RU2424238C2 - Thiophene compounds and thrombopoietin receptor activators - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where R¹ is a phenyl group (said phenyl group is substituted with one or more C_1-6alkyl groups, one C_1-3alkyl group (said C_1-3alkyl group is substituted with one or more halogen atoms), one C_1-3alkoxy group (said C_1-3alkoxy group is substituted with one or more halogen atoms) or one or more halogen atoms), R² is a C_1-3alkyl group, R³ is a phenyl group (said phenyl group is substituted with one or more substitutes selected from a group comprising halogen atoms or a (C=O)R^5' group (where R^5' is NR^6'R^7', (where R^6' is a hydrogen atom, and R^7' is a C_1-6alkyl group substituted with a hydroxyl group))), a thienyl group (said thienyl group is substituted with one or more substitutes selected from a group comprising hydrogen atoms and a (C=O)R⁵ group (where R⁵ is NR⁶R⁷ (where R⁶ is a hydrogen atom or a C_1-3alkyl group, and R⁷ is a C_1-6alkyl group (said C_1-6alkyl group can be substituted with one or more hydroxyl groups, one C_1-3alkoxy group or a 5-6-member aromatic heterocyclic group containing 1-2 heteroatoms selected from oxygen or nitrogen (where the 5-6-member aromatic heterocyclic group can be substituted with one or more C_1-3alkyl groups, one or more C_1-3alkoxy groups, and in case of a 5-6-member aromatic heterocyclic group containing one nitrogen atom, can be in be in form of N-oxides)), a pyridyl group, or overall NR⁶R⁷ is a nitrogen-containing heterocyclic group which is a 5-6-member hetero-monocyclic group which contains one or two nitrogen atoms and can additionally contain on oxygen atom (said nitrogen-containing heterocyclic group can be substituted with one or more hydrogen atoms, one or more C_1-6alkyl group, one or more hydroxyl groups)) or C_1-6alkyl group (said C_1-6alkyl group can be substituted with one or more halogen atoms and is substituted with one cyano group))), and R⁴ is a hydrogen atom or to a pharmaceutically acceptable salt of said compound. The invention also relates to a medicinal agent for preventing or treating diseases, in which activation of the thrombopoietin receptor is effective, based on said compounds.

EFFECT: obtaining novel compounds and agents based thereon, which can be used in medicine to increase the number of thrombocytes.

33 cl, 7 tbl, 43 ex

Description

BACKGROUND OF THE INVENTION

Field of Invention

The present invention relates to agents for preventing, treating or improving the condition of diseases in which the activation of the thrombopoietin receptor is effective, which have an affinity for the thrombopoietin receptor and an agonistic effect on this receptor. In particular, 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 having anti-arteriosclerosis activity that stimulate differentiation and proliferation of endothelial cells vessels and endothelial progenitor cells.

State of the art

Thrombopoietin is a 332-amino acid cytokine that increases platelet production by stimulating the differentiation and proliferation of hematopoietic stem cells, megakaryotic progenitor cells and megakaryocytes mediated by its receptor, and therefore is promising as a medicine for hematological disorders. Recent reports that it stimulates the differentiation and proliferation of vascular endothelial cells and endothelial progenitor cells have been the basis for expectations of therapeutic angiogenesis, anti-arteriosclerosis and prevention of cardiovascular disorders (e.g. non-patent document 1, non-patent document 2 and non-patent document 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 (e.g., patent document 1, patent document 2, patent document 3 and patent document 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 having an affinity for the thrombopoietin receptor have been reported (e.g., Patent Document 5 - Patent Document 26).

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

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

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

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

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

6) International Patent Laid-open Applications filed by Yamanouchi Pharmaceutical Co., Ltd. (patent document 22 and 23)

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

8) International Patent Application Laid-Open Filed by Nissan Chemical Industries, Ltd. (patent documents 25 and 26)

Patent Document 1 JP-A-10-72492

Patent Document 2 WO96 / 40750

Patent Document 3 WO96 / 40189

Patent Document 4 WO98 / 25965

Patent Document 5 JP-A-11-1477

Patent Document 6 JP-A-11-152276

Patent Document 7 WO01 / 07423

Patent Document 8 WO01 / 53267

Patent Document 9 WO02 / 059099

Patent Document 10 WO02 / 059100

Patent Document 11 WO00 / 35446

Patent Document 12 WO00 / 66112

Patent Document 13 WO01 / 34585

Patent Document 14 WO01 / 17349

Patent Document 15 WO01 / 39773

Patent Document 16 WO01 / 21180

Patent Document 17 WO01 / 89457

Patent Document 18 WO02 / 49413

Patent Document 19 WO02 / 085343

Patent Document 20 JP-A-2001-97948

Patent Document 21 WO99 / 11262

Patent Document 22 WO02 / 062775

Patent Document 23 WO03 / 062233

Patent Document 24 JP-A-2003-238565

Patent Document 25 WO04 / 033433

Patent Document 26 WO04 / 108683

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

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

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

Disclosure of invention

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

In addition, although it is probably possible to orally administer non-peptide, low molecular weight compounds, no drugs of practical interest have been marketed.

