RU2358970C2 - 3-alkylidenhydrazino-heteroaryl compounds as activators of thromboprotein receptor - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: in compounds with formula (1)

A is a nitrogen atom or CR⁴, where R⁴ is a hydrogen atom, halogen atom; B is a sulphur atom or NR⁹, where R⁹ is a hydrogen atom, hydroxyl group, formyl group, C_1-6 alkyl group, under the condition that, when A is a nitrogen atom, B is not NH; R¹ is a phenyl group, which can be substituted with one or several substitutes, chosen from a group comprising: a halogen atom, C_1-10 alkyl group, where C_1-10 alkyl group, can optionally be substituted with one or several substitutes, chosen from a group containing a halogen atom; L¹ is a bond; X is OR¹³, where R¹³ is a hydrogen atom; R² is a hydrogen atom, C_1-10 alkyl group, phenyl group; L² is a bond, CR³⁴R³⁵ where each of R³⁴ and R³⁵ independently represent a hydrogen atom or C_1-4 alkyl group; L³ is a NR¹⁹ bond, where R¹⁹ is a hydrogen atom; L⁴ is a bond or NR²², where R²² is a hydrogen atom; Y is an oxygen atom, sulphur atom; and R³ is an aryl group, chosen from phenyl or thienyl, where the aryl group is substituted with a substitute, chosen from a carboxyl group, sulphamide group, C_1-4 alkoxycarbonyl group, tetrazole group and possibly also substituted with a substitute, chosen from halogen atoms, nitro, hydroxyl group, C_1-10 alkylcarbonylamino group.

EFFECT: higher thrombocyte level.

33 cl, 13 dwg, 7 tbl, 181 ex

Description

The present invention relates to agents having an affinity for a thrombopoietin receptor and an agonistic effect on a thrombopoietin receptor, for the prevention, treatment or amelioration of diseases for which thrombopoietin receptor activation is effective. Specifically, it relates to pharmaceutical compositions comprising compounds that increase platelet count by stimulating differentiation and proliferation of hematopoietic stem cells, megakaryotic progenitor cells and megakaryocytes, or compounds for therapeutic angiogenesis or with anti-arteriosclerotic action that stimulate differentiation and proliferation of vascular endothelial cells precursor cells.

Thrombopoietin is a 332-amino acid cytokine that enhances platelet production by stimulating the differentiation and proliferation of hematopoietic stem cells, megakaryotic progenitor cells and megakaryocytes, mediated by its receptor, and therefore is a promising drug for hematological disorders. Recent reports that it stimulates the differentiation and proliferation of vascular endothelial cells and endothelial progenitor cells give rise to the expectation of therapeutic angiogenesis, anti-arteriosclerotic action and the prevention of cardiovascular disorders (e.g., non-patent publication 1, non-patent publication 2 and non-patent publication 3).

Biologically active substances that have been known to date to regulate platelet production through the thrombopoietin receptor include, in addition to thrombopoietin itself, low molecular weight peptides with affinity for the thrombopoietin receptor (for example, patent publication 1, patent publication 2, patent publication 3 and patent publication 4).

As a result of the search for non-peptide low molecular weight compounds that increase platelet production mediated by the thrombopoietin receptor, low molecular weight compounds with affinity for the thrombopoietin receptor have been reported (e.g., Patent Publications 5-24).

1) Applications filed by Hokuriku Seiyaku Co., Ltd. related to 1,4-benzodiazepine derivatives (Patent Publications 5 and 6);

2) International Patent Laid-open Applications filed by Shionogi & Co., Ltd. (patent publications 7-10);

3) International Patent Laid-open Applications filed by SmithKline Beecham Corp (Patent Publications 11-19);

4) Japanese Patent Application Laid-Open Submitted by Torii Pharmaceutical Co., Ltd. (patent publication 20);

5) International patent application laid out by Roche Diagnostics GMBH (Patent Publication 21);

6) International Patent Application Laid-Open Filed by Yamanouchi Pharmaceutical Co., Ltd. (Patent Publications 22 and 23);

7) Japanese Patent Application Laid-Open Filed by Japan Tabacco Inc. (Patent Publication 24)

Patent Publication 1 JP-A-10-72492

Patent Publication 2 WO96 / 40750

Patent Publication 3 WO96 / 40189

Patent Publication 4 WO98 / 25965

Patent Publication 5 JP-A-11-1477

Patent Publication 6 JP-A-11-152276

Patent Publication 7 WO01 / 07423

Patent Publication 8 WO01 / 53267

Patent Publication 9 WO02 / 059099

Patent Publication 10 WO02 / 059100

Patent Publication 11 WO00 / 35446

Patent Publication 12 WO00 / 66112

Patent Publication 13 WO01 / 34585

Patent Publication 14 WO01 / 17349

Patent Publication 15 WO01 / 39773

Patent Publication 16 WO01 / 21180

Patent Publication 17 WO01 / 89457

Patent Publication 18 WO02 / 49413

Patent Publication 19 WO02 / 085343

Patent Publication 20 JP-A-2001-97948

Patent Publication 21 WO99 / 11262

Patent Publication 22 WO02 / 062775

Patent Publication 23 WO03 / 062233

Patent Publication 24 JP-A-2003-238565

Non-Patent Publication 1 Microvasc. Res., 1999: 58, p. 108-113

Non-Patent Publication 2 Circ. Res., 1999: 84, p. 785-796

Non-Patent Publication 3 Blood 2001: 98, p. 71a-72a

SUMMARY OF THE INVENTION

Thrombopoietin and low molecular weight peptides with affinity for the thrombopoietin receptor are likely to readily degrade in the gastrointestinal tract and are usually difficult to administer orally. As for thrombopoietin itself, antibodies against thrombopoietin have been reported.

In addition, although oral administration of non-peptide low molecular weight compounds is possible, until now no practically useful drugs have been marketed.

Therefore, there is a need for orally administered low molecular weight compounds having excellent affinity for the thrombopoietin receptor and agonist action on this receptor, as prophylactic, therapeutic and condition enhancing agents for treating diseases in which activation of the thrombopoietin receptor has an effect. Specifically, there was a need for low molecular weight compounds that can serve as agents that increase the level of platelets or other blood cells by stimulating the differentiation and proliferation of hematopoietic stem cells, megakaryotic progenitor cells and megakaryocytes, or low molecular weight compounds that can be used for therapeutic angiogenesis or as prophylactic and therapeutic agents for the treatment of arteriosclerosis by stimulating endothelial cells and endothelial progenitor cells.

The inventors of the present invention have done a great deal of research to find low molecular weight compounds with an affinity for a thrombopoietin receptor and an agonistic effect on this receptor, and as a result have found that the compounds of the present invention have high affinity and an agonistic effect, whereby they exhibit a potent effect on increased platelet count by stimulating the differentiation and proliferation of megakaryotic progenitor cells and megakaryocytes. Based on this study, the present invention was created.

Namely, the present invention relates to

1. The compound represented by formula (1)

where A represents a nitrogen atom or CR ⁴ (where R ⁴ represents a hydrogen atom, a hydroxyl group (the hydroxyl group may be substituted by a C _2-6 alkenyl group or a C _2-6 alkynyl group), a thiol group (a thiol group may be substituted by C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group or C _1-10 alkylcarbonyl group), an amino group (the amino group may be substituted with one or two C _2-6 alkenyl groups or one or two C _{2- 6} alkynyl groups), a formyl group, a halogen atom, a nitro group, qi nogruppu, C _1-10 alkyl group, C _2-6 alkenyl, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino group, a mono- or di-C _1-10 alkylamino, C _1-10 alkoxy (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino group, a mono- or di-C _1-10 alkylamino C _1-10 and the alkoxy group may optionally be substituted with one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom and, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted with one or more halogen atoms) or one or more halogen atoms)), C _2-14 aryl groups, (C _2-14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group, (C _1-10 alkyl group may be substituted with one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino, hydroxyl th group, protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), C _2-14 aryloxy (C _2-14 aryloxy group may be optionally substituted with one or more substituents selected from the group consisting of C _{1 -10} alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group , C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoksikarbo yl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), SO ₂ R ^5, SOR ⁵ or COR ⁵ (where R ⁵ represents a hydroxyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy may optionally be substituted with one or more substituents selected from the group consisting carb ksilnuyu group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups ( C _1-6 alkyl group may be substituted by one or more halogen atoms) or one m or more halogen atoms)), a C _2-14 aryl group (C _2-14 aryl group, optionally can be substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, C _{1- 10} alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, am nogruppu, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), C _2-14 aryloxy (C _2-14 aryloxy group may optionally be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group , nitro, cyano, halogen, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _{2 -14} aryloxy group) or NR ⁶ R ⁷ (where each of R ⁶ and R ⁷ independently represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl groups (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group and the C _1-10 alkylcarbonyl group optionally may be substituted by one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, g an hydroxy group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _1-6 alkyl the group may be substituted by one or more halogen atoms) or one or more halogen atoms) or a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted by one or more substituents selected from the group consisting of C _{1- 10} alkyl group (C _1-10 alkyl group may be substituted one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy group, A C _1-10 alkoxycarbonyl group, a C _1-10 alkylcarbonylamino group, an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group), or R ⁶ and R ⁷ taken together mean - (CH ₂ ) _m1 -E- (CH ₂ ) _m2 - (where E represents an oxygen atom, a sulfur atom, CR ²⁶ R ²⁷ (where each of R ²⁶ and R ²⁷ independently represents a hydrogen atom, a C _1-10 alkyl group, a C _2-14 aryl group, a C _1-10 alkoxy group, a C _2-14 aryloxy group, a hydroxyl group or a protected hydroxyl group) or NR ⁸ (where R ⁸ represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group, C _{1- 10} alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl a group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group and a C _1-10 alkylcarbonyl group, optionally can be substituted with one or more substituents selected from the group consisting of a carboxyl group, nitro group, cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group protected hydroxyl group, C _2-14 aryl hydrochloric group and C _2-14 aryloxy (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted with one or more halogen atoms), or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted with one or more halogen atoms), C _2-6 alkenyl groups , C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group)), and each of m1 and m2, independently, is an integer of 0 up to 5, provided that m1 + m2 = 3, 4 or 5)))),

B represents an oxygen atom, a sulfur atom or NR ⁹ (where R ⁹ represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _{1- 10} alkoxy group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group and the C _1-10 alkylcarbonyl group may optionally be substituted with one or n Number of substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or several C _1-6 alkyl groups (C _1-6 alkyl group may t be substituted by one or more halogen atoms) or one or more halogen atoms)), a C _2-14 aryl group (C _2-14 aryl group, optionally, may be substituted by one or more substituents selected from the group consisting of C _{1 10} alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _{1- 10} alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group) or C _2-14 aryloxy group ( The C _2-14 aryloxy group may optionally be substituted with one or more substituents selected from the group consisting of a C _1-10 alkyl group (C _1-10 alkyl group may be substituted with one or more halogen atoms), C _2-6 alkenyl group , C _2-6 alkynyl group, carboxyl group, nitro group, c ianogruppu, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group)) (provided that when A represents a nitrogen atom, B is not NH),

R ¹ represents a C _2-14 aryl group (a C _2-14 aryl group may be substituted with one or more substituents selected from the group consisting of a halogen atom, a carboxyl group, a nitro group, OCHO, a cyano group, a hydroxyl group, a protected hydroxyl group, C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group and a C _1-10 alkoxycarbonyl group may optionally be substituted with one or more substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy , C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, C _{2- 14} aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted by one or more halogen atoms) or one or more halogen atoms)) C _2-14 aryl group (C _2-14 aryl group optionally may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more atoms halogen), C _2-6 alkenyl, C _2-6 alkynyl group, ct oxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _{1-10 an} alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group), a thiol group and an amino group (a thiol group and an amino group, optionally may be substituted with one or two substituents selected from the group comprising a formyl group, C _1-10 alkyl g group, C _2-6 alkenyl group, C _2-6 alkynyl group and C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group and C _1-10 alkylcarbonyl group optionally may be substituted by one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl a group, a C _1-10 alkylcarbonylamino group, an amino group, a mono or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl the group may be substituted by one or more halogen atoms) or one or more halogen atoms)))),

L ¹ represents a bond, CR ¹⁰ R ¹¹ (where each of R ¹⁰ and R ¹¹ independently represents a hydrogen atom or a C _1-6 alkyl group (a C _1-6 alkyl group may be substituted by one or more halogen atoms)) , an oxygen atom, a sulfur atom or NR ¹² (where R ¹² represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl a group, a C _2-6 alkynyl group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group and a C _1-10 alkylcarbonyl group optionally may be substituted with one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxy an alkyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (a C _1-6 alkyl group may be substituted one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms ), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group)),

X represents OR ¹³ , SR ¹³ or NR ¹⁴ R ¹⁵ (where R ¹³ represents a hydrogen atom, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group or a C _1-10 alkylcarbonyl group ( C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group and C _1-10 alkylcarbonyl group, optionally, can be substituted by one or more substituents selected from the group consisting of a carboxyl group, nitro group, cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoksika a rbonyl group, a C _1-10 alkylcarbonylamino group, an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted by one or more halogen atoms) or one or more halogen atoms)), and each of R ¹⁴ and R ¹⁵ , independently, represents a hydrogen atom, a formyl group, a C _1-10 alkyl group, a C _2-6 alk a nyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group, a C _1-10 alkyl carbonyl group (a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group and The C _1-10 alkylcarbonyl group may optionally be substituted with one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy group , C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or d -C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (a C _1-6 alkyl group may be substituted by one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted by one or more substituents, selected from the group consisting of C _1-10 alkyl group, (C _1-10 alkyl g Uppal may be substituted with one or more halogen atoms), C _2-6 alkenyl, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _{1 -10} alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group) ),

R ² represents a hydrogen atom, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkoxycarbonyl group C _1-10 alkylcarbonyloxy group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyloxy group and C _{1- 10} alkylcarbonyl group, optionally, can be substituted by one or more substituents selected from the group including carboxyl groups y, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _{1 -10} alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted by one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy group , C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, an amino group, m HO- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group),

L ² represents a bond, CR ³⁴ R ³⁵ (where each of R ³⁴ and R ³⁵ independently represents a hydrogen atom or a C _1-6 alkyl group (a C _1-6 alkyl group may be substituted by one or more halogen atoms)) , an oxygen atom, a sulfur atom or NR ¹⁶ (where R ¹⁶ represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl a group, a C _2-6 alkynyl group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group and a C _1-10 alkylcarbonyl group optionally may be substituted with one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxy an alkyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (a C _1-6 alkyl group may be substituted one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms ), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group)),

L ³ represents a bond, CR ¹⁷ R ¹⁸ (where each of R ¹⁷ and R ¹⁸ independently represents a hydrogen atom, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _{1 -10} alkoxy group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group and C _1-10 alkylcarbonyl group, optionally may be substituted one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, C _1-10 alkylcarbon yl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted by one or more halogen atoms) or one or more atoms halogen)) or a C _2-14 aryl group (C _2-14 aryl group, optional but may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group, (C _1-10 alkyl group may be substituted with one or more halogen atoms), C _2-6 alkenyl, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di -C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl th group, C _2-14 aryl and C _2-14 aryloxy group)), an oxygen atom, a sulfur atom or NR ¹⁹ (wherein R ¹⁹ represents a hydrogen atom, a hydroxyl group, a formyl group, C _1-10 alkyl group, C _{2 -6} alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkoxy and C _1-10 alkylcarbonyl group, optional o, may be substituted with one or more substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group , C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _{2- 14} aryloxy group may be substituted by one or more C _1-6 alkyl Rupp (C _1-6 alkyl group may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group may optionally be substituted with one or more substituents, selected from the group consisting of a C _1-10 alkyl group (a C _1-10 alkyl group may be substituted with one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, an atom halogen, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group uppu, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _{2 -14} aryloxy group)),

L ⁴ represents a bond, CR ²⁰ R ²¹ (where each of R ²⁰ and R ²¹ independently represents a hydrogen atom, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _{1 -10} alkoxy group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group and C _1-10 alkylcarbonyl group, optionally may be substituted one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, C _1-10 alkylcarbon yl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted by one or more halogen atoms) or one or more atoms halogen)) or a C _2-14 aryl group (C _2-14 aryl group, optional but may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group, (C _1-10 alkyl group may be substituted with one or more halogen atoms), C _2-6 alkenyl, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di -C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl th group, C _2-14 aryl and C _2-14 aryloxy group)), an oxygen atom, a sulfur atom or NR ²² (wherein R ²² represents a hydrogen atom, a hydroxyl group, a formyl group, C _1-10 alkyl group, C _{2 -6} alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group and the C _1-10 alkylcarbonyl group, optional o, may be substituted with one or more substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group , C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _{2- 14} aryloxy group may be substituted by one or more C _1-6 alkyl Rupp (C _1-6 alkyl group may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group may optionally be substituted with one or more substituents, selected from the group consisting of a C _1-10 alkyl group (a C _1-10 alkyl group may be substituted with one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, an atom halogen, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group uppu, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _{2 -14} aryloxy group)),

Y represents an oxygen atom, a sulfur atom or NR ²³ (where R ²³ represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _{1- 10} alkoxy group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group and the C _1-10 alkylcarbonyl group may optionally be substituted with one or ultiple substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or several C _1-6 alkyl groups (C _1-6 alkyl group can may be substituted by one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _{1- 10} alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoksika a carbonyl group, a C _1-10 alkylcarbonylamino group, an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group)) and

R ³ represents a C _2-14 aryl group (the C _2-14 aryl group may be substituted with one or more substituents independently representing —W ¹ (CW ² W ³ ) _m W ⁴ (where W ¹ represents (CR ²⁴ R ²⁵ ) _n (where each of R ²⁴ and R ²⁵ independently represents a hydrogen atom or a C _1-6 alkyl group, (a C _1-6 alkyl group may be substituted by one or more halogen atoms) and n has the value 0, 1, 2 or 3), an oxygen atom, a sulfur atom or NR ³⁶ (where R ³⁶ represents a hydrogen atom, a C _1-6 alkyl group, a formyl group or a C _1-6 alkylcarbonyl group y) each of W ² and W ³ independently represents a hydrogen atom or a C _1-3 alkyl group (a C _1-3 alkyl group may be substituted with one or more halogen atoms), m has the value 0, 1, 2 or 3, and W ⁴ represents a hydroxyl group, a thiol group, an amino group, a formyl group, a halogen atom, a nitro group, a cyano group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino group, a mono- or di-C _1-10 alkylamino (C _1-10 alkyl group, C _2-6 al enyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino and mono- or di-C _1-10 alkylamino group may optionally be substituted with one or more substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, protecting nnuyu hydroxyl group, C _2-14 aryl and C _2-14 aryloxy (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted by one or more halogen atoms) or one or more halogen atoms)), a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl a group (C _1-10 alkyl group may be substituted with one or more atoms halogen), C _2-6 alkenyl, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, thiol group, phosphonic acid group, sulfonic acid group, tetrazole group, C _2-14 aryl group and C _2-14 aryloxy group), SO ₂ R ²⁸ , SOR ²⁸ , COR ²⁸ (where R ²⁸ represents hydr oxyl group, C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group and a C _1-10 alkoxy group may optionally be substituted with one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy group , C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkyl nogroup, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _{1- 6 the} alkyl group may be substituted by one or more halogen atoms) or one or more halogen atoms)), a C _2-14 aryl group, a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group, optionally be substituted with one or more substituents selected from the group consisting of C _1-10 alkyl a group (C _1-10 alkyl group may be substituted with one or more halogen atoms), C _2-6 alkenyl, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _{1 -10} alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, C _2-14 aryl group and a C _2-14 aryloxy group) or NR ²⁹ R ³⁰ (where each of R ²⁹ and R ³⁰ , independently, representing represents a hydrogen atom, a hydroxyl group, a formyl group, a cyano group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group and C _1-10 alkylcarbonyl group may optionally be substituted with one or more substituents selected from the group enabling minutes carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di- C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted by one or more halogen atoms) and whether by one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted by one or more substituents selected from the group consisting of a C _1-10 alkyl group (C _1-10 alkyl the group may be substituted by one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, C _{1 -10} alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino a group, an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group), or R ²⁹ and R ³⁰ taken together mean - (CH ₂ ) _m3- G- (CH ₂ ) _m4 - (where G represents an oxygen atom, a sulfur atom, CR ³¹ R ³² (where each of R ³¹ and R ³² independently represents a hydrogen atom, a C _1-10 alkyl group , A C _2-14 aryl group, a C _1-10 alkoxy group, a C _2-14 aryloxy group, a hydroxyl group or a protected hydroxyl group) or NR ³³ (where R ³³ represents a hydrogen atom, a hydroxyl group, ph rmilnuyu group, C _1-10 alkyl group, C _2-6 alkenyl, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group ( C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group and C _1-10 alkylcarbonyl group optionally be substituted by one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom ene, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl Rupp (C _2-14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group, (C _1-10 alkyl group may be substituted with one or more halogen atoms), C _{2- 6} alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _{1- 10} alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino, hydro strong group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group)), and each of m3 and m4, independently, is an integer from 0 to 5, provided that the sum of m3 + m4 is 3 , 4 or 5))), a tetrazole group, or a phosphonic acid group)), a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

2. The invention relates to a compound of formula (1), wherein A represents a nitrogen atom and B represents a sulfur atom, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

3. The compound of formula (1), where A represents a nitrogen atom and B represents an oxygen atom, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

4. The compound of formula (1), where A represents a nitrogen atom and B represents NR ⁹ (where R ⁹ represents a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group and the C _1-10 alkylcarbonyl group may optionally be deputy scheny one or more substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _{1- 10} alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group substituted by one or more C _1-6 alkyl groups (C _1-6 Alki te a group may be substituted with one or more halogen atoms) or one or more halogen atoms)), C _2-14 aryl group (C _2-14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkilkarbo yloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group) or C _2-14 aryloxy group (C _2-14 aryloxy group may optionally be substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted with one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, a carboxyl group y, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _{1 -10} alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group)), a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

5. The compound of formula (1), where A represents CR ⁴ (where R ⁴ represents a hydrogen atom, a hydroxyl group (the hydroxyl group may be substituted with a C _2-6 alkenyl or C _2-6 alkynyl group), a thiol group (thiol group may be substituted with a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group or a C _1-10 alkylcarbonyl group), an amino group (the amino group may be substituted with one or two C _2-6 alkenyl groups, or one or two C _2-6 alkynyl groups), a formyl group, a halogen atom, a nitro group, n anogruppu, C _1-10 alkyl group, C _2-6 alkenyl, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino group, a mono- or di-C _1-10 alkylamino, C _1-10 alkoxy (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino group, a mono- or di-C _1-10 alkylamino C _1-10 and the alkoxy group may optionally be substituted with one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom on, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted with one or more halogen atoms) or one or more halogen atoms)), C _2-14 aryl group y (C _2-14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group, (C _1-10 alkyl group may be substituted with one or more halogen atoms), C _{2- 6} alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _{1- 10} alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino, hydroxyl hydrochloric group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), C _2-14 aryloxy (C _2-14 aryloxy group may be optionally substituted with one or more substituents selected from the group consisting of C _{1 -10} alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group , C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoksikarb nilnuyu group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), SO ₂ R ^5, SOR ⁵ or COR ⁵ (where R ⁵ represents a hydroxyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy may optionally be substituted with one or more substituents selected from the group consisting ct oxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups ( C _1-6 alkyl group may be substituted by one or more halogen atoms) or one by one or more halogen atoms)), a C _2-14 aryl group (C _2-14 aryl group, optionally may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, C _{1- 10} alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, and inogruppu, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), C _2-14 aryloxy (C _2-14 aryloxy group may optionally be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group , nitro, cyano, halogen, C _1-10 alkoxy, C _1-10 alkylcarbonyl th group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group) or NR ⁶ R ⁷ (where each of R ⁶ and R ⁷ independently represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, C _{2- 6} alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group y (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group and the C _1-10 alkylcarbonyl group optionally may be substituted by one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group, A C _1-10 alkylcarbonylamino group, an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _1-6 alkyl the group may be substituted by one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted by one or more substituents selected from the group consisting of C _{1 -10} alkyl group (C _1-10 alkyl group may be substituted with and one or more halogen atoms), C _2-6 alkenyl, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy , C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group), or R ⁶ and R ⁷ taken together mean - (CH ₂ ) _m1 -E- (CH ₂ ) _m2 - (where E represents an oxygen atom, a sulfur atom, CR ²⁶ R ²⁷ (where each of R ²⁶ and R ²⁷ independently represents a hydrogen atom, a C _1-10 alkyl group, a C _2-14 aryl group, a C _1-10 alkoxy group, a C _2-14 aryloxy group, a hydroxyl group or a protected hydroxyl group) or NR ⁸ (where R ⁸ represents a hydrogen atom, hydroxyl group, formyl group, C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _{1 -10} alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl a group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group and a C _1-10 alkylcarbonyl group, optionally can be substituted with one or more substituents selected from the group consisting of a carboxyl group, nitro group, cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group protected hydroxyl group, C _2-14 ari a group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (a C _1-6 alkyl group may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group pu, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino , an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group)), and each of m1 and m2, independently, is an integer of 0 to 5, provided that the sum m1 + m2 is 3, 4 or 5)))), and B represents an oxygen atom, a tautomer, a gap the quality or pharmaceutically acceptable salt of such a compound or a solvate thereof.

6. The compound of formula (1), where A represents CR ⁴ (where R ⁴ represents a hydrogen atom, a hydroxyl group (the hydroxyl group may be substituted by a C _2-6 alkenyl or C _2-6 alkynyl group), a thiol group (thiol group may be substituted with a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group or a C _1-10 alkylcarbonyl group), an amino group (the amino group may be substituted with one or two C _2-6 alkenyl groups, or one or two C _2-6 alkynyl groups), a formyl group, a halogen atom, a nitro group, n anogruppu, C _1-10 alkyl group, C _2-6 alkenyl, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino group, a mono- or di-C _1-10 alkylamino, C _1-10 alkoxy (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino group, a mono- or di-C _1-10 alkylamino C _1-10 and the alkoxy group may optionally be substituted with one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom on, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted with one or more halogen atoms) or one or more halogen atoms)), C _2-14 aryl group y (C _2-14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group, (C _1-10 alkyl group may be substituted with one or more halogen atoms), C _{2- 6} alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _{1- 10} alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino, hydroxyl hydrochloric group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), C _2-14 aryloxy (C _2-14 aryloxy group may be optionally substituted with one or more substituents selected from the group consisting of C _{1 -10} alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group , C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoksikarb nilnuyu group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), SO ₂ R ^5, SOR ⁵ or COR ⁵ (where R ⁵ represents a hydroxyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy may optionally be substituted with one or more substituents selected from the group consisting ct oxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups ( C _1-6 alkyl group may be substituted by one or more halogen atoms) or one by one or more halogen atoms)), a C _2-14 aryl group (C _2-14 aryl group, optionally may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, C _{1- 10} alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, and inogruppu, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), C _2-14 aryloxy (C _2-14 aryloxy group may optionally be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group , nitro, cyano, halogen, C _1-10 alkoxy, C _1-10 alkylcarbonyl th group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group) or NR ⁶ R ⁷ (where each of R ⁶ and R ⁷ independently represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, C _{2- 6} alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group y (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group and the C _1-10 alkylcarbonyl group optionally may be substituted by one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group, A C _1-10 alkylcarbonylamino group, an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _1-6 alkyl the group may be substituted by one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted by one or more substituents selected from the group consisting of C _{1 -10} alkyl group (C _1-10 alkyl group may be substituted with and one or more halogen atoms), C _2-6 alkenyl, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy , C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group), or R ⁶ and R ⁷ taken together mean - (CH ₂ ) _m1 -E- (CH ₂ ) _m2 - (where E represents an oxygen atom, a sulfur atom, CR ²⁶ R ²⁷ (where each of R ²⁶ and R ²⁷ independently represents a hydrogen atom, a C _1-10 alkyl group, a C _2-14 aryl group, a C _1-10 alkoxy group, a C _2-14 aryloxy group, a hydroxyl group or a protected hydroxyl group) or NR ⁸ (where R ⁸ represents a hydrogen atom, hydroxyl group, formyl group, C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _{1 -10} alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl a group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group and a C _1-10 alkylcarbonyl group, optionally can be substituted with one or more substituents selected from the group consisting of a carboxyl group, nitro group, cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group protected hydroxyl group, C _2-14 ari a group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (a C _1-6 alkyl group may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group pu, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino , an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group)), and each of m1 and m2, independently, is an integer of 0 to 5, provided that the sum m1 + m2 is 3, 4 or 5)))), and B represents a sulfur atom, a tautomer, a pro-drug wu or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

7. The compound of formula (1), where A represents CR ⁴ (where R ⁴ represents a hydrogen atom, a hydroxyl group (the hydroxyl group may be substituted by a C _2-6 alkenyl or C _2-6 alkynyl group), a thiol group (thiol group may be substituted with a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group or a C _1-10 alkylcarbonyl group), an amino group (the amino group may be substituted with one or two C _2-6 alkenyl groups, or one or two C _2-6 alkynyl groups), a formyl group, a halogen atom, a nitro group, n anogruppu, C _1-10 alkyl group, C _2-6 alkenyl, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino group, a mono- or di-C _1-10 alkylamino, C _1-10 alkoxy (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino group, a mono- or di-C _1-10 alkylamino C _1-10 and the alkoxy group may optionally be substituted with one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom on, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted with one or more halogen atoms) or one or more halogen atoms)), C _2-14 aryl group y (C _2-14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group, (C _1-10 alkyl group may be substituted with one or more halogen atoms), C _{2- 6} alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _{1- 10} alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino, hydroxyl hydrochloric group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), C _2-14 aryloxy (C _2-14 aryloxy group may be optionally substituted with one or more substituents selected from the group consisting of C _{1 -10} alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group , C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoksikarb nilnuyu group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), SO ₂ R ^5, SOR ⁵ or COR ⁵ (where R ⁵ represents a hydroxyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy may optionally be substituted with one or more substituents selected from the group consisting ct oxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups ( C _1-6 alkyl group may be substituted by one or more halogen atoms) or one by one or more halogen atoms)), a C _2-14 aryl group (C _2-14 aryl group, optionally may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, C _{1- 10} alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, and inogruppu, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), C _2-14 aryloxy (C _2-14 aryloxy group may optionally be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group , nitro, cyano, halogen, C _1-10 alkoxy, C _1-10 alkylcarbonyl th group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group) or NR ⁶ R ⁷ (where each of R ⁶ and R ⁷ independently represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, C _{2- 6} alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group y (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group and the C _1-10 alkylcarbonyl group optionally may be substituted by one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group, A C _1-10 alkylcarbonylamino group, an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _1-6 alkyl the group may be substituted by one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted by one or more substituents selected from the group consisting of C _{1 -10} alkyl group (C _1-10 alkyl group may be substituted with and one or more halogen atoms), C _2-6 alkenyl, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy , C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group), or R ⁶ and R ⁷ taken together mean - (CH ₂ ) _m1 -E- (CH ₂ ) _m2 - (where E represents an oxygen atom, a sulfur atom, CR ²⁶ R ²⁷ (where each of R ²⁶ and R ²⁷ independently represents a hydrogen atom, a C _1-10 alkyl group, a C _2-14 aryl group, a C _1-10 alkoxy group, a C _2-14 aryloxy group, a hydroxyl group or a protected hydroxyl group) or NR ⁸ (where R ⁸ represents a hydrogen atom, hydroxyl group, formyl group, C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _{1 -10} alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl a group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group and a C _1-10 alkylcarbonyl group, optionally can be substituted with one or more substituents selected from the group consisting of a carboxyl group, nitro group, cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group protected hydroxyl group, C _2-14 ari a group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (a C _1-6 alkyl group may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group pu, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino , an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group)), and each of m1 and m2, independently, is an integer of 0 to 5, provided that the sum m1 + m2 is 3, 4 or 5)))), and

B represents NR ⁹ (where R ⁹ represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group, C _{1- 10} alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _1-10 alkylcarbonyloxy group, The C _1-10 alkoxycarbonyl group and the C _1-10 alkylcarbonyl group may optionally be substituted with one or more substituents, selected rannymi from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono - or a di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _{1 -6} alkyl groups (C _1-6 alkyl group may be substituted with one or bore nly halogen atoms) or one or more halogen atoms)), C _2-14 aryl group (C _2-14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group , C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group) or C _2-14 aryloxy group (C _{2- A 14} aryloxy group may optionally be substituted with one or more substituents selected from the group consisting of a C _1-10 alkyl group (a C _1-10 alkyl group may be substituted with one or more halogen atoms), a C _2-6 alkenyl group, C _{2 -6} alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _{1-1 0} alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group)), a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

8. A compound of formula (1), wherein L ¹ is a bond, tautomer, prodrug or pharmaceutically acceptable salt of such a compound, or a solvate thereof.

9. A compound according to claim 2, wherein L ¹ is a bond, tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

10. A compound according to claim 3, wherein L ¹ is a bond, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

11. A compound according to claim 4, wherein L ¹ is a bond, tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

12. A compound according to claim 5, wherein L ¹ is a bond, tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

13. A compound according to claim 6, wherein L ¹ is a bond, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

14. A compound according to claim 7, wherein L ¹ is a bond, tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

15. The compound according to claim 1, wherein L ² is a bond, tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

16. A compound according to claim 2, wherein L ² is a bond, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

17. A compound according to claim 3, wherein L ² is a bond, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

18. The compound according to claim 4, where L ² is a bond, tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

19. A compound according to claim 5, wherein L ² is a bond, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

20. A compound according to claim 6, wherein L ² is a bond, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

21. A compound according to claim 7, wherein L ² is a bond, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

22. A compound according to claim 8, wherein L ² is a bond, tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

23. A compound according to claim 9, wherein L ² is a bond, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

24. A compound according to claim 10, wherein L ² is a bond, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

25. The compound according to claim 11, wherein L ² is a bond, tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

26. A compound according to claim 12, wherein L ² is a bond, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

27. A compound according to claim 13, wherein L ² is a bond, tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

28. A compound according to claim 14, wherein L ² is a bond, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

29. The compound in accordance with claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28, where L ³ represents NR ¹⁹ (where R ¹⁹ represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _{2- 6} alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkoxy and C _1-10 alkyl the carbonyl group may optionally be substituted with one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy group, C _{1- 10} alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one-quarter minutes or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group optionally, may be substituted by one or more substituents selected from the group consisting of a C _1-10 alkyl group (a C _1-10 alkyl group may be substituted by one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkox igruppu, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, C _{2 -14} aryl group and C _2-14 aryloxy group)), a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

30. The compound in accordance with claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28, where L ³ is NH, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

31. The compound according to clause 29, where L ⁴ represents NR ²² (where R ²² represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group and the C _1-10 alkylcarbonyl group may optionally be substituted ne or more substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 an alkylcarbonylamino group, an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group one or more C _1-6 alkyl groups (C _1-6 alkyl Rupp may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C _{1 -10} alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group C _1-10 alkylcarbonyl group C _1-10 alkylcarbonyl oxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group)), a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

32. The compound according to clause 30, where L ^{4 is} defined in clause 31, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

33. The compound according to clause 29, where L ⁴ represents NH, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

34. A compound according to claim 30, wherein L ⁴ is NH, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

35. The compound according to clause 29, where L ⁴ is a bond, tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

36. A compound according to claim 30, wherein L ⁴ is a bond, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

37. The compound according to p, where Y represents an oxygen atom, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

38. The compound according to p, where Y represents an oxygen atom, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

39. The compound according to claim 33, wherein Y is an oxygen atom, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

40. A compound according to claim 34, wherein Y represents an oxygen atom, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

41. A compound according to claim 35, wherein Y represents an oxygen atom, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

42. The compound according to clause 36, where Y represents an oxygen atom, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

43. The compound according to p, where Y represents a sulfur atom, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

44. The compound according to p, where Y represents a sulfur atom, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

45. A compound according to claim 33, wherein Y represents a sulfur atom, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

46. A compound according to claim 34, wherein Y is a sulfur atom, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

47. A compound according to claim 35, wherein Y represents a sulfur atom, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

48. A compound according to claim 36, wherein Y represents a sulfur atom, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

49. The compound in accordance with clause 37, where X represents a hydroxyl group, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

50. A compound according to claim 38, wherein X is a hydroxyl group, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

51. A compound according to claim 39, wherein X is a hydroxyl group, tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

52. The compound according to paragraph 40, where X represents a hydroxyl group, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

53. The compound according to paragraph 41, where X represents a hydroxyl group, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

54. The compound in accordance with paragraph 42, where X represents a hydroxyl group, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

55. The compound in accordance with paragraph 43, where X represents a hydroxyl group, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

56. A compound according to claim 44, wherein X is a hydroxyl group, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

57. A compound according to claim 45, wherein X is a hydroxyl group, tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

58. The compound according to paragraph 46, wherein X is a hydroxyl group, tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

59. The compound in accordance with item 47, where X represents a hydroxyl group, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

60. A compound according to claim 48, wherein X is a hydroxyl group, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

61. The compound according to clause 37, where R ³ represents a C _2-14 aryl group (C _2-14 aryl group, optionally substituted with one or more substituents selected from the group comprising a hydroxyl group, an amino group, a carboxyl group, phosphonic acid group, sulfonic acid group, urea group, sulfamido group, tetrazole group and C _1-10 alkoxycarbonyl group), tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

62. The compound according to clause 38, where R ^{3 is} defined in clause 61, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

63. The compound according to clause 39, where R ^{3 is} defined in clause 61, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

64. The compound according to paragraph 40, where R ^{3 is} defined in paragraph 61, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

65. The compound according to paragraph 41, where R ^{3 is} defined in paragraph 61, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

66. The compound according to paragraph 42, where R ^{3 is} defined in paragraph 61, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

67. The compound in accordance with § 49, where R ^{3 is} defined in § 61, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

68. The compound according to p. 50, where R ^{3 is} defined in p. 61, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

69. The compound according to paragraph 51, where R ^{3 is} defined in paragraph 61, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

70. The compound according to paragraph 52, where R ^{3 is} defined in paragraph 61, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

71. The compound in accordance with paragraph 53, where R ^{3 is} defined in paragraph 61, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

72. The compound according to paragraph 54, wherein R ³ is as defined in paragraph 61, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound, or a solvate thereof.

73. The compound according to claim 43, wherein R ³ is a C _2-14 aryl group (the C _2-14 aryl group is optionally substituted with one or more substituents selected from the group consisting of a hydroxyl group, an amino group, a carboxyl group, phosphonic acid group, sulfonic acid group, urea group, sulfamido group, tetrazole group and C _1-10 alkoxycarbonyl group), tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

74. The compound according to item 44, where R ^{3 is} defined in item 73, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

75. A compound according to claim 45, wherein R ³ is as defined in claim 73, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

76. A compound according to claim 46, wherein R ³ is as defined in claim 73, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

77. The compound according to clause 47, where R ^{3 is} defined in clause 73, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

78. A compound according to claim 48, wherein R ³ is as defined in claim 73, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

79. A compound according to claim 55, wherein R ³ is as defined in claim 73, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

80. The compound according to p, where R ^{3 is} defined in p, tautomer, prodrug or pharmaceutically acceptable salt of such a compound or their solvate.

81. The compound in accordance with clause 57, where R ^{3 is} defined in clause 73, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

82. A compound according to claim 58, wherein R ³ is as defined in claim 73, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

83. The compound in accordance with paragraph 59, where R ^{3 is} defined in paragraph 73, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

84. The compound according to p. 60, where R ^{3 is} defined in p. 73, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

85. The compound according to clause 37, where R ³ represents a C _2-14 aryl group (C _2-14 aryl group, optionally substituted with one or more substituents selected from the group comprising a C _1-10 alkoxy group, C _{1 -10} alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino and mono- or di-C _1-10 alkylamino group), tautomers, prodrugs or pharmaceutically acceptable salt of such compound or a solvate thereof.

86. The compound according to clause 38, wherein R ^{3 is} defined in clause 85, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

87. The compound according to clause 39, where R ^{3 is} defined in clause 85, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

88. A compound according to claim 40, wherein R ³ is as defined in claim 85, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

89. The compound according to paragraph 41, where R ^{3 is} defined in paragraph 85, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

90. The compound in accordance with paragraph 42, where R ^{3 is} defined in paragraph 85, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

91. A compound according to claim 49, wherein R ³ is as defined in claim 85, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

92. The compound according to p. 50, where R ^{3 is} defined in p. 85, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

93. The compound according to paragraph 51, where R ^{3 is} defined in paragraph 85, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

94. The compound in accordance with paragraph 52, where R ^{3 is} defined in paragraph 85, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

95. A compound according to claim 53, wherein R ³ is as defined in claim 85, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

96. A compound according to claim 54, wherein R ³ is as defined in claim 85, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

97. The compound according to paragraph 43, where R ³ represents a C _2-14 aryl group (C _2-14 aryl group optionally substituted with one or more substituents selected from the group consisting of C _1-10 alkoxy group, C _{1 -10} alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino and mono- or di-C _1-10 alkylamino group), tautomers, prodrugs or pharmaceutically acceptable salt of such compound or a solvate thereof.

98. A compound according to claim 44, wherein R ³ is as defined in claim 97, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

99. A compound according to claim 45, wherein R ³ is as defined in claim 97, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

100. A compound according to claim 46, wherein R ³ is as defined in claim 97, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

101. The compound according to clause 47, where R ^{3 is} defined in clause 97, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

102. The compound according to clause 48, wherein R ^{3 is} defined in clause 97, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

103. The compound according to paragraph 55, wherein R ³ is as defined in paragraph 97, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound, or a solvate thereof.

104. The compound according to paragraph 56, where R ^{3 is} defined in paragraph 97, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

105. The compound according to clause 57, where R ^{3 is} defined in clause 97, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

106. The compound according to p, where R ^{3 is} defined in p. 97, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

107. The compound in accordance with paragraph 59, where R ^{3 is} defined in paragraph 97, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

108. The compound according to p. 60, where R ^{3 is} defined in p. 97, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

109. The compound in accordance with clause 37, where R ³ represents a C _2-14 aryl group (C _2-14 aryl group, optionally substituted by one or more substituents selected from the group including

a hydroxyl group, an amino group, a carboxyl group, a phosphonic acid group, a sulfonic acid group, a urea group, a sulfamide group, a tetrazole group and a C _1-10 alkoxycarbonyl group,

and one or more substituents selected from the group including

a nitro group, a cyano group, a halogen atom, a C _1-10 alkyl group substituted by one or more fluorine atoms, a sulfamido group substituted by one or two C _1-10 alkyl groups, a urea group substituted by one or two C _1-10 alkyl groups, and C _{1 -10} alkylcarbonylamino group), tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

110. The compound according to clause 38, where R ^{3 is} defined in clause 109, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

111. The compound according to clause 39, where R ^{3 is} defined in clause 109, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

112. The compound according to paragraph 40, where R ^{3 is} defined in paragraph 109, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

113. The compound according to paragraph 41, where R ^{3 is} defined in paragraph 109, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

114. The compound in accordance with paragraph 42, where R ^{3 is} defined in paragraph 109, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

115. The compound in accordance with paragraph 49, where R ^{3 is} defined in paragraph 109, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

116. The compound according to p. 50, where R ^{3 is} defined in p. 109, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

117. The compound in accordance with paragraph 51, where R ^{3 is} defined in paragraph 109, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

118. The compound in accordance with paragraph 52, where R ^{3 is} defined in paragraph 109, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

119. The compound in accordance with paragraph 53, where R ^{3 is} defined in paragraph 109, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

120. The compound according to paragraph 54, where R ^{3 is} defined in paragraph 109, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

121. The compound in accordance with paragraph 43, where R ³ represents a C _2-14 aryl group (C _2-14 aryl group, optionally substituted with one or more substituents selected from the group including

hydroxyl group, amino group, carboxyl group, phosphonic acid group, sulfonic acid group, urea group, sulfamido group, tetrazole group and C _1-10 alkoxycarbonyl group

and one or more substituents selected from the group including

a nitro group, a cyano group, a halogen atom, a C _1-10 alkyl group substituted by one or more fluorine atoms, a sulfamido group substituted by one or two C _1-10 alkyl groups, a urea group substituted by one or two C _1-10 alkyl groups, and C _{1 -10} alkylcarbonylamino group), tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

122. The compound according to item 44, where R ^{3 is} defined in p. 121, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

123. A compound according to claim 45, wherein R ^{3 is} defined in paragraph 121, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound, or a solvate thereof.

124. A compound according to claim 46, wherein R ^{3 is} defined in paragraph 121, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

125. The compound according to clause 47, where R ^{3 is} defined in p. 121, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

126. The compound according to p, where R ^{3 is} defined in p. 121, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

127. A compound according to claim 55, wherein R ^{3 is} defined in 121, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

128. A compound according to claim 56, wherein R ^{3 is} defined in 121, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

129. A compound according to claim 57, wherein R ^{3 is} defined in paragraph 121, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

130. The compound in accordance with § 58, where R ^{3 is} defined in p. 121, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

131. A compound according to claim 59, wherein R ^{3 is} defined in paragraph 121, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

132. The compound according to p. 60, where R ^{3 is} defined in p. 121, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

133. The thrombopoietin receptor activator in accordance with claim 1.

134. The thrombopoietin receptor activator in accordance with claim 2.

135. The thrombopoietin receptor activator in accordance with claim 3.

136. The thrombopoietin receptor activator in accordance with paragraph 4.

137. The thrombopoietin receptor activator in accordance with paragraph 5.

138. The thrombopoietin receptor activator in accordance with claim 6.

139. The thrombopoietin receptor activator in accordance with paragraph 7.

140. The thrombopoietin receptor activator according to any one of claims 8-14.

141. The thrombopoietin receptor activator in accordance with any one of paragraphs.15-28.

142. The thrombopoietin receptor activator in accordance with clause 29.

143. The thrombopoietin receptor activator in accordance with paragraph 30.

144. Thrombopoietin receptor activator in accordance with paragraph 31 or 32.

145. The thrombopoietin receptor activator in accordance with paragraph 33 or 34.

146. Thrombopoietin receptor activator in accordance with clause 35 or 36.

147. The thrombopoietin receptor activator according to any one of claims 37-42.

148. The thrombopoietin receptor activator in accordance with any one of paragraphs 43-48.

149. The thrombopoietin receptor activator according to any one of claims 49-54.

150. A thrombopoietin receptor activator according to any one of claims 55-60.

151. The thrombopoietin receptor activator in accordance with any one of paragraphs 61-72.

152. The thrombopoietin receptor activator according to any one of claims 73-84.

153. The thrombopoietin receptor activator in accordance with any one of claims 85-96.

154. The thrombopoietin receptor activator in accordance with any one of claims 97-108.

155. The thrombopoietin receptor activator in accordance with any one of paragraphs 109-120.

156. The thrombopoietin receptor activator in accordance with any one of paragraphs 121-132.

157. An agent for the prophylaxis, treatment or amelioration of diseases against which the activation of a thrombopoietin receptor is effective, which includes, as an active ingredient, a thrombopoietin receptor activator according to any one of claims 133-156, a tautomer, prodrug or a pharmaceutically acceptable salt of such an activator or their solvate.

158. A platelet increasing agent comprising, as an active ingredient, a thrombopoietin receptor activator according to any one of claims 133-156, a tautomer, prodrug or pharmaceutically acceptable salt of such an activator or a solvate thereof.

159. A medicament comprising, as an active ingredient, a compound according to any one of claims 1 to 132, a tautomer, a prodrug or a pharmaceutically acceptable salt of such an activator or a solvate thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the proliferation of UT7 / EPO-mpl cells upon stimulation with the compound of the invention (Synthesis Example 3).

 Figure 2 shows the proliferation of UT7 / EPO cells upon stimulation with the compound of the invention (Synthesis Example 3).

Further, the present invention is described in detail.

In the present invention: “n” means normal, “i” means iso, “sec” means secondary, “tert” means tertiary, “c” means cyclo, “o” means ortho, “m” means meta, “p” means a pair, “Ph” means phenyl, “Py” means pyridyl, “Naphthyl” means naphthyl, “Me” means methyl, “Et” means ethyl, “Pr” means propyl and “Bu” means butyl.

First, the terms in the corresponding substituents R ¹ -R ^{36 are} explained.

As an example of a halogen atom, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom can be mentioned.

The C _1-3 alkyl group may be a linear, branched or C ₃ cycloalkyl group, and methyl, ethyl, n-propyl, isopropyl and cyclopropyl and the like can be mentioned as an example.

The C _1-6 alkyl group may be a linear, branched or C _3-6 cycloalkyl group, and as an example, in addition to the above, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, 1-methylcyclopropyl , 2-methylcyclopropyl, n-pentyl, 1-methyl-n-butyl, 2-methyl-n-butyl, 3-methyl-n-butyl, 1,1-dimethyl-n-propyl, 1,2-dimethyl-n propyl, 2,2-dimethyl-n-propyl, 1-ethyl-n-propyl, cyclopentyl, 1-methylcyclobutyl, 2-methylcyclobutyl, 3-methylcyclobutyl, 1,2-dimethylcyclopropyl, 2,3-dimethylcyclopropyl, 1-ethylcyclopropyl , 2-ethylcyclopropyl, n-hexyl, 1-methyl-n-p entyl, 2-methyl-n-pentyl, 3-methyl-n-pentyl, 4-methyl-n-pentyl, 1,1-dimethyl-n-butyl, 1,2-dimethyl-n-butyl, 1,3- dimethyl-n-butyl, 2,2-dimethyl-n-butyl, 2,3-dimethyl-n-butyl, 3,3-dimethyl-n-butyl, 1-ethyl-n-butyl, 2-ethyl-n- butyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 1-ethyl-1-methyl-n-propyl, 1-ethyl-2-methyl-n-propyl, cyclohexyl, 1-methylcyclopentyl, 2-methylcyclopentyl, 3-methylcyclopentyl, 1-ethylcyclobutyl, 2-ethylcyclobutyl, 3-ethylcyclobutyl, 1,2-dimethylcyclobutyl, 1,3-dimethylcyclobutyl, 2,2-dimethylcyclobutyl, 2,3-dimethylcyclobutyl, 2,4-dimethylcyclobutyl, 3,3-dimethylcyclobutyl, 1-n-pro ilcyclopropyl, 2-n-propylcyclopropyl, 1-isopropylcyclopropyl, 2-isopropylcyclopropyl, 1,2,2-trimethylcyclopropyl, 1,2,3-trimethylcyclopropyl, 2,2,3-trimethylcyclopropyl, 1-ethyl-2-methylcyclopropyl, 2- ethyl-1-methylcyclopropyl, 2-ethyl-2-methylcyclopropyl, 2-ethyl-3-methylcyclopropyl and the like.

