 2 hours. This solution (3.71mL) was added to a solution of compound 1h-1-5(2.88g, 7.42mmol) and pyridine (1.21mL, 15mmol) in dichloromethane (50mL) and stirred at room temperature for 16 h. Then, ethyl acetate was added to the reaction mixture, which was washed with a sodium carbonate aqueous solution and a saturated saline solution, and the organic layer was dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (680mg, 20%).

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.42(3H，s)，2.94(3H，s)，3.08(3H，s)，3.97(2H，s)，6.84(1H，m)，7.00(1H，dd，J＝7.8，7.8Hz)，7.10(2H，brs)，7.33(1H，m)，7.48(1H，d，J＝6.8Hz)，7.86(1H，d，J＝11.4Hz)，9.12(1H，brs).

ESI (LC/MS positive mode) m/z: 468(M +2H-Na).

Compound 1j-1-5-1 Na:

3- { 2-fluoro-3- (aminosulfonyl) aminobenzyl } -6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate sodium salt

To a mixture of the compound 1j-1-5-1 and methylene chloride was added dropwise a solution of sodium hydroxide in methanol at 1.0 equivalent at room temperature. After 30 minutes, the solvent was distilled off to obtain the title compound.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.39(3H，s)，2.94(3H，s)，3.09(3H，s)，3.88(2H，s)，5.43(1H，brs)，6.21(1H，m)，6.67(1H，m)，7.19(1H，m)，7.43(1H，d，J＝6.8Hz)，7.83(1H，d，J＝11.2Hz).

ESI (LC/MS positive mode) m/z: 468(M +2H-Na).

Compound 1 j-1-5-1K:

dimethylcarbamic acid 3- (2-fluoro-3- (aminosulfonyl) aminobenzyl) -6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester potassium salt

The title compound was synthesized under the same conditions as in the preparation of Compound 1j-1-5-1Na, using KOH instead of NaOH.

¹H NMR(CD₃OD)δ(ppm)：7.67(1.0H，d，J＝11.0Hz)，7.40-7.25(2H，m)，6.88(1.0H，t，J＝7.9Hz)，6.64(1.0H，t，J＝7.9Hz)，4.04(2.0H，s)，3.15(3H，s)，3.03(3H，s)，2.44(3H，s).

ESI (LC/MS positive mode) m/z: 468(M +2H-K).

Compound 1 j-1-1-1:

3- {3- (aminosulfonyl) aminobenzyl } -4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-1-1 was used instead of Compound 1 h-1-5.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.43(3H，s)，3.02(3H，s)，3.12(3H，s)，3.98(2H，s)，6.87-7.09(5H，m)，7.18(1H，dd，J＝8.1Hz)，7.60(1H，d，J＝8.1Hz).

ESI (LC/MS positive mode) m/z: 432(M + H).

Compound 1 j-1-2-1:

3- {3- (aminosulfonyl) aminobenzyl } -6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-1-2 was used instead of Compound 1 h-1-5.

¹H-NMR(CD₃OD，270MHz)δ(PPM)：2.46(3H，s)，3.01(3H，s)，3.15(3H，s)，4.02(2H，s)，6.95(1H，d，J＝7.3Hz)，7.06-7.22(3H，m)，7.27(1H，d，J＝6.8Hz)，7.64(1H，d，J＝11.1Hz).

ESI (LC/MS positive mode) m/z: 450(M + H).

Compound 1 j-1-3-1:

3- {3- (aminosulfonyl) aminobenzyl } -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-1-3 was used instead of Compound 1 h-1-5.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.42(3H，s)，3.05(3H，s)，3.22(3H，s)，3.95(2H，s)，6.80-7.20(4H，m)，7.25(1H，s)，7.60(1H，s).

ESI (LC/MS positive mode) m/z: 466(M + H).

Compound 1 j-1-4-1:

dimethylcarbamic acid 3- (3-aminosulfonylamino-2-fluoro-benzyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-1-4 was used instead of Compound 1 h-1-5.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.44(3H，s)，2.93(3H，s)，3.07(3H，s)，3.97(2H，s)，6.82(1H，brt，J＝8.6Hz)，6.99(1H，brt，J＝8.6Hz)，7.19(1H，dd，J＝8.9，2.3Hz)，7.25(1H，d，J＝2.3Hz)，7.33(1H，brt，J＝8.6Hz)，7.86(1H，d，J＝8.9Hz).

ESI (LC-MS positive mode) m/z: 450(M + H).

Compound 1j-1-4-1 Na:

3- (3- (aminosulfonyl) amino-2-fluoro-benzyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl ester sodium salt of dimethylcarbamic acid

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-1-4-1 in place of Compound 1 j-1-5-1.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.41(3H，s)，2.93(3H，s)，3.07(3H，s)，3.88(2H，s)，6.18-6.23(1H，m)，6.67(1H，dd，J＝7.6，7.9Hz)，7.14-7.22(2H，m)，7.24(1H，d，J＝2.3Hz)，7.83(1H，d，J＝8.6Hz).

ESI (LC/MS positive mode) m/z: 450(M +2H-Na).

Compound 1 j-1-7-1:

3- {3- (aminosulfonyl) aminobenzyl } -6-iodo-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-1-7 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.45(3H，s)，2.96(3H，s)，3.13(3H，s)，3.93(2H，s)，6.83(1H，d，J＝8.1Hz)，6.94(1H，s)，7.02-7.05(2H，m)，7.16(1H，dd，J＝8.1，8.1Hz)，7.38(1H，s)，8.24(1H，s).

ESI (LC/MS positive mode) m/z: 558(M + H).

Compound 1j-1-7-1 Na:

3- (3- (sulfamoylamino) benzyl) -6-iodo-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate sodium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-1-7-1 in place of Compound 1 j-1-5-1.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.44(3H，s)，2.96(3H，s)，3.13(3H，s)，3.83(2H，s)，6.36(1H，d，J＝7.6Hz)，6.68(1H，s)，6.77(1H，d，J＝7.9Hz)，6.88(1H，dd，J＝7.6，7.9Hz)，7.35(1H，s)，8.20(1H，s).

ESI (LC/MS positive mode) m/z: 558(M +2H-Na).

Compound 1 j-1-7-1K:

dimethylcarbamic acid 3- (3- (sulfamoylamino) benzil) -6-iodo-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester potassium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-1-7-1 was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.45(3H，s)，2.96(3H，s)，3.13(3H，s)，3.85(2H，s)，6.48(1H，d，J＝7.8Hz)，6.74(1H，s)，6.83(1H，d，J＝7.6Hz)，6.95(1H，dd，J＝7.6，7.8Hz)，7.36(1H，s)，8.21(1H，s).

ESI (LC/MS positive mode) m/z: 558(M +2H-K).

Compound 1 j-1-8-1:

3- {3- (aminosulfonyl) aminobenzyl } -6-methyl-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-1-8 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.22(3H，s)，2.45(3H，s)，2.94(3H，s)，3.09(3H，s)，3.93(2H，s)，6.83(1H，d，J＝8.1Hz)，6.95(1H，s)，7.02-7.05(2H，m)，7.16(1H，dd，J＝8.1，8.1Hz)，7.21(1H，s)，7.75(1H，s).

ESI (LC/MS positive mode) m/z: 446(M + H).

Compound 1 j-1-9-1:

3- {3- (aminosulfonyl) aminobenzyl } -6-cyano-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-1-9 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.97(3H，s)，3.12(3H，s)，3.94(2H，s)，6.84(1H，d，J＝8.1Hz)，6.97(1H，s)，7.02-7.05(2H，m)，7.16(1H，dd，J＝8.1，8.1Hz)，7.60(1H，s)，8.46(1H，s).

One peak of CH3 overlapped the DMSO peak.

ESI (LC/MS positive mode) m/z: 457(M + H).

Compound 1 j-1-4-1F:

3- (3-aminosulfuryl) dimethylcarbamic acidAcylamino-2-fluoro-benzyl) -4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester

Chlorosulfonyl isocyanate (0.150mL) and formic acid (0.065mL) were mixed at 0 ℃ and then stirred at room temperature for 1 hour. To the mixture was added dichloromethane (1.2mL) and dissolved, and further stirred at room temperature for 4 hours. From this solution, 0.060mL was taken, and added to a solution of 3- (3-amino-2-fluoro-benzyl) -4-fluoromethyl-2-oxo-2H-1-chromen-7-yl dimethylcarbamate (compound 1H-1-4F) (25.2mg) in dichloromethane (1.0 mL)/pyridine (0.0065mL) at 0 ℃ and then stirred at room temperature for 3 hours. Then, saturated sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography (aminated gel) (dichloromethane: methanol ═ 90: 10) to give the title compound (12.0 mg).

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.93(3H，s)，3.07(3H，s)，4.06(2H，s)，5.8 4(2H，d，J＝45.8Hz)，6.84(1H，brt，J＝7.7Hz)，7.01(1H，brt，J＝7.7Hz)，7.12(1H，brs)，7.29-7.40(2H，m)，7.92(1H，dd，J＝8.9，2.1Hz)，9.15(1H，brs).

ESI (LC-MS positive mode) m/z: 468(M + H).

Compound 1 j-1-3-1F-otherwise:

3- {3- ((tert-Butoxycarbonyl) aminosulfonyl) aminobenzyl } -6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

To a solution of 3- (3-aminobenzyl) -6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate (compound 1H-1-3F) (33mg, 0.082mmol) in anhydrous dichloromethane (1.0mL) was added triethylamine (34. mu.L, 0.025mol) and N- (tert-butoxycarbonyl) -N- {4- (dimethyldiazoniaylidene)) -1, 4-dihydropyridin-1-ylsulfonyl } azoalkylate (azanide) (49mg, 0.16mmol) in this order, and stirred at room temperature overnight. After that, the reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with saturated brine and dried over magnesium sulfate. Subsequently, a crude solid was obtained by concentration under reduced pressure, which was purified by fractionation using TLC (ethyl acetate: hexane, 1: 2) to obtain the title compound (30mg, 63%) as a white powder.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：8.07(s，1H)，7.56(s，1H)，7.20-6.80(m，6H)，5.86(d，J＝46.2Hz，2H)，4.03(s，2H)，3.11(s，3H)，2.95(s，3H)，1.29(s，9H).

ESIMS m/z：528(M-tBu+2H).

Compound 1 j-1-3-1F:

3- {3- (aminosulfonyl) aminobenzyl } -6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

To a solution of 3- {3- ((tert-butoxycarbonyloxy) aminosulfonyl) aminobenzyl } -6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate (compound 1 j-1-3-1F-others) (23mg, 0.039mmol) in anhydrous dichloromethane (1.0mL) was added trifluoroacetic acid (0.1mL) and stirred at room temperature for 3 hours. Thereafter, the reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic extract was washed with saturated brine and dried over magnesium sulfate. Subsequently, a crude solid was obtained by concentration under reduced pressure, which was purified by fractionation using TLC (ethyl acetate: hexane ═ 1: 1) to give the title compound (19mg, 100%) as a pale yellow powder.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：9.40(brs，1H)，8.07(s，1H)，7.56(s，1H)，7.17(t，J＝8.0Hz，1H)，7.05(s+d，3H)，6.96(s，1H)，6.82(d，J＝7.3Hz，1H)，5.86(d，J＝46.2Hz，2H)，4.03(s，2H)，3.11(s，3H)，2.95(s，3H).

ESIMS m/z：484(M+H).

Compound 1 j-1-1-1F:

3- {3- (aminosulfonyl) aminobenzyl } -4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1j-1-5-1 and the compound 1h-1-1F in place of the compound 1 h-1-5.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.93(3H，s)，3.07(3H，s)，4.02(2H，s)，5.83(2H，d，J＝46.0Hz)，6.81(1H，brd，J＝7.4Hz)，6.96(1H，brs)，7.05(3H，m)，7.15(1H，d，J＝7.6Hz)，7.22(1H，dd，J＝8.7，2.3Hz)，7.30(1H，d，J＝2.3Hz)、7.91(1H，dd，J＝8.7，2.3Hz)、9.39(1H，brs).

ESI (LC-MS positive mode) m/z: 450(M + H).

Compound 1 j-1-2-1F:

3- {3- (aminosulfonyl) aminobenzyl } -6-fluoro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-1-2F was used instead of Compound 1 h-1-5.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.94(3H，s)，3.09(3H，s)，4.03(2H，s)，5.82(2H，d，J＝46.0Hz)，6.81(1H，d，J＝8.1Hz)，6.96(1H，s)，7.05(2H，m)，7.17(1H，t，J＝7.7Hz)，7.54(1H，d，J＝6.9Hz)，7.89(1H，d，J＝9.7Hz)，9.36(1H，brs).

ESI (LC-MS positive mode) m/z: 468(M + H).

Compound 1j-1-3-1 OMe:

3- {3- (aminosulfonyl) aminobenzyl } -6-chloro-4-methoxymethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized by the same method as that for the production of compound 1j-1-5-1, except that compound 7d-1-3OMe was used instead of compound 1 h-1-5.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：9.38(s，1H)，8.01(s，1H)，7.50(s，1H)，7.17(t，1H，J＝8.0Hz)，7.06-6.95(m，4H)，6.82(d，1H，J＝7.3Hz)，4.72(s，2H)，4.00(s，2H)，3.34(s，3H)，3.10(s，3H)，2.95(s，3H).

ESIMS m/z：496(M+H).

Compound 1j-1-36-1

Dimethylcarbamic acid 3- { (3-aminosulfonyl) amino-4-fluorobenzyl) } -4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

Compound 1j-1-1-1300mg (0.70mmol) and N, N-difluoro-2, 2' -bipyridinium bis (tetrafluoroborate) (256mg, 0.70mmol) were stirred in acetonitrile at 50 ℃ for 10 hours. Silica gel chromatography was performed using a mixed solvent of ethyl acetate and hexane, whereby the title compound was obtained.

¹H-NMR(270MHz，THF-d₈)δ(ppm)：

2.96(3H，s)，3.08(3H，s)，4.00(2H，s)，6.29(2H，br)，6.96(2H，m)，7.10(2H，m)，7.58(1H，d，J＝8.2Hz)，7.72(1H，d、J＝8.6Hz)，8.30(1H，br).

One of the methyl groups overlaps with the solvent peak.

ESI (LC-MS positive mode) m/z: 450(M + H).

Compound 1j-1-37-1

Dimethylcarbamic acid 3- { (3-aminosulfonyl) amino-6-fluorobenzyl) } -4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

As an additional component of column chromatography, the title compound was obtained from the reaction mixture of compound 1 j-1-36-1.

¹H-NMR(270MHz，CD₃OD)δ(ppm)：2.50(3H，s)，

3.03(3H，s)，3.15(3H，s)，4.06(2H，s)，6.99(2H，m)，7.20(3H，m)，7.83(1H，dd，J＝8.6Hz，0.7Hz).

ESI (LC-MS positive mode) m/z: 450(M + H).

Compound 1j-1-38-1

3- (3- (aminosulfonyl) aminobenzyl) -6-carbamoyl-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-1-38 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.90(3H，s)，3.05(3H，s)，3.95(2H，s)，6.83(1H，d，J＝7.4Hz)，6.95-7.08(4H，m)，7.17(1H，dd，J＝7.4，8.1Hz)，7.29(1H，s)，7.50(1H，brs)，7.81(1H，brs)，8.00(1H，s)，9.37(1H，brs)，(CH₃Overlap with the peak of DMSO. )

ESI (LC/MS positive mode) M/z 475(M + H)

Compound 1j-1-39-1

3- (3- (aminosulfonyl) aminobenzyl) -4-methyl-2-oxo-6-trimethylsilylethynyl-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-1-39 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：0.23(9H，s)，2.46(3H，s)，2.94(3H，s)，3.10(3H，s)，3.93(2H，s)，6.83(1H，d，J＝7.8Hz)，6.93-7.09(4H，m)，7.16(1H，t，J＝7.8Hz)，7.15(1H，s)，7.70(1H，s)，9.13(1H，brs)

ESI (LC/MS positive mode) M/z 528(M + H)

Compound 1j-1-40-1

3- (3- (aminosulfonyl) aminobenzyl) -6-ethynyl-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-1-40 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.46(3H，s)，2.94(3H，s)，3.09(3H，s)，3.93(2H，s)，4.45(1H，s)，6.84(1H，d，J＝7.4Hz)，6.96(1H，s)，6.96-7.12(3H，m)，7.16(1H，t，J＝7.9Hz)，7.38(1H，s)，7.99(1H，s)，9.36(1H，brs)

ESI (LC/MS positive mode) M/z 456(M + H)

Compound 1j-1-72-1

Dimethylcarbamic acid 3- (3- (aminosulfonyl) aminobenzyl) -4-methyl-2-oxo-2H-pyrano [2, 3-b]Pyridin-7-yl esters

The title compound was synthesized using the same conditions as in the preparation example of compound 1j-1-5-1, but using dimethyl-carbamic acid 3- (3-amino-benzyl) -4-methyl-2-oxo-2H-pyrano [2, 3-b ] pyridin-7-yl ester (compound 1H-1-72) instead of compound 1H-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.47(3H，s)，2.95(3H，s)，3.06(3H，s)，3.94(2H，s)，6.85(1H，d，J＝7.6Hz)，6.90-7.22(1H，brs)，6.97(1H，s)，7.04(1H，d，J＝7.8Hz)，7.17(1H，dd，J＝7.6，7.8Hz)，7.27(1H，d，J＝8.1Hz)，8.43(1H，d，J＝8.1Hz)

ESI (LC/MS positive mode) M/z 433(M + H)

Compound 1j-1d-1

Pyrrolidine-1-carboxylic acid 3- (3- (aminosulfonyl) aminobenzyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1j-1-5-1 and the compound 1h-1d-1 in place of the compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：1.84-1.94(4H，m)，2.46(3H，s)，3.36(2H，t，J＝6.6Hz)，3.52(2H，t，J＝6.6Hz)，3.93(2H，s)，6.84(1H，d，J＝7.3Hz)，6.94-7.08(4H，m)，7.13-7.21(2H，m)，7.26(1H，d，J＝2.2Hz)，7.86(1H，d，J＝8.7Hz)

ESI (LC/MS positive mode) M/z 458(M + H)

Compound 1 j-2-4-1:

3- { 2-fluoro-3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-2-4 was used instead of Compound 1 h-1-5.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.46(3H，s)，3.99(2H，s)，6.80-6.88(1H，m)，6.97-7.05(1H，m)，7.06(2H，br.s)，7.28(1H，dd，J＝8.9，2.3Hz)，7.30-7.38(2H，m)，7.38(1H，d，J＝2.3Hz)，7.60(1H，d，J＝8.9Hz)，8.69(2H，d，J＝4.9Hz)，9.13(1H，br.s).

ESI (LC-MS positive mode) m/z: 457(M + H).

Compound 1j-2-4-1 Na:

3- { 2-fluoro-3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran sodium salt

The title compound was synthesized by using the same conditions as in the preparation of Compound 1j-1-5-1Na, but using Compound 1j-2-4-1 in place of Compound 1 j-1-5-1.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.43(3H，s)，3.89(2H，s)，6.12-6.21(1H，m)，6.60-6.70(1H，m)，7.13-7.29(2H，m)，7.33(1H，t，J＝4.8Hz)，7.36(1H，d，J＝2.3Hz)，7.88(1H，d，J＝8.9Hz)，8.69(2H，d，J＝4.8Hz).

ESI (LC-MS positive mode) m/z: 457(M +2H-Na).

Compound 1 j-2-4-1K:

3- (3-sulfamoylamino-2-fluorobenzyl) -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran potassium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-2-4-1 was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.44(3H，s)，3.91(2H，s)，6.27-6.32(1H，m)，6.73(1H，dd，J＝7.7，7.9Hz)，7.18-7.27(2H，m)，7.33(1H，t，J＝4.8Hz)，7.37(1H，d，J＝2.3Hz)，7.89(1H，d，J＝8.9Hz)，8.69(1H，d，J＝4.8Hz).

ESI (LC/MS positive mode) m/z: 457(M +2H-K).

Compound 1 j-3-1-1:

3- {3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-3-1 was used instead of Compound 1 h-1-5.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.49(3H，s)，4.04(2H，s)，6.92(1H，d，J＝3.8Hz)，7.04-7.09(3H，m)，7.11-7.14(1H，m)，7.22-7.31(3H，m)，7.67(1H，d，J＝8.9Hz).

ESI (LC/MS positive mode) m/z: 444(M + H).

Compound 1 j-3-3-1:

3- {3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-3-3 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：3.95(2H，s)，6.84(1H，d，J＝6.9Hz)，6.97(1H，s)，7.02-7.05(2H，m)，7.17(1H，dd，J＝6.9，6.9Hz)，7.29(1H，d，J＝3.7Hz)，7.34(1H，d，J＝3.7Hz)，7.75(1H，s)，8.12(1H，s).

CH₃The peaks of (a) and DMSO overlap.

ESI (LC/MS positive mode) m/z: 478(M + H).

Compound 1 j-3-4-1:

3- { 2-fluoro-3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-3-4 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.46(3H，s)，3.98(2H，s)，6.82-6.87(1H，m)，6.98-7.04(1H，m)，7.10(1H，brs)，7.31-7.39(4H，m)，7.49(1H，d，J＝2.0Hz)，7.95(1H，d，J＝8.9Hz).

ESI (LC/MS positive mode) m/z: 462(M + H).

Compound 1j-3-4-1 Na:

3- (3-sulfamoylamino-2-fluorobenzyl) -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran sodium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-3-4-1 in place of Compound 1 j-1-5-1.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.42(3H，s)，3.89(2H，s)，6.20-6.25(1H，m)，6.68(1H，dd，J＝7.9，8.1Hz)，7.19(1H，dd，J＝8.2，8.4Hz)，7.33-7.37(3H，m)，7.48(1H，d，J＝2.5Hz)，7.92(1H，d，J＝8.9Hz).

ESI (LC/MS positive mode) m/z: 462(M +2H-Na).

Compound 1 j-3-4-1K:

3- (3-sulfamoylamino-2-fluorobenzyl) -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran potassium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-3-4-1 was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.44(3H，s)，3.92(2H，s)，6.39-6.45(1H，m)，6.79(1H，dd，J＝7.1，8.1Hz)，7.24(1H，dd，J＝7.9，8.1Hz)，7.34-7.38(3H，m)，7.48(1H，d，J＝2.4Hz)，7.92(1H，d，J＝8.9Hz).

ESI (LC/MS positive mode) m/z: 462(M +2H-K).

Compound 1 j-3-8-1:

3- {3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -6-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-3-8 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.26(3H，s)，2.46(3H，s)，3.93(2H，s)，6.83(1H，d，J＝7.7Hz)，6.93-7.10(3H，m)，7.16(1H，dd，J＝7.7，7.7Hz)，7.26-7.30(2H，m)，7.44(1H，s)，7.85(1H，s).

ESI (LC/MS positive mode) m/z: 458(M + H).

Compound 1 j-3-6-1:

3- { 2-chloro-3- (aminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -2-oxo substituted-2H-1-benzopyrans

In the synthesis of compound 1j-3-4-1, the title compound was isolated as a by-product thereof.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.39(3H，s)，4.03(2H，s)，6.79(1H，d，J＝6.8Hz)，7.12-7.20(3H，m)，7.35-7.44(4H，m)，7.52(1H，d，J＝2.5Hz)，7.96(1H，d，J＝9.2Hz)，8.66(1H，s).

ESI (LC/MS positive mode) m/z: 478(M + H).

Compound 1 j-16-1-1:

4-methyl-3- (3- (aminosulfonyl) aminobenzyl) -7- (thiazol-5-yl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-16-1 was used instead of Compound 1 h-1-5.

¹H-NMR(Bruker(ARX-300)，300MHz，DMSO- )δ(ppm)：9.17(1H，s)，8.53(1H，s)，7.89(1H，d，J＝8.39Hz)，7.79(1H，s)，7.68(1H，dd，J＝8.39Hz，J＝1.91Hz)，7.17(1H，t，J＝7.63Hz)，7.03(1H，d，J＝9.54Hz)，6.99(1H，s)，6.84(1H，d，J＝7.63Hz)，3.95(2H，s)，2.47(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：450.02(M+Na)

Compound 1 j-17-1-1:

4-methyl-3- (3- (aminosulfonyl) aminobenzyl) -7- (thiazol-2-yl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-17-1 was used instead of Compound 1 h-1-5.

¹H-NMR(Bruker(ARX-300)，300MHz，DMSO- )δ(ppm)：8.03(1H，d，J＝3.05Hz)，7.96(2H，s)，7.92(2H，s)，7.17(1H，t，J＝6.87Hz)，7.06-6.99(3H，m)，6.86(1H，dd，J＝8.39Hz，J＝1.91Hz)，3.95(2H，s)，2.50(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：449.88(M+Na)

Compound 1 j-20-1-1:

4-methyl-3- (3- (aminosulfonyl) aminobenzyl) -7- (1-methyl-1H-imidazol-2-yl) -2-oxo-2H-1-benzopyran

Compound 1H-20-1 (4-methyl-3- (3-aminobenzyl) -7- (1-methyl-1H-imidazol-2-yl) -2-oxo-2H-1-benzopyran) was synthesized using the same conditions as in the preparation example of Compound 1H-1-5, except that Compound 1g-20-1 was used in place of Compound 1 g-1-5.

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-20-1 was used instead of Compound 1 h-1-5.

¹H-NMR(Bruker(ARX-300)，300MHz，DMSO- )δ(ppm)：7.93(1H，d，J＝8.39Hz)，7.75(1H，d，J＝8.39Hz)，7.70(1H，s)，7.34(1H，s)，7.17(1H，t，J＝7.63Hz)，7.05(1H，s)，7.03(1H，d，J＝6.10Hz)，6.99(1H，s)，6.84(1H，d，J＝7.63Hz)，3.97(2H，s)，3.85(3H，s)，2.50(3H，s)，

MS(Micromass，Quttromicro，ESI+)m/z：424.95(M+1)

Compound 1 j-32-1-1:

4-methyl-3- (3- (aminosulfonyl) aminobenzyl) -7- (3-methyl-3H-imidazol-4-yl) -2-oxo-2H-1-benzopyran

Compound 1H-32-1 (4-methyl-3- (3-aminobenzyl) -7- (3-methyl-3H-imidazol-4-yl) -2-oxo-2H-1-benzopyran) was synthesized using the same conditions as in the preparation example of Compound 1H-1-5, except that Compound 1g-32-1 was used instead of Compound 1 g-1-5.

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-1, except that Compound 1h-32-1 was used instead of Compound 1 h-1-5.

¹H-NMR(Bruker(ARX-300)，300MHz，DMSO- )δ(ppm)：9.34(1H，s)，7.89(1H，d，J＝8.7Hz)，7.78(1H，s)，7.54(2H，m)，7.27(1H，s)，7.17(1H，t，J＝8.1Hz)，7.02(4H，m)，6.85(1H，d，J＝7.8Hz)，3.95(2H，s)，3.78(2H，s)，2.48(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：425.01(M+1)

Compound 1 j-1-5-2:

dimethylcarbamic acid 6-fluoro-4-methyl-3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl ester

To a solution of compound 1h-1-5(26mg, 0.07mmol) in acetonitrile (4mL) was added N- (N-methylsulfamoyl) -2-oxazolidinone (27.0mg, 0.15mmol), and the mixture was stirred at 80 ℃ for 18 hours. Then, ethyl acetate was added to the reaction solution, which was washed with a sodium carbonate aqueous solution and a saturated saline solution, and the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (14.7mg, 45%).

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.43(3H，s)，2.53(3H，d，J＝ 5.1Hz)，2.94(3H，s)，3.09(3H，s)，3.98(2H，s)，6.88(1H，dd，J＝6.3，7.9Hz)，7.01(1H，dd，J＝7.9，7.9Hz)，7.22(1H，q，J＝5.1Hz)，7.27(1H，dd，J＝9.6，8.2Hz)，7.48(1H，d，J＝6.8Hz)，7.86(1H，d，J＝11.4Hz)，9.38(1H，s).

ESI (LC/MS positive mode) m/z: 482(M + H).

Compound 1 j-1-3-2:

3- (3- (N- (methylsulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The corresponding sulfamoyl chloride was prepared by dissolving sulfonyl chloride (2.04mL, 24.8mmol) in dichloromethane (120mL), adding methylamine in THF (11.64mL, 23.3mmol) and dimethylaminopyridine (also referred to as "DMAP" in this specification) (2.84g, 23.3mmol) at-78 ℃, and stirring at room temperature for 2 hours. To the reaction solution were added 3- (3-aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate (compound 1H-1-3) (3.0g, 7.76mmol), pyridine (3.2mL) and dichloromethane (60mL), and stirred at room temperature overnight. Thereafter, water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (540 mg).

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.44(3H，s)，2.68(3H，d，J＝5.1Hz)，3.05(3H，s)，3.17(3H，s)，4.02(2H，s)，4.57(1H，m)，6.54(1H，br)，6.90-7.00(2H，m)，7.09(1H，brs)，7.19-7.30(1H，m)，7.66(1H，s).

ESI (LC/MS positive mode) m/z: 480(M + H).

Compound 1j-1-3-2 Na:

dimethylcarbamic acid 6-chloro-4-methyl-3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl ester sodium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-1-3-2 instead of Compound 1 j-1-5-1.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.28(3H，s)，2.43(3H，s)，2.95(3H，s)，3.11(3H，s)，3.80(2H，s)，4.78(1H，br)，6.29(1H，d，J＝8.1Hz)，6.66(1H，brs)，6.73(1H，d，J＝8.1Hz)，6.82(1H，dd，J＝8.1，8.1Hz)，7.46(1H，s)，7.97(1H，s).

ESI (LC/MS positive mode) m/z: 480(M +2H-Na).

Compound 1 j-1-3-2K:

dimethylcarbamic acid 3- (3- (N-methylsulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester potassium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-1-3-2 was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

¹H NMR(CD₃OD)δ(ppm)：7.91(1H，d，J＝5.6Hz)，7.32(1H，s)，7.14-6.98(3H，m)，6.77(1H，d，J＝7.4Hz)，4.02(2H，s)，3.18(3H，s)，3.02(3H，s)，2.53(3H，s)，2.48(3H，s).

ESI (LC/MS positive mode) m/z: 480(M +2H-K).

Compound 1 j-1-1-2:

dimethyl carbamic acid 4-methyl-3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-3-2, except that Compound 1h-1-1 was used instead of Compound 1 h-1-3.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.44(3H，s)，2.64(3H，d，J＝5.1Hz)，3.08(3H，s)，3.17(3H，s)，4.01(2H，s)，4.55-4.65(1H，m)，6.54-7.30(6H，m)，7.59(1H，d，J＝5.4Hz).

ESI (LC/MS positive mode) m/z: 446(M + H).

Compound 1j-1-1S 3-2:

4-methyl-3- {3- (methylaminosulfonyl) amino dimethylcarbamato acid Benzyl } -2-thio-) 2H-1-benzopyran-7-yl substituted ester

Compound 1j-1-1 to 250 mg (0.11mmol) was dissolved in 1, 4-dioxane, 30mg (0.07mmol) of Lawesson's reagent was added thereto, and the mixture was refluxed under nitrogen atmosphere for 4 hours.

The reaction solution was purified by HPLC to obtain 5mg (10%) of Compound 1j-1-1S3-2 as a yellow powder.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.42(6H，s)，2.95(3H，s)，3.08(3H，s)，4.40(2H，s)，6.83(1H，d，J＝7.6Hz)，6.96(1H，s)，7.02(1H，d，J＝7.7Hz)，7.16(1H，dd，J＝7.7、7.6Hz)，7.22(1H，brs)，7.30(1H，dd，J＝9.0、2.0Hz)，7.49(1H，d，J＝2.0Hz)，7.96(1H，d，J＝9.0Hz)，9.53(1H，brs)

ESI (LC-MS positive mode) M/z 462(M + H)

Compound 1 j-1-2-2:

dimethylcarbamic acid 6-fluoro-4-methyl-3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-1-2 was used instead of Compound 1 h-1-5.