Therefore, there was a need for orally administered low molecular weight compounds having excellent affinity for a thrombopoietin receptor and an agonistic effect on this receptor as a means to prevent, treat, or improve the condition of diseases in which thrombopoietin receptor activation is effective. Specifically, there was a need for low molecular weight compounds that can serve as a means to increase platelet count or to increase the number of other blood cells by stimulating 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 a means to prevent and treat arteriosclerosis by stimulating endothelial cells current and endothelial progenitor cells.

The authors of the present invention conducted in-depth studies to identify low molecular weight compounds with an affinity and agonistic effect on the thrombopoietin receptor, and as a result, it was found that the compounds of the present invention have a high affinity and agonistic effect, which allows them to show a strong effect on increasing the number platelets by stimulating the differentiation and proliferation of megakaryotic progenitor cells and megakaryocytes. The present invention was created based on this discovery.

Namely, the present invention relates to:

1. The compound represented by formula (I):

where R ¹ represents a phenyl group (said phenyl group may be substituted by one or more C _1-6 alkyl groups, one or more C _1-3 alkyl groups (said C _1-3 alkyl groups are substituted by one or more halogen atoms), one or several C _1-3 alkoxy groups (said C _1-3 alkoxy groups may be substituted with one or more halogen atoms) or one or more halogen atoms),

R ² represents a hydrogen atom or a C _1-3 alkyl group (said C _1-3 alkyl group may be substituted by one or more halogen atoms),

R ³ represents a phenyl group, a pyridyl group or a thienyl group (said phenyl group, said pyridyl group and said thienyl group are substituted by one or more substituents selected from the group consisting of hydrogen atoms, nitro groups, halogen atom and C _1-3 alkyl groups ( said C _1-3 alkyl groups may be substituted by one or more halogen atoms) and a group (C = O) R ⁵ (where R ⁵ represents NR ⁶ R ⁷ (where R ⁶ represents a hydrogen atom or a C _1-3 alkyl group (indicated C _1-3 alkyl g the group may be substituted by one or more halogen atoms), and R ⁷ represents a C _1-6 alkyl group (said C _1-6 alkyl group may be substituted by one or more halogen atoms, one or more hydroxyl groups, one or more C _{1 -3} alkoxy groups or one or more C _2-14 aryl groups (said C _2-14 aryl groups may be substituted with one or more C _1-3 alkyl groups, one or more C _1-3 alkoxy groups, one or more carboxyl groups, one Or no ring carbamoyl groups, one or more cyano groups or one or more halogen atoms, and in the case of aryl groups containing one or more nitrogen atoms, can be in the form of their N-oxides)), phenyl group, thienyl group, pyridyl group or pyridyl- An N-oxide group (said phenyl group, said thienyl group, said pyridyl group and said pyridyl-N-oxide group may be substituted with one or more halogen atoms), or NR ⁶ R ⁷ represents, in general, nitrogen soda rusting heterocyclyl group (said nitrogen-containing heterocyclyl group may be substituted by one or more hydrogen atoms, one or more C _1-6 alkyl groups (said C _1-6 alkyl groups may be substituted by one or more halogen atoms), one or more atoms halogen, one or more hydroxyl groups, or one or more C _1-3 alkoxy groups (said C _1-3 alkoxy groups may be substituted by one or more halogen atoms))) or a C _1-6 alkyl group (said C _{The 1-6} alkyl group may be substituted by one or more halogen atoms, one or more pyridyl groups, one or more pyridyl-N-oxide groups, one or more furyl groups, one or more thienyl groups, or one or more phenyl groups and is substituted one or more cyano groups))), and

R ⁴ represents a hydrogen atom or a C _1-3 alkyl group (said C _1-3 alkyl group may be substituted by one or more halogen atoms), a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

2. The compound according to claim 1, where R ² represents a methyl group, and R ⁴ represents a hydrogen atom, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

3. The compound according to claim 2, where R ¹ represents a 3,4-dimethylphenyl group, 4-tert-butylphenyl group, 4-trifluoromethylphenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 4-fluorophenyl group, 3,4 a dichlorophenyl group, a 4-bromophenyl group or a 4-trifluoromethoxyphenyl group, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

4. The compound according to claim 3, where R ³ is represented by formula (II):

(where R ⁶ is a methyl group or ethyl group, and R ^{7 is a} C _1-6 alkyl group (said C _1-6 alkyl group may be substituted with one or more methoxy groups)), a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or their solvate.

5. The compound according to claim 3, where R ³ is represented by formula (II):

(where R ⁶ represents a methyl group or ethyl group, and R ⁷ represents a C _1-3 alkyl group (said C _1-3 alkyl group is substituted by one or more phenyl groups or one or more pyridyl groups)), tautomer, prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

6. The compound according to claim 3, where R ³ is represented by formula (II):

(where R ⁶ represents a hydrogen atom, and R ⁷ represents a C _1-6 alkyl group (said C _1-6 alkyl group is substituted by one or more methoxy groups) or a pyridyl group), a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or their solvate.