The C _1-10 alkyl group may be a linear, branched or C _3-10 cycloalkyl group, and as an example, in addition to the above, 1-methyl-1-ethyl-n-pentyl, 1-heptyl, 2-heptyl , 1-ethyl-1,2-dimethyl-n-propyl, 1-ethyl-2,2-dimethyl-n-propyl, 1-octyl, 3-octyl, 4-methyl-3-n-heptyl, 6-methyl -2-n-heptyl, 2-propyl-1-n-heptyl, 2,4,4-trimethyl-1-n-pentyl, 1-nonyl, 2-nonyl, 2,6-dimethyl-4-n-heptyl 3-ethyl-2,2-dimethyl-3-n-pentyl, 3,5,5-trimethyl-1-n-hexyl, 1-decyl, 2-decyl, 4-decyl, 3,7-dimethyl-1 n-octyl, 3,7-dimethyl-3-n-octyl and the like.

As an example of a C _2-6 alkynyl group, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3 can be mentioned. -pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 2 Ethyl 2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentinyl, 1-methyl-3-pentinyl, 1-methyl-4-pentinyl , 2-methyl-3-pentynyl, 2-methyl-4-pentinyl, 3-methyl-1-pentinyl, 3-methyl-4-pentinyl, 4-methyl-1-pentinyl, 4-methyl-2-pentinyl, 1 , 1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dim tyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 1-n-propyl-2- propynyl, 2-ethyl-3-butynyl, 1-methyl-1-ethyl-2-propynyl, 1-isopropyl-2-propynyl and the like.

The C _2-6 alkenyl group may be a linear, branched or C _3-6 cycloalkyl group, and ethenyl, 1-propenyl, 2-propenyl, 1-methyl-1-ethenyl, 1-butenyl, 2-butenyl can be mentioned as an example , 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-ethylethenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3 -pentenyl, 4-pentenyl, 1-n-propylene ethenyl, 1-methyl-1-butenyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 2-ethyl-2-propenyl, 2-methyl-1 -butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2 -propenyl, 1-isopropi letenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 1-methyl-2-pentenyl, 1-methyl-3-pentenyl, 1-methyl-4-pentenyl, 1-n-butylethenyl, 2-methyl-1-pentenyl, 2-methyl-2-pentenyl, 2-methyl-3-pentenyl, 2-methyl-4-pentenyl, 2-n-propyl-2-propenyl, 3-methyl-1-pentenyl, 3-methyl-2-pentenyl, 3-methyl-3-pentenyl, 3-methyl-4-pentenyl, 3-ethyl-3-butenyl, 4-methyl-1-pentenyl, 4-methyl-2-pentenyl, 4-methyl-3-pentenyl, 4- methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl -1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1-methyl-2-ethyl-2-propenyl, 1-sec-butylethenyl, 1,3-dimethyl-1 -butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 1-isobutylethenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3 dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 2-isopropyl-2-propenyl, 3,3-dimethyl-1-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl , 1-ethyl-3-butenyl, 1-n-propyl-1-propenyl, 1-n-propyl-2-propenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3 -butenyl, 1,1,2-trimethyl-2-propenyl, 1-tert-butyl-ethenyl, 1-methyl-1-ethyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, 1-ethyl-2 methyl 2-propenyl, 1-isopropyl-1-propenyl, 1-isopropyl-2-propenyl, 1-methyl-2-cyclopentenyl, 1-methyl-3-cyclopentenyl, 2-methyl-1-cyclopentenyl, 2-methyl-2-cyclopentenyl, 2- methyl-3-cyclopentenyl, 2-methyl-4-cyclopentenyl, 2-methyl-5-cyclopentenyl, 2-methylene cyclopentyl, 3-methyl-1-cyclopentenyl, 3-methyl-2-cyclopentenyl, 3-methyl-3-cyclopentenyl, 3-methyl-4-cyclopentenyl, 3-methyl-5-cyclopentenyl, 3-methylene cyclopentyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl and the like.

A C _2-14 aryl group may be a C _6-14 aryl group containing no heteroatoms as ring-forming atoms, or a C _2-9 aromatic heterocyclic group, and a C _2-9 aromatic heterocyclic group may be a 5-7 membered C _{A 2-6} heteromonocyclic group or an 8-10-membered C _5-9 fused heterobicyclic group containing from 1 to 3 oxygen atoms, nitrogen atoms or sulfur atoms, individually or in combination.

As an example of a C _6-14 aryl group containing no heteroatoms, mention may be made of a phenyl group, 1-indenyl group, 2-indenyl group, 3-indenyl group, 4-indenyl group, 5-indenyl group, 6-indenyl group, 7-indenyl group, α-naphthyl group, β-naphthyl group, 1-tetrahydronaphthyl group, 2-tetrahydronaphthyl group, 5-tetrahydronaphthyl group, 6-tetrahydronaphthyl group, o-biphenyl group, m-biphenyl group, p-biphenyl group, 1-antril group, 2-antril group, 9-antril th group, 1-phenanthryl group, 2-phenanthryl group, 3-phenanthryl group, 4-phenanthryl group, 9-phenanthryl group or the like

The 5-7 membered C _2-6 heteromonocyclic group may be a 2-thienyl group, 3-thienyl group, 2-furyl group, 3-furyl group, 2-pyranyl group, 3-pyranyl group, 4-pyranyl group, 1 -pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 1-pyrazolyl group, 3-pyrazolyl group, 4-pyrazolyl group, 2-thiazolyl group, 4 -thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-of thiazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2- pyrazinyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, 3-pyridazinyl group, 4-pyridazinyl group, 2-1,3,4-oxadiazolyl group, 2-1,3,4-thiadiazolyl group, 3-1,2,4-oxadiazolyl group, 5-1,2,4-oxadiazolyl group, 3-1,2,4-thiadiazolyl group, 5-1,2,4-thiadiazo a lyl group, a 3-1,2,5-oxadiazolyl group, a 3-1,2,5-thiadiazolyl group, or the like.

The 8-10 membered C _5-9 fused heterocyclic group may be a 2-benzofuranyl group, 3-benzofuranyl group, 4-benzofuranyl group, 5-benzofuranyl group, 6-benzofuranyl group, 7-benzofuranyl group, 1-isobenzofuranyl group, 4-isobenzofuranyl group, 5-isobenzofuranyl group, 2-benzothienyl group, 3-benzothienyl group, 4-benzothienyl group, 5-benzothienyl group, 6-benzothienyl group, 7-benzothienyl group, 1-isobenzothienyl group, 4-isobenzothienyl group 5-isobenzothienyl group, 2-chromenyl group, 3-chromenyl group, 4-chromenyl group, 5-chromenyl group, 6-chromenyl group, 7-chromenyl group, 8-chromenyl group, 1-indolysinyl group, 2-indolysinyl group, 3-indolisinyl group, 5-indolisinyl group, 6-indolisinyl group, 7-indolisinyl group, 8-indolisinyl group, 1-isoindolyl group, 2-isoindolyl group, 4-isoindolyl group, 5-isoindolyl group, 1-indolyl group, 2-indolyl group, 3-indolyl group, 4-indolyl group pu, 5-indolyl group, 6-indolyl group, 7-indolyl group, 1-indazolyl group, 2-indazolyl group, 3-indazolyl group, 4-indazolyl group, 5-indazolyl group, 6-indazolyl group, 7-indazolyl group, 1-purinyl group, 2-purinyl group, 3-purinyl group, 6-purinyl group, 7-purinyl group, 8-purinyl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolyl group, 8-quinolyl group, 1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group, 8-isoquinolyl group, 1-phthalazinyl group, 5-phthalazinyl group, 6-phthalazinyl group, 1-2,7-naphthyridinyl group, 3-2,7-naphthyridinyl group, 4-2,7-naphthyridinyl group, 1-2,6-naphthyridinyl group, 3-2,6-naphthyridinyl group, 4-2,6-naphthyridinyl group, 2-1 , 8-naphthyridinyl group, 3-1,8-naphthyridinyl group, 4-1,8-naphthyridinyl group, 2-1,7-naphthyridinyl group, 3-1,7-naphthyridinyl group, 4-1,7-naphthyridinyl ith group, 5-1,7-naphthyridinyl group, 6-1,7-naphthyridinyl group, 8-1,7-naphthyridinyl group, 2-1,6-naphthyridinyl group, 3-1,6-naphthyridinyl group, 4- 1,6-naphthyridinyl group, 5-1,6-naphthyridinyl group, 7-1,6-naphthyridinyl group, 8-1,6-naphthyridinyl group, 2-1,5-naphthyridinyl group, 3-1,5-naphthyridinyl group, 4-1,5-naphthyridinyl group, 6-1,5-naphthyridinyl group, 7-1,5-naphthyridinyl group, 8-1,5-naphthyridinyl group, 2-quinoxalinyl group, 5-quinoxalinyl group, 6- quinoxalinyl group, 2-quinazolinyl group pu, 4-quinazolinyl group, 5-quinazolinyl group, 6-quinazolinyl group, 7-quinazolinyl group, 8-quinazolinyl group, 3-cinnolinyl group, 4-cinnolinyl group, 5-cinnolinyl group, 6-cinnolinyl group, 7-cinnolinyl group group, 8-cinnolinyl group, 2-pteridinyl group, 4-pteridinyl group, 6-pteridinyl group, 7-pteridinyl group or the like.

A C _2-14 aryloxy group may be a C _6-14 aryloxy group containing no heteroatoms as ring-forming atoms, or a C _2-9 aromatic heterocyclic oxy group, and a C _2-9 aromatic heterocyclic oxy group may be a 5-7 membered C _{2- 6} hetero monocyclic oxy group or an 8-10-membered C _5-9 condensed heterobicyclic oxy group containing from 1 to 3 oxygen atoms, nitrogen atoms or sulfur atoms, individually or in combination.

As an example of a C _6-14 aryloxy group containing no heteroatoms, mention may be made of a phenyloxy group, 1-indenyloxy group, 3-indenyloxy group, 4-indenyloxy group, 5-indenyloxy group, 6-indenyloxy group, 7-indenyloxy group, α-naphthyl, β-naphthyloxy group, 1-tetrahydronaphthyloxy group, 2-tetrahydronaphthyloxy group, 5-tetrahydronaphthyloxy group, 6-tetrahydronaphthyloxy group, o-biphenylyloxy group, m-biphenylyloxy, p-antigyryl-1-cyclo-cyclo-cyclo-cyclo-cyclo-cyclo-cyclo-cyclo-cyclo-phenyryl-1-cyclo-cyclo-cyclo-cyclo-cyclo-cyclo-phenyl-phenyryl-1-cyclo-cyclo-cyclo-phenyl-cyclo-cyclo-phenyl-cyclo-phenyl-cyclo-phenyl-cyclo-phenyl-cyclo-phenyl-cyclo-cyclo-cyclo-cyclo-phenyl-cyclo-phenyl-cyclo-phenyl-cyclo-cyclo-cyclo-cyclo-phenyl-phenyl-cyclo-cyclo-phenyl-hydrogen enantriloksigruppu, 2-fenantriloksigruppu, fenantriloksigruppu-3, 4-fenantriloksigruppu, 9 or the like fenantriloksigruppu

The 5-7-membered C _2-6 heteromonocyclic oxy group may be a 2-thienyloxy group, 3-thienyloxy group, 2-furyloxy group, 3-furyloxy group, 2-pyranyloxy group, 3-pyranyloxy group, 4-pyranyloxy group, 1-pyrrolyloxy-pyrrolyloxy-group 3-pyrrolyloxy group, 1-imidazolyloxy group, 2-imidazolyloxy group, 4-imidazolyloxy group, 1-pyrazolyloxy group, 4-pyrazolyloxy group, 4-thiazoyl-5-thiazoyloxy-yazyloxy-yazyloxy-yazyloxy-yazyloxy-yazyloxy-yazyloxy-ylozyloxy isothiazole yloxy, 2-oksazoliloksigruppu, 4-oksazoliloksigruppu, 5-oksazoliloksigruppu, 3-izoksazoliloksigruppu, 4-izoksazoliloksigruppu, 5-izoksazoliloksigruppu, 2-pyridyloxy, 3-pyridyloxy, 4-pyridyloxy, 2-piraziniloksigruppu, 2-pyrimidinyloxy, 4-pyrimidinyloxy, 5-pyrimidinyl oxy group, 3-pyridazinyl oxy group, 4-pyridazinyl oxy group, 2-1,3,4-oxadiazolyloxy group, 2-1,3,4-thiadiazolyloxy group, 3-1,2,4-oxadiazolyloxy group, 5-1,2,4- oxadiazolyloxy group, 3-1,2,4-thiadiazolyloxy group, 5-1,2,4-thiadiazolyloxy group, 3-1,2, 5-oxadiazolyloxy group, 3-1,2,5-thiadiazolyloxy group or the like.

The 8-10 membered C _5-9 fused heterocyclic oxy group may be a 2-benzofuranyloxy group, 3-benzofuranyloxy group, 4-benzofuranyloxy group, 6-benzofuranyloxy group, 7-benzofuranyloxy group, 1-isobenzofuranoxyfuranoxy-4-phenoxyfuranyloxy-4-phenobuenofuoxy-phenyloxy-4-phenoxyfuranyloxy , 2-benzothienyloxy, 3-benzothienyloxy, 4-benzothienyloxy, 5-benzothienyloxy, 6-benzothienyloxy, 7-benzothienyloxy, 1-isobenzothienyloxy, 4-isobenzothienyloxy benzothienyloxy group, 2-chromenyloxy group, 3-chromenyloxy group, 4-chromenyloxy group, 6-chromenyloxy group, 7-chromenyloxy group, 8-chromenyloxy group, 1-indolysynyloxy-indyloxy-6-indyloxy-6-indyloxy-6-indyloxy-6-indyloxy-6-indyloxy-6-indyloxy-group 7-indolysinyl oxy group, 8-indolysinyl oxy group, 1-isoindolyloxy group, 2-isoindolyloxy group, 4-isoindolyloxy group, 5-isoindolyloxy group, 1-indolyloxy group, 2-indoleloxy group, 3-indole-4-indole-yl-indoleoxy a group, a 6-indolyloxy group, a 7-indolyloxy group, a 1-indazolyloxy group, a 3-indazolyloxy group, a 4-indazolyloxy group, a 5-indazolyloxy group, 6-indazolyloxy group, 6-indazyloxy group, 1-indazyloxy group, 1-indazyloxy group, 7 6-purynyloxy group, 7-purynyloxy group, 8-purynyloxy group, 2-quinolyloxy group, 3-quinolyloxy group, 4-quinolyloxy group, 5-quinolyloxy group, 6-quinolyloxy-group, iso-7-yloxy-1-yl-1, 8 isoquinolyloxy ppu, 5-isoquinolyloxy group, 6-isoquinolyloxy group, 7-isoquinolyloxy group, 8-isoquinolyloxy group, 1-phthalazynyloxy group, 5-phthalazynyloxy group, 6-phthalazinyloxy group, 1-2,7-naphthyridinyl-2-4-naphthyridinyl-4-naphthyridinyl-4-naphthyridinyl-4-naphthyridinyl-2-group 7-naphthyridinyl oxy group, 1-2,6-naphthyridinyl oxy group, 3-2,6-naphthyridinyl oxy group, 4-2,6-naphthyridinyl oxy group, 2-1,8-naphthyridinyl oxy group, 3-1,8-naphthyridinyl oxy group, 4-1,8- naphthyridinyl oxy group, 2-1,7-naphthyridinyl oxy group, 3-1,7-naphthyridinyl oxy group, 4-1,7-naphthyridinyl oxy group, 5-1,7-naphthyridinyl oxy group, 6-1,7-n aphthyridinyl oxy group, 8-1,7-naphthyridinyl oxy group, 2-1,6-naphthyridinyl oxy group, 3-1,6-naphthyridinyl oxy group, 4-1,6-naphthyridinyl oxy group, 5-1,6-naphthyridinyl oxy group, 7-1,6-naphthyridinyl oxy group, 8-1,6-naphthyridinyl oxy group, 2-1,5-naphthyridinyl oxy group, 3-1,5-naphthyridinyl oxy group, 4-1,5-naphthyridinyl oxy group, 6-1,5-naphthyridinyl oxy group, 7-1,5-naphthyridinyl oxy group, 8- 1,5-naphthyridinyl-oxy group, 2-quinoxalinyloxy-group, 5-quinoxalinyloxy-group, 6-quinoxalinyloxy-group, 2-quinazolinoyloxy-group, 4-quinazolinyloxy-group, 5-quinazolinyloxy-group 6-hinazoliniloksigruppu, 7 hinazoliniloksigruppu, 8-hinazoliniloksigruppu, 3-tsinnoliniloksigruppu, 4-tsinnoliniloksigruppu, 5-tsinnoliniloksigruppu, 6-tsinnoliniloksigruppu, 7 tsinnoliniloksigruppu, 8-tsinnoliniloksigruppu, 2-pteridiniloksigruppu, 4-pteridiniloksigruppu, 6-pteridiniloksigruppu 7 a pteridinyloxy group or the like.

The C _1-6 alkylcarbonyl group may be a linear, branched or C _3-6 cycloalkylcarbonyl group, and methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, cyclopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, may be mentioned as an example. , cyclobutylcarbonyl, 1-methylcyclopropylcarbonyl, 2-methylcyclopropylcarbonyl, n-pentylcarbonyl, 1-methyl-n-butylcarbonyl, 2-methyl-n-butylcarbonyl, 3-methyl-n-butylcarbonyl, 1,1-dimethyl-n-propylcarbonyl, 1 , 2-dimethyl-n-propylcarbonyl, 2,2-dimethyl-n-prop alkylcarbonyl, 1-ethyl-n-propylcarbonyl, cyclopentylcarbonyl, 1-methylcyclobutylcarbonyl, 2-methylcyclobutylcarbonyl, 3-methylcyclobutylcarbonyl, 1,2-dimethylcyclopropylcarbonyl, 2,3-dimethylcyclopropylcarbonyl, 1-ethylcyclopropylcarbonyl, 1-ethylcyclopropylcarbonyl, 2-ethylcyclopropylcarbonyl methyl-n-pentylcarbonyl, 2-methyl-n-pentylcarbonyl, 3-methyl-n-pentylcarbonyl, 4-methyl-n-pentylcarbonyl, 1,1-dimethyl-n-butylcarbonyl, 1,2-dimethyl-n-butylcarbonyl, 1,3-dimethyl-n-butylcarbonyl, 2,2-dimethyl-n-butylcarbonyl, 2,3-dimethyl-n-butylcarbonyl, 3,3-dimethyl-n-butylcarbonyl, 1-ethyl n-butylcarbonyl, 2-ethyl-n-butylcarbonyl, 1,1,2-trimethyl-n-propylcarbonyl, 1,2,2-trimethyl-n-propylcarbonyl, 1-ethyl-1-methyl-n-propylcarbonyl, 1- ethyl-2-methyl-n-propylcarbonyl, cyclohexylcarbonyl, 1-methylcyclopentylcarbonyl, 2-methylcyclopentylcarbonyl, 3-methylcyclopentylcarbonyl, 1-ethylcyclobutylcarbonyl, 2-ethylcyclobutylcarbonyl, 3-ethylcyclobutylcarbonyl, 1,2-2-dimethyl 2-dimethylcyclobutylcarbonyl, 2,3-dimethylcyclobutylcarbonyl, 2,4-dimethylcyclobutylcarbonyl, 3,3-dimethylcyclobutylcarbonyl, 1-n-propylcycle propylcarbonyl, 2-n-propylcyclopropylcarbonyl, 1-isopropylcyclopropylcarbonyl, 2-isopropylcyclopropylcarbonyl, 1,2,2-trimethylcyclopropylcarbonyl, 1,2,3-trimethylcyclopropylcarbonyl, 2,2,3-trimethylcyclopropylcarbonyl, 1-ethyl-2-methyl-2-methyl ethyl-1-methylcyclopropylcarbonyl, 2-ethyl-2-methylcyclopropylcarbonyl, 2-ethyl-3-methylcyclopropylcarbonyl or the like.

The C _1-10 alkylcarbonyl group may be a linear, branched or C _3-10 cycloalkylcarbonyl group, and as an example, in addition to the above, 1-methyl-1-ethyl-n-pentylcarbonyl, 1-heptylcarbonyl, 2- heptylcarbonyl, 1-ethyl-1,2-dimethyl-n-propylcarbonyl, 1-ethyl-2,2-dimethyl-n-propylcarbonyl, 1-octylcarbonyl, 3-octylcarbonyl, 4-methyl-3-n-heptylcarbonyl, 6- methyl-2-n-heptylcarbonyl, 2-propyl-1-n-heptylcarbonyl, 2,4,4-trimethyl-1-n-pentylcarbonyl, 1-nonylcarbonyl, 2-nonylcarbonyl, 2,6-dimethyl-4-n- heptylcarbonyl, 3-ethyl-2,2-dimethyl-3-n-pentylcarbon yl, 3,5,5-trimethyl-1-n-hexylcarbonyl, 1-decylcarbonyl, 2-decylcarbonyl, 4-decylcarbonyl, 3,7-dimethyl-1-n-octylcarbonyl, 3,7-dimethyl-3-n- octylcarbonyl or the like

The C _1-10 alkoxy group may be linear, branched or C _3-10 cycloalkoxy, and as an example, methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy , 1-methylcyclopropoxy, 2-methylcyclopropoxy, n-pentyloxy, 1-methyl-n-butoxy, 2-methyl-n-butoxy, 3-methyl-n-butoxy, 1,1-dimethyl-n-propoxy, 1,2 -dimethyl-n-propoxy, 2,2-dimethyl-n-propoxy, 1-ethyl-n-propoxy, cyclopentyloxy, 1-methylcyclobutoxy, 2-methylcyclobutoxy, 3-methylcyclobutoxy, 1,2-dimethylcyclopropoxy, 2,3-dimethyl cyclopropoxy, 1-ethylcyclopropoxy, 2-ethylcyclopropoxy, n-hexyloxy, 1-methyl-n-pentyloxy, 2-methyl-n-pentyloxy, 3-methyl-n-pentyloxy, 4-methyl-n-pentyloxy, 1,1- dimethyl-n-butoxy, 1,2-dimethyl-n-butoxy, 1,3-dimethyl-n-butoxy, 2,2-dimethyl-n-butoxy, 2,3-dimethyl-n-butoxy, 3,3- dimethyl-n-butoxy, 1-ethyl-n-butoxy, 2-ethyl-n-butoxy, 1,1,2-trimethyl-n-propoxy, 1,2,2-trimethyl-n-propoxy, 1-ethyl 1-methyl-n-propoxy, 1-ethyl-2-methyl-n-propoxy, cyclohexyloxy, 1-methylcyclopentyloxy, 2-methylcyclopentyloxy, 3-methylcyclopentyloxy, 1-ethylcyclobutoxy, 2-ethylcyclobutoxy, 3-ethylcyclic obutoxy, 1,2-dimethylcyclobutoxy, 1,3-dimethylcyclobutoxy, 2,2-dimethylcyclobutoxy, 2,3-dimethylcyclobutoxy, 2,4-dimethylcyclobutoxy, 3,3-dimethylcyclobutoxy, 1-n-propylcyclopropoxy, 2-n-propylcyclopropoxy, 1-isopropylcyclopropoxy, 2-isopropylcyclopropoxy, 1,2,2-trimethylcyclopropoxy, 1,2,3-trimethylcyclopropoxy, 2,2,3-trimethylcyclopropoxy, 1-ethyl-2-methylcyclopropoxy, 2-ethyl-1-methylcyclopropoxy, 2- ethyl 2-methylcyclopropoxy, 2-ethyl-3-methylcyclopropoxy, 1-methyl-1-ethyl-n-pentyloxy, 1-heptyloxy, 2-heptyloxy, 1-ethyl-1,2-dimethyl-n-propyloxy, 1- ethyl 2,2-dimet yl-n-propyloxy, 1-octyloxy, 3-octyloxy, 4-methyl-3-n-heptyloxy, 6-methyl-2-n-heptyloxy, 2-propyl-1-n-heptyloxy, 2,4,4- trimethyl-1-n-pentyloxy, 1-nonyloxy, 2-nonyloxy, 2,6-dimethyl-4-n-heptyloxy, 3-ethyl-2,2-dimethyl-3-n-pentyloxy, 3,5,5- trimethyl-1-n-hexyloxy, 1-decyloxy, 2-decyloxy, 4-decyloxy, 3,7-dimethyl-1-n-octyloxy, 3,7-dimethyl-3-n-octyloxy or the like.

The C _1-6 alkoxycarbonyl group may be a linear, branched or C _3-6 cycloalkoxycarbonyl group, and as an example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, cyclopropylcarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, sec-butoxycarbonyl , cyclobutoxycarbonyl, 1-methylcyclopropoxycarbonyl, 2-methylcyclopropoxycarbonyl, n-pentyloxycarbonyl, 1-methyl-n-butoxycarbonyl, 2-methyl-n-butoxycarbonyl, 3-methyl-n-butoxycarbonyl, 1,1-dimethyl-n-propoxycarbonyl, 1 2-d methyl-n-propoxycarbonyl, 2,2-dimethyl-n-propoxycarbonyl, 1-ethyl-n-propoxycarbonyl, cyclopentyloxycarbonyl, 1-methylcyclobutoxycarbonyl, 2-methylcyclobutoxycarbonyl, 3-methylcyclobutoxycarbonyl, 1,2-dimethylcyclopropoxycarbonyl, 2,3-dimethylcyclopropoxycarbonyl, 2,3-dimethylcyclopropoxycarbonyl 1-ethylcyclopropoxycarbonyl, 2-ethylcyclopropoxycarbonyl, n-hexyloxycarbonyl, 1-methyl-n-pentyloxycarbonyl, 2-methyl-n-pentyloxycarbonyl, 3-methyl-n-pentyloxycarbonyl, 4-methyl-n-pentyloxycarbonyl, 1,1-dimethyl- n-butoxycarbonyl, 1,2-dimethyl-n-butoxycarbonyl, 1,3-dimethyl-n-butoxy rbonyl, 2,2-dimethyl-n-butoxycarbonyl, 2,3-dimethyl-n-butoxycarbonyl, 3,3-dimethyl-n-butoxycarbonyl, 1-ethyl-n-butoxycarbonyl, 2-ethyl-n-butoxycarbonyl, 1, 1,2-trimethyl-n-propoxycarbonyl, 1,2,2-trimethyl-n-propoxycarbonyl, 1-ethyl-1-methyl-n-propoxycarbonyl, 1-ethyl-2-methyl-n-propoxycarbonyl, cyclohexyloxycarbonyl, 1- methylcyclopentyloxycarbonyl, 2-methylcyclopentyloxycarbonyl, 3-methylcyclopentyloxycarbonyl, 1-ethylcyclobutoxycarbonyl, 2-ethylcyclobutoxycarbonyl, 3-ethylcyclobutoxycarbonyl, 1,2-dimethylcyclobutoxycarbonyl, 1,3-dimethylcyclobutoxy rbonyl, 2,2-dimethylcyclobutoxycarbonyl, 2,3-dimethylcyclobutoxycarbonyl, 2,4-dimethylcyclobutoxycarbonyl, 3,3-dimethylcyclobutoxycarbonyl, 1-n-propylcyclopropoxycarbonyl, 2-n-propylcyclopropoxycarbonyl, 1-isopropylcyclopropoxycarbonyl, 2-isopropylcyclopropoxycarbonyl, 2-isopropylcyclopropoxycarbonyl, 2- 2-trimethylcyclopropoxycarbonyl, 1,2,3-trimethylcyclopropoxycarbonyl, 2,2,3-trimethylcyclopropoxycarbonyl, 1-ethyl-2-methylcyclopropoxycarbonyl, 2-ethyl-1-methylcyclopropoxycarbonyl, 2-ethyl-2-methylcyclopropoxycarbonyl, 2-ethyl-3- methylcyclopropoxycarbonyl or the like.

The C _1-10 alkoxycarbonyl group may be a linear, branched or C _3-10 cycloalkoxycarbonyl group, and as an example, in addition to the above, 1-methyl-1-ethyl-n-pentyloxycarbonyl, 1-heptyloxycarbonyl, 2- heptyloxycarbonyl, 1-ethyl-1,2-dimethyl-n-propyloxycarbonyl, 1-ethyl-2,2-dimethyl-n-propyloxycarbonyl, 1-octyloxycarbonyl, 3-octyloxycarbonyl, 4-methyl-3-n-heptyloxycarbonyl, 6- methyl-2-n-heptyloxycarbonyl, 2-propyl-1-n-heptyloxycarbonyl, 2,4,4-trimethyl-1-n-pentyloxycarbonyl, 1-nonyloxycarbonyl, 2-nonyloxycarbonyl, 2 6-dimethyl-4-n-heptyloxycarbonyl, 3-ethyl-2,2-dimethyl-3-n-pentyloxycarbonyl, 3,5,5-trimethyl-1-n-hexyloxycarbonyl, 1-decyloxycarbonyl, 2-decyloxycarbonyl, 4 β-decyloxycarbonyl, 3,7-dimethyl-1-n-octyloxycarbonyl, 3,7-dimethyl-3-n-octyloxycarbonyl or the like.

The C _1-10 alkylcarbonyloxy group may be linear, branched or C _3-10 cycloalkylcarbonyloxy, and as an example, methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, cyclopropylcarbonyloxy, t-butylobutylcarbonyloxybutylcarbonyloxybutylcarbonyloxybutylcarbonyloxybutylcarbonyloxybutylcarbonyloxybutylcarbonyloxy , 1-methylcyclopropylcarbonyloxy, 2-methylcyclopropylcarbonyloxy, n-pentylcarbonyloxy, 1-methyl-n-butylcarbonyloxy, 2-methyl-n-butylcarbonyloxy, 3-methyl-n-butylcarbonyloxy, 1,1-d methyl-n-propylcarbonyloxy, 1,2-dimethyl-n-propylcarbonyloxy, 2,2-dimethyl-n-propylcarbonyloxy, 1-ethyl-n-propylcarbonyloxy, cyclopentylcarbonyloxy, 1-methylcyclobutylcarbonyloxy, 2-methylcyclobutylcarbonyloxy, 3-methylcyclobutyloxy 2-dimethylcyclopropylcarbonyloxy, 2,3-dimethylcyclopropylcarbonyloxy, 1-ethylcyclopropylcarbonyloxy, 2-ethylcyclopropylcarbonyloxy, n-hexylcarbonyloxy, 1-methyl-n-pentylcarbonyloxy, 2-methyl-n-pentylcarbonyloxy, 3-methyl-n-pentylcarbonyloxy, 3-methyl-n-pentylcarbonyloxy, 3-methyl-n-pentylcarbonyloxy, 3-methyl-n-pentylcarbonyloxy, 3-methyl-n-pentylcarbonyloxy n-pentylcarbonyloxy, 1,1-dimethyl-n-butylcarbonium hydroxy, 1,2-dimethyl-n-butylcarbonyloxy, 1,3-dimethyl-n-butylcarbonyloxy, 2,2-dimethyl-n-butylcarbonyloxy, 2,3-dimethyl-n-butylcarbonyloxy, 3,3-dimethyl-n- butylcarbonyloxy, 1-ethyl-n-butylcarbonyloxy, 2-ethyl-n-butylcarbonyloxy, 1,1,2-trimethyl-n-propylcarbonyloxy, 1,2,2-trimethyl-n-propylcarbonyloxy, 1-ethyl-1-methyl- n-propylcarbonyloxy, 1-ethyl-2-methyl-n-propylcarbonyloxy, cyclohexylcarbonyloxy, 1-methylcyclopentylcarbonyloxy, 2-methylcyclopentylcarbonyloxy, 3-methylcyclopentylcarbonyloxy, 1-ethylcyclobutylcarbonyloxy, 2-ethylcyclobutylcarbonyloxy -ethylcyclobutylcarbonyloxy, 1,2-dimethylcyclobutylcarbonyloxy, 1,3-dimethylcyclobutylcarbonyloxy, 2,3-dimethylcyclobutylcarbonyloxy, 2,4-dimethylcyclobutylcarbonyloxy, 3,3-dimethylcyclobutylcarbonyloxy-propyloxy-2-propyl-1-cyclobonyloxy , 1-Isopropylcyclopropylcarbonyloxy, 2-isopropylcyclopropylcarbonyloxy, 1,2,2-trimethylcyclopropylcarbonyloxy, 1,2,3-trimethylcyclopropylcarbonyloxy, 2,2,3-trimethylcyclopropylcarbonyloxy, 1-ethyl-2-methylcyclopropylcarbonyloxy, 2-ethyl-1 ethylcyclopropylcarbonyloxy, 2-ethyl-2-methylcyclopropylcarbonyloxy, 2-ethyl-3-methylcyclopropylcarbonyloxy, 1-methyl-1-ethyl-n-pentylcarbonyloxy, 1-heptylcarbonyloxy, 2-heptylcarbonyloxy, 1-ethyl-1,2-dimethyl-n- propylcarbonyloxy, 1-ethyl-2,2-dimethyl-n-propylcarbonyloxy, 1-octylcarbonyloxy, 3-octylcarbonyloxy, 4-methyl-3-n-heptylcarbonyloxy, 6-methyl-2-n-heptylcarbonyloxy, 2-propyl-1- n-heptylcarbonyloxy, 2,4,4-trimethyl-1-n-pentylcarbonyloxy, 1-nonylcarbonyloxy, 2-nonylcarbonyloxy, 2,6-dimethyl-4-n-heptylcarbonyloxy, 3-ethyl-2,2-dimethyl-3- n-pentylcarbonyl xi, 3,5,5-trimethyl-1-n-hexylcarbonyloxy, 1-decylcarbonyloxy, 2-decylcarbonyloxy, 4-decylcarbonyloxy, 3,7-dimethyl-1-n-octylcarbonyloxy, 3,7-dimethyl-3-n- octylcarbonyloxy or the like.

The C _1-10 alkylcarbonylamino group may be linear, branched or C _3-10 cycloalkylcarbonylamino, and methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, cyclopropylcarbonylamino-carbonylamino-carbonylamino-carbonylamino , 1-methylcyclopropylcarbonylamino, 2-methylcyclopropylcarbonylamino, n-pentylcarbonylamino, 1-methyl-n-butylcarbonylamino, 2-methyl-n-butylcarbonylamino, 3-methyl-n-buty lcarbonylamino, 1,1-dimethyl-n-propylcarbonylamino, 1,2-dimethyl-n-propylcarbonylamino, 2,2-dimethyl-n-propylcarbonylamino, 1-ethyl-n-propylcarbonylamino, cyclopentylcarbonylamino, 1-methylcyclobutylcarbonylamino, 2-methylcyclobutylcarbonylamino 3-methylcyclobutylcarbonylamino, 1,2-dimethylcyclopropylcarbonylamino, 2,3-dimethylcyclopropylcarbonylamino, 1-ethylcyclopropylcarbonylamino, 2-ethylcyclopropylcarbonylamino, n-hexylcarbonylamino, 1-methyl-n-pentylcarbonylamino-2-methyl pentylcarbonylamino, 4-methyl-n-pentyl bonilamino, 1,1-dimethyl-n-butylcarbonylamino, 1,2-dimethyl-n-butylcarbonylamino, 1,3-dimethyl-n-butylcarbonylamino, 2,2-dimethyl-n-butylcarbonylamino, 2,3-dimethyl-n- butylcarbonylamino, 3,3-dimethyl-n-butylcarbonylamino, 1-ethyl-n-butylcarbonylamino, 2-ethyl-n-butylcarbonylamino, 1,1,2-trimethyl-n-propylcarbonylamino, 1,2,2-trimethyl-n- propylcarbonylamino, 1-ethyl-1-methyl-n-propylcarbonylamino, 1-ethyl-2-methyl-n-propylcarbonylamino, cyclohexylcarbonylamino, 1-methylcyclopentylcarbonylamino, 2-methylcyclopentylcarbonylamino, 3-methylcyclopentylcarbonylamino, 1-ethylcyclopentylcarbonylamino acylbutylcarbonylamino, 2-ethylcyclobutylcarbonylamino, 3-ethylcyclobutylcarbonylamino, 1,2-dimethylcyclobutylcarbonylamino, 2,2-dimethylcyclobutylcarbonylamino, 2,3-dimethylcyclobutylcarbonyl-3-dimethyl propylcyclopropylcarbonylamino, 2-n-propylcyclopropylcarbonylamino, 1-isopropylcyclopropylcarbonylamino, 2-isopropylcyclopropylcarbonylamino, 1,2,2-trimethylcyclopropylcarbonylamino, 1,2,3-trimethylcyclopropylcarbonylamino, 2,2,3-trimethyl cyclopropylcarbonylamino, 1-ethyl-2-methylcyclopropylcarbonylamino, 2-ethyl-1-methylcyclopropylcarbonylamino, 2-ethyl-2-methylcyclopropylcarbonylamino, 2-ethyl-3-methylcyclopropylcarbonylamino, 1-methyl-1-ethyl-n-pentylcarbonyl 2-heptylcarbonylamino, 1-ethyl-1,2-dimethyl-n-propylcarbonylamino, 1-ethyl-2,2-dimethyl-n-propylcarbonylamino, 1-octylcarbonylamino, 3-octylcarbonylamino, 4-methyl-3-n-heptylcarbonylamino, 6-methyl-2-n-heptylcarbonylamino, 2-propyl-1-n-heptylcarbonylamino, 2,4,4-trimethyl-1-n-pentylcarbonylamino, 1-nonylcarbonylamino , 2-nonylcarbonylamino, 2,6-dimethyl-4-n-heptylcarbonylamino, 3-ethyl-2,2-dimethyl-3-n-pentylcarbonylamino, 3,5,5-trimethyl-1-n-hexylcarbonylamino, 1-decylcarbonylamino , 2-decylcarbonylamino, 4-decylcarbonylamino, 3,7-dimethyl-1-n-octylcarbonylamino, 3,7-dimethyl-3-n-octylcarbonylamino or the like.

The C _1-10 monoalkylamino group may be linear, branched or C _3-10 cycloalkylamino, and as an example, methylamino, ethylamino, n-propylamino, isopropylamino, cyclopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, cyclobylamino , 1-methylcyclopropylamino, 2-methylcyclopropylamino, n-pentylamino, 1-methyl-n-butylamino, 2-methyl-n-butylamino, 3-methyl-n-butylamino, 1,1-dimethyl-n-propylamino, 1,2 -dimethyl-n-propylamino, 2,2-dimethyl-n-propylamino, 1-ethyl-n-propylamino, cyclopentylamino, 1-methylcyclobutylamine o, 2-methylcyclobutylamino, 3-methylcyclobutylamino, 1,2-dimethylcyclopropylamino, 2,3-dimethylcyclopropylamino, 1-ethylcyclopropylamino, 2-ethylcyclopropylamino, n-hexylamino, 1-methyl-n-pentylamino, 2-methyl-n-pentylamino, 3-methyl-n-pentylamino, 4-methyl-n-pentylamino, 1,1-dimethyl-n-butylamino, 1,2-dimethyl-n-butylamino, 1,3-dimethyl-n-butylamino, 2,2- dimethyl-n-butylamino, 2,3-dimethyl-n-butylamino, 3,3-dimethyl-n-butylamino, 1-ethyl-n-butylamino, 2-ethyl-n-butylamino, 1,1,2-trimethyl- n-propylamino, 1,2,2-trimethyl-n-propylamino, 1-ethyl-1-methyl-n-propylamino, 1-ethyl-2-methyl-n-propyl otherwise, cyclohexylamino, 1-methylcyclopentylamino, 2-methylcyclopentylamino, 3-methylcyclopentylamino, 1-ethylcyclobutylamino, 2-ethylcyclobutylamino, 3-ethylcyclobutylamino, 1,2-dimethylcyclobutylamino, 1,3-dimethylcyclobutylamino, 2,2-dimethylcylobutylamino dimethylcyclobutylamino, 2,4-dimethylcyclobutylamino, 3,3-dimethylcyclobutylamino, 1-n-propylcyclopropylamino, 2-n-propylcyclopropylamino, 1-isopropylcyclopropylamino, 2-isopropylcyclopropylamino, 1,2,2-trimethylcyclopropylamino, 1,2 2,2,3-trimethylcyclopropylamino, 1-ethyl-2-m ethylcyclopropylamino, 2-ethyl-1-methylcyclopropylamino, 2-ethyl-2-methylcyclopropylamino, 2-ethyl-3-methylcyclopropylamino, 1-methyl-1-ethyl-n-pentylamino, 1-heptylamino, 2-heptylamino, 1-ethyl- 1,2-dimethyl-n-propylamino, 1-ethyl-2,2-dimethyl-n-propylamino, 1-octylamino, 3-octylamino, 4-methyl-3-n-heptylamino, 6-methyl-2-n- heptylamino, 2-propyl-1-n-heptylamino, 2,4,4-trimethyl-1-n-pentylamino, 1-nonylamino, 2-nonylamino, 2,6-dimethyl-4-n-heptylamino, 3-ethyl 2,2-dimethyl-3-n-pentylamino, 3,5,5-trimethyl-1-n-hexylamino, 1-decylamino, 2-decylamino, 4-decylamino, 3,7-dimethyl-1-n-octylamino, 3,7-dimeti -3-n-octylamino or the like

The C _1-10 dialkylamino group may be symmetric or asymmetric. The symmetric C _1-10 dialkylamino group may be linear, branched or C _3-10 cycloalkylamino, and as an example, dimethylamino, diethylamino, di-n-propylamino, di-isopropylamino, di-cyclopropylamino, di-n-butylamino, di- isobutylamino, di-sec-butylamino, di-tert-butylamino, d-cyclobutylamino, di- (1-methylcyclopropyl) amino, di- (2-methylcyclopropyl) amino, di-n-pentylamino, di- (1-methyl-n -butyl) amino, di- (2-methyl-n-butyl) amino, di- (3-methyl-n-butyl) amino, di- (1,1-dimethyl-n-propyl) amino, di- (1 , 2-dimethyl-n-propyl) amino, di- (2,2-dimethyl-n-propi k) amino, di- (1-ethyl-n-propyl) amino, dicyclopentylamino, di- (1-methylcyclobutyl) amino, di- (2-methylcyclobutyl) amino, di- (3-methylcyclobutyl) amino, di- (1 , 2-dimethylcyclopropyl) amino, di- (2,3-dimethylcyclopropyl) amino, di- (1-ethylcyclopropyl) amino, di- (2-ethylcyclopropyl) amino, di-n-hexylamino, di- (1-methyl-n -pentyl) amino, di- (2-methyl-n-pentyl) amino, di- (3-methyl-n-pentyl) amino, di- (4-methyl-n-pentyl) amino, di- (1,1 -dimethyl-n-butyl) amino, di- (1,2-dimethyl-n-butyl) amino, di- (1,3-dimethyl-n-butyl) amino, di- (2,2-dimethyl-n- butyl) amino, di- (2,3-dimethyl-n-butyl) amino, di- (3,3-dimethyl-n-butyl) amino, d - (1-ethyl-n-butyl) amino, di- (2-ethyl-n-butyl) amino, di- (1,1,2-trimethyl-n-propyl) amino, di- (1,2,2 trimethyl-n-propyl) amino, di- (1-ethyl-1-methyl-n-propyl) amino, di- (1-ethyl-2-methyl-n-propyl) amino, di-cyclohexylamino, di- ( 1-methylcyclopentyl) amino, di- (2-methylcyclopentyl) amino, di- (3-methylcyclopentyl) amino, di- (1-ethylcyclobutyl) amino, di- (2-ethylcyclobutyl) amino, di- (3-ethylcyclobutyl) amino di- (1,2-dimethylcyclobutyl) amino, di- (1,3-dimethylcyclobutyl) amino, di- (2,2-dimethylcyclobutyl) amino, di- (2,3-dimethylcyclobutyl) amino, di- (2, 4-dimethylcyclobutyl) amino, di- (3,3-dimethylcyclobutyl) amino, di- (1-n-propylcyclopropyl) amino, di- (2-n-propylcyclopropyl) amino, di- (1-isopropylcyclopropyl) amino, di- (2-isopropylcyclopropyl) amino, di- (1,2,2-trimethylcyclopropyl ) amino, di- (1,2,3-trimethylcyclopropyl) amino, di- (2,2,3-trimethylcyclopropyl) amino, di- (1-ethyl-2-methylcyclopropyl) amino, di- (2-ethyl- 1-methylcyclopropyl) amino, di- (2-ethyl-2-methylcyclopropyl) amino, di- (2-ethyl-3-methylcyclopropyl) amino, di- (1-methyl-1-ethyl-n-pentyl) amino, di - (1-heptyl) amino, di- (2-heptyl) amino, di- (1-ethyl-1,2-dimethyl-n-propyl) amino, di- (1-ethyl-2,2-dimethyl-n propyl) amino, di- (1-octyl) amino, di- (3-octyl) amino, d i- (4-methyl-3-n-heptyl) amino, di- (6-methyl-2-n-heptyl) amino, di- (2-propyl-1-n-heptyl) amino, di- (2, 4,4-trimethyl-1-n-pentyl) amino, di- (1-nonyl) amino, di- (2-nonyl) amino, di- (2,6-dimethyl-4-n-heptyl) amino, di - (3-ethyl-2,2-dimethyl-3-n-pentyl) amino, di- (3,5,5-trimethyl-1-n-hexyl) amino, di- (1-decyl) amino, di- (2-decyl) amino, di- (4-decyl) amino, di- (3,7-dimethyl-1-n-octyl) amino, di- (3,7-dimethyl-3-n-octyl) amino or etc.

The asymmetric C _1-10 dialkylamino group may be linear, branched or C _3-10 cycloalkylamino, and (methyl, ethyl) amino, (methyl, n-propyl) amino, (methyl, isopropyl) amino, (methyl, cyclopropyl) amino, (methyl, n-butyl) amino, (methyl, isobutyl) amino, (methyl, sec-butyl) amino, (methyl, tert-butyl) amino, (methyl, n-pentyl) amino, (methyl, cyclopentyl) amino, (methyl, n-hexyl) amino, (methyl, cyclohexyl) amino, (ethyl, n-propyl) amino, (ethyl, isopropyl) amino, (ethyl, cyclopropyl) amino, (ethyl, n-butyl) amino, (ethyl, isobutyl) amino, (ethyl, sec- butyl) amino, (ethyl, tert-butyl) amino, (ethyl, n-pentyl) amino, (ethyl, cyclopentyl) amino, (ethyl, n-hexyl) amino, (ethyl, cyclohexyl) amino, (n-propyl, isopropyl) amino, (n-propyl, cyclopropyl) amino, (n-propyl, n-butyl) amino, (n-propyl, isobutyl) amino, (n-propyl, sec-butyl) amino, (n-propyl, tert -butyl) amino, (n-propyl, n-pentyl) amino, (n-propyl, cyclopentyl) amino, (n-propyl, n-hexyl) amino, (n-propyl, cyclohexyl) amino, (isopropyl, cyclopropyl) amino, (isopropyl, n-butyl) amino, (isopropyl, isobutyl) amino, (isopropyl, sec-butyl) amino, (isopropyl, tert-butyl) amino, (isopropyl il, n-pentyl) amino, (isopropyl, cyclopentyl) amino, (isopropyl, n-hexyl) amino, (isopropyl, cyclohexyl) amino, (cyclopropyl, n-butyl) amino, (cyclopropyl, isobutyl) amino, (cyclopropyl, sec-butyl) amino, (cyclopropyl, tert-butyl) amino, (cyclopropyl, n-pentyl) amino, (cyclopropyl, cyclopentyl) amino, (cyclopropyl, n-hexyl) amino, (cyclopropyl, cyclohexyl) amino, (n- butyl, isobutyl) amino, (n-butyl, sec-butyl) amino, (n-butyl, tert-butyl) amino, (n-butyl, n-pentyl) amino, (n-butyl, cyclopentyl) amino, (n -butyl, n-hexyl) amino, (n-butyl, cyclohexyl) amino, (isobutyl, sec- butyl) amino, (isobutyl, tert-butyl) amino, (isobutyl, n-pentyl) amino, (isobutyl, cyclopentyl) amino, (isobutyl, n-hexyl) amino, (isobutyl, cyclohexyl) amino, (sec-butyl, tert-butyl) amino, (sec-butyl, n-pentyl) amino, (sec-butyl, cyclopentyl) amino, (sec-butyl, n-hexyl) amino, (sec-butyl, cyclohexyl) amino, (tert-butyl , n-pentyl) amino, (tert-butyl, cyclopentyl) amino, (tert-butyl, n-hexyl) amino, (tert-butyl, cyclohexyl) amino, (n-pentyl, cyclopentyl) amino, (n-pentyl, n-hexyl) amino, (n-pentyl, cyclohexyl) amino, (cyclopentyl, n-hexyl) amino, (cyclopentyl, cyclo exyl) amino, (n-hexyl, cyclohexyl) amino, (methyl, n-heptyl) amino, (methyl, n-octyl) amino, (methyl, n-nonanyl) amino, (methyl, n-decyl) amino, ( methyl, n-heptyl) amino, (ethyl, n-octyl) amino, (ethyl, n-nonanyl) amino, (ethyl, n-decyl) amino or the like.