¹H-NMR(CD₃OD，270MHz)δ(PPM)：2.47(3H，s)，2.50(3H，s)，3.02(3H，s)，3.15(3H，s)，4.03(2H，s)，6.93(1H，d，J＝7.8Hz)，7.03-7.13(2H，m)，7.19(1H，dd，J＝7.8，7.8Hz)，7.29(1H，d，J＝6.8Hz)，7.66(1H，d，J＝11.0Hz).

ESI (LC/MS positive mode) m/z: 464(M + H).

Compound 1 j-1-4-2:

dimethylcarbamic acid 3- (3-methylaminosulfonylamino-2-fluoro-benzyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-1-4 was used instead of Compound 1 h-1-5.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.44(3H，s)，2.93(3H，s)，3.07(3H，s)，3.98(2H，s)，6.87(1H，brt，J＝7.6Hz)，7.01(1H，t，J＝7.6Hz)，7.15-7.32(4H，m)，7.86(1H，d，J＝8.7Hz)，9.37(1H，brs).

CH₃Overlaps with the peak of DMSO.

ESI (LC-MS positive mode) m/z: 464(M + H).

Compound 1j-1-4-2 Na:

3- (3- (N-Methylsulfamoyl) amino-2-fluorobenzyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate sodium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-1-4-2 instead of Compound 1 j-1-5-1.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.35(3H，s)，2.41(3H，s)，2.93(3H，s)，3.07(3H，s)，3.88(2H，s)，6.20-6.25(1H，m)，6.66(1H，dd，J＝7.7，7.9Hz)，7.14-7.21(2H，m)，7.24(1H，d，J＝2.3Hz)，7.83(1H，d，J＝8.6Hz).

ESI (LC/MS positive mode) m/z: 464(M +2H-Na).

Compound 1 j-1-7-2:

dimethylcarbamic acid 6-iodo-4-methyl-3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2 except that Compound 1h-1-7 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.43(3H，d，J＝2.7Hz)，2.45(3H，s)，2.96(3H，s)，3.13(3H，s)，3.93(2H，s)，6.86(1H，d，J＝8.1Hz)，6.98-7.03(2H，m)，7.14-7.23(2H，m)，7.38(1H，s)，8.24(1H，s).

ESI (LC/MS positive mode) m/z: 572(M + H).

Compound 1j-1-7-2 Na:

3- (3- (N-Methylsulfamoyl) amino-benzyl) -6-iodo-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate sodium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-1-7-2 instead of Compound 1 j-1-5-1.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.34(3H，s)，2.45(3H，s)，2.96(3H，s)，3.13(3H，s)，3.86(2H，s)，6.52(1H，d，J＝7.7Hz)，6.79(1H，s)，6.85(1H，d，J＝7.8Hz)，6.96(1H，dd，J＝7.7，7.8Hz)，7.36(1H，s)，8.22(1H，s).

ESI (LC/MS positive mode) m/z: 572(M +2H-Na).

Compound 1 j-1-7-2K:

dimethylcarbamic acid 3- (3- (N-methylsulfamoyl) amino-benzyl) -6-iodo-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester potassium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-1-7-2 was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.36(3H，s)，2.42(3H，s)，2.96(3H，s)，3.14(3H，s)，3.88(2H，s)，6.61(1H，d，J＝7.6Hz)，6.84(1H，s)，6.89(1H，d，J＝8.1Hz)，7.02(1H，dd，J＝7.6，8.1Hz)，7.37(1H，s)，8.22(1H，s).

ESI (LC/MS positive mode) m/z: 572(M +2H-K).

Compound 1 j-1-8-2:

dimethylcarbamic acid 6-methyl-4-methyl-3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2 except that Compound 1h-1-8 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.23(3H，s)，2.42(3H，d，J＝5.4Hz)，2.46(3H，s)，2.94(3H，s)，3.10(3H，s)，3.93(2H，s)，6.86(1H，d，J＝8.1Hz)，7.00-7.04(2H，m)，7.14-7.22(3H，m)，7.75(1H，s).

ESI (LC/MS positive mode) m/z: 460(M + H).

Compound 1j-1-8-2 Na:

3- (3- (N-Methylsulfamoyl) amino-benzyl) -4, 6-dimethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate sodium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-1-8-2 instead of Compound 1 j-1-5-1.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.22(3H，s)，2.32(3H，s)，2.44(3H，s)，2.94(3H，s)，3.09(3H，s)，3.84(2H，s)，6.44(1H，d，J＝7.4Hz)，6.75(1H，s)，6.81(1H，d，J＝8.1Hz)，6.91(1H，dd，J＝7.4，8.1Hz)，7.20(1H，s)，7.72(1H，s).

ESI (LC/MS positive mode) m/z: 460(M +2H-Na).

Compound 1 j-1-8-2K:

3- (3- (N-methylsulfamoyl) amino dimethylcarbamate-benzyl) -4, 6-dimethyl-2-oxo-2H-1-benzopyran-7-yl ester potassium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-1-8-2 was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.22(3H，s)，2.33(3H，s)，2.44(3H，s)，2.94(3H，s)，3.09(3H，s)，3.84(2H，s)，6.48(1H，d，J＝7.5Hz)，6.78(1H，s)，6.83(1H，d，J＝8.3Hz)，6.93(1H，dd，J＝7.5，8.3Hz)，7.19(1H，s)，7.72(1H，s).

ESI (LC/MS positive mode) m/z: 460(M +2H-K).

Compound 1 j-1-9-2:

dimethylcarbamic acid 6-cyano-4-methyl-3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-1-9 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.42(3H，d，J＝5.4Hz)，2.97(3H，s)，3.12(3H，s)，3.94(2H，s)，6.87(1H，d，J＝8.1Hz)，7.01-7.04(2H，m)，7.15-7.25(2H，m)，7.60(1H，s)，8.46(1H，s).

CH₃Overlaps with the peak of DMSO.

ESI (LC/MS positive mode) m/z: 471(M + H).

Compound 1j-1-9-2 Na:

dimethylcarbamic acid 6-cyano-4-methyl-3- (3- (methylaminosulfonyl) aminobenzyl) -2-oxo-2H-benzopyran-7-yl ester sodium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-1-9-2 instead of Compound 1 j-1-5-1.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.42(s，1H)，7.57(s，1H)，6.82(t，1H，J＝7.5Hz)，6.74(d，1H，J＝7.9Hz)，6.65(s，1H)，6.30(d，1H，J＝7.4Hz)，3.81(s，2H)，3.11(s，3H)，2.96(s，3H)，2.45(s，3H)，2.28(s，3H).

ESIMS m/z：471(M+2H-Na).

Compound 1 j-1-9-2K:

dimethylcarbamic acid 6-cyano-4-methyl-3- (3- (methylaminosulfonyl) aminobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester potassium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-1-9-2 was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.44(s，1H)，7.59(s，1H)，6.89(t，1H，J＝7.5Hz)，6.78(d，1H，J＝7.9Hz)，6.62(s，1H)，6.33(d，1H，J＝7.4Hz)，3.84(s，2H)，3.12(s，3H)，2.97(s，3H)，2.48(s，3H)，2.30(s，3H).

ESIMS m/z：471(M+2H-K).

Compound 1 j-1-10-2:

dimethyl carbamic acid 4-methyl-3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-1-10 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.40-2.60(6H，m)，2.93(3H，s)，3.07(3H，s)，3.96(2H，s)，6.75-6.84(2H，m)，6.85-7.10(1H，brs)，7.18(1H，dd，J＝8.9，2.4Hz)，7.27(1H，d，J＝2.4Hz)，7.87(1H，d，J＝8.6Hz)，8.04-8.10(1H，m).

ESI (LC/MS positive mode) m/z: 447(M + H).

Compound 1 j-1-11-2:

4-methyl-3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -6-fluoro-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-1-11 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.40-2.60(6H，m)，2.92(3H，s)，3.04(3H，s)，4.02(2H，s)，6.75-6.82(2H，m)，6.82-7.05(1H，brs)，7.48(1H，d，J＝6.2Hz)，7.87(1H，d，J＝10.2Hz)，8.07(1H，m)，10.00-10.25(1H，brs).

ESI (LC/MS positive mode) m/z: 465(M + H).

Compound 1j-1-11-2 Na:

3- (2- (N-Methylsulfamoyl) aminopyridin-4-ylmethyl) -6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester, sodium salt of dimethylcarbamic acid

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-1-11-2 instead of Compound 1 j-1-5-1.

¹H NMR(CD₃OD，270MHz)δ(ppm)：2.45(3H，s)，2.50(3H，s)，2.65(3H，s)，3.02(3H，s)，3.95(2H，s)，6.55(1H，dd，J＝5.1Hz，J＜1.0Hz)，6.61(1H，brs)，7.30(1H，d，J＝6.8Hz)，7.67(1H，d，J＝11.1Hz)，7.90(1H，d，J＝5.1Hz).

ESI (LC/MS positive mode) m/z: 465(M +2H-Na).

Compound 1 j-1-11-2K:

dimethylcarbamic acid 3- (2- (N-methylsulfamoyl) aminopyridin-4-ylmethyl) -6-fluoro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester potassium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-1-11-2 was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

ESI (LC/MS positive mode) m/z: 465(M +2H-K).

Compound 1 j-1-12-2:

dimethyl carbamic acid 4-methyl-3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -6-chloro-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1g-1-5 and using the compound 5d-0-12 in place of the compound 1e-0-5 to synthesize 2-oxo-2H-3- (2-aminopyridin-4-ylmethyl) -4-methyl-6-chloro-1-benzopyran-7-yl dimethylcarbamate (compound 1H-1-12), and then using the same conditions as in the preparation example of the compound 1j-1-5-2 and using the compound 1H-1-12 in place of the compound 1H-1-5.

¹H-NMR(CD₃OD，270MHz)δ(PPM)：2.51(3H，s)，2.63(3H，s)，3.04(3H，s)，3.18(3H，s)，4.13(2H，s)，7.07(1H，s)，7.08(1H，d，J＝7.8Hz)，7.35(1H，s)，7.97(1H，s)，8.12(1H，d，J＝7.8Hz).

ESI (LC/MS positive mode) m/z: 481(M + H).

Compound 1 j-1-13-2:

dimethyl carbamic acid 4-methyl-3- {6- (methylaminosulfonyl) aminopyridin-2-ylmethyl } -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-1-13 was used instead of Compound 1 h-1-5.

¹H-NMR(CD₃OD，270MHz)δ(PPM)：2.50(3H，d，J＝8.1Hz)，3.01(3H，s)，3.13(3H，s)，4.15(2H，s)，6.79(1H，d，J＝8.1Hz)，6.99(1H，d，J＝8.1Hz)，7.10-7.20(2H，m)，7.63(1H，dd，J＝8.1Hz)，7.81(1H，d，J＝8.1Hz).

ESI (LC/MS positive mode) m/z: 447(M + H).

Compound 1 j-1-14-2:

dimethyl carbamic acid 4-methyl-3- {6- (methylaminosulfonyl) aminopyridin-2-ylmethyl } -6-fluoro-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2 except that Compound 1h-1-14 was used instead of Compound 1 h-1-5.

¹H-NMR(CD₃OD，270MHz)δ(PPM)：2.25(3H，d，J＝1.9Hz)，3.01(3H，s)，3.15(3H，s)，4.15(2H，s)，6.79(1H，d，J＝8.1Hz)，7.00(1H，d，J＝8.1Hz)，7.31(1H，d，J＝6.5Hz)，7.62(1H，dd，J＝8.1Hz)，7.66(1H，d，J＝11.0Hz).

ESI (LC/MS positive mode) m/z: 465(M + H).

Compound 1 j-1-15-2:

dimethyl carbamic acid 4-methyl-3- {6- (methylaminosulfonyl) aminopyridin-2-ylmethyl } -6-chloro-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2 except that Compound 1h-1-15 was used instead of Compound 1 h-1-5.

¹H-NMR(CD₃OD，270MHz)δ(PPM)：2.50(3H，brs)，3.02(3H，s)，3.17(3H，s)，4.14(2H，s)，6.79(1H，d，J＝7.6Hz)，6.99(1H，d，J＝7.6Hz)，7.32(1H，s)，7.62(1H，dd，J＝7.6Hz)，7.89(1H，s).

ESI (LC/MS positive mode) m/z: 481(M + H).

Compound 1 j-1-4-2F:

dimethylcarbamic acid 3- (3-methylaminosulfonylamino-2-fluoro-benzyl) -4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester

To 3- (3-amino-2-fluoro-benzyl) -4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate (compound 1H-1-4F) (18.5mg) was added acetonitrile (1.0mL) to obtain a suspension, and while stirring at room temperature, triethylamine (0.022mL) and 2-oxo-oxazolidinone-3-sulfonic acid carboxamide (19.0mL) were added, and the mixture was refluxed for 11 hours. Subsequently, triethylamine (0.022mL) and 2-oxo-oxazolidinone-3-sulfonic acid formamide (19.0mg) were added, and the mixture was refluxed for further 8 hours. The reaction mixture was cooled to room temperature, diluted with a mixed solvent of ethyl acetate and THF (volume ratio: 1), and the organic layer was washed with a 0.5M sodium carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography (aminated gel) (dichloromethane: methanol ═ 95: 5) to give the title compound (9.8 mg).

¹H-NMR(270MHz，CDCl₃)δ(ppm)：2.74(3H，d，J＝5.4Hz)，3.04(3H，s)，3.13(3H，s)，4.11(2H，s)，5.67(2H，d，J＝46.7Hz)，6.97-7.05(2H，m)，7.10-7.30(2H，m)，7.37-7.45(1H，m)，7.78(1H，dt，J＝7.2，1.8Hz).

ESI (LC-MS positive mode) m/z: 482(M + H).

Compound 1 j-1-1-2F:

3- {3- (Methylaminosulfonyl) aminobenzyl } -4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-4-2F, except that Compound 1h-1-1F was used instead of Compound 1 h-1-4F.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.42(3H，d，J＝5.1Hz)，2.93(3H，s)，3.07(3H，s)，4.02(2H，brs)，5.84(2H，d，J＝46.2Hz)，6.84(1H，brd，J＝7.7Hz)，7.00(1H，brs)，7.02(1H，d，J＝7.7Hz)，7.10-7.30(3H，m)，7.31(1H，d，J＝2.3Hz)、7.91(1H，dd，J＝8.7，2.3Hz)，9.56(1H，brs).

ESI (LC-MS positive mode) m/z: 464(M + H).

Compound 1 j-1-2-2F:

3- {3- (Methylaminosulfonyl) aminobenzyl } -6-fluoro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-4-2F, except that Compound 1h-1-2F was used instead of Compound 1 h-1-4F.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.42(1H，d，J＝5.1Hz)，2.94(3H，s)，3.09(3H，s)，4.03(2H，brs)，5.83(2H，d，J＝46.3Hz)，6.84(1H，d，J＝7.7Hz)，7.00(1H，s)，7.02(1H，brd，J＝7.7Hz)，7.18(1H，t，J＝7.7Hz)，7.23(1H，q，J＝5.1Hz)，7.54(1H，d，J＝6.8Hz)，7.89(1H，dd，J＝11.9、2.3Hz)，9.55(1H，brs).

ESI (LC-MS positive mode) m/z: 482(M + H).

Compound 1 j-1-3-2F:

dimethylcarbamic acid 6-chloro-4-fluoromethyl-3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1j-1-4-2F and the compound 1h-1-3F in place of the compound 1 h-1-4F.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：9.57(brs，1H)，8.07(s，1H)，7.56(s，1H)，7.24(m，1H)，7.17(d，J＝7.9Hz，1H)，7.04(d，J＝9.1Hz，1H)，7.00(s，1H)，6.84(d，J＝7.3Hz，1H)，5.86(d，J＝46.2Hz，2H)，4.04(s，2H)，3.11(s，3H)，2.95(s，3H)，2.42(d，J＝4.8Hz，3H).

ESIMS m/z：498(M+H).

Compound 1j-1-3-2 FNa:

3- (3- (methylaminosulfonyl) aminobenzyl) -6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate sodium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-1-3-2F instead of Compound 1 j-1-5-1.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.29(3H，s)，2.95(3H，s)，3.11(3H，s)，3.90(2H，s)，5.84(1H，d，J＝46.2Hz)，6.31(1H，brd，J＝7.3Hz)，6.65(1H，brs)，6.76(1H，brd，J＝7.3Hz)，6.84(1H，t，J＝7.3Hz)，7.53(1H，s)，8.02(1H，s).

ESI (LC/MS positive mode) m/z: 498(M +2H-Na).

Compound 1j-1-3-2 FK:

dimethylcarbamic acid 3- (3- (methylaminosulfonyl) aminobenzyl) -6-chloro-4-fluoromethyl-2-oxo-2H-1-benzopyran-7-yl ester potassium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-1-3-2F was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

ESI (LC/MS positive mode) m/z: 498(M +2H-K).

Compound 1j-1-3-2 OH:

dimethylcarbamic acid 6-chloro-4- (2-hydroxyethyl) -3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1j-1-4-2F, except that Compound 7d-1-3OH was used instead of Compound 1 h-1-4F.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：8.07(s，1H)，7.51(s，1H)，7.23(m，1H)，7.16(d，J＝7.9Hz，1H)，7.03(d，J＝9.1Hz，1H)，6.98(s，1H)，6.84(d，J＝7.3Hz，1H)，4.89(m，1H)，3.98(s，2H)，3.60(m， 2H)，3.11(s，3H)，3.00(m，2H)，2.95(s，3H)，2.42(d，J＝4.8Hz，3H).

ESIMS m/z：510(M+H).

Compound 1j-1-1-2 OH:

dimethyl carbamic acid 4- (2-hydroxyethyl) -3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl ester

The introduction of a hydroxymethyl group into the compound 1g-1-1 (Compound 7c-1-1OH) was carried out under the same conditions as in the production example of the compound 7c-1-3OH, and then the reduction of a nitro group (Compound 7d-1-1OH) was carried out under the same conditions as in the production example of the compound 1 h-1-5. Then, the sulfonamide reaction was performed under the same conditions as in the production example of the compound 1j-1-4-2F, whereby the title compound was obtained.

¹H-NMR(CDCl₃，270MHz)δ(ppm)：7.62(d，J＝8.4Hz，1H)，7.26(s，1H)，7.20-6.80(m，5H)，5.25(d，J＝5.3Hz，1H)，4.00(s，2H)，3.58(m，2H)，3.10(s，3H)，3.05(m，2H)，3.02(s，3H)，2.60(d，J＝4.9Hz，3H)，1.79(s，1H).

ESIMS m/z：476(M+H).

Compound 1j-1-3-2 CO:

dimethylcarbamic acid 6-chloro-3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-4- (2-oxopropyl) -2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1j-1-4-2F, except that Compound 7g-1-3CO was used instead of Compound 1 h-1-4F.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：9.56(s，1H)，7.91(s，1H)，7.51(s，1H)，7.22(q，J＝5.1Hz，1H)，7.15(t，J＝8.1Hz，1H)，7.02(d，J＝8.0Hz，1H)，6.97(s，1H)，6.80(d，J＝8.0Hz，1H)，4.30(s，2H)，3.91(s，2H)，3.10(s，3H)，2.95(s，3H)，2.42(d，J＝4.8Hz，3H)2.22(s，3H).

ESIMS m/z：522(M+H).

Compound 1j-1-3-2 MeOH:

dimethylcarbamic acid 6-chloro-4- (2-hydroxypropyl) -3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was obtained by reducing the nitro group of 6-chloro-4- (2-hydroxypropyl) -3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate (compound 7c-1-3MeOH) under the same conditions as in the preparation of compound 1H-1-5 (Compound 7d-1-3MeOH), and then conducting sulfonylation under the same conditions as in the preparation of compound 1 j-1-4-2F.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：9.54(s，1H)，8.07(s，1H)，7.49(s，1H)，7.24(q，J＝5.1Hz，1H)，7.17(t，J＝8.1Hz，1H)，7.03(d，J＝8.0Hz，1H)，6.97(s，1H)，6.82(d，J＝8.0Hz，1H)，4.87(d，J＝5.4Hz，1H)，4.02(d，J＝14.8Hz，1H)，3.98(d，J＝14.8Hz，1H)，3.85(m，1H)，3.10(s，3H)，3.00(m，2H)，2.95(s，3H)，2.4 2(d，J＝4.8Hz，3H)1.21(d，J＝5.5Hz，3H).

ESIMS m/z：524(M+H).

Compound 1j-1-3-2 COOMe:

{3- (3- (methylaminosulfonyl) aminobenzyl) -7-dimethylcarbamoyloxy-2-oxo-2H-1-benzene Pyrano-4-yl } acetic acid methyl ester

The title compound was obtained by reducing the nitro group of methyl 3- (3-nitrobenzyl) -7-dimethylcarbamoyloxy-2-oxo-2H-1-benzopyran-4-ylacetate (compound 7F-1-1COOMe) (compound 7g-1-1COOMe) under the same conditions as in the preparation of compound 1H-1-5, and then performing sulfonylation under the same conditions as in the preparation of compound 1 j-1-4-2F.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：7.76(d，J＝8.7Hz，1H)，7.29(d，J＝2.5Hz，1H)，7.23-7.13(m，3H)，7.03(d，J＝8.1Hz，1H)，6.98(s，1H)，6.81(d，J＝7.6Hz，1H)，4.10(s，2H)，3.95(s，2H)，3.52(s，2H)，3.07(s，3H)，2.93(s，2H)，2.43(d，J＝4.8Hz，3H).

ESIMS m/z：504(M+H).

Compound 1j-1-3-2CONH 2:

dimethylcarbamic acid 4-carbamoylmethyl-6-chloro-3- (3- (methylaminosulfonyl) aminobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by the same method as that for the production of compound 1j-1-5-2, except that compound 7g-1-3CONH2 was used instead of compound 1 h-1-5.

¹H NMR(270MHz，DMSO-d₆+CD₃OD(1∶4))δ(ppm)：8.57(s，1H)，8.07(s，1H)，7.89(t，1H，J＝8.1Hz)，7.76-7.73(m，2H)，7.65(d，1H，J＝5.4Hz)，4.72(s，2H)，4.63(s，2H)，3.81(s，3H)，3.70(s，3H)，3.17(s，3H).

ESIMS m/z：523(M+H).

Compound 1j-1-3-2CONMe 2:

dimethylcarbamic acid 6-chloro-4-dimethylcarbamoylmethyl-3- (3- (methylaminosulfonyl) aminobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by the same method as that for the production of compound 1j-1-5-2, except that compound 7g-1-3CONMe2 was used instead of compound 1 h-1-5.

¹H NMR(270MHz，CDCl₃)δ(ppm)：7.32(s，1H)，7.30-7.15(m，2H)，6.99(s，1H)，6.80(d，1H，J＝7.2Hz)，6.45(s，1H)，6.02(m，1H)，3.95(s，2H)，3.91(s，2H)，3.19(s，3H)，3.12(s，3H)，3.07(s，3H)，2.98(s，3H)，2.56(s，3H).

ESIMS m/z：551(M+H).

Compound 1j-1-37-2

3- (3- (methylaminosulfonyl) amino-6-fluorobenzyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized by using the compound 1j-1-1-2 in place of the compound 1j-1-1-1 under the same conditions as those for the compound 1 j-1-36-1.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.37(3H，s)，2.44(3H，s)，2.93(3H，s)，3.02(3H，s)，3.93(2H，s)，6.87(1H，m)，7.04-7.22(4H，m)，7.27(1H，br)，7.88(1H，d，J＝10.8Hz)，9.40(1H，br)

ESI (LC/MS positive mode) M/z 464(M + H)

Compound 1j-1-65-2

Dimethyl carbamic acid 3- (3- (methyl amino sulfonyl) amideYl) amino-6-fluorobenzyl) -4, 6-dimethyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by using the compound 1j-1-8-2 in place of the compound 1j-1-1-1 under the same conditions as the compound 1 j-1-36-1.

¹H-NMR(CD₃OD 270MHz)δ(PPM)：2.30(3H，s)，2.49(3H，s)，2.52(3H，s)，3.02(3H，s)，3.17(3H，s)，4.03(2H，s)，6.99-7.04(2H，m)，7.22(1H，m)，7.14(1H，s)，7.71(1H，s)

ESI (LC/MS positive mode) M/z 478(M + H)

Compound 1j-1-39-2

3- (3- (methylaminosulfonyl) aminobenzyl) -4-methyl-2-oxo-6-trimethylsilylethynyl-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1j-1-5-2, but replacing the compound 1h-1-5 with the compound 1 h-1-39.

¹H-NMR(DMSO-d₆270MHz) δ (PPM): 0.24(9H, s), 2.43(3H, d, J ═ 4.6Hz), 2.47(3H, s), 2.95(3H, s), 3.11(3H, s), 3.94(2H, s), 6.63(1H, d, J ═ 6.9Hz), 6.74-6.82(3H, M), 6.89-7.03(2H, M), 7.15(1H, s), 7.70(1H, s) ESI (LC/MS positive mode) M/z 542(M + H)

Compound 1j-1-40-2

Dimethyl-ammoniaCarbamic acid 3- (3- (methylaminosulfonyl) aminobenzyl) -6-ethynyl-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-1-40 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.42(3H，d，J＝4.6Hz)，2.46(3H，s)，2.94(3H，s)，3.09(3H，s)，3.93(2H，s)，4.45(1H，s)，6.86(1H，d，J＝7.6Hz)，6.93-7.10(2H，m)，7.07-7.35(2H，m)，7.38(1H，s)，7.99(1H，s)，9.54(1H，brs)

ESI (LC/MS positive mode) M/z 470(M + H)

Compound 1j-1-72-2

Dimethylcarbamic acid 3- (3- (methylaminosulfonyl) aminobenzyl) -4-methyl-2-oxo-2H-pyrano [2, 3-b]Pyridin-7-yl esters

3- (3-amino-benzyl) -4-methyl-2-oxo-2H-pyrano [2, 3-b ] pyridin-7-yl dimethylcarbamate (compound 1H-1-72) was synthesized using the same conditions as in the preparation of compound 1H-1-5, except that compound 1g-1-72 was used instead of compound 1 g-1-5.

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2 except that Compound 1h-1-72 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.42(3H，s)，2.47(3H，s)，2.95(3H，s)，3.06(3H，s)，3.94(2H，s)，6.87(1H，d，J＝7.3Hz)，7.01(1H，s)，7.02(1H，d，J＝7.1Hz)，7.14-7.20(2H，m)，7.27(1H，d，J＝8.2Hz)，8.43(1H，d，J＝8.2Hz)，9.53(1H，brs)

ESI (LC/MS positive mode) M/z 447(M + H)

Compound 1j-1c-1-2

3- {3- (methylaminosulfonyl) aminobenzyl } -7- (2-fluoroethoxy) -4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized by the same method as that for the production of compound 1j-1-5-2, except that compound 1h-1c-1 was used instead of compound 1 h-1-5.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.41(3H，s)，3.90(2H，s)，4.28-4.33(1H，m)，4.39-4.44(1H，m)，4.67-4.71(1H，m)，4.84-4.88(1H，m)，6.64(1H，d，J＝7.6Hz)，6.99-7.06(4H，m)，7.16(1H，dd，J＝8.1、7.8Hz)，7.21(1H，br.s)，7.77(1H，d，J＝8.6Hz)，9.51(1H，br.s).(-CH₃Overlaps with the peak of DMSO. )

ESI (LC-MS positive mode) m/z: 421(M + H).

Compound 1j-1d-1-2

Pyrrolidine-1-carboxylic acid 3- (3- (methylaminosulfonyl) aminobenzyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1j-1-5-2, but replacing the compound 1h-1-5 with the compound 1h-1 d-1.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：1.84-1.94(4H，m)，2.42(3H，d，J＝3.3Hz)，2.46(3H，s)，3.36(2H，t，J＝6.6Hz)，3.52(2H，t，J＝6.6Hz)，3.93(2H，s)，6.86(1H，d，J＝7.8Hz)，6.98-7.05(2H，m)，7.13-7.23(3H，m)，7.26(1H，d，J＝2.3Hz)，7.86(1H，d，J＝8.9Hz)，9.53(1H，brs)

ESI (LC/MS positive mode) M/z 472(M + H)

Compound 1 j-2-4-2:

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-2-4 was used instead of Compound 1 h-1-5.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.45(3H，s)，3.99(2H，s)，6.83-6.92(1H，m)，6.97-7.06(1H，m)，7.17(1H，br.s)，7.34-7.40(4H，m)，7.91(1H，d，J＝8.4Hz)，8.69(2H，dd，J＝4.8、1.2Hz)，9.38(1H，br.s).

One peak of CH3 overlapped the peak of DMSO.

ESI (LC-MS positive mode) m/z: 471(M + H).

Compound 1j-2-4-2 Na:

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran sodium salt

The title compound was synthesized by using the compound 1j-2-4-2 in place of the compound 1j-1-5-1 under the same conditions as those for the compound 1j-1-5-1 Na.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.33(3H，d，J＝3.3Hz)，2.43(3H，s)，3.89(2H，s)，6.10-6.19(1H，m)，6.58-6.66(1H，m)，7.17(1H，ddd，J＝8.3、1.5Hz、J_HF＝8.3Hz)，7.25(1H，dd，J＝8.7、2.3Hz)，7.33(1H，t，J＝4.8Hz)，7.37(1H，d，J＝2.3Hz)，7.88(1H，d，J＝8.7Hz)，8.69(2H，d，J＝4.8Hz).

ESI (LC-MS positive mode) m/z: 471(M +2H-Na).

Compound 1 j-2-4-2K:

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran potassium salt

The title compound was synthesized by using the compound 1j-2-4-2 in place of the compound 1j-1-5-1 and KOH in place of NaOH under the same conditions as the compound 1j-1-5-1 Na.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.69(d，2H，J＝4.8Hz)，7.88(d，1H，J＝8.7Hz)，7.36(d，1H，J＝2.3Hz)，7.33(t，1H，J＝4.8Hz)，7.25(dd，1H，J＝8.7，2.3Hz)，7.16(td，1H，J＝8.5，1.4Hz)，6.59(t，1H，J＝7.8Hz)，6.10(t，1H，J＝6.3Hz)，4.76(q，1H，J＝5.8Hz)，3.88(s，2H)，2.43(s，3H)，2.32(d，3H，J＝5.6Hz).

ESI (LC-MS positive mode) m/z: 471(M +2H-K).

Compound 1j-2-4S 1-2:

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-ylthio) -2-oxo-2H-1-benzopyran

Compound 1h-2-4S1 was synthesized under the same conditions as in the preparation example of Compound 1h-2-4 (Synthesis method 2) except that Compound 5d-2-4S1 was used in place of Compound 4 a-0-4.

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-2-4S1 was used instead of Compound 1 h-2-16.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.48(3H，s)，4.01(2H，s)，6.83-6.92(1H，m)，6.98-7.05(1H，m)，7.16(1H，brs)，7.25-7.35(2H，m)，7.60(1H，d，J＝8.5Hz)，7.70-7.74(1H，m)，7.92(1H，d，J＝8.5Hz)，8.64(2H，d，J＝4.8Hz)

ESI (LC-MS positive mode) M/z 487(M + H).

Compound 1j-2-4S 2-2:

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzothiopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-2-4S2 was used instead of Compound 1 h-2-16.