7. The compound according to claim 3, where R ³ is represented by formula (II):

(where the group NR ⁶ R ⁷ is generally represented by formula (III):

(where R ⁹ represents a C _1-3 alkyl group)), a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

8. The compound according to claim 3, where R ³ is represented by formula (IV):

(where R ⁶ represents a hydrogen atom, R ⁷ represents a C _1-3 alkyl group (said C _1-3 alkyl group may be substituted with one or more hydroxyl groups), and R ⁸ represents a methyl group or chlorine atom), tautomer , a prodrug or a pharmaceutically acceptable salt of such a compound, or a solvate thereof.

9. The compound according to claim 3, where R ³ is represented by formula (V):

(where R ¹⁰ represents a hydrogen atom or a C _1-3 alkyl group), a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof.

10. The compound according to claim 3, where R ³ is represented by formula (II):

(where R ⁶ represents a hydrogen atom and R ⁷ represents an isopropyl group, methyl group, ethyl group or normal propyl group (said methyl group, said ethyl group and said normal propyl group are unsubstituted or substituted by one or more pyridyl groups, one or several pyridyl-N-oxide groups, one or more furyl groups, one or more pyrazinyl groups, one or more imidazolyl groups, one or more pyrazolyl groups or one or more isoxazolyl groups (said pyridyl groups, said pyridyl-N-oxide groups, said furyl groups, said pyrazinyl groups, said imidazolyl groups, said pyrazolyl groups and said isoxazolyl groups may be substituted by one or more methyl groups, one or more methoxy groups, one or more carboxyl groups, or one or more halogen atoms))), a tautomer, prodrug, or pharma evticheski acceptable salt of such compound or a solvate thereof.

11. The compound according to any one of paragraphs. 4-10, where R ¹ represents a 3,4-dimethylphenyl group, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

12. The compound according to any one of paragraphs. 4-10, where R ¹ represents a 3,4-dichlorophenyl group, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

13. The compound according to any one of paragraphs. 4-10, where R ¹ represents a 4-chlorophenyl group, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

14. The compound according to any one of paragraphs. 4-10, where R ¹ represents a 4-trifluoromethylphenyl group, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

15. The compound according to any one of paragraphs. 4-10, where R ¹ represents a 4-bromophenyl group, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

16. The compound according to any one of paragraphs. 4-10, where R ¹ represents a 4-trifluoromethoxyphenyl group, a tautomer, a prodrug or a pharmaceutically acceptable salt of such a compound or a solvate thereof.

17. The thrombopoietin receptor activator containing the compound according to any one of paragraphs. 1-16, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof, as an active ingredient.

18. An agent for preventing, treating, or improving the condition of diseases in which thrombopoietin receptor activation is effective, which comprises the thrombopoietin receptor activator of claim 17 as an active ingredient.

19. An agent for increasing platelet count comprising a thrombopoietin receptor activator according to claim 17 as an active ingredient.

20. A drug containing a compound according to any one of paragraphs. 1-16, a tautomer, prodrug or pharmaceutically acceptable salt of such a compound or a solvate thereof as an active ingredient.

Effects Provided by the Present Invention

The thiophene compounds of the present invention have an affinity for the thrombopoietin receptor and an agonistic effect on this receptor and exhibit a strong effect on increasing platelet count by stimulating differentiation and proliferation of megakaryotic progenitor cells and megakaryocytes.

The thiophene compounds of the present invention are readily absorbed from the gastrointestinal tract and have a strong stimulating effect on the formation of colonies of megakaryocytes. Orally absorbed thiophene compounds are held in large quantities in the blood and are therefore particularly useful as oral medications.

Although Patent Document 26 discloses compounds having an increase in platelet count, it does not disclose the thiophene compounds of the present invention sufficiently to predict particularly high oral absorbability and high stimulation activity of the megakaryocyte colony of thiophene compounds of the present invention.

Therefore, the thiophene compounds of the present invention are useful as medicaments and are used as agents for preventing, treating, or improving the condition of diseases in which activation of a thrombopoietin receptor is effective, especially as agents for increasing platelet count.

The best way of carrying out the invention

The following is a detailed description of the present invention.

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

First, an explanation of the terms in the corresponding substituents R ¹ to R ¹⁰ will be provided.

As the halogen atom, you can specify a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

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

The C _1-6 alkyl group may be a linear, branched or a C _3-6 cycloalkyl group, and in addition to the above groups, 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-pentyl, 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- ropylcyclopropyl, 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 _1-3 alkoxy group may include a linear, branched or C ₃ cycloalkoxy group; methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy and the like can also be mentioned.

The C _2-14 aryl group may be a C _6-14 aryl group containing no heteroatoms as constituting ring atoms, or a C _2-9 aromatic heterocyclic group, and such a C _2-9 aromatic heterocyclic group may be 5-7 a C _2-6 membered 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 the C _6-14 aryl group that does not contain any 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, and α-naphthyl group, a β-naphthyl group, 1-tetrahydronaphthyl group, 2-tetrahydronaphthyl group, 5-tetrahydronaphthyl group, 6-tetrahydronaphthyl group, and o-biphenyl group, m-biphenylyl group, p-biphenylyl group, 1-antril group, 2-antril group, 9-antril g uppu, 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 lyl group, 3-1,2,5-oxadiazolyl group, 3-1,2,5-thiadiazolyl group, 3-4H-1,2,4-triazolyl group, 3-1H-1,2,4-triazolyl group 5-1H-1,2,4-triazolyl group, 4-2H-1,2,3-triazolyl group, 5-2H-1,2,3-triazolyl group, 4-1H-1,2,3- a triazolyl group, a 5-1H-1,2,3-triazolyl 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-pterdinyl group, 4-pterdinyl group, 6-pterdinyl group, 7-pterdinyl group or the like.