The protective group in the protected hydroxyl group may be a C _1-4 alkoxymethyl group (such as MOM: methoxymethyl, MEM: 2-methoxyethoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, iBM: isobutyloxymethyl, BUM: tert-butoxide POM: pivaloyloxymethyl, SEM: trimethylsilylethoxymethyl and the like, preferably C _1-2 alkoxymethyl or the like), aryloxymethyl (such as BOM: benzyloxymethyl, PMBM: p-methoxybenzyloxymethyl, p-AOM: p-anisyloxymethyl and t .p., preferably benzyloxymethyl or the like), a C _1-4 alkylaminomethyl group (such as dimethylaminomethyl), a substituted acetamidomethyl group (such as Acm: acetamidomethyl, Tacm: trimethylacetamide methyl, and the like), a substituted thiomethyl group (such as MTM: methylthiomethyl, PTM: phenylthiomethyl, Btm: benzylthiomethyl, etc.), carboxyl group, C _1-7 acyl group (such as formyl, acetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, propionyl, Pv: pivaloyl, tigloyl, etc.), arylcarbonyl group (such as benzoyl, benzoylformyl , benzoilpropionil, phenylpropionyl, etc.), C _1-4 alkoxycarbonyl, group (such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, BOC: tert-butoxycarbonyl, AOC: tert-amyloxycarbonyl, VOC: vinyloxycarbonyl, ethocyclyl-triethyl, Teoc: 2 Troc: 2,2,2-trichloroethoxycarbonyl and the like, preferably BOC and the like), an aryloxycarbonyl group (such as Z: benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, MOZ: p-methoxybenzyloxycarbonyl and the like), C _1-4 alkylaminocarbonyl group (such as methylcarbamoyl, Ec: ethylcarbamoyl, n-propi lcarbamoyl and the like), an arylaminocarbonyl group (such as phenylcarbamoyl and the like), a trialkylsilyl group (such as TMS: trimethylsilyl, TES: triethylsilyl, TIPS: triisopropylsilyl, DEIPS: diethylisopropylsilyl, DMIPS: dimethylisilylmethyl tert-butylmethylsilyl, IPDMS: isopropyl dimethylsilyl, TBDMS: tert-butyldimethylsilyl, TDS: tert-hexyldimethylsilyl and the like, preferably a tert-butyldimethylsilyl and the like), a trialkylarylsilyl group (such as DPMS: diphenylmethylsilyl, TB butyl diphenylsilyl, TBMPS: tert-butyldimethoxyphenylsilyl, TPS: triphenylsilyl, and t .p), an alkylsulfonyl group (such as Ms: methanesulfonyl, ethanesulfonyl and the like) or an arylsulfonyl group (such as benzenesulfonyl, Ts: p-toluenesulfonyl, p-chlorobenzenesulfonyl, MBS: p-methoxybenzenesulfonyl, m-nitrobenzenes : 2,6-dimethoxy-4-methylbenzenesulfonyl, Mds: 2,6-dimethyl-4-methoxybenzenesulfonyl, Mtb: 2,4,6-trimethoxybenzenesulfonyl, Mte: 2,3,5,6-tetramethyl-4-methoxybenzenesulfonyl, Mtr : 2,3,6-trimethyl-4-methoxybenzenesulfonyl, Mts: 2,4,6-trimethylbenzenesulfonyl, Pme: pentamethylbenzenesulfonyl, etc.).

Specific preferred examples of the substituent R ¹ include a phenyl group, thienyl groups (2-thienyl group and 3-thienyl group), furyl groups (2-furyl group and 3-furyl group), pyridazinyl groups (3-pyridazinyl group and 4-pyridazinyl group ), pyridyl groups (2-pyridyl group, 3-pyridyl group and 4-pyridyl group), quinolyl groups (2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7 -quinolyl group and 8-quinolyl group) and isoquinolyl groups (1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group and 8-isoquinolyl group) optionally substituted with one or more of the following substituents.

Substituents: C _1-10 alkyl group, halogen atom, C _1-10 alkyl group substituted by one or more halogen atoms, nitro group, amino group, amino group substituted by one or two C _1-10 alkyl groups, amino group substituted by C _1-10 an alkylcarbonyl group, a thiol group substituted with a C _1-10 alkyl group, a thiol group substituted with a C _1-10 alkylcarbonyl group, a hydroxyl group, a C _1-6 alkoxy group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group, and a C _{1- 10} alkylcarbonyl group.

Particularly preferred examples of the substituent R ¹ include a phenyl group, thienyl groups (2-thienyl group and 3-thienyl group), furyl groups (2-furyl group and 3-furyl group), pyridazinyl groups (3-pyridazinyl group and 4-pyridazinyl group ), pyridyl groups (2-pyridyl group, 3-pyridyl group and 4-pyridyl group), quinolyl groups (2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7 -quinolyl group and 8-quinolyl group) and isoquinolyl e groups (1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group and 8-isoquinolyl group) optionally substituted with one or more of the following substituents.

 Substituents: methyl group, tert-butyl group, trifluoromethyl group, chlorine atom, fluorine atom, methoxy group, methylamino group, dimethylamino group, tert-butyloxy group and tert-butylamino group.

Other preferred specific examples of the substituent include a 3-methylphenyl group, 4-methylphenyl group, 3,4-dimethylphenyl group, 3-tert-butylphenyl group, 4-tert-butylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 3,4 -ditrifluoromethylphenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 3,4-dichlorophenyl group, 3,4-difluorophenyl group, 4-methoxyphenyl group, 4-methylaminophenyl group, 4- methyl 2-thienyl group, 5-methyl-2-thium an alkyl group, 4,5-dimethyl-2-thienyl group, 4-tert-butyl-2-thienyl group, 5-tert-butyl-2-thienyl group, 4-trifluoromethyl-2-thienyl group, 5-trifluoromethyl-2 -thienyl group, 4,5-dithrifluoromethyl-2-thienyl group, 4-chloro-2-thienyl group, 5-chloro-2-thienyl group, 4-fluoro-2-thienyl group, 5-fluoro-2-thienyl group 4,5-dichloro-2-thienyl group, 4,5-dithrifluoromethyl-2-thienyl group, 5-methoxy-2-thienyl group, 5-methylamino-2-thienyl group, 4-methyl-2-furyl group, 5-methyl-2-furyl group, 4,5-dimethyl-2-furyl group, 4-tert-butyl -2-furyl group, 5-tert-butyl-2-furyl group, 4-trifluoromethyl-2-furyl group, 5-trifluoromethyl-2-furyl group, 4,5-ditrifluoromethyl-2-furyl group, 4-chloro 2-furyl group, 5-chloro-2-furyl group, 4-fluoro-2-furyl group, 5-fluoro-2-furyl group, 4,5-dichloro-2-furyl group, 5-methoxy-2-furyl group, 5-methylamino-2-furyl group, 6-chloro-3-pyridazinyl group, 6-methyl-3-pyridazinyl group, 6-methoxy-3-pyridazinyl group, 6-chloro-3-pyridazinyl group, 6-methylpyridazinyl group, 6-methoxy-3-pyridazinyl group, 6-tr t-butoxy-3-pyridazinyl group, 5,6-dimethyl-3-pyridazinyl group, 5,6-dichloro-3-pyridazinyl group, 6-tert-butyl-3-pyridazinyl group, 5-chloro-2-pyridyl group , 5-trifluoromethyl-2-pyridyl group, 5-methyl-2-pyridyl group, 4,5-dimethyl-2-pyridyl group, 5,6-dimethyl-2-pyridyl group, 5-tert-butyl-2-pyridyl group, 4,5-dichloro-2-pyridyl group, 5,6-dichloro-2-pyridyl group and the like.

Specific preferred examples of L ¹ include a bond, CH ₂ , an oxygen atom, a sulfur atom, NH, N-Me, N-CHO, CHMe, CMe ₂ , N-CH ₂ Ph and the like, and particularly preferred examples include a bond, CH ₂ , an oxygen atom, a sulfur atom, NH, NMe and the like.

Specific preferred examples of the substituent R ² include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a tert-butyl group and a phenyl group (methyl group, ethyl group, n-propyl group, isopropyl group, tert-butyl group and the phenyl group optionally can be substituted by an amino group, a monomethylamino group, a dimethylamino group, a monoethylamino group, a diethylamino group, a methoxy group, an ethoxy group, a methoxycarbonyl group, an ethoxycarbonyl group, methylcarbonyloxy group, ethylcarbonyloxy group, methylcarbonylamino group or ethylcarbonylamino group and the like), and particularly preferred examples include a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a tert-butyl group, a phenyl group, and the like.

Specific preferred examples of L ² include a bond, CH ₂ , an oxygen atom, a sulfur atom, NH, N-Me, N-CHO, CHMe, CMe ₂ , N-CH ₂ Ph, and the like, and particularly preferred examples are a bond, CH ₂ , an oxygen atom, a sulfur atom, NH, NMe and the like.

Specific preferred examples of L ³ include a bond, CH ₂ , an oxygen atom, a sulfur atom, NH, NH-OH, N-Me, N-CHO, CHMe, CMe ₂ , N-CH ₂ PH and the like, and are particularly preferred examples are a bond, CH ₂ , an oxygen atom, a sulfur atom, NH, NMe and the like.

Specific preferred examples of the substituent R ³ include a phenyl group, thienyl groups (2-thienyl group and 3-thienyl group), furyl groups (2-furyl group and 3-furyl group), pyridazinyl groups (3-pyridazinyl group and 4-pyridazinyl group ), pyridyl groups (2-pyridyl group, 3-pyridyl group and 4-pyridyl group), quinolyl groups (2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7 -quinolyl group and 8-quinolyl group) and isoquinolyl groups (1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group and 8-isoquinolyl group) optionally substituted with one or more of the following substituents.

Substituents: hydroxyl group, amino group, carboxyl group, phosphonic acid group, sulfonic acid group, urea group, hydroxycarbamido group, cyanocarbamido group, sulfamido group, hydroxy sulfamido group, cyano sulfamido group, -CH ₂ CO ₂ H ₂ CO ₂ H ₂ H ₂ CO ₂ H ₂ H ₂ CO ₂ H ₂ H ₂ CO ₂ H ₂ H ₂ CO ₂ H _{2 2} H, —CH ₂ CH ₂ CO ₂ H, an alkoxycarbonyl group and the following heterocyclic groups substituted with a hydroxyl group.

 Heterocyclic groups: 1,3,4-oxadiazole group, 1,3,4-thiadiazole group, 1,2,4-oxadiazole group, 1,2,4-thiadiazole group, 1,2,5-oxadiazole group, 1, 2,5-thiadiazole group, 1,2-oxazole group and 1,2-thiazole group.

Other specific preferred examples of the substituent R ³ include a phenyl group, thienyl groups (2-thienyl group and 3-thienyl group), furyl groups (2-furyl group and 3-furyl group), pyridazinyl groups (3-pyridazinyl group and 4-pyridazinyl group group), pyridyl groups (2-pyridyl group, 3-pyridyl group and 4-pyridyl group), quinolyl groups (2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group, 7-quinolyl group and 8-quinolyl group) and isoch nolyl groups (1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group and 8-isoquinolyl group), optionally substituted with one or more substituents, optionally selected from the group substituents A, and one or more substituents, optionally selected from the group of substituents B.

Substituent group A comprises a hydroxyl group, an amino group, a carboxyl group, a phosphonic acid group, a sulfonic acid group, karbamidogruppu, gidroksikarbamidogruppu, tsianokarbamidogruppu, sulfamidogruppu, gidroksisulfamidogruppu, tsianosulfamidogruppu, a tetrazole group, -CH ₂ CO ₂ H, -OCH ₂ CO ₂ H, -NHCH ₂ CO ₂ H, —CH ₂ CH ₂ CO ₂ H and an alkoxycarbonyl group.

Substituent group B includes a nitro group, a cyano group, a halogen atom, a C _1-10 alkyl group substituted by one or more fluorine atoms, a sulfamido group substituted by one or more C _1-10 alkyl groups, a urea group substituted by one or more C _1-10 alkyl groups and a C _1-10 alkylcarbonylamino group.

Specific, particularly preferred examples of the substituent R ³ include a phenyl group, thienyl groups (2-thienyl group and 3-thienyl group), furyl groups (2-furyl group and 3-furyl group), pyridazinyl groups (3-pyridazinyl group and 4 -pyridazinyl group), pyridyl groups (2-pyridyl group, 3-pyridyl group and 4-pyridyl group), quinolyl groups (2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group a group, a 7-quinolyl group and an 8-quinolyl group) and ohinolilnye group (1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group and a 8-isoquinolyl group) optionally substituted by one or more of the following substituents.

Substituents: hydroxyl group, amino group, carboxyl group, phosphonic acid group, sulfonic acid group, urea group, sulfamido group, tetrazole group, —CH ₂ CO ₂ H, —OCH ₂ CO ₂ H, —NHCH ₂ CO ₂ H and —CH ₂ CH ₂ CO ₂ H.

Other specific, particularly preferred examples of the substituent R ³ include a phenyl group, thienyl groups (2-thienyl group and 3-thienyl group), furyl groups (2-furyl group and 3-furyl group), pyridazinyl groups (3-pyridazinyl group and 4 -pyridazinyl group), pyridyl groups (2-pyridyl group, 3-pyridyl group and 4-pyridyl group), quinolyl groups (2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl group, 6-quinolyl group group, 7-quinolyl group and 8-quinolyl group pu) and isoquinolyl groups (1-isoquinolyl group, 3-isoquinolyl group, 4-isoquinolyl group, 5-isoquinolyl group, 6-isoquinolyl group, 7-isoquinolyl group and 8-isoquinolyl group), optionally substituted with one or more substituents, optionally selected from substituent group A, and one or more substituents optionally selected from substituent group B.

Substituent group A includes a hydroxyl group, an amino group, a carboxyl group, a phosphonic acid group, a sulfonic acid group, a urea group, a sulfamido group, a tetrazole group, —CH ₂ CO ₂ H, —OCH ₂ CO ₂ H, —NHCH ₂ CO ₂ H and —CH ₂ CH ₂ CO ₂ H.

Substituent group B includes a nitro group, a cyano group, a halogen atom, a C _1-10 alkyl group substituted by one or more fluorine atoms, a sulfamido group substituted by one or more C _1-10 alkyl groups, a urea group substituted by one or more C _1-10 alkyl groups and a C _1-10 alkylcarbonylamino group.

Specific preferred examples of L ⁴ include a bond, CH ₂ , an oxygen atom, a sulfur atom, NH, N-Me, N-CHO, CHMe, CMe ₂ , N-CH ₂ Ph and the like, and particularly preferred examples are a simple bond , CH ₂ , an oxygen atom, a sulfur atom, NH, NMe and the like.

Specific preferred examples of X include OH, SH, NH ₂ , OMe, SMe, NHMe, NHEt, NH-CHO, NH-CH ₂ Ph, OCH ₂ Ph, SCH ₂ Ph, OC (= O) CH ₃ , SC (= O ) CH ₃ , NC (= O) CH ₃ and the like, and OH, SH, NH ₂ and the like are particularly preferred examples.

Specific preferred examples of Y include an oxygen atom, a sulfur atom, NH, N-OH, N-CHO, N-Me, N-CH ₂ Ph, N-OMe, N-OCH ₂ Ph and the like, and particularly preferred examples are an oxygen atom, a sulfur atom, NH, N-OH, and the like.

Preferred compounds suitable as thrombopoietin receptor activators, agents for the prophylaxis, treatment or improvement of diseases for which thrombopoietin receptor activation is effective, and agents for increasing platelet count according to the present invention are as follows.

 1) The compounds represented by formula (1), where A represents a nitrogen atom and B represents a sulfur atom, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

2) The compounds represented by formula (1), where A represents a nitrogen atom and B represents an oxygen atom, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

3) The compounds represented by formula (1), where A represents a nitrogen atom and B represents NR ⁹ (where R ⁹ represents a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, C _{2 -6} alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group and the C _1-10 alkylcarbonyl group, optional o, may be substituted with one or more substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group , C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _{2- 14} aryloxy group may be substituted by one or more C _1-6 alkyl Rupp (C _1-6 alkyl group may be substituted with one or more halogen atoms) or one or more halogen atoms)), C _2-14 aryl group (C _2-14 aryl group may optionally be substituted with one or more substituents, selected from the group consisting of a C _1-10 alkyl group (a C _1-10 alkyl group may be substituted with one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, an atom halogen, C _1-10 alkoxy, C _1-10 alkylcarbonyl groups y, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _{2 -14} aryloxy group) or C _2-14 aryloxy group (C _2-14 aryloxy group optionally may be substituted by one or more substituents selected from the group consisting of a C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or several halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, ka rboksilnuyu group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group)), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

4) The compounds represented by formula (1), where A represents CR ⁴ (where R ⁴ represents a hydrogen atom, a hydroxyl group (the hydroxyl group may be substituted with a C _2-6 alkenyl or C _2-6 alkynyl group), a thiol group ( the thiol group may be substituted with a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group or a C _1-10 alkylcarbonyl group), an amino group (the amino group may be substituted with one or two C _2-6 alkenyl groups, or one or two C _2-6 alkynyl groups), a formyl group, a halogen atom a, nitro, cyano, C _1-10 alkyl group, C _2-6 alkenyl, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino group, a mono- or di-C _1-10 alkylamino group, C _1-10 alkoxy (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino group, a mono- or di-C _1-10 alkylamino and C _1-10 alkoxy may optionally be substituted with one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyanogen uppu, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _1-6 alkyl the group may be substituted by one or more halogen atoms) or one or more halogen atoms)), C _2-14 aryl group (C _2-14 aryl group optionally may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms) , C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group , C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino Rupp, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), C _2-14 aryloxy (C _2-14 aryloxy group may be optionally substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _{1- 10} alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group , C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group), SO ₂ R ⁵ , SOR ⁵ or COR ⁵ (where R ⁵ represents a hydroxyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group (C _1-10 alkyl group The C _2-6 alkenyl group, the C _2-6 alkynyl group and the C _1-10 alkoxy group may optionally be substituted with one or more substituents selected from the groups s, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted by one or more atoms halogen) or one or more halogen atoms)), a C _2-14 aryl group (C _2-14 aryl group, optionally may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _{1- 10} alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxy carbonyl group, C _1-10 alkilkarbo ylamino group, an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), C _2-14 aryloxy (C _2-14 aryloxy, optionally, may be substituted by one or more substituents selected from the group consisting of a C _1-10 alkyl group (a C _1-10 alkyl group may be substituted by one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group) or NR ⁶ R ⁷ (where each of R ⁶ and R ⁷ independently represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, C _{2- 6} alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkilk an carbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group and C _1-10 alkylcarbonyl group, optionally, they can be substituted by one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group , C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 a an alkyl group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _{1- 6, the} alkyl group may be substituted by one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group, optionally may be substituted by one or more substituents selected from the group including C _1-10 alkyl group, (C _1-10 alkyl group ozhet be substituted with one or more halogen atoms), C _2-6 alkenyl, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _{1- 10} alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group), or R ⁶ and R ⁷ taken together represent - (CH _{2) m1} -E- (CH _{2) m2} - (wherein E represents a sour genus, a sulfur atom, CR ²⁶ R ²⁷ (wherein each of R ²⁶ and R ²⁷ independently represents a hydrogen atom, C _1-10 alkyl, C _2-14 aryl group, C _1-10 alkoxy, C _2-14 an aryloxy group, a hydroxyl group or a protected hydroxyl group) or NR ⁸ (where R ⁸ represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _{1 -10} alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl groups a, a C _2-6 alkynyl group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group and a C _1-10 alkylcarbonyl group optionally may be substituted with one or more substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group protected by hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 an alkylcarbonylamino group, an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group)), and each of m1 and m2, independently, is an integer from 0 to 5, provided that the sum m1 + m2 is 3, 4 or 5)))), and B represents an oxygen atom , tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

5) Compounds represented by formula (1), where A represents CR ⁴ (where R ⁴ represents a hydrogen atom, a hydroxyl group (the hydroxyl group may be substituted with a C _2-6 alkenyl or C _2-6 alkynyl group), a thiol group ( the thiol group may be substituted with a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group or a C _1-10 alkylcarbonyl group), an amino group (the amino group may be substituted with one or two C _2-6 alkenyl groups, or one or two C _2-6 alkynyl groups), a formyl group, a halogen atom a, nitro, cyano, C _1-10 alkyl group, C _2-6 alkenyl, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino group, a mono- or di-C _1-10 alkylamino group, C _1-10 alkoxy (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino group, a mono- or di-C _1-10 alkylamino and C _1-10 alkoxy may optionally be substituted with one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyanogen uppu, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _1-6 alkyl the group may be substituted by one or more halogen atoms) or one or more halogen atoms)), C _2-14 aryl group (C _2-14 aryl group optionally may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms) , C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group , C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino Rupp, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), C _2-14 aryloxy (C _2-14 aryloxy group may be optionally substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _{1- 10} alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group , C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group), SO ₂ R ⁵ , SOR ⁵ or COR ⁵ (where R ⁵ represents a hydroxyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group (C _1-10 alkyl group The C _2-6 alkenyl group, the C _2-6 alkynyl group and the C _1-10 alkoxy group may optionally be substituted with one or more substituents selected from the groups s, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted by one or more atoms halogen) or one or more halogen atoms)), a C _2-14 aryl group (C _2-14 aryl group, optionally may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _{1- 10} alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxy carbonyl group, C _1-10 alkilkarbo ylamino group, an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), C _2-14 aryloxy (C _2-14 aryloxy, optionally, may be substituted by one or more substituents selected from the group consisting of a C _1-10 alkyl group (a C _1-10 alkyl group may be substituted by one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group) or NR ⁶ R ⁷ (where each of R ⁶ and R ⁷ independently represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, C _{2- 6} alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkilk an carbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group and C _1-10 alkylcarbonyl group, optionally, they can be substituted by one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group , C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 a an alkyl group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _{1- 6, the} alkyl group may be substituted by one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group, optionally may be substituted by one or more substituents selected from the group including C _1-10 alkyl group, (C _1-10 alkyl group ozhet be substituted with one or more halogen atoms), C _2-6 alkenyl, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _{1- 10} alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group), or R ⁶ and R ⁷ taken together represent - (CH _{2) m1} -E- (CH _{2) m2} - (wherein E represents a sour genus, a sulfur atom, CR ²⁶ R ²⁷ (wherein each of R ²⁶ and R ²⁷ independently represents a hydrogen atom, C _1-10 alkyl, C _2-14 aryl group, C _1-10 alkoxy, C _2-14 an aryloxy group, a hydroxyl group or a protected hydroxyl group) or NR ⁸ (where R ⁸ represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _{1 -10} alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl groups a, a C _2-6 alkynyl group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group and a C _1-10 alkylcarbonyl group optionally may be substituted with one or more substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group protected by hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group)), and each of m1 and m2, independently, is an integer from 0 to 5, provided that the sum m1 + m2 is 3, 4 or 5)))), and B represents a sulfur atom, taut omers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

6) The compounds represented by formula (1), where A represents CR ⁴ (where R ⁴ represents a hydrogen atom, a hydroxyl group (the hydroxyl group may be substituted with a C _2-6 alkenyl or C _2-6 alkynyl group), a thiol group ( the thiol group may be substituted with a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group or a C _1-10 alkylcarbonyl group), an amino group (the amino group may be substituted with one or two C _2-6 alkenyl groups, or one or two C _2-6 alkynyl groups), a formyl group, a halogen atom a, nitro, cyano, C _1-10 alkyl group, C _2-6 alkenyl, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino group, a mono- or di-C _1-10 alkylamino group, C _1-10 alkoxy (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino group, a mono- or di-C _1-10 alkylamino and C _1-10 alkoxy may optionally be substituted with one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyanogen uppu, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _1-6 alkyl the group may be substituted by one or more halogen atoms) or one or more halogen atoms)), C _2-14 aryl group (C _2-14 aryl group optionally may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms) , C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group , C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino Rupp, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), C _2-14 aryloxy (C _2-14 aryloxy group may be optionally substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _{1- 10} alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group , C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group), SO ₂ R ⁵ , SOR ⁵ or COR ⁵ (where R ⁵ represents a hydroxyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group (C _1-10 alkyl group The C _2-6 alkenyl group, the C _2-6 alkynyl group and the C _1-10 alkoxy group may optionally be substituted with one or more substituents selected from the groups s, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted by one or more atoms halogen) or one or more halogen atoms)), a C _2-14 aryl group (C _2-14 aryl group, optionally may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _{1- 10} alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxy carbonyl group, C _1-10 alkilkarbo ylamino group, an amino group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group), C _2-14 aryloxy (C _2-14 aryloxy, optionally, may be substituted by one or more substituents selected from the group consisting of a C _1-10 alkyl group (a C _1-10 alkyl group may be substituted by one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group) or NR ⁶ R ⁷ (where each of R ⁶ and R ⁷ independently represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, C _{2- 6} alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkilk an carbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group and C _1-10 alkylcarbonyl group, optionally, they can be substituted by one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group , C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 a an alkyl group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _{1- 6, the} alkyl group may be substituted by one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group, optionally may be substituted by one or more substituents selected from the group including C _1-10 alkyl group, (C _1-10 alkyl group ozhet be substituted with one or more halogen atoms), C _2-6 alkenyl, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _{1- 10} alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group), or R ⁶ and R ⁷ taken together represent - (CH _{2) m1} -E- (CH _{2) m2} - (wherein E represents a sour genus, a sulfur atom, CR ²⁶ R ²⁷ (wherein each of R ²⁶ and R ²⁷ independently represents a hydrogen atom, C _1-10 alkyl, C _2-14 aryl group, C _1-10 alkoxy, C _2-14 an aryloxy group, a hydroxyl group or a protected hydroxyl group) or NR ⁸ (where R ⁸ represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _{1 -10} alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl groups a, a C _2-6 alkynyl group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group and a C _1-10 alkylcarbonyl group optionally may be substituted with one or more substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group protected by hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted by one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group)), and each of m1 and m2, independently, is an integer from 0 to 5, provided that the sum m1 + m2 is 3, 4 or 5)))), and B is NR ⁹ (where R ^{9 is} represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyloxy group, a C _1-10 alkoxycarbonyl group C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group and C _{1 -10} alkylcarbonyl group optionally can be substituted with one or more substituents selected from the group consisting of carbo ksilnuyu group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups ( C _1-6 alkyl group may be substituted with one or more halogen atoms) or one or more halogen atoms)), C _2-14 aryl group (C _2-14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group, (C _1-10 alkyl group may be substituted by one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, a carboxyl group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, ami a lego group, a mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group) or a C _2-14 aryloxy group (C _2-14 aryloxy group, optionally substituted by one or more substituents selected from the group consisting of a C _1-10 alkyl group (a C _1-10 alkyl group may be substituted by one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, a carboxyl group , nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl hydrochloric group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group)), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

7) Compounds represented by formula (1) according to claim 4), 5) or 6), where A represents CR ³⁷ (where R ³⁷ represents a hydrogen atom, a hydroxyl group (the hydroxyl group may be substituted with C _2-6 an alkenyl or C _2-6 alkynyl group), a thiol group (the thiol group may be substituted with a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group or a C _1-10 alkylcarbonyl group), an amino group (amino group may be substituted by one or two C _2-6 alkenyl groups or one or two C _2-6 alkynyl groups), ph rmilnuyu group, halogen atom, nitro, cyano, C _1-10 alkyl group, C _2-6 alkenyl, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxy, C _1-10 alkylcarbonylamino, mono - or di-C _1-10 alkylamino (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxy, C _1-10 alkylcarbonylamino and mono- - or di-C _1-10 alkylamino group may be substituted by one or more substituents selected from the group consisting of a halogen atom, a carboxylic acid group group, nitro group and cyano group), SO ₂ R ³⁸ , SOR ³⁸ or COR ³⁸ (where R ³⁸ represents a hydroxyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _{1- 10} alkoxy group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group and C _1-10 alkoxy group may be substituted by one or more substituents selected from the group consisting of a halogen atom, a carboxyl group, a nitro group and cyano), C _2-14 aryl group or C _2-14 aryloxy (C _2-14 aryl group and C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted with one or more halogen atoms) or one or more halogen atoms)), tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof. The terms in the corresponding substituents R ³⁷ and R ³⁸ have the same meanings as in the corresponding substituents R ¹ - R ³⁶ .

8) Compounds represented by formula (1) according to claim 3) or 6), where B represents NR ³⁹ (where R ³⁹ represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, C _{2 -6} alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group and the C _1-10 alkylcarbonyl group can be substituted with one or more substituents selected from the group consisting of a carboxyl group, a halogen atom, a nitro group and a cyano group), C _2-14 aryl group or C _2-14 aryloxy (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group and halogen atom )), prodrug tautomers or pharmaceutically acceptability salts of such compounds or solvates thereof. The terms in the substituent R ³⁹ have the same meanings as in the corresponding substituents R ¹ - R ³⁶ .

9) Compounds represented by formula (1) according to claim 1), 2), 3), 4), 5), 6), 7) or 8), where L ¹ is a bond, prodrug tautomers or pharmaceutically acceptable salts of such compounds or solvates thereof.

 10) Compounds represented by formula (1) according to claim 1), 2), 3), 4), 5), 6), 7), 8) or 9), where L2 is a bond, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or solvates thereof.

11) Compounds represented by formula (1) according to claim 1), 2), 3), 4), 5), 6), 7), 8), 9) or 10), where L ³ represents NR ¹⁹ (where R ¹⁹ represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _{1- 10} alkoxy and C _1-10 alkilkarbo yl group may optionally be substituted with one or more substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _{1- 10} alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted with one or several C _1-6 alkyl groups (C _1-6 alkyl group may be substituted by one or more halogen atoms) or one or more halogen atoms)) or C _2-14 aryl group (C _2-14 aryl group, optionally, may be substituted by one or more substituents selected from the group consisting of a C _1-10 alkyl group (a C _1-10 alkyl group may be substituted by one or more halogen atoms), a C _2-6 alkenyl group, a C _2-6 alkynyl group, a carboxyl group , nitro group, cyano group, halogen atom, C _1-10 alkoksigrup y, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, C _{2 -14} aryl group and C _2-14 aryloxy group)), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

12) Compounds according to claim 1), 2), 3), 4), 5), 6), 7), 8), 9) or 10), where L ³ is NH, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or solvates thereof.

13) Compounds in accordance with paragraph 1), 2), 3), 4), 5), 6), 7), 8), 9) or 10), where L ³ represents CH ₂ , tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or solvates thereof.

14) Compounds according to 11), 12) or 13), where L ⁴ is a bond, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

15) Compounds in accordance with paragraph 11), 12) or 13), where L ⁴ represents NR ²² (where R ²² represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group and the C _1-10 alkylcarbonyl group may optionally be amescheny one or more substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _{1- 10} alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group substituted by one or more C _1-6 alkyl groups (C _1-6 and kilnaya group may be substituted with one or more halogen atoms) or one or more halogen atoms)) or a C _2-14 aryl group (C _2-14 aryl group may be optionally substituted with one or more substituents selected from the group consisting of C _1-10 alkyl group (C _1-10 alkyl group may be substituted by one or more halogen atoms), C _2-6 alkenyl group, C _2-6 alkynyl group, carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 Alki carbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and C _2-14 aryloxy group)), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or solvates thereof.

16) Compounds according to 11), 12) or 13), where L ⁴ represents NH, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

17) Compounds in accordance with 11), 12) or 13), where L ⁴ represents CH ₂ , tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

18) Compounds according to 14), 15), 16) or 17), where R ² represents a hydrogen atom, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _1-10 alkoxy group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _1-10 alkylcarbonyloxy group and C _1-10 alkoxycarbonyl group may optionally be substituted with one or more substituents selected from the group consisting of a carboxyl group, a nitro group, a cyano group, and ohm halogen, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted by one or more halogen atoms) or one or more halogen atoms)), C _2-14 aryl or a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (a C _1-6 alkyl group may be substituted by one or more halogen atoms) or one or more halogen atoms), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

19) Compounds according to 14), 15), 16) or 17), where R ² represents a hydrogen atom, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _1-3 alkoxy group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group and C _1-3 alkoxy group, optionally, can be substituted by one or more substituents selected from the group comprising a carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino group, amino group, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, phenyl group and phenyloxy group (phenyl group and phenyloxy group may be substituted by one or more C _1-6 alkyl groups (C _{1- 6} alkyl group may be substituted with one or more halogen atoms) or one or more halogen atoms)), a phenyl group or a phenyloxy group (the phenyl group and the phenyloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 lkilnaya group may be substituted with one or more halogen atoms) or one or more halogen atoms), tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.

20) Compounds according to 14), 15), 16) or 17), where R ² represents a hydrogen atom, a C _1-10 alkyl group, a C _2-6 alkenyl group or a C _2-6 alkynyl group (C _1-10 alkyl group, C _2-6 alkenyl group and C _2-6 alkynyl group optionally can be substituted by one or more substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy group , C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, s ogruppu, mono- or di-C _1-10 alkylamino group, a hydroxyl group and a protected hydroxyl group), tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.

21) Compounds according to 14), 15), 16) or 17), where R ² represents a hydrogen atom or a C _1-6 alkyl group (C _1-6 alkyl group, optionally, may be substituted by one or more substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino mono- or di-C _1-10 alkylamino group, a hydroxyl group and a protected hydroxyl c PUF), tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.

22) Compounds according to 14), 15), 16) or 17), where R ² represents a hydrogen atom or a C _1-3 alkyl group (C _1-3 alkyl group, optionally, may be substituted by one or more substituents selected from the group consisting of halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group and a protected hydroxyl group), tautomers, prodrugs or a Pharmaceutical and acceptable salts of the compounds or solvates thereof.

23) Compounds according to claim 18), 19), 20), 21) or 22), wherein R ¹ is a C _2-14 aryl group (C _2-14 aryl group optionally may be substituted with one or more substituents selected from the group consisting of a halogen atom, a carboxyl group, a nitro group, OCHO, a cyano group, a hydroxyl group, a protected hydroxyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, C _{1- 10} alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyloxy (C _1-10 alkyl group and, C _2-6 alkenyl group, C _2-6 alkynyl group and a C _1-10 alkylcarbonyl group may optionally be substituted with one or more substituents selected from the group consisting of carboxyl group, nitro group, cyano group, halogen atom, C _{1 -10} alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, a hydroxyl group, a protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy (C _2-14 and yl group, and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted with one or more halogen atoms) or one or more halogen atoms)), C _2-14 aryl a group, a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more substituents selected from the group consisting of a C _1-6 alkyl group (a C _1-6 alkyl group may be substituted with one or several halogen atoms) or one or more halogen atoms ene), a thiol group and an amino group (a thiol group and an amino group, optionally, can be substituted with one or more substituents selected from the group consisting of formyl group, C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl a group and a C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group and C _1-10 alkylcarbonyl group optionally may be substituted with one or more substituents selected from the group including carboxyl group, nitro group, cyano group y, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl the group may be substituted by one or more halogen atoms) or one or more halogen atoms)))), that Tomer, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.

24) Compounds according to claim 18), 19), 20), 21) or 22), wherein R ¹ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl a group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group, and an isoquinolyl group optionally can be substituted with one or more substituents selected from the group consisting of a halogen atom, a carboxyl group, a nitro group, OCHO, a cyano group, a hydroxy a strong group, a protected hydroxyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkoxycarbonyl group, C _{1 -10} alkylcarbonyloxy group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy group and C _1-10 alkoxycarbonyl group optionally may be substituted by one or more substituents selected from the group consisting of a carboxyl group, nit ogruppu, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 an alkylamino group, a hydroxyl group, a protected hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (C _{1- 6 the} alkyl group may be substituted by one or more halogen atoms) or one or more atoms halogen)), a thiol group and an amino group (a thiol group and an amino group, optionally, may be substituted with one or more substituents selected from the group consisting of formyl group, C _1-10 alkyl group, C _2-6 alkenyl group, C _{2- 6 an} alkynyl group and a C _1-10 alkylcarbonyl group (a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group and a C _1-10 alkylcarbonyl group, optionally may be substituted with one or more substituents selected from the group comprising a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group, protected hydroxyl group, C _2-14 aryl group and C _2-14 aryloxy group (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl the group may be substituted by one or more halogen atoms) or one or more gal atoms gene)))), tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.

25) Compounds according to claim 18), 19), 20), 21) or 22), where R ¹ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl a group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group, and an isoquinolyl group optionally can be substituted with one or more substituents selected from the group consisting of a halogen atom, a carboxyl group, a nitro group, OCHO, a cyano group, a hydroxy a strong group, a protected hydroxyl group, a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkoxycarbonyl group, C _{1 -10} alkylcarbonyloxy group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkoxycarbonyl group and C _1-10 alkylcarbonyloxy group optionally may be substituted by one or more substituents selected from the group consisting of a halogen atom, a carboxyl th group, nitro group and cyano group), C _2-14 aryl, C _2-14 aryloxy (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 the alkyl group may be substituted by one or more halogen atoms) or one or more halogen atoms), a thiol group and an amino group (a thiol group and an amino group, optionally may be substituted by one or more substituents selected from the group consisting of a formyl group, C _{1- 10} alkyl group, C _2-6 alkenyl groups , C _2-6 alkynyl group and a C _1-10 alkylcarbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group and a C _1-10 alkylcarbonyl group may optionally be substituted with one or by several substituents selected from the group consisting of a halogen atom, a carboxyl group, a nitro group, a cyano group, a hydroxyl group and a protected hydroxyl group))), tautomers, prodrugs or pharmaceutically acceptable salts of these compounds or their solvates.

26) Compounds according to claim 18), 19), 20), 21) or 22), wherein R ¹ is a phenyl group (the phenyl group may optionally be substituted with one or more substituents selected from the group consisting of atom halogen, carboxyl group, nitro group, OCHO, cyano group, hydroxyl group, protected hydroxyl group, C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyloxy group (C _1-10 alkyl group, C _2-6 an alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkoxycarbonyl group and a C _1-10 alkylcarbonyloxy group optionally may be substituted with one or more substituents selected from the group a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di- C _1-10 alkylamino group, a hydroxy group, Protective ennuyu hydroxyl group, C _2-14 aryl and C _2-14 aryloxy (C _2-14 aryl group and C _2-14 aryloxy group may be substituted by one or more C _1-6 alkyl groups (C _1-6 alkyl group may be substituted by one or more halogen atoms) or one or more halogen atoms)), a thiol group and an amino group (a thiol group and an amino group, optionally can be substituted by one or more substituents selected from the group consisting of a formyl group, a C _1-10 alkyl group , C _2-6 alkenyl group, C _2-6 alk an initial group and a C _1-10 alkyl carbonyl group (C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group and C _1-10 alkyl carbonyl group, optionally can be substituted with one or more substituents selected from group, a carboxyl group, a nitro group, a cyano group, a halogen atom, C _1-10 alkoxy, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonylamino, amino, mono- or di-C _1-10 alkylamino group, hydroxyl group protected by a hydroxyl group, a C _2-14 aryl group and a C _2-14 aryloxy group (a C _2-14 group and a C _2-14 aryloxy group may be substituted with one or more C _1-6 alkyl groups (a C _1-6 alkyl group may be substituted with one or several halogen atoms) or one or more halogen atoms)))), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

27) Compounds according to claim 18), 19), 20), 21) or 22), wherein R ¹ is a phenyl group (the phenyl group may optionally be substituted with one or more substituents selected from the group consisting of atom halogen, carboxyl group, nitro group, OCHO, cyano group, hydroxyl group, protected hydroxyl group, C _1-10 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-10 alkoxy group, C _1-10 alkylcarbonyl group, C _1-10 alkoxycarbonyl group, C _1-10 alkylcarbonyloxy group (C _1-10 alkyl group, C _2-6 an alkenyl group, a C _2-6 alkynyl group, a C _1-10 alkoxy group, a C _1-10 alkylcarbonyl group, a C _1-10 alkoxycarbonyl group and a C _1-10 alkylcarbonyloxy group optionally may be substituted with one or more substituents selected from the group including a halogen atom, a carboxyl group, a nitro group and a cyano group), a C _2-14 aryl group, a C _2-14 aryloxy group (a C _2-14 aryl group and a C _2-14 aryloxy group can be substituted with one or more C _1-6 alkyl groups ( C _1-6 alkyl group may be substituted with one or more atoms ami halogen) or one or more halogen atoms), a thiol group and an amino group (thiol group and the amino group may optionally be substituted with one or more substituents selected from the group consisting of formyl group, C _1-10 alkyl group, C _2-6 an alkenyl group, a C _2-6 alkynyl group and a C _1-10 alkyl carbonyl group (a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group and a C _1-10 alkyl carbonyl group, optionally may be substituted one or more substituents selected from the group, incl. a halogen atom, a carboxyl group, a nitro group, a cyano group, a hydroxyl group and a protected hydroxyl group))), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

 28) Compounds according to paragraph 23), 24), 25), 26) or 27), where Y represents an oxygen atom, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

 29) Compounds according to 23), 24), 25), 26) or 27), where Y represents a sulfur atom, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

 30) Compounds in accordance with p. 28) or 29), where X is a hydroxyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

31) Compounds in accordance with p. 28), 29) or 30), where R ³ represents a C _2-14 aryl group (C _2-14 aryl group, optionally, may be substituted by one or more substituents selected from the group, including a hydroxyl group, an amino group, a carboxyl group, a phosphonic acid group, a sulfonic acid group, a urea group, a sulfamido group, a hydroxycarbamido group, a hydroxy sulfamido group, a tetrazole group, a nitro group, a cyano group, a halogen atom, a C _1-10 alkyl group substituted by one or more a sulfamido group substituted with one or more C _1-10 alkyl groups, a urea group substituted with one or more C _1-10 alkyl groups, a C _1-10 alkoxycarbonyl group, a C _1-10 alkoxy group, a C _1-10 alkyl group, C _{1- 10} alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino and mono- or di-C _1-10 alkylamino (C _1-10 alkoxycarbonyl group, C _1-10 alkoxy, C _1-10 alkyl group, C _{1- 10} alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino and mono- or di-C _1-10 alkyls the other group may optionally be substituted with one or more substituents selected from the group consisting of a hydroxyl group, an amino group, a mono or di-C _1-10 alkylamino group, a carboxyl group, a nitro group, a cyano group and a halogen atom)), tautomers, prodrugs, or pharmaceutically acceptable salts of such compounds or solvates thereof.

32) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a thienyl, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl group, thienyl, furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group and an isoquinolyl group optionally can be substituted with one or more substituents selected from the group consisting of a hydroxyl group, an amino group, a carboxyl group, a phosphonic acid group, a sulfoca group lots karbamidogruppu, sulfamidogruppu, gidroksikarbamidogruppu, gidroksisulfamidogruppu, a tetrazole group, a nitro group, a cyano group, a halogen atom, C _1-10 alkyl group substituted by one or more fluorine atoms, sulfamidogruppu substituted by one or more C _1-10 alkyl groups, karbamidogruppu substituted one or more C _1-10 alkyl groups, C _1-10 alkoxycarbonyl group, C _1-10 alkoxy, C _1-10 alkyl, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino and mono- or di-C _1-10 alkylamino (C _1-10 alkoxycarbonyl group, C _1-10 alkoxy, C _1-10 alkyl group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino and the mono- or di-C _1-10 alkylamino group may optionally be substituted with one or more substituents selected from the group consisting of a hydroxyl group, an amino group, a mono- or di-C _1-10 alkylamino group, a carboxyl group, a nitro group, a cyano group, and halogen atom)), tautomers, prodrugs or pharmaceutically acceptable salts x compounds or their solvates.

33) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group (the phenyl group may optionally be substituted with one or more substituents selected from the group consisting of a hydroxyl group, an amino group, a carboxyl group , phosphonic acid group, sulfonic acid group, urea group, sulfamido group, hydroxycarbamido group, hydroxy sulfamido group, tetrazole group, nitro group, cyano group, halogen atom, C _1-10 alkyl group substituted by one or more fluorine atoms, sul a family group substituted with one or more C _1-10 alkyl groups, a urea group substituted with one or more C _1-10 alkyl groups, a C _1-10 alkoxycarbonyl group, a C _1-10 alkoxy group, a C _1-10 alkyl group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino and mono- or di-C _1-10 alkylamino (C _1-10 alkoxycarbonyl group, C _1-10 alkoxy, C _1-10 alkyl group, C _1-10 alkylcarbonyl group, C _1-10 alkylcarbonyloxy, C _1-10 alkylcarbonylamino and mono- or di-C _1-10 alkilaminogr uppa optionally can be substituted by one or more substituents selected from the group consisting of a hydroxyl group, an amino group, a mono or di-C _1-10 alkylamino group, a carboxyl group, a nitro group, a cyano group and a halogen atom)), tautomers, prodrugs, or pharmaceutically acceptable salts of such compounds or solvates thereof.

34) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl group, thienyl group, furyl a group, a pyridazinyl group, a pyridyl group, a quinolyl group and an isoquinolyl group are optionally substituted with one or more substituents selected from the group consisting of a carboxyl group, a phosphonic acid group, a sulfonic acid group, a urea group, ulfamidogruppu, gidroksikarbamidogruppu, gidroksisulfamidogruppu, a tetrazole group, a nitro group, a cyano group, a halogen atom, C _1-10 alkyl group substituted by one or more fluorine atoms, sulfamidogruppu substituted by one or more C _1-10 alkyl groups, karbamidogruppu substituted by one or more C _1-10 alkyl groups, and a C _1-10 alkylcarbonylamino group), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

35) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group (the phenyl group is optionally substituted with a carboxyl group, a phosphonic acid group, a sulfonic acid group, a urea group, a sulfamide group, a hydroxycarbamido group, a hydroxy sulfamido group or tetrazole group), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

36) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl group, thienyl group, furyl group, pyridazinyl group, pyridyl group, quinolyl group and isoquinolyl group optionally substituted by carboxyl group, phosphonic acid group, sulfonic acid group or tetrazole group), tautomers, prodrugs or pharmaceutically acceptable whether such compounds or their solvates.

37) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group (the phenyl group is optionally substituted with a carboxyl group, a phosphonic acid group, a sulfonic acid group or a tetrazole group), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or solvates thereof.

38) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl group, thienyl group, furyl group, pyridazinyl group, pyridyl group, quinolyl group and isoquinolyl group substituted by carboxyl group), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

39) Compounds in accordance with 28), 29) or 30), where R ³ represents a phenyl group substituted by a carboxyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

40) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl group, thienyl group, furyl group, pyridazinyl group, pyridyl group, quinolyl group and isoquinolyl group optionally substituted with a sulfonic acid group), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

41) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group substituted by a sulfonic acid group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

42) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a pyridyl group, a thienyl group, a furyl group, a pyridazinyl group, a 1,3,4-oxadiazole group, 1,3, 4-thiadiazole group, 1,2,4-oxadiazole group, 1,2,4-thiadiazole group, 1,2,5-oxadiazole group, 1,2,5-thiadiazole group, 1,2-oxazole group, 1, 2-thiazole group, quinolyl group or isoquinolyl group (phenyl group, pyridyl group, thienyl group, furyl group, pyridazinyl group, 1,3,4-oxadiazole group, 1,3, 4-thiadiazole group, 1,2,4-oxadiazole group, 1,2,4-thiadiazole group, 1,2,5-oxadiazole group, 1,2,5-thiadiazole group, 1,2-oxazole group, 1, The 2-thiazole group, the quinolyl group and the isoquinolyl group are optionally substituted with one or more hydroxyl groups), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

43) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a pyridyl group, a thienyl group, a furyl group, a pyridazinyl group, a quinolyl group or an isoquinolyl group (phenyl group, pyridyl group, thienyl a group, a furyl group, a pyridazinyl group, a quinolyl group and an isoquinolyl group are optionally substituted with an azole group optionally substituted with one or more hydroxyl groups (the azole group is a 1,3,4-oxadiazole group, 1,3,4 adiazole group, 1,2,4-oxadiazole group, 1,2,4-thiadiazole group, 1,2,5-oxadiazole group, 1,2,5-thiadiazole group, 1,2-oxazole group or 1,2- thiazole group)), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

44) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl group, thienyl group, furyl a group, a pyridazinyl group, a pyridyl group, a quinolyl group and an isoquinolyl group are optionally substituted with one or more —CH ₂ CO ₂ H) groups, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or solvates thereof.

45) Compounds according to 28), 29) or 30), wherein R ³ is a phenyl group substituted with one or more —CH ₂ CO ₂ H groups, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

46) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl group, thienyl group, furyl a group, a pyridazinyl group, a pyridyl group, a quinolyl group and an isoquinolyl group are substituted with one or more groups —OCH ₂ CO ₂ H), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

47) Compounds according to 28), 29) or 30), wherein R ³ is a phenyl group substituted with one or more —OCH ₂ CO ₂ H groups, tautomers, prodrugs or pharmaceutically acceptable salts of these compounds or their solvates.

48) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl group, thienyl group, furyl a group, a pyridazinyl group, a pyridyl group, a quinolyl group and an isoquinolyl group are substituted by one or more groups —NHCH ₂ CO ₂ H), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

49) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group substituted by one or more —NHCH ₂ CO ₂ H groups, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

50) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl group, thienyl group, furyl a group, a pyridazinyl group, a pyridyl group, a quinolyl group and an isoquinolyl group are substituted with one or more groups —CH ₂ CH ₂ CO ₂ H), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

51) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group substituted by one or more —CH ₂ CH ₂ CO ₂ H groups, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

52) Compounds according to 28), 29) or 30), wherein R ³ is a phenyl group (the phenyl group is optionally substituted with one or more substituents optionally selected from the group consisting of

a carboxyl group, a phosphonic acid group, a sulfonic acid group, a urea group, a sulfamido group, a hydroxycarbamido group, a hydroxy sulfamido group and a tetrazole group,

and a substituent, optionally selected from the group including

a nitro group, a cyano group, a halogen atom, a C _1-10 alkyl group substituted by one or more fluorine atoms, a sulfamido group substituted by one or two C _1-10 alkyl groups, a urea group substituted by one or two C _1-10 alkyl groups, and C _{1 -10} alkylcarbonylamino group), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

53) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl group, thienyl group, furyl a group, a pyridazinyl group, a pyridyl group, a quinolyl group and an isoquinolyl group are optionally substituted with one or more substituents selected from the group consisting of

a carboxyl group, a phosphonic acid group, a sulfonic acid group and a tetrazole group,

and one or more substituents, optionally selected from the group including

a nitro group, a cyano group, a halogen atom, a C _1-10 alkyl group substituted by one or more fluorine atoms, a sulfamido group substituted by one or two C _1-10 alkyl groups, a urea group substituted by one or two C _1-10 alkyl groups, and C _{1 -10} alkylcarbonylamino group), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

54) Compounds according to 28), 29) or 30), wherein R ³ is a phenyl group (the phenyl group is optionally substituted with one or more substituents selected from the group consisting of

a carboxyl group, a phosphonic acid group, a sulfonic acid group and a tetrazole group,

and one or more substituents, optionally selected from the group including

a nitro group, a cyano group, a halogen atom, a C _1-10 alkyl group substituted by one or more fluorine atoms, a sulfamido group substituted by one or two C _1-10 alkyl groups, a urea group substituted by one or two C _1-10 alkyl groups, and C _{1 -10} alkylcarbonylamino group), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

55) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl group, thienyl group, furyl a group, a pyridazinyl group, a pyridyl group, a quinolyl group and an isoquinolyl group are substituted with a carboxyl group and a substituent optionally selected from a nitro group, a cyano group, a halogen atom, a C _1-10 alkyl group substituted with one or more fluorine atoms RA, a sulfamido group substituted with one or two C _1-10 alkyl groups, a urea group substituted with one or two C _1-10 alkyl groups and a C _1-10 alkylcarbonylamino group), tautomers, prodrugs or pharmaceutically acceptable salts of these compounds or their solvates.