¹H-NMR(270MHz，DMSO-d₆) δ (ppm): 2.54(3H, s), 4.08(2H, s), 6.70(1H, dd, J ═ 7.3, Hz, JHF ═ 7.3Hz), 6.99(1H, dd, J ═ 7.9, Hz, JHF ═ 7.9Hz), 7.14(1H, brs), 7.28(1H, dd, J ═ 8.0, 8.0Hz), 7.34(1H, dt, J ═ 4.9, 1.3Hz), 7.40(1H, dd, J ═ 8.7, 2.2Hz), 7.64(1H, d, J ═ 2.4Hz), 8.16(1H, d, J ═ 8.7Hz), 8.70(2H, dd, J ═ 4.9, 1.2), 9.44 (CH, 1H, brs) (1H, 1.9 Hz), and 44.6 (1H, brs)₃Overlap with peaks of DMSO)

ESI (LC-MS positive mode) M/z 487(M + H).

Compound 1 j-2-5-2:

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -6-fluoro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-2-5 was used instead of Compound 1 h-1-5.

¹H-NMR(CD₃OD，270MHz)δ(PPM)：2.40(3H，s)，2.68(3H，s)，4.09(2H，s)，6.78-7.04(3H，m)，7.17-7.39(4H，m)，7.70-7.89(1H，m)，8.61-8.63(2H，m).

ESI (LC/MS positive mode) m/z: 489(M + H).

Compound 1 j-2-6-2:

3- { 2-methyl-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-2-6 was used instead of Compound 1 h-2-16.

¹H NMR(Bruker，300MHz，CDCl₃)δ(ppm)：8.61(2H，d，J＝4.6Hz)，7.72(1H，d，J＝8.4Hz)，7.32(1H，d，J＝7.6Hz)，7.27(1H，d，J＝3.1Hz)，7.21(1H，dd，J＝2.3，8.4Hz)，7.13(1H，t，J＝5.0Hz)，7.07(1H，t，J＝7.8Hz)，6.73(1H，d，J＝7.6Hz)，6.17(1H，s)，4.36(1H，q)，4.03(2H，s)，2.79(3H，d，J＝5.3Hz)，2.41(3H，s)，2.38(3H，s).

MS(Micromass，Quttromicro，ESI-)m/z：465.08(M-H).

Compound 1 j-2-4-2F:

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-fluoromethyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-2-4F was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：9.36(s，1H)，8.68(d，J＝4.9Hz，2H)，7.96(dd，J＝8.9，2.2Hz，1H)，7.42(d，J＝2.4Hz，1H)，7.36-7.18(m，3H)，7.02(t，J＝7.0Hz，1H)，6.88(t，J＝7.0Hz，1H)，5.86(d，J＝46.2Hz，2H)，4.07(s，2H)，2.51(d，J＝5.1Hz，3H).

ESIMS m/z：489(M+H).

Compound 1j-2-4-2 FNa:

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-fluoromethyl-7- (pyrimidin-2-yl)Oxy) -2-oxo-2H-1-benzopyran sodium salt

The title compound was synthesized by using the same conditions as in the preparation of Compound 1j-1-5-1Na, but using Compound 1j-2-4-2F instead of Compound 1 j-1-5-1.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：8.68(d，J＝4.9Hz，2H)，7.92(dd，J＝8.9，2.7Hz，1H)，7.40(d，J＝2.2Hz，1H)，7.32(t，J＝4.7Hz，1H)，7.28(dd，J＝8.8，2.3Hz，1H)，7.15(t，J＝8.9Hz，1H)，6.58(t，J＝7.7Hz，1H)，6.09(t，J＝7.8Hz，1H)，5.81(d，J＝46.2Hz，2H)，4.71(q，J＝5.7Hz， 1H)，3.94(s，2H)，2.30(d，J＝5.7Hz，3H).

ESIMS m/z：489(M+2H-Na).

Compound 1j-2-4-2 FK:

3- (2-fluoro-3- (methylaminosulfonyl) aminobenzyl) -4-fluoromethyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran potassium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-2-4-2F was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.69(d，2H，J＝4.8Hz)，7.94(dd，1H，J＝8.8，2.2Hz)，7.42(d，1H，J＝2.3Hz)，7.34(t，1H，J＝4.7Hz)，7.30(dd，1H，J＝8.8，2.3Hz)，7.18(t，1H，J＝8.9Hz)，6.62(t，1H，J＝7.7Hz)，6.13(t，1H，J＝7.8Hz)，5.92(d，2H，J＝46.2Hz)，4.80(q，1H，J＝5.7Hz)，3.96(s，2H)，2.33(d，3H，J＝5.7Hz).

Compound 1 j-2-10-2:

3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-2-10 was used instead of Compound 1 h-1-5.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.53(3H，s)，2.82(3H，s)，4.18(2H，s)，7.10-7.35(4H，m)，7.70-7.80(2H，m)，8.01(1H，d，J＝6.2Hz)，8.61(2H，brs).

ESI (LC/MS positive mode) m/z: 454(M + H).

Compound 1 j-2-12-2:

3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-2-12 was used instead of Compound 1 h-1-5.

¹H-NMR(CD₃OD，270MHz)δ(PPM)：2.52(3H，s)，2.64(3H，s)，4.11(2H，s)，7.11(1H，d，J＝6.5Hz)，7.13(1H，s)，7.27(1H，dd，J＝4.9Hz)，7.37(1H，s)，8.00(1H，s)，8.12(1H，d，J＝6.5Hz)，8.62(2H，d，J＝4.9Hz).

ESI (LC/MS positive mode) m/z: 488(M + H).

Compound 1 j-2-16-2:

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The corresponding sulfamoyl chloride was prepared by dissolving sulfonyl chloride (28 μ L, 340 μmol) in dichloromethane (2mL), adding methylamine (158 μ L, 317 μmol) and DMAP (38.7mg, 317 μmol) at-78 ℃, and stirring at room temperature for 2 hours. To the reaction solution were added 3- (2-amino-3-fluoropyridin-4-ylmethyl) -7- (pyrimidin-2-yloxy) -4-methyl-2-oxo-2H-1-benzopyran (compound 1H-2-16) (60mg, 159. mu. mol), pyridine (65. mu.L, 795. mu. mol) and dichloromethane (2mL), and the mixture was stirred at room temperature for 4 hours. Then, water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (32mg, 43%).

¹H NMR(CD₃OD，270MHz)δ(ppm)：2.54(3H，s)，2.62(3H，s)，4.22 (2H，s)，6.84(1H，dd，J＝5.4Hz)，7.20-7.30(3H，m)，7.80-7.95(2H，m)，8.63(2H，d，J＝4.9Hz).

ESI (LC/MS positive mode) m/z: 472(M + H).

Compound 1j-2-16-2 Na:

3- (2- (N-methylsulfamoyl) amino-3-fluoropyridin-4-ylmethyl) -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran sodium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-2-16-2 in place of Compound 1 j-1-5-1.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.30(3H，s)，2.46(3H，s)，3.89(2H，s)，5.68(1H，brs)，6.09-6.23(1H，m)，7.20(1H，dd，J＝2.4，8.7Hz)，7.34(1H，t，J＝4.8Hz)，7.38(1H，d，J＝2.4Hz)，7.55(1H，d，J＝5.3Hz)，7.90(1H，d，J＝8.7Hz)，8.69(1H，d，J＝4.8Hz).

ESI (LC/MS positive mode) m/z: 472(M +2H-Na).

Compound 1 j-2-16-2K:

3- (2- (N-methylsulfamoyl) amino-3-fluoropyridin-4-ylmethyl) -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran potassium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-2-16-2 was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.36(3H，s)，2.47(3H，s)，3.93(2H，s)，6.26-6.40(1H，m)，7.27(1H，dd，J＝2.3，8.6Hz)，7.34(1H，t，J＝4.8Hz)，7.39(1H，d，J＝2.3Hz)，7.64(1H，d，J＝4.8Hz)，7.91(1H，d， J＝8.6Hz)，8.69(1H，d，J＝4.8Hz).

ESI (LC/MS positive mode) m/z: 472(M +2H-K).

Compound 1j-2-16-2 a:

3- {2- (Ethylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized using ethylamine in place of methylamine under the same conditions as in the preparation example of compound 1 j-2-16-2.

¹H NMR(CD₃OD，270MHz)δ(ppm)：1.11(3H，t，J＝7.2Hz)，2.54(3H，s)，3.03(2H，q，J＝7.2Hz)，4.12(2H，s)，6.84(1H，dd，J＝5.4Hz)，7.20-7.30(3H，m)，7.80-7.95(2H，m)，8.63(2H，d，J＝4.6Hz).

ESI (LC/MS positive mode) m/z: 486(M + H).

Compound 1j-2-16-2 b:

3- {2- (isopropylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that isopropylamine was used instead of methylamine.

¹H NMR(CD₃OD，270MHz)δ(ppm)：0.85-1.30(6H，m)，2.52(3H，s)，3.45-4.20(1H，m)，4.11(2H，s)，6.82(1H，dd，J＝5.4Hz)，7.20-7.30(3H，m)，7.80-7.95(2H，m)，8.63(2H，d，J＝4.6Hz).

ESI (LC/MS positive mode) m/z: 500(M + H).

Compound 1 j-2-17-2:

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-fluoro-7- (pyrimidine Pyridin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-2-17 was used instead of Compound 1 h-2-16.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.40-2.70(3H，m)，4.03(2H，s)，6.75-6.83(1H，m)，6.97(1H，brs)，7.38(1H，dd，J＝4.5Hz)，7.66(1H，d，J＝6.5Hz)，7.93(1H，d，J＝11.1Hz)，7.90-7.95(1H，m)，8.70(2H，d，J＝4.5)，10.36(1H，brs).

ESI (LC/MS positive mode) m/z: 490(M + H).

Compound 1j-2-17-2 c:

3- {2- (cyclopropylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-fluoro-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1j-2-16-2, but using the compound 1h-2-17 instead of the compound 1h-2-16 and cyclopropylamine instead of methylamine.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：0.40-0.60(4H，m)，2.24-2.35(1H，m)，2.40-2.70(3H，m)，4.02(2H，s)，6.75-6.85(1H，m)，7.38(1H，dd，J＝4.5Hz)，7.66(1H，d，J＝6.5Hz)，7.93(1H，d，J＝11.1Hz)，7.90-7.95(1H，m)，8.70(2H，d，J＝4.5).

ESI (LC/MS positive mode) m/z: 516(M + H).

Compound 1 j-2-18-2:

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-chloro-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

Using the same conditions as in the preparation example of Compound 1H-2-4 (Synthesis method 2), 3- { 2-amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-chloro-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran (Compound 1H-2-18) was synthesized using Compound 5d-0-18 in place of Compound 4 a-0-4.

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-2-18 was used instead of Compound 1 h-2-16.

¹H NMR(CDCl₃，270MHz)δ(ppm)：2.47(3H，s)，2.76(3H，s)，4.08(2H，s)，6.85(1H，dd，J＝5.1Hz)，7.13(1H，dd，J＝4.9Hz)，7.31(1H，s)，7.73(1H，s)，7.93(1H，d，J＝5.1Hz)，8.61(2H，d，J＝4.9Hz).

ESI (LC/MS positive mode) m/z: 506(M + H).

Compound 1 j-2-19-2:

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-2-19 was used instead of Compound 1 h-2-16.

¹H NMR(CD₃OD，270MHz)δ(ppm)：2.24(3H，s)，2.53(3H，s)，2.62(3H，s)，4.11(2H，s)，6.81(1H，dd，J＝5.1Hz)，7.19(1H，s)，7.25(1H，t，J＝4.7Hz)，7.79(1H，s)，7.92(1H，d，J＝5.1Hz)，8.61(2H，d，J＝4.9Hz).

ESI (LC/MS positive mode) m/z: 486(M + H).

Compound 1j-2-19-2 Na:

3- (2- (N-Methylsulfamoyl) amino-3-fluoropyridin-4-ylmethyl) -4, 6-dimethyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran-2-one sodium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-2-19-2 in place of Compound 1 j-1-5-1.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.15(3H，s)，2.30(3H，s)，2.45(3H，s)，3.89(2H，s)，5.66(1H，brs)，6.07-6.21(1H，m)，7.29-7.33(2H，m)，7.54(1H，d，J＝5.3Hz)，7.82(1H，s)，8.67(2H，dd，J＝0.9，4.8Hz).

ESI (LC/MS positive mode) m/z: 486(M +2H-Na).

Compound 1 j-2-19-2K:

3- (2- (N-methylsulfamoyl) amino-3-fluoropyridin-4-ylmethyl) -4, 6-dimethyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzenePyropyran potassium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-2-19-2 was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.15(3H，s)，2.37(3H，s)，2.47(3H，s)，3.93(2H，s)，6.30-6.42(1H，m)，7.29-7.33(2H，m)，7.67(1H，d，J＝5.3Hz)，7.83(1H，s)，8.67(2H，dd，J＝0.8，4.8Hz).

ESI (LC/MS positive mode) m/z: 486(M +2H-K).

Compound 1j-2-19-2 Me:

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-ethyl-6-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-2-16-2 and compound 1h-2-19Me instead of Compound 1 h-2-16.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：1.13(1H，t，J＝7.4Hz)，2.17(3H，s)，2.46(3H，s)，2.92(1H，brq，J＝7.4Hz)，4.00(2H)，6.82(1H，brt，J＝4.9Hz)，7.00(1H，brq，J＝4.8Hz)，7.32(1H，t，J＝4.8Hz)，7.34(1H，s)，7.86(1H，s)，7.93(1H，d，J＝4.9Hz)，8.67(2H，d，J＝4.8Hz)，10.36(1H，s).

One peak of methyl overlaps with the peak of DMSO.

ESI (LC/MS positive mode) m/z: 500(M + H).

Compound 1j-2-19-2 MeNa:

3- (2- (methylamino sulfamoyl) amino-3-fluoropyridin-4-ylmethyl) -4-ethyl-6-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran sodium salt

The title compound was synthesized by using the same conditions as in the preparation of Compound 1j-1-5-1Na, but using Compound 1j-2-19-2Me instead of Compound 1 j-1-5-1.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：1.12(1H，t，J＝7.4Hz)，2.16(3H，s)，2.28(1H，d，J＝5.8Hz)，2.87(1H，brq，J＝7.4Hz)，3.17(3H，s)，3.85(2H，s)，5.50(1H，q，J＝5.8Hz)，6.04(1H，t，J＝5.1Hz)，7.32(1H，s)，7.32(1H，t，J＝4.8Hz)，7.50(1H，d，J＝5.1Hz)，7.82(1H，s)，8.67(2H，d，J＝4.8Hz).

ESI (LC/MS positive mode) m/z: 500(M +2H-Na).

Compound 1j-2-19-2 MeK:

3- (2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl) -4-ethyl-6-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran potassium salt

The title compound was synthesized by using the same conditions as in the preparation of Compound 1j-1-5-1Na, except that Compound 1j-2-19-2Me was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

ESI (LC/MS positive mode) m/z: 500(M +2H-K).

Compound 1j-2-19-2 c:

3- {2- (cyclopropylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1j-2-16-2, but using the compound 1h-2-19 instead of the compound 1h-2-16 and cyclopropylamine instead of methylamine.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：0.46-0.55(4H，m)，2.16(3H，s)，2.26-2.37(1H，m)，4.03(2H，s)，6.76-6.86(1H，m)，7.30-7.33(2H，m)，7.54(1H，brs)，7.85(1H，s)，7.93(1H，d，J＝5.4Hz)，8.67(2H，d，J＝4.8Hz)，10.50(1H，brs).

CH₃The peak of (a) overlaps with the peak of DMSO.

ESI (LC/MS positive mode) m/z: 512(M + H).

Compound 1j-2-16-2 c:

3- {2- (cyclopropylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that cyclopropylamine was used instead of methylamine.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：0.40-0.60(4H，m)，2.24-2.35(1H，m)，2.40-2.70(3H，m)，4.02(2H，s)，6.75-6.85(1H，m)，7.28(1H，dd，J＝1.9，8.4Hz)，7.32(1H，dd，J＝4.5Hz)，7.39(1H，d，J＝2.4Hz)，7.52(1H，brs)，7.93(1H，d，J＝8.4Hz)，7.90-7.95(1H，m)，8.69(2H，d，J＝4.5)，10.49(1H，brs).

ESI (LC/MS positive mode) m/z: 498(M + H).

Compound 1 j-2-41-2:

3- {2- (methylaminosulfonyl) amino-3-chloropyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

2- (di-tert-butoxycarbonyl) amino-3-chloro-4-methylpyridine (compound 5b-0-41) was synthesized from 3-chloro-4-methyl-2-aminopyridine under the same conditions as in the preparation example of compound 5 b-0-13.

Using the same conditions as in the preparation example of Compound 5c-0-13, 2- (di-t-butoxycarbonyl) amino-3-chloro-4-bromomethylpyridine (Compound 5c-0-41) was synthesized from Compound 5 b-0-41.

Ethyl 2- (2- (di-tert-butoxycarbonyl) amino-3-chloropyridin-4-ylmethyl) -3-oxobutanoate (Compound 5t-0-41) was synthesized from Compound 5c-0-41 under the same conditions as in the preparation example of Compound 5 t-0-10.

3- (3-chloro-2-aminopyridin-4-ylmethyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran (Compound 5d-0-41) was synthesized using Compound 5t-0-41 under the same conditions as in the preparation of Compound 5 d-0-12.

Using the same conditions as in the preparation example of Compound 1H-2-4 (Synthesis method 2), 3- (3-chloro-2-aminopyridin-4-ylmethyl) -7- (pyrimidin-2-yloxy) -4-methyl-2-oxo-2H-1-benzopyran (Compound 1H-2-41) was synthesized using Compound 5d-0-41 in place of Compound 4 a-0-4.

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-2-41 was used instead of Compound 1 h-2-16.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.44(3H，s)，4.04(2H，s)，6.75(1H，m)，7.29(1H，dd，J＝2.2，8.9Hz)，7.34(1H，t，J＝4.8Hz)，7.41(1H，d，J＝2.2Hz)，7.65(1H，brd，J＝4.8Hz)，7.94(1H，d，J＝8.9Hz)，8.04(1H，m)，8.69(2H，d，J＝4.8Hz).

One peak of methyl overlaps with the peak of DMSO.

ESI (LC/MS positive mode) m/z: 488(M + H).

Compound 1 j-2-45-2:

3- {2- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-2-45 was used instead of Compound 1 h-2-16.

¹H-NMR(Bruker，300MHz，DMSO- )δ(ppm)：8.94(1H，s)，8.69(2H，d，J＝5.0Hz)，7.89(1H，d，J＝8.8Hz)，7.39(1H，d，J＝2.3Hz)，7.33(2H，m)，7.26(1H，dd，J＝2.3Hz，8.8Hz)，7.23～7.04(3H，m)，6.91(1H，d，J＝7.6Hz)，4.09(2H，s)，2.61(3H，d，J＝5.0Hz)，2.37(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：452.97(M+H)

Compound 1 j-2-46-2:

3- {4- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-2-46 was used instead of Compound 1 h-2-16.

¹H-NMR(Bruker，300MHz， )δ(ppm)：8.59(2H，d，J＝5.0Hz)，7.69(1H，d，J＝8.7Hz)，7.23(3H，m)，7.18(1H，dd，J＝2.1Hz，8.7Hz)，7.13～7.09(3H，m)，6.43(1H，s)，4.40(1H，m)，4.03(2H，s)，2.71(3H，d，J＝5.4Hz)，2.48(3H，s)

MS(Micromass，Quttromicro，ESI-)m/z：451.03(M-H)

Compound 1 j-2-52-2:

3- (3- (methylaminosulfonyl) amino-phenoxy) -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-2-52 was used instead of Compound 1 h-2-16.

H1-NMR(300MHz，DMSO-d_6..)δ(ppm)：9.67(1H，bs)，8.69(2H，d，J＝5.0Hz)，7.90(1H，d，J＝8.8Hz)，7.46(1H，d，J＝2.3Hz)，7.34(3H，m)，7.19(1H，m)，6.88(1H，m)，6.82(1H，m)，6.63(1H，dd，J＝2.3Hz，J＝8.4Hz)，2.45(3H，d，J＝4.6Hz)，2.37(3H，s)

MS(ESI+)m/z：455.09(M+H)

Compound 1 j-2-53-2:

3- (3- (methylaminosulfonyl) amino-thiophenoxy) -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-2-53 was used instead of Compound 1 h-2-16.

H1-NMR(300MHz，DMSO-d_6..)δ(ppm)：9.65(1H，bs)，8.70(2H，d，J＝5.0Hz)，8.00(1H，d，J＝8.8Hz)，7.44(1H，d，J＝2.7Hz)，7.35(2H，m)，7.32(1H，dd，J＝2.3Hz，J＝8.8Hz)，7.20(1H，m)，7.00(1H，m)，6.96(1H，m)，6.85(1H，m)，2.75(3H，s)，2.42(3H，d，J＝4.6Hz)

MS(ESI+)m/z：471.03(M+H)

Compound 1 j-3-1-2:

3- {3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-3-1 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.43(3H，d，J＝3.1Hz)，3.94(2H，s)，6.87(1H，d，J＝7.3Hz)，6.99-7.05(2H，m)，7.13-7.25(2H，m)，7.32-7.40(3H，m)，7.49(1H，d，J＝2.5Hz)，7.94(1H，d，J＝8.9Hz).

One peak of methyl overlaps with the peak of DMSO.

ESI (LC/MS positive mode) m/z: 458(M + H).

Compound 1j-3-1-2 Na:

3- (3- (N-Methylsulfamoyl) amino-benzyl) -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran sodium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-3-1-2 instead of Compound 1 j-1-5-1.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.47(3H，s)，3.91(2H，s)，6.71(1H，d，J＝7.5Hz)，6.85-7.04(2H，m)，7.07(1H，t，J＝7.7Hz)， 7.33-7.38(3H，m)，7.48(1H，d，J＝2.5Hz)，7.92(1H，d，J＝8.7Hz).

CH₃The peak of (a) overlaps with the peak of DMSO.

ESI (LC/MS positive mode) m/z: 458(M +2H-Na).

Compound 1 j-3-1-2K:

3- (3- (N-Methylsulfamoyl) amino-benzyl) -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran potassium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-3-1-2 was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.47(3H，s)，3.86(2H，s)，6.53(1H，d，J＝6.9Hz)，6.78-6.85(2H，m)，6.94(1H，t，J＝7.8Hz)，7.32-7.38(3H，m)，7.47(1H，dd，J＝1.2，2.3Hz)，7.92(1H，d，J＝8.9Hz).

CH₃The peak of (a) overlaps with the peak of DMSO.

ESI (LC/MS positive mode) m/z: 458(M +2H-K).

Compound 1 j-3-3-2:

3- {3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-3-3 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.42(3H，d，J＝4.9Hz)，3.95(2H，s)，6.87(1H，d，J＝7.9Hz)，7.01-7.04(2H，m)，7.18(1H，dd，J＝7.9，7.9Hz)，7.25(1H，d，J＝4.9Hz)，7.29(1H，d，J＝3.8Hz)，7.34(1H，d，J＝3.8Hz)，7.75(1H，s)，8.13(1H，s)，9.56(1H，s).

CH₃Overlaps with the DMSO peak.

ESI (LC/MS positive mode) m/z: 492(M + H).

Compound 1 j-3-4-2:

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-3-4 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.46(3H，s)，3.98(2H，s)，6.85-6.90(1H，m)，6.98-7.04(1H，m)，7.20(1H，d，J＝5.0Hz)，7.29(1H，ddd，J＝1.5，7.8Hz，J_HF＝7.8Hz)，7.34-7.39(3H，m)，7.49(1H，d，J＝2.5Hz)，7.95(1H，d，J＝8.9Hz)，9.39(1H，brs).

CH₃Overlaps with the DMSO peak.

ESI (LC/MS positive mode) m/z: 476(M + H).

Compound 1j-3-4-2 Na:

3- (3- (N-Methylsulfamoyl) amino-2-fluoro-benzyl) -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran sodium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-3-4-2 instead of Compound 1 j-1-5-1.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.37(3H，s)，2.43(3H，s)，3.89(2H，s)，5.36(1H，brs)，6.28-6.32(1H，m)，6.69(1H，dd，J＝7.8，8.1Hz)，7.19(1H，dd，J＝7.8，8.6Hz)，7.31-7.40(3H，m)，7.47(1H，m)，7.92(1H，d，J＝8.6Hz).

ESI (LC/MS positive mode) m/z: 476(M +2H-Na).

Compound 1 j-3-4-2K:

3- (3- (N-Methylsulfamoyl) -amino-2-fluorobenzyl) -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran potassium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-3-4-2 was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.40(3H，s)，2.44(3H，s)，3.91(2H，s)，5.66(1H，brs)，6.37-6.42(1H，m)，6.75(1H，dd，J＝7.9，8.0Hz)，7.24(1H，dd，J＝8.0，8.4Hz)，7.34-7.38(3H，m)，7.48(1H，dd，J＝1.3，2.3Hz)，7.92(1H，d，J＝8.9Hz).

ESI (LC/MS positive mode) m/z: 476(M +2H-K).

Compound 1 j-3-8-2:

3- {3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (thiazol-2-yloxy) benzene) -6-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2 except that Compound 1h-3-8 was used instead of Compound 1 h-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.26(3H，s)，2.41(3H，d，J＝4.1Hz)，2.46(3H，s)，3.93(2H，s)，6.85(1H，d，J＝7.4Hz)，6.97-7.04(2H，m)，7.13-7.24(2H，m)，7.26-7.30(2H，m)，7.44(1H，s)，7.85(1H，s).

ESI (LC/MS positive mode) m/z: 472(M + H).

Compound 1j-3-8-2 Na:

3- (3- (N-Methylsulfamoyl) aminobenzyl) -4, 6-dimethyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran sodium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-3-8-2 instead of Compound 1 j-1-5-1.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.27(3H，s)，2.34(3H，s)，2.46(3H，s)，3.87(2H，s)，6.53(1H，d，J＝7.1Hz)，6.80-6.99(4H，m)，7.27-7.31(2H，m)，7.44(1H，s)，7.84(1H，s).

ESI (LC/MS positive mode) m/z: 472(M +2H-Na).

Compound 1 j-3-8-2K:

3- (3- (N-Methylsulfamoyl) aminobenzyl) -4, 6-dimethyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran potassium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-3-8-2 was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.27(3H，s)，2.34(3H，s)，2.46(3H，s)，3.87(2H，s)，6.53(1H，d，J＝6.9Hz)，6.79-6.99(4H，m)，7.27-7.31(2H，m)，7.44(1H，s)，7.84(1H，s).

ESI (LC/MS positive mode) m/z: 472(M +2H-K).

Compound 1 j-3-12-2:

3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-6-chloro-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

Using the same conditions as in the preparation example of Compound 1H-2-4 (Synthesis method 2), 3- { 2-aminopyridin-4-ylmethyl } -4-methyl-6-chloro-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran (Compound 1H-3-12) was synthesized by using Compound 5d-0-12 in place of Compound 4 a-0-4.

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-3-12 was used instead of Compound 1 h-2-16.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.42(3H，s)，2.48(3H，s)，3.95(2H，s)，6.74-6.77(2H，m)，7.25-7.35(2H，m)，7.75(1H，s)，8.03(1H，d，J＝4.9Hz)，8.13(s，1H).

ESI (LC/MS positive mode) m/z: 493(M + H).

Compound 1 j-3-19-2:

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

3- (3-fluoro-2-aminopyridin-4-ylmethyl) -7- (thiazol-2-ylmethyl) -6-methyl-4-methyl-2-oxo-2H-1-benzopyran (compound 1H-3-19) was synthesized using the same conditions as in the preparation example of Compound 1H-2-4 (Synthesis method 2) but using Compound 5d-0-18 instead of Compound 4 a-0-4.

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-3-19 was used instead of Compound 1 h-2-16.

¹H NMR(CD₃OD，270MHz)δ(ppm)：2.34(3H，s)，2.51(3H，s)，2.62(3H，s)，4.10(2H，s)，6.81(1H，dd，J＝5.1Hz)，7.13(1H，d，J＝3.8Hz)，7.20-7.30(2H，m)，7.80(1H，s)，7.92(1H，d，J＝5.1Hz).

ESI (LC/MS positive mode) m/z: 491(M + H).

Compound 1j-3-19-2 Na:

3- (2- (N-Methylsulfamoyl) amino-3-fluoropyridin-4-ylmethyl) -4, 6-dimethyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran sodium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-3-19-2 instead of Compound 1 j-1-5-1.

¹H NMR(DMSO-d₆)δ(ppm)：7.86(1H，s)，7.50(1H，d，J＝5.2Hz)，7.45(1H，s)，7.35-7.25(2H，m)，6.09(1H，br)，3.87(2H，s)，2.45(3H，s)，2.28(3H，s)，2.27(3H，s).

ESI (LC/MS positive mode) m/z: 491(M +2H-Na).

Compound 1j-3-19-2 c:

3- {2- (cyclopropylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-6-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1j-2-16-2, but using the compound 1h-3-19 instead of the compound 1h-2-16 and cyclopropylamine instead of methylamine.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：0.47-0.55(4H，m)，2.23-2.37(1H，m)，2.28(3H，s)，2.49(3H，s)，4.02(2H，s)，6.76-6.87(1H，m)，7.29(2H，s)，7.47(1H，s)，7.55(1H，brs)，7.89(1H，s)，7.89-7.94(1H，m)，10.48(1H，brs).

ESI (LC/MS positive mode) m/z: 517(M + H).

Compound 1 j-3-20-2:

3- {2- (methylaminosulfonyl) aminopyridin-4-ylmethyl } -4-methyl-6-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

3- (2-Aminopyridin-4-ylmethyl) -7-hydroxy-6-methyl-4-methyl-2-oxo-2H-1-benzopyran (Compound 5d-0-20) was synthesized using compound 5t-0-10 and 4-methylresorcinol under the same conditions as in the preparation of Compound 5 d-0-12.

3- (2-Aminopyridin-4-ylmethyl) -7- (thiazol-2-ylmethyl) -6-methyl-4-methyl-2-oxo-2H-1-benzopyran (Compound 1H-3-20) was synthesized using the same conditions as in the preparation example of Compound 1H-2-4 (Synthesis method 2) except that Compound 5d-0-20 was used instead of Compound 4 a-0-4.

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-3-20 was used instead of Compound 1 h-2-16.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.28(3H，s)，2.45(3H，s)，2.47(3H，s)，3.96(2H，s)，6.82-6.84(2H，m)，6.96(1H，br)，7.27-7.31(2H，m)，7.45(1H，s)，7.87(1H，s)，8..07(1H，d，J＝4..3Hz)，10.25(1H，br).

ESI (LC/MS positive mode) m/z: 473(M + H).

Compound 1 j-3-20-4:

{4- [4, 6-dimethyl-2-oxo-7- (thiazol-2-yloxy) -2H-1-benzopyran-3-ylmethyl]Pyridin-2-yl-sulfamic acid

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.28(3H，s)，2.46(3H，s)，3.90(2H)，6.50-6.55(1H，m)，7.13(1H，s)，7.25-7.35(2H，m)，7.43(1H，s)，7.80-8.00(3H，m).

ESI (LC/MS positive mode) m/z: 460(M + H).

Compound 1 j-3-44-2:

3- {2- (methylaminosulfonyl) amino-3-chloropyridin-4-ylmethyl } -4-methyl-6-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

3- (3-chloro-2-aminopyridin-4-ylmethyl) -7-hydroxy-6-methyl-4-methyl-2-oxo-2H-1-benzopyran (Compound 5d-0-44) was synthesized using compound 5t-0-41 and 4-methylresorcinol under the same conditions as in the preparation example of Compound 5 d-0-12.

Using the same conditions as in the preparation example of Compound 1H-2-4 (Synthesis method 2), 3- (3-chloro-2-aminopyridin-4-ylmethyl) -7- (thiazol-2-yloxy) -6-methyl-4-methyl-2-oxo-2H-1-benzopyran (Compound 1H-0-44) was synthesized using Compound 5d-0-44 in place of Compound 4 a-0-4.