The nitrogen-containing heterocyclyl group is a C _2-9 heteromonocyclic or fused heterobicyclic group that contains one or more nitrogen atoms and may optionally contain one or more atoms, optionally selected from oxygen atoms and sulfur atoms, and you can specifically specify:

Specific preferred examples of the substituent R ¹ are phenyl groups substituted with one or more of the following substituents.

Substituents: C _1-6 alkyl group, C _1-3 alkyl group (said C _1-3 alkyl group is substituted with one or more halogen atoms), C _1-3 alkoxy group (said C _1-3 alkoxy group is substituted by one or more halogen atoms) and a halogen atom.

Particularly preferred examples of the substituent R ¹ are a 3,4-dimethylphenyl group, 4-tert-butylphenyl group, 4-trifluoromethylphenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 4-fluorophenyl group, 3,4-dichlorophenyl group, 4- bromophenyl group and 4-trifluoromethoxyphenyl group.

Specific preferred examples of the substituent R ² are a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, an n-propyl group and a trifluoromethyl group.

A particularly preferred example of the substituent R ² is a methyl group.

Specific preferred examples of the substituent R ³ are a phenyl group, pyridyl groups (2-pyridyl group, 3-pyridyl group and 4-pyridyl group) and thienyl group (2-thienyl group and 3-thienyl group) substituted with one or more substituents selected from the group of substituents A below and one or more substituents selected from the group of substituents B below.

Substituent group A: a hydrogen atom, a nitro group, a halogen atom, a C _1-3 alkyl group and a C _1-3 alkyl group substituted with one or more fluorine atoms.

Substituent group B: (C = O) R ⁵ (where R ⁵ represents NR ⁶ R ⁷ (where R ⁶ represents a hydrogen atom or a C _1-3 alkyl group (said C _1-3 alkyl group may be substituted by one or more halogen atoms), and R ⁷ represents a C _1-6 alkyl group (said C _1-6 alkyl group may be substituted by one or more halogen atoms, one or more hydroxyl groups, one or more C _1-3 alkoxy groups, or one or more C _2-14 aryl groups (said C _2-14 aryl group may be substituted with a hydrochloric or more C _1-3 alkyl groups, one or more C _1-3 alkoxy groups with one or more carboxyl groups, one or more carbamoyl groups, one or more cyano groups, or with one or more halogen atoms and in the case aryl groups containing one or several nitrogen atoms, their N-oxides may be present)), a phenyl group, a thienyl group, a pyridyl group or a pyridyl-N-oxide group (said phenyl group, thienyl group, pyridyl group and pyridyl-N-oxide oxide the group may be substituted by one or more halogen atoms), or NR ⁶ R ⁷ generally represents a nitrogen-containing heterocyclyl group (said nitrogen-containing heterocyclyl group may be substituted by one or more hydrogen atoms, one or more C _1-6 alkyl groups (these C _1-6 alkyl groups may be substituted with one or more halogen atoms), one or more halogen atoms, one or more hydroxyl groups, or one or more C _1-3 alkoxy groups (indicated C _{1- 3} alkoxy groups may be substituted by one or more halogen atoms))), or a C _1-6 alkyl group (said C _1-6 alkyl group may be substituted by one or more halogen atoms, one or more pyridyl groups, one or more pyridyl-N -oxide groups, one or more furyl groups, one or more thienyl groups or one or more phenyl groups, and is substituted by one or more cyano groups)).

A particularly preferred example of the substituent R ³ is represented by the formula (II):

(where R ⁶ represents a methyl group or ethyl group, and R ⁷ represents a C _1-6 alkyl group (said C _1-6 alkyl group may be substituted with one or more methoxy groups)).

Another particularly preferred example of the substituent R ³ is represented by formula (II):

(where R ⁶ represents a methyl group or ethyl group, and R ⁷ represents a C _1-3 alkyl group (said C _1-3 alkyl group is substituted by one or more phenyl groups or one or more pyridyl groups)).

Another particularly preferred example of the substituent R ³ is represented by the formula (II):

(where R ⁶ represents a hydrogen atom and R ⁷ represents a C _1-6 alkyl group (said C _1-6 alkyl group is substituted by one or more methoxy groups) or a pyridyl group).

The following particularly preferred example of substituent R ³ is represented by formula (IV):

(where R ⁶ represents a hydrogen atom, R ⁷ represents a C _1-3 alkyl group (said C _1-3 alkyl group may be substituted with one or more hydroxyl groups), and R ⁸ represents a methyl group or chlorine atom).

Another particularly preferred example of the substituent R ³ is a group represented by formula (II) or formula (IV), wherein the group NR ⁶ R ⁷ is generally represented by formula (III):

(where R ⁹ represents a C _1-3 alkyl group).