56) Compounds according to 28), 29) or 30), wherein R ³ is a phenyl group substituted with a carboxy group and a substituent optionally selected from a nitro group, a cyano group, a halogen atom, a C _1-10 alkyl group substituted one or more fluorine atoms, a sulfamido group substituted with one or two C _1-10 alkyl groups, a urea group substituted with one or two C _1-10 alkyl groups, and C _1-10 alkylcarbonylamino groups, tautomers, prodrugs, or pharmaceutically acceptable salts of such compounds or their solvate .

57) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl group, thienyl group, furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group and the isoquinolyl group are optionally substituted by a sulphonic acid group and a substituent optionally selected from a nitro group, a cyano group, a halogen atom, C _1-10 alkyl group substituted by one or MULTI of fluorine atoms sulfamidogruppy substituted with one or two C _1-10 alkyl groups, karbamidogruppy substituted with one or two C _1-10 alkyl groups and C _1-10 alkylcarbonylamino group), tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof .

58) Compounds according to 28), 29) or 30), wherein R ³ is a phenyl group substituted with a sulfonic acid group and a substituent optionally selected from a nitro group, a cyano group, a halogen atom, a C _1-10 alkyl group substituted one or more fluorine atoms, a sulfamido group substituted with one or two C _1-10 alkyl groups, a urea group substituted with one or two C _1-10 alkyl groups, and C _1-10 alkylcarbonylamino groups, tautomers, prodrugs, or pharmaceutically acceptable salts of such compounds or their solvate .

59) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a pyridyl group, a thienyl group, a furyl group, a pyridazinyl group, a quinolyl group or an isoquinolyl group (phenyl group, pyridyl group, thienyl a group, a furyl group, a pyridazinyl group, a quinolyl group and an isoquinolyl group are optionally substituted with one or more hydroxyl groups and a substituent optionally selected from a nitro group, a cyano group, a halogen atom, a C _1-10 alkyl group, substituted substituted by one or more fluorine atoms, a sulfamido group substituted by one or two C _1-10 alkyl groups, a urea group substituted by one or two C _1-10 alkyl groups, and a C _1-10 alkylcarbonylamino group), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

60) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl group, thienyl group, furyl a group, a pyridazinyl group, a pyridyl group, a quinolyl group and an isoquinolyl group are optionally substituted with a —CH ₂ CO ₂ H group and a substituent optionally selected from a nitro group, a cyano group, a halogen atom, a C _1-10 alkyl group substituted with one or more atoms fluorine, a sulfamido group substituted with one or two C _1-10 alkyl groups, a urea group substituted with one or two C _1-10 alkyl groups, and a C _1-10 alkylcarbonylamino group), tautomers, prodrugs or pharmaceutically acceptable salts of these compounds or their solvates.

61) Compounds according to 28), 29) or 30), wherein R ³ is a phenyl group substituted with a —CH ₂ CO ₂ H group and a substituent optionally selected from a nitro group, a cyano group, a halogen atom, C _{1- 10} alkyl groups substituted by one or more fluorine atoms, a sulfamido group substituted by one or two C _1-10 alkyl groups, a urea group substituted by one or two C _1-10 alkyl groups, and C _1-10 alkylcarbonylamino groups, tautomers, prodrugs, or pharmaceutically acceptable salts of such compounds or solvates thereof.

62) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl group, thienyl group, furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group and isoquinolyl group substituted by a group -OCH ₂ CO ₂ H and a substituent optionally selected from a nitro group, a cyano group, a halogen atom, C _1-10 alkyl group substituted by one or more fluorine atoms, sul famidogruppy substituted with one or two C _1-10 alkyl groups, karbamidogruppy substituted with one or two C _1-10 alkyl groups and C _1-10 alkylcarbonylamino group), tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.

63) Compounds according to 28), 29) or 30), wherein R ³ is a phenyl group substituted with a group —OCH ₂ CO ₂ H and a substituent, optionally selected from a nitro group, a cyano group, a halogen atom, C _{1- 10} alkyl groups substituted by one or more fluorine atoms, a sulfamido group substituted by one or two C _1-10 alkyl groups, a urea group substituted by one or two C _1-10 alkyl groups, and C _1-10 alkylcarbonylamino groups, tautomers, prodrugs, or pharmaceutically acceptable salts of such compounds or solvates thereof.

64) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl group, thienyl group, furyl a group, a pyridazinyl group, a pyridyl group, a quinolyl group and an isoquinolyl group are substituted by an —NHCH ₂ CO ₂ H group and a substituent optionally selected from a nitro group, a cyano group, a halogen atom, a C _1-10 alkyl group substituted with one or more fluorine atoms, sul famido group substituted with one or two C _1-10 alkyl groups, urea group substituted with one or two C _1-10 alkyl groups and C _1-10 alkylcarbonylamino groups), tautomers, prodrugs or pharmaceutically acceptable salts of these compounds or their solvates.

65) Compounds according to 28), 29) or 30), wherein R ³ is a phenyl group substituted with a group —NHCH ₂ CO ₂ H and a substituent optionally selected from a nitro group, a cyano group, a halogen atom, C _1-10 an alkyl group substituted by one or more fluorine atoms, a sulfamido group substituted by one or two C _1-10 alkyl groups, a urea group substituted by one or two C _1-10 alkyl groups, and a C _1-10 alkylcarbonylamino group, tautomers, prodrugs, or pharmaceutically acceptable salts such compounds or their solvates.

66) Compounds according to 28), 29) or 30), where R ³ represents a phenyl group, a thienyl group, a furyl group, a pyridazinyl group, a pyridyl group, a quinolyl group or an isoquinolyl group (phenyl group, thienyl group, furyl a group, a pyridazinyl group, a pyridyl group, a quinolyl group and an isoquinolyl group are substituted with a —CH ₂ CH ₂ CO ₂ H group and a substituent optionally selected from a nitro group, a cyano group, a halogen atom, a C _1-10 alkyl group substituted with one or more fluorine atoms, sous lfamido group substituted with one or two C _1-10 alkyl groups, urea group substituted with one or two C _1-10 alkyl groups and C _1-10 alkylcarbonylamino groups), tautomers, prodrugs or pharmaceutically acceptable salts of these compounds or their solvates.

67) Compounds according to 28), 29) or 30), wherein R ³ is a phenyl group substituted with a —CH ₂ CH ₂ CO ₂ H group and a substituent optionally selected from a nitro group, cyano group, halogen atom, C _{A 1-10} alkyl group substituted with one or more fluorine atoms, a sulfamido group substituted with one or two C _1-10 alkyl groups, a urea group substituted with one or two C _1-10 alkyl groups, and a C _1-10 alkylcarbonylamino group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or solvates thereof.

68) Compounds where A, B, R ¹ , L ¹ , R ² , L ² , L ³ , Y, L ⁴ , R ³ and X are any of the following combinations shown in Table 1, tautomers, prodrugs, or pharmaceutically acceptable salts of such compounds or solvates thereof. The symbols shown in table 1 mean the following substituents.

See table 1 at the end of the description.

69) Compounds where A, B, R ¹ , L ¹ , R ² , L ² , L ³ , Y, L ⁴ , R ³ and X are any of the following combinations shown in Table 2, tautomers, prodrugs, or pharmaceutically acceptable salts of such compounds or solvates thereof. The symbols shown in table 2 mean the following substituents.

Table 2 see at the end of the description.

70) Compounds where A, B, R ¹ , L ¹ , R ² , L ² , L ³ , Y, L ⁴ , R ³ and X are any of the following combinations shown in Table 3, tautomers, prodrugs, or pharmaceutically acceptable salts of such compounds or solvates thereof. The symbols shown in table 3 mean the following substituents.

See table 3 at the end of the description.

71) Compounds where A, B, R ¹ , L ¹ , R ² , L ² , L ³ , Y, L ⁴ , R ³ and X are any of the following combinations shown in Table 4, tautomers, prodrugs, or pharmaceutically acceptable salts of such compounds or solvates thereof. The symbols shown in table 4 mean the following substituents.

See table 4 at the end of the description.

72) Compounds where A, B, R ¹ , L ¹ , R ² , L ² , L ³ , Y, L ⁴ , R ³ and X are any of the following combinations shown in Table 5, tautomers, prodrugs, or pharmaceutically acceptable salts of such compounds or solvates thereof. The symbols shown in table 5 mean the following substituents.

See table 5 at the end of the description.

73) Compounds where A, B, R ¹ , L ¹ , R ² , L ² , L ³ , Y, L ⁴ , R ³ and X are any of the following combinations shown in Table 6, tautomers, prodrugs, or pharmaceutically acceptable salts of such compounds or solvates thereof. The symbols shown in table 6 mean the following substituents.

a bond = bond

Table 6 see at the end of the description.

74) The compounds shown in table 1, where X is converted to SH, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

75) The compounds shown in table 2, where X is converted to SH, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

76) The compounds shown in table 3, where X is converted to SH, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

77) The compounds shown in table 4, where X is converted to SH, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

78) The compounds shown in table 5, where X is converted to SH, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

79) The compounds shown in table 6, where X is converted to SH, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

80) The compounds shown in table 1, where X is converted to NH ₂ , tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

81) The compounds shown in table 2, where X is converted to NH ₂ , tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

82) The compounds shown in table 3, where X is converted to NH ₂ , tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

83) The compounds shown in table 4, where X is converted to NH ₂ , tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

84) The compounds shown in table 5 or 6, where X is converted to NH ₂ , tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

 85) Thrombopoietin receptor activators described in paragraph 1).

 86) Thrombopoietin receptor activators described in paragraph 2).

 87) Thrombopoietin receptor activators presented in paragraph 3).

 88) Thrombopoietin receptor activators described in paragraph 4).

 89) Thrombopoietin receptor activators presented in paragraph 5).

 90) Thrombopoietin receptor activators presented in paragraph 6).

 91) Thrombopoietin receptor activators described in paragraph 7).

 92) Thrombopoietin receptor activators presented in paragraph 8).

 93) Thrombopoietin receptor activators presented in paragraph 9).

 94) Thrombopoietin receptor activators presented in paragraph 10).

 95) Thrombopoietin receptor activators presented in paragraph 11).

 96) Thrombopoietin receptor activators presented in paragraph 12).

 97) Thrombopoietin receptor activators presented in paragraph 13).

 98) Thrombopoietin receptor activators presented in paragraph 14).

 99) Thrombopoietin receptor activators described in clause 15).

 100) Thrombopoietin receptor activators described in clause 16).

 101) Thrombopoietin receptor activators presented in paragraph 17).

 102) Thrombopoietin receptor activators presented in p. 18).

 103) Thrombopoietin receptor activators presented in paragraph 19).

 104) Thrombopoietin receptor activators described in paragraph 20).

 105) Thrombopoietin receptor activators presented in paragraph 21).

 106) Thrombopoietin receptor activators presented in paragraph 22).

 107) Thrombopoietin receptor activators presented in paragraph 23).

 108) Thrombopoietin receptor activators described in paragraph 24).

 109) Thrombopoietin receptor activators presented in paragraph 25).

 110) Thrombopoietin receptor activators presented in paragraph 26).

 111) Thrombopoietin receptor activators described in paragraph 27).

 112) Thrombopoietin receptor activators presented in paragraph 28).

 113) Thrombopoietin receptor activators described in clause 29).

 114) Thrombopoietin receptor activators described in paragraph 30).

 115) Thrombopoietin receptor activators presented in paragraph 31).

 116) Thrombopoietin receptor activators described in clause 32).

 117) Thrombopoietin receptor activators presented in paragraph 33).

 118) Thrombopoietin receptor activators presented in paragraph 34).

 119) Thrombopoietin receptor activators presented in paragraph 35).

 120) Thrombopoietin receptor activators described in clause 36).

 121) Thrombopoietin receptor activators described in clause 37).

 122) Thrombopoietin receptor activators presented in paragraph 38).

 123) Thrombopoietin receptor activators presented in § 39).

 124) Thrombopoietin receptor activators presented in paragraph 40).

 125) Thrombopoietin receptor activators described in paragraph 41).

 126) Thrombopoietin receptor activators presented in paragraph 42).

 127) Thrombopoietin receptor activators described in paragraph 43).

 128) Thrombopoietin receptor activators presented in paragraph 44).

 129) Thrombopoietin receptor activators presented in paragraph 45).

 130) Thrombopoietin receptor activators presented in paragraph 46).

 131) Thrombopoietin receptor activators presented in paragraph 47).

132) Thrombopoietin receptor activators presented in paragraph 48).

 133) Thrombopoietin receptor activators presented in 49).

 134) Thrombopoietin receptor activators presented in paragraph 50).

 135) Thrombopoietin receptor activators presented in paragraph 51).

 136) Thrombopoietin receptor activators presented in paragraph 52).

 137) Thrombopoietin receptor activators presented in paragraph 53).

 138) Thrombopoietin receptor activators presented in paragraph 54).

 139) Thrombopoietin receptor activators described in paragraph 55).

 140) Thrombopoietin receptor activators presented in paragraph 56).

 141) Thrombopoietin receptor activators presented in paragraph 57).

 142) Thrombopoietin receptor activators presented in paragraph 58).

 143) Thrombopoietin receptor activators, presented in paragraph 59).

 144) Thrombopoietin receptor activators presented in paragraph 60).

 145) Thrombopoietin receptor activators described in paragraph 61).

 146) Thrombopoietin receptor activators presented in paragraph 62).

 147) Thrombopoietin receptor activators presented in paragraph 63).

 148) Thrombopoietin receptor activators presented in paragraph 64).

 149) Thrombopoietin receptor activators presented in paragraph 65).

 150) Thrombopoietin receptor activators, presented in paragraph 66).

 151) Thrombopoietin receptor activators presented in clause 67).

 152) Thrombopoietin receptor activators presented in paragraph 68).

 153) Thrombopoietin receptor activators described in p. 69).

 154) Thrombopoietin receptor activators presented in paragraph 70).

 155) Thrombopoietin receptor activators presented in paragraph 71).

 156) Thrombopoietin receptor activators presented in paragraph 72).

 157) Thrombopoietin receptor activators presented in p. 73).

 158) Thrombopoietin receptor activators presented in paragraph 74).

 159) Thrombopoietin receptor activators presented in paragraph 75).

 160) Thrombopoietin receptor activators presented in paragraph 76).

 161) Thrombopoietin receptor activators, presented in clause 77).

 162) Thrombopoietin receptor activators presented in p. 78).

 163) Thrombopoietin receptor activators described in p. 79).

 164) Thrombopoietin receptor activators presented in paragraph 80).

 165) Thrombopoietin receptor activators presented in p. 81).

 166) Thrombopoietin receptor activators presented in paragraph 82).

 167) Thrombopoietin receptor activators presented in paragraph 83).

 168) Thrombopoietin receptor activators described in p. 84).

 169) Means for the prophylaxis, treatment and improvement of conditions in diseases against which thrombopoietin receptor activation is effective, containing thrombopoietin receptor activators as an active ingredient, presented in any one of paragraphs 85) to 168) or formula (1), tautomers, prodrugs or pharmaceutically acceptable salts of such activators or solvates thereof.

 170) Platelet elevating agents, containing thrombopoietin receptor activators as active ingredient represented in any one of claims 85) to 168) or formula (1), tautomers, prodrugs or pharmaceutically acceptable salts of such activators or their solvates.

 171) Medicines containing, as an active ingredient, compounds represented in any of claims 1) to 84) or formula (1), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

 The compounds of the invention represented by formula (1) may be in the form of tautomers or geometric isomers that undergo endocyclic or exocyclic isomerization, mixtures of tautomers or geometric isomers or mixtures thereof. If the compounds of the present invention have an asymmetric center resulting from isomerization, the compounds of the present invention can be in the form of individual optical isomers or in the form of mixtures thereof in any proportions.

 For example, the furan, thiophene, and pyrrole compounds of the present invention may be in the form of tetronic acid analogues (4-hydroxy-2 (5H) -furanone), thiotetronic acid analogues (4-hydroxy-2 (5H) -thiophenone), and tetraminic acid analogues (4-hydroxy-3-pyrrolin-2-one), as shown by formulas (2), (3) and (4), mixtures thereof or mixtures of their isomers.

 The compounds of the present invention represented by formula (1), or pharmaceutically acceptable salts thereof, can be prepared in the form of arbitrary crystals or arbitrary hydrates, depending on the conditions of preparation. The present invention covers such crystals, hydrates and mixtures. They may be in the form of solvates with organic solvents such as acetone, ethanol and tetrahydrofuran, and the present invention covers all such forms.

 The compounds of the present invention represented by formula (1) can be converted to pharmaceutically acceptable salts, or they can be isolated from the formed salts, if necessary. The pharmaceutically acceptable salts of the present invention can be, for example, salts with alkali metals (such as lithium, sodium and potassium), alkaline earth metals (such as magnesium and calcium), ammonium, organic bases and amino acids. They can form salts with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid) and organic acids (such as acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid and p-toluenesulfonic acid).

Compounds serving as prodrugs are derivatives containing chemically or metabolically degradable groups, which upon solvolysis or physiological conditions in vivo form compounds according to the invention. Methods for selecting or preparing suitable prodrugs are disclosed, for example, in Design of Prodrug (Elsevier, Amsterdam 1985). According to the present invention, if the compound contains a hydroxyl group, for example, acyloxy derivatives obtained by reacting this compound with suitable acyl halides or suitable acid anhydrides can be mentioned as prodrugs. Acyloxy compounds, especially preferred as prodrugs, include —OCOC ₂ H ₅ , —OCO (tert-Bu), —OCOC ₁₅ H ₃₁ , —OCO (m — CO ₂ Na — Ph), —OCOCH ₂ CH ₂ CO ₂ Na, -OCOCH (NH ₂ ) CH ₃ , -OCOCH ₂ N (CH ₃ ) _2, and the like. If the compound of the present invention contains an amino group, for example, amide derivatives obtained by reacting the compound containing the amino group with suitable acid anhydrides or with suitable mixed anhydrides can be mentioned as prodrugs. Amides particularly preferred as prodrugs include —NHCO (CH ₂ ) ₂₀ OCH ₃ , —NHCOCH (NH ₂ ) CH _3, and the like. If the compound of the present invention contains a carboxyl group, for example, carboxylic esters with aliphatic alcohols or carboxylic esters obtained by reaction with the non-alcoholic hydroxyl group of 1,2- or 1,3-diglycerides can be mentioned as prodrugs. Particularly preferred prodrugs are methyl esters and ethyl esters.

Means for the prophylaxis, treatment and improvement of diseases against which thrombopoietin receptor activation is effective, or thrombocyte-raising agents, containing the thrombopoietin receptor activators of the present invention, tautomers, prodrugs or pharmaceutically acceptable salts of such activators or their solvates as an active ingredient as a rule, you can enter in the form of oral medications, such as tablets, capsules, powders, granules, pills and syrups, in the form of rectal lek own funds, percutaneous medicines or as injections. The agents of the present invention can be administered as a separate therapeutic agent or as a mixture with other therapeutic agents. Although they can be administered as such, they are usually administered in the form of medical compositions. Such pharmaceutical preparations can be obtained by adding pharmacologically and pharmaceutically acceptable additives by conventional methods. Namely, for oral medicines, conventional excipients, lubricants, binders, disintegrants, moisturizers, plasticizers and coating agents can be used. Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be supplied in the form of dry syrups which are mixed with water or other suitable solvents before use. Such liquid preparations may contain conventional additives, such as suspending agents, perfumes, diluents and emulsifiers. In the case of rectal administration, they can be administered in the form of suppositories. As a basis for suppositories, a suitable substance such as cocoa butter, lauric fat, Macrogol, glycerogelatin, Witepsol, sodium stearate and mixtures thereof can be used, and if necessary, they may include an emulsifier, suspending agent, preservative, and the like. In the case of injections, pharmaceutical ingredients such as distilled water for injection, physiological saline, 5% glucose solution, propylene glycol and other solvents or solubilizing agents can be used to prepare aqueous dosage forms or dosage forms that need to be dissolved before use. pH, a substance that makes the solution isotonic, and a stabilizer.

The dose of the agents of the present invention for administration to humans is usually from about 0.1 to 1000 mg / patient / day for oral drugs or rectal administration and from about 0.05 mg to 500 mg / patient / day for injections, although this depends on the age and condition of the patient. The above limits are given only as examples, and the dose is determined depending on the condition of the patient.

The present invention is used when it can be expected that the use of compounds having an affinity for a thrombopoietin receptor and acting as thrombopoietin receptor agonists will lead to an improvement in the pathological condition. For example, hematological disorders accompanied by an abnormal platelet count can be indicated. In particular, the administration of such compounds is effective for the treatment or prophylaxis of human and mammalian diseases caused by abnormal megakaryopoiesis, especially accompanied by thrombocytopenia. Examples of such diseases include thrombocytopenia during chemotherapy or radiation therapy for cancer, thrombocytopenia caused by bone marrow transplantation, surgery and severe infections, or gastrointestinal bleeding, but such diseases are not limited to the above. Typical thrombocytopenia, such as aplastic anemia, idiopathic thrombocytopenic purpura, myelodiplastic syndrome, and thrombopoietin deficiency, are also indications for the use of the agents of the present invention. The compounds and agents of the invention can be used as a stem cell mobilizer, inducer of differentiation of megakaryoblastic or megakaryocytic leukemia cells, and a platelet elevator for platelet donors. In addition, potential applications include therapeutic angiogenesis based on the differentiation and proliferation of vascular endothelial cells and endothelial progenitor cells, the prevention and treatment of arteriosclerosis, myocardial infarction, unstable angina pectoris, but not limited to peripheral artery disease.

 Compounds represented by formula (1) are prepared by the method represented by scheme (5), as shown below.

By reacting compound (I) with —NH ₂ compound (II) in a solvent, if necessary, in the presence of a catalyst, heating and stirring gives the desired compound or its precursor. The precursor, if necessary, can be hydrolyzed, deprotected, reduced or oxidized to give the desired compound. The compounds of the present invention are usually purified by column chromatography, thin layer chromatography, high performance liquid chromatography (HPLC) or liquid chromatography-mass spectrometry (LC-MC) and, if necessary, they can be obtained with high purity by recrystallization or washing with solvents.

For the synthesis of intermediate compounds (I), the following reference documents describing the synthesis of the following heterocyclic compounds may be indicated.

1) Pyrazole (formula (6))

J. Chem. Soc. Perkin. TransI, p. 81, (1985)

2) Isothiazole (formula (7))

Liebigs. Annalen. der. Chemie., 10, 1534-1546 (1979)

3) Isoxazole (formula (8))

Synthesis, 10, 664-665 (1975)

4) Thiophene (formula (9))

JP-A-48-026755

5) Furan (formula (10))

J. Org. Chem., 21, 1492-1509 (1956)

6) Pyrrole (formula (11))

J. Heterocyclic Chem., 30, 1253 (1993) and Tetrahedron, 50 (26), 7849-56 (1994)

7) An analog of tetronic acid (4-hydroxy-2 (5H) -furanone) (formula (12))

Synthesis, 7, 564-566 (1988) and Yakugaku Zasshi, 96 (4), 536-543 (1976)

8) An analog of tetraminic acid (4-hydroxy-3-pyrrolin-2-one) (formula (13))

Synthesis, 2, 190-192 (1987) and Agric. Biol. Chem., 43 (8), 1641-1646 (1979)

For the synthesis of —NH ₂ compounds (II), for example, when L ³ = NH, the following reference documents may be mentioned.

1) L ⁴ = bond, Y = O

Synthetic Commun., 28 (7), 1223-1231 (1998), J. Chem. Soc., 1225 (1948) and J. Chem. Soc., 2831 (1952)

2) L ⁴ = NH, Y = O

J. Am. Chem. Soc., 46, 2813 (1924) and J. Chem. Soc., 2654 (1952)

3) L ⁴ = NH, Y = S

Can. J. Chem., 35, 834 (1957)

4) L ⁴ = CH ₂ , Y = O

J. Org. Chem., 30, 2487 (1965)

5) L ⁴ = O, Y = O

Bull. Soc. Chim. Belg., 68, 409, (1959).

EXAMPLES

Further, the present invention is described in more detail with reference to reference examples of synthesis, examples of synthesis, examples of studies and examples of compositions. However, it should be borne in mind that the present invention is not limited to these specific examples.

¹ H-NMR analysis was performed at 300 MHz.

REFERENCE EXAMPLE OF SYNTHESIS 1

Synthesis of 2-oxopropanal methylhydrazone

 A mixed solution of methylhydrazine (8.34 ml, 158.22 mmol) in acetic acid (15 ml) and water (60 ml) was added to a 10% aqueous solution of methylglyoxal (92.5 ml, 151.21 mmol) and the mixture was stirred at room temperature for about 24 hours. The reaction solution was extracted three times with chloroform and the extract was dried, filtered and concentrated. Purification of the resulting black solution by vacuum distillation gave the desired product as a yellow solid (5.357 g, 35% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 6.86 (s, 1H), 6.59 (br s, 1H), 2.98 (d, J = 4.2 Hz, 3H), 2.30 (s, 3H)

LC-MS (ESI) 100 (M ⁺ ).

REFERENCE EXAMPLE OF SYNTHESIS 2

Synthesis of 2-oxopropanal ethylhydrazone

Ethyl hydrazine (8.46 mmol, 556 mg) was dissolved in methanol (4 ml) and the reactor was cooled to 0 ° C. Methylglyoxal (40% in H ₂ O, 9.3 mmol, 1.42 ml) was added and the mixture was stirred for 15 minutes at the same temperature and then for 2.5 hours at room temperature. After adding water, the mixture was extracted three times with chloroform. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated using an evaporator. The residue was dried using a vacuum pump to obtain the desired product as an orange liquid (0.955 g (crude product), 99% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 9.29 (s, 1H), 6.32 (br s, 1H), 3.58 (q, J = 7.1 Hz, 1H), 3.57 (q, J = 7.1 Hz, 1H), 1.79 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H).

REFERENCE EXAMPLE OF SYNTHESIS 3

Synthesis of (3,4-dichlorophenyl) (oxo) acetaldehyde

 3,4-Dichloroacetophenone (5.39 mmol, 1.02 g) was dissolved in dimethyl sulfoxide (13 ml) and 48% hydrobromic acid solution (1.83 ml) was gradually added at room temperature. The mixture was stirred overnight at 60 ° C and then the reactor was cooled to room temperature. The reaction solution was poured into water (50 ml) at 0 ° C and stirred for about 1 hour. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump to obtain the desired product as a pale yellow solid (0.780 g, 71% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 8.26 (d, J = 2.0 Hz, 1H), 8.01 (dd, J = 2.0, 8.6 Hz, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.01 (d, J = 6.6 Hz, 2H, H ₂ O), 5.61 (br s, 1H)

MS (EI) 173 (M ⁺ -CHO).

REFERENCE EXAMPLE OF SYNTHESIS 4

Synthesis of (4-tert-butylphenyl) (oxo) acetaldehyde

 4-tert-Butylacetophenone (100 mmol, 18.74 ml) was dissolved in dimethyl sulfoxide (104 ml), then the reactor was cooled to 0 ° C and 48% hydrobromic acid solution (34 ml) was gradually added. After 18 hours of stirring at 70 ° C, the reaction solution was poured into water (400 ml) and stirred for 24 hours. The yellow precipitated solid was isolated by filtration, washed several times with n-hexane and dried using a vacuum pump to obtain the desired product as a pale yellow solid (13.89 g, 73% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 8.01 (AVq, J = 8.4 Hz, 2H), 7.51 (ABq, J = 8.4 Hz, 2H), 6.01 (s, 1H), 1.30 (s, 9H)

LC-MS (ESI) 190 (M ⁺ ).

REFERENCE EXAMPLE OF SYNTHESIS 5

Synthesis of (3,4-dimethylphenyl) (oxo) acetaldehyde

 3,4-dimethylacetophenone (13.52 mmol, 2.0 g) was dissolved in dimethyl sulfoxide (13 ml) and 48% hydrobromic acid solution (5.4 ml) was gradually added at room temperature. After 16 hours of stirring at 70 ° C, the reactor was cooled to room temperature. The reaction solution was poured into water and stirred for about 16 hours. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump to obtain the desired product as a white solid (1.234 g, yield 57%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 7.83-7.80 (multi, 2H), 7.33 (br s, 2H, H ₂ O), 7.26 (d, J = 7.5 Hz, 1H), 5.96 (br s, 1H), 2.28 (s, 3H), 2.22 (s, 3H).

REFERENCE EXAMPLE OF SYNTHESIS 6

Synthesis of (4-n-pentylphenyl) (oxo) acetaldehyde

 4-n-Pentylacetophenone (10.66 mmol, 2.028 g) was dissolved in dimethyl sulfoxide (13 ml) and 48% hydrobromic acid solution (5.4 ml) was gradually added at room temperature. After 9.5 hours of stirring at 70 ° C, the reactor was cooled to room temperature. The reaction solution was poured into water and stirred for about 16 hours. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump to obtain the desired product as a pale yellow solid (2.1784 g (crude product), 100%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 7.99 (AVq, J = 8.3 Hz, 2H), 7.33 (ABq, J = 8.3 Hz, 2H), 6.67 (br s, 2H, H ₂ O), 5, 67 (br s, 1H), 2.69-2.61 (multi, 2H), 1.66-1.50 (multi, 2H), 1.36-1.20 (multi, 4H), 0, 88-0.83 (multi, 3H).

REFERENCE EXAMPLE OF SYNTHESIS 7

Synthesis of (4-trifluoromethylphenyl) (oxo) acetaldehyde

 4-Trifluoromethylacetophenone (11.14 mmol, 2.096 g) was dissolved in dimethyl sulfoxide (13 ml) and 48% hydrobromic acid solution (5.4 ml) was gradually added at room temperature. After 9.5 hours of stirring at 70 ° C, the reactor was cooled to room temperature. The reaction solution was poured into water and stirred for about 16 hours. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump to obtain the desired product as a yellow solid (1.3116 g, 59% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 8.27 (ABq, J = 8.3 Hz, 2H), 7.90 (ABq, J = 8.3 Hz, 2H), 6.97 (br s, 2H, H ₂ O), 5, 68 (br s, 1H).

REFERENCE EXAMPLE OF SYNTHESIS 8

Synthesis of oxo [3- (trifluoromethyl) phenyl] acetaldehyde

 3-Trifluoromethylacetophenone (11.80 mmol, 2.22 g) was dissolved in dimethyl sulfoxide (13 ml) and 48% hydrobromic acid solution (5.4 ml) was gradually added at room temperature. After stirring overnight at 70 ° C., the reactor was cooled to room temperature. After adding water, the reaction solution was extracted with chloroform, the extract was dried and filtered, the solvent was evaporated to give the desired product as a yellow liquid (3.04 g (crude product), 128% yield).

REFERENCE EXAMPLE OF SYNTHESIS 9

Synthesis of (3-bromo-4-fluorophenyl) (oxo) acetaldehyde

 Starting from 3-bromo-4-fluoroacetophenone, the desired product was obtained in the same manner as in reference synthesis example 8, as a yellow liquid (crude product yield 114%).

REFERENCE EXAMPLE OF SYNTHESIS 10

Synthesis of (3,5-dimethylphenyl) (oxo) acetaldehyde

 Starting from 3,5-dimethylacetophenone, the desired product was obtained in the same manner as in Referential Synthesis Example 8, as a yellow solid (104% crude product yield).

REFERENCE EXAMPLE OF SYNTHESIS 11

Synthesis of (4-ethylphenyl) (oxo) acetaldehyde

 4-Ethylacetophenone (26.72 mmol, 4 ml) was dissolved in dimethyl sulfoxide (27 ml) and 48% hydrobromic acid solution (11 ml) was gradually added at room temperature. After stirring overnight at 70 ° C., the reactor was cooled to room temperature. The reaction solution was poured into water (50 ml) and stirred for about 1 hour. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump to obtain the desired product as a white solid (2.44 g, 56% yield).

REFERENCE EXAMPLE SYNTHESIS 12

Synthesis of (4-isopropylphenyl) (oxo) acetaldehyde

 Starting from 4-isopropylacetophenone, the desired product was obtained in the same manner as in reference synthesis example 8, as a yellow solid (yield of crude product 103%).

REFERENCE EXAMPLE OF SYNTHESIS 13

Synthesis of oxo (4-n-propylphenyl) acetaldehyde

 Starting from 4-n-propylacetophenone, the desired product was obtained in the same manner as in Referential Synthesis Example 11, as a yellow liquid (yield of the crude product 92%).

REFERENCE EXAMPLE OF SYNTHESIS 14

Synthesis of (4-n-hexylphenyl) (oxo) acetaldehyde

 Starting from 4-n-hexylacetophenone, the desired product was obtained in the same manner as in Reference Synthesis Example 11, as a yellow solid (yield of crude product 131%).

REFERENCE EXAMPLE OF SYNTHESIS 15

Synthesis of (4-isobutylphenyl) (oxo) acetaldehyde

 Starting from 4-isobutylacetophenone, the desired product was obtained in the same manner as in Reference Synthesis Example 8, as a yellow liquid (108% crude yield).

REFERENCE EXAMPLE OF SYNTHESIS 16

Synthesis of 2- (4-tert-butylphenyl) -3-methoxymethyloxy-4-ethoxycarbonylthiophene

 60% sodium hydride (28 mg, 0.69 mmol) was added to a solution of 2- (4-tert-butylphenyl) -3-hydroxy-4-ethoxycarbonylthiophene (0.20 g, 0.66 mmol) obtained in accordance with JP -A-48-26755, in dimethylformamide (1.0 ml) at room temperature, and the reaction solution was stirred at 60 ° C. for 15 minutes. Then, the reaction solution was cooled to room temperature, chloromethyl methyl ether (0.055 ml, 0.73 mmol) was added dropwise and the reaction solution was stirred at room temperature for another 5 hours. After adding a saturated aqueous solution of ammonium chloride, the reaction solution was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The organic layer was concentrated and purified by silica gel column chromatography (chloroform) to obtain the desired product as a colorless oil (212 mg, 91% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 1.34 (s, 9H), 1.38 (t, J = 7.2 Hz, 3H), 3.23 (s, 3H), 4.34 (q, J = 7.2 Hz, 2H) 5.00 (s, 2H); 7.41-7.44 (m, 2H); 7.60-7.63 (m, 2H); 7.97 (s, 1H).

LC / MS (ES ⁺ ) 371 (Na ⁺ adduct).

REFERENCE EXAMPLE OF SYNTHESIS 17

Synthesis of 2- (3,4-dichlorophenyl) -3-methoxymethyloxy-4-ethoxycarbonylthiophene

 Starting from 2- (3,4-dichlorophenyl) -3-hydroxy-4-ethoxycarbonylthiophene (7.7 g, 24 mmol), the desired product was obtained in the same manner as in reference synthesis example 16, as a colorless oil (5, 4 g, yield 62%).

¹ H-NMR (ppm in CDCl ₃ )

δ 1.38 (t, J = 7.2 Hz, 3H), 3.27 (s, 3H), 4.34 (q, J = 7.2 Hz, 2H), 5.06 (s, 2H) 7.46-7.54 (m, 2H); 7.86 (d, J = 1.9 Hz, 1H); 8.04 (s, 1H).

REFERENCE EXAMPLE OF SYNTHESIS 18

Synthesis of 2- (4-trifluoromethylphenyl) -3-methoxymethyloxy-4-ethoxycarbonylthiophene

 Starting from 2- (4-trifluoromethylphenyl) -3-hydroxy-4-ethoxycarbonylthiophene (1.6 g, 5.2 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 16 as a brown oil (1, 8 g, 95% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 1.39 (t, J = 7.2 Hz, 3H), 3.21 (s, 3H), 4.35 (q, J = 7.2 Hz, 2H), 5.05 (s, 2H) 7.67 (d, J = 8.3 Hz, 2H); 7.83 (d, J = 8.3 Hz, 2H); 8.07 (s, 1H).

REFERENCE EXAMPLE OF SYNTHESIS 19

Synthesis of 2- (4-tert-butylphenyl) -3-methoxymethyloxy-4-hydroxymethylthiophene

 To a solution of lithium aluminum hydride (27 mg, 0.72 mmol) in THF (0.86 ml) was added dropwise 2- (4-tert-butylphenyl) -3-methoxymethyloxy-4-ethoxycarbonylthiophene (0.21 g, 0 , 60 mmol) in THF (0.86 ml) and the reaction solution was stirred under ice cooling for 1 hour. After adding a saturated aqueous solution of ammonium chloride, the reaction solution was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/1) to obtain the desired product in as a colorless oil (87 mg, 47% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 1.25 (s, 9H), 3.05 (br s, 1H), 3.40 (s, 3H), 4.46 (d, J = 5.8 Hz, 2H), 4.81 ( s, 2H), 7.02 (s, 1H), 7.30-7.34 (m, 2H), 7.47-7.50 (m, 2H).

LC / MS (ES ⁺ ) 329 (Na ⁺ adduct).

REFERENCE EXAMPLE OF SYNTHESIS 20

Synthesis of 2- (3,4-dichlorophenyl) -3-methoxymethyloxy-4-hydroxymethylthiophene

 Starting from 2- (3,4-dichlorophenyl) -3-methoxymethyloxy-4-ethoxycarbonylthiophene (5.0 g, 14 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 19, as a colorless oil (4, 3 g, 98%).

¹ H-NMR (ppm in CDCl ₃ )

δ 3.51 (s, 3H), 4.56 (d, J = 5.8 Hz, 2H), 4.91 (s, 2H), 7.21 (s, 1H), 7.43-7, 51 (m, 2H); 7.89 (s, 1H).

LC / MS (ES ⁺ ) 340, 342 (Na ⁺ adduct).

LC / MS (ES ^- ) 363, 364, 365 (HCO ₂ ^- adduct).

REFERENCE EXAMPLE OF SYNTHESIS 21

Synthesis of 2- (4-trifluoromethylphenyl) -3-methoxymethyloxy-4-hydroxymethylthiophene

 Starting from 2- (4-trifluoromethylphenyl) -3-methoxymethyloxy-4-ethoxycarbonylthiophene (1.8 g, 4.9 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 19, as a yellow oil (1, 4 g, yield 92%).

¹ H-NMR (ppm in CDCl ₃ )

δ 3.50 (s, 3H), 4.57 (s, 2H), 4.91 (s, 2H), 7.24 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H).

LC / MS (ES ⁺ ) 341 (Na ⁺ adduct).

REFERENCE EXAMPLE OF SYNTHESIS 22

Synthesis of 2- (4-tert-butylphenyl) -3-methoxymethyloxy-4-formylthiophene

 Dimethyl sulfoxide (0.050 ml, 0.70 mmol) in dichloromethane (0.28 ml) was added to oxalyl chloride (0.049 ml, 0.56 mmol) in dichloromethane (2.8 ml) at -78 ° C and after 10 minutes stirring was added dropwise at -78 ° C 2- (4-tert-butylphenyl) -3-methoxymethyloxy-4-hydroxymethylthiophene (87 mg, 0.28 mmol) in dichloromethane (0.93 ml). Upon completion of the addition, the reaction solution was stirred at -78 ° C for 20 minutes and at a temperature of from -40 to -50 ° C for 1 hour. Triethylamine (0.28 ml, 2.0 mmol) was added dropwise and the reaction solution was stirred for another 20 minutes under ice-cooling. After adding a saturated aqueous solution of ammonium chloride, the reaction solution was extracted with chloroform, and the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated to obtain the desired product as a brown oil (58 mg, 68% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 1.25 (s, 9H), 3.24 (s, 3H), 4.91 (s, 2H), 7.34-7.38 (m, 2H), 7.50-7.54 (m , 2H), 7.91 (s, 1H), 9.82 (s, 1H).

LC / MS (ES ⁺ ) 305.

REFERENCE EXAMPLE SYNTHESIS 23

Synthesis of 2- (3,4-dichlorophenyl) -3-methoxymethyloxy-4-formylthiophene

 Starting from 2- (3,4-dichlorophenyl) -3-methoxymethyloxy-4-hydroxymethylthiophene (4.3 g, 14 mmol), the desired product was obtained in the same manner as in reference synthesis example 22, as a colorless oil (5, 2 g, yield 122%).

¹ H-NMR (ppm in CDCl ₃ )

δ 3.50 (s, 3H), 5.04 (s, 2H), 7.48-7.54 (m, 2H), 7.84 (d, J = 1.7 Hz, 1H), 8, 04 (s, 1H); 9.88 (s, 1H).

REFERENCE EXAMPLE OF SYNTHESIS 24

Synthesis of 2- (4-trifluoromethylphenyl) -3-methoxymethyloxy-4-formylthiophene

 2- (4-trifluoromethylphenyl) -3-methoxymethyloxy-4-hydroxymethylthiophene (1.4 g, 4.3 mmol) in chloroform (22 ml) was stirred with manganese dioxide (3.7 g, 43 mmol) at room temperature for 20 hours and at 50 ° C for 3 hours. The reaction solution was filtered and the filtrate was concentrated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/1) to obtain the desired product as a colorless oil (0.79 g, yield 57%).

¹ H-NMR (ppm in CDCl ₃ )

δ 3.29 (s, 3H), 5.03 (s, 2H), 7.68 (d, J = 8.5 Hz, 2H), 7.82 (d, J = 8.5 Hz, 2H) 8.08 (s, 1H); 9.91 (s, 1H).

LC / MS (ES ⁺ ) 339 (Na ⁺ adduct).

REFERENCE EXAMPLE OF SYNTHESIS 25

Synthesis of 2- (4-tert-butylphenyl) -3-hydroxy-4-formylthiophene

 To 2- (4-tert-butylphenyl) -3-methoxymethyloxy-4-formylthiophene (0.20 g, 0.66 mmol) in 1,4-dioxane (1.3 ml) was added dropwise a 1 M solution of hydrochloric acid ( 0.66 ml, 0.66 mmol) and the reaction solution was stirred at 65 ° C for 1 hour and at 80 ° C for 1 hour. After adding water, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (chloroform) to obtain the desired product as a reddish-brown oil (0.12 g, yield 68%).

¹ H-NMR (ppm in CDCl ₃ )

δ 1.38 (s, 9H), 7.43 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.88 (s, 1H) 9.24 (s, 1H); 9.85 (s, 1H).

REFERENCE EXAMPLE OF SYNTHESIS 26

Synthesis of 2- (3,4-dichlorophenyl) -3-hydroxy-4-formylthiophene

 Starting from 2- (3,4-dichlorophenyl) -3-methoxymethyloxy-4-formylthiophene (1.7 g, 5.4 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 25 as a brown oil ( 1.2 g, 83% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 7.68 (s, 2H), 7.80 (s, 1H), 8.48 (s, 1H), 9.89 (s, 1H), 10.07 (s, 1H).

LC / MS (ES ^- ) 271, 273.

REFERENCE EXAMPLE OF SYNTHESIS 27

Synthesis of 2- (4-tert-butylphenyl) -3-methoxymethyloxy-4- (1-hydroxyethyl) thiophene

 3.0 M A solution of methyl magnesium bromide in ethyl ether (2.0 ml, 6.0 mmol) was added dropwise under ice-cooling to a solution of 2- (4-tert-butylphenyl) -3-methoxymethyloxy-4-formylthiophene (0.77 g , 2.5 mmol) in THF (2.5 ml) and the reaction solution was stirred for 1 hour while cooling with ice. After adding a saturated aqueous solution of ammonium chloride, the reaction solution was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 9/1) to obtain the desired product in as a pale yellow oil (0.64 g, 80% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 1.34 (s, 9H), 1.58-1.60 (m, 3H), 3.24 (br s, 1H), 3.48 (s, 3H), 4.83-4.85 (m, 1H), 4.92-4.95 (m, 2H), 7.08 (s, 1H), 7.38-7.42 (m, 2H), 7.54-7.57 (m , 2H).

LC / MS (ES ⁺ ) 343 (Na ⁺ adduct).

REFERENCE EXAMPLE OF SYNTHESIS 28

Synthesis of 2- (3,4-dichlorophenyl) -3-methoxymethyloxy-4- (1-hydroxyethyl) thiophene

 Starting from 2- (3,4-dichlorophenyl) -3-methoxymethyloxy-4-formylthiophene (0.75 g, 2.4 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 27, as pale yellow oil (0.76 g, 95% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 1.57-1.62 (m, 3H), 3.05 (br s, 1H), 3.50 (s, 3H), 4.82-4.85 (m, 1H), 4.90 -4.95 (m, 2H), 7.17 (d, J = 2.5 Hz, 1H), 7.53-7.59 (m, 2H), 7.77 (s, 1H).

REFERENCE EXAMPLE OF SYNTHESIS 29

Synthesis of 2- (4-trifluoromethylphenyl) -3-methoxymethyloxy-4- (1-hydroxyethyl) thiophene

 Starting from 2- (4-trifluoromethylphenyl) -3-methoxymethyloxy-4-formylthiophene (0.79 g, 2.5 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 27, as a yellow oil (0, 76 g, yield 92%).

¹ H-NMR (ppm in CDCl ₃ )

δ 1.59 (d, J = 6.3 Hz, 3H), 3.09 (br s, 1H), 3.48 (s, 3H), 4.83 (d, J = 6.3 Hz, 1H), 4.92 (s, 2H), 7.20 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H).

REFERENCE EXAMPLE OF SYNTHESIS 30

Synthesis of 2- (4-tert-butylphenyl) -3-methoxymethyloxy-4-methylcarbonylthiophene

 2- (4-tert-Butylphenyl) -3-methoxymethyloxy-4- (1-hydroxyethyl) thiophene (0.64 g, 2.0 mmol) in dichloromethane (13 ml) was stirred at room temperature for 1 hour with celite ( 2.0 g) and pyridinium chlorochromate (0.86 g, 4.0 mmol). The reaction solution was filtered through celite, and the filtrate was concentrated and purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/1) to obtain the desired product as a brown solid (0.53 g, 83% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 1.34 (s, 9H), 2.57 (s, 3H), 3.23 (s, 3H), 4.93 (s, 2H), 7.41-7.44 (m, 2H), 7.57-7.61 (m, 2H); 7.88 (s, 1H).

REFERENCE EXAMPLE OF SYNTHESIS 31

Synthesis of 2- (3,4-dichlorophenyl) -3-methoxymethyloxy-4-methylcarbonylthiophene

 Starting from 2- (3,4-dichlorophenyl) -3-methoxymethyloxy-4- (1-hydroxyethyl) thiophene (0.76 g, 2.3 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 30, as a colorless solid (0.62 g, 81% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 2.56 (s, 3H), 3.27 (s, 3H), 4.98 (s, 2H), 7.46-7.54 (m, 2H), 7.84 (d, J = 1 9 Hz, 1H); 7.95 (s, 1H).

REFERENCE EXAMPLE OF SYNTHESIS 32

Synthesis of 2- (4-trifluoromethylphenyl) -3-methoxymethyloxy-4-methylcarbonylthiophene

 Starting from 2- (4-trifluoromethylphenyl) -3-methoxymethyloxy-4- (1-hydroxyethyl) thiophene (0.76 g, 2.3 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 30, as yellow oil (0.64 g, 84% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 2.57 (s, 3H), 3.20 (s, 3H), 4.96 (s, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.82 (d, J = 8.6 Hz, 2H), 7.98 (s, 1H).

REFERENCE EXAMPLE OF SYNTHESIS 33

Synthesis of 2- (4-tert-butylphenyl) -3-hydroxy-4-methylcarbonylthiophene

 Starting from 2- (4-tert-butylphenyl) -3-methoxymethyloxy-4-methylcarbonylthiophene (0.53 g, 1.7 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 25, as a yellow solid (0.38 g, yield 80%).

¹ H-NMR (ppm in CDCl ₃ )

δ 1.33 (s, 9H), 2.56 (s, 3H), 7.40-7.44 (m, 2H), 7.69-7.74 (m, 2H), 7.85 (s , 1H); 10.28 (s, 1H).

LC / MS (ES ⁺ ) 275.

REFERENCE EXAMPLE OF SYNTHESIS 34

Synthesis of 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene

 Starting from 2- (3,4-dichlorophenyl) -3-methoxymethyloxy-4-methylcarbonylthiophene (0.62 g, 1.9 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 25, as a yellow solid (0.31 g, yield 57%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 2.58 (s, 3H), 7.65-7.66 (m, 2H), 7.97 (d, J = 1.0 Hz, 1H), 8.71 (s, 1H), 10, 59 (s, 1H).

REFERENCE EXAMPLE OF SYNTHESIS 35

Synthesis of 2- (4-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene

 Starting from 2- (4-trifluoromethylphenyl) -3-methoxymethyloxy-4-methylcarbonylthiophene (0.64 g, 1.9 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 25, as a yellow solid (0 47 g, yield 86%).

¹ H-NMR (ppm in CDCl ₃ )

δ 2.59 (s, 3H), 7.63 (d, J = 8.3 Hz, 2H), 7.91 (d, J = 8.3 Hz, 2H), 7.96 (s, 1H) 10.57 (s, 1H).