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-3-44 was used instead of Compound 1 h-2-16.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.29(3H，s)，2.43(3H，s)，3.17(3H，dd，J＝1.3，5.3Hz)，4.03(2H，s)，6.73(1H，d，J＝3.3Hz)，9.95(1H，brs).

ESI (LC/MS positive mode) m/z: 507(M + H).

Compound 1j-2a-4-2

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (5-fluoropyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-2a-4 was used instead of Compound 1 h-2-16.

¹H-NMR(Bruker，300MHz， )δ(ppm)：8.44(2H，s)，7.71(1H，d，J＝8.8Hz)，7.40(1H，m)，7.22(1H，d，J＝2.7Hz)，7.17(1H，dd，J＝2.3Hz，J＝9.2Hz)，7.0(2H，m)，6.58(1H，brs)，4.38(1H，m)，4.08(2H，s)，2.76(3H，d，J＝5.3Hz)，2.47(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：488.76(M+H)

Compound 1j-2b-4-2

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (4-chloropyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-2b-4 was used instead of Compound 1 h-2-16.

¹H-NMR(Bruker，300MHz， )δ(ppm)：8.51(1H，d，J＝5.7Hz)，7.72(1H，d，J＝8.8Hz)，7.41(1H，m)，7.20(1H，d，J＝2.3Hz)，7.15(1H，J＝2.3Hz，J＝8.8Hz)，7.01(2H，m)，6.93(1H，d，J＝5.7Hz)，6.58(1H，brs)，4.39(1H，m)，4.09(2H，s)，2.77(3H，d，J＝5.3Hz)，2.48(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：504.63(M+H)

Compound 1j-5-4-2

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (2, 4-dimethoxypyrimidin-6-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-5-4 was used instead of Compound 1 h-2-16.

¹H-NMR(Bruker，300MHz， )δ(ppm)：7.66(1H，d，J＝8.8Hz)，7.40(1H，m)，7.16(1H，d，J＝2.3Hz)，7.12(1H，dd，J＝2.3Hz，J＝8.8Hz)，7.02(1H，m)，6.97(1H，m)，6.61(1H，b r s)，5.88(1H，s)，4.43(1H，m)，4.08(2H，s)，3.98(3H，s)，3.89(3H，s)，2.76(3H，d，J＝5.3Hz)，2.46(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：531.07(M+H)

Compound 1j-3 a-4-2:

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (benzothiazol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-3a-4 was used instead of Compound 1 h-2-16.

¹H NMR(Bruker，300MHz，CDCl₃)δ(ppm)：7.74(2H，m)，7.72(1H，d，J＝8.8Hz)，7.49(1H，d，J＝2.3Hz)，7.38(4H，m)，7.02(1H，m)，6.99(1H，m)，6.62(1H，bs)，4.44(1H，m)，4.09(2H，s)，2.76(3H，d，J＝5.3Hz)，2.48(3H，s).

MS(Micromass，Quttromicro，ESI+)m/z：526.01(M+H).

Compound 1j-3b-4-2

3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (5-bromothiazol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-3b-4 was used instead of Compound 1 h-2-16.

¹H-NMR(Bruker，300MHz， )δ(ppm)：7.69(1H，d，J＝8.8Hz)，7.40(1H，m)，7.30(1H，d，J＝2.3Hz)，7.24(1H，dd，J＝2.3Hz，J＝8.8Hz)，7.20(1H，s)，7.01(1H，m)，6.96(1H，m)，6.61(1H，brs)，4.43(1H，m)，4.07(2H，s)，2.76(3H，d，J＝5.3Hz)，2.46(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：553.79(M)，555.78(M+2)

Compound 1j-1 a-4-2:

dimethylthiocarbamic acid 4-methyl-3- {3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-1a-4 was used instead of Compound 1 h-2-16.

¹H-NMR(Bruker，300MHz， )δ(ppm)：7.66(1H，m)，7.40(1H，m)，7.06(2H，m)，7.01(1H，d，J＝8.0Hz)，6.96(1H，m)，6.58(1H，m)，4.40(1H，m)，4.07(2H，s)，3.47(3H，s)，3.38(3H，s)，2.76(3H，d，J＝5.3Hz)，2.45(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：480.09(M+H)

Compound 1j-2a-16-2

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (5-fluoropyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-2a-16 was used instead of Compound 1 h-2-16.

MS(Micromass，Quttromicro，ESI+)m/z：488.76(M+H)

Compound 1j-2b-16-2

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (4-chloropyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-2b-16 was used instead of Compound 1 h-2-16.

¹H-NMR(Bruker，300MHz， )δ(ppm)：8.52(1H，d，J＝5.7Hz)，7.96(1H，m)，7.73(1H，d，J＝8.8Hz)，7.21(1H，d，J＝2.3Hz)，7.17(1H，dd，J＝2.7Hz，J＝8.8Hz)，7.09(1H，m)，6.94(1H，d，J＝5.7Hz)，6.90(1H，m)，5.47(1H，m)，4.09(2H，s)，2.76(3H，d，J＝5.3Hz)，2.49(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：505.87(M)，507.86(M+2)

Compound 1j-5-16-2

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (2, 4-dimethoxypyrimidin-6-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-5-16 was used instead of Compound 1 h-2-16.

¹H-NMR(Bruker，300MHz， )δ(ppm)：7.94(1H，m)，7.67(1H，d，J＝8.8Hz)，7.18(1H，d，J＝2.3Hz)，7.14(1H，dd，J＝2.3Hz，8.8Hz)，7.09(1H，m)，6.88(1H，m)，5.89(1H，s)，5.47(1H，m)，4.08(2H，s)，3.98(3H，s)，3.89(3H，s)，2.76(3H，d，J＝5.3Hz)，2.47(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：531.91(M+H)

Compound 1j-3 a-16-2:

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-7- (benzothiazol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-3a-16 was used instead of Compound 1 h-2-16.

¹H NMR(Bruker，300MHz，CDC1₃)δ(ppm)：7.94(1H，d，J＝5.3Hz)，7.73(3H，m)，7.52(1H，d，J＝2.3Hz)，7.43(1H，m)，7.39(1H，dd，J＝2.7，8.8Hz)，7.33(1H，m)，7.15(1H，m)，6.88(1H，m)，5.48(1H，m)，4.09(2H，s)，2.76(3H，d，J＝5.3Hz)，2.48(3H，s).

MS(Micromass，Quttromicro，ESI+)m/z：526.73(M+H).

Compound 1j-3b-16-2

3- {2- (A)Aminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (5-bromothia-ne Azol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-3b-16 was used instead of Compound 1 h-2-16.

¹H-NMR(Bruker，300MHz， )δ(ppm)：7.94(1H，m)，7.70(1H，d，J＝8.8Hz)，7.32(1H，d，J＝2.3Hz)，7.26(1H，d，J＝2.7Hz)，7.20(1H，s)，7.09(1H，m)，6.89(1H，m)，5.47(1H，m)，4.07(2H，s)，2.76(3H，d，J＝5.3Hz)，2.46(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：554.62(M)，556.54(M+2)

Compound 1 j-4-16-2:

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (pyrazin-2-yloxy) -2-oxo-2H-1-benzopyran

3- { 2-amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (pyrazin-2-yloxy) -2-oxo-2H-1-benzopyran (compound 1H-4-16) was synthesized using the same conditions as in the preparation of Compound 1H-2-4 (Synthesis method 2) except that Compound 5d-0-16 was used in place of Compound 4a-0-4 and bromopyrazine was used in place of 2-bromopyrimidine.

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-4-16 was used instead of Compound 1 h-2-16.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.44(3H，s)，2.52(3H，s)，4.01(2H，s)，3.96(2H，s)，6.72(1H，d，J＝5.0Hz)，7.10-7.20(2H，m)，7.78-7.85(2H，m)，8.09(1H，dd，J＝1.3，2.5Hz)，8.27(1H，d，J＝2.5Hz)8.42(1H，brs).

ESI (LC/MS positive mode) m/z: 472(M + H).

Compound 1 j-6-16-2:

3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (pyridin-2-yloxy) -2-oxo-2H-1-benzopyran

3- { 2-amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (pyridin-2-yloxy) -2-oxo-2H-1-benzopyran (compound 1H-6-16) was synthesized using the same conditions as in the preparation of Compound 1H-2-4 (Synthesis method 2) except that Compound 5d-0-16 was used instead of Compound 4a-0-4 and 2-bromopyridine was used instead of 2-bromopyrimidine.

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-2-16-2, except that Compound 1h-6-16 was used instead of Compound 1 h-2-16.

¹H NMR(CD₃OD，270MHz)δ(ppm)：2.52(3H，s)，2.60(3H，s)，4.09(2H)，6.75(1H，brt，J＝5.3Hz)，7.07-7.28(4H，m)，7.73(1H，m)，7.83-7.95(2H，m)，8.21(1H，dd，J＝1.2，4.9Hz).

ESI (LC/MS positive mode) m/z: 471(M + H).

Compound 1j-2-47-2

3- (3- (methylaminosulfonyl) aminobenzyl) -4-hydroxyBase-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized by the same method as that for the production of the compound 1j-1-3-2, except that the compound 1h-2-47 was used instead of the compound 1 h-1-3.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：9.51(s，1H)，8.68(d，2H，J＝4.8Hz)，8.00(d，1H，J＝8.2Hz)，7.33(t，1H，J＝4.8Hz)，7.28(d，1H，J＝2.1Hz)，7.19(dd，1H，J＝8.2，2.6Hz)，7.13(d，1H，J＝7.6Hz)，7.02-7.00(m，2H)，6.87(d，1H，J＝7.4Hz)，3.81(s，2H)，2.43(d，3H，J＝4.9Hz).

ESIMS m/z：455(M+H).

Compound 1j-2-51-2

3- (3- (methylaminosulfonyl) aminophenylamino) -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized by the same method as that for the production of the compound 1j-1-3-2, except that the compound 1h-2-51 was used instead of the compound 1 h-1-3.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：9.42(s，1H)，8.69(d，2H，J＝4.8Hz)，7.83(d，1H，J＝8.7Hz)，7.68(s，1H)，7.39(d，1H，J＝2.0Hz)，7.33(t，1H，J＝4.8Hz)，7.28(d，1H，J＝8.7Hz)，7.14(d，1H，J＝5.1Hz)，7.05(t，1H，J＝8.4Hz)，6.61(d，1H，J＝8.4Hz)，6.44(m，2H)，2.42(d，3H，J＝5.4Hz)，2.26(s，3H).

ESIMS m/z：454(M+H).

Compound 1j-1-59-2

3- (2- (methylaminosulfonyl) aminobenzoylamino) -methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized by the same method as that for the production of compound 1j-1-5-2, except that compound 1h-1-59 was used instead of compound 1 h-1-5.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：10.67(s，1H)，10.33(s，1H)，8.07(d，1H，J＝8.1Hz)，7.89(d，1H，J＝8.7Hz)，7.69(q，1H，J＝4.9Hz)，7.62-6.59(m，2H)，7.34(d，1H.J＝2.3Hz)，7.26-7.22(m，2H)，3.08(s，3H)，2.95(s，3H)，2.48(d，3H，J＝4.9Hz)，2.42(s，3H).

ESIMS m/z：475(M+H).

Compound 1 j-20-1-2:

4-methyl-3- (3- (methylaminosulfonyl) aminobenzyl) -7- (1-methyl-1H-imidazol-2-yl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-20-1 was used instead of Compound 1 h-1-5.

¹H-NMR(Bruker(ARX-300)，300MHz，DMSO- )δ(ppm)：9.57(1H，s)，7.93(1H，d，J＝8.39Hz)，7.75(1H，d，J＝8.39Hz)，7.71(1H，s)，7.34(1H，s)，7.21-7.16(2H，m)，7.05(3H，s)，6.88(1H，d，J＝7.25Hz)，3.97(2H，s)，3.85(3H，s)，2.50(3H，s)，2.43(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：439.00(M+1)

Compound 1 j-30-1-2:

N-methyl-N-2-hydroxyethylcarbamic acid 4-methyl-3- (3- (methylaminosulfonyl) aminobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

Compound 1j-0-1-2 (7-hydroxy-4-methyl-3- (3- (methylaminosulfonyl) aminobenzyl) -2-oxo-2H-1-benzopyranyl) was synthesized using the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 4a-0-1 was used instead of Compound 1H-1-5.

The title compound was synthesized using the same conditions as in the preparation example of compound 1j-31-1-2, substituting N-methyl-N-2-hydroxyethylamine for N-methyl-N-carbamoylmethylamine.

¹H-NMR(Bruker(ARX-300)，300MHz，MeOD- )δ(ppm)：7.83(1H，d，J＝8.77Hz)，7.25～7.09(5H，m)，7.03(1H，d，J＝7.25Hz)，4.06(2H，s)，3.78(2H，t)，3.60(2H，t)，3.22-3.10(3H，bs)，2.50(3H，s)，2.46(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：498.35(M+Na)

Compound 1 j-31-1-2:

n-methyl-N-carbamoylmethylcarbamic acid 4-methyl-3- (3- (methylaminosulfonyl) aminobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

Compound 1j-0-1-2 (7-hydroxy-4-methyl-3- (3- (methylaminosulfonyl) aminobenzyl) -2-oxo-2H-1-benzopyran) was synthesized using the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 4a-0-1 was used instead of Compound 1H-1-5.

To a solution of compound 1j-0-1-2(33.4mg, 0.09mmol) in dimethylformamide (1mL) at room temperature were added triethylamine (86. mu.L, 0.62mmol) and p-NO₂PhCOCl (27. mu.L, 0.13mmol) was stirred for 30 minutes, and then N-methyl-N-carbamoylmethylamine (33. mu.L, 0.27mmol) was added and further stirred for 10 minutes. Water was added, the organic layer was extracted with ethyl acetate 2 times, and the extract was purified by silica gel chromatography (dichloromethane: methanol 20: 1) to give the title compound 18mg, 41%.

¹H-NMR(Bruker(ARX-300)，300MHz，MeOD- .(ppm)：7.85(1H，dd，J＝8.39Hz)，7.27～7.10(5H，m)，6.97(1H，d，J＝7.63Hz)，4.09(1H，s)，4.06(3H，s)，3.30-3.21(3H，bs)，2.50(3H，s)，2.46(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：511.42(M+1)

Compound 1 j-1-3-3:

dimethylcarbamic acid 6-chloro-4-methyl-3- {3- (dimethylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl ester

Compound 1h-1-3(50mg, 0.129mmol) was dissolved in dichloromethane (1mL), pyridine (42. mu.L, 0.516mmol) and dimethylsulfamoyl chloride (41. mu.L, 0.387mmol) were added, and the mixture was stirred at room temperature for 24 hours. Subsequently, the reaction solution was distilled under reduced pressure to remove the solvent, and the obtained residue was purified by aminated gel column chromatography (dichloromethane) to give the title compound (50mg, 79%) as a white solid.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.45(3H，s)，2.76(6H，s)，3.05(3H，s)，3.22(3H，s)，4.05(2H，s)，6.80-7.60(5H，m)，7.68(1H，s).

ESI (LC/MS positive mode) m/z: 494(M + H).

Compound 1j-1-3-3 Na:

3- (3- (N, N-Dimethylsulfamoyl) -aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester sodium salt of dimethylcarbamic acid

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-1-3-3 in place of Compound 1 j-1-5-1.

¹H NMR(CD₃OD)δ(ppm)：7.90(1H，s)，7.31(1H，s)，7.03-6.90(3H，m)，6.65(1H，d，J＝7.4Hz)，4.01(2H，s)，3.18(3H，s)，3.02(3H，s)，2.61(6H，s)，2.46(3H，s).

ESI (LC/MS positive mode) m/z: 494(M +2H-Na).

Compound 1 j-1-3-3K:

dimethyl carbamic acid 3- (3- (N)N-Dimethylsulfamoyl) -aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester potassium salt

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-1-3-3 was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

ESI (LC/MS positive mode) m/z: 494(M +2H-K).

Compound 1 j-2-4-3:

3- { 2-fluoro-3- (dimethylaminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-3-3, except that Compound 1h-2-4 was used instead of Compound 1 h-1-3.

¹H-NMR(270MHz，DMSO-d₆) δ (ppm): 2.48(3H, s), 2.69(6H, s), 4.00(2H, s), 6.88-6.97 (1H, m), 6.97-7.06(1H, m), 7.24-7.40(4H, m), 7.91(1H, d, J ═ 8.9Hz), 8.69(2H, d, J ═ 4.8Hz), 9.66(1H, br.s). ESI (LC-MS positive mode) m/z: 485(M + H).

Compound 1j-1b-1-3

3- {3- (dimethyl)Aminosulfonyl) aminobenzyl } -7-isobutoxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-3-3 and substituting Compound 1h-1b-1 for Compound 1 h-1-3.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：0.98(3H，s)，1.00(3H，s)，1.98-2.10(1H，m)，2.41(3H，s)，2.61(6H，s)，3.86(2H，d，J＝6.6Hz)，3.90(2H，s)，6.91(1H，d，J＝7.8Hz)，6.94-7.04(4H，m)，7.18(1H，dd，J＝7.8、7.6Hz)，7.75(1H，d，J＝9.6Hz)，9.79(1H，br.s).

ESI (LC-MS positive mode) m/z: 445(M + H).

Compound 1j-1c-1-3

3- {3- (dimethylaminosulfonyl) aminobenzyl } -7- (2-fluoro-ethoxy) -4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-3-3 and substituting Compound 1h-1c-1 for Compound 1 h-1-3.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.4 3(3H，s)，2.61(6H，s)，3.91(2H，s)，4.28-4.33(1H，m)，4.40-4.44(1H，m)，4.67-4.71(1H，m)，4.84-4.89(1H，m)，6.91(1H，d，J＝7.4Hz)，6.97-7.06(4H，m)，7.18(1H，dd，J＝8.0、7.6Hz)，7.77(1H，d，J＝8.6Hz)，9.79(1H，br.s).

ESI (LC-MS positive mode) m/z: 435(M + H).

Compound 1j-1c-3

3- {3- (dimethylaminosulfonyl) aminobenzyl } -6-chloro-7- (2-fluoro-ethoxy) -4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-3-3 and substituting Compound 1h-1c-3 for Compound 1 h-1-3.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.43(3H，s)，2.62(6H，s)，3.91(2H，s)，4.38-4.43(1H，m)，4.40-4.45(1H，m)，4.70-4.75(1H，m)，4.87-4.92(1H，m)，6.91(1H，d，J＝7.9Hz)，7.00(1H，d，J＝7.9Hz)，7.03(1H，s)，7.18(1H，dd，J＝7.9、7.9Hz)，7.30(1H，s)，7.93(1H，s)，9.80(1H，br.s).

ESI (LC-MS positive mode) m/z: 469(M + H).

Compound 1j-1d-1-3

Pyrrolidine-1-carboxylic acid 3- (3- (dimethylaminosulfonyl) aminobenzyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1j-1-2-3 and the compound 1h-1d-1 in place of the compound 1 h-1-3.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：1.92-2.04(4H，m)，2.45(3H，s)，2.80(6H，s)，3.50(2H，t，J＝6.7Hz)，3.59(2H，t，J＝6.7Hz)，4.03(2H，s)，6.37(1H，brs)，6.97-7.08(3H，m)，7.12-7.16(2H，m)，7.19(1H，d，J＝7.4Hz)，7.61(1H，d，J＝9.4Hz)

ESI (LC/MS positive mode) M/z 486(M + H)

Compound 1 j-11-3-3:

4-methyl-3- (3- (dimethylaminosulfonyl) aminobenzyl) -7- (thiophen-3-yl) -6-chloro-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-3-3, except that Compound 1h-11-3 was used instead of Compound 1 h-1-3.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：7.70(1H，s)，7.58(1H，dd，J＝3.05Hz，J＝1.53Hz)，7.42(1H，dd，J＝4.96Hz，J＝0.60Hz)，7.38Hz(1H，s)，7.35(1H，dd，J＝4.96Hz，J＝1.53hz)，7.22(1H，t，J＝7.63Hz)，7.10(1H，s)，7.02(2H，dd，J＝8.01Hz，J＝1.91Hz)，6.43(1H，s)，4.05(2H，s)，2.82(6H，s)，2.47(3H，s)

MS(Micromass，Quttromicro，ESI-)m/z：487.25(M-1)

Compound 1 j-12-1-3:

4-methyl-3- (3- (dimethylaminosulfonyl) aminobenzyl) -7- (pyridin-4-yl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-3-3, except that Compound 1h-12-1 was used instead of Compound 1 h-1-3.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：8.72(2H，d，J＝4.58Hz)，7.75(1H，d，J＝8.77Hz)，7.59(1H，s)，7.56(1H，dd，J＝6.87Hz，J＝1.91Hz)，7.53(2H，d，J＝5.72Hz)，7.22(1H，d，J＝8.01Hz)，7.10(1H，s)，7.05(1H，d，8.39Hz)，7.02(1H，d，J＝7.25Hz)，6.43(1H，s)，4.08(2H，s)，2.82(6H，s)，2.52(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：450.42(M+1)

Compound 1 j-17-1-2:

4-methyl-3- (3- (methylaminosulfonyl) aminobenzyl) -7- (thiazol-2-yl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-5-2, except that Compound 1h-17-1 was used instead of Compound 1 h-1-5.

¹H-NMR(Bruker(ARX-300)，300MHz，DMSO- )δ(ppm)：9.53(1H，s)，8.02(1H，d，J＝3.05Hz)，7.96(2H，s)，7.92(2H，d，J＝3.43Hz)，7.17(2H，t，J＝8.01Hz)，7.02(2H，s)，6.87(1H，d，J＝7.63Hz)，3.96(2H，s)，2.50(3H，s)，2.42(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：463.98(M+Na)

Compound 1 j-18-1-3:

4-methyl-3- (3- (dimethylaminosulfonyl) aminobenzyl) -7- (pyridin-3-yl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-3-3, except that Compound 1h-18-1 was used instead of Compound 1 h-1-3.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：8.91(1H，s)，8.67(1H，s)，7.92(1H，d，J＝8.01Hz)，7.74(1H，d，J＝8.77Hz)，7.55(1H，s)，7.53(1H，dd，J＝6.10Hz，J＝1.53Hz)，7.43(1H，dd，J＝7.25Hz，J＝0.90Hz)，7.22(1H，d，J＝8.01Hz)，7.11(1H，s)，7.05(1H，d，J＝8.01Hz)，7.02(1H，dd，J＝8.77Hz，J＝1.91Hz)，6.40(1H，s)，4.07(2H，s)，2.82(6H，s)，2.52(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：450.44(M+1)

Compound 1 h-19-3-3:

4-methyl-3- (3- (dimethylaminosulfonyl) aminobenzyl) -6-chloro-7- (3-methoxyphenyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-3-3, except that Compound 1h-19-3 was used instead of Compound 1 h-1-3.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：7.71(1H，s)，7.39(1H，td，J＝9.16Hz，J＝1.14Hz)，7.32(1H，s)，7.22(1H，t，J＝8.01Hz)，7.10(1H，t，J＝1.53Hz)，7.04-6.96(5H，m)，6.40(1H，s)，4.06(2H，s)，3.86(3H，s)，2.82(6H，s)，2.49(3H，s)

MS(Micromass，Quttromicro，ESI-)m/z：511.03(M-1)

Compound 1 h-21-3-3:

4-methyl-3- (3- (dimethylaminosulfonyl) aminobenzyl) -6-chloro-7- (5-acetylthiophen-2-yl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-3-3, except that Compound 1h-21-3 was used instead of Compound 1 h-1-3.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：7.77(2H，m)，7.44(2H，m)，7.26(1H，t)，7.02～7.00(3H，m)，6.76(1H，s)，4.04(2H，s)，2.81(6H，s)，2.59(3H，s)，2.46(3H，s)

MS(Micromass，Quttromicro，ESI-)m/z：529.15(M-H)

Compound 1 j-22-1-3:

4-methyl-3- (3- (dimethylaminosulfonyl) aminobenzyl) -7- (3-acetyl-phenyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-3-3, except that Compound 1h-22-1 was used instead of Compound 1 h-1-3.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：8.22(1H，s)，8.00(1H，d，J＝7.63Hz)，7.81(1H，d，J＝8.01Hz)，7.69(1H，d，J＝8.77Hz)，7.62～7.54(4H，m)，7.22(1H，t)，7.14～7.00(2H，m)，6.48(1H，bs)，3.95(2H，s)，2.81(6H，s)，2.61(3H，s)，2.51(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：513.14(M+Na)

Compound 1 j-23-1-3:

4-methyl-3- (3- (dimethylaminosulfonyl) aminobenzyl) -7- (4-acetyl-phenyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1j-1-3-3 and the compound 1h-23-1 in place of the compound 1 h-1-3.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：8.08(2H，d，J＝8.77Hz)，7.73(4H，d，J＝8.77Hz)，7.56(2H，m)，7.19(3H，m)，6.48(1H，bs)，4.15(2H，s)，2.81(6H，s)，2.65(3H，s)，2.51(3H，s)

MS(Micromass，Quttromicro，ESI-)m/z：489.07(M-1)

Compounds 1j-1 e-1-3:

trifluoromethanesulfonic acid 4-methyl-3- (3- (dimethylaminosulfonyl) aminobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-3-3 and substituting Compound 1h-1e-1 for Compound 1 h-1-3.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：7.63(2H，d，J＝8.77Hz)，7.22(2H，m)，7.09(3H，m)，6.23(1H，bs)，4.02(2H，s)，2.72(6H，s)，2.46(3H，s)

MS(Micromass，Quttromicro，ESI-)m/z：519.14(M-1)

Compound 1 j-24-1-3:

4-methyl-3- (3- (dimethylaminosulfonyl) aminobenzyl) -7- (3-cyano-phenyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1g-11-3, but using the compound 1j-1e-1-3 in place of the compound 1g-1e-3 and 3-cyanophenylboronic acid in place of the thiophene-3-boronic acid.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：7.91(1H，t)，7.82(1H，d，J＝7.63Hz)，7.78～7.65(2H，m)，7.60(1H，t)，7.46(2H，m)，7.20(1H，t)，7.06(1H，s)7.03(2H，t)，6.29(1H，bs)，4.15(2H，s)，2.81(6H，s)，2.51(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：474.27(M+1)

Compound 1 j-25-1-3:

4-methyl-3- (3- (dimethylaminosulfonyl) aminobenzyl) -7- (2-methoxy-phenyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1g-11-3 and using the compound 1j-1e-1-3 in place of the compound 1g-1e-3 and 2-methoxyphenylboronic acid in place of the thiophene-3-boronic acid.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：7.66(1H，d，J＝8.77Hz)，7.58(2H，dd，J＝8.77Hz)，7.51(2H，m)，7.25(1H，t)，7.18(1H，s)，7.05(4H，m)，6.45(1H，bs)，4.15(2H，s)，3.81(3H，s)，2.81(6H，s)，2.49(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：479.37(M+1)

Compound 1 j-26-1-3:

4-methyl-3- (3- (dimethylaminosulfonyl) aminobenzyl) -7- (4-cyano-phenyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1g-11-3, but using the compound 1j-1e-1-3 in place of the compound 1g-1e-3 and 4-cyanophenylboronic acid in place of the thiophene-3-boronic acid.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：7.80～7.70(5H，m)，7.72(2H，m)，7.22(1H，t)，7.10(1H，s)7.03(2H，m)，6.29(1H，bs)，4.15(2H，s)，2.81(6H，s)，2.51(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：474.27(M+1)

Compound 1 j-27-1-3:

4-methyl-3- (3- (dimethylaminosulfonyl) aminobenzyl) -7- (4-methoxy-phenyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1g-11-3 and using the compound 1j-1e-1-3 in place of the compound 1g-1e-3 and 4-methoxyphenylboronic acid in place of the thiophene-3-boronic acid.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：8.08(1H，d，J＝8.01Hz)，7.55(1H，d，J＝1.91Hz)，7.48(1H，dd，J＝8.39Hz)，7.41～7.32(2H，m)，7.22(1H，t)，7.10～6.99(5H，m)，6.29(1H，bs)，4.08(2H，s)，3.84(3H，s)，2.81(6H，s)，2.51(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：474.27(M+1)

Compound 1 j-28-1-3:

4-methyl-3- (3- (dimethylaminosulfonyl) aminobenzyl) -7- (4-N, N-dimethylaminophenyl) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 1j-1-3-3, except that Compound 1h-28-1 was used instead of Compound 1 h-1-3.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：7.61(5H，m)，7.25(1H，t)，7.15～7.08(3H，s，t)，6.82(2H，d，J＝8.77Hz)，6.39(1H，bs)，4.04(2H，s)，3.02(6H，s)，2.79(6H，s)，2.43(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：492.32(M+1)

Compound 1 j-29-1-3:

4-methyl-3- (3- (dimethylaminosulfonyl) aminobenzyl) -7- (benzo [1, 3)]Dioxol-4-yl) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1g-11-3, but using the compound 1j-1e-1-1 in place of the compound 1g-1e-3 and the benzo [1, 3] dioxole-4-boronic acid in place of the thiophene-3-boronic acid.

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：7.63(1H，d，J＝8.77Hz)，7.46(2H，m)，7.23(1H，t)，7.13(5H，m)，6.92(1H，d，J＝8.01Hz)，6.48(1H，s)，6.02(2H，s)，4.04(2H，s)，2.80(6H，s)，2.47(3H，s)

MS(Micromass，Quttromicro，ESI-)m/z：491.34(M-1)

Compound 1 j-1-21-2:

3- (3- (N- (2-cyanoethyl) sulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The corresponding sulfamoyl chloride was prepared by dissolving sulfonyl chloride (66.5. mu.L, 872. mu. mol) in dichloromethane (4mL), adding 2-cyanoethylamine (57.2. mu.L, 776. mu. mol) and DMAP (94.7mg, 776. mu. mol) at-78 ℃ and stirring at room temperature for 2 hours. To the reaction solution were added 3- (3-aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-chromen-7-yl dimethylcarbamate (100mg, 258.5. mu. mol), pyridine (0.5mL) and dichloromethane (2mL), and the mixture was stirred at room temperature overnight. Thereafter, water was added to the reaction solution, followed by extraction with dichloromethane. After washing with an aqueous sodium hydrogencarbonate solution and a saturated saline solution, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol: dichloromethane ═ 1: 20) to obtain the title compound (111mg, 83%).

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.44(3H，s)，2.44-2.55(2H，m)，3.04(3H，s)3.17(3H，s)，3.15-3.30(2H，m)，3.99(2H，s)，6.92-7.15(3H，m)，7.20(1H，s)，7.15-7.25(1H，m)，7.66(1H，s).

ESI (LC/MS positive mode) m/z: 519(M + H).

Compound 1j-1-21-2 Na:

3- (3- (N- (2-cyanoethyl) sulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester sodium salt of dimethylcarbamic acid

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, but using Compound 1j-1-21-2 instead of Compound 1 j-1-5-1.

¹H NMR(CD₃OD)δ(ppm)：7.89(1H，s)，7.30(1H，s)，7.04-6.98(3H，m)，6.70(1H，d，J＝7.4Hz)，3.99(2H，s)，3.17(3H，s)，3.02(3H，s)，2.57-2.52(2H，m)，2.48(3H，s).

ESI (LC/MS positive mode) m/z: 519(M +2H-Na).

Compound 1 j-1-21-2K:

3- (3- (N- (2-cyanoethyl) sulfamoyl) aminobenzyl) -6-chloro-4-methyl dimethylcarbamate Potassium salt of a 2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by using the same conditions as in the preparation example of Compound 1j-1-5-1Na, except that Compound 1j-1-21-2 was used instead of Compound 1j-1-5-1 and KOH was used instead of NaOH.

ESI (LC/MS positive mode) m/z: 519(M +2H-K).