Another particularly preferred example of the substituent R ³ is represented by the formula (V):

(where R ¹⁰ represents a hydrogen atom or a C _1-3 alkyl group).

Another particularly preferred example of the substituent R ³ is represented by the formula (II):

(where R ⁶ represents a hydrogen atom, and R ⁷ represents an isopropyl group, a methyl group, an ethyl group or a normal propyl group (said methyl group, said ethyl groups and said normal propyl group are unsubstituted or substituted by one or more pyridyl groups, one or several pyridyl-N-oxide groups, one or more furyl groups, one or more pyrazinyl groups, one or more imidazolyl groups, one or more irazolyl groups or one or more isoxazolyl groups (said pyridyl groups, pyridyl-N-oxide groups, furyl groups, pyrazinyl groups, imidazolyl groups, pyrazolyl groups and isoxazolyl groups may be substituted by one or more methyl groups, one or more methoxy groups, one or several carboxyl groups or one or more halogen atoms))).

Specific preferred examples of the substituent R ⁴ are a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, an n-propyl group and a trifluoromethyl group.

A particularly preferred example of the substituent R ⁴ is a hydrogen atom.

Preferred compounds for use as a thrombopoietin receptor activator, an agent for preventing, treating, or improving the condition of diseases in which activation of a thrombopoietin receptor is effective, and an agent for increasing platelet count of the present invention are as follows.

1) The compounds represented by formula (I), where R ² represents a methyl group, and R ⁴ represents a hydrogen atom, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

2) The compounds according to claim 1), where R ¹ represents a 3,4-dimethylphenyl group, 4-tert-butylphenyl group, 4-trifluoromethylphenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 4-fluorophenyl group, 3, 4-dichlorophenyl group, 4-bromophenyl group or 4-trifluoromethoxyphenyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their

3) Compounds according to claim 2), where R ³ is represented by formula (II):

(where R ⁶ represents a methyl group or ethyl group, and R ⁷ represents a C _1-6 alkyl group (said C _1-6 alkyl group may be substituted with one or more methoxy groups)), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

4) Compounds according to claim 2), where R ³ is represented by formula (II):

(where R ⁶ represents a methyl group or ethyl group, and R ⁷ represents a C _1-3 alkyl group (said C _1-3 alkyl group is substituted by one or more phenyl groups or one or more pyridyl groups)), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or solvates thereof.

5) Compounds according to claim 2), where R ³ is represented by formula (II):

(where R ⁶ represents a hydrogen atom and R ⁷ represents a C _1-6 alkyl group (said C _1-6 alkyl group is substituted by one or more methoxy groups) or a pyridyl group), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

6) The compounds of claim 2), wherein the group NR ⁶ R ⁷ in the formula (II) is generally represented by the formula (III):

(where R ⁹ represents a C _1-3 alkyl group), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

7) Compounds according to claim 2), wherein R ³ is represented by formula (IV):

(where R ⁶ represents a hydrogen atom, R ⁷ represents a C _1-3 alkyl group (said C _1-3 alkyl group may be substituted by one or more hydroxyl groups), and R ⁸ represents a methyl group or chlorine atom), tautomers , prodrugs or pharmaceutically acceptable salts of such compounds or solvates thereof.

8) Compounds according to claim 2), wherein R ³ is represented by formula (V):

(where R ¹⁰ represents a hydrogen atom or a C _1-3 alkyl group), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

9) Compounds according to claim 2), wherein R ³ is represented by formula (II):

(where R ⁶ represents a hydrogen atom and R ⁷ represents an isopropyl group, methyl group, ethyl group or normal propyl group (said methyl group, said ethyl group and said normal propyl group are unsubstituted or substituted by one or more pyridyl groups, one or several pyridyl-N-oxide groups, one or more furyl groups, one or more pyrazinyl groups, one or more imidazolyl groups, one or more pyrazolyl groups or one or more isoxazolyl groups (these pyridyl groups, pyridyl-N-oxide groups, furyl groups, pyrazinyl groups, imidazolyl groups, pyrazolyl groups and isoxazolyl groups can be substituted by one or more methyl groups, one or more methoxy groups, one or several carboxyl groups or one or more halogen atoms))), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

10) Compounds according to any one of paragraphs. 3) - 9), where R ¹ represents a 3,4-dimethylphenyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

11) Compounds according to any one of paragraphs. 3) - 9), where R ¹ represents a 3,4-dichlorophenyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

12) Compounds according to any one of paragraphs. 3) - 9), where R ¹ represents a 4-chlorophenyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

13) Compounds according to any one of paragraphs. 3) - 9), where R ¹ represents a 4-trifluoromethylphenyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

14) Compounds according to any one of paragraphs. 3) - 9), where R ¹ represents a 4-bromophenyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

15) Compounds according to any one of paragraphs. 3) - 9), where R ¹ represents a 4-trifluoromethoxyphenyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

16) Compounds wherein R ⁴ is a hydrogen atom and R ¹ , R ² and R ³ 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 indicate the following substituents.