LC / MS (ES ⁺ ) 287.

REFERENCE EXAMPLE OF SYNTHESIS 36

Synthesis of oxo (phenyl) acetaldehyde methylhydrazone

 A mixed solution of methylhydrazine (0.554 ml, 10.5 mmol) / acetic acid (1 ml) / water (7.6 ml) was added to phenylglyoxal (1.34 g, 10 mmol) in water (130 ml) and the mixture was stirred at room temperature for 20 hours. The reaction solution was extracted with chloroform and the extract was dried, filtered, evaporated and dried using a vacuum pump to give oxo (phenyl) acetaldehyde methylhydrazone (1.44 g (crude product), 89% yield) as a yellow solid.

REFERENCE EXAMPLE OF SYNTHESIS 37

Synthesis of 4-hydrazinocarbonylmethylbenzoate

 The known method disclosed in the literature (Synthetic Communications, 28 (7), 1223-1231, (1998)) was used using monomethyl terephthalate and tetramethyl fluoroformamidinium hexafluorophosphate to obtain 1.36 g of the desired product as a colorless solid (70% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 3.86 (s, 3H), 4.56 (s, 2H), 7.93 (d, J = 8.3 Hz, 2H), 8.02 (d, J = 8.3 Hz, 2H) 9.96 (br s, 1H).

REFERENCE EXAMPLE OF SYNTHESIS 38

Synthesis of 5-methoxycarbonyl-2-thiophenecarboxylic acid

 Thiophene-2,5-dicarboxylic acid (1.72 g, 10 mmol) and sodium carbonate (3.18 g, 30 mmol) suspended in dimethylformamide (25 ml) were stirred with methyl iodide (623 μl) at room temperature for nights. The sodium salt of the desired product was extracted with water, and a 12 M hydrochloric acid solution was added to the combined aqueous layer. The desired product was extracted with ethyl acetate, and the combined organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate and purified by silica gel column chromatography to obtain 0.49 g of the desired product as a colorless solid (28% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 3.93 (s, 3H), 7.77 (d, J = 4.2 Hz, 1H), 7.83 (d, J = 4.2 Hz, 1H).

LC / MS (ESI) 186 (M ⁺ ).

REFERENCE EXAMPLE OF SYNTHESIS 39

Synthesis of methyl 5-hydrazinocarbonyl-2-thiophenecarboxylate

  The known method disclosed in the literature (J. Heterocyclic Chem., 28, 17, (1991).) Was used using 5-methoxycarbonyl-2-thiophenecarboxylic acid synthesized in Reference Synthesis Example 38, thionyl chloride and hydrazine monohydrate to give 144 mg of the desired the product in the form of a white solid (yield 72%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 3.84 (s, 3H), 4.57 (br s, 2H), 7.72 (d, J = 4.2 Hz, 1H), 7.79 (d, J = 4.2 Hz, 1H), 10.06 (br s, 1H).

LC / MS ESI 200 (M ⁺ ).

REFERENCE EXAMPLE OF SYNTHESIS 40

Synthesis of methyl 2-nitro-4-hydrazinocarbonylbenzoate

 Starting from 4-methoxycarbonyl-3-nitrobenzoic acid, thionyl chloride and hydrazine monohydrate, 758 mg of the desired product was obtained in the same manner as in Reference Synthesis Example 39 as a white solid (79% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 3.88 (s, 3H), 4.67 (br s, 2H), 7.96 (d, J = 7.8 Hz, 1H), 8.24 (dd, J = 1.8, 7 8 Hz, 1H), 8.44 (d, J = 1.8 Hz, 1H).

LC / MS (ESI) 239 (M ⁺ ).

REFERENCE EXAMPLE OF SYNTHESIS 41

Synthesis of methyl 2-chloro-4-hydrazinocarbonylbenzoate

1) Synthesis of 3-chloro-4-methoxycarbonylbenzoic acid

 To 3-amino-4-methoxycarbonylbenzoic acid (0.98 g, 5 mmol) suspended in a 12 M solution of hydrochloric acid (25 ml) and acetic acid (25 ml), an aqueous solution (10 ml) was added at -10 ° C. sodium nitrite (0.35 g, 5 mmol) and the resulting solution was stirred for 30 minutes. The resulting solution was added to copper (I) chloride (0.99 g, 10 mmol) in a 12 M solution of hydrochloric acid (25 ml) at -10 ° C, and the resulting reaction mixture was stirred at room temperature for 1 hour. After adding ethyl acetate, the reaction mixture was washed with water, dried over magnesium sulfate, filtered through celite and purified by silica gel column chromatography to obtain 0.44 g of the desired product as a colorless solid (yield 39%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 3.98 (s, 3H), 7.89 (d, J = 8.1 Hz, 1H), 8.02 (dd, J = 1.5, 8.1 Hz, 1H), 8.17 ( d, J = 1.5 Hz, 1H).

LC / MS (ESI) 214 (M ^{+ 35} Cl), 216 (M ^{+ 37} Cl).

2) Synthesis of methyl 2-chloro-4-hydrazinocarbonylbenzoate

 Starting from 3-chloro-4-methoxycarbonylbenzoic acid, thionyl chloride and hydrazine monohydrate, 423 mg of the desired product was obtained in the same manner as in Reference Synthesis Example 39 as a white solid (93% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 3.88 (s, 3H), 4.63 (br s, 2H), 7.87-7.96 (m, 3H), 10.05 (br s, 1H).

LC / MS (ESI) 228 (M ^{+ 35} Cl), 230 (M ^{+ 37} Cl).

REFERENCE EXAMPLE OF SYNTHESIS 42

Synthesis of methyl 2-bromo-4-hydrazinocarbonylbenzoate

1) Synthesis of 3-bromo-4-methoxycarbonylbenzoic acid

 An aqueous solution (20 ml) was added to 3-amino-4-methoxycarbonylbenzoic acid (1.95 g, 10 mmol) suspended in 48% solution of hydrobromic acid (50 ml) and acetic acid (50 ml) sodium nitrite (0.69 g, 10 mmol) and the resulting solution was stirred for 30 minutes. The solution was added to copper (I) bromide (1.44 g, 10 mmol) in 48% hydrobromic acid solution (50 ml) at -10 ° C and the resulting reaction mixture was stirred at room temperature for 1 hour. After ethyl acetate was added, the reaction mixture was washed with water, dried over magnesium sulfate, filtered through celite and purified by silica gel column chromatography to obtain 1.70 g of the desired product as a colorless solid (yield 59%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 3.97 (s, 3H), 7.84 (d, J = 8.1 Hz, 1H), 8.07 (dd, J = 1.5, 8.1 Hz, 1H), 8.37 ( d, J = 1.5 Hz, 1H).

LC / MS (ESI) 258 (M ^{+ 79} Br), 260 (M ^{+ 81} Br).

2) Synthesis of methyl 2-bromo-4-hydrazinocarbonylbenzoate

 Starting from 3-bromo-4-methoxycarbonylbenzoic acid, thionyl chloride and hydrazine monohydrate, 489 mg of the desired product was obtained in the same manner as in Reference Synthesis Example 39 as a white solid (90% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 3.88 (s, 3H), 4.60 (br s, 2H), 7.83 (d, J = 8.1 Hz, 1H), 7.90 (dd, J = 1.5, 8 , 1 Hz, 1H), 8.13 (d, J = 1.5 Hz, 1H), 10.04 (br s, 1H).

LC / MS (ESI) 272 (M ^{+ 79} Br), 274 (M ^{+ 81} Br).

REFERENCE EXAMPLE OF SYNTHESIS 43

Synthesis of methyl 4-hydrazinocarbonyl-2-hydroxybenzoate

1) Synthesis of 3-hydroxy-4-methoxycarbonylbenzoic acid

 To 3-amino-4-methoxycarbonylbenzoic acid (1.95 g, 10 mmol) suspended in a 3 M solution of hydrochloric acid (12.5 ml) and acetic acid (20 ml) was added an aqueous solution at -10 ° C (20 ml) sodium nitrite (0.69 g, 10 mmol) and the resulting solution was stirred for 30 minutes. The solution was added to a 10% aqueous solution of sulfuric acid (30 ml) at 0 ° C, and the resulting reaction mixture was heated under reflux for 1 hour. The desired product was extracted with ethyl acetate, and the extract was dried over magnesium sulfate and purified by silica gel column chromatography to obtain 1.04 g of the desired product as a white solid (yield 53%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 3.86 (s, 3H), 7.43 (d, J = 8.1 Hz, 1H), 7.49 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H) 10.55 (br s, 1H).

LC / MS (ESI) 196 (M ⁺ ).

2) Synthesis of methyl 4-hydrazinocarbonyl-2-hydroxybenzoate

 Starting from 3-hydroxy-4-methoxycarbonylbenzoic acid, thionyl chloride and hydrazine monohydrate, 241 mg of the desired product was obtained in the same manner as in Reference Synthesis Example 39 as a white solid (yield 57%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 3.90 (s, 3H), 4.55 (br s, 2H), 7.34 (dd, J = 1.5, 8.1 Hz, 1H), 7.38 (d, J = 1 5 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 9.91 (br s, 1H), 10.52 (br s, 1H).

LC / MS (ESI) 210 (M ⁺ ).

REFERENCE EXAMPLE OF SYNTHESIS 44

Synthesis of 2- (3-trifluoromethylphenyl) -3-methoxymethyloxy-4-ethoxycarbonylthiophene

 Starting from 2- (3-trifluoromethylphenyl) -3-hydroxy-4-ethoxycarbonylthiophene (1.2 g, 3.9 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 16 as a brown oil (1, 2 g, 88% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 1.36-1.42 (m, 3H), 3.19 (s, 3H), 4.33-4.37 (m, 2H), 5.05 (s, 2H), 7.53-7 56 (m, 2H); 7.83-7.85 (m, 1H); 8.02-8.07 (m, 2H).

LC / MS (ES ⁺ ) 383 (Na ⁺ adduct).

REFERENCE EXAMPLE OF SYNTHESIS 45

Synthesis of 2- (3-trifluoromethylphenyl) -3-methoxymethyloxy-4-hydroxymethylthiophene

 Starting from 2- (3-trifluoromethylphenyl) -3-methoxymethyloxy-4-ethoxycarbonylthiophene (1.2 g, 3.4 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 19, as a pale yellow oil ( 1.0 g, 95% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 3.50 (s, 3H), 4.57 (d, J = 5.2 Hz, 2H), 4.91 (s, 2H), 7.23 (s, 1H), 7.48-7, 56 (m, 2H), 7.80-7.82 (m, 1H), 7.96 (s, 1H).

LC / MS (ES ⁺ ) 341 (Na ⁺ adduct).

REFERENCE EXAMPLE OF SYNTHESIS 46

Synthesis of 2- (3-trifluoromethylphenyl) -3-methoxymethyloxy-4-formylthiophene

 Starting from 2- (3-trifluoromethylphenyl) -3-methoxymethyloxy-4-hydroxymethylthiophene (1.0 g, 3.2 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 24 as a brown oil (0, 97 g, 96% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 3.29 (s, 3H), 5.03 (s, 2H), 7.53-7.62 (m, 2H), 7.83-8.06 (m, 3H), 9.91 (s , 1H).

LC / MS (ES ⁺ ) 339 (Na ⁺ adduct).

REFERENCE EXAMPLE OF SYNTHESIS 47

Synthesis of 2- (3-trifluoromethylphenyl) -3-methoxymethyloxy-4- (1-hydroxyethyl) thiophene

 Starting from 2- (3-trifluoromethylphenyl) -3-methoxymethyloxy-4-formylthiophene (0.97 g, 3.1 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 27 as a brown oil (0, 97 g, 96% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 1.59-1.62 (m, 3H), 3.47 (s, 3H), 4.82-4.94 (m, 3H), 7.19 (s, 1H), 7.48-7 56 (m, 2H); 7.79-7.81 (m, 1H); 7.94 (s, 1H).

LC / MS (ES ⁺ ) 355 (Na ⁺ adduct).

REFERENCE EXAMPLE OF SYNTHESIS 48

Synthesis of 2- (3-trifluoromethylphenyl) -3-methoxymethyloxy-4-methylcarbonylthiophene

 Starting from 2- (3-trifluoromethylphenyl) -3-methoxymethyloxy-4- (1-hydroxyethyl) thiophene (0.99 g, 2.3 mmol), the desired product was obtained in the same manner as in Synthesis Reference Example 30, as brown oil (0.76 g, 77% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 2.57 (s, 3H), 3.19 (s, 3H), 4.97 (s, 2H), 7.54-7.58 (m, 2H), 7.83-8.01 (m , 3H).

LC / MS (ES ⁺ ) 353 (Na ⁺ adduct).

REFERENCE EXAMPLE OF SYNTHESIS 49

Synthesis of 2- (3-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene

 Starting from 2- (3-trifluoromethylphenyl) -3-methoxymethyloxy-4-methylcarbonylthiophene (0.76 g, 2.3 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 25, as a pale brown solid (0.59 g, 90% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 2.58 (s, 3H), 7.48-7.52 (m, 2H), 7.94-8.05 (m, 3H), 10.52 (s, 1H).

LC / MS (ES ⁺ ) 287.

REFERENCE EXAMPLE OF SYNTHESIS 50

Synthesis of methyl 2-acetamino-4-hydrazinocarbonylbenzoate

1) Synthesis of 3-acetamino-4-methoxycarbonylbenzoic acid

 Acetic anhydride (1.89 ml, 20 mmol) was added to a suspension of 3-amino-4-methoxycarbonylbenzoic acid (1.95 g, 10 mmol) in acetic acid (10 ml) and the mixture was heated under reflux for 6 hours . After cooling, the precipitated solid was filtered to obtain 2.12 g of the desired product as a colorless solid (89% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 2.13 (s, 3H), 3.87 (s, 3H), 7.71 (d, 1H, J = 8.4 Hz), 7.96 (d, 1H, J = 8.4 Hz) 8.68 (s, 1H); 10.51 (br s, 1H).

LC / MS (ESI) 237 (M ⁺ ).

2) Synthesis of methyl 2-acetamino-4-hydrazinocarbonylbenzoate

 1-Hydroxybenzotriazole (HOBt) (270 mg, 2 mmol) and 1- (3- (dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (WSC) (498 mg, 2.6 mmol) were added to a solution of 3-acetamino-4- methoxycarbonylbenzoic acid (474 mg, 2 mmol) in dimethylformamide (10 ml) and the mixture was stirred at room temperature for 3 hours. Then, hydrazine monohydrate (485 μl, 10 mmol) was added at 0 ° C and the mixture was stirred overnight at room temperature. The precipitated solid was filtered and then washed with water to obtain 400 mg of the desired product as a white solid (80% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 2.12 (s, 3H), 3.85 (s, 3H), 4.55 (br s, 2H), 7.55 (d, 1H, J = 8.1 Hz), 7.90 ( d, 1H, J = 8.1 Hz), 8.49 (s, 1H), 9.92 (br s, 1H), 10.48 (br s, 1H).

LC / MS (ESI) 251 (M ⁺ ).

REFERENCE EXAMPLE OF SYNTHESIS 51

Synthesis of methyl 2-fluoro-4-hydrazinocarbonylbenzoate

1) Synthesis of methyl 4-bromo-2-fluorobenzoate

 Methyl iodide (1.49 ml, 24 mmol) was added to a suspension of 4-bromo-2-fluorobenzoic acid (4.38 g, 20 mmol) and sodium carbonate (6.36 g, 60 mmol) in dimethylformamide (50 ml) and the mixture stirred overnight at room temperature. After completion of the reaction, ethyl acetate was added and the mixture was washed with water and a saturated aqueous solution of ammonium chloride. After drying over magnesium sulfate, the solution was concentrated to obtain 4.50 g of the desired product as a colorless solid (yield 97%).

¹ H-NMR (ppm in CDCl ₃ )

δ 3.93 (s, 3H), 7.33-7.38 (m, 2H), 7.80-7.85 (m, 1H).

2) Synthesis of methyl 4-benzyloxycarbonyl-2-fluorobenzoate

 Palladium diacetate (4.5 mg, 0.02 mmol), 1,4- (bis diphenylphosphino) butane (8.5 mg, 0.02 mmol), triethylamine (55.8 μl, 0.4 mmol) and benzyl alcohol ( 1 ml) was added to a solution of methyl 4-bromo-2-fluorobenzoate (46.6 mg, 0.2 mmol) in dimethylformamide (1 ml). Carbon monoxide was bubbled into the solution for several minutes, and then the solution was heated at 120 ° C. for 12 hours in a carbon monoxide atmosphere. After completion of the reaction, ethyl acetate was added and the resulting product was washed with a saturated aqueous solution of ammonium chloride and purified by silica gel column chromatography (hexane / ethyl acetate = 19/1) to obtain 35.4 mg of the desired product as a yellow viscous liquid (61% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 3.95 (s, 3H), 5.38 (s, 2H), 7.35-7.46 (m, 5H), 7.79-8.02 (m, 3H).

3) Synthesis of 3-fluoro-4-methoxycarbonylbenzoic acid

 To a solution of methyl 4-benzyloxycarbonyl-2-fluorobenzoate (35.4 mg, 0.123 mmol) in ethanol (2 ml) was added a catalytic amount of 10 wt.% Palladium on carbon and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated to obtain 26.0 mg of the desired product as a colorless solid (100% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 3.97 (s, 3H), 7.83-8.06 (m, 3H).

LC / MS (ESI) 198 (M ⁺ ).

4) Synthesis of methyl 2-fluoro-4-hydrazinocarbonylbenzoate

 Starting from 3-fluoro-4-methoxycarbonylbenzoic acid (198 mg, 1 mmol), 1-hydroxybenzotriazole (HOBt) (135 mg, 1 mmol), 1- (3- (dimethylamino) propyl) -3-ethylcarbodiimide hydrochloride (WSC) (249 mg, 1.3 mmol) and hydrazine monohydrate (73 μl, 1.5 mmol), 45.6 mg of the desired product was obtained in the same manner as in reference synthesis example 50, as a white solid (yield 22%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 3.87 (s, 3H), 4.60 (br s, 2H), 7.71-7.77 (m, 2H), 7.94-7.99 (m, 1H), 10.06 (br s, 1H).

LC / MS (ESI) 212 (M ⁺ ).

REFERENCE EXAMPLE OF SYNTHESIS 52

Synthesis of 2- (4-tert-butylphenyl) -3-methoxymethyloxy-4- (1-hydroxyisobutyl) thiophene

 To a solution of 2- (4-tert-butylphenyl) -3-methoxymethyloxy-4-formylthiophene (3.0 g, 10 mmol) in THF (2.5 ml) was added dropwise under ice-cooling a 2.0 M solution of isopropylmagnesium bromide in ethyl ether (6.0 ml, 12 mmol), followed by stirring for 2.5 hours while cooling with ice. A saturated aqueous solution of ammonium chloride was added to the reaction solution, then extraction was performed with ethyl acetate, and the organic layer was washed with a saturated solution of sodium chloride and then dried over anhydrous sodium sulfate. The resulting organic layer was concentrated and then purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/1) to obtain the desired product as a pale yellow oil (1.18 g, 34% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 0.91 (d, J = 6.6 Hz, 3H), 1.10 (d, J = 6.6 Hz, 3H), 1.34 (s, 9H), 2.15-2.25 ( m, 1H), 3.46 (s, 3H), 4.35 (d, J = 8.0 Hz, 1H), 4.86 (s, 2H), 7.04 (s, 1H), 7, 39 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H).

LC / MS (ES ^- ) 303.

REFERENCE EXAMPLE OF SYNTHESIS 53

Synthesis of 2- (4-tert-butylphenyl) -3-methoxymethyloxy-4-isopropylcarbonylthiophene

Using 2- (4-tert-butylphenyl) -3-methoxymethyloxy-4- (1-hydroxyisobutyl) thiophene (1.07 g, 3.07 mmol) as the starting material, the desired product was obtained in the same manner as in the reference example. synthesis 30, in the form of a brown oil (0.85 g, yield 80%).

¹ H-NMR (ppm in CDCl ₃ )

δ 1.20 (s, 3H), 1.23 (s, 3H), 1.34 (s, 9H), 3.21 (s, 3H), 3.39-3.45 (m, 1H), 4.92 (s, 2H), 7.42 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 8.7 Hz, 2H), 7.83 (s, 1H).

LC / MS (ES ⁺ ) 369 (Na ⁺ adduct).

REFERENCE EXAMPLE OF SYNTHESIS 54

Synthesis of 2- (4-tert-butylphenyl) -3-hydroxy-4-isopropylcarbonylthiophene

Using 2- (4-tert-butylphenyl) -3-methoxymethyloxy-4- (isopropylcarbonyl) thiophene (0.85 g, 2.5 mmol) as the starting material, the desired product was obtained in the same manner as in Reference Synthesis Example 25 , as a pale brown solid (0.42 g, 56% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 1.26 (s, 3H), 1.28 (s, 3H), 1.34 (s, 9H), 3.36-3.41 (m, 1H), 7.42 (d, J = 8 8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.89 (s, 1H), 10.50 (s, 1H).

LC / MS (ES ⁺ ) 303.

REFERENCE EXAMPLE OF SYNTHESIS 55

Synthesis of 2-bromo-5- (4-tert-butylphenyl) -4-hydroxy-3-methylcarbonylthiophene

 2- (4-tert-butylphenyl) -3-hydroxy-4-methylcarbonylthiophene (2.66 g, 9.7 mmol), n-bromosuccinimide (1.73 g, 9.7 mmol) and benzoyl peroxide (153 mg, 0 , 63 mmol) was heated at the boil under reflux for 2 hours in 65 ml of chloroform. Water was added and the reaction solution was extracted three times with chloroform, the organic layer was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The resulting organic layer was concentrated and then purified by silica gel column chromatography (n-hexane / chloroform = 3/2) to obtain the desired product as a yellow solid (2.93 g, 86% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 1.33 (s, 9H), 2.79 (s, 3H), 7.39-7.43 (m, 2H), 7.62-7.66 (m, 2H), 10.91 (s , 1H).

LC / MS (ES ^- ) 351, 353.

REFERENCE EXAMPLE OF SYNTHESIS 56

Synthesis of methyl 4-hydrazinocarbonothioylamino-2-nitrobenzoate

1) Synthesis of methyl 4-amino-2-nitrobenzoate

 To a suspension of 4-amino-2-nitrobenzoic acid (200 mg, 1.10 mmol) synthesized in accordance with the synthesis method described in WO96 / 35666 and sodium carbonate (349 mg, 3.29 mmol) in dimethylformamide (5, 5 ml) methyl iodide (0.21 ml) was added and the mixture was stirred overnight at room temperature. Water was added to the reaction solution and extraction was performed with ethyl acetate, the combined organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. Concentration of the obtained organic layer gave 216 mg of the desired product as a yellow solid (100% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 7.69 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 2.4, 8.5 Hz, 1H), 4.31 (br s, 2H), 3.84 (s, 3H).

LC / MS (ESI) 196.

2) Synthesis of 4-methoxycarbonyl-3-nitrophenylisothiocyanate

 A solution of methyl 4-amino-2-nitrobenzoate (50 mg, 0.25 mmol) synthesized as described above and 1,1'-thiocarbonyldi-2 (1H) -pyridone (59 mg, 0.25 mmol) in dichloromethane (4.2 ml) was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was evaporated, then purification was carried out by silica gel column chromatography to obtain 42 mg of the desired product as a colorless oil (yield 69%).

¹ H-NMR (ppm in CDCl ₃ )

δ 7.79 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.47 (dd, J = 2.1, 8.3 Hz, 1H), 3.92 (s, 3H).

LC / MS (ES ^- ) 224 (M ⁺ -CH ₂ ).

3) Synthesis of methyl 4-hydrazinocarbonothioylamino-2-nitrobenzoate

 A solution of 4-methoxycarbonyl-3-nitrophenylisothiocyanate (149 mg, 0.62 mmol) synthesized as described above in tetrahydrofuran (2.2 ml) was added dropwise to a solution of hydrazine monohydrate (94 mg, 1.87 mmol) in tetrahydrofuran ( 4.0 ml) at 0 ° C for 20 minutes. After stirring at 0 ° C. for another 40 minutes, water was added and the precipitated solid was filtered to obtain 142 mg of the desired product as a colorless solid (yield 85%).

¹ H-NMR (ppm in DMSO)

δ 9.67 (br s, 1H), 8.71 (br s, 1H), 8.18-8.21 (m, 1H), 7.76-7.83 (m, 2H), 3 82 (s, 3H).

LC / MS (ESI) 270.

REFERENCE EXAMPLE OF SYNTHESIS 57

Synthesis of methyl 5-hydrazinocarbonothioylamino-2-thiophenecarboxylate

1) Synthesis of methyl 5-nitro-2-thiophenecarboxylate

Starting from 5-nitrothiophene-2-carboxylic acid (3 g, 17.3 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 56 as a pale pink solid (2.97 g, 92% yield) )

¹ H-NMR (ppm in CDCl ₃ )

δ 7.88 (d, J = 4.3 Hz, 1H), 7.70 (d, J = 4.3 Hz, 1H), 3.96 (s, 3H).

2) Synthesis of 5-methoxycarbonyl-2-thiophenisothiocyanate

To a solution of methyl 5-nitro-2-thiophenecarboxylate (2.67 g, 14.3 mmol) synthesized as described above and iron (2.63 g, 47.1 mmol) in ethanol (50 ml) and water ( 9.9 ml) was added at 90 ° C concentrated hydrochloric acid (0.12 ml, 1.43 mmol). The mixture was stirred at 90 ° C for 30 minutes. After completion of the reaction, a 1 M aqueous solution of sodium hydroxide (1.43 ml, 1.43 mmol) was added to the mixture. Insoluble matters were filtered off and the filtrate was concentrated and extracted with ethyl acetate, then dried over anhydrous sodium sulfate. The resulting organic layer was concentrated and dried using a vacuum pump. From the obtained crude solid product, the desired product was obtained in the same manner as in Reference Example Synthesis 56, as a pale yellow oil (904 mg, 32% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 7.56 (d, J = 4.0 Hz, 1H), 6.83 (d, J = 4.0 Hz, 1H), 3.88 (s, 3H).

LC / MS (ES ⁺ ) 199.

3) Synthesis of methyl 5-hydrazinocarbonothioylamino-2-thiophenecarboxylate

Starting from methyl 5-methoxycarbonyl-2-thiophenisothiocyanate (484 mg, 2.43 mmol) synthesized as described above, the desired product was obtained in the same manner as in Reference Synthesis Example 56 as a colorless solid (435 mg, yield 77%).

¹ H-NMR (ppm in DMSO)

δ 9.63 (br s, 1H), 7.55-7.57 (m, 1H), 7.12 (br s, 1H), 6.95 (br s, 1H), 3.76 (s, 3H).

LC / MS (ESI) 231.

REFERENCE EXAMPLE OF SYNTHESIS 58

Synthesis of methyl 4-hydrazinocarbonothioylamino-2-chlorobenzoate

1) Synthesis of methyl 4-amino-2-chlorobenzoate

Starting from 4-amino-2-chlorobenzoic acid (500 mg, 2.91 mmol), the desired product was obtained in the same manner as in Reference Synthesis Example 56 as a pale brown solid (535 mg, 99% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 7.78 (d, J = 8.5 Hz, 1H), 6.70 (d, J = 2.2 Hz, 1H), 6.53 (dd, J = 2.2 Hz, 8.5 Hz , 1H); 4.07 (br s, 2H); 3.86 (s, 3H).

LC / MS (ES ⁺ ) 185.

2) Synthesis of 4-methoxycarbonyl-3-chlorophenylisothiocyanate

 Starting from methyl 4-amino-2-chlorobenzoate (505 mg, 2.72 mmol) synthesized as described above, the desired product was obtained in the same manner as in Reference Synthesis Example 56 as a colorless solid (424 mg, yield 69 %).

¹ H-NMR (ppm in CDCl ₃ )

δ 7.87 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 2.0 Hz, 8.3 Hz , 1H); 3.93 (s, 3H).

LC / MS (ES ⁺ ) 227.

3) Synthesis of methyl 4-hydrazinocarbonothioylamino-2-chlorobenzoate

Starting from 4-methoxycarbonyl-3-chlorophenylisothiocyanate (420 mg, 1.85 mmol) synthesized as described above, the desired product was obtained in the same manner as in Reference Synthesis Example 56 as a colorless solid (364 mg, 76% yield) )

¹ H-NMR (ppm in DMSO)

δ 9.54 (br s, 1H), 8.24 (br s, 1H), 7.77-7.84 (m, 3H), 3.83 (s, 3H).

LC / MS (ESI) 259.

SYNTHESIS EXAMPLE 1

Synthesis of 4 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

1) Synthesis of 1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone

 2-Oxopropanalmethylhydrazone (1.525 mmol, 152.7 mg) synthesized in reference synthesis example 1, and (3,4-dichlorophenyl) (oxo) acetaldehyde (1.525 mmol, 310 mg) synthesized in synthesis reference example 3 was dissolved in acetic acid (10 ml) and was stirred at 110 ° C for 1.5 hours. Then, the solvent was evaporated and the residue was dried using a vacuum pump, the product was isolated by thin layer chromatography on silica gel (n-hexane / AcOEt = 3/2) and purified by thin layer chromatography on silica gel (n-hexane / AcOEt = 2/1) to obtain the desired product in as a yellow solid (57.8 mg, 13% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 8.25 (s, 1H), 7.58 (br s, 1H), 7.55 (br s, 1H), 7.33 (brd, 1H), 3.92 (s, 3H ), 2.58 (s, 3H).

¹³ C-NMR (ppm in CDCl ₃ )

δ 198.1, 143.8, 135.6, 133.2, 132.7, 130.9, 130.4, 127.8, 127.6, 125.8, 39.3, 25.6.

LC-MS (ESI) 284 (M ⁺ ).

2) Synthesis of 4 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] methylbenzoate

 1- [5- (3,4-Dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.1336 mmol, 38 mg), 4-hydrazinocarbonylmethylbenzoate (0.1336 mmol, 26 mg) and p-tolylsulfonic acid monohydrate (30 mol%, 6.9 mg) were dissolved in isopropyl alcohol (2.5 ml) and stirred at 100 ° C for 3.5 hours. The reactor was then cooled to 0 ° C and the precipitated solid was isolated by filtration and dried using a vacuum pump to obtain the desired product as a white solid (30.5 mg, 50% yield).

¹ H-NMR (ppm in DMSO- d ₆ )

δ 11.46 (s, 1H), 9.95 (s, 1H), 8.10 (AVq, J = 8.3 Hz, 2H), 8.04 (AVq, J = 8.3 Hz, 2H) 7.86 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.61 (dd, J = 2.0, 8.3 Hz, 1H), 3.90 (s, 3H), 3.90 (s, 3H), 2.45 (s, 3H).

LC-MS (ESI) 460 (M ⁺ ).

3) Synthesis of 4 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

 K 4 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] methylbenzoate (0.0518 mmol, 23.9 mg) methanol (3 ml) was added and a 1 M aqueous solution of sodium hydroxide (0.259 mmol, 0.259 ml) was added at room temperature. After 20 minutes of stirring at room temperature and 2 hours of stirring at 60 ° C, the reactor was cooled to room temperature and a 1 M solution of hydrochloric acid (0.259 mmol, 0.259 ml) and water were added. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump to obtain the desired product as a yellow solid (8.7 mg, 37% yield).

¹ H-NMR (ppm in DMSO- d ₆ )

δ 11.43 (s, 1H), 9.96 (s, 1H), 8.13-7.98 (multi, 4H), 7.86-7.78 (multi, 2H), 7.62-7 51 (multi, 1H); 3.90-3.87 (multi, 3H); 2.46-2.45 (multi, 3H).

LC-MS (ESI) 446 (M ⁺ ).

SYNTHESIS EXAMPLE 2

Synthesis of 4 - {[(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

 1- [5- (3,4-Dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.139 mmol, 39.7 mg) synthesized in synthesis example 1, and 4-hydrazinocarbonothioylaminobenzoic acid (0.139 mmol, 29.4 mg) was stirred with dimethylformamide (4 ml) and two drops of concentrated hydrochloric acid at room temperature for 22 hours. After adding water, the precipitated yellow solid was isolated by filtration, washed with water and dried using a vacuum pump. The resulting solid was stirred for some time with chloroform / n-hexane, then isolated by filtration and dried using a vacuum pump to obtain the desired product as a yellow solid (39.5 mg, 59% yield).

¹ H-NMR (ppm in DMSO- d ₆ )

δ 10.36 (s, 1H), 10.33 (s, 1H), 9.15 (s, 1H), 7.93 (ABq, J = 8.6 Hz, 2H), 7.85-7, 83 (multi, 2H), 7.79 (ABq, J = 8.6 Hz, 2H), 7.58 (d, J = 8.4 Hz, 1H), 3.85 (s, 3H), 2, 39 (s, 3H).

LC-MS (ESI) 477 (M ⁺ ).

SYNTHESIS EXAMPLE 3

Synthesis of 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

1) Synthesis of 1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone

 2-Oxopropanalmethylhydrazone (46.375 mmol, 4.64 g) synthesized in Reference Example Synthesis 1, and (4-tert-butylphenyl) (oxo) acetaldehyde synthesized in Reference Synthesis Example 4 (46.375 mmol, 8.82 g) were dissolved in acetic acid (140 ml) and stirred at 100 ° C for 2 hours. The reactor was cooled to room temperature and after adding water (100 ml) and a saturated aqueous solution of sodium chloride (50 ml), the mixture was extracted three times with chloroform. The resulting organic layer was dried and filtered, and the solvent was evaporated. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1) to obtain the desired product as a yellow solid (5.79 g, 46% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 8.16 (s, 1H, capable of exchange with D ₂ O), 7.51 (AVq, J = 8.4 Hz, 2H), 7.40 (ABq, J = 8.4 Hz, 2H), 3.91 (s, 3H); 2.58 (s, 3H); 1.35 (s, 9H).

¹ H-NMR (ppm in DMSO- d ₆ )

δ 8.50 (s, 1H), 7.53 (ABq, J = 8.6 Hz, 2H), 7.44 (ABq, J = 8.6 Hz, 2H), 3.83 (s, 3H) 2.46 (s, 3H); 1.32 (s, 9H).

¹³ C-NMR (ppm in CDCl ₃ )

δ 198.2, 151.6, 143.4, 135.6, 128.5, 128.3, 125.8, 124.7, 39.1, 34.7, 31.2, 25.6.

LC-MS (ESI) 272 (M ⁺ ).

2) Synthesis of 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] methylbenzoate

 1- [5- (4-tert-Butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.441 mmol, 120.0 mg), 4-hydrazinocarbonylmethylbenzoate (0.441 mmol, 85.6 mg) and p-tolylsulfonic acid monohydrate (30 mol%, 22.8 mg) were dissolved in isopropyl alcohol (10 ml) and stirred at 100 ° C for about 3 hours and then at 50 ° C overnight. The reactor was cooled to 0 ° C and the reaction solution was filtered and dried using a vacuum pump to obtain the desired product as a white solid (145.1 mg, 73% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 8.98 (s, 1H), 8.78 (br s, 1H), 8.16-8.13 (multi, 2H), 7.92-7.80 (multi, 2H), 7.51 -7.32 (multi, 4H), 3.95-3.88 (multi, 6H), 2.54 and 2.44 (sx2, 3H), 1.35 (s, 9H).

LC-MS (ESI) 448 (M ⁺ ).

3) Synthesis of 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

K 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] methylbenzoate (0.0816 mmol, 36.6 mg) methanol (2.5 ml) was added, and then 1 M aqueous sodium hydroxide solution (0.408 mmol, 0.408 ml) was added. After 22 hours of stirring at room temperature, a solution of 1 M hydrochloric acid (0.408 mmol, 0.408 ml) and water were added. The precipitated solid was isolated by filtration, washed with water, dried using a vacuum pump and purified by silica gel thin-layer chromatography (chloroform / methanol = 5/1) to obtain the desired product as a yellow solid (35.0 mg, 99% yield).

¹ H-NMR (ppm in DMSO- d ₆ )

δ 8.13-7.98 (multi, 4H), 7.59-7.43 (multi, 4H), 3.88 and 3.84 (sx2, 3H), 2.46 and 2.45 (sx2, 3H), 1.34 and 1.32 (cx2, 9H).

LC-MS (ESI) 434 (M ⁺ ).

SYNTHESIS EXAMPLE 4

Synthesis of 3 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] methylbenzoate

 1- [5- (4-tert-Butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.192 mmol, 52.2 mg) synthesized in the synthesis example 3, 3-hydrazinocarbonylmethylbenzoate ( 0.192 mmol, 37.2 mg) and p-tolylsulfonic acid monohydrate (30 mol%, 9.9 mg) were dissolved in isopropyl alcohol (7 ml) and stirred at 100 ° C for about 15 hours. Then the reactor was cooled to room temperature and the reaction solution was filtered and dried using a vacuum pump to obtain the desired product as a white solid (65.3 mg, 76% yield).

¹ H-NMR (ppm in DMSO- d ₆ )

δ 11.42 (s, 1H), 9.70 (s, 1H), 8.47 (s, 1H), 8.19 (br t, 2H), 7.71 (t, J = 7.7 Hz, 1H), 7.55 (ABq, J = 8.7 Hz, 2H), 7.51 (ABq, J = 8.7 Hz, 2H), 3.92 (s, 3H), 3.85 ( s, 3H), 2.46 (s, 3H), 1.34 (s, 9H).

LC-MS (ESI) 448 (M ⁺ ).

SYNTHESIS EXAMPLE 5

Synthesis of 3 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

K 3 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] methylbenzoate (0.119 mmol, 53, 4 mg) methanol (2.5 ml) was added, and then 1 M aqueous sodium hydroxide solution (0.595 mmol, 0.595 ml) was added. After 1 hour of stirring at room temperature and 1 hour of stirring at 60 ° C, the reactor was cooled to room temperature and a solution of 1 M hydrochloric acid (0.595 mmol, 0.595 ml) and water were added. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump. The resulting mixture was isolated by thin layer chromatography on silica gel (CHCl ₃ / MeOH = 10/1) to obtain the desired product as a pale yellow solid (34 mg, 66% yield).

¹ H-NMR (ppm in DMSO- d ₆ )

δ 11.41 (s, 1H), 9.72 (s, 1H), 8.55 and 8.46 (sx2, 1H), 8.16-8.14 (multi, 2H), 7.71-7 63 (multi, 1H), 7.58-7.50 (multi, 4H), 3.94 and 3.85 (sx2, 3H), 2.46 (s, 3H), 1.34 (s, 9H )

LC-MS (ESI) 434 (M ⁺ ).

SYNTHESIS EXAMPLE 6

Synthesis of 4 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

 1- [5- (4-tert-Butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.163 mmol, 44.4 mg) synthesized in synthesis example 3, and 4-hydrazinocarbonothioylaminobenzoic acid (0.163 mmol, 34.4 mg) was stirred with dimethylformamide (3 ml) and two drops of concentrated hydrochloric acid at room temperature for 20 hours. After adding water, the precipitated yellow solid was isolated by filtration, washed with water and dried using a vacuum pump. The resulting solid was stirred for some time with chloroform / n-hexane, then isolated by filtration and dried using a vacuum pump to obtain the desired product as a yellow solid (37 mg, 48% yield).

¹ H-NMR (ppm in DMSO- d ₆ )

δ 10.88 (s, 1H), 10.34 (s, 1H), 8.86 (s, 1H), 7.95-7.84 (multi, 4H), 7.59-7.47 (multi , 4H), 3.83 and 3.81 (cx2, 3H), 2.46 and 2.39 (cx2, 3H), 1.34 and 1.33 (cx2, 9H).

LC-MS (ESI) 465 (M ⁺ ).

SYNTHESIS EXAMPLE 7

Synthesis of 4 - {[(2- {1- [5- (4-tert-butylphenyl) -1-ethyl-4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

1) Synthesis of 1- [5- (4-tert-butylphenyl) -1-ethyl-4-hydroxy-1H-pyrazol-3-yl] ethanone

 2-Oxopropanalethylhydrazone (4.736 mmol, 540.6 mg) synthesized in reference synthesis example 2, and (4-tert-butylphenyl) (oxo) acetaldehyde (4.736 mmol, 901.0 mg) synthesized in reference synthesis example 4, was dissolved in acetic acid (20 ml) and stirred at 100 ° C for about 3.5 hours. Then, the solvent was evaporated, and the residue was dried using a vacuum pump and purified by silica gel thin-layer chromatography (n-hexane / AcOEt = 1/2, 3/1, and 4/1) to obtain the desired product as an orange liquid (212 mg, 16% yield) )

¹ H-NMR (ppm in CDCl ₃ )

δ 8.12 (s, 1H), 7.50 (ABq, J = 8.6 Hz, 2H), 7.36 (ABq, J = 8.6 Hz, 2H), 4.19 (q, J = 7.2 Hz, 2H), 2.59 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H), 1.36 (s, 9H).

LC-MS (ESI) 286 (M ⁺ ).

2) Synthesis of 4 - {[(2- {1- [5- (4-tert-butylphenyl) -1-ethyl-4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) -carbonothioyl] amino} benzoic acid

 1- [5- (4-tert-Butylphenyl) -1-ethyl-4-hydroxy-1H-pyrazol-3-yl] ethanone (0.1718 mmol, 49.2 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.1718 mmol, 36.3 mg) was stirred with dimethylformamide (3 ml) and two drops of concentrated hydrochloric acid at room temperature for 21 hours. After adding water, the precipitated yellow solid was isolated by filtration, washed with water and dried using a vacuum pump. The resulting solid was stirred for some time with chloroform / n-hexane, then isolated by filtration and dried using a vacuum pump to obtain the desired product as a yellow solid (59 mg, 72% yield).

¹ H-NMR (ppm in DMSO- d ₆ )

δ 10.89 (s, 1H), 10.33 (s, 1H), 8.77 (s, 1H), 7.94-7.84 (multi, 4H), 7.60-7.41 (multi , 4H), 4.08 (q, J = 7.2 Hz, 2H), 2.47 and 2.41 (сx2, 3H), 1.34 and 1.33 (сx2, 9H), 1.27 ( t, J = 7.2 Hz, 3H).

LC-MS (ESI) 479 (M ⁺ ).

SYNTHESIS EXAMPLE 8

Synthesis of 4 - {[(2- {1- [5- (4-tert-butylphenyl) -1-benzyl-4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) -carbonothioyl] amino} benzoic acid

1) Synthesis of 1- [5- (4-tert-butylphenyl) -1-benzyl-4-hydroxy-1H-pyrazol-3-yl] ethanone

 2-Oxopropanal benzylhydrazone (2,314 mmol, 408 mg) synthesized in the same manner as in reference synthesis examples 1 and 2, and (4-tert-butylphenyl) (oxo) acetaldehyde (1,929 mmol, 366.9 mg) synthesized in Referential Synthesis Example 4, was dissolved in acetic acid (9 ml) and stirred at 100 ° C. for about 6 hours. Then, the solvent was evaporated, and the residue was dried using a vacuum pump and purified by silica gel column chromatography (n-hexane / AcOEt = 3/1 and 4/1) to obtain the desired product as a yellow solid (74.1 mg, 11% yield) .

¹ H-NMR (ppm in CDCl ₃ )

δ 8.15 (s, 1H), 7.43-7.40 (multi, 2H), 7.30-7.25 (multi, 5H), 7.06-7.03 (multi, 2H), 5 34 (s, 2H); 2.60 (s, 3H); 1.32 (s, 9H).

LC-MS (ESI) 348 (M ⁺ ).

2) Synthesis of 4 - {[(2- {1- [5- (4-tert-butylphenyl) -1-benzyl-4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

 1- [5- (4-tert-Butylphenyl) -1-benzyl-4-hydroxy-1H-pyrazol-3-yl] ethanone (0.218 mmol, 76 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.218 mmol, 46 mg) were mixed with dimethylformamide (3.5 ml) and three drops of concentrated hydrochloric acid at room temperature for 22 hours. After adding water, the precipitated yellow solid was isolated by filtration, washed with water and dried using a vacuum pump. The resulting solid was stirred with chloroform / n-hexane for some time, then was isolated by filtration and dried using a vacuum pump to obtain the desired product as a pale yellow solid (83 mg, 70% yield).

¹ H-NMR (ppm in DMSO- d ₆ )

δ 10.94 (br s, 1H), 10.36-10.34 (br s, 1H), 8.90 (s, 1H), 7.94-7.85 (multi, 4H), 7 56-7.47 (multi, 2H), 7.39-7.21 (multi, 5H), 7.09-6.95 (multi, 2H), 5.34 and 5.29 (sx2, 2H) 2.47 and 2.40 (cx2, 3H), 1.33 and 1.30 (cx2, 9H).

LC-MS (ESI) 541 (M ⁺ ).

SYNTHESIS EXAMPLE 9

Synthesis of 4 - {[(2- {1- [5- (3,4-dimethylphenyl) -1-methyl-4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

1) Synthesis of 1- [5- (3,4-dimethylphenyl) -1-methyl-4-hydroxy-1H-pyrazol-3-yl] ethanone

2-Oxopropanalmethylhydrazone (8.18 mmol, 819 mg) synthesized in reference synthesis example 1, and (3,4-dimethylphenyl) (oxo) acetaldehyde (7.57 mmol, 1.227 g) synthesized in reference synthesis example 5, was dissolved in acetic acid (30 ml) and stirred at 100 ° C for about 5 hours. Then, the solvent was evaporated, and the residue was dried using a vacuum pump and purified by column chromatography on silica gel (n-hexane / AcOEt = 2/1 and 4/1) to obtain a crude product. The crude product was stirred for some time with CHCl ₃ / n-hexane and then isolated by filtration. The solid obtained by filtration was combined with the solid obtained by purification of the filtrate by thin layer chromatography on silica gel (n-hexane / AcOEt = 4/1) to obtain the desired product as an orange solid (237.5 mg, 13% yield) )

¹ H-NMR (ppm in CDCl ₃ )

δ 8.13 (br s, 1H), 7.23-7.15 (multi, 3H), 3.88 (s, 3H), 2.58 (s, 3H), 2.34-2.31 (multi, 6H).

LC-MS (ESI) 244 (M ⁺ ).

2) Synthesis of 4 - {[(2- {1- [5- (3,4-dimethylphenyl) -1-methyl-4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

 1- [5- (3,4-Dimethylphenyl) -1-methyl-4-hydroxy-1H-pyrazol-3-yl] ethanone (0.2423 mmol, HPLC purity 84.3%, 70.2 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.2423 mmol, 51.2 mg) was stirred with dimethylformamide (3 ml) and three drops of concentrated hydrochloric acid at room temperature for 8.5 hours. After adding water, the precipitated yellow solid was isolated by filtration, washed with water and dried using a vacuum pump. The resulting solid was stirred for some time with chloroform / n-hexane, then isolated by filtration and dried using a vacuum pump to obtain the desired product as a pale yellow solid (72.3 mg, 68% yield).

¹ H-NMR (ppm in DMSO- d ₆ )

δ 10.84 (br s, 1H), 10.33 (s, 1H), 8.82 and 8.32 (sx2, 1H), 7.94-7.83 (multi, 4H), 7.32 -7.23 (multi, 3H), 3.81 and 3.79 (cx2, 3H), 2.46 and 2.39 (cx2, 3H), 2.30-2.29 (multi, 6H).

LC-MS (ESI) 437 (M ⁺ ).

SYNTHESIS EXAMPLE 10

Synthesis of 4 - {[(2- {1- [5- (4-n-pentylphenyl) -1-methyl-4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

1) Synthesis of 1- [5- (4-n-pentylphenyl) -1-methyl-4-hydroxy-1H-pyrazol-3-yl] ethanone

 2-Oxopropanalmethylhydrazone (8.6 mmol, 861 mg) synthesized in Reference Example Synthesis 1 and (4-n-pentylphenyl) (oxo) acetaldehyde (8.6 mmol, 1.757 g) synthesized in Reference Example Synthesis 6 were dissolved in acetic acid (30 ml) and stirred at 100 ° C for about 5 hours. Then, the solvent was evaporated, and the residue was dried using a vacuum pump and purified by silica gel column chromatography (n-hexane / AcOEt = 2/1 and 4/1) to obtain the desired product as an orange solid (252.5 mg, yield 10.3 %, crude product).

¹ H-NMR (ppm in CDCl ₃ )

δ 8.16 (br s, 1H), 7.37 (ABq, J = 8.3 Hz, 2H), 7.29 (ABq, J = 8.3 Hz, 2H), 3.90 (s, 3H), 2.70-2.62 (multi, 2H), 2.58 (s, 3H), 1.70-1.60 (multi, 2H), 1.39-1.32 (multi, 4H) 0.93-0.87 (multi, 3H).

LC-MS (ESI) 286 (M ⁺ ).

2) Synthesis of 4 - {[(2- {1- [5- (4-n-pentylphenyl) -1-methyl-4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

 1- [5- (4-n-Pentylphenyl) -1-methyl-4-hydroxy-1H-pyrazol-3-yl] ethanone (0.2381 mmol, HPLC purity 86.3%, 79.0 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.2381 mmol, 50.3 mg) was stirred with dimethylformamide (3 ml) and three drops of concentrated hydrochloric acid at room temperature for 8.5 hours. After adding water, the precipitated yellow solid was isolated by filtration, washed with water and dried using a vacuum pump. The resulting solid was stirred for some time with chloroform / n-hexane, then isolated by filtration and dried using a vacuum pump to obtain the desired product as a pale yellow solid (86.4 mg, 76% yield).

¹ H-NMR (ppm in DMSO- d ₆ )

δ 10.90 (br s, 1H), 10.34 (s, 1H), 8.85 (s, 1H), 7.94-7.84 (multi, 4H), 7.48-7.32 (multi, 4H), 3.82 and 3.80 (cx2, 3H), 2.65-2.60 (multi, 2H), 2.46 and 2.39 (cx2, 3H), 1.64-1 57 (multi, 2H), 1.34-1.30 (multi, 4H), 0.90-0.86 (multi, 3H).

LC-MS (ESI) 479 (M ⁺ ).