Compound 1 j-1-22-2:

3- (3- (N- (2-hydroxyethyl) sulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized using 2-aminoethanol instead of 2-cyanoethylamine under the same conditions as in the preparation example of compound 1 j-1-21-2.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.44(3H，s)，3.05(3H，s)，3.12(2H，m)3.17(3H，s)，3.52(2H，br)，4.02(2H，s)，6.92-7.05(2H，m)，7.09(1H，brs)，7.19-7.30(1H，m)，7.66(1H，s).

ESI (LC/MS positive mode) m/z: 510(M + H).

Compound 1 j-1-23-2:

3- (3- (N- (2-methoxyethyl) sulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized using 2-methoxyethylamine instead of 2-cyanoethylamine under the same conditions as in the preparation example of compound 1 j-1-21-2.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.44(3H，s)，3.05(3H，s)，3.17(3H，s)，3.15-3.25(2H，s)，3.41(3H，s)，3.45-3.55(2H，m)，4.01(2H，s)，6.95-7.20(2H，m)，7.09(1H，s)，7.19-7.30(1H，m)，7.25(1H，s)，7.66(1H，s).

ESI (LC/MS positive mode) m/z: 524(M + H).

Compound 1 j-1-24-2:

3- (3- (N- (2-aminoethyl) sulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester hydrochloride

The title compound was synthesized using 1, 2-ethylenediamine instead of 2-cyanoethylamine under the same conditions as in the preparation example of compound 1 j-1-21-2.

¹H-NMR(CD₃OD，270MHz)δ(PPM)：2.51(3H，s)，2.95-3.05(2H，m)，3.05(3H，s)，3.14-3.25(2H，m)，3.17(3H，s)，4.05(2H，s)，6.97(1H，d，J＝8.1Hz)，7.08(1H，d，J＝8.1Hz)，7.12(1H，brs)，7.22(1H，dd，J＝8.1Hz)，7.32(1H，s)，7.93(1H，s).

ESI (LC/MS positive mode) m/z: 509(M-Cl).

Compound 1 j-1-25-2:

3- (3- (N- (2, 3-dihydroxypropyl) sulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized using 2, 3-dihydroxypropylamine instead of 2-cyanoethylamine under the same conditions as in the preparation example of compound 1 j-1-21-2.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.38(3H，s)，3.05(3H，s)，3.16(3H，s)，3.30-3.50(2H，m)，3.52-3.70(1H，m)，3.89(2H，s)，6.86(1H，d，J＝7.7Hz)，6.99(1H，d，J＝7.7Hz)，7.05(1H，s)，7.07(1H，d，J＝7.7Hz)，7.13(1H，s)，7.60(1H，s).

ESI (LC/MS positive mode) m/z: 540(M + H).

Compound 1 j-1-26-2:

dimethylcarbamic acid 6-chloro-4-methyl-3- [3- (4-methylpiperazin-1-ylsulfonylamino) -benzyl]-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized using 1-methylpiperazine instead of 2-cyanoethylamine under the same conditions as in the preparation example of the compound 1 j-1-21-2.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.22(3H，s)，2.25-2.36(4H，m)，2.43(3H，s)，3.05(3H，s)，3.18(3H，s)，3.20-3.30(2H，m)，4.01(2H，s)，6.95-7.08(2H，m)，7.15-7.30(3H，m)，7.65(1H，s).

ESI (LC/MS positive mode) m/z: 549(M + H).

Compound 1 j-1-28-2:

3- (3- (N- (N' -methyl-2-aminoethyl) methylsulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester hydrochloride

The title compound was synthesized using 2-methylaminoethylamine instead of 2-cyanoethylamine under the same conditions as in the preparation example of the compound 1 j-1-21-2.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.41(3H，brs)，3.00(6H，s)，3.05(3H，brs)，3.17(3H，brs)，3.50-3.65(2H，m)，3.65-3.75(2H，m)，3.98(2H，brs)，6.70-7.60(5H，m)，7.60(1H，brs).

ESI (LC/MS positive mode) m/z: 523(M-Cl).

Compound 1 j-1-29-2:

dimethylcarbamic acid 6-chloro-3- [3- (3, 4-dihydro-1H-isoquinolin-2-ylsulfonylamino) -benzyl]-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized using isoquinoline in place of 2-cyanoethylamine under the same conditions as in the preparation of compound 1 j-1-21-2.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.30(3H，s)，2.74(2H，m)，3.10(3H，s)，3.17(3H，s)，3.48(2H，m)，3.95(2H，s)，4.42(2H，s)，6.92-7.27(9H，m)，7.56(1H，s).

ESI (LC/MS positive mode) m/z: 582(M + H).

Compound 1 j-1-30-2:

3- (3- (N-2, 2, 2-trifluoroethyl-sulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized using 2, 2, 2-trifluoroethylamine instead of 2-cyanoethylamine under the same conditions as in the preparation example of the compound 1 j-1-21-2.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.45(3H，s)，3.04(3H，s)，3.18(3H，s)，3.55-3.70(2H，m)，4.02(2H，s)，7.00-7.10(3H，m)，7.20-7.30(1H，m)，7.62(1H，s).

ESI (LC/MS positive mode) m/z: 548(M + H).

Compound 1 j-1-31-2:

3- (3- (N-Methoxysulfamoyl) aminobenzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized using o-methylhydroxylamine instead of 2-cyanoethylamine under the same conditions as in the preparation of compound 1 j-1-21-2.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：2.45(3H，s)，3.04(3H，s)，3.18(3H，s)，3.76(3H，s)，4.02(2H，s)，6.78(1H，brs)，7.00-7.30(3H，m)，7.65(1H，s).

ESI (LC/MS positive mode) m/z: 496(M + H).

Compound 1 j-1-32-2:

dimethylcarbamic acid 3- [3- (2-acetylamino-ethanesulfonylamino) -benzyl ]-6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-ylEsters

Compound 1h-1-3(5.8g, 15mmol), 2-phthalimidoethanesulfonyl chloride (6.1g), triethylamine (10.4ml) were stirred at room temperature in dichloromethane overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic extract was washed with hydrochloric acid, soda water, and saturated saline. After drying over magnesium sulfate, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain compound (9.4 g).

The compound (5.0g) obtained above and hydrazine monohydrate (0.94mL) were stirred overnight at room temperature in a mixed solvent of ethanol and THF. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic extract was washed with soda water and saturated brine. After drying over magnesium sulfate, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain compound (848 mg).

The compound (50.8mg) obtained above was stirred with acetyl chloride (9.5. mu.L) and triethylamine (28.5. mu.L) in dichloromethane at 0 ℃ for 2 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic extract was washed with soda water and saturated brine. After drying over magnesium sulfate, the reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title compound (56 mg).

¹H-NMR(CDCl₃，270MHz)δ(PPM)1.88(3H，s)，2.25(3H，s)，3.04(3H，s)，3.10-3.30(5H，m)，3.50-3.70(2H，m)，4.00(2H，s)，6.95-8.00(6H，m)

ESI (LC/MS positive mode) M/z 536(M + H)

Compound 1j-1-33-2

Dimethylcarbamic acid 6-chloro-4-methyl-2-oxo-3- [3- (2-oxo-oxazolidine-3-sulfonylamino) Radical) -benzyl radical]-2H-1-benzopyran-7-yl ester

The title compound was synthesized by the same method as that for the production of compound 1j-1-21-2, using oxazolidinone instead of 2-cyanoethylamine.

¹H-NMR(CDCl₃，270MHz)δ(PPM)2.25(3H，s)，2.95(3H，s)，3.10(3H，s)，3.60-3.80(2H，m)，3.98(2H，s)，4.10-4.30(2H，m)，6.95-7.10(3H，m)，7.25(1H，t，J＝7.7Hz)，7.50(1H，s)，8.05(1H，s)，10.80(1H，brs)

ESI (LC/MS positive mode) M/z 536(M + H)

Compound 1j-1d-1-2

Pyrrolidine-1-carboxylic acid 3- (3- (N-methylsulfamoyl) -amino-benzyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by the same method as that for the production of compound 1j-1-3-2, except that compound 1h-1d-1 was used instead of compound 1 h-1-3.

ESI (LC/MS positive mode) M/z 472(M + H)

Compound 1j-1-72-2

Dimethyl-carbamic acid 3- (3- (N-methylsulfamoyl) -amino-benzyl) -4-methyl-2-oxo-2H-pyrano [2, 3-b]Pyridin-7-yl esters

The title compound was synthesized by the same method as that for the production of compound 1j-1-3-2, except that compound 1h-1-72 was used instead of compound 1 h-1-3.

ESI (LC/MS positive mode) M/z 447(M + H)

Compound 1 o-2-4-2:

2- { 2-fluoro-3- [ 4-methyl-2-oxo-7- (pyrimidin-2-yloxy) -2H-1-benzopyran-3-ylmethyl]Phenylsulfamoyl } -N-methyl-acetamide

Procedure 1 (preparation of THF solution of Compound 11-1):

to a solution of chlorosulfonylacetyl chloride (1180. mu.L, 1.69mmol) in THF (3mL) at 0 ℃ was added 2-propanol (130. mu.L, 1.69mmol) under a nitrogen atmosphere, and the mixture was stirred at 0 ℃ for 20 minutes. After that, the mixture was stirred at room temperature for 2 hours to quantitatively obtain a THF solution of Compound 11-1.

Step 2 (Synthesis of Compound 1 m-2-4):

to a solution of compound 1h-2-4(214.4mg, 0.568mmol) and diisopropylethylamine (228. mu.L, 1.306mmol) in THF (8mL) under a nitrogen atmosphere was added dropwise a solution of compound 11-1 obtained in step 1 in THF (1.04mL, 0.585 mmol). After stirring at room temperature for 40 minutes, a solution of sodium hydroxide (46.9mg, 2.346mmol) dissolved in water (8mL) and methanol (0.5mL) were added and the mixture was stirred for 1 hour. Then, ethyl acetate (40mL) was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid (20mL) 2 times and then with saturated saline (30mL) 1 time. The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (dichloromethane: methanol ═ 10: 1), to give compound 1m-2-4(65.9mg, 23%) as a pale yellow solid.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.4 7(3H，s)，3.67(2H，s)，4.00(2H，s)，6.80-6.88(1H，m)，6.95-7.04(1H，m)，7.22-7.36(3H，m)，7.38(1H，d，J＝2.3Hz)，7.91(1H，d，J＝8.9Hz)，8.69(2H，d，J＝4.8Hz).

ESI (LC-MS positive mode) m/z: 500(M + H).

Step 3 (Synthesis of Compound 1 o-2-4-2):

to the compounds 1M-2-4(32mg, 0.064mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (14.5mg, 0.076mmol) and 3-hydroxy-3, 4-dihydro-4-oxo-1, 2, 3-benzotriazole (12.4mg, 0.076mmol) were added N, N-dimethylformamide (1mL), and then 2.0M methylamine in THF (96. mu.L, 0.192mmol) and diisopropylethylamine (22.3. mu.L, 0.128mmol) were added, followed by stirring at room temperature under a nitrogen atmosphere for 19 hours. Then, ethyl acetate (20mL) was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid (20mL) for 2 times, then washed with a saturated aqueous sodium bicarbonate solution (20mL) for 3 times, and further washed with a saturated saline solution for 1 time. The obtained organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 10: 1) to give the title compound (9mg, 28%) as a white solid.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.48(3H，s)，2.61(3H，d，J＝4.5Hz)，4.00(2H，s)，6.95-7.11(2H，m)，7.25-7.30(4H，m)，7.92(1H，d，J＝8.9Hz)，8.15-8.23(1H，m)，8.69(2H，d，J＝4.8Hz)，9.71(1H，s).

ESI (LC-MS positive mode) m/z: 513(M + H).

Compound 1 o-1-3-1:

dimethylcarbamic acid 3- (3-carbamoylmethanesulfonylamino-benzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by substituting the compound 1h-1-3 for the compound 1h-2-4 in the step 2 and the methylamine in the step 3 with ammonia under the same conditions as in the preparation example of the compound 1 o-2-4-2.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.47(3H，s)，2.95(3H，s)，3.11(3H，s)，3.86(2H，s)，3.96(2H，s)，6.96(1H，d，J＝5.4Hz)，7.03-7.08(2H，m)，7.21(1H，m)，7.34(1H，br)，7.50(1H，s)，7.60(1H，br)，8.02(1H，s)，9.78(1H，br).

ESI (LC/MS positive mode) m/z: 508(M + H).

Compound 1o-1-8-1

Dimethyl-carbamic acid 3- (3-carbamoylmethanesulfonylamino-benzyl) -4, 6-dimethyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by using the same conditions as in the preparation example of the compound 1o-2-4-2, but using the compound 1h-1-8 instead of the compound 1h-2-4 and ammonia instead of methylamine.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.18(3H，s)，2.23(3H，s)，2.94(3H，s)，3.09(3H，s)，3.86(2H，s)，3.95(2H，s)，6.43-6.69(1H，m)，6.76-7.31(4H，m)，7.74(1H，s)

ESI (LC/MS positive mode) M/z 488(M + H)

Compound 1 o-1-3-2:

dimethylcarbamic acid 3- (3-methylcarbamoylmethanesulfonylamino-benzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by using the compound 1h-1-3 in place of the compound 1h-2-4 in the step 2 under the same conditions as in the preparation example of the compound 1 o-2-4-2.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.47(3H，s)，2.56(3H，d，J＝5.4Hz)，2.95(3H，s)，3.11(3H，s)，3.87(2H，s)，3.96(2H，s)，6.98(1H，d，J＝8.1Hz)，7.03-7.09(2H，m)，7.22(1H，m)，7.50(1H，s)，8.02(1H，s)，8.14(1H，d，J＝5.4Hz)，9.78(1H，br).

ESI (LC/MS positive mode) m/z: 522(M + H).

Compound 1o-1-8-2

Dimethyl-carbamic acid 4, 6-dimethyl-3- (3-methylcarbamoylmethanesulphonylamino-benzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 1o-2-4-2, except that Compound 1h-1-8 was used instead of Compound 1 h-2-4.

¹H-NMR(DMSO-d₆270MHz) δ (PPM): 2.17(3H, s), 2.23(3H, s), 2.94(3H, s), 3.09(3H, s), 3.88(2H, s), 3.95(2H, s), 6.97(1H, d, J ═ 8.4Hz), 7.05-7.12(2H, m), 7.17-7.27(2H, m), 7.75(1H, s) (-one peak of CH3 overlaps with the DMSO peak.)

ESI (LC/MS positive mode) M/z 502(M + H)

Compound 1o-1-40-2

Dimethyl-carbamic acid 6-ethynyl-4-methyl-3- (3-methylcarbamoylmethanesulphonylamino-benzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 1o-2-4-2, except that Compound 1h-1-40 was used instead of Compound 1 h-2-4.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.17(3H，s)，2.94(3H，s)， 3.09(3H，s)，3.88(2H，s)，3.96(2H，s)，4.43(1H，s)，6.99(1H，d，J＝6.3Hz)，7.05-7.13(2H，m)，7.20-7.26(2H，m)，7.38(1H，s)，7.99(1H，s)，9.77(1H，s)(-CH₃Overlaps with the peak of DMSO. )

ESI (LC/MS positive mode) M/z 512(M + H)

Compound 1 o-1-1-3:

dimethyl-carbamic acid 3- (3-dimethylcarbamoylmethanesulphonylamino-benzyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by the same method as that for the preparation of compound 1o-2-4-2, except that compound 1h-1-1 was used instead of compound 1h-2-4 and dimethylamine was used instead of methylamine.

¹H-NMR(CDCl₃，270MHz)δ(PPM)2.46(3H，s)，2.75(3H，s)，2.94(6H，s)，3.06(3H，s)，3.94(2H，s)，6.92(1H，d，J＝6.5Hz)，7.00-7.25(5H，m)，7.83(1H，d，J＝7.8Hz)

ESI (LC/MS positive mode) M/z 502(M + H)

Compound 1 o-1-3-3:

dimethylcarbamic acid 3- (3-dimethylcarbamoylmethanesulfonylamino-benzyl) -6-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by using the same conditions as in the preparation example of compound 1o-2-4-2, except that compound 1h-1-3 was used instead of compound 1h-2-4 in step 2 and dimethylamine was used instead of methylamine in step 3.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.47(3H，s)，2.76(3H，s)，2.91(3H，s)，2.94(3H，s)，3.10(3H，s)，3.96(2H，s)，4.19(2H，s)，6.98(1H，d，J＝8.1Hz)，7.03-7.09(2H，m)，7.23(1H，m)，7.50(1H，s)，8.02(1H，s)，9.85(1H，br).

ESI (LC/MS positive mode) m/z: 537(M + H).

Compound 1 o-3-1-1:

2- {3- [ 4-methyl-2-oxo-7- (thiazol-2-yloxy) -2H-1-benzopyran-3-ylmethyl]-phenylsulfamoyl } -acetamide

The title compound was synthesized by the same method as that for the preparation of compound 1o-2-4-2, except that compound 1h-3-1 was used instead of compound 1h-2-4 and ammonia was used instead of methylamine.

¹H-NMR(CDCl₃，270MHz)δ(PPM)2.46(3H，s)，3.88(2H，s)，4.00(2H，s)，6.90-7.65(9H，m)，

ESI (LC/MS positive mode) M/z 486(M + H)

Compound 1 o-3-1-2:

n-methyl-2- {3- [ 4-methyl-2-oxo-7- (thiazol-2-yloxy) -2H-1-benzopyran-3-ylmethyl]-phenylsulfamoyl } -acetamide

The title compound was synthesized by the same method as that for the preparation of compound 1o-2-4-2, except that compound 1h-3-1 was used instead of compound 1 h-2-4.

¹H-NMR(CDCl₃，270MHz)δ(PPM)2.46(3H，s)，2.76-2.78(1H，m)，3.88(2H，s)，4.00(2H，s)，6.90-7.65(9H，m)，

ESI (LC/MS positive mode) M/z 500(M + H)

Compound 1 o-3-4-2:

2- { 2-fluoro-3- [ 4-methyl-2-oxo-7- (thiazol-2-yloxy) -2H-1-benzopyran-3-ylmethyl]Phenylsulfamoyl } -N-methyl-acetamide

The title compound was synthesized by using the compound 1h-3-4 in step 2 instead of the compound 1h-2-4 under the same conditions as in the preparation example of the compound 1 o-2-4-2.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.46(3H，s)，2.60(3H，d，J＝4.6Hz)，3.97(2H，s)，3.99(2H，s)，6.92-7.07(2H，m)，7.28-7.39(4H，m)，7.50(1H，d，J＝2.6Hz)，7.95(1H，d，J＝8.7Hz)，8.18(1H，d，J＝4.6Hz).

ESI (LC/MS positive mode) m/z: 518(M + H).

Compound 1 o-3-1-3:

n, N-dimethyl-2- {3- [ 4-methyl-2-oxo-7- (thiazol-2-yloxy) -2H-1-benzopyran-3-ylmethyl ]-phenylsulfamoyl } -acetamide

The title compound was synthesized by the same method as that for the preparation of compound 1o-2-4-2, except that compound 1h-3-1 was used instead of compound 1h-2-4 and dimethylamine was used instead of methylamine.

¹H-NMR(CDCl₃，270MHz)δ(PPM)2.46(3H，s)，2.98(3H，s)，3.04(3H，s)，3.88(2H，s)，4.00(2H，s)，6.90-7.65(9H，m)，

ESI (LC/MS positive mode) M/z 514(M + H)

Compound 1 j-1-6-4:

dimethyl-carbamic acid 3- (3-methanesulfonylamino-benzyl) -4, 6-dimethyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by the same method as that for the production of the compound 1j-2-16-2 except that the compound 1h-1-6 was used in place of the compound 1h-2-16 and methane sulfonic acid chloride was used in place of N-methylaminosulfonyl chloride.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.22(3H，s)，2.49(3H，s)，2.89(6H，s)，3.04(3H，s)，3.95(2H，s)，6.96(1H，d，J＝7.6Hz)，7.00-7.08(2H，m)，7.18-7.28(2H，m)，7.75(1H，s)，9.63(1H，brs)

ESI (LC/MS positive mode) M/z 445(M + H)

Compound 1 j-1-10-4:

3- (2-Methanesulfonylaminopyridin-4-ylmethyl) -4-methyl-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized by the same method as that for the production of the compound 1j-2-16-2 except that the compound 1h-1-10 was used in place of the compound 1h-2-16 and methanesulfonyl chloride was used in place of N-methylaminosulfonyl chloride.

¹H NMR(300MHz，DMSO-d₆)δ(ppm)：10.73(brs，1H)，8.06(d，1H，J＝5.1Hz)，7.87(d，1H，J＝9.0Hz)，7.26(d，1H，J＝2.1Hz)，7.19(dd，1H，J＝8.7，6.0Hz)，6.85(d，1H，J＝5.4Hz)，6.78(s，1H)，3.96(s，2H)，3.20(s，3H)，3.07(s，3H)，2.93(s，3H)，2.46(s，3H).

ESIMS m/z：432(M+H).

Compound 1j-1-3-4CONH 2:

dimethylcarbamic acid 4-carbamoylmethyl-6-chloro-3- (3- (methanesulfonyl) aminobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

To a solution of 3- (3-aminobenzyl) -4-carbamoylmethyl-6-chloro-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate (20mg, 0.047mmol) in dichloromethane (1.0mL) was added Et3N (13L, 0.093mmol) and methanesulfonyl chloride (3.6L, 0.050mmol), and the mixture was stirred at room temperature for 2 hours. The solvent was removed by distillation by concentration under reduced pressure, and the obtained residue was purified by column chromatography to give the title compound (5.0mg, 22%) as a white solid.

¹H NMR(270MHz，DMSO-d₆+CD₃OD(1∶4))δ(ppm)：8.57(s，1H)，8.07(s，1H)，7.90(m，1H)，7.82-7.74(m，3H)，4.74(s，2H)，4.64(s，2H)， 3.86(s，3H)，3.76(s，3H)，3.70(s，3H).

ESIMS m/z：508(M+H).

Compound 1j-1-3-4CONMe 2:

dimethylcarbamic acid 6-chloro-4-dimethylcarbamoylmethyl-3- (3- (methanesulfonyl) aminobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the production method of the compound 1j-1-3-4CONH2, using the compound 7d-1-3CONMe2 in place of the compound 7d-1-3CONH 2.

¹H NMR(270MHz，CDCl₃)δ(ppm)：7.40(s，1H)，7.24-7.19(m，2H)，7.07-7.00(m，3H)，3.97(s，2H)，3.80(s，2H)，3.16(s，3H)，3.12(s，3H)，3.04(s，3H)，2.95(s，3H)，2.92(s，3H).

ESIMS m/z：536(M+H).

(general preparation methods-2 and-3)

Next, production examples related to the above-mentioned general production methods-2 and-3 will be explained.

Compound 2 a-1:

2-fluoro-1-methyl-3-nitrobenzene

Cesium fluoride (97.5g, 642mmol) was added to a DMSO (185mL) solution of 2-chloro-1-methyl-3-nitrobenzene (73.4g, 428mmol) under a nitrogen atmosphere and stirred at 140 ℃ for 10 hours. Thereafter, the reaction mixture was poured into 0.5N hydrochloric acid, and extracted 2 times with ethyl acetate. The organic extract was washed with saturated brine and dried over magnesium sulfate. Then, the crude product was obtained by concentration under reduced pressure, and purified by distillation under reduced pressure (boiling point 118 to 122 ℃/15mmHg) to obtain the title compound (54.4g, 82%) as a yellow oil.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：7.9 6(m，1H)，7.73(m，1H)，7.34(t，J＝8.2Hz，1H)，2.35(d，J＝2.4Hz，3H).

HPLC Rt＝2.03min.

HPLC conditions:

column: combi ODS (ODS, 5 μm, 4.6mm I.D.x.50 mm, Wauters Co., Ltd.), COSMOSIL (ODS, 5 μm, 4.6mm I.D.x.50 mm, manufactured by nacalai tesque), Intersil C18(ODS, 5 μm, 4.6mm I.D.x.50 mm, manufactured by GL sciences), or SunAire C18(ODS, 5 μm, 4.6mm I.D.x.50 mm, manufactured by Waters);

Mobile phase: water (a) containing 0.05% trifluoroacetic acid, and acetonitrile (B) containing 0.05% trifluoroacetic acid;

dissolution method: stepwise solvent gradient dissolution (after changing the solvent composition from 10% B to 95% B over 3.5 minutes, change to 10% B over 1 minute, and hold at 10% B for 0.5 minutes);

flow rate: 4.0 mL/min.

Compound 1 a-1:

1-bromomethyl-2-fluoro-3-nitrobenzene

Benzoyl peroxide (10.7g, 44mmol) was added to a solution of 2-fluoro-1-methyl-3-nitrobenzene (compound 2a-1) (68.2g, 440mmol) and N-bromosuccinimide (95.0g, 528mmol) in carbon tetrachloride (1500mL) under nitrogen atmosphere at reflux, and the mixture was stirred at reflux for 5 hours. Thereafter, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. This was purified by column chromatography (hexane) to give the title compound (68.7g, 65%) as a yellow to pale brown oil.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：8.14(dd，J＝7.0，1.6Hz，1H)，7.97(dd，J＝6.5，1.6Hz，1H)，7.46(td，J＝8.4，1.4Hz，1H)，4.81(d，J＝1.4Hz，2H).

HPLC Rt＝2.25min.

HPLC conditions were the same as those in the production example of Compound 2 a-1.

Compound 3 a-1:

2-chloro-3-nitrobenzoic acid methyl ester

Concentrated sulfuric acid (2.0mL) was added to a solution of 2-chloro-3-nitrobenzoic acid (10.0g, 49.6mmol) in methanol (80mL) and stirred at reflux overnight. After methanol was removed by concentration under reduced pressure, water was added, and extraction was performed with ethyl acetate. The organic extract was washed with water, a saturated aqueous sodium bicarbonate solution and a saturated saline in this order, and dried over magnesium sulfate. Subsequently, concentration under reduced pressure gave the title compound (10.6g, 99%) as a white solid.

¹H-NMR(CDCl₃)δ(ppm)：7.95(dd，1H)，7.84(dd，1H)，7.48(t，1H)，3.98(s，3H).

HPLC Rt＝11.88min.

HPLC conditions:

column: YMC-ODS A (150X6.0 mm);

eluent: mecn/H2O ═ 10/90to 100/0 (gradient);

mecn/H2O ═ 100/0 (isocratic);

flow rate: 1mL/min.

Compound 2 b-1:

2-fluoro-3-nitrobenzoic acid methyl ester

To a solution of methyl 2-chloro-3-nitrobenzoate (10.6g, 49.0mmol) in DMSO (49mL) was added cesium fluoride (11.2g), and the mixture was stirred at 140 ℃ for 40 minutes. After that, the reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and saturated brine in this order, and dried over magnesium sulfate. Subsequently, concentration under reduced pressure gave the title compound (9.23g, 95%) as a pale yellow solid.

¹H-NMR(CDCl₃)δ(ppm)：8.24-8.11(m， 2H)，7.37(t，1H)，3.98(s，3H).

HPLC Rt＝14.62min.

HPLC conditions were the same as those in the preparation example of Compound 3 a-1.

Compound 2 c-1:

(2-fluoro-3-nitrophenyl) methanol

DIBAL (115.7mL, 1.0M in toluene) was added to a solution of methyl 2-fluoro-3-nitrobenzoate (compound 2b-1) (9.22g, 46.3mmol) in toluene (92mL) at-78 deg.C, and the reaction mixture was stirred at-78 deg.C for 30min and at 0 deg.C for 30min. The resulting reaction solution was cooled again to-78 ℃, methanol, a saturated aqueous solution of Rochelle salt and ethyl acetate were added, stirred at room temperature for 1 hour, and the reaction mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. Subsequently, concentration under reduced pressure gave the title compound (7.52g, 95%) as a tan oil.

¹H-NMR(CDCl₃)δ(ppm)：7.95(m，1H)，7.84(t，1H)，7.31(t，1H)，4.87(s，2H).

HPLC Rt＝7.52min.

Compound 2c-2

4-fluoro-3-nitrobenzyl alcohol

To a solution of 4-fluoro-3-nitrobenzaldehyde (2.0g, 11.83mmol) in methanol (15mL) + water (3.0mL) was added sodium borohydride (1.36g, 35.95mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.10g, 95%) as a pale red oil.

¹H NMR(270MHz，CDCl₃)δ(ppm)：8.06(dd，1H，J＝7.1，2.2Hz)， 7.64(m，1H)，7.28(dd，1H，J＝10.7，8.6Hz)，4.76(s，2H).

Compound 1 a-1:

1-bromomethyl-2-fluoro-3-nitrobenzene

To a solution of (2-fluoro-3-nitrophenyl) methanol (compound 2c-1) (7.52g, 46.3mmol) in anhydrous diethyl ether (130mL) at 0 ℃ was added a solution of phosphorus tribromide (4.8mL) in anhydrous diethyl ether (100mL), and the mixture was stirred at 0 ℃ for 30 minutes. After that, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic extract was washed with a saturated aqueous sodium bicarbonate solution, water and a saturated saline solution in this order, and dried over magnesium sulfate. Subsequently, concentration under reduced pressure gave the title compound (7.10g, 70%) as a tan oil.

HPLC Rt＝2.25min.

Compound 1a-2

2-bromomethyl-4-fluoro-3-nitrobenzene

To a solution of 4-fluoro-3-nitrobenzyl alcohol (2.1g, 11.23mmol) in diethyl ether (40mL) was added phosphorus tribromide (1.13mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution. After drying over magnesium sulfate, the residue obtained by concentration under reduced pressure was purified by column chromatography, whereby the title compound (2.50mg, 95%) was obtained as a pale yellow solid.

¹H NMR(270MHz，CDCl₃)δ(ppm)：8.10(dd，1H，J＝7.1，2.2Hz)， 7.67(m，1H)，7.29(dd，1H，J＝10.7，8.6Hz)，4.49(s，2H).

Compound 2c-73

(5-Nitro-thiophen-2-yl) methanol

To a solution of (5-nitrothiophen-2-yl) aldehyde (1.03g, 6.55mmol) in methanol (10mL) under ice-cooling was slowly added NaBH₄(248mg, 6.55 mmol). After warming to room temperature and stirring for 4 hours, 1N HCl solution (20mL) was added and extracted 2 times with ethyl acetate (40 mL). The organic layer was purified by silica gel chromatography (hexane: ethyl acetate 3: 1) to give the title compound (917mg, 88%).

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：7.82(1H，d，J＝3.82Hz)，6.93(1H，d，J＝4.20Hz)，4.88(2H，s)，2.21(1H，s)

Compounds 1a-73

Methanesulfonic acid (5-nitro-thiophen-2-yl) methanol ester

Dichloromethane (8.5mL), triethylamine (0.90mL, 6.42mmol), methanesulfonyl chloride (0.43mL, 5.61mmol) were mixed to compound 2c-73(851mg, 5.35mmol) at 0 ℃. After stirring at 0 ℃ for 1 hour, water (10mL) was added. After the organic layer was extracted with dichloromethane (10mL), the solvent was distilled off to obtain the title compound (1.25g, 98.5%).

¹H-NMR(Bruker(ARX-300)，300MHz， )δ(ppm)：7.84(1H，d，J＝4.20Hz)，7.13(1H，d，J＝4.20Hz)，5.36(2H，s)，3.06(3H，s)

(general preparation method-4)

Next, a production example according to the above general production method-4 will be described.

Compound 4 a-0-4:

2-oxo-2H-3- (2-fluoro-3-amino)Phenylbenzyl) -4-methyl-7-hydroxy-1-benzopyran

Tin (II) chloride dihydrate (561mg, 2.49mmol) was added to a solution of starting material 1e-0-4(150mg, 0.46mmol) in ethyl acetate (4mL) under a nitrogen atmosphere, and the mixture was refluxed for 1 hour. After that, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 30: 1 to 10: 1) to obtain the title compound (91.8mg, 88%) as a white solid.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.35(3H，s)，3.85(2H，s)，5.06(2H，br.s)，6.20(1H，ddd，J＝7.6、1.5Hz、J_HF＝7.6Hz)，6.59(1H，ddd，J＝8.2、1.5Hz、J_HF＝8.2Hz)，6.67-6.75(2H，m)，6.81(1H，dd，J＝8.7、2.4Hz)，7.64(1H，d，J＝2.4Hz)，10.47(1H，br.s).