Table 1

Table 1 (continued)

17) Compounds where R ⁴ represents a hydrogen atom, and R ¹ , R ² and R ³ are any of the following combinations shown in table 1, tautomers, prodrugs or pharmaceutically acceptable salts of these compounds or their solvates (provided that in case 17) Q1a, Q1b, Q1c, Q1d, Q1e, Q1f, Q1g, Q1h, Q3a, Q3b, Q3c, Q3d, Q3e, Q3f, Q3g, Q3h, Q3i, Q3j, Q3k and Q3l in the table below indicate the following substituents) .

18) Compounds where R ⁴ represents a hydrogen atom, and R ¹ , R ² and R ³ are any of the following combinations shown in Table 1, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates (provided that in case 18) Q1a, Q1b, Q1c, Q1d, Q1e, Q1f, Q1g, Q1h, Q3a, Q3b, Q3c, Q3d, Q3e, Q3f, Q3g, Q3h, Q3i, Q3j, Q3k and Q3l in the table below indicate the following substituents) .

19) Compounds where R ⁴ represents a hydrogen atom, and R ¹ , R ² and R ³ are any of the following combinations shown in Table 2, tautomers, prodrugs or pharmaceutically acceptable salts of these compounds or their solvates.

The symbols shown in table 2 indicate the following substituents.

table 2

20) Compounds where R ⁴ represents a hydrogen atom and R ¹ , R ² and R ³ are any of the following combinations shown in Table 3, tautomers, prodrugs or pharmaceutically acceptable salts of these compounds or their solvates.

The symbols shown in table 3 indicate the following substituents.

Table 3

21) Compounds where R ⁴ represents a hydrogen atom, and R ¹ , R ² and R ³ are any of the following combinations shown in Table 4, tautomers, prodrugs or pharmaceutically acceptable salts of these compounds or their solvates.

The symbols shown in table 4 indicate the following substituents.

Table 4

22) Compounds where R ⁴ represents a hydrogen atom and R ¹ , R ² and R ³ are any of the following combinations shown in Table 5, tautomers, prodrugs or pharmaceutically acceptable salts of these compounds or their solvates.

The symbols shown in table 5 indicate the following substituents.

Table 5

23) Compounds where R ⁴ represents a hydrogen atom and R ¹ , R ² and R ³ are any of the following combinations shown in Table 6, tautomers, prodrugs or pharmaceutically acceptable salts of these compounds or their solvates.

The symbols shown in table 6 indicate the following substituents.

Table 6

24) Compounds 16) - 23), where R ^{2 is} converted to a hydrogen atom, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

25) Compounds 16) - 23), where R ^{2 is} converted to a trifluoromethyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

26) Compounds 16) - 23), where R ^{2 is} converted to an ethyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

27) Compounds 16) - 23), where R ^{2 is} converted to an n-propyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

28) Compounds 16) - 23), where R ^{2 is} converted to isopropyl, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

29) Compounds 16) - 28), where R ^{4 is} converted to a methyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

30) Compounds 16) - 28), where R ^{4 is} converted to a trifluoromethyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

31) Compounds 16) - 28), where R ^{4 is} converted to an ethyl group, tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or their solvates.

32) Thrombopoietin receptor activators containing compounds of 1) to 31), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or solvates thereof as an active ingredient.

33) Means for preventing, treating, or improving the condition of diseases in which thrombopoietin receptor activation is effective, which contain the thrombopoietin receptor activators of claim 32) as an active ingredient.

34) Means for increasing the number of platelets containing thrombopoietin receptor activators according to claim 32) as an active ingredient.

35) Medicines containing any of the compounds of paragraphs. 1) to 31) or compounds represented by the formula (I), tautomers, prodrugs or pharmaceutically acceptable salts of such compounds or solvates thereof as an active ingredient.

In the present invention, the compounds of the present invention represented by formula (I) may be present in the form of tautomers or geometric isomers that undergo endocyclic or exocyclic isomerization, mixtures of tautomers or geometric isomers or mixtures thereof. When the compounds of the present invention contain an asymmetric center, regardless of whether this is the result of isomerization, the compounds of the present invention can be in the form of separated optical isomers or in the form of mixtures containing them in certain ratios.

The compounds of the present invention represented by formula (I), or pharmaceutically acceptable salts thereof, may be in the form of arbitrary crystals or arbitrary hydrates, depending on the preparation conditions. 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 encompasses any of these forms.

The compounds of the present invention represented by formula (I) may be converted to pharmaceutically acceptable salts or may be isolated from the resulting salts, if necessary. The pharmaceutically acceptable salts of the present invention can, for example, be 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 be 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, tartaric acid, benzenesulfonic acid and p-toluenesulfonic acid acid).