SYNTHESIS EXAMPLE 11

Synthesis of 4 - {[(2- {1- [5- (4-trifluoromethylphenyl) -1-methyl-4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

1) Synthesis of 1- [5- (4-trifluoromethylphenyl) -1-methyl-4-hydroxy-1H-pyrazol-3-yl] ethanone

 2-Oxopropanalmethylhydrazone (8.540 mmol, 855 mg), synthesized in Reference Example Synthesis 1, and (4-trifluoromethylphenyl) (oxo) acetaldehyde (6.432 mmol, 1.3 g), synthesized in Reference Example Synthesis 7, were dissolved in acetic acid ( 30 ml) and stirred at 100 ° C for about 5 hours. Then, the solvent was evaporated, and the residue was dried using a vacuum pump and purified by silica gel column chromatography (n-hexane / AcOEt = 2/1 and 4/1) to obtain the desired product as an orange solid (157.3 mg, yield 8.6 %).

¹ H-NMR (ppm in CDCl ₃ )

δ 8.28 (s, 1H), 7.75 (ABq, J = 8.3 Hz, 2H), 7.62 (ABq, J = 8.3 Hz, 2H), 3.95 (s, 3H) 2.59 (s, 3H).

LC-MS (ESI) 284 (M ⁺ ).

2) Synthesis of 4 - {[(2- {1- [5- (4-trifluoromethylphenyl) -1-methyl-4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

 1- [5- (4-Trifluoromethylphenyl) -1-methyl-4-hydroxy-1H-pyrazol-3-yl] ethanone (0.1694 mmol, HPLC purity 80%, 60.2 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.1694 mmol, 35.8 mg) was stirred with dimethylformamide (3 ml) and three drops of concentrated hydrochloric acid at room temperature for 8.5 hours. After adding water, the precipitated yellow solid was isolated by filtration, washed with water and dried using a vacuum pump. Chloroform / n-hexane was added to the obtained solid, and the precipitated solid was isolated by filtration and dried using a vacuum pump to obtain the desired product as a pale yellow solid (72.2 mg, 89% yield).

¹ H-NMR (ppm in DMSO- d ₆ )

δ 10.93 (br s, 1H), 10.36 and 10.35 (br sx2, 1H), 9.14 (s, 1H), 7.95-7.80 (multi, 8H), 3 88 (s, 3H); 2.47 and 2.41 (sx2, 3H).

LC-MS (ESI) 477 (M ⁺ ).

SYNTHESIS EXAMPLE 12

Synthesis of 4 - [(2- {1- [5- (3,4-dimethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

1) Synthesis of methyl 4 - [(2- {1- [5- (3,4-dimethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate

 1- [5- (3,4-Dimethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.365 mmol, 105.8 mg), 4-hydrazinocarbonylmethylbenzoate (0.365 mmol, 70.9 mg) and p-tolylsulfonic acid monohydrate (30 mol%, 18.9 mg) were dissolved in isopropyl alcohol (12 ml) and stirred at 100 ° C for about 19 hours. The reactor was cooled to room temperature, and the precipitated solid was isolated by filtration, dried using a vacuum pump and purified by silica gel thin-layer chromatography (chloroform / methanol = 10/1) to obtain the desired product as a white solid (21.7 mg, yield 14 %).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.39 (br s, 1H), 9.66 (br s, 1H), 8.10 (AVq, J = 8.3 Hz, 2H), 8.04 (AVq, J = 8.3 Hz, 2H), 7.34 (br s, 1H), 7.28 (br s, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 2.45 (s , 3H); 2.30 (s, 3H); 2.28 (s, 3H).

LC-MS (ESI) 420 (M ⁺ ).

2) Synthesis of 4 - [(2- {1- [5- (3,4-dimethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

 K methyl 4 - [(2- {1- [5- (3,4-dimethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate (0.051 mmol, 21 , 6 mg) was added at room temperature methanol (2.0 ml) and a 1 M aqueous solution of sodium hydroxide (5 eq., 0.257 ml). After 30 minutes of stirring at room temperature and 1.5 hours of stirring at 60 ° C, the reactor was cooled to room temperature and a 1 M solution of hydrochloric acid (5 eq., 0.257 ml) and water were added. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump to obtain the desired product as a yellow solid (17.5 mg, 84% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.35 (br s, 1H), 9.69 (br s, 1H), 8.07-7.96 (multi, 4H), 7.88-7.26 (multi, 3H), 3 82 (s, 3H); 2.45 (s, 3H); 2.30 (s, 3H); 2.28 (s, 3H).

LC-MS (ESI) 406 (M ⁺ ).

SYNTHESIS EXAMPLE 13

Synthesis of 4 - [(2- {1- [4-hydroxy-1-methyl-5- (4-n-pentylphenyl) -1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

1) Synthesis of methyl 4 - [(2- {1- [4-hydroxy-1-methyl-5- (4-n-pentylphenyl) -1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate

 1- [4-Hydroxy-1-methyl-5- (4-n-pentylphenyl) -1H-pyrazol-3-yl] ethanone (0.309 mmol, 102.4 mg), 4-hydrazinocarbonylmethylbenzoate (0.309 mmol, 59.9 mg) and p-tolylsulfonic acid monohydrate (30 mol%, 15.9 mg) were dissolved in isopropyl alcohol (12 ml) and stirred at 100 ° C for about 20 hours. The reactor was cooled to room temperature and the precipitated solid was isolated by filtration and dried using a vacuum pump to obtain the desired product as a white solid (87.9 mg, 62% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.27 (br s, 1H), 9.94 (br s, 1H), 8.10-8.05 (multi, 4H), 7.48 (AVq, J = 8.1 Hz, 2H ), 7.34 (ABq, J = 8.1 Hz, 2H), 3.90 (s, 3H), 3.84 (s, 3H), 2.63 (t, J = 7.1 Hz, 2H ), 2.44 (s, 3H), 1.62 (multi, 2H), 1.33-1.32 (multi, 4H), 0.88 (t, J = 7.1 Hz, 3H).

LC-MS (ESI) 462 (M ⁺ ).

2) Synthesis of 4 - [(2- {1- [4-hydroxy-1-methyl-5- (4-n-pentylphenyl) -1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

 K methyl 4 - [(2- {1- [4-hydroxy-1-methyl-5- (4-n-pentylphenyl) -1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate (0.121 mmol, 66 , 5 mg) methanol (3.5 ml) was added, and a 1 M aqueous solution of sodium hydroxide (5 eq., 0.605 ml) was added at room temperature. After 30 minutes of stirring at room temperature and 1.5 hours of stirring at 60 ° C, the reactor was cooled to room temperature and 1 M hydrochloric acid solution (5 eq., 0.605 ml) and water were added. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump to obtain the desired product as a yellow solid (40.4 mg, 74% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.36 (br s, 1H), 9.69 (br s, 1H), 8.07 (AVq, J = 8.3 Hz, 2H), 8.01 (AVq, J = 8.3 Hz, 2H), 7.48 (AVq, J = 8.0 Hz, 2H), 7.34 (AVq, J = 8.0 Hz, 2H), 3.84 (s, 3H), 2.63 ( t, J = 7.7 Hz, 2H), 2.45 (s, 3H), 1.62 (multi, 2H), 1.33-1.32 (multi, 4H), 0.88 (t, J = 6.8 Hz, 3H).

LC-MS (ESI) 448 (M ⁺ ).

SYNTHESIS EXAMPLE 14

Synthesis of 4 - {[2- (1- {4-hydroxy-1-methyl-5- [4- (trifluoromethyl) phenyl] -1H-pyrazol-3-yl} ethylidene) hydrazino] carbonyl} benzoic acid

1) Synthesis of methyl 4 - {[2- (1- {4-hydroxy-1-methyl-5- [4- (trifluoromethyl) phenyl] -1H-pyrazol-3-yl} ethylidene) hydrazino] carbonyl} benzoate

 1- [4-Hydroxy-1-methyl-5- (4-trifluoromethylphenyl) -1H-pyrazol-3-yl] ethanone (0.231 mmol, 82.1 mg), 4-hydrazinocarbonylmethylbenzoate (0.231 mmol, 44.9 mg) and p-tolylsulfonic acid monohydrate (30 mol%, 11.9 mg) was dissolved in isopropyl alcohol (12 ml) and stirred at 100 ° C. for about 20 hours. The reactor was cooled to room temperature and the precipitated solid was isolated by filtration and dried using a vacuum pump to obtain the desired product as a pale yellow solid (66.5 mg, 63% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.46 (br s, 1H), 9.97 (br s, 1H), 8.11 (AVq, J = 8.6 Hz, 2H), 8.04 (AVq, J = 8.6 Hz, 2H), 7.89 (ABq, J = 8.6 Hz, 2H), 7.84 (ABq, J = 8.6 Hz, 2H), 3.92 (s, 3H), 3.90 ( s, 3H); 2.47 (s, 3H).

LC-MS (ESI) 460 (M ⁺ ).

2) Synthesis of 4 - {[2- (1- {4-hydroxy-1-methyl-5- [4- (trifluoromethyl) phenyl] -1H-pyrazol-3-yl} ethylidene) hydrazino] carbonyl} benzoic acid

 K methyl 4 - {[2- (1- {4-hydroxy-1-methyl-5- [4- (trifluoromethyl) phenyl] -1H-pyrazol-3-yl} ethylidene) hydrazino] carbonyl} benzoate (0.116 mmol, 53.4 mg) methanol (2 ml) was added and a 1 M aqueous solution of sodium hydroxide (5 eq., 0.580 ml) was added at room temperature. After 30 minutes of stirring at room temperature and 1 hour of stirring at 60 ° C, the reactor was cooled to room temperature and a solution of 1 M hydrochloric acid solution (5 eq., 0.580 ml) and water were added. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump to obtain the desired product as a yellow solid (37.7 mg, 73% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.43 (br s, 1H), 9.98 (br s, 1H), 8.07 (AVq, J = 8.4 Hz, 2H), 8.01 (ABq, J = 8.4 Hz, 2H), 7.89 (ABq, J = 8.3 Hz, 2H), 7.84 (ABq, J = 8.3 Hz, 2H), 3.92 (s, 3H), 2.47 and 2.42 (cx2, 3H).

LC-MS (ESI) 446 (M ⁺ ).

SYNTHESIS EXAMPLE 15

Synthesis of 4 - {[2- (1- {4-hydroxy-1-methyl-5- [3- (trifluoromethyl) phenyl] -1H-pyrazol-3-yl} ethylidene) hydrazino] carbonyl} benzoic acid

1) Synthesis of 1- [4-hydroxy-1-methyl-5- (3-trifluoromethylphenyl) -1H-pyrazol-3-yl] ethanone

 2-Oxopropanalmethylhydrazone (7.49 mmol, 750 mg) and (oxo) [3-trifluoromethylphenyl] acetaldehyde (7.0 mmol, 1.42 g) synthesized in Reference Synthesis Example 8 were dissolved in acetic acid (20 ml) and stirred at 100 ° C for 4 hours. Then, the solvent was evaporated and the residue was dried using a vacuum pump and purified by silica gel column chromatography (n-hexane / ethyl acetate = 2/1), and then thin-layer chromatography on silica gel (chloroform / methanol = 30/1) to obtain the desired product as reddish yellow liquid (221 mg, 11% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 8.26 (s, 1H), 7.70-7.60 (multi, 4H), 3.93 (s, 3H), 2.59 (s, 3H).

LC-MS (ESI) 284 (M ⁺ ).

2) Synthesis of methyl 4 - {[2- (1- {4-hydroxy-1-methyl-5- [3- (trifluoromethyl) phenyl] -1H-pyrazol-3-yl} ethylidene) hydrazino] carbonyl} benzoate

 1- [4-Hydroxy-1-methyl-5- (3-trifluoromethylphenyl) -1H-pyrazol-3-yl] ethanone (0.502 mmol, 142.7 mg), 4-hydrazinocarbonylmethylbenzoate (0.502 mmol, 97.5 mg) and p-tolylsulfonic acid monohydrate (30 mol%, 26.0 mg) was dissolved in isopropyl alcohol (13 ml) and stirred at 100 ° C. for about 11 hours. The reactor was cooled to room temperature and the precipitated solid was isolated by filtration, dried using a vacuum pump and purified by silica gel thin-layer chromatography (chloroform / methanol = 10/1), and then silica gel thin-layer chromatography (n-hexane / ethyl acetate = 1/2) to obtain the desired product as a yellow solid (36.7 mg, 16% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.46 (br s, 1H), 9.94 (br s, 1H), 8.10 (AVq, J = 8.1 Hz, 2H), 8.05 (AVq, J = 8.1 Hz, 2H), 7.95-7.90 (multi, 2H), 7.81-7.77 (multi, 2H), 3.91 (br s, 6H), 2.47 (s, 3H) .

LC-MS (ESI) 460 (M ⁺ ).

3) Synthesis of 4 - {[2- (1- {4-hydroxy-1-methyl-5- [3- (trifluoromethyl) phenyl] -1H-pyrazol-3-yl} ethylidene) hydrazino] carbonyl} benzoic acid

 K methyl 4 - {[2- (1- {4-hydroxy-1-methyl-5- [3- (trifluoromethyl) phenyl] -1H-pyrazol-3-yl} ethylidene) hydrazino] carbonyl} benzoate (0.072 mmol, 33.1 mg) methanol (2 ml) was added and a 1 M aqueous solution of sodium hydroxide (5 eq., 0.360 ml) was added at room temperature. After 30 minutes of stirring at room temperature and 1.5 hours of stirring at 60 ° C, the reactor was cooled to 0 ° C and a 1 M solution of hydrochloric acid (5 eq., 0.360 ml) and water were added. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump to obtain the desired product as a yellow solid (17.6 mg, 55% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.40 (br s, 1H), 9.99 (br s, 1H), 8.06-7.69 (multi, 8H), 3.91 and 3.89 (br x 2, 3H) 2.47 and 2.39 (br sx2, 3H).

LC-MS (ESI) 446 (M ⁺ ).

SYNTHESIS EXAMPLE 16

Synthesis of 4 - [(2- {1- [5- (3,5-dimethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

1) Synthesis of 1- [5- (3,5-dimethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone

 2-Oxopropanalmethylhydrazone (7.29 mmol, 730 mg) and (3,5-dimethylphenyl) (oxo) acetaldehyde (7.29 mmol, 1.18 g), synthesized in reference synthesis example 10, were dissolved in acetic acid (25 ml ) and stirred at 100 ° C for 5 hours. Then, the solvent was evaporated and the residue was dried using a vacuum pump and purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/1), and then thin-layer chromatography on silica gel (n-hexane / ethyl acetate = 3/1) to obtain the desired product in as an orange liquid (93 mg, 5% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 8.15 (s, 1H), 7.05 (br s, 3H), 3.88 (s, 3H), 2.58 (s, 3H), 2.37 (s, 6H).

LC-MS (ESI) 244 (M ⁺ ).

2) Synthesis of methyl 4 - [(2- {1- [5- (3,5-dimethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate

 1- [5- (3,5-Dimethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.120 mmol, 29.3 mg) and 4-hydrazinocarbonylmethylbenzoate (0.120 mmol, 23.3 mg) was dissolved in dimethylformamide (5 ml) and stirred at 110 ° C for 23 hours. Then the reactor was cooled to room temperature and the solvent was evaporated using a centrifugal evaporator. The residue was dried and purified by flash chromatography on silica gel (chloroform / methanol = 10/1) to obtain the desired product as a yellow solid (23.4 mg, 46% yield).

LC-MS (ESI) 420 (M ⁺ ).

3) Synthesis of 4 - [(2- {1- [5- (3,5-dimethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

 K methyl 4 - [(2- {1- [5- (3,5-dimethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate (0.015 mmol, 6 , 5 mg) methanol (1 ml) was added, and a 1 M aqueous solution of sodium hydroxide (5 eq., 0.077 ml) was added at room temperature. After 20 minutes of stirring at room temperature and 1.5 hours of stirring at 60 ° C, the reactor was cooled to room temperature and a solution of 1 M hydrochloric acid (5 eq., 0.077 ml) and water were added. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump, and the residue was then purified by thin-layer chromatography on silica gel (chloroform / methanol = 10/1). After adding chloroform / n-hexane, the precipitated solid was isolated by filtration and dried to obtain the desired product as a yellow solid (1.7 mg, 27% yield).

LC-MS (MSI) 406 (M ⁺ ).

SYNTHESIS EXAMPLE 17

Synthesis of 4 - [(2- {1- [4-hydroxy-5- (4-isopropylphenyl) -1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

1) Synthesis of 1- [5- (4-isopropylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone

 2-Oxopropanalmethylhydrazone (10.44 mmol, 1.05 g) and (4-isopropylphenyl) (oxo) acetaldehyde (10.44 mmol, 1.84 g) synthesized in reference synthesis example 12 were dissolved in acetic acid (37 ml ) and stirred at 100 ° C for 4.5 hours. Then, the solvent was evaporated and the residue was dried using a vacuum pump and purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/1), and then thin-layer chromatography on silica gel (n-hexane / ethyl acetate = 3/1) to obtain the desired product in as an orange solid (113 mg, 4% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 8.15 (s, 1H), 7.39 (ABq, J = 8.3 Hz, 2H), 7.34 (ABq, J = 8.3 Hz, 2H), 3.90 (s, 3H) 2.96 (sept, J = 6.9 Hz, 1H); 2.58 (s, 3H); 1.28 (d, J = 6.9 Hz, 6H).

LC-MS (ESI) 258 (M ⁺ ).

2) Synthesis of methyl 4 - [(2- {1- [4-hydroxy-5- (4-isopropylphenyl) -1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate

 1- [5- (4-Isopropylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.170 mmol, 44.0 mg) and 4-hydrazinocarbonylmethylbenzoate (0.170 mmol, 33.1 mg) dissolved in dimethylformamide (5.5 ml) and stirred at 110 ° C for 23 hours. Then the reactor was cooled to room temperature and the solvent was evaporated using a centrifugal evaporator. The residue was dried and chloroform was added. The precipitated solid was isolated by filtration to obtain the desired product as a yellow solid (39.1 mg, 53% yield).

LC-MS (ESI) 434 (M ⁺ ).

3) Synthesis of 4 - [(2- {1- [4-hydroxy-5- (4-isopropylphenyl) -1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

K methyl 4 - [(2- {1- [4-hydroxy-5- (4-isopropylphenyl) -1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate (0.037 mmol, 16.0 mg) methanol (3 ml) was added and a 1 M aqueous solution of sodium hydroxide (5 equiv., 0.184 ml) was added at room temperature. After 15 minutes of stirring at room temperature and 1.5 hours of stirring at 60 ° C, the reactor was cooled to room temperature and a 1 M solution of hydrochloric acid (5 equiv., 0.184 ml) and water were added. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump, and the residue was then purified by thin-layer chromatography on silica gel (chloroform / methanol = 10/1). After adding chloroform / n-hexane, the precipitated solid was dried to obtain the desired product as a yellow solid (6.8 mg, 44% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.33 (br s, 1H), 9.70 (br s, 1H), 8.09-7.93 (multi, 4H), 7.51-7.38 (multi, 4H), 3 86 and 3.84 (cx2, 3H), 2.99-2.94 (multi, 1H), 2.45 and 2.43 (cx2, 3H), 1.26 (d, J = 6.9 Hz , 6H).

LC-MS (ESI) 420 (M ⁺ ).

SYNTHESIS EXAMPLE 18

Synthesis of 4 - [(2- {1- [4-hydroxy-5- (4-isobutylphenyl) -1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

1) Synthesis of 1- [4-hydroxy-5- (4-isobutylphenyl) -1-methyl-1H-pyrazol-3-yl] ethanone

 2-Oxopropanalmethylhydrazone (11.60 mmol, 1.16 g) and (4-isobutylphenyl) (oxo) acetaldehyde (11.60 mmol, 2.21 g) synthesized in Reference Synthesis Example 15 were dissolved in acetic acid (38 ml ) and stirred at 100 ° C for 4.5 hours. Then the solvent was evaporated and the residue was dried using a vacuum pump and purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/1), then by silica gel thin-layer chromatography (chloroform) and thin-layer chromatography on silica gel (n-hexane / ethyl acetate = 3 / 1) to obtain the desired product as a brown solid (154 mg, 5% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 8.17 (s, 1H), 7.37 (ABq, J = 8.3 Hz, 2H), 7.26 (ABq, J = 8.3 Hz, 2H), 3.90 (s, 3H) , 2.58 (s, 3H), 2.52 (d, J = 6.9 Hz, 2H), 1.91 (sept, J = 6.9 Hz, 1H), 0.94 (d, J = 6.9 Hz, 6H).

LC-MS (ESI) 272 (M ⁺ ).

2) Synthesis of methyl 4 - [(2- {1- [4-hydroxy-5- (4-isobutylphenyl) -1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) -carbonyl] benzoate

 1- [4-Hydroxy-5- (4-isobutylphenyl) -1-methyl-1H-pyrazol-3-yl] ethanone (0.353 mmol, 96.0 mg) and 4-hydrazinocarbonylmethylbenzoate (0.353 mmol, 68.5 mg) dissolved in dimethylformamide (7 ml) and stirred at 110 ° C for 23 hours. Then the reactor was cooled to room temperature and the solvent was evaporated using a centrifugal evaporator. The residue was dried and chloroform was added. The precipitated solid was isolated by filtration to obtain the desired product as a yellow solid (93.2 mg, 59% yield).

LC-MS (ESI) 448 (M ⁺ ).

3) Synthesis of 4 - [(2- {1- [4-hydroxy-5- (4-isobutylphenyl) -1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

 K methyl 4 - [(2- {1- [4-hydroxy-5- (4-isobutylphenyl) -1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate (0.129 mmol, 57.7 mg) methanol (2.5 ml) was added and a 1 M aqueous sodium hydroxide solution (5 eq., 0.643 ml) was added at room temperature. After 15 minutes of stirring at room temperature and 1.5 hours of stirring at 60 ° C, the reactor was cooled to room temperature and a 1 M solution of hydrochloric acid (5 eq., 0.643 ml) and water were added. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump, and the residue was then purified by silica gel thin-layer chromatography (chloroform / methanol = 10/1). After addition of chloroform / n-hexane, the precipitated solid was dried to obtain the desired product as a yellow solid (25.6 mg, 46% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.34 (s, 1H), 9.72 (s, 1H), 8.10-7.95 (multi, 4H), 7.50-7.46 (multi, 2H), 7.34-7 30 (multi, 2H), 3.87 and 3.84 (sx2, 3H), 2.45 (s, 3H), 1.90 (sept, J = 6.8 Hz, 1H), 0.91 ( d, J = 6.8 Hz, 6H).

LC-MS (ESI) 434 (M ⁺ ).

SYNTHESIS EXAMPLE 19

Synthesis of 4 - [(2- {1- [5- (3-bromo-4-fluorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

1) Synthesis of 1- [5- (3-bromo-4-fluorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone

 2-Oxopropanalmethylhydrazone (10.56 mmol, 1.06 g) and (3-bromo-4-fluorophenyl) (oxo) acetaldehyde (10.56 mmol, 2.44 g) synthesized in reference synthesis example 9 were dissolved in acetic acid (37 ml) and was stirred at 100 ° C for 4.5 hours. Then the solvent was evaporated and the residue was dried using a vacuum pump and purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/1), then by silica gel thin-layer chromatography (chloroform) and thin-layer chromatography on silica gel (n-hexane / ethyl acetate = 3 / 1) to obtain the desired product as a brown solid (160 mg, 5% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 8.21 (s, 1H), 7.69-7.66 (multi, 1H), 7.41-7.37 (multi, 1H), 7.27-7.22 (multi, 1H), 3 89 (s, 3H); 2.58 (s, 3H).

LC-MS (ESI) 312, 314 (M ⁺ ).

2) Synthesis of methyl 4 - [(2- {1- [5- (3-bromo-4-fluorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate

 1- [5- (3-Bromo-4-fluorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.269 mmol, 84.1 mg) and 4-hydrazinocarbonylmethylbenzoate (0.269 mmol, 52 , 2 mg) was dissolved in dimethylformamide (7 ml) and stirred at 110 ° C for 23 hours. Then the reactor was cooled to room temperature and the solvent was evaporated using a centrifugal evaporator. The residue was dried and chloroform was added. The precipitated solid was isolated by filtration to obtain the desired product as a yellow solid (60.1 mg, 46% yield).

LC-MS (ESI) 488 (M ⁺ ).

3) Synthesis of 4 - [(2- {1- [5- (3-bromo-4-fluorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

 K methyl 4 - [(2- {1- [5- (3-bromo-4-fluorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate (0.051 mmol , 24.9 mg) methanol (2.5 ml) was added, and a 1 M aqueous solution of sodium hydroxide (5 eq., 0.255 ml) was added at room temperature. After 10 minutes of stirring at room temperature and 1.5 hours of stirring at 60 ° C, the reactor was cooled to room temperature and a 1 M solution of hydrochloric acid (5 eq., 0.255 ml) and water were added. The precipitated solid was isolated by filtration, washed with water, dried using a vacuum pump and the residue was then purified by thin-layer chromatography on silica gel (chloroform / methanol = 10/1). After adding chloroform / n-hexane, the precipitated solid was dried to obtain the desired product as a yellow solid (9.0 mg, 37% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.40 (s, 1H), 9.87 (s, 1H), 8.12-7.91 (multi, 5H), 7.62-7.52 (multi, 2H), 3.86 (s , 3H); 2.45 and 2.43 (cx2, 3H).

LC-MS (ESI) 474 (M ⁺ ).

SYNTHESIS EXAMPLE 20

Synthesis of 4 - [(2- {1- [5- (4-ethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

1) Synthesis of 1- [5- (4-ethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone

 2-Oxopropanalmethylhydrazone (13.7 mmol, 1.37 g) and (4-ethylphenyl) (oxo) acetaldehyde (13.5 mmol, 2.19 g), synthesized in reference synthesis example 11, were dissolved in acetic acid (30 ml ) and stirred at 100 ° C for 6 hours. Then the solvent was evaporated and the residue was dried using a vacuum pump and purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/1), then by silica gel thin-layer chromatography (chloroform) and thin-layer chromatography on silica gel (n-hexane / ethyl acetate = 7 / 2) to obtain the desired product as a brown solid (255 mg, 8% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 8.15 (s, 1H), 7.38 (ABq, J = 8.4 Hz, 2H), 7.32 (ABq, J = 8.4 Hz, 2H), 3.90 (s, 3H) 2.70 (q, J = 7.8 Hz, 2H); 2.58 (s, 3H); 1.28 (t, J = 7.8 Hz, 3H).

LC-MS (ESI) 244 (M ⁺ ).

2) Synthesis of methyl 4 - [(2- {1- [5- (4-ethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate

 1- [5- (4-Ethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.459 mmol, 112.1 mg) and 4-hydrazinocarbonylmethylbenzoate (0.459 mmol, 89.1 mg) dissolved in dimethylformamide (9 ml) and stirred at 110 ° C for 23 hours. Then the reactor was cooled to room temperature and the solvent was evaporated using a centrifugal evaporator. The residue was dried and chloroform was added. The precipitated solid was isolated by filtration to obtain the desired product as a yellow solid (130.5 mg, 68% yield).

LC-MS (ESI) 420 (M ⁺ ).

3) Synthesis of 4 - [(2- {1- [5- (4-ethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

 K methyl 4 - [(2- {1- [5- (4-ethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate (0.172 mmol, 72.4 mg) methanol (4 ml) was added and a 1 M aqueous solution of sodium hydroxide (5 eq., 0.861 ml) was added at room temperature. After 10 minutes stirring at room temperature and 2 hours stirring at 60 ° C, the reactor was cooled to room temperature and 1 M hydrochloric acid solution (5 eq., 0.861 ml) and water were added. The precipitated solid was isolated by filtration, washed with water, dried using a vacuum pump and the residue was then purified by thin-layer chromatography on silica gel (chloroform / methanol = 10/1). After adding chloroform / n-hexane, the precipitated solid was dried to obtain the desired product as a yellow solid (29.1 mg, 42% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.36 (s, 1H), 9.68 (s, 1H), 8.13-7.96 (multi, 4H), 7.50-7.35 (multi, 4H), 3.87 and 3 84 (sx2, 3H), 2.72-2.64 (multi, 2H), 2.45 (s, 3H), 1.26-1.21 (multi, 3H).

LC-MS (ESI) 406 (M ⁺ ).

SYNTHESIS EXAMPLE 21

Synthesis of 4 - [(2- {1- [4-hydroxy-1-methyl-5- (4-n-propylphenyl) -1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

1) Synthesis of 1- [5- (4-n-propylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone

 2-Oxopropanalmethylhydrazone (19.36 mmol, 1.94 g) and oxo (4-n-propylphenyl) acetaldehyde (19.0 mmol, 3.35 g), synthesized in reference synthesis example 13, were dissolved in acetic acid (42 ml ) and stirred at 100 ° C for 6 hours. Then the solvent was evaporated and the residue was dried using a vacuum pump and purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/1), then by silica gel thin-layer chromatography (chloroform) and thin-layer chromatography on silica gel (n-hexane / ethyl acetate = 7 / 2) to obtain the desired product as a brown solid (304 mg, 6% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 8.15 (s, 1H), 7.37 (ABq, J = 8.3 Hz, 2H), 7.29 (ABq, J = 8.3 Hz, 2H), 3.90 (s, 3H) 2.64 (t, J = 7.5 Hz, 2H), 2.58 (s, 3H), 1.68 (q, J = 7.2 Hz, 2H), 0.97 (t, J = 7.2 Hz, 3H).

LC-MS (ESI) 258 (M ⁺ ).

2) Synthesis of methyl 4 - [(2- {1- [4-hydroxy-1-methyl-5- (4-n-propylphenyl) -1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate

 1- [4-Hydroxy-1-methyl-5- (4-n-propylphenyl) -1H-pyrazol-3-yl] ethanone (0.445 mmol, 115.0 mg) and 4-hydrazinocarbonylmethylbenzoate (0.445 mmol, 86.5 mg) was dissolved in dimethylformamide (9 ml) and stirred at 110 ° C for 23 hours. Then the reactor was cooled to room temperature and the solvent was evaporated using a centrifugal evaporator. The residue was dried and chloroform was added. The precipitated solid was isolated by filtration to obtain the desired product as a yellow solid (143.3 mg, 74% yield).

LC-MS (ESI) 434 (M ⁺ ).

3) Synthesis of 4 - [(2- {1- [4-hydroxy-1-methyl-5- (4-n-propylphenyl) -1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

 K methyl 4 - [(2- {1- [4-hydroxy-1-methyl-5- (4-n-propylphenyl) -1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate (0.166 mmol, 72 , 2 mg) methanol was added, and a 1 M aqueous solution of sodium hydroxide (5 eq., 0.831 ml) was added at room temperature. After 10 minutes of stirring at room temperature and 2 hours of stirring at 60 ° C, the reactor was cooled to room temperature and a 1 M solution of hydrochloric acid (5 eq., 0.831 ml) and water were added. The precipitated solid was isolated by filtration, washed with water, dried using a vacuum pump and the residue was then purified by thin-layer chromatography on silica gel (chloroform / methanol = 10/1). After adding chloroform / n-hexane, the precipitated solid was isolated by filtration and dried to obtain the desired product as a yellow solid (47.1 mg, 67% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.36 (s, 1H), 9.69 (s, 1H), 8.12-7.96 (multi, 4H), 7.50-7.45 (multi, 2H), 7.39-7 33 (multi, 2H), 3.87 and 3.84 (sx2, 3H), 2.66-2.59 (multi, 2H), 2.45 (s, 3H), 1.71-1.58 (multi, 2H); 0.96-0.91 (multi, 3H).

LC-MS (ESI) 420 (M ⁺ ).

SYNTHESIS EXAMPLE 22

Synthesis of 4 - [(2- {1- [5- (4-n-hexylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

1) Synthesis of 1- [5- (4-n-hexylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone

 2-Oxopropanalmethylhydrazone (16.1 mmol, 1.62 g) and (4-n-hexylphenyl) (oxo) acetaldehyde (16 mmol, 4.57 g), synthesized in Reference Synthesis Example 14, were dissolved in acetic acid (35 ml ) and stirred at 100 ° C for 6 hours. Then the solvent was evaporated and the residue was dried using a vacuum pump and purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/1), then by silica gel thin-layer chromatography (chloroform) and thin-layer chromatography on silica gel (n-hexane / ethyl acetate = 7 / 2) to obtain the desired product as a brown solid (308 mg, 6% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 8.16 (s, 1H), 7.37 (ABq, J = 8.1 Hz, 2H), 7.29 (ABq, J = 8.1 Hz, 2H), 3.90 (s, 3H) 2.65 (t, J = 7.8 Hz, 2H), 2.58 (s, 3H), 1.64-1.62 (multi, 2H), 1.41-1.28 (multi, 6H ), 0.92-0.87 (multi, 3H).

LC-MS (ESI) 300 (M ⁺ ).

2) Synthesis of methyl 4 - [(2- {1- [5- (4-n-hexylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate

 1- [5- (4-n-hexylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.431 mmol, 129.6 mg) and 4-hydrazinocarbonylmethylbenzoate (0.431 mmol, 83.8 mg) was dissolved in dimethylformamide (8 ml) and stirred at 110 ° C for 23 hours. Then the reactor was cooled to room temperature and the solvent was evaporated using a centrifugal evaporator. The residue was dried and chloroform was added. The precipitated solid was isolated by filtration to obtain the desired product as a yellow solid (125.1 mg, 61% yield).

LC-MS (ESI) 476 (M ⁺ ).

3) Synthesis of 4 - [(2- {1- [5- (4-n-hexylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

 K methyl 4 - [(2- {1- [5- (4-n-hexylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate (0.158 mmol, 75 , 2 mg) methanol was added, and a 1 M aqueous solution of sodium hydroxide (5 eq., 0.789 ml) was added at room temperature. After 10 minutes of stirring at room temperature and 2 hours of stirring at 60 ° C, the reactor was cooled to room temperature and a 1 M solution of hydrochloric acid (5 eq., 0.789 ml) and water were added. The precipitated solid was isolated by filtration, washed with water, dried using a vacuum pump and the residue was then purified by thin-layer chromatography on silica gel (chloroform / methanol = 10/1). After adding chloroform / n-hexane, the precipitated solid was dried to obtain the desired product as a yellow solid (29.4 mg, yield 40%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.36 (s, 1H), 9.69 (s, 1H), 8.13-7.95 (multi, 4H), 7.49-7.45 (multi, 2H), 7.38-7 33 (multi, 2H), 3.87 and 3.84 (sx2, 3H), 2.67-2.61 (multi, 2H), 2.45 (s, 3H), 1.66-1.56 (multi, 2H), 1.36-1.24 (multi, 6H), 0.89-0.85 (multi, 3H).

LC-MS (ESI) 462 (M ⁺ ).

SYNTHESIS EXAMPLE 23

Synthesis of 4 - ({[2- (1- {4-hydroxy-1-methyl-5- [3- (trifluoromethyl) phenyl] -1H-pyrazol-3-yl} ethylidene) hydrazino] carbonothioyl} amino) benzoic acid

 1- [4-Hydroxy-1-methyl-5- (3-trifluoromethylphenyl) -1H-pyrazol-3-yl] ethanone (0.229 mmol, 65.0 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.229 mmol, 48.3 mg ) was stirred with dimethylformamide (2.5 ml) and three drops of concentrated hydrochloric acid at room temperature for 24 hours. After adding water, the precipitated yellow solid was isolated by filtration, washed with water and dried using a vacuum pump. Chloroform / n-hexane was added to the obtained solid, and the precipitated solid was isolated by filtration and dried using a vacuum pump to obtain the desired product as a yellow solid (74.7 mg, 68% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 10.36 and 10.33 (br sx2, 1H), 9.12 (s, 1H), 7.95-7.77 (multi, 8H), 3.86 (s, 3H), 2.41 (s, 3H).

LC-MS (ESI) 477 (M ⁺ ).

SYNTHESIS EXAMPLE 24

Synthesis of 4 - {[(2- {1- [5- (3,5-dimethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

 1- [5- (3,5-Dimethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.122 mmol, 29.9 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.122 mmol, 25, 9 mg) was stirred with dimethylformamide (2 ml) and two drops of concentrated hydrochloric acid at room temperature for 24 hours. After adding water, the precipitated yellow solid was isolated by filtration, washed with water and dried using a vacuum pump. The resulting solid was stirred for some time with chloroform / n-hexane, then isolated by filtration and dried using a vacuum pump to obtain the desired product as a pale yellow solid (34.7 mg, 65% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 10.87 (br s, 1H), 10.33 and 10.32 (br sx2, 1H), 8.84 (s, 1H), 7.93 (AVq, J = 8.1 Hz, 2H ), 7.84 (ABq, J = 8.1 Hz, 2H), 7.16-7.14 (multi, 2H), 7.06 (br s, 1H), 3.81 and 3.79 ( cx2, 3H), 2.46 and 2.39 (cx2, 3H), 2.35-2.31 (multi, 6H).

LC-MS (ESI) 437 (M ⁺ ).

SYNTHESIS EXAMPLE 25

Synthesis of 4 - {[(2- {1- [4-hydroxy-5- (4-isopropylphenyl) -1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

 1- [4-Hydroxy-5- (4-isopropylphenyl) -1-methyl-1H-pyrazol-3-yl] ethanone (0.116 mmol, 29.9 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.116 mmol, 24.5 mg ) was stirred with dimethylformamide (2 ml) and two drops of concentrated hydrochloric acid at room temperature for 24 hours. After adding water, the precipitated yellow solid was isolated by filtration, washed with water and dried using a vacuum pump. The resulting solid was stirred with chloroform / n-hexane for some time, then was isolated by filtration and dried using a vacuum pump to obtain the desired product as a pale yellow solid (37.7 mg, 72% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 10.90 (br s, 1H), 10.35 and 10.33 (br sx2, 1H), 8.85 (s, 1H), 7.93 (AVq, J = 8.6 Hz, 2H ), 7.85 (ABq, J = 8.6 Hz, 2H), 7.47 (ABq, J = 8.1 Hz, 2H), 7.39 (AWq, J = 8.1 Hz, 2H), 3.83 and 3.81 (cx2, 3H), 2.95 (sept, J = 6.9 Hz, 1H), 2.46 and 2.39 (cx2, 3H), 1.27-1.24 ( multi, 6H).

LC-MS (ESI) 451 (M ⁺ ).

SYNTHESIS EXAMPLE 26

Synthesis of 4 - {[(2- {1- [4-hydroxy-5- (4-isobutylphenyl) -1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

 1- [4-Hydroxy-5- (4-isobutylphenyl) -1-methyl-1H-pyrazol-3-yl] ethanone (0.179 mmol, 48.8 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.179 mmol, 37.9 mg ) was stirred with dimethylformamide (2.5 ml) and three drops of concentrated hydrochloric acid at room temperature for 24.5 hours. After adding water, the precipitated yellow solid was isolated by filtration, washed with water and dried using a vacuum pump. The resulting solid was stirred for some time with chloroform / n-hexane, then isolated by filtration and dried using a vacuum pump to obtain the desired product as a pale yellow solid (62.6 mg, 75% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 10.87 (br s, 1H), 10.34 (br s, 1H), 8.85 (s, 1H), 7.93 (ABq, J = 8.6 Hz, 2H), 7, 85 (ABq, J = 8.6 Hz, 2H), 7.46 (ABq, J = 8.3 Hz, 2H), 7.30 (AWq, J = 8.3 Hz, 2H), 3.83 and 3.81 (sx2, 3H), 2.54-2.51 (multi, 2H), 2.46 and 2.39 (sx2, 3H), 1.89 (sept, J = 6.8 Hz, 1H) 0.92-0.89 (multi, 6H).

LC-MS (ESI) 465 (M ⁺ ).

SYNTHESIS EXAMPLE 27

Synthesis of 4 - {[(2- {1- [5- (3-bromo-4-fluorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -benzoic acid

 1- [5- (3-Bromo-4-fluorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.139 mmol, 43.6 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.139 mmol, 29.4 mg) was stirred with dimethylformamide (2.5 ml) and three drops of concentrated hydrochloric acid at room temperature for 24.5 hours. After adding water, the precipitated yellow solid was isolated by filtration, washed with water and dried using a vacuum pump. The resulting solid was stirred with chloroform / n-hexane for some time, then isolated by filtration and dried using a vacuum pump to obtain the desired product as a yellow solid (51.8 mg, 74% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 10.35 and 10.32 (br sx2, 1H), 9.08 (s, 1H), 7.98-7.79 (multi, 5H), 7.65-7.51 (multi, 2H) 3.83 (s, 3H); 2.46 and 2.39 (sx2, 3H).

LC-MS (ESI) 505, 507 (M ⁺ ).

SYNTHESIS EXAMPLE 28

Synthesis of 4 - {[(2- {1- [5- (4-ethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

 1- [5- (4-Ethylphenyl) -1-methyl-4-hydroxy-1H-pyrazol-3-yl] ethanone (0.159 mmol, 38.8 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.159 mmol, 33.6 mg ) was stirred with dimethylformamide (2.3 ml) and three drops of concentrated hydrochloric acid at room temperature for 23.5 hours. After adding water, the precipitated yellow solid was isolated by filtration, washed with water and dried using a vacuum pump. The resulting solid was stirred for some time with chloroform / n-hexane, then isolated by filtration and dried using a vacuum pump to obtain the desired product as a pale yellow solid (50.6 mg, 73% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 10.87 (br s, 1H), 10.33 (br s, 1H), 8.85 (s, 1H), 7.93 (ABq, J = 8.7 Hz, 2H), 7, 85 (ABq, J = 8.7 Hz, 2H), 7.46 (ABq, J = 8.1 Hz, 2H), 7.36 (AWq, J = 8.1 Hz, 2H), 3.82 and 3.80 (sx2, 3H), 2.67 (q, J = 7.5 Hz, 2H), 2.46 and 2.39 (sx2, 3H), 1.26-1.20 (multi, 3H) .

LC-MS (ESI) 437 (M ⁺ ).

SYNTHESIS EXAMPLE 29

Synthesis of 4 - {[(2- {1- [4-hydroxy-1-methyl-5- (4-n-propylphenyl) -1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

 1- [4-Hydroxy-1-methyl-5- (4-n-propylphenyl) -1H-pyrazol-3-yl] ethanone (0.157 mmol, 40.5 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.157 mmol, 33, 1 mg) was stirred with dimethylformamide (2.3 ml) and three drops of concentrated hydrochloric acid at room temperature for 23.5 hours. After adding water, the precipitated yellow solid was isolated by filtration, washed with water and dried using a vacuum pump. The resulting solid was stirred for some time with chloroform / n-hexane, then isolated by filtration and dried using a vacuum pump to obtain the desired product as a pale yellow solid (56.2 mg, 79% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 10.32 (br s, 1H), 8.85 (s, 1H), 7.93 (AVq, J = 8.7 Hz, 2H), 7.85 (AVq, J = 8.7 Hz, 2H), 7.46 (ABq, J = 8.1 Hz, 2H), 7.34 (ABq, J = 8.1 Hz, 2H), 3.82 and 3.80 (cx2, 3H), 2, 62 (t, J = 7.7 Hz, 2H), 2.46 and 2.39 (cx2, 3H), 1.70-1.57 (multi, 2H), 0.97-0.91 (multi, 3H).

LC-MS (ESI) 451 (M ⁺ ).

SYNTHESIS EXAMPLE 30

Synthesis of 4 - {[(2- {1- [5- (4-n-hexylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

 1- [5- (4-n-Hexylphenyl) -1-methyl-4-hydroxy-1H-pyrazol-3-yl] ethanone (0.117 mmol, 35.1 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.117 mmol, 24, 7 mg) was stirred with dimethylformamide (2.3 ml) and three drops of concentrated hydrochloric acid at room temperature for 23.5 hours. After adding water, the precipitated yellow solid was isolated by filtration, washed with water and dried using a vacuum pump. The resulting solid was stirred for some time with chloroform / n-hexane, then isolated by filtration and dried using a vacuum pump to obtain the desired product as a pale yellow solid (46.3 mg, 80% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 10.87 (br s, 1H), 10.33 (br s, 1H), 8.84 (s, 1H), 7.93 (ABq, J = 8.6 Hz, 2H), 7, 84 (AVq, J = 8.6 Hz, 2H), 7.45 (ABq, J = 8.1 Hz, 2H), 7.33 (AVq, J = 8.1 Hz, 2H), 3.82 and 3.80 (sx2, 3H), 2.63 (t, J = 7.7 Hz, 2H), 2.46 and 2.39 (sx2, 3H), 1.61 (multi, 2H), 1.30 (multi, 6H); 0.86 (multi, 3H).

LC-MS (ESI) 493 (M ⁺ ).

SYNTHESIS EXAMPLE 31

Synthesis of 4 - [(2- {1- [5- (4-tert-butylphenyl) -1-ethyl-4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

1) Synthesis of methyl 4 - [(2- {1- [5- (4-tert-butylphenyl) -1-ethyl-4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate

 1- [5- (4-tert-Butylphenyl) -1-ethyl-4-hydroxy-1H-pyrazol-3-yl] ethanone (0.313 mmol, 89.5 mg), 4-hydrazinocarbonylmethylbenzoate (0.313 mmol, 60.7 mg) and p-tolylsulfonic acid monohydrate (30 mol%, 16.1 mg) were dissolved in isopropyl alcohol (16 ml) and stirred at 100 ° C for 19 hours. The reactor was cooled to room temperature and the solvent was evaporated. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol = 10/1), then silica gel column chromatography (n-hexane / ethyl acetate = 1/2) to obtain the desired product as a yellow solid (16.8 mg, yield) 12%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.39 (br s, 1H), 9.60 (br s, 1H), 8.10 (AVq, J = 8.3 Hz, 2H), 8.04 (AVq, J = 8.3 Hz, 2H), 7.55 (AVq, J = 8.1 Hz, 2H), 7.44 (AVq, J = 8.1 Hz, 2H), 4.12 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 2.46 (s, 3H), 1.34 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H).

LC-MS (ESI) 462 (M ⁺ ).

2) Synthesis of 4 - [(2- {1- [5- (4-tert-butylphenyl) -1-ethyl-4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

 K methyl 4 - [(2- {1- [5- (4-tert-butylphenyl) -1-ethyl-4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate (0.032 mmol, 15 , 0 mg) methanol (1.5 ml) was added at room temperature and a 1 M aqueous solution of sodium hydroxide (0.162 mmol, 0.162 ml) was added. After 30 minutes of stirring at room temperature and 1.25 hours of stirring at 60 ° C, the reactor was cooled to 0 ° C and a 1 M solution of hydrochloric acid (0.162 mmol, 0.162 ml) and water were added. The precipitated solid was isolated by filtration, washed with water, dried using a vacuum pump and purified by silica gel thin-layer chromatography (chloroform / methanol = 10/1) to obtain the desired product as a yellow solid (6.4 mg, 44% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.33 (br s, 1H), 9.64 (br s, 1H), 8.06-7.94 (multi, 4H), 7.58-7.43 (multi, 4H), 4 12 (q, J = 7.5 Hz, 2H), 2.46 and 2.44 (sx2, 3H), 1.34 (s, 9H), 1.27 (t, J = 7.5 Hz, 3H).

LC-MS (ESI) 448 (M ⁺ ).

SYNTHESIS EXAMPLE 32

Synthesis of 4 - [(2- {1- [1-benzyl-5- (4-tert-butylphenyl) -4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

1) Synthesis of methyl 4 - [(2- {1- [1-benzyl-5- (4-tert-butylphenyl) -4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate

 1- [1-Benzyl-5- (4-tert-butylphenyl) -4-hydroxy-1H-pyrazol-3-yl] ethanone (0.610 mmol, 212.6 mg), 4-hydrazinocarbonylmethylbenzoate (0.610 mmol, 118.5 mg) and p-tolylsulfonic acid monohydrate (30 mol%, 31.5 mg) were dissolved in isopropyl alcohol (20 ml) and stirred at 100 ° C for 18 hours. The reactor was cooled to room temperature and the solvent was evaporated. The resulting crude product was purified by silica gel column chromatography (chloroform / methanol = 10/1), then silica gel column chromatography (n-hexane / ethyl acetate = 1/2) to obtain the desired product as a yellow solid (56.6 mg, yield eighteen%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.44 (br s, 1H), 9.72 (br s, 1H), 8.11 (AVq, J = 8.1 Hz, 2H), 8.05 (AVq, J = 8.1 Hz, 2H), 7.49 (ABq, J = 8.3 Hz, 2H), 7.37 (ABq, J = 8.3 Hz, 2H), 7.32-7.22 (multi, 3H), 6.99-6.97 (multi, 2H), 5.38 (s, 2H), 3.91 (s, 3H), 2.46 (s, 3H), 1.30 (s, 9H).

LC-MS (ESI) 524 (M ⁺ ).

2) Synthesis of 4 - [(2- {1- [1-benzyl-5- (4-tert-butylphenyl) -4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

 K methyl 4 - [(2- {1- [1-benzyl-5- (4-tert-butylphenyl) -4-hydroxy-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate (0.045 mmol, 23 5 mg) methanol was added and a 1 M aqueous solution of sodium hydroxide (0.224 mmol, 0.224 ml) was added at room temperature. After 30 minutes of stirring at room temperature and 1.5 hours of stirring at 60 ° C, the reactor was cooled to 0 ° C and a 1 M solution of hydrochloric acid (0.224 mmol, 0.224 ml) and water were added. The precipitated solid was isolated by filtration, washed with water, dried using a vacuum pump and purified by silica gel thin-layer chromatography (chloroform / methanol = 10/1) to obtain the desired product as a yellow solid (15.8 mg, 69% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.41 (br s, 1H), 9.74 (br s, 1H), 8.06-6.97 (multi, 13H), 5.38 (s, 2H), 2.46 (s , 3H); 1.30 (s, 9H).

LC-MS (ESI) 510 (M ⁺ ).