ESI (LC-MS positive mode) m/z: 300(M + H).

Compound 4 a-0-5:

2-oxo-2H-3- (2-fluoro-3-aminobenzyl) -4-methyl-6-fluoro-7-hydroxy-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 4a-0-4, except that Compound 1e-0-5 was used instead of Compound 1 e-0-4.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.32(3H，s)，3.84(2H，s)，6.20(1H，dd，J＝7.1，7.1Hz)，6.58-6.87(3H，m)，7.55(1H，d，J＝11.0Hz).

ESI (LC/MS positive mode) m/z: 318(M + H).

Compound 4 a-0-1:

2-oxo-2H-3- (3-aminobenzyl) -4-methyl-7-hydroxy-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 4a-0-4, except that Compound 1e-0-1 was used instead of Compound 1 e-0-4.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.36(3H，s)，3.32(2H，brs)，3.75(2H，s)，4.96(1H，brs)，6.32-6.43(3H，m)，6.71(1H，d，J＝2.4Hz)，6.81(1H，dd，J＝2.4，8.7Hz)，6.89(1H，ddd，J＝2.1，7.3，7.3Hz)，7.64(1H，d，J＝8.7Hz).

ESI (LC/MS positive mode) m/z: 282(M + H).

Compound 4 a-0-3:

2-oxo-2H-3- (3-aminobenzyl) -4-methyl-6-chloro-7-hydroxy-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 4a-0-4, except that Compound 1e-0-3 was used instead of Compound 1 e-0-4.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.36(3H，s)，3.32(2H，brs)，3.79(2H，s)，4.93(1H，brs)，6.29-6.43(3H，m)，6.82-6.93(2H，m)，7.79(1H，s).

ESI (LC/MS positive mode) m/z: 316(M + H).

Compound 4 a-0-6:

3- (2-methyl-3-aminobenzyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 4a-0-4 except that Compound 1e-0-6 was used instead of Compound 1 e-0-4.

¹H NMR(Bruker，300MHz，DMSO-d₆)δ(ppm)：10.49(1H，s)，7.63(1H，d，J＝8.8Hz)，6.82(1H，dd，J＝2.3，8.8Hz)，6.72-6.68(2H，m)，6.48(1H，d，J＝7.6Hz)，5.99(1H，d，J＝7.6Hz)，4.77(2H，s)，3.79(2H，s)，2.25(3H，s)，2.07(3H，s).

MS(Micromass，Quttromicro，ESI+)m/z：295.95(M+H).

Compound 4 a-0-45:

3- (2-aminobenzyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

To a methanol solution (1mL) of compound 1e-0-45(75mg, 2.4mmol) was added 10% Pd/C (15mg, 20 w/w%) and the mixture was stirred under a hydrogen molecular atmosphere at 1 atm for 1 hour. After Pd/C was removed by filtration, the filtrate was purified by silica gel chromatography (dichloromethane: methanol ═ 10: 1) to give the title compound (25mg, 37%).

1H-NMR(Bruke]r，300MHz，DMSO-d_6..)δ(ppm)：10.44(1H，s)，7.64(1H，d，J＝8.8Hz)，6.88(1H，t，J＝7.4Hz)，6.82(1H，dd，J＝2.3Hz，8.8Hz)，6.73(1H，d，J＝1.9Hz)，6.65(1H，d，J＝8.0Hz)，6.58(1H，d，J＝7.6Hz)，6.41(1H，t，7.6Hz)，5.00(2H，s)，3.65(2H，s)，2.36(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：281.84(M+H)

Compound 4 a-0-46:

3- (4-aminobenzyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 4a-0-4 except that Compound 1e-0-46 was used instead of Compound 1 e-0-4.

¹H-NMR(Bruker，300MHz，DMSO-d_6..)δ(ppm)：10.44(1H，s)，7.61(1H，d，J＝8.8Hz)，6.85(2H，d，J＝8.4Hz)，6.79(1H，dd，J＝2.3Hz，8.8Hz)，6.68(1H，d，J＝2.3Hz)，6.45(2H，d，J＝8.4Hz)，4.84(2H，s)，3.72(2H，s)，2.37(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：281.65(M+H)

Compound 4 a-0-51:

3- (3-Aminophenylamino) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized by the same method as that for the production of compound 4a-0-4, except that compound 4a-0-51 was used instead of compound 1 e-0-4.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：10.37(s，1H)，7.59(d，1H，J＝8.9Hz)，7.02(s，1H)，6.84(dd，1H，J＝8.6，2.3Hz)，6.80-6.73(m，3H)，5.98-5.88(m，2H)，5.80(m，1H)，5.05(brs，1H)，2.22(s，3H).

ESIMS m/z：283(M+H).

Compound 4 a-0-73:

3- (5-Nitro-thiophen-2-ylmethyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

A mixture of compound 1e-0-73(30mg, 0.095mmol) in acetic acid (0.15mL) was mixed with a mixture of tin (II) chloride 2 hydrate (129mg, 0.57mmol) and concentrated hydrochloric acid (0.25mL) at room temperature, and stirred for 2 hours. Water (10mL) was added, stirred for 10 min, and then saturated NaHCO was added₄Adjusting the pH of the reaction solution to 10 with an aqueous solution. The organic layer was extracted 2 times with a mixed solvent (20mL) of dichloromethane: methanol 5: 1. Purification by silica gel chromatography (hexane: ethyl acetate 1: 3) to give the title compound (5mg, 18)&)。

¹H-NMR(Bruker(ARX-300)，300MHz，DMSO- )δ(ppm)：10.36(1H，s)，7.63(1H，d，J＝8.77Hz)，6.97(1H，dd，J＝8.77Hz，J＝2.30Hz)，6.69(1H，d，J＝2.30Hz)，6.30(1H，d，J＝3.43Hz)，5.63(1H，d，J＝3.43Hz)，5.17(2H，s)，3.82(2H，s)，2.40(3H，s)

MS(Micromass，Quttromicro，ESI+)m/z：288.03(M+1)

Compound 1 h-2-4:

4-methyl-3- (2-fluoro-3-aminobenzyl) -7- (pyrimidine-2-oxo-2H-1-benzopyran

(Synthesis method 2)

To a solution of starting material 4a-0-4(90.6mg, 0.30mmol) in N, N-dimethylformamide (2mL) under a nitrogen atmosphere was added 60% sodium hydride (11.5mg, 0.28mmol), and the mixture was stirred at room temperature for 1 hour. Subsequently, 2-bromopyrimidine (48mg, 0.30mmol) was added, and the mixture was stirred at 100 ℃ for 5 hours. Then, ethyl acetate was added to the reaction solution, and the mixture was washed with an aqueous sodium hydrogencarbonate solution, water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol 1: 0 to 40: 1) to obtain the title compound (60.5mg, 56%) as a white solid.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.45(3H，s)，3.93(2H，s)，5.08(2H，br.s)，6.25(1H，ddd，J＝7.2、1.7Hz、J_HF＝7.2Hz)，6.61(1H，ddd，J＝8.2、1.7Hz、J_HF＝8.2Hz)，6.73(1H，dd，J＝8.2、7.2Hz)，726(1H，dd，J＝8.8、2.4Hz)，7.34(1H， t，J＝4.8Hz)，7.37(1H，d，J＝2.4Hz)，7.89(1H，d，J＝8.8Hz)，8.68(2H，d，J＝4.8Hz).

ESI (LC-MS positive mode) m/z: 378(M + H).

Compound 1 h-3-4:

(Synthesis method 2)

Starting material 4a-0-4(5.0g, 16.9mmol) was dissolved in N, N-dimethylformamide (75mL), 2-bromothiazole (6.0mL, 67.6mmol) and cesium carbonate (11.0g, 33.8mmol) were added, and the mixture was stirred at 100 ℃ for 19 hours. Then, ethyl acetate was added to the reaction solution, which was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol 50: 1) to obtain the title compound (2.4g, 38%) as a pale yellow powder.

ESI (LC/MS positive mode) m/z: 383(M + H).

(general preparation method-5)

Next, a production example according to the above-mentioned general production method-5 will be described.

Compound 5 b-0-13:

2- (di-tert-butoxycarbonyl) amino-6-methylpyridine

2-amino-6-methylpyridine (15g, 138.7mmol) and Boc₂O (41.4mL, 180.3mmol) was stirred overnight at 60 deg.C, and then 100mL of THF was added at room temperature. Dropwise adding the reaction solution to Boc₂A mixed solution of O (95.6mL, 416.1mmol) and DMAP (59.3g, 485.5mmol) was stirred at room temperature for 4 hours. After that, ethyl acetate was added to the reaction solution, and the mixture was washed with an ammonium chloride aqueous solution, a sodium hydrogencarbonate aqueous solution and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (34.8g, 82%) as a white solid.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：1.31-1.39(18H，m)，2.42(3H，s)，7.14(1H，d，J＝7.6Hz)，7.17(1H，d，J＝7.6Hz)，7.74(1H，dd，J＝7.6Hz).

ESI (LC/MS positive mode) m/z: 309(M + H).

Compound 5 c-0-13:

2- (di-tert-butoxycarbonyl) amino-6- (bromomethyl) pyridine

6- (di-tert-Butoxycarbonyl) amino-2-methylpyridine (compound 5b-0-13) (6.0g, 19.5mmol), N-bromosuccinimide (4.5g, 25.3mmol) and benzoyl peroxide (675mg, 1.95mmol) were stirred at 80 ℃ for 4 hours under a nitrogen atmosphere. After that, the reaction solution was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (4.34 g).

¹H-NMR(CDCl₃，270MHz)δ(PPM)：1.31-1.39(18H，m)，4.51(2H，s)，7.20(1H，d，J＝8.1Hz)，7.31(1H，d，J＝8.1Hz)，7.73(1H，dd，J＝8.1Hz).

ESI (LC/MS positive mode) m/z: 388(M + H).

Compound 5 t-0-10:

2- (2- (di-tert-Butoxycarbonyl) aminopyridin-4-ylmethyl) -3-oxobutanoic acid ethyl ester

Ethyl acetoacetate (109.6. mu.L, 0.86mmol) was dissolved in THF (2.0mL), and 2- (di-t-butoxycarbonyl) amino-4- (bromomethyl) pyridine obtained by the method described in Bioorganic & Medicinal Chemistry Letters 2004, 14, 2227-one 2231 and NaH (39.0mg, 0.97mmol) were added and stirred at room temperature for 12 hours. Thereafter, water was added to the reaction solution, followed by extraction with ethyl acetate. Subsequently, the mixture was washed with a sodium hydrogencarbonate aqueous solution and a saturated saline solution, and the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (206.2mg, 83%).

¹H-NMR(CDCl₃，270MHz)δ(PPM)：1.22(3H，t，J＝6.7Hz)，1.31-1.39(18H，m)，2.23(3H，s)，3.17(1H，dd，J＝8.1，5.4Hz)，3.78(1H，dd，J＝8.1Hz)，4.10-4.22(2H，m)，7.02(1H，d，J＝5.4Hz)，7.05(1H，brs)，8.37(1H，d，J＝5.4Hz).

ESI (LC/MS positive mode) m/z: 437(M + H).

Compound 5 t-0-13:

2- (2- (di-tert-Butoxycarbonyl) aminopyridin-6-ylmethyl) -3-oxobutanoic acid ethyl ester

The title compound was synthesized by using the compound 5c-0-13 in place of 2- (di-t-butoxycarbonyl) amino-4- (bromomethyl) pyridine under the same conditions as in the preparation of the compound 5 t-0-10.

¹H-NMR(CDCl₃，270MHz)δ(PPM)：1.22(3H，t，J＝6.7Hz)，1.31-1.39(18H，m)，3.20-3.44(2H，m)，4.11-4.28(3H，m)，7.06(1H，d，J＝8.1Hz)，7.10(1H，d，J＝8.1Hz)，7.63(1H，dd，J＝8.1Hz).

ESI (LC/MS positive mode) m/z: 437(M + H).

Compound 5 d-0-12:

3- (2-Aminopyridin-4-ylmethyl) -6-chloro-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

Compound 5t-0-10(180.9mg, 414. mu. mol) and 4-chlororesorcinol (71.9mg, 497.3. mu. mol) were stirred in concentrated sulfuric acid (66.3. mu.L, 1.24mmol) at room temperature for 24 hours. After that, ethyl acetate was added to the reaction solution, which was washed with a sodium hydrogencarbonate aqueous solution and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 5: 1) to obtain the title compound (28.0 mg).

¹H-NMR(CD₃OD，270MHz)δ(PPM)：2.36(3H，s)，3.87(2H，s)，6.41(1H，brs)，6.51(1H，d，J＝5.4Hz)，6.69(1H，s)，7.66(1H，s)，7.75(1H，d，J＝5.4Hz).

ESI (LC/MS positive mode) m/z: 317(M + H).

Compound 5 d-0-10:

3- (2-aminopyridin-4-ylmethyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from compound 5t-0-10 and resorcinol under the same conditions as in the preparation of compound 5 d-0-12.

¹H-NMR(300MHz)(DMSO-d₆)δ(ppm)：2.35(3H，s)，3.76(2H，s)，5.76(2H，brs)，6.20(1H，s)，6.35(1H，d，J＝5.34Hz)，6.72(1H，d，J＝2.29Hz)，6.82(1H，dd，J＝2.67，8.77Hz)，7.65(1H，d，J＝8.77Hz)，7.75(1H，d，J＝5.34Hz)，10.46(1H，brs).

Mass(Micromass，Quttromicro)(ESI+)m/z：282.87(M+H).

Compound 5 d-0-11:

3- (2-aminopyridin-4-ylmethyl) -6-fluoro-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from compound 5t-0-10 and 4-fluororesorcinol under the same conditions as in the preparation of compound 5 d-0-12.

¹H-NMR(300MHz)(DMSO-d₆)δ：2.35(3H，s)，3.76(2H，s)，5.74(2H，brs)，6.19(1H，s)，6.34(1H，d，J＝5.72Hz)，6.90(1H，d，J＝7.63Hz)，6.64(1H，d，J＝11.83Hz)，7.75(1H，d，J＝5.34Hz)，11.02(1H，brs).

Compound 5 d-0-13:

3- (2-aminopyridin-6-ylmethyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from compound 5t-0-13 and resorcinol under the same conditions as in the preparation of compound 5 d-0-12.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.42(3H，s)，3.82(2H，s)，5.75-5.85(2H，m)，6.10-6.20(2H，m)，6.70(1H，brs)，6.78(1H，d，J＝8.1Hz)，7.23(1H，dd，J＝8.1Hz)，7.64(1H，d，J＝8.1Hz).

ESI (LC/MS positive mode) m/z: 283(M + H).

Compound 5 d-0-14:

3- (2-Aminopyridin-6-ylmethyl) -6-fluoro-7-hydroxy-4-2-oxo-2H-1-benzopyran

The title compound was synthesized from compound 5t-0-13 and 4-fluororesorcinol under the same conditions as in the preparation of compound 5 d-0-12.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.38(3H，s)，3.82(2H，s)，5.78(2H，brs)，6.22(1H，d，J＝7.6Hz)，6.25(1H，d，J＝7.6Hz)，6.89(1H，d，J＝7.5Hz)，7.23(1H，t，J＝7.6Hz)，7.62(1H，d，J＝11.9Hz)，11.0(1H，brs).

ESI (LC/MS positive mode) m/z: 301(M + H).

Compound 5 d-0-15:

3- (2-Aminopyridin-6-ylmethyl) -6-chloro-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from compound 5t-0-13 and 4-chlororesorcinol under the same conditions as in the preparation of compound 5 d-0-12.

¹H-NMR(DMSO-d₆，270MHz)δ(PPM)：2.38(3H，s)，3.82(2H，s)，5.80(2H，brs)，6.24(1H，d，J＝7.6Hz)，6.27(1H，d，J＝7.6Hz)，6.89(1H，s)，7.23(1H，t，J＝7.6Hz)，7.78(1H，s).

ESI (LC/MS positive mode) m/z: 317(M + H).

Compound 5 d-0-16:

3- (3-fluoro-2-aminopyridin-4-ylmethyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from compound 5t-0-16a and resorcinol under the same conditions as in the preparation of compound 5 d-0-12.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.37(3H，s)，3.86(2H，s)，6.16(2H，brs)，6.23(1H，dd，J＝5.1Hz)，6.91(1H，s)，7.60(1H，d，J＝5.1Hz)，7.85(1H，s).

ESI (LC/MS positive mode) m/z: 301(M + H).

Compound 5 d-0-17:

3- (3-fluoro-2-aminopyridin-4-ylmethyl) -7-hydroxy-6-fluoro-4-methyl-2-oxo-2H-1-benzene And pyrans

The title compound was synthesized from compound 5t-0-16a and 4-fluororesorcinol under the same conditions as in the preparation of compound 5 d-0-12.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.36(3H，s)，3.86(2H，s)，6.10(2H，br)，6.23(1H，dd，J＝5.1Hz)，6.89(1H，d，J＝6.6Hz)，7.57(1H，d，J＝5.1Hz)，7.65(1H，d，J＝12Hz).

ESI (LC/MS positive mode) m/z: 319(M + H).

Compound 5 d-0-18:

3- (3-fluoro-2-aminopyridin-4-ylmethyl) -7-hydroxy-6-chloro-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from compound 5t-0-16a and 4-chlororesorcinol under the same conditions as in the preparation of compound 5 d-0-12.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.40(3H，s)，3.86(2H，s)， 6.36(1H，dd，J＝5.1Hz)，6.91(1H，s)，7.60(1H，d，J＝5.1Hz)，7.85(1H，s).

ESI (LC/MS positive mode) m/z: 335(M + H).

Compound 5 d-0-19:

3- (3-fluoro-2-aminopyridin-4-ylmethyl) -7-hydroxy-6-methyl-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from compound 5t-0-16a and 4-methylresorcinol using the same conditions as in the preparation of compound 5 d-0-12.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：2.19(3H，s)，2.37(3H，s)，3.85(2H，s)，6.09(2H，brs)，6.21(1H，dd，J＝5.1Hz)，6.71(1H，s)，7.54(1H，s)，7.56(1H，d，J＝5.1Hz).

ESI (LC/MS positive mode) m/z: 315(M + H).

Compound 5d-0-19 Me:

3- (2-amino-3-fluoropyridin-4-ylmethyl) -4-ethyl-7-hydroxy-6-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from the compound 5t-0-16Meb and 4-methylresorcinol under the same conditions as in the preparation of the compound 5 d-0-12.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：1.06(2H，t，J＝7.4Hz)，2.20(3H，s)，2.79(2H，brq，J＝7.4Hz)，3.83(2H，s)，6.10(2H，s)，6.20(1H，t，J＝5.1Hz)，6.75(1H，s)，7.55(1H，s)，7.57(1H，d，J＝5.1Hz)，10.50(1H，s).

ESI (LC/MS positive mode) m/z: 329(M + H).

Compound 5d-0-4S1

3- (2-fluoro-3-aminobenzyl) -7-mercapto-4-methyl-2-oxo-2H-1-benzopyran

152mg (1.21mmol) of 3-hydroxy-thiophenol and 153mg (0.60mmol) of ethyl 2- (2-fluoro-3-aminobenzyl) -3-butanoate were added to 6g of phosphoric acid at most, and the mixture was stirred and heated at 70 ℃ for 2 and a half hours.

Water was added to the reaction solution, and the precipitated solid was collected by filtration. The obtained solid was purified by silica gel column chromatography (dichloromethane: methanol at 50: 1 to 20: 1), whereby compound 5d-0-4S 112 mg (1%) was obtained as a pale yellow powder.

ESI (LC-MS positive mode) M/z 316(M + H)

Compound 5d-7-4S2

3- (2-fluoro-3-aminobenzyl) -7-methoxy-4-methyl-2-oxo-2H-1-benzothiopyran

The title compound was synthesized from 3-methoxy-thiophenol and ethyl 2- (2-fluoro-3-aminobenzyl) -3-butanoate using the same conditions as in the preparation of compound 5d-0-4S 1.

¹H-NMR(270MHz，CDCl₃)δ(ppm)：2.46(3H，s)，3.70(2H，brs)，3.88(3H，s)，4.12(2H，s)，6.39(1H，ddd，J＝8.1Hz、1.3Hz、JHF＝8.1Hz)，6.61(1H，ddd，J＝8.2Hz、1.4Hz、JHF＝8.2Hz)，6.77(1H，dd，J＝7.9Hz、7.9Hz)，6.91(1H，d，J＝2.6Hz)，6.96(1H，dd，J＝9.1Hz、2.6Hz)，7.8 0(1H，d，J＝9.1Hz)

ESI (LC-MS positive mode) M/z 330(M + H).

Compound 5d-0-4S 2:

3- (2-fluoro-3-aminobenzyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzothiopyran

Compound 5d-7-4 S213.5 mg (0.041mmol) was dissolved in dichloromethane (1ml), and 410. mu.l (0.41mmol) of a solution of boron tribromide in dichloromethane (1 mol/l) was added and the mixture was stirred under a nitrogen stream for 18 hours.

Water was added to the reaction solution, and the precipitated solid was collected by filtration to give compound 5d-0-4S27.6mg (59%) as a white powder.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.42(3H，s)，3.95(2H，s)，5.61(2H，brs)，6.07(1H，ddd，J＝7.2Hz、1.1Hz、JHF＝7.2Hz)，6.58(1H，ddd，J＝8.2Hz、1.2Hz、JHF＝8.2Hz)，6.69(1H，dd，J＝8.2Hz、7.2Hz)，6.80-6.62(2H，m)，7.91(1H，d，J＝9.7Hz)

ESI (LC-MS positive mode) M/z 316(M + H).

Compound 5c-0-53

N- (3-mercaptophenyl) acetamide

3-aminothiophenol (1.0g, 7.99mmol), acetic anhydride (0.83mL), and triethylamine (1.7mL) were dissolved in dichloromethane and stirred at room temperature for 2 hours. Purification by silica gel chromatography (hexane: ethyl acetate 3: 1) gave the title compound (1.16g, 87%).

H1-NMR(300MHz， δ(ppm)：7.18(1H，t，J＝7.6Hz)，6.80(1H，d，J＝7.6Hz)，6.75(1H，m)，6.71(1H，dd，J＝2.3Hz，8.0Hz)，3.72(2H，bs)，2.40(3H，s)

MS(ESI+)m/z：167.91(M+H)

Compound 5t-0-53

2- (3-acetylamino-thiophenoxy) -3-oxobutanoic acid ethyl ester

Compound 5c-0-53(600mg, 3.59mmol) and ethyl 2-chloro-3-oxobutanoate (0.50mL) were dissolved in dichloromethane (6mL), triethylamine (0.52mL) was slowly added dropwise at 0 ℃, then the temperature was raised to room temperature, and the mixture was stirred overnight. Purification by silica gel chromatography (hexane: ethyl acetate 5: 1) gave the title compound (181mg, 17%).

H1-NMR(300MHz， )δ(ppm)：11.8(1H，s)，7.24(1H，m)，7.01(1H，m)，6.87(2H，m)，4.1(3H，m)，2.27(6H，s)，1.18(3H，m)

MS(ESI+)m/z：294.99(M)

Compound 5d-0-53

3- (3-amino-thiophenoxy) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

Compound 5t-0-53(163mg, 0.552mmol) and resorcinol (61mg) were mixed with 70% sulfuric acid (0.5mL) under ice-cooling, and then warmed to room temperature and stirred overnight. The reaction mixture was added to ice water, and the resulting solid was collected by filtration to obtain (149mg, 90%).

H1-NMR(300MHz，DMSO-d_6..)δ(ppm)：10.7(1H，s)，7.74(1H，d，J＝8.8Hz)，6.93(1H，t，J＝8.0Hz)，6.86(1H，dd，J＝2.3Hz，J＝8.4Hz)，6.74(1H，d，J＝2.3Hz)，6.37(3H，m)，5.59(2H，bs)，2.66(3H，s)

MS(ESI+)m/z：300.08(M+H)

Compound 5t-0-52

2- (3-Acetylaminophenoxy) -3-oxobutanoic acid ethyl ester

A solution of 3-acetylaminophenol (1g, 6.61mmol) in tetrahydrofuran (3.3mL) was added to a mixture of NaH (264mg) in tetrahydrofuran (2.6mL) at 0 ℃. After stirring at room temperature for 1 hour, tetramethylenediamine (1.0mL) and ethyl 2-chloro-3-oxobutyrate (1.0mL) were added. After refluxing with heat for 8 hours, the residue was purified by silica gel chromatography (dichloromethane: methanol 50: 1) to give the title compound (210mg, 11%).

H1-NMR(300MHz， )δ(ppm)：7.34(1H，s)，7.29(1H，s)，7.21(2H，m)，7.04(1H，d，J＝7.6Hz)，6.65(1H，dd，J＝2.3Hz，J＝8.4Hz)，5.09(1H，s)，4.29(2H，q，J-7.2Hz)，2.38(3H，s)，2.16(3H，s)，1.29(3H，t，J＝6.9Hz)

MS(ESI+)m/z：280.05(M+H)

Compound 5d-0-52P

3- (3-acetylamino-phenoxy) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was obtained from compound 5t-0-52 and resorcinol under the same conditions as in the preparation of compound 5 d-0-53.

H1-NMR(300MHz，DMSO- )δ(ppm)：10.5(1H，s)，9.91(1H，s)，7.66(1H，d，J＝8.8Hz)，7.23(3H，m)，6.89(1H，dd，J＝2.3Hz，J＝8.8Hz)，6.79(1H，d，J＝2.3Hz)，6.66(1H，m)，2.29(3H，s)，1.99(3H，s)

MS(ESI+)m/z：326.02(M+H)

Compound 5d-0-52

3- (3-amino-phenoxy) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

H1-NMR(300MHz，DMSO- )δ(ppm)：7.61(1H，m)，6.91(1H，m)，6.85(1H，m)，6.74(1H，m)，6.21(1H，J＝8.4Hz)，6.08(2H，m)，5.12(2H，bs)，2.26(3H，s)

MS(ESI+)m/z：283.97(M+H)

Compound 5t-0-74

2- (2-acetylamino-thiazol-4-ylmethyl) -3-butanoic acid ethyl ester

The title compound was synthesized using the same conditions as in the preparation example of compound 1c-2, but using 2-acetylamino-4-chloromethyl-thiazole instead of 1-bromomethyl-2-fluoro-3-nitrobenzene.

¹H-NMR(Bruker(ARX-300)，CDCl₃).(ppm)：9.42(1H，s)，9.60(1H，s)，4.21～4.14(2H，m)，3.94(1H，t，J＝7.4Hz)，3.19(2H，q)，2.24(3H，s)，2.23(3H，s)，1.23(3H，t，J＝7.1Hz)

Compound 5 d-0-74P:

3- (2-acetylamino-thiazol-4-ylmethyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from compound 5t-0-74 under the same conditions as in the preparation of compound 5 d-0-12. As an additional component of compound 5d-0-74, it was isolated by silica gel chromatography.

¹H-NMR(Bruker(ARX-300)，DMSO- )δ(ppm)：11.97(1H，s)，10.42(1H，s)，7.42(1H，d，J＝8.4)，6.80(1H，dd，J＝9.0Hz，J＝2.4Hz)，6.72(1H，s)，6.70(1H，d，J＝2.7Hz)，3.90(2H，s)，2.38(3H，s)，2.08(3H，s)

Compound 5 d-0-74:

3- (2-amino-thiazol-4-ylmethyl) -7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran

The title compound was synthesized from compound 5t-0-74 under the same conditions as in the preparation of compound 5 d-0-12. As an additional component of compound 5d-0-74P, it was isolated by silica gel chromatography.

¹H-NMR(Bruker(ARX-300)， )δ(ppm)：10.40(1H，s)，7.63(1H，d，J＝9.0Hz)，6.81(2H，s)，6.79(1H，dd，J＝9.3Hz，J＝2.7Hz)，6.69(1H，d，J＝2.1Hz)，6.04(1H，s)，3.71(2H，s)，2.38(3H，s)

(general preparation method-6)

Next, a production example relating to the above-mentioned general production method-6 will be described.

Compound 6 b-1-4:

dimethylcarbamic acid 4-bromomethyl-3- (2-fluoro-3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

To 3- (2-fluoro-3-nitrobenzyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate (Compound 1g-1-4) (47.6mg) was added THF (0.9mL) to give a suspension, which was then stirred at-78 ℃ for 20 minutes to give a dark brown solution. This solution was added to a solution of N-bromosuccinimide (28mg) in THF (0.8mL) previously prepared in another vessel at 0 ℃ and then stirred at 0 ℃ for further 40 minutes. The reaction mixture was poured into 1N hydrochloric acid (0.119mL) diluted with ice water (20mL), and extracted with ethyl acetate. The obtained organic layer extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off under reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography (hexane: ethyl acetate 1: 1) to give the title compound (24.3 mg).

¹H-NMR(270MHz，CDCl₃)δ(ppm)：3.04(3H，s)，3.13(3H，s)，4.15(2H，s)，4.62(2H，s)，7.11-7.35(3H，m)，7.62-7.76(1H，m)，7.65(1H，ddd，J＝9.0，8.2，1.8Hz)，7.71(1H，d，J＝9.5Hz)，7.92(1H，ddd，J＝9.0，8.2，1.8Hz).

ESI (LC-MS positive mode) m/z: 479(M), 481(M +2H).

Compound 6 b-1-1:

dimethylcarbamic acid 4-bromomethyl-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 6b-1-4 except that Compound 1g-1-1 was used instead of Compound 1 g-1-4.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.94(3H，s)，3.07(3H，s)，4.20(2H，s)，5.07(2H，s)，7.25(1H，dd，J＝8.7，2.3Hz)，7.30(1H，d，J＝2.3Hz)，7.58(1H，t，J＝ 8.1Hz)，7.77(1H，brd，J＝8.1Hz)，7.96(1H，d，J＝8.7Hz)，8.05-8.13(1H，m)，8.22(1H，t，J＝1.9Hz).

ESI (LC-MS positive mode) m/z: 502(M + acetonitrile), 504(M + acetonitrile +2H).

Compound 6 b-1-2:

dimethylcarbamic acid 4-bromomethyl-6-fluoro-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 6b-1-4 except that Compound 1g-1-2 was used instead of Compound 1 g-1-4.

¹H-NMR(270MHz，CDCl₃)δ(ppm)：3.05(3H，s)，3.15(3H，s)，4.18(2H，s)，4.50(2H，s)，7.45-7.55(2H，m)，7.66(1H，d，J＝8.1Hz)，8.05-8.20(2H，m).

One peak of protons on benzene ring and CDCl₃Overlap.

ESI (LC-MS positive mode) m/z: 479(M), 481(M +2H).

Compound 6 b-1-3:

dimethylcarbamic acid 6-chloro-4-bromomethyl-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 6b-1-4 except that Compound 1g-1-3 was used instead of Compound 1 g-1-4.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：8.22(s，1H)，8.15(s，1H)，8.09(d，J＝8.1Hz，1H)，7.77(d，J＝8.2Hz，1H)，7.58(t，J＝7.9Hz，1H)，7.50(s，1H)，5.11(s，2H)，4.21(s，2H)，3.11(s，3H)，2.95(s，3H).

ESIMS m/z：497(M+H).

Compound 6 b-2-4:

4-bromomethyl-3- (2-fluoro-3-nitrobenzyl) -7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized under the same conditions as in the preparation example of Compound 6b-1-4 except that Compound 1g-2-4 was used instead of Compound 1 g-1-4.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：8.70(d，J＝4.9Hz，2H)，8.05-8.00(m，2H)，7.63(t，J＝6.4Hz，1H)，7.45(d，J＝2.4Hz，1H)7.40-7.30(m，3H)，5.03(s，2H)，4.16(s，2H).