Compounds that serve as prodrugs are derivatives of the present invention containing chemically or metabolically degradable groups that produce pharmacologically active compounds of the present invention as a result of solvolysis or in physiological conditions in vivo. Methods for the selection or preparation of appropriate prodrugs are disclosed, for example, in Design of Prodrugs (Elsevier, Amsterdam 1985). In the present invention, when the compound contains a hydroxyl group, for example, acyloxy derivatives obtained by reacting the compound with suitable acyl halides or suitable acid anhydrides can be mentioned as prodrugs. Acyloxy derivatives, especially preferred as prodrugs, include -OCOC ₂ H ₅ , -OCO (t-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. When 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 halides or suitable mixed acid 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. When the compound of the present invention contains a carboxyl group, for example, carboxylic acid esters with aliphatic alcohols or carboxylic acid 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 preventing, treating, or improving the condition of diseases in which the activation of the thrombopoietin receptor is effective, or agents for increasing the number of platelets that contain the thrombopoietin receptor activators of the present invention as an active ingredient, can generally be administered as oral medicaments, such like tablets, capsules, powder, granules, pills and syrup, in the form of rectal drugs, transdermal drugs or injections. The agents of the present invention can be administered as a single 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 may be supplied in the form of dry syrups for mixing 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. Suitable suppositories can be used as appropriate substances such as cocoa butter, lauric fat, Macrogol, glycerogelatin, Witepsol, sodium stearate and mixtures thereof, and, if necessary, they may contain an emulsifier, suspending agent, preservative, and the like. For injection, pharmaceutical ingredients such as distilled water for injection, saline, 5% glucose solution, propylene glycol and other solvents or solubilizing agents, a pH adjuster, an isotonicity agent and a stabilizer can be used to prepare aqueous dosage forms or dosage forms that must be dissolved before application.

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

The present invention is used when it is expected that the use of compounds that have an affinity for a thrombopoietin receptor and act as thrombopoietin receptor agonists will improve the pathological condition. For example, hematologic disorders accompanied by an abnormal platelet count can be indicated. Specifically, it is effective for treating or preventing human and mammalian diseases caused by abnormal megakaryopoiesis, especially those accompanied by thrombocytopenia. Examples of such diseases include thrombocytopenia in cancer chemotherapy or radiotherapy, thrombocytopenia resulting from antiviral therapy in the treatment of diseases such as hepatitis C, thrombocytopenia caused by bone marrow transplantation, surgical intervention and severe infections, or gastrointestinal bleeding, but such diseases are not limited the above. Typical thrombocytopenia, such as aplastic anemia, idiopathic thrombocytopenic purpura, myelodysplastic syndrome, liver diseases, HIV infection and thrombopoietin deficiency, are also targets for the agents of the present invention. The present invention can be used as a mobilizer of peripheral stem cells, an inducer of differentiation of megakaryoblastic or megakaryotic leukemia cells, and an agent for increasing platelet count for platelet donors. Potential applications also 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, and peripheral arterial occlusive disease, but there are no restrictions.

Compounds represented by formula (I) are prepared, for example, by the method represented by formula (1) below.

The interaction of compound (IV) with the amino compound (VII) in a solvent and, if necessary, in the presence of a catalyst, by heating and stirring, gives the desired compound or its precursor. The precursor can, if necessary, be hydrolyzed, deprotected, reduced or oxidized to the desired compound. The compounds of the present invention can usually be purified by column chromatography, thin layer chromatography, high performance liquid chromatography (HPLC) or high performance liquid chromatography-mass spectrometry (LC-MS) and, if necessary, they can be obtained with high purity by recrystallization or solvent washings.

For the synthesis of intermediate compounds (VI), you can, for example, specify the following method disclosed in JP-A-48-026755:

For the synthesis of amino compounds (VII), for example, methods disclosed in Synthetic Commun., 28 (7), 1223-1231 (1998), J. Chem. Soc., 1225 (1948) and J. Chem. Soc., 2831 (1952).

Compounds represented by formula (I) can also be prepared by the method represented by formula (3) below.

The interaction of compound (VIII) with compound (IX) in a solvent and, if necessary, in the presence of a catalyst, a dehydrating condensation agent or a base, by heating and stirring gives the desired compound or its precursor. The precursor can, if necessary, be hydrolyzed, deprotected, reduced or oxidized to the desired compound. The compounds of the present invention can usually be purified by column chromatography, thin layer chromatography, high performance liquid chromatography (HPLC) or high performance liquid chromatography-mass spectrometry (LC-MS) and, if necessary, they can be obtained with high purity by recrystallization or solvent washings.

Compound (VIII) can be obtained by mixing compound (VI) with hydrazine or a derivative thereof in a solvent and, if necessary, in the presence of a catalyst, by heating.

EXAMPLES

The present invention will now be described in more detail with reference to reference synthesis examples, synthesis examples, test examples, and formulation examples. However, it should be understood that the present invention should not be limited to these specific examples.

¹ H-NMR analysis was performed at 300 MHz, and LC / MS determinations were carried out under the following conditions.