SYNTHESIS EXAMPLE 33

Synthesis of methyl 5 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-thiophenecarboxylate

 1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (38.0 mg, 0.14 mmol) and methyl 5-hydrazinocarbonyl-2-thiophenecarboxylate (27.9 mg, 0.14 mmol) was dissolved in dimethylformamide (2.0 ml) and stirred at 110 ° C. for 12 hours. After cooling, the solvent was evaporated, and ethyl acetate was added to the resulting crude product. The precipitated solid was isolated by filtration to obtain 20.0 mg of the desired product as a pale yellow solid (31% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 7.78 (d, J = 3.6 Hz, 1H), 7.42-7.52 (multi, 5H), 3.92 (s, 3H), 3.88 (s, 3H), 2, 45 (s, 3H); 1.36 (s, 9H).

LC-MS (ESI) 454 (M ⁺ ).

SYNTHESIS EXAMPLE 34

Synthesis of 5 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-thiophenecarboxylic acid

 Methyl 5 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-thiophenecarboxylate (16, 0 mg, 0.035 mmol) in methanol (1.5 ml) was stirred with a 1 M aqueous sodium hydroxide solution (176 μl, 0.176 mmol) at room temperature for 17 hours. After stirring, a 1 M hydrochloric acid solution (176 μl, 0.176 mmol) was added and the precipitated solid was isolated by filtration to obtain 6.2 mg of the desired product as yellow crystals (yield 40%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.36 (br s, 1H), 9.50 (br s, 1H), 8.02 (d, J = 4.5 Hz, 1H), 7.79 (d, J = 4.5 Hz, 1H), 7.48-7.56 (multi, 4H), 3.84 (s, 3H), 2.45 (s, 3H), 1.33 (s, 9H).

LC-MS (ESI) 440 (M ⁺ ).

SYNTHESIS EXAMPLE 35

Synthesis of methyl 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate

 2- (4-tert-Butylphenyl) -3-hydroxy-4-methylcarbonylthiophene (100 mg, 0.36 mmol) synthesized in Reference Example Synthesis 33, and 4-hydrazinocarbonylmethylbenzoate (70 mg, 0.36 mmol) was stirred in dimethylformamide (3.6 ml) at 120 ° C overnight. The reaction solution was partitioned between ethyl acetate-saturated aqueous ammonium chloride and the organic layer was washed with saturated aqueous sodium chloride. The precipitated solid was isolated from the solution by filtration to obtain the desired product as a pale yellow solid (58 mg, 36% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.30 (s, 9H), 3.91 (s, 3H), 7.43 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H) 7.99-8.13 (m, 5H); 11.48 (s, 1H); 12.23 (s, 1H).

¹ H-NMR (ppm in MeOH-d ₄ )

δ 1.34 (s, 9H), 2.48 (s, 3H), 3.95 (s, 3H), 7.39-8.16 (m, 9H).

LC / MS (ES ⁺ ) 451.

SYNTHESIS EXAMPLE 36

Synthesis of methyl 4 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate

 2- (3,4-Dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (100 mg, 0.35 mmol) synthesized in reference synthesis example 34, and 4-hydrazinocarbonylmethylbenzoate (68 mg, 0.35 mmol) was stirred in dimethylformamide (3.6 ml) at 120 ° C with heating overnight. The resulting reaction solution was concentrated, and ethyl acetate / n-hexane was added. The precipitated solid was isolated by filtration to obtain the desired product as a pale yellow solid (141 mg, 87% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 3.91 (s, 3H), 7.64-7.73 (m, 2H), 8.05-8.13 (m, 6H), 11.55 (br s, 1H).

LC / MS (ES ^- ) 461, 462, 464.

SYNTHESIS EXAMPLE 37

Synthesis of methyl 4 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate

 Starting from 2- (4-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene (100 mg, 0.35 mmol) synthesized in Synthesis Reference Example 35, the desired product was obtained in the same manner as in Synthesis Example 36 as a pale yellow solid (132 mg, 82% yield).

¹ H-NMR (ppm in MeOH-d ₄ )

δ 2.49 (s, 3H), 3.95 (s, 3H), 7.64-7.67 (m, 2H), 7.88 (s, 1H), 8.03-8.04 (m , 4H), 8.15-8.18 (m, 2H).

LC / MS (ES ⁺ ) 463.

SYNTHESIS EXAMPLE 38

Synthesis of methyl 2-nitro-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate

 2- (4-tert-Butylphenyl) -3-hydroxy-4-methylcarbonylthiophene (80 mg, 0.29 mmol) and methyl 2-nitro-4-hydrazinocarbonylbenzoate (69 mg, 0.29 mmol) were stirred in dimethylformamide (2, 9 ml) at 120 ° C with heating overnight. The resulting reaction solution was concentrated, and ethyl acetate / n-hexane was added. The precipitated solid was isolated by filtration to obtain the desired product as a brown solid (92 mg, 64% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.30 (s, 9H), 3.90 (s, 3H), 7.43 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H) 8.02-8.07 (m, 2H), 8.36 (d, J = 7.4 Hz, 1H), 8.59 (s, 1H).

LC / MS (ES ⁺ ) 496.

SYNTHESIS EXAMPLE 39

Synthesis of methyl 5 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] -2-thiophenecarboxylate

 2- (4-tert-Butylphenyl) -3-hydroxy-4-methylcarbonylthiophene (80 mg, 0.29 mmol) and methyl 5-hydrazinocarbonyl-2-thiophenecarboxylate (58 mg, 0.29 mmol) were stirred in dimethylformamide (2, 9 ml) at 120 ° C with heating overnight. The resulting reaction solution was concentrated, and chloroform / n-hexane was added. The precipitated solid was isolated by filtration to obtain the desired product as a yellow solid (79 mg, 60% yield).

¹ H-NMR (ppm in MeOH-d ₄ )

δ 1.34 (s, 9H), 2.48 (s, 3H), 3.91 (s, 3H), 7.38-7.81 (m, 7H).

LC / MS (ES ⁺ ) 457.

SYNTHESIS EXAMPLE 40

Synthesis of methyl 4 - [(2 - {[5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] methylene} hydrazino) carbonyl] benzoate

 2- (4-tert-Butylphenyl) -3-hydroxy-4-formylthiophene (100 mg, 0.38 mmol) synthesized in reference synthesis example 25, and 4-hydrazinocarbonylmethylbenzoate (74 mg, 0.38 mmol) was stirred in dimethylformamide (3.8 ml) at room temperature overnight. The reaction solution was partitioned between ethyl acetate-water and the organic layer was washed with a saturated aqueous solution of sodium chloride. The resulting organic layer was concentrated and purified by silica gel column chromatography (chloroform) to obtain the desired product as a light brown solid (74 mg, 46% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.30 (s, 9H), 3.91 (s, 3H), 7.44 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H) 7.93-7.95 (m, 2H), 8.06-8.15 (m, 4H), 8.57 (s, 1H), 10.87 (s, 1H), 12.40 (s , 1H).

LC / MS (ES ⁺ ) 437.

SYNTHESIS EXAMPLE 41

Synthesis of methyl 4 - [(2 - {[5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] methylene} hydrazino) carbonyl] benzoate

 2- (3,4-Dichlorophenyl) -3-hydroxy-4-formylthiophene (104 mg, 0.38 mmol) synthesized in Reference Example Synthesis 26, and 4-hydrazinocarbonylmethylbenzoate (74 mg, 0.38 mmol) was stirred in dimethylformamide (3.8 ml) at room temperature overnight. Water was added to the reaction solution, and the precipitated solid was isolated by filtration to obtain the desired product as a pale yellow solid (175 mg, 100% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 3.91 (s, 3H), 7.65-7.72 (m, 2H), 7.96-8.14 (m, 7H), 8.62 (s, 1H), 11.37 (broad .s, 1H).

LC / MS (ES ⁺ ) 451, 452, 453.

SYNTHESIS EXAMPLE 42

Synthesis of 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoic acid

 Methyl 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate (50 mg, 0.11 mmol) synthesized in the synthesis example 35 was dissolved in methanol (1.1 ml) and stirred with a 1 M aqueous solution of sodium hydroxide (0.55 ml, 0.55 mmol) at 45 ° C. for 1.5 hours. After stirring, a 1 M hydrochloric acid solution (0.55 ml, 0.55 mmol) was added and the precipitated pale yellow solid was isolated by filtration. The resulting solid was purified by silica gel chromatography (chloroform: methanol = 9: 1). The resulting solid was stirred with chloroform at room temperature and isolated by filtration to obtain the desired product as a pale yellow solid (11 mg, 23% yield).

¹ H-NMR (ppm in MeOH-d ₄ )

δ 1.34 (s, 9H), 2.48 (s, 3H), 7.39-8.08 (m, 9H).

LC / MS （ES ⁺ ） 437.

SYNTHESIS EXAMPLE 43

Synthesis of 4 - [(2 - {[5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] methylene} hydrazino) carbonyl] benzoic acid

 Starting from methyl 4 - [(2 - {[5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] methylene} hydrazino) carbonyl] benzoate (62 mg, 0.14 mmol) synthesized in the synthesis example 40, the desired product was obtained in the same manner as in Synthesis Example 42, as a pale yellow solid (34 mg, 57% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.30 (s, 9H), 7.44 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.93 (s, 1H) 8.03-8.09 (m, 4H), 8.58 (s, 1H), 10.88 (s, 1H), 12.38 (br s, 1H).

LC / MS (ES ⁺ ) 423.

SYNTHESIS EXAMPLE 44

Synthesis of 4 - [(2 - {[5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] methylene} hydrazino) carbonyl] benzoic acid

 Starting from methyl 4 - [(2 - {[5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] methylene} hydrazino) carbonyl] benzoate (120 mg, 0.27 mmol) synthesized in the synthesis example 41, the desired product was obtained in the same manner as in Synthesis Example 42, as a pale yellow solid (44 mg, 37% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 7.66-7.72 (m, 2H), 8.03-8.21 (m, 6H), 8.58 (s, 1H), 11.37 (br s, 1H).

SYNTHESIS EXAMPLE 45

Synthesis of 4 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoic acid

 Starting from methyl 4 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate (100 mg, 0.22 mmol) synthesized in Synthesis Example 36, the desired product was obtained in the same manner as in Synthesis Example 42, as a pale yellow solid (9 mg, 9% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 7.64-7.73 (m, 2H), 8.01-8.12 (m, 6H).

¹ H-NMR (ppm in MeOH-d ₄ )

δ 2.47 (s, 3H); 7.47-8.16 (m, 8H).

LC / MS (ES ⁺ ) 449, 450, 451.

SYNTHESIS EXAMPLE 46

Synthesis of 4 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoic acid

 Starting from methyl 4 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate (100 mg, 0.22 mmol) synthesized in the synthesis example 37, the desired product was obtained in the same manner as in Synthesis Example 42, as a colorless solid (34 mg, 34% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 7.75-7.78 (m, 2H), 8.00-8.15 (m, 7H), 11.51 (br s, 1H).

LC / MS (ES ^- ) 447.

SYNTHESIS EXAMPLE 47

Synthesis of 2-nitro-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoic acid

 Starting from methyl 2-nitro-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate (60 mg, 0.12 mmol ) synthesized in synthesis example 38, the desired product was obtained in the same manner as in synthesis example 42, as a yellow solid (10 mg, 17% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.30 (s, 9H), 7.43 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.95-8.03 ( m, 2H), 8.30 (d, J = 8.0 Hz, 1H), 8.51 (s, 1H).

¹ H-NMR (ppm in MeOH-d ₄ )

δ 1.34 (s, 9H), 2.49 (s, 3H), 7.39-8.46 (m, 8H).

LC / MS (ES ⁺ ) 482.

SYNTHESIS EXAMPLE 48

Synthesis of 5 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] -2-thiophenecarboxylic acid

 Starting from methyl 5 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] -2-thiophenecarboxylate (72 mg, 0.16 mmol) synthesized in synthesis example 39, the desired product was obtained in the same manner as in synthesis example 42, as a yellow solid (12 mg, 17% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.30 (s, 9H), 7.43 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 4.1 Hz, 1H), 8.00 (s, 1H), 8.04 (d, J = 4.1 Hz, 1H).

LC / MS (ES ^- ) 442.

SYNTHESIS EXAMPLE 49

Synthesis of 4 - {[(2 - {[5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] methylene} hydrazino) carbonothioyl] amino} benzoic acid

 2- (4-tert-Butylphenyl) -3-hydroxy-4-formylthiophene (50 mg, 0.19 mmol) synthesized in reference synthesis example 25, and 4-hydrazinocarbonothioylaminobenzoic acid (40 mg, 0.19 mmol) was mixed with dimethylformamide (1.9 ml) and concentrated hydrochloric acid (0.1 ml) at room temperature for 12 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The resulting organic layer was concentrated and purified by silica gel column chromatography (chloroform). Methanol / chloroform was added to the resulting crude product, and the precipitated yellow solid was isolated by filtration to obtain the desired product as a pale yellow solid (20 mg, 23% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.30 (s, 9H), 7.43 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 8.5 Hz, 2H), 7.93-7.99 (m, 3H), 8.24 (s, 1H), 10.32 (s, 1H), 11.93 (s, 1H).

LC / MS (ES ⁺ ) 454.

SYNTHESIS EXAMPLE 50

Synthesis of 4 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

 2- (4-tert-Butylphenyl) -3-hydroxy-4-methylcarbonylthiophene (31 mg, 0.11 mmol) synthesized in reference synthesis example 33, and 4-hydrazinocarbonothioylaminobenzoic acid (23 mg, 0.11 mmol) was mixed with dimethylformamide (1.1 ml) and concentrated hydrochloric acid (0.05 ml) at room temperature for 30 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The resulting organic layer was concentrated and purified by silica gel column chromatography (chloroform) to obtain the desired product as a light brown solid (27 mg, 52% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.30 (s, 9H), 2.39 (s, 3H), 7.43 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H) 7.86-7.95 (m, 5H); 10.40 (s, 1H); 11.08 (s, 1H).

LC / MS (ES ⁺ ) 468.

SYNTHESIS EXAMPLE 51

Synthesis of 4 - {[(2 - {[5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] methylene} hydrazino) carbonothioyl] amino} benzoic acid

 2- (3,4-Dichlorophenyl) -3-hydroxy-4-formylthiophene (52 mg, 0.19 mmol) synthesized in Reference Example Synthesis 26, and 4-hydrazinocarbonothioylaminobenzoic acid (40 mg, 0.19 mmol) were mixed with dimethylformamide (1.9 ml) and concentrated hydrochloric acid (0.1 ml) at room temperature for 14 hours. Water was added to the reaction solution, and the precipitated solid was isolated by filtration and dried. The crude product was stirred with chloroform at room temperature and isolated by filtration to obtain the desired product as a pale yellow solid (58 mg, yield 65%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 7.67-8.10 (m, 8H), 8.25 (s, 1H), 10.34 (s, 1H), 11.95 (s, 1H).

LC / MS (ES ⁺ ) 465, 467, 469.

SYNTHESIS EXAMPLE 52

Synthesis of 4 - {[(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

 Starting from 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (50 mg, 0.17 mmol) synthesized in reference synthesis example 34, the desired product was obtained in the same manner as in synthesis example 51, in as a pale yellow solid (23 mg, 28% yield).

LC / MS (ES ⁺ ) 480, 481, 482, 484.

SYNTHESIS EXAMPLE 53

Synthesis of 4 - {[(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

 Starting from 2- (4-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene (50 mg, 0.17 mmol) synthesized in Synthesis Reference Example 35, the desired product was obtained in the same manner as in Synthesis Example 51 as a pale a yellow solid (48 mg, 59%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 2.41 (s, 3H), 7.74-8.11 (m, 9H), 10.49 (s, 1H), 11.18 (s, 1H).

LC / MS (ES ⁺ ) 480.

SYNTHESIS EXAMPLE 54

Synthesis of 4 - ({2 - [[5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] (phenyl) methylene] hydrazino} carbonyl) benzoic acid

1) Synthesis of [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] (phenyl) methanone

 Oxo (phenyl) acetaldehyde methylhydrazone (5.46 mmol, 886 mg) synthesized in reference synthesis example 36, and (4-tert-butylphenyl) (oxo) acetaldehyde (5 mmol, 951 mg) was dissolved in acetic acid (26 ml) and stirred at 100 ° C for about 2 hours. Then, the solvent was evaporated, and the residue was recrystallized from chloroform / n-hexane to obtain the desired product as a yellow solid (993 mg, 59% yield).

¹ H-NMR (ppm in CDCl ₃ )

δ 9.04 (s, 1H), 8.51-8.48 (multi, 2H), 7.61-7.59 (multi, 1H), 7.55-7.44 (multi, 6H), 3 98 (s, 3H); 1.37 (s, 9H).

LC-MS (ESI) 334 (M ⁺ ).

2) Synthesis of methyl 4 - ({2 - [[5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] (phenyl) methylene] hydrazino} carbonyl) benzoate

 [5- (4-tert-Butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] (phenyl) methanone (0.299 mmol, 99.9 mg), 4-hydrazinocarbonylmethylbenzoate (0.299 mmol, 58, 0 mg) and p-tolylsulfonic acid monohydrate (30 mol%, 15.4 mg) were dissolved in isopropyl alcohol (12 ml) and stirred at 100 ° C for about 24 hours. The reactor was then cooled to room temperature and the precipitated solid was isolated by filtration and dried using a vacuum pump to obtain the desired product as a pale yellow solid (119 mg, 78% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.29 (s, 1H), 9.85 (s, 1H), 8.03 (AVq, J = 8.3 Hz, 2H), 7.84 (ABq, J = 8.3 Hz, 2H) 7.62-7.55 (multi, 9H), 3.90 and 3.87 (sx2, 3H), 3.77 and 3.73 (sx2, 3H), 1.34 and 1.32 (sx2, 9H).

LC-MS (ESI) 510 (M ⁺ ).

3) Synthesis of 4 - ({2 - [[5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] (phenyl) methylene] hydrazino} carbonyl) benzoic acid

 K methyl 4 - ({2 - [[5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] (phenyl) methylene] hydrazino} carbonyl) benzoate (0.196 mmol, 100 mg) methanol (4 ml) was added and a 1 M aqueous solution of sodium hydroxide (0.981 mmol, 0.981 ml) was added at room temperature. After 15 minutes of stirring at room temperature and 1 hour of stirring at 60 ° C, the reactor was cooled to room temperature and a 1 M solution of hydrochloric acid (0.981 mmol, 0.981 ml) and water were added. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump to obtain the desired product as a yellow solid (93 mg, 95% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.25 (s, 1H), 9.86 (s, 1H), 8.00 (AVq, J = 8.3 Hz, 2H), 7.81 (ABq, J = 8.3 Hz, 2H) 7.62-7.55 (multi, 9H), 3.77 and 3.73 (cx2, 3H), 1.34 and 1.32 (cx2, 9H).

LC-MS (ESI) 496 (M ⁺ ).

SYNTHESIS EXAMPLE 55

Synthesis of 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene] hydrazino} carbonyl) -N-methylbenzenesulfonamide

 1- [5- (4-tert-Butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.228 mmol, 62 mg), 4- (hydrazinocarbonyl) -N-methylbenzenesulfonamide (0.228 mmol , 52 mg) and p-tolylsulfonic acid monohydrate (30 mol%, 11.8 mg) were dissolved in isopropyl alcohol (6 ml) and stirred at 100 ° C for 19 hours. Then, the solvent was evaporated, and the residue was purified by silica gel thin-layer chromatography (chloroform / methanol = 10/1) to obtain the desired product as a yellow solid (30.3 mg, 28% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.40 (s, 1H), 9.65 (s, 1H), 8.32 (s, 1H), 8.10 (ABq, J = 8.4 Hz, 2H), 7.91 (ABq, J = 8.4 Hz, 2H), 7.57-7.49 (multi, 4H), 3.89 and 3.85 (sx2, 3H), 2.46 (s, 3H), 2.45 (s , 3H); 1.34 (s, 9H).

LC-MS (ESI) 483 (M ⁺ ).

SYNTHESIS EXAMPLE 56

Synthesis of 4 - ({2 - [[5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] (phenyl) methylene] hydrazino} carbonyl) -N-methylbenzenesulfonamide

 [5- (4-tert-Butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] (phenyl) methanone (0.254 mmol, 85 mg), 4- (hydrazinocarbonyl) -N-methylbenzenesulfonamide (0.254 mmol, 58 mg) and p-tolylsulfonic acid monohydrate (30 mol%, 13 mg) were dissolved in isopropyl alcohol (8.5 ml) and stirred at 100 ° C for 19 hours. Then, the solvent was evaporated, and the residue was purified by silica gel thin-layer chromatography (chloroform / methanol = 10/1) to obtain the desired product as a yellow solid (30.3 mg, 22% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.69 and 11.32 (sx2, 1H), 9.84 and 8.64 (sx2, 1H), 8.64 (s, 1H), 8.09-7.82 (multi, 4H), 7 69-7.44 (multi, 9H), 3.91-3.73 (multi, 3H), 2.47 and 2.38 (multi, 3H), 1.34-1.33 (sx2, 9H) .

LC-MS (ESI) 545 (M ⁺ ).

SYNTHESIS EXAMPLE 57

Synthesis of N '- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} -4- (1H-tetrazol-5-yl) benzhydrazide

 1- [5- (4-tert-Butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.404 mmol, 110 mg) and 4- (1-H-tetrazol-5-yl ) benzhydrazide (0.404 mmol, 83 mg) synthesized in accordance with WO03 / 037328 was dissolved in dimethylformamide (5 ml) and stirred at 100 ° C. for 26 hours. Insoluble matters were filtered off and washed with methanol, the filtrate was concentrated and separated by silica gel chromatography (chloroform / MeOH = 4/1) to obtain the desired product as a yellow solid (25 mg, 13% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.22 (s, 1H), 9.76 (s, 1H), 8.13 (AVq, J = 8.3 Hz, 2H), 7.99 (ABq, J = 8.3 Hz, 2H) 7.57-7.50 (multi, 4H), 3.91 and 3.85 (sx2, 3H), 2.46 and 2.42 (sx2, 3H), 1.34 (s, 9H).

LC-MS (ESI) 458 (M ⁺ ).

SYNTHESIS EXAMPLE 58

Synthesis of 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-nitrobenzoic acid

1) Synthesis of methyl 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-nitrobenzoate

 1- [5- (4-tert-Butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (1.149 mmol, 312.9 mg) synthesized in synthesis example 3, methyl 2-nitro -4-hydrazinocarbonyl benzoate (1.149 mmol, 274.8 mg) synthesized in Reference Example Synthesis 40, and p-tolylsulfonic acid monohydride (30 mol%, 59.4 mg) were dissolved in isopropyl alcohol (30 ml) and stirred at boiling with reflux for 6 hours and the reactor was cooled to 0 ° C. The reaction solution was filtered and dried using a vacuum pump to obtain the desired product as a yellow solid (470 mg, 83% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.54 (s, 1H), 9.57 (s, 1H), 8.57 (s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.55 (AVq, J = 8.4 Hz, 2H), 7.50 (AVq, J = 8.4 Hz, 2H), 3.90 (s, 3H) 3.85 (s, 3H); 2.46 (s, 3H); 1.33 (s, 9H)

LC-MS (ESI) 493 (M ⁺ )

2) Synthesis of 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-nitrobenzoic acid

 K methyl 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-nitrobenzoate (0.945 mmol, 466.2 mg) methanol (33 ml) was added and then a 1 M aqueous solution of sodium hydroxide (4.7 mmol, 4.7 ml) was added. After about 26 hours of stirring at room temperature and 3 hours of stirring at 40 ° C, a 1 M solution of hydrochloric acid (4.7 mmol, 4.7 ml) and water were added. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump. The resulting yellow solid (359.5 mg) was dissolved in THF (50 ml) and stirred at room temperature for 2 days. Insoluble matters were filtered off and the filtrate was concentrated and dried using a vacuum pump. After addition of chloroform, the precipitated solid was isolated by filtration and dried using a vacuum pump to obtain the desired product as a pale yellow solid (260.7 mg, 58% yield).

¹ H-NMR (ppm in DMSO- d ₆ )

δ 11.50 (s, 1H), 9.58 (s, 1H), 8.47 (s, 1H), 8.27 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.55 (AVq, J = 8.4 Hz, 2H), 7.50 (AVq, J = 8.4 Hz, 2H), 3.85 (s, 3H) 2.46 (s, 3H); 1.33 (s, 9H).

LC-MS (ESI) 479 (M ⁺ ).

SYNTHESIS EXAMPLE 59

Synthesis of 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-chlorobenzoic acid

1) Synthesis of methyl 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-chlorobenzoate

 1- [5- (4-tert-Butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.568 mmol, 154.8 mg) synthesized in synthesis example 3, methyl 2-chloro -4-hydrazinocarbonylbenzoate (0.568 mmol, 130.0 mg) synthesized in Reference Synthesis Example 41, and p-tolylsulfonic acid monohydride (30 mol%, 29.4 mg) were dissolved in isopropyl alcohol (15 ml) and stirred while boiling with reflux for 8 hours and the reactor was cooled to 0 ° C. The reaction solution was filtered and dried using a vacuum pump to obtain the desired product as a white solid (233.7 mg, 85% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.42 (s, 1H), 9.61 (s, 1H), 8.10 (s, 1H), 7.95 (s, 2H), 7.55 (AVq, J = 8.6 Hz, 2H), 7.50 (ABq, J = 8.6 Hz, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 2.45 (s, 3H), 1.33 ( s, 9H).

LC-MS (ESI) 482 (M ⁺ ).

2) Synthesis of 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-chlorobenzoic acid

 K methyl 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-chlorobenzoate (0.465 mmol, 224.8 mg) methanol (20 ml) was added and then a 1 M aqueous solution of sodium hydroxide (2.3 mmol, 2.3 ml) was added. After 5 hours of stirring at 50 ° C, 14 hours of stirring at room temperature, and 4 hours of stirring at 50 ° C, a 1 M solution of hydrochloric acid (2.3 mmol, 2.3 ml) and water were added. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump to obtain the crude desired product as a yellow solid (193.3 mg). Then 169 mg of the crude desired product was dissolved in THF (35 ml) and stirred at room temperature for 2 days. Insoluble matters were filtered off and the filtrate was concentrated and dried using a vacuum pump. After addition of chloroform, the precipitated solid was isolated by filtration and dried using a vacuum pump to obtain the desired product as a pale yellow solid (142.3 mg, 75% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.40 (s, 1H), 9.63 (s, 1H), 8.06 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.55 (AVq, J = 8.4 Hz, 2H), 7.50 (AVq, J = 8.4 Hz, 2H), 3.85 (s, 3H) 2.45 (s, 3H); 1.33 (s, 9H).

LC-MS (ESI) 468 (M ⁺ ).

SYNTHESIS EXAMPLE 60

Synthesis of 2-bromo-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

1) Synthesis of methyl 2-bromo-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate

 1- [5- (4-tert-Butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.554 mmol, 150.9 mg) synthesized in synthesis example 3, methyl 2-bromo -4-hydrazinocarbonyl benzoate (0.554 mmol, 150.8 mg) synthesized in reference synthesis example 42, and p-tolylsulfonic acid monohydride (30 mol%, 28.6 mg) were dissolved in isopropyl alcohol (15 ml) and stirred while boiling with reflux for 8 hours and the reactor was cooled to 0 ° C. The reaction solution was filtered and dried using a vacuum pump to obtain the desired product as a white solid (252.3 mg, 86% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.42 (s, 1H), 9.61 (s, 1H), 8.25 (d, J = 2.7 Hz, 1H), 8.00 (dd, J = 2.7, 8.2 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.55 (AVq, J = 8.4 Hz, 2H), 7.50 (AVq, J = 8.4 Hz, 2H), 3.90 (s, 3H), 3.85 (s, 3H), 2.45 (s, 3H), 1.33 (s, 9H).

LC-MS (ESI) 526 and 528 (M ⁺ ).

2) Synthesis of 2-bromo-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

 K methyl 2-bromo-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoate ( 0.455 mmol, 239.8 mg) methanol (20 ml) was added and then a 1 M aqueous solution of sodium hydroxide (2.3 mmol, 2.3 ml) was added. After 5 hours of stirring at 50 ° C, 14 hours of stirring at room temperature, and 4 hours of stirring at 50 ° C, a 1 M solution of hydrochloric acid (2.3 mmol, 2.3 ml) and water were added. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump to obtain the crude desired product as a yellow solid (203.8 mg). Then 178 mg of the crude desired product was dissolved in THF (35 ml) and stirred at room temperature for 2 days. Insoluble matters were filtered off and the filtrate was concentrated and dried using a vacuum pump. After addition of chloroform, the precipitated solid was isolated by filtration and dried using a vacuum pump to obtain the desired product as a pale yellow solid (150.9 mg, 74% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.39 (s, 1H), 9.63 (s, 1H), 8.21 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.55 (AVq, J = 8.7 Hz, 2H), 7.50 (AVq, J = 8.7 Hz, 2H), 3.85 (s, 3H) 2.45 (s, 3H); 1.33 (s, 9H).

LC-MS (ESI) 512 and 514 (M ⁺ ).

SYNTHESIS EXAMPLE 61

Synthesis of 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-hydroxybenzoic acid

1) Synthesis of methyl 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-hydroxybenzoate

 1- [5- (4-tert-Butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.578 mmol, 157.5 mg) synthesized in synthesis example 3, methyl 4-hydrazinocarbonyl -2-hydroxybenzoate (0.578 mmol, 121.6 mg) synthesized in Reference Example Synthesis 43 and p-tolylsulfonic acid monohydride (30 mol%, 30 mg) were dissolved in isopropyl alcohol (15 ml), stirred at reflux for 8 hours and the reactor was cooled to 0 ° C. The reaction solution was filtered and dried using a vacuum pump to obtain the desired product as a white solid (216.6 mg, 81% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.33 (s, 1H), 10.61 (s, 1H), 9.65 (s, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.56-7, 43 (multi, 6H), 3.92 (s, 3H), 3.85 (s, 3H), 2.45 and 2.44 (cx2, 3H), 1.33 (s, 9H).

LC-MS (ESI) 464 (M ⁺ ).

2) Synthesis of 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-hydroxybenzoic acid

 K methyl 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-hydroxybenzoate (0.438 mmol, 203.3 mg) methanol (20 ml) was added and then a 1 M aqueous solution of sodium hydroxide (2.2 mmol, 2.2 ml) was added. After 5 hours of stirring at 50 ° C, 14 hours of stirring at room temperature and 4 hours of stirring at 50 ° C, a 1 M solution of hydrochloric acid (2.2 mmol, 2.2 ml) and water were added. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump to obtain the crude desired product as a yellow solid (175.0 mg). This material was then dissolved in THF (35 ml) and stirred at room temperature for 2 days. Insoluble matters were filtered off and the filtrate was concentrated and dried using a vacuum pump. After addition of chloroform, the precipitated solid was isolated by filtration and dried using a vacuum pump to obtain the desired product as a pale yellow solid (151.6 mg, 77% yield).

¹ H-NMR (ppm in DMSO- d ₆ )

δ 11.30 (s, 1H), 10.61 (s, 1H), 9.66 (s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.56-7, 38 (multi, 6H), 3.85 (s, 3H), 2.44 (s, 3H), 1.33 (s, 9H).

LC-MS (ESI) 450 (M ⁺ ).

SYNTHESIS EXAMPLE 62

Synthesis of methyl 4 - [(2- {1- [5- (3-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate

 Starting from 2- (3-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene (100 mg, 0.35 mmol) synthesized in Synthesis Reference Example 49, the desired product was obtained in the same manner as in Synthesis Example 36 as a light brown solid (143 mg, 91% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 3.91 (s, 3H), 7.57-7.66 (m, 2H), 7.97-8.20 (m, 7H).

LC / MS (ES ⁺ ) 463.

SYNTHESIS EXAMPLE 63

Synthesis of 4 - [(2- {1- [5- (3-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoic acid

 Starting from methyl 4 - [(2- {1- [5- (3-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate (120 mg, 0.26 mmol) synthesized in the synthesis example 62, the desired product was obtained in the same manner as in Synthesis Example 42, as a pale yellow solid (50 mg, 43% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 7.58-7.68 (m, 2H), 7.97-8.60 (m, 7H).

LC / MS (ES ^- ) 447.

SYNTHESIS EXAMPLE 64

Synthesis of 4 - {[(2- {1- [5- (3-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} benzoic acid

 Starting from 2- (3-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene (50 mg, 0.17 mmol) synthesized in reference synthesis example 49, the desired product was obtained in the same manner as in synthesis example 51, as a light brown solid (38 mg, 47%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 2.41 (s, 3H); 7.57-8.44 (m, 9H).

LC / MS (ES ⁺ ) 480.

SYNTHESIS EXAMPLE 65

Synthesis of methyl 2-acetamino-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate

 To a suspension of 2- (4-tert-butylphenyl) -3-hydroxy-4-methylcarbonylthiophene (54.8 mg, 0.2 mmol) and methyl 2-acetamino-4-hydrazinocarbonylbenzoate (50.2 mg, 0.2 mmol) in isopropyl alcohol (2 ml), tolyl sulfonic acid monohydrate (11.4 mg, 0.06 mmol) was added and the mixture was heated at the boil under reflux for 12 hours. The precipitated solid was filtered to obtain 84 mg of the desired product as a pale yellow solid (yield 83%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.29 (s, 9H), 2.13 (s, 3H), 2.49 (s, 3H), 3.86 (s, 3H), 7.42 (d, 2H, J = 8.4 Hz), 7.68-7.71 (m, 3H), 7.96-7.98 (m, 2H), 8.53 (s, 1H), 10.54 (br s, 1H), 11 48 (br s, 1H); 12.21 (br s, 1H).

LC / MS (ESI) 507 (M ⁺ ).

SYNTHESIS EXAMPLE 66

Synthesis of 2-acetamino-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoic acid

 To a suspension of methyl 2-acetamino-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate (50.8 mg, 0, 1 mmol) in isopropyl alcohol (1.0 ml) was added a 0.2 M aqueous solution of sodium hydroxide (1.1 ml, 0.22 mmol) and the mixture was stirred at room temperature for 6 hours. After stirring was completed, a 1 M hydrochloric acid solution (220 μl) was added and the precipitated solid was filtered and then washed with methanol to obtain 17.5 mg of the desired product as a pale yellow solid (35% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.29 (s, 9H), 2.16 (s, 3H), 2.49 (s, 3H), 7.42 (d, 2H, J = 8.4 Hz), 7.64 (d, 1H, J = 8.1 Hz), 7.70 (d, 2H, J = 8.4 Hz), 7.98 (s, 1H), 8.07 (d, 1H, J = 8.1 Hz) 8.87 (s, 1H); 11.05 (br s, 1H); 11.47 (br s, 1H); 12.22 (br s, 1H).

LC / MS (ESI) 493 (M ⁺ ).

SYNTHESIS EXAMPLE 67

Synthesis of methyl 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] -2-thiophenecarboxylate

 Starting from 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (57.4 mg, 0.2 mmol), methyl 5-hydrazinocarbonyl-2-thiophenecarboxylate (40.0 mg, 0.2 mmol) and tolyl sulfonic acid monohydrate (11.4 mg, 0.06 mmol), 81.2 mg of the desired product was obtained in the same manner as in Synthesis Example 65, as a pale yellow solid (87% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 3.88 (s, 3H), 7.64-7.71 (m, 2H), 7.91 (d, 1H, J = 3.6 Hz), 8.05-8.13 (m, 3H ), 11.57 (br s, 1H).

LC / MS (ESI) 468, 470 (M ⁺ ).

SYNTHESIS EXAMPLE 68

Synthesis of 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] -2-thiophenecarboxylic acid

 Starting from methyl 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] -2-thiophenecarboxylate (56.3 mg, 0.12 mmol) and 0.2 M aqueous sodium hydroxide solution (1.89 ml, 0.38 mmol), 7.5 mg of the desired product were obtained in the same manner as in Synthesis Example 66, as a pale yellow solid (yield 14 %).

¹ H-NMR (ppm in DMSO-d ₆ )

δ = 7.64-7.72 (m, 2H), 7.91 (d, 1H, J = 3.6 Hz), 8.06-8.14 (m, 3H), 11.54 (br. s, 1H).

LC / MS (ESI) 454, 456 (M ⁺ ).

SYNTHESIS EXAMPLE 69

Synthesis of methyl 5 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] -2-thiophenecarboxylate

 Starting from 2- (4-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene (57.3 mg, 0.2 mmol), methyl 5-hydrazinocarbonyl-2-thiophenecarboxylate (40.0 mg, 0.2 mmol) and monohydrate tolylsulfonic acid (11.4 mg, 0.06 mmol), 68.0 mg of the desired product was obtained in the same manner as in Synthesis Example 65, as a pale yellow solid (yield 73%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 3.86 (s, 3H), 7.75 (d, 2H, J = 8.4 Hz), 7.90 (d, 1H, J = 4.2 Hz), 7.98 (d, 2H, J = 8.4 Hz), 8.08 (d, 1H, J = 4.2 Hz), 8.15 (s, 1H), 11.56 (br s, 1H).

LC / MS (ESI) 468 (M ⁺ ).

SYNTHESIS EXAMPLE 70

Synthesis of 5 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] -2-thiophenecarboxylic acid

 To a suspension of methyl 5 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] -2-thiophenecarboxylate (56.2 mg, 0.12 mmol) in tert-butanol (1.2 ml) was added a 0.2 M aqueous solution of sodium hydroxide (1.26 ml, 0.25 mmol) and the mixture was stirred at room temperature for 4 hours. After stirring, a 1 M hydrochloric acid solution (252 μl) was added and the precipitated solid was filtered and washed with methanol to obtain 14.9 mg of the desired product as an orange solid (27% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 7.76 (d, 2H, J = 8.4 Hz), 7.81 (d, 1H, J = 3.9 Hz), 8.00 (d, 2H, J = 8.4 Hz), 8 06 (d, 1H, J = 3.9 Hz), 8.16 (s, 1H), 11.53 (br s, 1H).

LC / MS (ESI) 454 (M ⁺ ).

SYNTHESIS EXAMPLE 71

Synthesis of methyl 2-nitro-4 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate

 Starting from 2- (4-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene (57.3 mg, 0.2 mmol), methyl 4-hydrazinocarbonyl-2-nitrobenzoate (47.8 mg, 0.2 mmol) and monohydrate tolylsulfonic acid (11.4 mg, 0.06 mmol), 81.7 mg of the desired product was obtained in the same manner as in Synthesis Example 65, as a pale yellow solid (81% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ = 3.89 (s, 3H), 7.75 (d, 2H, J = 8.4 Hz), 8.00 (d, 2H, J = 8.4 Hz), 8.04 (d, 1H , J = 7.8 Hz), 8.17 (s, 1H), 8.35 (d, 1H, J = 7.8 Hz), 8.58 (s, 1H), 11.69 (br s , 1H).

LC / MS (ESI) 507 (M ⁺ ).

SYNTHESIS EXAMPLE 72

Synthesis of 2-nitro-4 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoic acid

 Starting from methyl 2-nitro-4 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate (60.9 mg, 0.12 mmol ) and 0.2 M aqueous sodium hydroxide solution (1.26 ml, 0.25 mmol), 38.2 mg of the desired product was obtained in the same manner as in Synthesis Example 70, as a pale yellow solid (yield 65%) )

¹ H-NMR (ppm in DMSO-d ₆ )

δ 7.76 (d, 2H, J = 8.1 Hz), 8.00-8.05 (m, 3H), 8.18 (s, 1H), 8.31 (d, 1H, J = 8 , 1 Hz), 8.52 (s, 1H), 11.68 (br s, 1H).

LC / MS (ESI) 493 (M ⁺ ).

SYNTHESIS EXAMPLE 73

Synthesis of methyl 2-fluoro-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate

 Starting from 2- (4-tert-butylphenyl) -3-hydroxy-4-methylcarbonylthiophene (59.0 mg, 0.215 mmol), methyl 2-fluoro-4-hydrazinocarbonylbenzoate (45.6 mg, 0.215 mmol) and tolyl sulfonic acid monohydrate ( 12.3 mg, 0.0645 mmol), 94.9 mg of the desired product was obtained in the same manner as in Synthesis Example 65, as a pale yellow solid (yield 94%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.29 (s, 9H), 3.91 (s, 3H), 7.43 (d, 2H, J = 8.4 Hz), 7.71 (d, 2H, J = 8.4 Hz) 7.85-7.94 (m, 2H), 8.01-8.08 (m, 2H), 11.50 (br s, 1H), 12.17 (br s, 1H).

LC / MS (ESI) 468 (M ⁺ ).

SYNTHESIS EXAMPLE 74

Synthesis of 2-fluoro-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoic acid

 Starting from methyl 2-fluoro-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate (56.2 mg, 0, 12 mmol) and 0.2 M aqueous sodium hydroxide solution (1.26 ml, 0.25 mmol), 46.3 mg of the desired product was obtained in the same manner as in Synthesis Example 70, as a pale yellow solid (yield 85%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.29 (s, 9H), 7.43 (d, 2H, J = 8.4 Hz), 7.71 (d, 2H, J = 8.4 Hz), 7.83-7.94 ( m, 2H), 7.99-8.04 (m, 2H), 11.48 (br s, 1H), 12.18 (br s, 1H).

LC / MS (ESI) 452 (M ⁺ ).

SYNTHESIS EXAMPLE 75

Synthesis of methyl 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] (isopropyl) methylene} hydrazino) carbonyl] benzoate

 A suspension of 2- (4-tert-butylphenyl) -3-hydroxy-4-isopropylcarbonylthiophene (100 mg, 0.33 mmol), 4-hydrazinocarbonylmethylbenzoate (70 mg, 0.36 mmol) and p-tolylsulfonic acid monohydrate in isopropyl alcohol was dehydrated at reflux for 2 days. After completion of the reaction, the reaction solution was cooled to room temperature and filtered to obtain the desired product as a yellow solid (92 mg, 58% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.30 (s, 9H), 1.38 (s, 3H), 1.41 (s, 3H), 3.91 (s, 3H), 7.43 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 8.02-8.13 (m, 5H).

LC / MS (ES ⁺ ) 479.

SYNTHESIS EXAMPLE 76

Synthesis of 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] (isopropyl) methylene} hydrazino) carbonyl] benzoic acid

 Using methyl 4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] (isopropyl) methylene} hydrazino) carbonyl] benzoate (80 mg, 0.17 mmol) in as the starting material, the desired product was obtained in the same manner as in Synthesis Example 70, as a pale yellow solid (19 mg, 24% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.30 (s, 9H), 1.39-1.41 (m, 6H), 7.42-7.44 (m, 2H), 7.70-7.73 (m, 2H), 8 00-8.10 (m, 6H).

LC / MS (ES ⁺ ) 465.

SYNTHESIS EXAMPLE 77

Synthesis of methyl 2-nitro-4 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate

 Using 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (100 mg, 0.35 mmol) and methyl 2-nitro-4-hydrazinocarbonylbenzoate (93 mg, 0.39 mmol) as starting materials, the desired product was obtained in the same manner as in Synthesis Example 65, as a yellow solid (147 mg, 83% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 3.91 (s, 3H), 7.55-7.75 (m, 2H), 8.05-8.20 (m, 3H), 8.30-8.40 (m, 1H), 8 50-8.65 (m, 1H).

LC / MS (ES ^- ) 507.

SYNTHESIS EXAMPLE 78

Synthesis of 2-nitro-4 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoic acid

 Using methyl 2-nitro-4 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate (137 mg, 0.27 mmol) as the starting material, the desired product was obtained in the same manner as in Synthesis Example 66, as a yellow solid (68 mg, 51% yield).

LC / MS (ES ⁺ ) 494, 495.

SYNTHESIS EXAMPLE 79

Synthesis of methyl 2-bromo-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate

 Using 2- (4-tert-butylphenyl) -3-hydroxy-4-methylcarbonylthiophene (55 mg, 0.20 mmol) and methyl 2-bromo-4-hydrazinocarbonylbenzoate (60 mg, 0.22 mmol) as starting materials, the desired product was obtained in the same manner as in Synthesis Example 65, as a yellow solid (92 mg, 87% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.30 (s, 9H), 3.91 (s, 3H), 7.43 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H) 7.91 (d, J = 8.0 Hz, 1H); 8.01-8.03 (m, 2H); 8.27 (s, 1H).

LC / MS (ES ^- ) 528.

SYNTHESIS EXAMPLE 80

Synthesis of 2-bromo-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoic acid

 Using methyl 2-bromo-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate (82 mg, 0.15 mmol) as the starting material, the desired product was obtained in the same manner as in Synthesis Example 66, as a yellow solid (67 mg, 87% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.31 (s, 9H), 7.43 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.87-7.89 ( m, 1H), 7.97-8.01 (m, 2H), 8.24 (s, 1H).

LC / MS (ES ⁺ ) 517, 519.

SYNTHESIS EXAMPLE 81

Synthesis of methyl 2-chloro-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate

 Using 2- (4-tert-butylphenyl) -3-hydroxy-4-methylcarbonylthiophene (55 mg, 0.20 mmol) and methyl 2-chloro-4-hydrazinocarbonylbenzoate (50 mg, 0.22 mmol) as starting materials, the desired product was obtained in the same manner as in Synthesis Example 65, as a pale yellow solid (86 mg, 89% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.30 (s, 9H), 3.91 (s, 3H), 7.43 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H) 7.97-8.01 (m, 3H); 8.12 (s, 1H).

LC / MS (ES ^- ) 483, 485.

SYNTHESIS EXAMPLE 82

Synthesis of 2-chloro-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoic acid

 Using methyl 2-chloro-4 - [(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate (76 mg, 0.16 mmol) as the starting material, the desired product was obtained in the same manner as in Synthesis Example 66, as a pale yellow solid (60 mg, 80% yield).

LC / MS (ES ⁺ ) 471, 473.

SYNTHESIS EXAMPLE 83

Synthesis of methyl 4 - [(2- {1- [2-bromo-5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonyl] benzoate

 To a suspension of 2-bromo-5- (4-tert-butylphenyl) -4-hydroxy-3-methylcarbonylthiophene (1.00 g, 2.83 mmol) synthesized in reference synthesis example 55, and 4-hydrazinocarbonylmethyl benzoate (550 mg, 2.83 mmol) in isopropyl alcohol (28.3 ml), tolyl sulfonic acid monohydrate (146 mg, 0.85 mmol) was added and the mixture was heated under reflux for about 1 hour. The reaction solution was concentrated and then purified by silica gel column chromatography (chloroform and then chloroform / ethyl acetate = 95/5) to obtain the desired product as a yellow solid (935 mg, 62% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 1.29 (s, 9H), 2.61 (s, 3H), 3.91 (s, 3H), 7.44 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 8.06-8.14 (m, 4H), 11.69 (s, 1H), 12.29 (s, 1H).

LC / MS (ES ⁺ ) 529, 531.

SYNTHESIS EXAMPLE 84

Synthesis of methyl 4 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-nitrobenzoate

 Starting from 1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (0.70 mmol, 200 mg) synthesized in synthesis example 1, methyl 2 nitro-4-hydrazinocarbonylbenzoate (0.70 mmol, 167.8 mg) of Reference Example Synthesis 40 and tolyl sulfonic acid monohydrate (36.2 mg, 0.21 mmol), 311.1 mg of the desired product was obtained in the same manner as in Example synthesis 58, as a yellow solid (88% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.61 (s, 1H), 9.85 (s, 1H), 8.58 (d, J = 1.4 Hz, 1H), 8.34 (dd, J = 1.4, 8.0 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 1.9 Hz, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.61 (dd, J = 1.9, 8.4 Hz, 1H), 3.90 (s, 6H), 2.46 (s, 3H).

LC-MS (ESI) 505 (M ⁺ ).

SYNTHESIS EXAMPLE 85

Synthesis of 4 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-nitrobenzoic acid

 Starting from methyl 4 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-nitrobenzoate ( 0.40 mmol, 200 mg) and 1 M aqueous sodium hydroxide solution (1.98 ml, 1.98 mmol), 130.5 mg of the desired product were obtained in the same manner as in Synthesis Example 58, as a yellow solid ( yield 67%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.58 (s, 1H), 9.86 (s, 1H), 8.50 (s, 1H), 8.27-8.32 (m, 1H), 8.01 (d, J = 8 , 0 Hz, 1H), 7.85-7.86 (m, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.60-7.62 (m, 1H), 3 90 (s, 3H); 2.46 (s, 3H).

LC-MS (ESI) 491 (M ⁺ ).

SYNTHESIS EXAMPLE 86

Synthesis of methyl 4 - {[2- (1- [4-hydroxy-1-methyl-5- [4- (trifluoromethyl) phenyl] -1H-pyrazol-3-yl] ethylidene) hydrazino] carbonyl} -2-nitrobenzoate

 Starting from 1- [4-hydroxy-1-methyl-5- (4-trifluoromethylphenyl) -1H-pyrazol-3-yl] ethanone (0.70 mmol, 200 mg) synthesized in synthesis example 11, methyl 2-nitro -4-hydrazinocarbonyl benzoate (0.70 mmol, 168.3 mg) of Reference Example Synthesis 40 and tolyl sulfonic acid monohydrate (36.4 mg, 0.21 mmol), 214.7 mg of the desired product was obtained in the same manner as in Synthesis Example 58 , in the form of a yellow solid (yield 60%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.62 (s, 1H), 9.88 (s, 1H), 8.58 (d, J = 1.5 Hz, 1H), 8.35 (dd, J = 1.5, 8.0 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.90 (AVq, J = 8.7 Hz, 2H), 7.84 (AVq, J = 8.7 Hz, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 2.48 (s, 3H).

LC-MS (ESI) 505 (M ⁺ ).