ESIMS m/z：486(M+H).

Compound 6 c-1-4:

dimethyl carbamic acid 4-fluoromethyl-3- (2-fluoro-3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

After acetonitrile (1.0mL) was added to 4-bromomethyl-3- (2-fluoro-3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate (compound 6b-1-4) (24.0mg) to obtain a suspension, potassium fluoride (3.1mg) and 18-crown compound (crown) -6(13.2mg) were added thereto at room temperature with stirring, and the mixture was stirred at 60 ℃ for 4 hours. To the reaction mixture were added potassium fluoride (3.1mg) and 18-crown-compound-6 (13.2mg), and the mixture was stirred at 60 ℃ for 1.5 hours. The reaction mixture was poured into 1N hydrochloric acid (0.110mL) diluted with ice water (20mL), and extracted with ethyl acetate. The obtained organic layer extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off under reduced pressure, and the obtained residue was purified by thin layer silica gel chromatography (hexane: ethyl acetate 1: 1) to give the title compound (14.7 mg).

¹H-NMR(270MHz，CDCl₃)δ(ppm)：3.03(3H，s)，3.13(3H，s)，4.17(2H，s)，5.75(2H，d，J＝46.8Hz)，7.11-7.20(2H，m)，7.22(1H，td，J＝8.2，1.3Hz)，7.70(1H，td，J＝8.2，1.4Hz)，7.78(1H，dt，J＝7.4，1.8Hz)，7.92(1H，ddd，J＝8.2，6.8，1.4Hz).

ESI (LC-MS positive mode) m/z: 419(M + H).

Compound 6 c-1-1:

dimethyl carbamic acid 4-fluoromethyl-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by using the compound 6b-1-1 in place of the compound 6b-1-4 under the same conditions as in the preparation example of the compound 6 c-1-4.

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：2.93(3H，s)，3.07(3H，s)，4.07(2H，brs)，5.88(2H，d，J＝46.3Hz)，7.23(1H，dd，J＝8.7，2.3Hz)，7.30(1H，d，J＝2.3Hz)，7.58(1H，t，J＝8.1Hz)，7.73(1H，d，J＝8.7Hz)，7.93(1H，dd，J＝8.1，1.8Hz)，8.02-8.12(1H，m)，8.15(1H，t，J＝1.8Hz).

ESI (LC-MS positive mode) m/z: 401(M + H).

Compound 6 c-1-2:

dimethylcarbamic acid 6-fluoro-4-fluoromethyl-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 6c-1-4 except that Compound 6b-1-2 was used instead of Compound 6 b-1-4.

¹H-NMR(270MHz，CDCl₃)δ(ppm)：3.05(3H，s)，3.15(3H，s)，4.21(2H，brs)，5.65(2H，d，J＝46.8Hz)，7.45-7.65(3H，m)，8.05-8.18(2H，m).

One peak of protons on benzene ring and CDCl₃Overlap.

ESI (LC-MS positive mode) m/z: 419(M + H).

Compound 6 c-1-3:

dimethylcarbamic acid 6-chloro-4-fluoromethyl-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation example of Compound 6c-1-4 except that Compound 6b-1-3 was used instead of Compound 6 b-1-4.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：8.12(s，1H)，8.09(s+d，2H)，7.72(d，J＝7.8Hz，1H)，7.58(t，J＝7.8Hz，1H)，7.56(s，1H)，5.95(d，J＝46.0Hz，2H)，4.22(s，2H)，3.11(s，3H)，2.95(s，3H).

ESIMS m/z：435(M+H).

Compound 6 c-2-4:

4-fluoromethyl-3- (2-fluoro-3-nitrobenzyl) -7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized by using the compound 6b-2-4 in place of the compound 6b-1-4 under the same conditions as in the preparation example of the compound 6 c-1-4.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：8.68(d，J＝4.9Hz，2H)，8.02-7.96(m，2H)，7.62(t，J＝6.5Hz，1H)，7.43(d，J＝2.4Hz，1H)7.35-7.29(m，3H)，5.91(d，J＝46.2Hz，2H)，4.18(s，2H).

ESIMS m/z：426(M+H).

Compound 6 a-3-4-1P:

3- (2-fluoro-3- { [ 1-phenyl-mes- (Z) -ylidene]-amino } -benzyl) -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

Methanol (4.0mL) was added to 3- (3-amino-2-fluoro-benzyl) -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran (compound 1H-3-4) (200mg) to give a suspension, and then benzaldehyde (0.053mL) was added thereto while stirring at room temperature, followed by heating and refluxing for 3 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (aminated gel) (dichloromethane) to give the title compound (233 mg).

¹H-NMR(270MHz，DMSO-d₆)δ(ppm)：4.04(2H，s)，6.92-7.20(3H，m)，7.31-7.40(4H，m)，7.45-7.60(4H，m)，7.91-8.00(3H，m)，8.66(1H，s).

CH₃The peak of (a) overlaps with the peak of DMSO.

Compound 6 b-3-4-1P:

4-bromomethyl-3- (2-fluoro-3- { [ phenyl-mes- (Z) -ylidene]-amino } -benzyl) -7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

After THF (4.5mL) was added to 3- (2-fluoro-3- { [ 1-phenyl-mes- (Z) -ylidene ] -amino } -benzyl) -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran (Compound 6a-3-4-1P) (226mg), the mixture was stirred at-78 ℃ for 20 minutes and further at 0 ℃ for 1 hour to give a dark brown solution. This solution was added to a solution of N-bromosuccinimide (178mg) in THF (3.0mL) prepared in advance in another vessel over 10 minutes at 0 ℃ and then stirred for further 1 hour at 0 ℃. The reaction mixture was added to water (5mL) to complete the reaction, and the mixture was extracted with ethyl acetate. The obtained organic layer extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off under reduced pressure to give a residue (320mg) containing the title compound.

In that¹H-NMR(270MHz，CD₃OD), a peak of bromomethyl was observed around. delta.4.9 (ppm).

Compound 6 c-3-4-1P:

4-fluoromethyl-3- (2-fluoro-3-aminobenzyl) -7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran Pyran

To the residue (315mg) containing 4-bromomethyl-3- (2-fluoro-3- { [ 1-phenyl-mes- (Z) -ylidene ] -amino } -benzyl) -7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran (compound 6b-3-4-1P) obtained by the preceding reaction was added THF (5.0mL) to give a suspension, and then potassium fluoride (84.0mg) and 18-crown-6 (381mg) were added thereto under stirring at room temperature, followed by heating and refluxing for 2.5 hours. After the reaction solution was cooled to room temperature, ethyl acetate and water were added to conduct extraction. The obtained organic layer extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and ethyl acetate (3.0mL) and 1N hydrochloric acid (3.0mL) were added to the resulting residue, followed by stirring at room temperature for 10 minutes, and then ethyl acetate and saturated sodium bicarbonate were added to conduct extraction. The obtained organic layer extract was washed with saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane: ethyl acetate 4: 1 to 1: 1) to obtain a mixture (20.6mg) containing the title compound.

In that¹H-NMR(270MHz，CDCl₃) A peak of a fluoromethyl group was observed at around δ 5.5 (ppm).

(general preparation method-7)

Next, a production example related to the above-mentioned general production method-7 will be described.

Compound 7c-1-3 OH:

dimethylcarbamic acid 6-chloro-4- (2-hydroxyethyl) -3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

LiHMDS (57.5mL in THF, 1.0M) was added to a suspension of dimethylcarbamic acid 6-chloro-4-methyl-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester (compound 1g-1-3) (20.0g, 48.0mmol) in anhydrous THF (250mL) at-78 deg.C under a nitrogen atmosphere, and the reaction mixture was stirred at-78 deg.C for 30 min and at 0 deg.C for 30 min. Further, paraformaldehyde (2.88g, 96.0mmol) was added thereto, and the mixture was stirred at room temperature overnight. After that, the reaction mixture was poured into water and extracted 2 times with ethyl acetate. The organic extract was washed with saturated brine and dried over magnesium sulfate. Subsequently, a crude solid was obtained by concentration under reduced pressure, which was washed with ethyl acetate to obtain the title compound (18.5g, 86%) as a white powder.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：8.10(m，2H)，8.06(s，1H)，7.65(d，J＝8.1Hz，1H)，7.57(t，J＝8.1Hz，1H)，7.52(s，1H)，4.91(t，J＝5.4Hz，1H)，4.16(s，2H)，3.63(q，J＝5.4Hz，2H)，3.14(m，2H)，3.12(s，3H)，2.95(s，3H).

ESIMS m/z：447(M+H).

Compound 7d-1-3 OH:

dimethylcarbamic acid 6-chloro-4- (2-hydroxyethyl) -3- (3-aminobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 7c-1-3OH was used in place of Compound 1 g-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：8.04(s，1H)，7.49(s，1H)，6.90(t，J＝8.0Hz，1H)，6.36(m，3H)，4.96(s，2H)，4.88(t，J＝5.4Hz，1H)，3.87(s，2H)，3.60(q，J＝5.4Hz，2H)，3.11(s，3H)，3.04(t，J＝6.0Hz，2H)，2.95(s，3H).

ESIMS m/z：417(M+H).

Compound 7c-1-1 OH:

dimethyl carbamic acid 4- (2-hydroxyethyl) -3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 7c-1-3OH, except that Compound 1g-1-1 was used instead of Compound 1 g-1-3.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.13(d，1H，J＝1.8Hz)，8.06(dd，1H，J＝8.1，1.4Hz)，7.91(d，1H，J＝8.7Hz)，7.73(d，1H，J＝8.3Hz)，7.58(t，1H，J＝8.1Hz)，7.27(d，1H，J＝2.3Hz)，7.20(dd，1H，J＝8.7，2.5Hz)，4.91(t，1H，J＝5.6Hz)，4.15(s，2H)，3.70(m，2H)，3.11(m，2H)，3.07(s，3H)，2.95(s，3H).

ESIMS m/z：413(M+H).

Compound 7d-1-1 OH:

dimethyl carbamic acid 4- (2-hydroxyethyl) -3- (3-aminobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by the same method as that for the preparation of compound 1h-1-5, except that compound 7c-1-1OH was used instead of compound 1 g-1-5.

¹H NMR(270MHz，CDCl₃)δ(ppm)：7.62(d，1H，J＝8.7Hz)，7.25-7.00(m，3H)，6.70-6.42(m，3H)，4.00(s，2H)，3.71(t，2H，J＝7.1Hz)，3.20-3.10(s+t，5H)，3.03(s，3H).

ESIMS m/z：383(M+H).

Compound 7f-1-3 CO:

dimethylcarbamic acid 6-chloro-3- (3-nitrobenzyl) -2-oxo-4- (2-oxopropyl) -2H-1-benzopyran-7-yl ester

LiHMDS (11.5mL in THF, 1.0M) was added to a suspension of dimethylcarbamic acid 6-chloro-4-methyl-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester (compound 1g-1-3) (4.0g, 9.60mmol) in anhydrous THF (100mL) at-78 deg.C under a nitrogen atmosphere, stirred at-78 deg.C for 30 min and at 0 deg.C for 30 min. Acetyl chloride (1.36mL, 19.2mmol) was further added, and the mixture was stirred at room temperature for 1 hour. After that, the reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with saturated brine and dried over magnesium sulfate. Subsequently, the crude solid was obtained by concentration under reduced pressure, which was purified by column chromatography (ethyl acetate: hexane ═ 1: 3) to give the title compound (1.28g, 29%) as a white powder.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：8.12(s，1H)，8.05(d，J＝5.4Hz，1H)，7.92(s，1H)，7.67(d，J＝8.1Hz，1H)，7.55(t，J＝8.1Hz，1H)，7.51(s，1H)，4.44(s，2H)，4.07(s，2H)，3.10(s，3H)，2.95(s， 3H)，2.27(s，3H).

ESIMS m/z：459(M+H).

Compound 7g-1-3 CO:

dimethylcarbamic acid 6-chloro-3- (3-aminobenzyl) -2-oxo-4- (2-oxopropyl) -2H-1-benzopyran-7-yl ester

The title compound was synthesized under the same conditions as in the preparation of Compound 1h-1-5 except that Compound 7f-1-3CO was used instead of Compound 1 g-1-5.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：7.89(s，1H)，7.53(s，1H)，6.88(t，J＝8.1Hz，1H)，6.37-6.32(m，3H)，5.76(s，2H)，4.96(s，2H)，3.76(s，2H)，3.10(s，3H)，2.95(s，3H)，2.23(s，3H).

ESIMS m/z：429(M+H).

Compound 7c-1-3 MeOH:

dimethylcarbamic acid 6-chloro-4- (2-hydroxypropyl) -3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran Pyran-7-yl esters

To a solution of 6-chloro-3- (3-nitrobenzyl) -2-oxo-4- (2-oxopropyl) -2H-1-benzopyran-7-yl dimethylcarbamate (compound 7f-1-3CO) (300mg, 0.65mmol) in anhydrous THF (5.0mL) was added sodium borohydride (49mg, 1.30mmol), and the mixture was stirred at 0 ℃ for 2 hours. After that, the reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with saturated brine and dried over magnesium sulfate. Subsequently, concentration under reduced pressure gave the title compound (280mg, 93%) as a pale yellow powder.

¹H-NMR(DMSO-d₆，270MHz)δ(ppm)：8.12-8.05(m，3H)，7.71(d，J＝8.2Hz，1H)，7.60-7.50(m，2H)，4.88(d，J＝5.4Hz，1H)，4.22(d，J＝14.8Hz，1H)，4.11(d，J＝14.8Hz，1H)，3.86(m，1H)，3.11(s，3H)，3.00(m，2H)，2.95(s，3H)，1.23(d，J＝5.5Hz，3H).

ESIMS m/z：461(M+H).

Compound 7f-1-1 COOH:

{3- (3-nitrobenzyl) -7-dimethylcarbamoyloxy-2-oxo-2H-1-benzopyran-4-yl } acetic acid

4- (2-hydroxyethyl) -3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate (compound 7c-1-1OH) was synthesized using the same conditions as in the preparation example of compound 7c-1-3OH, except that compound 1g-1-1 was used instead of compound 1 g-1-3. Jones reagent (3.2mL, 2.67M, 8.58mmol) was added to a solution of compound 7c-1-1OH (1.18g, 2.86mmol) in acetone (25mL) at 0 deg.C and stirred at room temperature for 30 min. To the reaction mixture was slowly added 2-propanol until the red color disappeared, which was then poured into water and extracted with ethyl acetate. The organic extract was washed with water and dried over magnesium sulfate. Subsequently, concentration under reduced pressure gave the title compound (865mg, 71%) as a pale yellow powder.

¹H-NMR(CDCl₃，270MHz)δ(ppm)：8.12(s，1H)，8.07(d，J＝8.2Hz，1H)，7.86(d，J＝8.6Hz，1H)，7.71(d，J＝8.2Hz，1 H)，7.58(t，J＝7.6Hz，1H)，7.26(d，J＝2.1Hz，1H)，7.19(dd，J＝8.7，2.2Hz，1H)，4.14(s，2H)，3.29(s，2H)，3.07(s，3H)，2.93(s，3H).

ESIMS m/z：427(M+H).

Compound 7 f-1-3-COOH:

(3- (3-nitrobenzyl) -6-chloro-7-dimethylcarbamoyloxy-2-oxo-2H-1-benzopyran-4-yl) -acetic acid

The title compound was synthesized by the same method as that for the production of compound 7i-1-1COOH, except that compound 7c-1-3OH was used instead of compound 7c1-1 OH.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.12(s，1H)，8.07(d，1H，J＝5.4Hz)，8.03(s，1H)，7.71(d，2H，J＝8.1Hz)，7.57(t，1H，J＝8.1Hz)，7.50(s，1H)，4.14(s，2H)，3.28(s，2H)，3.10(s，3H)，2.95(s，3H).

ESIMS m/z：461(M+H).

Compound 7f-1-1 COOMe:

{3- (3-nitrobenzyl) -7-dimethylcarbamoyloxy-2-oxo-2H-1-benzopyran-4-yl } acetic acid methyl ester

To a solution of {3- (3-nitrobenzyl) -7-dimethylcarbamoyloxy-2-oxo-2H-1-benzopyran-4-yl } acetic acid (compound 7f-1-1COOH) (350mg, 0.82mmol) in methanol (5.0 mL)/dichloromethane (8.0mL) was added trimethylsilyldiazomethane (0.82mL in hexane, 2.0M), and the mixture was stirred at room temperature for 10 minutes. After acetic acid (2.0mL) was added to the reaction mixture, concentration was performed under reduced pressure to obtain the title compound (338mg, 94%) as a pale yellow powder.

¹H-NMR(CDCl₃，270MHz)δ(ppm)：8.12(s，1H)，8.07(d，J＝8.2Hz，1H)，7.76(d，J＝8.7Hz，1H)，7.70(d，J＝8.1Hz，1H)，7.57(t，J＝7.6Hz，1H)，7.22(s，1H)，7.19(d，J＝8.5Hz，1H)，4.24(s，2H)，4.16(s，2H)，3.50(s，3H)，3.06(s，3H)，2.93(s，3H).

ESIMS m/z：441(M+H).

Compound 7f-1-3CONH 2:

3- (3-nitrobenzyl) -4-carbamoylmethyl-6-chloro-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

To compound 7f-1-3 COOH: to a solution of (185mg, 0.40mmol) in DMF (4.0mL) were added HODhbt (78mg, 0.50mmol) and WSC (91mg, 0.50mmol), and the mixture was stirred at room temperature for 2 hours. Adding NH dropwise to the reaction mixture ₃(0.33M in THF, 6.1mL, 2.00mmol), and further stirred at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (170mg, 93%) as a white solid.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.19(s，1H)，8.06(m，1H)，7.98(s，1H)，7.76-7.70(m，2H)，7.57(t，1H，J＝8.1Hz)，7.52(s，1H)，7.26(s，1H)，4.13(s，2H)，3.96(s，2H)，3.10(s，3H)，2.95(s，3H).

ESIMS m/z：460(M+H).

Compound 7g-1-3CONH 2:

3- (3-aminobenzyl) -4-carbamoylmethyl-6-chloro-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized by the same method as that for the production of compound 4a-0-4, except that compound 7f-1-3CONH2 was used instead of compound 1 e-0-4.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.00(s，1H)，7.68(m，1H)，7.56(s，1H)，7.25(m，1H)，6.90(t，1H，J＝8.1Hz)，6.36(m，3H)，4.96(s，2H)，3.83(s，2H)，3.83(s，2H)，3.10(s，3H)，2.95(s，3H).

ESIMS m/z：430(M+H).

Compound 7g-1-3CONMe 2:

3- (3-aminobenzyl) -4-dimethylcarbamoylmethyl-6-chloro-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

Dimethyl carbamic acid 3- (3-nitrobenzyl) -4-dimethylcarbamoylmethyl-6-chloro-2-oxo-2H-1-benzopyran-7-yl ester (compound 7f-1-3CONMe2) was synthesized using dimethylamine instead of ammonia under the same conditions as in the method for producing compound 7f-1-3CONH 2.

The title compound was synthesized by the same method as that for the production of compound 4a-0-4, except that compound 7f-1-3CONMe2 was used instead of compound 1 e-0-4.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：7.84(s，1H)，7.49(s，1H)，6.88(m，1H)，6.37-6.33(m，3H)，4.93(s，2H)，4.05(s，2H)，3.75(s，2H)，3.10(s，6H)，2.95(s，3H)，2.81(s，3H).

ESIMS m/z：458(M+H).

Compound 7c-1-3 OMe:

dimethylcarbamic acid 6-chloro-4-methoxymethyl-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

To a solution of 6-chloro-4-bromomethyl-3- (3-nitrobenzyl) -2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate (compound 6b-1-3) (500mg, 1.01mmol) in THF (7.5mL) -methanol (5.0mL) was added potassium carbonate (279mg, 2.01mmol) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was removed by concentration under reduced pressure, and the obtained residue was purified by column chromatography to give the title compound (40mg, 10%) as a white solid.

¹H NMR(270MHz，CDCl₃)δ(ppm)：8.14(s，1H)，8.05(d，1H，J＝8.1Hz)，7.95(s，1H)，7.70(d，1H，J＝8.0Hz)，7.47(t，1H，J＝8.1Hz)，7.27(s，1H)，4.71(s，2H)，4.13(s，2H)m 3.48(s，3H)，3，17(s，3H)，3.00(s，3H).

ESIMS m/z：447(M+H).

Compound 7d-1-3OMe

Dimethylcarbamic acid 6-chloro-4-methoxymethyl-3- (3-aminobenzyl) -2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by the same method as that for the preparation of compound 4a-0-4, except that compound 7c-1-3OMe was used instead of compound 1 e-0-4.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.00(s，1H)，7.51(s，1H)，6.90(t，1H，J＝8.0Hz)，6.38-6.34(m，3H)，4.98(s，2H)，4.71(s，2H)，3.90(s，2H)，3.37(s，3H)，3.10(s，3H)，2.95(s，3H).

(general preparation method-8)

Next, a production example relating to the above general production method-8 will be described.

Compound 8 c-1:

(2-chloro-3-fluoropyridin-4-yl) -methanol

A2.0M solution of lithium diisopropylamide in THF (7.44mL, 14.9mmol) was dissolved in THF (24mL) under a nitrogen atmosphere, and 2-chloro-3-fluoropyridine (1.51mL, 14.9mmol) was added dropwise at-78 deg.C and stirred for 2 hours. Subsequently, DMF (11.4mL, 149mmol) was added dropwise and stirred at 0 ℃ for 2 h. Sodium borohydride (731mg, 19.3mmol) was added thereto, and the mixture was stirred at 0 ℃ for 1 hour. Subsequently, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, an aqueous sodium hydrogencarbonate solution and a saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (1.4g, 58%).

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：4.65(2H，d，J＝5.8Hz)，5.70(1H，t，J＝5.8Hz)，7.56(1H，dd，J＝4.6Hz)，8.27(1H，d，J＝4.6Hz).

ESI (LC/MS positive mode) m/z: 162(M + H).

Compound 8 c-2:

4- (tert-Butyldimethylsilanyloxymethyl) -2-chloro-3-fluoropyridine

(2-chloro-3-fluoropyridin-4-yl) -methanol (200mg, 1.24mmol), imidazole (253mg, 3.72mmol) and tert-butyldimethylsilyl chloride (373mg, 2.48mmol) were stirred at room temperature in DMF for 2 h. Dichloromethane was added to the reaction solution, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (319mg, 93%).

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：0.12(6H，s)，0.86(9H，s)，4.87(2H，s)，7.51(1H，dd，J＝4.9Hz)，8.30(1H，d，J＝4.9Hz).

ESI (LC/MS positive mode) m/z: 276(M + H).

Compound 8 c-3:

diphenylmethylene- [4- (tert-butyldimethylsilyloxymethyl) -3-fluoropyridin-2-yl]-ammonia

4- (tert-Butyldimethylsilanyloxymethyl) -2-chloro-3-fluoropyridine (30mg, 108. mu. mol), benzophenone imine (14. mu.L, 84. mu. mol), tris (dibenzylideneacetone) dipalladium (0) (7.7mg, 8.4. mu. mol), (S) - (-) -2, 2 '-bis (diphenylphosphino) -1, 1' -bibenzoyl (15.7mg, 25.3. mu. mol) and sodium tert-butoxide (10.4mg, 108. mu. mol) were stirred in toluene (0.5mL) at 60 ℃ overnight. Subsequently, ethyl acetate was added to the reaction solution, and the mixture was washed with a sodium hydrogencarbonate aqueous solution and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (27mg, 60%).

¹H NMR(CD₃OD，270MHz)δ(ppm)：0.00(6H，s)，0.86(9H，s)，4.60(2H，s)，5.42(1H，s)，7.00-7.80(11H，m)，7.97(1H，d，J＝5.1Hz).

ESI (LC/MS positive mode) m/z: 421(M + H).

Compound 8 c-4:

[2- (diphenylmethylene-amino) -3-fluoropyridin-4-yl]-methanol

Diphenylmethylene- [4- (tert-Butyldimethylsilanyloxymethyl) -3-fluoropyridin-2-yl ] -amine (14mg, 32. mu. mol) and a 1mol/LTHF solution of tetrabutylammonium fluoride (65. mu.L, 65. mu. mol) were stirred in THF (0.5mL) for 30 min at room temperature. Ethyl acetate was added to the reaction solution, which was washed with a sodium hydrogencarbonate aqueous solution and a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：4.47(2H，d，J＝5.6Hz)，5.47(1H，t，J＝5.6Hz)，7.04-7.20(3H，m)，7.25-7.40(3H，m)，7.45-7.75(5H，m)，8.04(1H，d，J＝5.0Hz).

ESI (LC/MS positive mode) m/z: 307(M + H).

Compound 5t-0-16 a:

2- [2- (diphenylmethylene-amino) -3-fluoropyridin-4-ylmethyl]-3-Butyronic acid ethyl ester

[2- (Diphenylmethylene-amino) -3-fluoropyridin-4-yl ] -methanol (compound 8c-4) (5g, 16.3mmol), methanesulfonyl chloride (1.52mL, 19.6mmol) and a solution of lithium tert-butoxide in THF (18mL, 18mmol) were stirred in THF (40mL) at 0 ℃ for 1 h. Subsequently, the reaction solution was added to a solution of ethyl acetoacetate (4.16mL, 32.7mmol), lithium tert-butoxide in THF (19.6mL, 19.6mmol) and NaI (2.5g, 16.3mmol) in THF (18 mL). After stirring at 50 ℃ for 3 hours, 0.2N aqueous lithium hydroxide solution and ethyl acetate were added, and the mixture was washed with 0.2N aqueous lithium hydroxide solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (6.98g, quant.).

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：1.10(3H，t，J＝7.0Hz)，2.13(3H，s)，2.90-3.05(2H，m)，3.94(1H，t，J＝7.7Hz)，4.05(2H，q，J＝7.0Hz)，6.91(1H，dd，J＝4.3Hz)，7.05-7.15(2H，m)，7.30-7.75(8H，m)，7.93(1H，d，J＝4.3Hz).

ESI (LC/MS positive mode) m/z: 419(M + H).

Compound 5t-0-16 Meb:

2- (2-amino-3-fluoropyridin-4-ylmethyl) -3-oxopentanoic acid ethyl ester

Using the same conditions as in the preparation example of Compound 5t-0-16a, a reaction was carried out using ethyl propionylacetate instead of ethyl acetoacetate, and then deprotection was carried out using 3N HCl to obtain the title compound.

¹H NMR(DMSO-d₆，270MHz)δ(ppm)：0.91(3H，t，J＝7.3Hz)，1.11(3H，t，J＝7.1Hz)，2.50-2.61(2H，m)，2.94-3.02(2H，m)，3.98-4.12(3H，m)，6.10(2H，s)，6.39(1H，t，J＝5.1Hz)，7.61(1H，d，J＝5.1Hz).

ESI (LC/MS positive mode) m/z: 269(M + H).

Compound 5d-0-Me

7-hydroxy-3, 4-dimethyl-2-oxo-2H-1-benzopyran

The title compound was synthesized by the same method as that for the preparation of compound 1e-0-4, except that ethyl 2-methylacetoacetate was used instead of compound 1 c-2.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：10.36(s，1H)，7.61(d，1H，J＝8.7Hz)，6.79(dd，1H，J＝8.7，2.5Hz)，6.68(d，1H，J＝2.5Hz)，2.34(s，3H)，2.05(s，3H).

ESIMS m/z：191(M+H).

Compound 1h-3-Me

3, 4-dimethyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized by the same method as that for the preparation of compound 1g-3-3, using 7-hydroxy-3, 4-dimethyl-2-oxo-2H-1-benzopyran (compound 5d-0-Me) instead of compound 1 e-0-3.

¹H NMR(270MHz，DMSO-d₆)δ7.89(d，1H，J＝9.1Hz)，7.45(d，1H， J＝2.5Hz)，7.36-7.32(m，3H)，2.42(s，3H)，2.13(s，3H).

ESIMS m/z：274(M+H).

Compound 1h-3-CH2Br

3-bromomethyl-4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

To a solution of compound 1h-3-Me (1.50g, 5.49mmol) in carbon tetrachloride (80mL) were added N-bromosuccinimide (1.17g, 6.59mmol) and AIBN (45mg, 0.27mmol), and the mixture was stirred at 75 ℃ for 2 hours. The solvent was removed by concentration under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate: hexane ═ 1: 2) to give the title compound (1.25g, 65%) as a white solid.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：7.99(d，1H，J＝8.7Hz)，7.51(d，1H，J＝2.5Hz)，7.41(d，1H，J＝2.5Hz)，7.38(m，2H)，4.68(s，2H)，2.54(s，3H).

ESIMS m/z：354(M+H).

Compound 1h-3-57P

N- (2- (4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran-3-ylmethoxy) phenyl) acetamide

To a solution of compound 1h-3-CH2Br (250mg, 0.71mmol) in THF (5.0mL) were added o-acetaminophenol (118mg, 0.78mmol) and potassium carbonate (118mg, 0.85mmol), and the mixture was stirred at 40 ℃ for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The residue was purified by column chromatography (ethyl acetate: hexane ═ 1: 2) to give the title compound (100mg, 33%) as a white solid.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.97(s，1H)，8.02(d，1H，J＝ 8.7Hz)，7.97(d，1H，J＝9.6Hz)，7.53(d，1H，J＝2.5Hz)，7.40(dd，1H，J＝8.9，2.5Hz)，7.37(s，2H)，7.25(d，1H，J＝6.8Hz)，7.08(t，1H，J＝8.2Hz)，6.95(t，1H，J＝7.3Hz)，5.10(s，2H)，2.56(s，3H)，2.04(s，3H).

ESIMS m/z：423(M+H).

Compound 1h-3-57

3- (2-Aminophenoxymethyl) -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

To a solution of compound 1h-3-57P (85mg, 0.20mmol) in ethanol (3.0mL), THF (3.0mL) and water (0.5mL) was added concentrated sulfuric acid, and the mixture was stirred at 75 ℃ for 3 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The residue was purified by fractional LCMS to give the title compound as a pale yellow solid (30mg, 39%).

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：7.99(d，1H，J＝8.9Hz)，7.52(m，1H)，7.41(m，1H)，7.38-7.35(m，3H)，6.96(d，1H，J＝8.1Hz)，6.70(d，1H，J＝7.4Hz)，6.63(d，1H，J＝7.6Hz)，6.52(t，1H，J＝7.6Hz)，5.02(s，2H)，4.71(s，2H)，2.55(s，3H).

ESIMS m/z：381(M+H).

Compound 1j-3-57-2

3- (2- (methylaminosulfonyl) aminophenoxymethyl) -4-methyl-7- (thiazol-2-yloxy) -2-oxo substituted-2H-1-benzopyrans

The title compound was synthesized by the same method as that for the production of the compound 1j-1-3-2, except that the compound 1h-3-57 was used instead of the compound 1 h-1-3.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.41(s，1H)，8.02(d，1H，J＝ 8.9Hz)，7.53(d，1H，J＝2.3Hz)，7.39(m，4H)，7.22(dd，1H，J＝8.2，1.2Hz)，7.10(m，2H)，6.94(td，1H，J＝7.7，1.3Hz)，5.08(s，2H)，2.56(s，3H)，2.41(d，3H，J＝4.9Hz).

ESIMS m/z：474(M+H).