SYNTHESIS EXAMPLE 87

Synthesis of 4 - {[2- (1- {4-hydroxy-1-methyl-5- [4- (trifluoromethyl) phenyl] -1H-pyrazol-3-yl} ethylidene) hydrazino] carbonyl} -2-nitrobenzoic acid

 Starting from methyl 4 - {[2- (1- {4-hydroxy-1-methyl-5- [4- (trifluoromethyl) phenyl] -1H-pyrazol-3-yl} ethylidene) hydrazino] carbonyl} -2-nitrobenzoate (0.30 mmol, 150 mg) and 1 M aqueous sodium hydroxide solution (1.48 ml, 1.48 mmol), 106.0 mg of the desired product was obtained in the same manner as in Synthesis Example 58, as a pale yellow solid (yield 73%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.59 (s, 1H), 9.88 (s, 1H), 8.50 (s, 1H), 8.28-8.31 (m, 1H), 8.02 (d, J = 8 , 0 Hz, 1H), 7.90 (ABq, J = 8.7 Hz, 2H), 7.84 (ABq, J = 8.7 Hz, 2H), 3.93 (s, 3H), 2, 47 (s, 3H).

LC-MS (ESI) 491 (M ⁺ ).

SYNTHESIS EXAMPLE 88

Synthesis of methyl 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-thiophenecarboxylate

 Starting from 1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (200 mg, 0.70 mmol) synthesized in Synthesis Example 1, methyl 5 -hydrazinocarbonyl-2-thiophenecarboxylate (0.70 mmol, 140.4 mg) of Reference Example Synthesis 39 and tolyl sulfonic acid monohydrate (36.2 mg, 0.21 mmol), 314.1 mg of the desired product was obtained in the same manner as in Example synthesis 58, as a yellow solid (yield 96%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.47 (s, 1H), 9.76 (s, 1H), 8.04-8.07 (m, 1H), 7.79-7.91 (m, 3H), 7.56-7 61 (s, 1H); 3.87 (s, 6H); 2.46 (s, 3H).

LC-MS (ESI) 466 (M ⁺ ).

SYNTHESIS EXAMPLE 89

Synthesis of 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-thiophenecarboxylic acid

 Starting from methyl 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-thiophenecarboxylate ( 200 mg, 0.43 mmol) and 1 M aqueous sodium hydroxide solution (2.13 ml, 2.13 mmol), 153.3 mg of the desired product was obtained in the same manner as in Synthesis Example 58, as a yellow solid ( yield 84%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.43 (s, 1H), 9.78 (s, 1H), 8.03-8.32 (m, 1H), 7.79-7.85 (m, 3H), 7.58-7 61 (m, 1H); 3.89 (s, 3H); 2.46 (s, 3H).

LC-MS (ESI) 452 (M ⁺ ).

SYNTHESIS EXAMPLE 90

Synthesis of methyl 5 - {[2- (1- {4-hydroxy-1-methyl-5- [4- (trifluoromethyl) phenyl] -1H-pyrazol-3-yl} ethylidene) hydrazino] carbonyl} -2-thiophenecarboxylate

 Starting from 1- [4-hydroxy-1-methyl-5- (4-trifluoromethylphenyl) -1H-pyrazol-3-yl] ethanone (200 mg, 0.70 mmol) synthesized in Synthesis Example 11, methyl 5-hydrazinocarbonyl -2-thiophenecarboxylate (0.70 mmol, 140.9 mg) of Reference Example Synthesis 39 and tolyl sulfonic acid monohydrate (36.4 mg, 0.21 mmol), 188.2 mg of the desired product was obtained in the same manner as in Synthesis Example 58 , as a pale yellow solid (yield 57%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.48 (s, 1H), 9.78 (s, 1H), 8.06-8.08 (m, 1H), 7.82-7.91 (m, 5H), 3.92 (s , 3H); 3.87 (s, 3H); 2.47 (s, 3H).

LC-MS (ESI) 466 (M ⁺ ).

SYNTHESIS EXAMPLE 91

Synthesis of 5 - {[2- (1- {4-hydroxy-1-methyl-5- [4- (trifluoromethyl) phenyl] -1H-pyrazol-3-yl} ethylidene) hydrazino] carbonyl} -2-thiophenecarboxylic acid

 Starting from methyl 5 - {[2- (1- {4-hydroxy-1-methyl-5- [4- (trifluoromethyl) phenyl] -1H-pyrazol-3-yl} ethylidene) hydrazino] -carbonyl} -2- thiophenecarboxylate (150 mg, 0.32 mmol) and 1 M aqueous sodium hydroxide solution (1.60 ml, 1.60 mmol), 89.0 mg of the desired product was obtained in the same manner as in Synthesis Example 58, as a pale yellow solid (yield 61%).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.44 (s, 1H), 9.80 (s, 1H), 8.03-8.04 (m, 1H), 7.80-7.91 (m, 5H), 3.92 (s , 3H); 2.47 (s, 3H).

LC-MS (ESI) 452 (M ⁺ ).

SYNTHESIS EXAMPLE 92

Synthesis of methyl 4 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoate

 Dimethylformamide (1.3 ml) and concentrated hydrochloric acid (1 drop) were added to 2- (4-tert-butylphenyl) -3-hydroxy-4-methylcarbonylthiophene (71 mg, 0.26 mmol) synthesized in Reference Synthesis Example 33 and methyl 4-hydrazinocarbonothioylamino-2-nitrobenzoate (70 mg, 0.26 mmol) synthesized in Synthesis Reference Example 56, and the mixture was stirred at room temperature for 2 days. The precipitated solid was filtered to give 110 mg of the desired product as a pale yellow solid (81% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.29 (br s, 1H), 10.67 (br s, 1H), 8.57 (br s, 1H), 7.87-8.03 (m, 3H), 7.67 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 3.83 (s, 3H), 2.40 (s, 3H), 1.28 (s, 9H).

LC / MS (ESI) 526.

SYNTHESIS EXAMPLE 93

Synthesis of 4 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoic acid

 Methyl 4 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoate (95 mg, 0.18 mmol ), synthesized in synthesis example 92, was dissolved in isopropyl alcohol (1.8 ml) and a 0.2 M aqueous solution of sodium hydroxide (2.0 ml, 0.40 mmol) was added to the mixture, followed by stirring overnight at room temperature . Upon completion of stirring, a 1 M solution of hydrochloric acid (0.40 ml, 0.40 mmol) was added to the mixture, and water and the precipitated solid were filtered to obtain 57 mg of the desired product as a pale yellow solid (61% yield).

¹ H-NMR (ppm in DMSO-d ₆ )

δ 11.29 (br s, 1H), 10.64 (br s, 1H), 8.50 (br s, 1H), 7.87-8.00 (m, 3H), 7.69 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 2.41 (s, 3H), 1.29 (s, 9H).

LC / MS (ESI) 512.

SYNTHESIS EXAMPLE 94

Synthesis of methyl 4 - {[(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoate

Starting from 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (60 mg, 0.21 mmol) synthesized in Reference Synthesis Example 34, the desired product was obtained in the same manner as in Synthesis Example 92, in as a yellow solid (88 mg, 78% yield).

¹ H-NMR (ppm in DMSO)

δ 11.35 (br s, 1H), 10.70 (br s, 1H), 8.57 (br s, 1H), 8.14 (s, 1H), 8.01-8.04 (m, 2H), 7.89-7.91 (m, 1H), 7.65-7.74 (m, 2H), 3.84 (s, 3H), 2.42 (s, 3H).

LC / MS (ESI) 538.

SYNTHESIS EXAMPLE 95

Synthesis of 4 - {[(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoic acid

Starting from methyl 4 - {[(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoate (70 mg, 0, 13 mmol) synthesized in synthesis example 94, the desired product was obtained in the same manner as in synthesis example 93, as a pale yellow solid (43 mg, 63% yield).

¹ H-NMR (ppm in DMSO)

δ 11.32 (br s, 1H), 10.66 (br s, 1H), 8.48 (br s, 1H), 8.13 (s, 1H), 7.87-8.02 (m, 3H); 7.64-7.74 (m, 2H); 2.41 (s, 3H).

LC / MS (ESI) 524.

SYNTHESIS EXAMPLE 96

Synthesis of methyl 4 - {[(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoate

Starting from 2- (4-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene (60 mg, 0.21 mmol) synthesized in Synthesis Reference Example 35, the desired product was obtained in the same manner as in Synthesis Example 92 as yellow solid (103 mg, 91% yield).

¹ H-NMR (ppm in DMSO)

δ 11.36 (br s, 1H), 10.72 (br s, 1H), 8.58 (br s, 1H), 8.17 (s, 1H), 7.89-8.04 (m, 4H), 7.76 (d, J = 8.3 Hz, 2H), 3.84 (s, 3H), 2.43 (s, 3H).

LC / MS (ESI) 538.

SYNTHESIS EXAMPLE 97

Synthesis of 4 - {[(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoic acid

Starting from methyl 4 - {[(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoate (90 mg, 0.17 mmol ) synthesized in synthesis example 96, the desired product was obtained in the same manner as in synthesis example 93, as a pale yellow solid (69 mg, 79% yield).

¹ H-NMR (ppm in DMSO)

δ 11.34 (br s, 1H), 10.65-10.67 (m, 1H), 8.49 (br s, 1H), 8.16 (s, 1H), 7.88-8 01 (m, 4H), 7.76 (d, J = 8.5 Hz, 2H), 2.43 (s, 3H).

LC / MS (ESI) 524.

SYNTHESIS EXAMPLE 98

Synthesis of methyl 5 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-thiophenecarboxylate

Dimethylformamide (1.3 ml) and concentrated hydrochloric acid (1 drop) were added to 2- (4-tert-butylphenyl) -3-hydroxy-4-methylcarbonylthiophene (70 mg, 0.26 mmol) synthesized in Reference Synthesis Example 33 and methyl 5-hydrazinocarbonothioylamino-2-thiophenecarboxylate (59 mg, 0.26 mmol) synthesized in Synthesis Reference Example 57, and the mixture was stirred overnight at room temperature. Water was added and the precipitated solid was filtered. The resulting solid was extracted with chloroform, dried over anhydrous sodium sulfate. The organic layer was concentrated and purified by silica gel column chromatography (chloroform / methanol = 95/5) to obtain the desired product as a pale yellow solid (112 mg, 90% yield).

¹ H-NMR (ppm in DMSO)

δ 11.63 (br s, 1H), 11.18 (br s, 1H), 8.01 (br s, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 4.4 Hz, 1H), 7.46 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 4.4 Hz, 1H), 3, 82 (s, 3H); 2.41 (s, 3H); 1.32 (s, 9H).

LC / MS (ESI) 487.

SYNTHESIS EXAMPLE 99

Synthesis of 5 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-thiophenecarboxylic acid

Methyl 5 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-thiophenecarboxylate (85 mg, 0.18 mmol ), synthesized in Synthesis Example 98, was dissolved in isopropyl alcohol (1.8 ml) and a 0.2 M aqueous solution of sodium hydroxide (1.95 ml, 0.39 mmol) was added to the mixture, followed by stirring overnight at room temperature . Then, a 0.2 M aqueous solution of sodium hydroxide (0.96 ml, 0.19 mmol) was added to the mixture, followed by stirring overnight at 45 ° C. After stirring, a 1 M hydrochloric acid solution (0.58 ml, 0.58 mmol) was added. The precipitated solid was filtered to obtain 2.7 mg of the desired product as a pale yellow solid (3% yield).

LC / MS (ESI) 473.

SYNTHESIS EXAMPLE 100

Synthesis of methyl 4 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-chlorobenzoate

Starting from 2- (4-tert-butylphenyl) -3-hydroxy-4-methylcarbonylthiophene (60 mg, 0.22 mmol) synthesized in Synthesis Reference Example 33, the desired product was obtained in the same manner as in Synthesis Example 92, in as a yellow solid (118 mg, 100% yield).

¹ H-NMR (ppm in DMSO)

δ 11.21 (br s, 1H), 10.50 (br s, 1H), 8.21 (br s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.68-7.71 (m, 3H), 7.43 (d, J = 8.3 Hz, 2H), 3.85 (s , 3H); 2.40 (s, 3H); 1.29 (s, 9H).

LC / MS (ESI) 515.

SYNTHESIS EXAMPLE 101

Synthesis of 4 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-chlorobenzoic acid

Methyl 4 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-chlorobenzoate (100 mg, 0.19 mmol ), synthesized in synthesis example 100, was dissolved in isopropyl alcohol (1.9 ml), and 0.2 M aqueous sodium hydroxide solution (2.1 ml, 0.42 mmol) was added to the mixture, followed by stirring overnight at room temperature , then at 45 ° C for 1 day. Then, a 0.2 M aqueous sodium hydroxide solution (1.1 ml, 0.22 mmol) was added to the mixture, followed by stirring at 45 ° C. for 5.5 hours. After stirring, a 1 M hydrochloric acid solution (0.64 ml, 0.64 mmol) was added. The precipitated solid was filtered and purified on silica gel plates (chloroform / methanol = 9/1) to obtain the desired product as a yellow solid (24 mg, 25% yield).

¹ H-NMR (ppm in DMSO)

δ 10.48 (br s, 1H), 8.18 (br s, 1H), 7.84-7.94 (m, 2H), 7.65-7.68 (m, 3H), 7 40-7.43 (m, 2H); 2.41 (s, 3H); 1.29 (s, 9H).

LC / MS (ESI) 501.

SYNTHESIS EXAMPLE 102

Synthesis of methyl 4 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2- nitrobenzoate

Starting from 1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (63 mg, 0.23 mmol) synthesized in synthesis example 3, the desired product obtained in the same manner as in synthesis example 92, as a yellow solid (121 mg, 100% yield).

¹ H-NMR (ppm in DMSO)

δ 10.53 (br s, 1H), 8.60-8.61 (m, 1H), 7.87-8.06 (m, 2H), 7.47-7.60 (m, 4H) 3.84 (s, 3H); 3.82 (s, 3H); 2.41 (s, 3H); 1.33 (s, 9H).

LC / MS (ESI) 524.

SYNTHESIS EXAMPLE 103

Synthesis of 4 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoic acid

Methyl 4 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoate (100 mg, 0.19 mmol) synthesized in synthesis example 102 was dissolved in methanol (6.7 ml) and a 1 M aqueous solution of sodium hydroxide (0.96 ml, 0.96 mmol) was added to the mixture, followed by stirring in overnight at room temperature. After stirring, the reaction solution was washed with ethyl acetate, and a 1 M solution of hydrochloric acid was added to the aqueous layer. The precipitated solid was filtered to obtain 27 mg of the desired product as a pale yellow solid (28% yield).

¹ H-NMR (ppm in DMSO)

δ 11.10 (br s, 1H), 10.50 (br s, 1H), 8.49 (br s, 1H), 7.86-7.97 (m, 2H), 7.47 -7.59 (m, 4H), 3.82-3.83 (m, 3H), 2.41 (s, 3H), 1.33-1.34 (m, 9H).

LC / MS (ESI) 510.

SYNTHESIS EXAMPLE 104

Synthesis of methyl 4 - {[(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2- nitrobenzoate

Dimethylformamide (1 ml) and concentrated hydrochloric acid (1 drop) were added to 1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (60 mg, 0 , 21 mmol) synthesized in Synthesis Example 1 and methyl 4-hydrazinocarbonothioylamino-2-nitrobenzoate (57 mg, 0.21 mmol) synthesized in Reference Synthesis Example 56, and the mixture was stirred at room temperature for 21 hours. Water was added and the precipitated solid was filtered, purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/1, then chloroform / methanol = 95/5). The resulting solid was extracted with ethyl acetate, washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium chloride. The organic layer was concentrated to give the desired product as a pale yellow solid (104 mg, 92% yield).

¹ H-NMR (ppm in DMSO)

δ 8.57 (br s, 1H), 8.03-8.05 (m, 1H), 7.78-7.90 (m, 3H), 7.56-7.59 (m, 1H) 3.86 (s, 3H); 3.84 (s, 3H); 2.41 (s, 3H).

LC / MS (ESI) 536.

SYNTHESIS EXAMPLE 105

Synthesis of 4 - {[(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoic acid

Methyl 4 - {[(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoate (100 mg, 0.19 mmol) synthesized in Synthesis Example 104 was dissolved in methanol (3 ml) and a 1 M aqueous solution of sodium hydroxide (0.74 ml, 0.74 mmol) was added to the mixture, followed by stirring overnight at room temperature. After stirring, a 1 M solution of hydrochloric acid (0.74 ml, 0.74 mmol) and water were added to the mixture. The precipitated solid was isolated by filtration, washed with water, isopropyl alcohol and chloroform. The resulting solid was stirred in chloroform and then filtered to obtain 37 mg of the desired product as a yellow solid (48% yield).

¹ H-NMR (ppm in DMSO)

δ 8.47 (br s, 1H), 7.77-7.93 (m, 4H), 7.56-7.59 (m, 1H), 3.86 (s, 3H), 2.42 (s, 3H).

LC / MS (ESI) 522.

SYNTHESIS EXAMPLE 106

Synthesis of 4 - {[(2- {1- [5- (4-chlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoic acid

Starting from 1- [5- (4-chlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone synthesized in the same manner as in Synthesis Example 1, the desired product was obtained in the same manner as in synthesis examples 102 and 103, as a yellow solid (22.6 mg).

¹ H-NMR (ppm in DMSO)

δ 8.48 (br s, 1H), 7.50-8.00 (m, 6H), 3.88 (s, 3H), 2.42 (s, 3H).

LC / MS (ESI) 488.

SYNTHESIS EXAMPLE 107

Synthesis of 4 - [(2- {1- [5- (4-chlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-nitrobenzoic acid

Starting from 1- [5- (4-chlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone synthesized in the same manner as in Synthesis Example 1, the desired product was obtained in the same manner as in Synthesis Example 58, as a pale yellow solid (19.1 mg).

¹ H-NMR (ppm in DMSO)

δ 11.5 (1H, s), 9.73 (1H, s), 8.49 (1H, s), 8.28 (1H, d, J = 8 Hz), 8.01 (1H, d, J = 8 Hz), 7.65-7.55 (4H, m), 3.87 (3H, s), 2.46 (3H, s).

LC / MS (ESI) 457.

SYNTHESIS EXAMPLE 108

Synthesis of 5 - [(2- {1- [5- (4-chlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] -2-thiophenecarboxylic acid

Starting from 1- [5- (4-chlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone synthesized in the same manner as in Synthesis Example 1, the desired product was obtained in the same manner as in synthesis examples 33 and 34, as a yellow solid (20.2 mg).

¹ H-NMR (ppm in DMSO)

δ 11.4 (1H, s), 9.64 (1H, s), 8.02 (1H, d, J = 3 Hz), 7.80 (1H, d, J = 3 Hz), 7.5 -7.7 (4H, m), 3.86 (3H, s), 2.45 (3H, s).

LC / MS (ESI) 418.

SYNTHESIS EXAMPLE 109

Synthesis of 4 - [(2- {1- [5- (4-chlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonyl] benzoic acid

Starting from 1- [5- (4-chlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone synthesized in the same manner as in Synthesis Example 1, the desired product was obtained in the same manner as in synthesis example 3, as a yellow solid (47.4 mg).

¹ H-NMR (ppm in DMSO)

δ 11.4 (1H, s), 9.83 (1H, s), 7.90-8.20 (4H, m), 7.50-7.70 (4H, m), 3.86 (3H s) 2.45 (3H, s).

LC / MS (ESI) 412.

SYNTHESIS EXAMPLE 110

Synthesis of 4 - {[(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoic acid

Starting from methyl 4 - {[(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoate (70 mg, 0.13 mmol), the desired product was obtained in the same manner as in Synthesis Examples 104 and 105, as a yellow solid (42 mg, yield 62%).

¹ H-NMR (ppm in DMSO)

δ 8.48 (br s, 1H), 7.80-8.00 (m, 6H), 3.88 (s, 3H), 2.42 (s, 3H).

LC / MS (ESI) 522.

SYNTHESIS EXAMPLE 111

Synthesis of 4 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2-chlorobenzoic acid

Starting from methyl 4 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2 -chlorobenzoate (82 mg, 0.16 mmol), the desired product was obtained in the same manner as in synthesis examples 104 and 105, as a brown solid (40 mg, 50% yield).

¹ H-NMR (ppm in DMSO)

δ 8.12-8.26 (m, 1H), 7.50-7.81 (m, 6H), 3.82 (s, 3H), 2.41 (s, 3H), 1.32 (s , 9H).

LC / MS (ESI) 499.

SYNTHESIS EXAMPLE 112

Synthesis of 4 - {[(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2-chlorobenzoic acid

Starting from methyl 4 - {[(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2 -chlorobenzoate (105 mg, 0.20 mmol), the desired product was obtained in the same manner as in synthesis examples 104 and 105, as a pale yellow solid (54 mg, yield 52%).

¹ H-NMR (ppm in DMSO)

δ 8.09 (br s, 1H), 7.77-7.85 (m, 3H), 7.65-7.68 (m, 1H), 7.55-7.58 (m, 1H) 3.84 (s, 3H); 2.39 (s, 3H).

LC / MS (ESI) 511.

SYNTHESIS EXAMPLE 113

Synthesis of 4 - {[(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2-chlorobenzoic acid

Starting from methyl 4 - {[(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) -carbonothioyl] amino} -2- chlorobenzoate (60 mg, 0.11 mmol), the desired product was obtained in the same manner as in synthesis examples 104 and 105, as a pale yellow solid (25 mg, 42% yield).

¹ H-NMR (ppm in DMSO)

δ 8.11 (br s, 1H), 7.80-7.94 (m, 5H), 7.67-7.70 (m, 1H), 3.88 (s, 3H), 2.41 (s, 3H).

LC / MS (ESI) 511.

SYNTHESIS EXAMPLE 114

Synthesis of 5 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2-thiophenecarboxylic acid

1) Synthesis of 5-hydrazinocarbonothioylamino-2-thiophenecarboxylic acid

 To methyl 5-hydrazinocarbonothioylamino-2-thiophenecarboxylate (1.21 mmol, 280 mg) obtained in Synthesis Reference Example 57, methanol (2.4 ml) was added and a 0.2 M aqueous solution of sodium hydroxide (3 eq.) Was added at room temperature. ., 18.2 ml). After stirring for 1.5 hours at 60 ° C, the reactor was cooled to room temperature and a 1 M hydrochloric acid solution (3 eq, 3.63 ml) was added. The precipitated solid was isolated by filtration, washed with water and chloroform, and dried using a vacuum pump. The desired product was obtained as a pale yellow solid (230 mg, 87.6% yield (purity according to LC 90%)).

¹ H-NMR (ppm in DMSO)

δ 9.56 (br s, 1H), 7.47 (d, J = 4.1 Hz, 1H), 7.07 (br s, 1H), 6.91 (br s, 1H).

LC / MS (ESI) 217.

2) Synthesis of 5 - {[(2- {1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) -carbonothioyl] amino} - 2-thiophenecarboxylic acid

 Starting from 1- [5- (4-tert-butylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (40.0 mg, 0.15 mmol) and 5-hydrazinocarbonothioylamino-2- thiophenecarboxylic acid (35.5 mg, 0.15 mmol), the desired product was obtained in the same manner as in Synthesis Example 2, as a yellow solid (57.3 mg, 83% yield).

¹ H-NMR (ppm in DMSO)

δ 7.47-7.56 (m, 5H), 6.90 (br s, 1H), 3.82 (s, 3H), 2.39 (s, 3H), 1.34 (s, 9H )

LC / MS (ESI) 471.

SYNTHESIS EXAMPLE 115

Synthesis of 5 - {[(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2-thiophenecarboxylic acid

 Starting from 1- [5- (3,4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (40.0 mg, 0.14 mmol) and 5-hydrazinocarbonothioylamino-2- thiophenecarboxylic acid (33.9 mg, 0.14 mmol), the desired product was obtained in the same manner as in Synthesis Example 114, as a pale yellow solid (62.2 mg, yield 92%).

¹ H-NMR (ppm in DMSO)

δ 7.84 (d, J = 1.7 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.54-7.60 (m, 2H), 6.90 ( broad s, 1H), 3.86 (s, 3H), 2.39 (s, 3H).

LC / MS (ESI) 483.

SYNTHESIS EXAMPLE 116

Synthesis of 5 - {[(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2-thiophenecarboxylic acid

 Starting from 1- [5- (4-trifluoromethylphenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (40.0 mg, 0.14 mmol) and 5-hydrazinocarbonothioylamino-2-thiophenecarboxylic acid (34.0 mg, 0.14 mmol), the desired product was obtained in the same manner as in Synthesis Example 114, as a pale yellow solid (55.8 mg, 82% yield).

¹ H-NMR (ppm in DMSO)

δ 7.81-7.91 (m, 4H), 7.55 (d, J = 4.1 Hz, 1H), 6.90 (br s, 1H), 3.89 (s, 3H), 2.40 (s, 3H).

LC / MS (ESI) 483.

SYNTHESIS EXAMPLE 117

Synthesis of 5 - {[(2- {1- [5- (4-chlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2-thiophenecarboxylic acid

 Starting from 1- [5- (4-chlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (37.5 mg, 0.15 mmol) and 5-hydrazinocarbonothioylamino-2-thiophenecarboxylic acid (33 mg, 0.14 mmol), the desired product was obtained in the same manner as in Synthesis Example 114, as a pale yellow solid (62.0 mg, 83% yield).

¹ H-NMR (ppm in DMSO)

δ 7.45-7.56 (m, 5H), 6.94 (br s, 1H), 3.87 (s, 3H), 2.43 (s, 3H).

LC / MS (ESI) 449.

SYNTHESIS EXAMPLE 118

Synthesis of 4 - {[(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-chlorobenzoic acid

1) Synthesis of 4-hydrazinocarbonothioylamino-2-chlorobenzoic acid

 To methyl 4-hydrazinocarbonothioylamino-2-chlorobenzoate (1.16 mmol, 300 mg) obtained in Reference Example Synthesis 58, methanol (2.3 ml) was added and a 0.2 M aqueous solution of sodium hydroxide was added at room temperature (2, 1 eq., 12.1 ml). After stirring for 1.5 hours at 60 ° C, the reactor was cooled to room temperature and a 1 M hydrochloric acid solution (2.1 eq, 2.43 ml) was added. The precipitated solid was isolated by filtration, washed with water and dried using a vacuum pump. 4-Hydrazinocarbonothioylamino-2-chlorobenzoic acid was obtained as a colorless solid (262.8 mg, yield 92.6%).

¹ H-NMR (ppm in DMSO)

δ 9.48 (br s, 1H), 8.22 (br s, 1H), 7.75-7.77 (m, 3H).

LC / MS (ESI) 245.

2) Synthesis of 4 - {[(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-chlorobenzoic acid

 Based on 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (50 mg, 0.17 mmol) and 4-hydrazinocarbonothioylamino-2-chlorobenzoic acid (42.8 mg, 0.17 mmol), desired the product was obtained in the same manner as in Synthesis Example 50, as a pale yellow solid (61.1 mg, 68% yield).

¹ H-NMR (ppm in DMSO)

δ 11.20 (br s, 1H), 10.46 (br s, 1H), 8.14 (br s, 1H), 8.11 (s, 1H), 8.02 (d, J = 1.9 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.64-7.74 (m, 3H), 2.40 (s, 3H).

LC / MS (ESI) 513.

SYNTHESIS EXAMPLE 119

Synthesis of 4 - {[(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-chlorobenzoic acid

 Starting from 2- (4-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene (50.0 mg, 0.17 mmol) and 4-hydrazinocarbonothioylamino-2-chlorobenzoic acid (42.9 mg, 0.17 mmol), desired the product was obtained in the same manner as in synthesis example 118, as a pale yellow solid (58.3 mg, yield 65%).

¹ H-NMR (ppm in DMSO)

δ 11.22 (br s, 1H), 10.47 (br s, 1H), 8.13-8.15 (m, 2H), 8.00 (d, J = 8.3 Hz, 2H ), 7.87 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.3 Hz, 2H), 7.65-7.68 (m, 1H), 2.41 (s, 3H).

LC / MS (ESI) 513.

SYNTHESIS EXAMPLE 120

Synthesis of 4 - {[(2- {1- [5- (4-chlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethylidene} hydrazino) carbonothioyl] amino} -2-chlorobenzoic acid

 Starting from 1- [5- (4-dichlorophenyl) -4-hydroxy-1-methyl-1H-pyrazol-3-yl] ethanone (37.5 mg, 0.15 mmol) and 4-hydrazinocarbonothioylamino-2-chlorobenzoic acid (36.9 mg, 0.15 mmol), the desired product was obtained in the same manner as in Synthesis Example 114, as a yellow solid (59.5 mg, yield 92%).

¹ H-NMR (ppm in DMSO)

δ 7.40-8.40 (m, 7H), 3.78-3.84 (m, 3H), 2.40 (s, 3H).

LC / MS (ESI) 477.

SYNTHESIS EXAMPLE 121

Synthesis of 5 - {[(2- {1- [5- (4-chlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-thiophenecarboxylic acid

Starting from 2- (4-chlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (25.3 mg, 0.10 mmol) and 5-hydrazinocarbonothioylamino-2-thiophenecarboxylic acid (21.8 mg, 0.10 mmol), desired the product was obtained in the same manner as in Synthesis Example 50, as a pale yellow solid (37.1 mg, 82% yield).

¹ H-NMR (ppm in DMSO)

δ 11.50 (br s, 1H), 11.13 (br s, 1H), 8.04 (s, 1H), 7.80-7.82 (m, 2H), 7.87 (d , J = 4.1 Hz, 1H), 7.46-7.50 (m, 2H), 6.86-6.87 (m, 1H), 2.39 (s, 3H).

LC / MS (ESI) 451.

SYNTHESIS EXAMPLE 122

Synthesis of 4 - {[(2- {1- [5- (4-chlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-chlorobenzoic acid

 Starting from 2- (4-chlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (25.2 mg, 0.1 mmol) and 4-hydrazinocarbonothioylamino-2-chlorobenzoic acid (24.5 mg, 0.1 mmol), desired the product was obtained in the same manner as in Synthesis Example 50, as a pale yellow solid (41.9 mg, 88% yield).

¹ H-NMR (ppm in DMSO)

δ 11.21 (br s, 1H), 10.47 (br s, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.87 (d, J = 8 , 3 Hz, 1H), 7.77-7.81 (m, 2H), 7.66 (d, J = 8.3 Hz, 1H), 7.46-7.48 (m, 2H), 2 40 (s, 3H).

LC / MS (ESI) 479.

SYNTHESIS EXAMPLE 123

Synthesis of 4 - {[(2- {1- [5- (4-chlorophenyl) -4-hydroxy-3-thienyl] ethylidene} hydrazino) carbonothioyl] amino} -2-nitrobenzoic acid

 Starting from 2- (4-chlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (21 mg, 0.083 mmol), the desired product was obtained in the same manner as in Synthesis Examples 92 and 93, as a pale yellow solid (35, 2 mg, yield 86%).

¹ H-NMR (ppm in DMSO)

δ 11.32 (br s, 1H), 10.67 (br s, 1H), 8.49 (s, 1H), 8.07 (s, 1H), 7.95-7.98 (m , 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H ), 2.41 (s, 3H).

LC / MS (ESI) 490.

 The structural formulas of the compounds obtained in the synthesis examples are presented below.

EXAMPLE OF RESEARCH 1

Stimulation of proliferation of thrombopoietin (TPO) -dependent cell line (1)

The ability of the compound of Synthesis Example 3 of the present invention to interact with a thrombopoietin receptor (TPO) was tested using a human leukemia cell line, UT7 / EPO-mpl.

(1) Cells and cell culture

UT7 / EPO-mpl is a stable transformed cell line obtained by introducing into the human leukemia cell line UT7 / EPO a vector inducing expression of the human TPO receptor ( c-mpl) under the control of the cytomegalovirus promoter, according to the method of Takatoku et al. (J. Biol. Chem., 272: 7259-7263 (1997)). The proliferation of this cell line was stimulated by TPO, while the maternal cell line UT7 / EPO did not show any response to TPO. These two cell lines were subcultured in a modified Iscove Dulbecco medium (IMDM; GIBCO) containing 10% fetal bovine serum (FBS; TRACE SCIENTIFIC) using a CO ₂ incubator (5% CO ₂ , 37 ° C).

(2) Cell Proliferation Assay

The subcultured cells described above were washed twice with phosphate buffered saline (PBS) and suspended in IMDM containing 10% FBS at a cell density of 6 × 10 ⁴ cells / ml. The cell suspension was transferred to a 96-well tissue culture plate (CORNING) in 100 μl aliquots. Then, both TPO (PeproTech EC) and the compound of Synthesis Example 3 dissolved in dimethyl sulfoxide (DMSO) were diluted 83-fold using IMDM containing 10% FBS and added to the above cell suspension in 20 μl aliquots. The suspension was incubated in a CO ₂ incubator (5% CO ₂ , 37 ° C) for 4 days. Cell proliferation was determined using reagent WST-8 (Kishida Chemical Co., Ltd.), in accordance with the manufacturer's instructions. A 10-μl aliquot of a 5 mM WST-8 reagent solution was added to each well of a tissue culture plate, and the plate was incubated at 37 ° C for 4 hours. The formed formazan pigment was determined by measuring absorbance at 450 nm using a 96-well microplate reader (Nihon Molecular Devices, Spectramax 190).

Figure 1 presents the results obtained using UT7 / EPO-mpl cells, while Figure 2 presents the results obtained using UT7 / EPO-cells in which TPO receptor expression was absent.

STUDY EXAMPLE 2

TPO receptor mediated signal transduction activity

TPO receptor-mediated signal transduction-related activity of the compound of Synthesis Example 3 of the present invention was determined by the method of Komatsu et al. (Blood, 87: 4552-4560 (1996)). The human leukemia cell line UT7 / EPO-mpl was washed three times with PBS and suspended in IMDM containing 10% FBS at a cell density of 9 × 10 ⁵ cells / ml. The cell suspension was incubated in a CO ₂ incubator (5% CO ₂ , 37 ° C) for 18 hours. To 2 ml of this cell suspension (7 × 10 ⁶ cells / ml), either TPO (final concentration 30 ng / ml) or a solution in DMSO of the compound of synthesis example 3 (final concentration 1 μg / ml) was added. After incubating the mixture at 37 ° C for 1-15 minutes, the cells were lysed in 1.4 ml of TNE buffer (20 mM Tris-HCl buffer (pH 7.4) containing 150 mM NaCl, 1 mM EDTA, 1% Triton X- 100, 1 mm PMSF, 1 mm Na ₃ VO ₄ and 1/400-diluted protease inhibitor cocktail (SIGMA)). The cell lysate was centrifuged to collect the supernatant for immunoprecipitation using antibodies against proteins involved in signal transduction (anti-STAT3 (SANTA CRUZ BIOTECHNOLOGY) and anti-STAT5A (UPSTATE BIOTECHNOLOGY), and Sepharose Protein G (PHARMACIA). The protein fraction obtained by immunoprecipitation was collected and denatured in an assay buffer for separation by SDS-polyacrylamide gel electrophoresis (7.5%). The separated proteins were transferred onto a polyvinylidene difluoride (PVDF) membrane (Atto Corporation, pore size 0.2 μm) at 100 V for 1 hour to detect tyrosine phosphorylation using an alkaline phosphatase-labeled anti-phosphorylated tyrosine antibody (RC20, TRANSDUCTION LABORATORIES). The antigen-antibody complex formed on the PVDF membrane was visually determined using 150 μg / ml NBT (BIO-RAD) and 300 μg / ml BCIP (BIO-RAD). The results are presented in table 7.

Table 7

DMSO SYNTHESIS EXAMPLE 3 TPO STAT 3 - + + STAT 5A - + +

 Figure 1 shows that the proliferation of TPO-responsive UT7 / EPO-mpl cells is stimulated by the compound of Synthesis Example 3 in a concentration-dependent manner, whereas, as shown in Figure 2, in the case of UT7 / EPO, the maternal cell line, no the effect of this compound on proliferation. These results show that the compound of Synthesis Example 3 of the present invention, as an activator, has a selective effect on the TPO receptor.

Table 7 shows that the compound of Synthesis Example 3 stimulates the phosphorylation of STAT3 and STAT5A in the same manner as TPO. The results show that the compound of the present invention exhibits an agonistic effect through signal transduction similar to that induced by TPO.

RESEARCH EXAMPLE 3

The compounds of the following synthesis examples were tested in accordance with the method of test example 1 to determine the maximum growth rate (efficiency), which was expressed on the basis of the value obtained for the cell line of human leukemia UT7 / EPO-mpl observed in the presence of 10 ng / ml TPO , which was taken for 100% control, and the concentration of each compound, providing a growth rate corresponding to 50% of the maximum cell growth observed using the same compound (EC ₅₀ ). The results are presented in table 8.

Table 8 SYNTHESIS EXAMPLE No. EC ₅₀ (ng / ml) one 3,5 2 4,5 3 2.7 four 10.5 5 45.0 6 3,5 7 3.8 8 3,7 9 5.9 10 21.3 eleven 2.9

STUDY EXAMPLE 4

Activity associated with stimulation of a colony of megakaryocytes

The effect of the compound of Synthesis Example 2 of the present invention on the proliferation, differentiation and maturation of megakaryocytes was measured by the method of colony formation of megakaryocytes using human bone marrow cells. CD34 ⁺ human bone marrow cells (Cambrex Bio Science Walkersville) were incubated on a 2-well slide for 11 days in a CO ₂ incubator (5% CO ₂ , 37 ° C) using MegaCult ^™ -C (StemCell Technologies) containing 0 , 1% (v / v) of the compound of Synthesis Example 2 dissolved in DMSO. After dehydration and fixation, cells were stained with anti-glycoprotein IIb / IIIa antibody in accordance with the manufacturer's instructions. Colonies consisting of at least 8 stained megakaryocytes in each well were counted using a microscope. The values obtained by counting the colonies of megakaryocytes were averaged based on two or more repetitions of experiments.

 The results show that the compound of the present invention has excellent colony-stimulating activity against megakaryocytes and increases platelet count through such activity.

The results are presented in table 9.

Table 9 SYNTHESIS EXAMPLE 2 Concentration (μg / ml) 0.3 one Megakaryocyte colony count 25 48

EXAMPLE OF COMPOSITION 1

The preparation was obtained in the form of granules containing the following ingredients.

Ingredients The compound of formula (1) 10 mg Lactose 700 mg Corn starch 274 mg HPC-L 16 mg 1000 mg

The compound of formula (1) and lactose were sieved through a 60 mesh sieve. Corn starch was sieved through a 120 mesh sieve. They were mixed in a V-type mixer. The powder mixture was mixed with a low viscosity hydroxypropyl cellulose aqueous solution (HPC-L), granulated (granulation using an extruder, head opening size 0.5-1 mm) and dried. The resulting dry granules were sieved through a swinging sieve (12/60 mesh) to obtain a preparation in the form of granules.

EXAMPLE OF COMPOSITION 2

A powdered encapsulation preparation was prepared containing the following ingredients.

Ingredients The compound of formula (1) 10 mg Lactose 79 mg Corn starch 10 mg Magnesium stearate 1 mg 100 mg

 The compound of formula (1) and lactose were sieved through a 60 mesh sieve. Corn starch was sieved through a 120 mesh sieve. They were mixed with magnesium stearate in a V-type mixer. 10% powder was placed in No. 5 hard capsules, 100 mg each.

EXAMPLE OF COMPOSITION 3

The preparation was obtained in the form of granules containing the following ingredients.

Ingredients The compound of formula (1) 15 mg Lactose 90 mg Corn starch 42 mg HPC-L 3 mg 150 mg

The compound of formula (1) and lactose were sieved through a 60 mesh sieve. Corn starch was sieved through a 120 mesh sieve. They were mixed in a V-type mixer. The powder mixture was mixed with a low viscosity hydroxypropyl cellulose aqueous solution (HPC-L), granulated and dried. The resulting dry granules were sieved through a swing sieve (12/60 mesh). The granules were placed in No. 4 hard capsules of 150 mg each.

EXAMPLE OF COMPOSITION 4

 Received the drug in the form of tablets containing the following ingredients.

Ingredients The compound of formula (1) 10 mg Lactose 90 mg Microcrystalline cellulose 30 mg Magnesium stearate 5 mg CMC-Na 15 mg 150 mg

The compound of formula (1), lactose, microcrystalline cellulose and CMC-Na (sodium carboxymethyl cellulose) were sieved through a 60 mesh sieve and mixed. The powder mixture was mixed with magnesium stearate to give a bulk powder mixture. The powder mixture was directly compressed into tablets of 150 mg each.

EXAMPLE OF COMPOSITION 5

An intravenous preparation was prepared as described below.

The compound of formula (1) 100 mg Saturated Fatty Acid Glyceride 1000 ml

 Solutions having the above composition are usually administered to patients intravenously at a rate of 1 ml per minute.

INDUSTRIAL APPLICABILITY

 Compounds of the present invention having an affinity for a thrombopoietin receptor and acting as thrombopoietin receptor agonists are useful as agents for the prophylaxis, treatment and improvement of conditions for diseases for which the activation of the thrombopoietin receptor is effective, in particular as agents for treating hematological disorders accompanied by an abnormal platelet count, and as agents for treating diseases that can be treated or prevented by stimulating diff rentsiatsii and proliferation of vascular endothelial cells and endothelial progenitor cells, and are useful as medicaments.

The compounds synthesized in the following examples were tested in accordance with the method of example of studies 1 to determine the concentration of each compound, providing a growth rate corresponding to 50% of the growth of the cell line of human leukemia UT-7 / EPO-mpl observed in the presence of 10 ng / ml SRW. The results are presented in table A.

SYNTHESIS EXAMPLE No. EC ₅₀ (ng / ml) 42 0.46 43 3.9 49 fourteen fifty 2.8 67 fourteen 68 0.4 76 5.8 78 0.26 80 2.1 82 1.8 93 3.7 97 4.7 118 3.2 119 3.6

Claims (33)

1. The compound represented by formula (1)

where A represents a nitrogen atom or CR ⁴ where R ⁴ represents a hydrogen atom, a halogen atom;
B represents a sulfur atom or NR ⁹ , where R ⁹ represents a hydrogen atom, a hydroxyl group, a formyl group, a C _1-6 alkyl group, provided that when A represents a nitrogen atom, B is not NH;
R ¹ represents a phenyl group which may be substituted by one or more substituents selected from the group consisting of: a halogen atom,
C _1-10 alkyl group, where C _1-10 alkyl group, optionally, may be substituted by one or more substituents selected from the group comprising a halogen atom;
L ¹ represents a bond;
X represents OR ¹³ , where R ¹³ represents a hydrogen atom;
R ² represents a hydrogen atom, a C _1-10 alkyl group, a phenyl group;
L ² represents a bond, CR ³⁴ R ³⁵ , where each of R ³⁴ and R ³⁵ independently represents a hydrogen atom or a C _1-4 alkyl group;
L ³ represents a bond NR ¹⁹ , where R ¹⁹ represents a hydrogen atom;
L ⁴ represents a bond or NR ²² , where R ²² represents a hydrogen atom;
Y represents an oxygen atom, a sulfur atom; and
R ³ represents an aryl group selected from phenyl or thienyl, where the aryl group is substituted with a substituent selected from a carboxyl group, a sulfamide group, a C _1-4 alkoxycarbonyl group, a tetrazole group and optionally substituted with a substituent selected from halogen, nitro, hydroxy groups C _1-10 alkylcarbonylamino groups;
or a pharmaceutically acceptable salt of this compound. 2. The compound according to claim 1, where
A represents a nitrogen atom, and B represents NR ⁹ , where R ⁹ represents a C _1-6 alkyl group;
or a pharmaceutically acceptable salt of this compound. 3. The compound according to claim 1, where
A represents CR ⁴ , where R ⁴ represents a hydrogen atom;
B represents a sulfur atom; or a pharmaceutically acceptable salt of this compound. 4. The compound according to claim 2, where
L ⁴ represents NR ²² , where R ²² represents a hydrogen atom;
Y represents a sulfur atom;
or a pharmaceutically acceptable salt of this compound. 5. The compound according to claim 3, where
L ⁴ represents NR ²² , where R ²² represents a hydrogen atom;
Y represents a sulfur atom;
or a pharmaceutically acceptable salt of this compound. 6. The compound according to claim 2, where L ⁴ represents a bond;
Y represents an oxygen atom;
or a pharmaceutically acceptable salt of this compound. 7. The compound according to claim 3, where L ⁴ represents a bond;
Y represents an oxygen atom;
or a pharmaceutically acceptable salt of this compound. 8. The compound according to claim 4, where
R ³ represents a phenyl or 2-thienyl group, wherein said groups are substituted with substituents selected from the group consisting of a carboxyl group, a C _1-4 alkoxycarbonyl group and a tetrazole group;
or a pharmaceutically acceptable salt of this compound. 9. The compound of claim 8, where
R ³ represents a phenyl group substituted by a carboxyl group;
or a pharmaceutically acceptable salt of this compound. 10. The compound of claim 8, where
R ³ represents a 2-thienyl group substituted by a carboxyl group;
or a pharmaceutically acceptable salt of this compound. 11. The compound according to claim 5, where
R ³ represents a phenyl or 2-thienyl group, wherein said groups are substituted with substituents selected from the group consisting of a carboxyl group, a C _1-4 alkoxycarbonyl group and a tetrazole group;
or a pharmaceutically acceptable salt of this compound. 12. The compound according to claim 11, where
R ³ represents a phenyl group substituted by a carboxyl group;
or a pharmaceutically acceptable salt of this compound. 13. The compound according to claim 11, where
R ³ represents a 2-thienyl group substituted by a carboxyl group;
or a pharmaceutically acceptable salt of this compound. 14. The compound according to claim 6, where
R ³ represents a phenyl or 2-thienyl group, wherein said groups are substituted with substituents selected from the group consisting of a carboxyl group, a C _1-4 alkoxycarbonyl group and a tetrazole group;
or a pharmaceutically acceptable salt of this compound. 15. The compound of claim 14, where
R ³ represents a phenyl group substituted by a carboxyl group;
or a pharmaceutically acceptable salt of this compound. 16. The compound of claim 14, where
R ³ represents a 2-thienyl group substituted by a carboxyl group;
or a pharmaceutically acceptable salt of this compound. 17. The compound according to claim 7, where
R ³ represents a phenyl or 2-thienyl group, wherein said groups are substituted with substituents selected from the group consisting of a carboxyl group, a C _1-4 alkoxycarbonyl group and a tetrazole group;
or a pharmaceutically acceptable salt of this compound. 18. The compound according to 17, where
R ³ represents a phenyl group substituted by a carboxyl group;
or a pharmaceutically acceptable salt of this compound. 19. The compound according to 17, where
R ³ represents a 2-thienyl group substituted by a carboxyl group;
or a pharmaceutically acceptable salt of this compound. 20. The compound according to claim 4, where
R ³ represents a phenyl or 2-thienyl group, where these groups
are substituted substituents selected from the group consisting of:
carboxyl group and
With _1-4 alkoxycarbonyl group, and a substituent selected from the group consisting of:
a halogen atom, a nitro, hydroxy group and a C _1-10 alkylcarbonylamino group;
or a pharmaceutically acceptable salt of this compound. 21. The compound according to claim 20, where
R ³ represents a phenyl group, which is a substituted carboxyl group, and
substituents selected from the group consisting of:
a halogen atom, a nitro group and a hydroxy group;
or a pharmaceutically acceptable salt of this compound. 22. The compound according to claim 5, where
R ³ represents a phenyl or 2-thienyl group, where these groups are substituted substituents selected from the group consisting of: a carboxyl group and a C _1-4 alkoxycarbonyl group, and a substituent selected from the group consisting of: halogen atom, nitro, hydroxy groups and C _1-10 alkylcarbonylamino groups;
or a pharmaceutically acceptable salt of this compound. 23. The compound according to item 22, where
R ³ represents a phenyl group, which is a substituted carboxyl group, and
substituents selected from the group consisting of:
a halogen atom, a nitro group and a hydroxy group;
or a pharmaceutically acceptable salt of this compound. 24. The compound according to claim 6, where
R ³ represents a phenyl or 2-thienyl group, where these groups are substituted with substituents selected from the group consisting of:
a carboxyl group and a C _1-4 alkoxycarbonyl group, and a substituent selected from the group consisting of: a halogen atom, nitro, hydroxy group and a C _1-4 alkylcarbonylamino group;
or a pharmaceutically acceptable salt of this compound. 25. The compound according to paragraph 24, where
R ³ represents a phenyl group, which is a substituted carboxyl group, and
substituents selected from the group consisting of:
a halogen atom, a nitro group and a hydroxy group;
or a pharmaceutically acceptable salt of this compound. 26. The compound according to claim 7, where
R ³ represents a phenyl or 2-thienyl group, where these groups are substituted substituents selected from the group consisting of: a carboxyl group and a C _1-4 alkoxycarbonyl group, and a substituent selected from the group consisting of: halogen atom, nitro, hydroxy groups and C _1-4 alkylcarbonylamino groups;
or a pharmaceutically acceptable salt of this compound. 27. The compound of claim 26, wherein
R ³ represents a phenyl group which is
substituted carboxyl group, and
substituents selected from the group consisting of:
a halogen atom, a nitro group and a hydroxy group;
or a pharmaceutically acceptable salt of this compound. 28. The compound of claims ¹ to 27, wherein P ¹ is 3,4-dichlorophenyl, 4-tert-butylphenyl, 3,4-dimethylphenyl, 4-p-pentylphenyl, 4-trifluoromethylphenyl, 3,5-dimethylphenyl, 3 trifluoromethylphenyl, 4-isopropylphenyl, 4-isobutylphenyl, 4-ethylphenyl, 3-bromo-4-fluorophenyl, 4-propylphenyl, 4-p-hexylphenyl or 4-chlorophenyl, or a pharmaceutically acceptable salt of this compound. 29. The compound of claim 28, wherein
R ¹ represents 3,4-dichlorophenyl, 4-tert-butylphenyl or 4-trifluoromethylphenyl,
or a pharmaceutically acceptable salt of this compound. 30. The thrombopoietin receptor activator, which is a compound according to any one of claims 1 to 29. 31. A drug having the properties of stimulating cell proliferation, which includes as an active ingredient the thrombopoietin receptor activator according to claim 30, or a pharmaceutically acceptable salt of such an activator in an effective amount. 32. A medication that increases platelet count, comprising as an active ingredient the thrombopoietin receptor activator of claim 30, or a pharmaceutically acceptable salt of such an activator in an effective amount. 33. A drug having the properties of an activator of a thrombopoietin receptor, comprising, as an active ingredient, a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt of such a compound in an effective amount.

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