Compound 1h-3-58P

N- (3- ((4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran-3-ylmethyl) amino) phenyl) acetamide

To a solution of compound 1h-3-CH2Br (250mg, 0.71mmol) in THF (5.0mL) were added m-acetylaminoaniline (118mg, 0.78mmol) and potassium carbonate (118mg, 0.85mmol), and the mixture was stirred at 75 ℃ for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The residue was purified by column chromatography (ethyl acetate: hexane ═ 1: 2) to give the title compound (110mg, 37%) as a white solid.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：9.68(s，1H)，7.95(d，1H，J＝8.9Hz)，7.49(d，1H，J＝2.5Hz)，7.39-7.34(m，3H)，7.02(s，1H)，6.97(d，1H，J＝7.9Hz)，6.73(d，1H，J＝7.6Hz)，6.33(d，1H，J＝8.2Hz)，5.72(t，1H，J＝4.9Hz)，4.12(d，2H，J＝4.9Hz)，2.51(s，3H).

ESIMS m/z：422(M+H).

Compound 1h-3-58

3- ((3-Aminophenylamino) methyl) -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

To a solution of compound 1h-3-58P (92mg, 0.218mmol) in ethanol (4.0mL), THF (4.0mL), and water (1.0mL) was added concentrated sulfuric acid (0.5mL), and the mixture was stirred at 75 ℃ for 2 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product. The residue was purified by fractional LCMS to give the title compound as a pale yellow solid (38mg, 46%).

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：7.94(d，1H，J＝8.9Hz)，7.49(d，1H，J＝2.6Hz)，7.38-7.34(m，3H)，6.73(t，1H，J＝7.4Hz)，5.88-5.84(m，3H)，5.29(t，1H，J＝5.3Hz)，4.74(s，2H)，4.08(d，2H，J＝5.3Hz)，2.50(s，3H).

ESIMS m/z：380(M+H).

Compound 1j-3-58-2

3- ((3- (methylaminosulfonyl) aminophenylamino) methyl) -4-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran

The title compound was synthesized by the same method as that for the production of the compound 1j-1-3-2, except that the compound 1h-3-58 was used instead of the compound 1 h-1-3.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：9.40(s，1H)，7.95(d，1H，J＝8.7Hz)，7.50(d，1H，J＝2.5Hz)，7.38-7.35(m，3H)，7.11(q，1H，J＝4.9Hz)，6.98(5，1H，J＝7.9Hz)，6.48-6.42(m，2H)，6.33(d，1H，J＝7.1Hz)，5.71(d，1H，J＝4.5Hz)，4.12(d，2H，J＝4.8Hz)，2.51(s，3H)，2.45(d，3H，J＝4.8Hz).

ESIMS m/z：473(M+H).

Compound 1e-0-NAc

N- (7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran-3-yl) -acetamide

The title compound was synthesized by the same method as that for the production of compound 1e-0-4, except that ethyl 2-acetylamino-3-oxobutanoate known in the literature was used instead of compound 1 c-2.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：10.52(s，1H)，9.39(s，1H)，7.63(d，1H，J＝8.6Hz)，6.84(dd，1H，J＝8.5，2.2Hz)，6.73(d，1H，J＝2.3 Hz)，2.21(s，3H)，2.03(s，3H).

ESIMS m/z：234(M+H).

Compound 1e-0-NH2

7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran-3-ammonium chloride

To a solution of compound 1e-0-NAc (600mg, 2.57mmol) in THF (6.0mL) and water (0.6mL) was added a 5-6 equivalent hydrochloric acid-isopropanol solution (3, 0mL), and the mixture was stirred at 80 ℃ overnight. After cooling to room temperature, the reaction mixture was concentrated to 1/3volumn by concentration under reduced pressure, and the precipitated solid was collected by filtration to obtain the title compound (510mg, 87%) as a pale orange solid.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：7.41(d，1H，J＝8.7Hz)，6.78(dd，1H，J＝8.7，2.5Hz)，6.69(d，1H，J＝2.3Hz)，5.69(brs，3H)，2.19(s，3H).

ESIMS m/z：192(M-HCl+H).

Compound 1e-0-60

N- (7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran-3-yl) -2-nitrobenzenesulfonamide

To a solution of compound 1e-0-NH2(250mg, 1.10mmol) in THF (5.0mL) were added pyridine (0.18mL, 2.20mmol) and o-nitrobenzenesulfonyl chloride (487mg, 2.20mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate, and the organic extract was washed with water and saturated brine. After drying over magnesium sulfate, the reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the title compound (268mg, 65%) as a yellow solid.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：10.66(s，1H)，9.86(s，1H)，8.04(m，1H)，7.94-7.83(m，3H)，7.67(d，1H，J＝8.7Hz)，6.86(dd，1H，J＝8.8，2.4Hz)，6.70(d，1H，J＝2.8Hz)，2.38(s，3H).

ESIMS m/z：377(M+H).

Compound 1g-1-60

Dimethylcarbamic acid 3- (2-nitrobenzenesulfonylamino) -4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by the same method as that for the production of compound 1g-1-5, except that compound 1e-0-60 was used instead of compound 1 e-0-5.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：10.09(s，1H)，8.05(m，1H)，7.86-7.80(m，4H)，7.26-7.20(m，2H)，3.06(s，3H)，2.93(s，3H)，2.43(s，3H).

ESIMS m/z：448(M+H).

Compound 1h-1-60

3- (2-Aminobenzenesulphonylamino) -4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized by the same method as that for the production of compound 4a-0-4, except that compound 1g-1-60 was used instead of compound 1 e-0-4.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：7.78(d，1H，J＝8.7Hz)，7.36(d，1H，J＝8.4Hz)，7.27-7.16(m，3H)，6.77(d，1H，J＝8.4Hz)，6.52(t，1H，J＝7.5Hz)，3.06(s，3H)，2.93(s，3H)，2.32(s，3H).

ESIMS m/z：418(M+H).

Compound 1j-1-60-2

3- (2- (methylaminosulfonyl) aminobenzenesulfonylamino) -4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized by the same method as that for the production of compound 1j-1-5-2, except that compound 1h-1-60 was used instead of compound 1 h-1-5.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：10.18(s，1H)，8.99(s，1H)，7.79(m，2H)，7.62(d，1H，J＝8.7Hz)，7.60-6.55(m，2H)，7.23-7.15(m，2H)，7.08(m，1H)，3.06(s，3H)，2.93(s，3H)，2.47(d，3H，J＝4.8Hz)，2.40(s，3H).

ESIMS m/z：511(M+H).

Compound 5d-0-CO2H

7-hydroxy-4-methyl-2-oxo-2H-1-benzopyranyl-3-carboxylic acid

To 7-hydroxy-4-methyl-3-carbonitrile-2-oxo-2H-1-benzopyran (1.0g, 4.97mmol) were added pyridine (0.1mL) and 1 equivalent aqueous sodium hydroxide solution (20mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water and 6 equivalents of aqueous hydrochloric acid (to pH 2), and the precipitated precipitate was collected by filtration. Subsequently, washing with methanol gave the title compound (577mg, 53%).

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：10.74(s，1H)，7.72(d，1H，J＝8.6Hz)，6.86(d，1H，J＝8.6Hz)，6.75(s，1H)，2.41(s，3H).

ESIMS m/z：221(M+H).

Compound 5d-0-56P

7-hydroxy-4-methyl-2-oxo-2H-1-benzopyranyl-3-carboxylic acid (3-acetylaminophenyl) amide

To a solution of compound 5d-0-CO2H (300mg, 1.36mmol) in DMF (10mL) were added HOBt (221mg, 1.64mmol) and WSC (313mg, 1.64mmol), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 3-aminoacetamide (225mg, 1.50mmol), and the mixture was further stirred at room temperature for 1.5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (217mg, 45%) as a pale yellow solid.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：10.73(s，1H)，10.45(s，1H)，9.99(s，1H)，7.98(s，1H)，7.73(d，1H，J＝8.7Hz)，7.34(m，2H)，7.24(t，1H，J＝7.8Hz)，6.88(m，2H)，6.77(d，1H，J＝2.3Hz)，2.39(s，3H)，2.04(s，3H).

ESIMS m/z：353(M+H).

Compound 5d-0-56

7-hydroxy-4-methyl-2-oxo-2H-1-benzopyranyl-3-carboxylic acid (3-aminophenyl) amide

To a suspension of compound 5d-0-56P (200mg, 0.57mmol) in ethanol (5.0mL), THF (3.0mL) or water (0.5mL) was added concentrated sulfuric acid (0.3mL), and the mixture was stirred under reflux for 4 hours. After cooling to room temperature, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. The organic extract was dried over magnesium sulfate and then concentrated under reduced pressure to obtain the title compound (143mg, 81%) as a pale yellow solid.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：10.70(s，1H)，10.11(s，1H)，7.72(d，1H，J＝8.7Hz)，7.01(s，1H)，6.95(t，1H，J＝7.9Hz)，6.86(dd，1H，J＝8.4，2.1Hz)，6.77(d，1H，J＝1.6Hz)，6.71(d，1H，J＝7.6Hz)，6.30(d，1H，J＝5.8Hz)，5.13(brs，2H)，2.38(s，3H).

ESIMS m/z：311(M+H).

Compound 1h-1-56

Dimethylcarbamic acid 3- (3-aminophenylcarbamoyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl ester

The title compound was synthesized by the same method as that for the production of compound 1g-1-5, except that compound 5d-0-56 was used instead of compound 1 e-0-5.

¹H NMR(270MHz，CD₃OD)δ(ppm)：8.13(d，1H，J＝1.8Hz)，7.92(d，1H，J＝8.6Hz)，7.49(m，2H)，7.24m，2H)，7.14(dt，1H，J＝5.6，1.3Hz)，3.15(s，3H)，3.02(s，3H)，2.55(s，3H).

ESIMS m/z：382(M+H).

Compound 1j-1-56-2

3- (3- (Methylaminosulfonyl) aminophenylcarbamoyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl dimethylcarbamate

The title compound was synthesized by the same method as that for the production of compound 1j-1-3-2, except that compound 1h-1-56 was used instead of compound 1 h-1-3.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：10.52(s，1H)，9.74(s，1H)，7.92(d，1H，J＝8.6Hz)，7.47-7.42(m，2H)，7.34(m，1H)，7.30-7.22(m，3H)，6.97(d，1H，J＝7.4Hz)，3.08(s，3H)，2.95(s，3H)，2.47(d，3H，J＝4.0Hz)，2.45(s，3H).

ESIMS m/z：475(M+H).

2-hydroxy-4- (pyrimidin-2-yloxy) -benzoic acid

The title compound was synthesized by the same method as that for the preparation of compound 1g-2-4, but using 2, 4-dihydroxybenzoic acid instead of compound 1 e-0-4.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.69(d，2H，J＝4.8Hz)，7.85 (d，1H，J＝8.6Hz)，7.33(t，1H，J＝4.8Hz)，6.81(d，1H，J＝2.3Hz)，6.77(dd，1H，J＝8.6，2.3Hz).

ESIMS m/z：233(M+H).

3-aminoethyl-2-fluoro-phenylamine

After refluxing a solution of hexamethyltetramine (595mg, 4.24 mmol) in chloroform (4.0mL) under heating, a solution of N- (3-bromomethyl-2-fluoro-phenyl) -acetamide (950mg, 3.86 mmol) in chloroform (8.0mL) was added over 40 minutes. After further heating and refluxing for 1 hour, the reaction solution was returned to room temperature, and then a white precipitate was filtered and washed with chloroform. Methanol (24mL) and concentrated hydrochloric acid (3.0mL) were added to the white precipitate, and the mixture was stirred at room temperature for 30 hours. The reaction solution was cooled to 0 degrees, and then made basic with 6 equivalents of aqueous sodium hydroxide (16.5 mL). After extraction with dichloromethane, the organic extract was washed with saturated saline, dried over magnesium sulfate, and washed with saturated saline. After drying over magnesium sulfate, the crude product was obtained by concentration under reduced pressure, which was purified by column chromatography to give the title compound (337mg, 48%) as a brown solid.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：6.79(t，1H，J＝7.6Hz)，6.52-6.67(m，2H)，4.98(s，2H).

ESIMS m/z：141(M+H).

Compound 1h-1-73

3- (3-amino-2-fluoro-benzyl) -7- (pyrimidin-2-yloxy) -benzo [ e][1，3]Oxazine-2, 4-diones

To a mixture of 2-hydroxy-4- (pyrimidin-2-yloxy) -benzoic acid (100mg, 0.431 mmol) and chloroform (5.0mL) was added triethylamine (0.180mL, 1.29 mmol) at room temperature. After the brown solution was cooled to 4 degrees, methyl chloroformate (0.073mL, 0.945 mmol) was added. The pale purple solution was stirred at room temperature for 2.5 hours and then concentrated under reduced pressure. Then, the mixture was dissolved in chloroform (5.0mL), and triethylamine (0.120mL, 0.861 mmol) and 3-aminoethyl-2-fluoro-aniline (60.0mg, 0.428 mmol) in chloroform (1.0mL) were added to the mixture, followed by stirring at room temperature for 64 hours. Thereafter, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic extract was washed with saturated saline, dried over magnesium sulfate, and then washed with saturated saline. After drying over magnesium sulfate, the crude product was obtained by concentration under reduced pressure, which was purified by column chromatography to obtain the title compound (25.8mg, 16%) as a white solid.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.72(d，2H，J＝4.8Hz)，8.05(d，1H，J＝8.7Hz)，7.47(d，1H，J＝2.1Hz)，7.38(t，1H，J＝4.8Hz)，7.35(dd，1H，J＝8.7，2.1Hz)，6.78(t，1H，J＝7.8Hz)，6.67(m，1H)，6.45(m，1H)，5.15(s，2H)，5.06(s，2H).

ESIMS m/z：381(M+H).

Compound 1j-1-73-2

3- (3- (methylaminosulfonyl) -2-fluoro-benzyl) -7- (pyrimidin-2-yloxy) -benzo [ e][1，3]Oxazine-2, 4-diones

The title compound was synthesized by the same method as that for the production of compound 1j-1-3-2, using 3- (3-amino-2-fluoro-benzyl) -7- (pyrimidin-2-yloxy) -benzo [ e ] [1, 3] oxazine-2, 4-dione (compound 1h-1-73) instead of compound 1 h-1-3.

¹H NMR(270MHz，DMSO-d₆) δ (ppm): 9.44(s, 1H), 8.71(d, 2H, J ═ 4.8Hz), 8.05(d, 1H, J ═ 8.7Hz), 7.48(d, 1H, J ═ 2.2Hz), 7.38(t, 1H, J ═ 4.8Hz), 7.29-7.36(m, 2H), 7.25(brq, 1H, J ═ 5.1Hz), 7.15(m, 1H), 7.07(t, 1H, J ═ 7.9Hz), 5.11(s, 2H) · (one peak of methyl overlaps with DMSO)

ESIMS m/z：474(M+H).

2- (3-methyl-benzo [ b ]]Thiophen-6-yloxy) -pyrimidines

The title compound was synthesized by the same method as that for the preparation of compound 1g-2-4, but using 4-hydroxyphthalic acid instead of compound 1 e-0-4.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.64(d，2H，J＝4.5Hz)，7.85(d，1H，J＝2.1Hz)，7.79(d，1H，J＝8.7Hz)，7.39(d，1H，J＝1.1Hz)，7.27(t，1H，J＝4.8Hz)，7.27(dd，1H，J＝8.7，2.1Hz)，2.42(s，3H).

ESIMS m/z：243(M+H).

Compound 1g-2-74

2- (2- (2-fluoro-3-nitro-benzyl) -3-methyl-benzo [ b)]Thien-6-yloxy) -pyrimidines

To a solution of 2- (3-methyl-benzo [ b ] thiophen-6-yloxy) -pyrimidine (114mg, 0.470 mmol) in dichloromethane (1.0mL) was added 1-bromomethyl-2-fluoro-3-nitro-benzene (120mg, 0.513 mmol) and zinc chloride (71mg, 0.520 mmol), and the mixture was refluxed for 17.5 hours. After cooling to room temperature, 1-bromomethyl-2-fluoro-3-nitro-benzene (120mg, 0.513 mmol) and zinc chloride (71mg, 0.520 mmol) were added and heated under reflux for 23 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography to give the title compound (67.5mg, 36%) as a white solid.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.63(d，2H，J＝4.8Hz)，8.05(m，1H)，7.70-7.80(m，3H)，7.41(m 1H)，7.26(t，1H，J＝4.8Hz)，7.24(dd，1H，J＝8.5，2.1Hz)，4.40(s，2H)，2.41(s，3H).

ESIMS m/z：366(M+H).

Compound 1h-2-74

2-fluoro-3- (3-methyl-6- (pyrimidin-2-yloxy) benzo [ b ]Thien-2-ylmethyl) -phenylamines

The title compound was synthesized by the same method as for the preparation of compound 1h-1-5, using 2- (2- (2-fluoro-3-nitro-benzyl) -3-methyl-benzo [ b ] thiophen-6-yloxy) -pyrimidine (compound 1g-2-74) instead of compound 1 e-1-5.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.62(d，2H，J＝4.8Hz)，7.72(m，2H)，7.26(t，1H，J＝4.8Hz)，7.33(dd，1H，J＝8.7，2.1Hz)，6.79(t，1H，J＝7.9Hz)，6.61(m，1H)，6.43(m，1H)，5.10(s，2H)，4.14(s，2H)，2.39(s，3H).

ESIMS m/z：366(M+H).

Compound 1j-2-74-2

[ 2-fluoro-3- (3-methyl-6- (pyrimidin-2-yloxy) benzo [ b ]]Thien-2-ylmethyl) -phenyl]-methylaminosulfonamides

The title compound was synthesized by the same method as that for the preparation of compound 1j-1-3-2, using 2-fluoro-3- (3-methyl-6- (pyrimidin-2-yloxy) benzo [ b ] thiophen-2-ylmethyl) -phenylamine (compound 1h-2-74) instead of compound 1 h-1-3.

¹H NMR(270MHz，DMSO-d₆) δ (ppm): 9.40(s, 1H), 8.62(d, 2H, J ═ 4.8Hz), 7.72(m, 2H), 7.33(td, 1H, J ═ 7.8, 2.0Hz), 7.18-7.28(m, 4H), 7.00-7.15(m, 2H), 4.25(s, 2H), 2.39(s, 3H). (one peak of methyl overlapping with DMSO)

ESIMS m/z：459(M+H).

4- (pyrimidin-2-yloxy) -phthalic acid

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.68(d，2H，J＝4.8Hz)，7.78(d，1H，J＝8.3Hz)，7.39-7.46(m，2H)，7.32(t，1H，J＝4.8Hz).

ESIMS m/z：261(M+H).

Compound 1h-2-75

2- (3-amino-2-fluoro-benzyl) -5- (pyrimidin-2-yloxy) -isoindole-1, 3-dione

To a solution of 4- (pyrimidin-2-yloxy) -phthalic acid (94.1mg, 0.362 mmol) in DMF (2.0mL) was added 3-aminomethyl-2-fluoro-aniline (50.8mg, 0.362 mmol) and imidazole (26.0mg, 0.382 mmol), and the mixture was stirred at 150 ℃ for 5 minutes under 300W with microwaves. To the reaction mixture was added water, followed by extraction with ethyl acetate, and then the organic extract was washed with saturated brine. After drying over magnesium sulfate, the crude product was obtained by concentration under reduced pressure, which was purified by column chromatography to obtain the title compound (13.4mg, 10%) as a white solid.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.70(d，2H，J＝4.8Hz)，7.97(d，1H，J＝8.2Hz)，7.80(d，1H，J＝2.2Hz)，7.69(dd，1H，J＝8.2，2.2Hz)，7.36(t，1H，J＝4.8Hz)，6.79(t，1H，J＝7.9Hz)，6.66(m，1H)，6.40(m，1H)，5.17(s，2H)，4.75(s，2H).

ESIMS m/z：365(M+H).

Compound 1j-2-75-2

2- (3- (methylaminosulfonyl) -2-fluoro-benzyl) -5- (pyrimidin-2-yloxy) -isoindole-1, 3-dione

The title compound was synthesized by the same method as that for the preparation of compound 1j-1-3-2, using 2- (3-amino-2-fluoro-benzyl) -5- (pyrimidin-2-yloxy) -isoindole-1, 3-dione (compound 1h-2-75) instead of compound 1 h-1-3.

¹H NMR(270MHz，DMSO-d₆)δ(ppm)：8.70(d，2H，J＝4.8Hz)，7.98(d，1H，J＝7.9Hz)，7.81(d，1H，J＝2.0Hz)，7.69(dd，1H，J＝7.9，2.0Hz)，7.36(m，2H)，7.24(brq，1H，J＝5.1Hz)，7.09(m，2H)，4.82(s，2H)，3.17(d，1H，J＝5.1Hz)，.

ESIMS m/z：458(M+H).

(3-Acetylaminophenylsulfamoyl) acetic acid ethyl ester

Ethanol was added to a solution of chlorosulfonyl acetyl chloride (1.0g, 5.7mmol) in an ester (6mL) at 0 ℃, and after stirring for 2 hours, the solvent was removed. N- (3-aminophenyl) acetamide (0.89g), triethylamine (1.2mL) and tetrahydrofuran (10mL) were added thereto, and the mixture was stirred at room temperature overnight. Purification by silica gel chromatography (dichloromethane: methanol 50: 1) gave the title compound (0.77g, 46%).

¹H-NMR(Bruker(ARX-300)，300MHz， .(ppm)：7.49(1H，bs)，7.44(1H，bs)，7.31(1H，t，J＝8.0Hz)，7.19(1H，bs)，7.06(1H，d，J＝8.0Hz)，6.94(1H，bs)，4.28(2H，q，J＝7.2Hz)，3.95(2H，s)，2.18(3H，s)，1.32(3H，t，J＝7.2Hz)

MS(ESI+)m/z：301.11(M+1)

Compound 5d-0-61P

4-methyl-3- (3- (acetylamino) phenylamino-sulfonyl) -7-hydroxy-2-oxo-2H-1-benzopyran

To ethyl (3-acetylaminophenylsulfamoyl) acetate (280mg, 0.93mmol), 2, 4-dihydroxybenzaldehyde (516mg) and piperidine (10mg) was added 9mL of ethanol, and the mixture was refluxed overnight. Purification by silica gel chromatography (dichloromethane: methanol 30: 1) gave the title compound (304mg, 87%).

¹H-NMR(Bruker(ARX-300)，300MHz，DMSO- .(ppm)：11.2(1H，s)，10.4(1H，s)，9.89(1H，bs)，8.71(1H，s)，7.78(1H，d，J＝8.8Hz)，7.45(1H，bs)，7.22(1H，d，J＝8.0Hz)，7.11(1H，t，J＝8.0Hz)，6.86(1H，dd，J＝2.3Hz，J＝8.0Hz)，6.80(1H，d，J＝8.0Hz)，6.74(1H，s)，1.98(3H，s)

MS(ESI+)m/z：374.80(M+1)

Compound 5d-0-61

4-methyl-3- (3-aminophenylaminosulfonyl) -7-hydroxy-2-oxo-2H-1-benzopyran

The compound 5d-0 to 61P and 4 equivalents of methanesulfonic acid were used, and the reaction mixture was heated under reflux using a mixed solvent of ethanol and water.

¹H-NMR(Bruker(ARX-300)，300MHz，DMSO- (ppm)：11.2(1H，bs)，10.0(1H，s)，8.67(1H，s)，7.79(1H，d，J＝8.8Hz)，6.86(1H，dd，J＝2.3Hz，J＝8.0Hz)，6.82(1H，t，J＝8.0Hz)，6.74(1H，s)，6.36(1H，m)，6.30(1H，d，J＝8.0Hz)，6.20(1H，d，J＝8.0Hz)，5.15(2H，bs)

MS(ESI+)m/z：332.92(M+1)

[ test example ]

(test example 1: measurement of cell growth inhibitory Activity)

The cell growth inhibitory activity of the compounds or salts shown in tables 1-1, 1-2 and Table 2 was measured as follows using human colon cancer cell line HCT116(American Type Culture Collection, Va., USA). Human colon cancer cell line HCT116 was added to a 96-well culture plate, 2000 to 3000 cells were added per well, and test substances were added at predetermined concentrations (0.00038. mu.M, 0.00076. mu.M, 0.0015. mu.M, 0.0031. mu.M, 0.0061. mu.M, 0.012. mu.M, 0.024. mu.M, 0.049. mu.M, 0.098. mu.M, 0.195. mu.M, 0.39. mu.M, 0.78. mu.M, 1.56. mu.M, 3.13. mu.M, 6.25. mu.M, 12.5. mu.M, 25. mu.M and 50. mu.M), followed by incubation at 37 ℃ with 5% CO₂The culture was carried out for 4 days in the environment. On day 4 of the culture, a solution of Cell counting kit-8 (Cell counting kit-8) (Kyodo chemical research institute, Co., Ltd.) was added, and the absorbance (measurement wavelength 450nm, reference wavelength 615nm) was measured according to the experimental design attached to the kit, and the 50% growth inhibitory concentration (IC50) was calculated. The results are shown in tables 1-1, 1-2 and 2.

(test example 2: calculation of AUC value)

The test substance was administered to animals, and the plasma concentration thereof was measured to calculate the AUC (area under the blood concentration-time curve) of the compound or salt shown in Table 2 (Compound 1j-2-16-2 is a sodium salt, and the others are free bodies). As animals, BALB/c (nu/nu) mice (4-6 weeks old) obtained from Charles river, Japan, after one-week acclimation period were used. The test substances other than Comp.1 were administered with 5mg/mL of the drug solution in an amount of 0.2mL/10g of body weight (test substance dose: 100mg/kg of body weight). In addition, for Comp.1, 10mg/mL of the drug solution was administered in an amount of 0.2mL/10g of the body weight (the amount of the test substance administered: 200mg/kg of the body weight). Administration of the drug solution to the mice was forcibly performed using an oral gavage apparatus for mice. Blood was collected from the orbital using heparin-treated hematocrit tubes at 15 minutes, 2 hours, 7 hours, and 24 hours after administration of the drug solution. After paraoxon (final 1mM) was added as a stabilizer to the collected blood, it was centrifuged at 10000rpm for 3 minutes to separate plasma. Prior to the assay, the plasma was stored in a refrigerator set at-80 ℃. The assay was performed as follows: after adding 100. mu.L of distilled water to which an internal standard substance (structure-similar substance. concentration is appropriately adjusted depending on the compound used) was added to 5. mu.L of plasma, a sample for measurement was prepared by solid-phase extraction treatment using Oasis HLB. mu.Elution plates (Waters), and analyzed by LC/MS/MS. The plasma concentration was calculated from a calibration curve prepared from the ratio of the standard substance to the internal standard substance in mouse blank plasma. AUC is calculated from the plasma concentration data of the drug by the trapezoidal method using Microsoft Excel 2003 (Microsoft). The results are shown in table 2.

In tables 1-1, 1-2 and 2 below, the compounds or salts of the present invention are represented by the compound numbers used in the present specification. Further, "Comp.1" represents the compounds of example Nos. 20 to 44 of WO2002/008217, i.e., the compounds represented by the following formula (A). "Comp.2" denotes the compound of example 2 of WO2002/008217, i.e.the compound of formula (B) below (2-oxo-2H-3-benzyl-4-methyl-6-chloro-1-benzopyran-7-yl dimethylcarbamate).

TABLE 1-1

Compound (I)	IC50(μM)
		1j-1-4-1	0.0176
1j-1-4-2	0.0093
		1j-1-4-2F	0.0106
1j-1-5-1	0.0083
		1j-1-5-2	0.0029
1j-1-3-2	0.0041
		1j-1-2-3	0.0120
1j-1-3-2F	0.0195
		1j-1-7-1	0.0114
1j-1-7-2	0.0079
		1j-1-8-2	0.0217
1j-1-9-2	0.0242
		1j-1-21-2	0.0230
1j-1-23-2	0.0360
		1o-1-3-2	0.0210
1o-1-3-3	0.0160

Tables 1 to 2

Compound (I)	IC50(μM )
		1j-1-10-2	0.0319
1j-1-11-2	0.0183
		1j-1-12-2	0.0064
1j-2-17-2	0.0211
		1j-2-18-2	0.0059

1j-2-19-2	0.0178
		1j-2-19-2Me	0.0084
1j-3-4-1	0.0225
		1j-3-4-2	0.0109
1j-3-20-2	0.0089
		1j-3-12-2	0.0122
1j-3-19-2	0.0015
		1j-3-44-2	0.0129
Com p.1	0.1600
		Com p.2	1.3000

TABLE 2

Compound (I)	AUC(μM·h)	IC50(μM)
			1j-1-13-2	313.6	0.2711
1j-2-4-1	811	0.1496
			1j-2-4-2	425	0.0447
1j-2-4-2F	317	0.1654
			1j-2-5-2	344	0.0751
1j-2-12-2	252	0.2816
			1j-2-16-2	3203(*)	0.0408
1j-3-1-2	199.3	0.1636
			1j-3-8-2	148.9	0.0968
1o-3-4-2	367	0.3253
			Com p.1	97.6	0.1600

^(*)Na salt was used.

As is clear from tables 1-1, 1-2 and 2, the compound or salt of the present invention showed significantly smaller IC50 values than the existing compound, or showed sufficiently smaller IC50 values and showed larger AUC values than the existing compound. This indicates that the compound or salt of the present invention has significantly higher antitumor activity than the conventional compounds, or has sufficiently higher antitumor activity equivalent to the conventional compounds and higher exposure to living bodies than the conventional compounds.

It is shown by experimental examples 1 and 2 that the compound of the present invention or a pharmaceutically acceptable salt thereof is useful as a drug for cell proliferative diseases, particularly cancer.

Industrial applicability

The compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition and a medicament for cell proliferative diseases can be used for the treatment of cell proliferative diseases, particularly cancer.

Claims

1. A compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof:

wherein X is selected from the group consisting of thiazol-2-yl, pyrimidin-2-yl and R³R⁴NCO-，

Y¹And Y²Are each independently selected from-N ═ and-CR¹¹＝，

Y³And Y⁴And, when the same indicates-CH ═ CH,

R¹selected from the group consisting of hydrogen atoms, halogen atoms, cyano groups and C_1-6An alkyl group, a carboxyl group,

R³and R⁴Each independently represents C_1-6An alkyl group, a carboxyl group,

R⁶selected from hydrogen atoms and C_1-6Alkyl radical, wherein, the C_1-6Alkyl groups may be selected from cyano and C_1-6The substituent of the alkoxy group is replaced by the substituent,

R⁷represents a hydrogen atom, and is represented by,

R⁹and R¹⁰Each independently represents a hydrogen atom and C_1-6An alkyl group, a carboxyl group,

R⁵and R⁸Each represents a hydrogen atom, and each represents a hydrogen atom,

R¹¹selected from hydrogen atoms, halogen atoms and C_1-6An alkyl group.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: r¹Selected from the group consisting of hydrogen atoms, halogen atoms and methyl groups.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

R⁶selected from hydrogen atoms and methyl groups.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: r³And R⁴Are all methyl.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: r ²Is C which may be substituted by fluorine atoms_1-2An alkyl group.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein: r²Is selected from-CH₃、-CH₂F and-CH₂CH₃。

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (1) is selected from the group consisting of:

3- {2- (methylaminosulfonyl) amino-3-chloropyridin-4-ylmethyl } -4-methyl-6-methyl-7- (thiazol-2-yloxy) -2-oxo-2H-1-benzopyran, and

dimethylcarbamic acid 6-fluoro-4-methyl-3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -2-oxo-2H-1-benzopyran-7-yl ester.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (1) is 3- { 2-fluoro-3- (methylaminosulfonyl) aminobenzyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (1) is 3- {2- (methylaminosulfonyl) amino-3-fluoropyridin-4-ylmethyl } -4-methyl-7- (pyrimidin-2-yloxy) -2-oxo-2H-1-benzopyran.

10. A pharmaceutical composition, comprising:

a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient.

11. A therapeutic agent for a cell proliferative disease, characterized by:

12. The agent for treating a cell proliferative disease according to claim 11, wherein:

the cell proliferative disorder is cancer.