LC / MS condition 1

Column: Waters SunFire C18 (3.5 μm, 4.6 × 30 mm)

Eluent: acetonitrile / 0.1% aqueous solution of formic acid (10/90 to 30/70)

LC / MS condition 2

Column: Waters SunFire C18 (3.5 μm, 4.6 × 30 mm)

Eluent: acetonitrile / 0.1% aqueous solution of formic acid (10/90 to 60/40)

LC / MS conditions 3

Column: Waters SunFire C18 (3.5 μm, 4.6 × 30 mm)

Eluent: acetonitrile / 0.1% aqueous solution of formic acid (10/90 to 85/15)

LC / MS conditions 4

Column: Waters Xterra MSC18 (5 μm, 4.6 × 50 mm)

Eluent: acetonitrile / 0.1% aqueous solution of formic acid (10/90 to 30/70)

LC / MS conditions 5

Column: Waters Xterra MSC18 (5 μm, 4.6 × 50 mm)

Eluent: acetonitrile / 0.1% aqueous solution of formic acid (10/90 to 60/40)

LC / MS conditions 6

Column: Waters Xterra MSC18 (5 μm, 4.6 × 50 mm)

Eluent: acetonitrile / 0.1% aqueous solution of formic acid (10/90 to 85/15)

LC / MS conditions 7

Column: Waters Xterra MSC18 (5 μm, 4.6 × 50 mm)

Eluent: acetonitrile / 0.1% aqueous solution of formic acid (20/80 to 100/0)

LC / MS conditions 8

Column: Waters Xterra MSC18 (3.5 μm, 2.1 × 20 mm)

Eluent: acetonitrile / 0.2% aqueous solution of formic acid (20/80 to 90/10)

REFERENCE EXAMPLE OF SYNTHESIS 1

Synthesis of 5- (4-Isopropylpiperazine-1-carbonyl) thiophene-2-carbohydrazide

A solution of 59 mg (0.02 mmol) of methyl 5- (4-isopropylpiperazine-1-carbonyl) thiophene-2-carboxylate dissolved in 2 ml of ethanol was heated with 100 μl of hydrazine monohydrate at 80 ° C for 5 hours at boiling with reflux condenser. After cooling, the reaction solution was poured into a liquid mixture of 5 ml of water and 5 ml of a saturated aqueous solution of sodium chloride, and extracted with 20 ml of ethyl acetate and 20 ml of chloroform.

The extract was dried over magnesium sulfate and the solvent was evaporated at 40 ° C to obtain 30 mg of the desired product, 5- (4-isopropylpiperazine-1-carbonyl) thiophene-2-carbohydrazide (51% yield).

Morphology: colorless solid

LC / MS: conditions 4, retention time 0.32 (min)

LC / MS (ESI ⁺ ) m / z; 297 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 295 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 2

Synthesis of 5- (morpholine-4-carbonyl) thiophene-2-carbohydrazide

The procedure of Synthesis Reference Example 1 was followed using methyl 5- (morpholine-4-carbonyl) thiophene-2-carboxylate to give the desired product, 5- (morpholine-4-carbonyl) thiophene-2-carbohydrazide (51% yield).

Morphology: colorless solid

LC / MS: conditions 5, retention time 0.34 (min)

LC / MS (ESI ⁺ ) m / z; 256 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 254 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 3

Synthesis of 5-hydrazinocarbonylthiophene-2-carboxylic acid diethylamide

The procedure of reference synthesis example 1 was followed using methyl 5- (diethylcarbamoyl) thiophene-2-carboxylate to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid diethylamide (89% yield).

Morphology: white solid

LC / MS: conditions 8, retention time 0.63 (min)

LC / MS (ESI ⁺ ) m / z; 242 [M + 1] ⁺

REFERENCE EXAMPLE OF SYNTHESIS 4

Synthesis of 5- (pyrrolidine-1-carbonyl) thiophene-2-carbohydrazide

The procedure of Synthesis Reference Example 1 was followed using methyl 5- (pyrrolidine-1-carbonyl) thiophene-2-carboxylate to give the desired product, 5- (pyrrolidine-1-carbonyl) thiophene-2-carbohydrazide.

Morphology: white solid

LC / MS: conditions 8, retention time 0.50 (min)

LC / MS (ESI ⁺ ) m / z; 240 [M + 1] ⁺

REFERENCE EXAMPLE OF SYNTHESIS 5

Synthesis of 5-hydrazinocarbonylthiophene-2-carboxylic acid dimethylamide

The procedure of reference synthesis example 1 was followed using methyl 5- (dimethylcarbamoyl) thiophene-2-carboxylate to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid dimethylamide (yield 23%).

Morphology: colorless solid

LC / MS: conditions 6, retention time 0.37 (min)

LC / MS (ESI ⁺ ) m / z; 214 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 212 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 6

Synthesis of 5-hydrazinocarbonylthiophene-2-carboxylic acid 2-methoxyethylamide

The procedure for Synthesis Example 1 was followed using methyl 5- (2-methoxyethylcarbamoyl) thiophene-2-carboxylate to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid 2-methoxyethylamide (84% yield).

Morphology: white solid

LC / MS: conditions 1 retention time 0.34 (min)

LC / MS (ESI ⁺ ) m / z; 244 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 242 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 7

Synthesis of 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-pyridylamide

The procedure of Synthesis Reference Example 1 was followed using methyl 5- (3-pyridylcarbamoyl) thiophene-2-carboxylate to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-pyridylamide (78% yield).

Morphology: colorless solid

LC / MS: conditions 1, retention time 0.34 (min)

LC / MS (ESI ⁺ ) m / z; 263 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 261 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 8

Synthesis of 2-chloro-4-hydrazinocarbonyl-N- (2-hydroxyethyl) benzamide

The procedure of synthesis example 1 was followed using methyl 3-chloro-N- (2-hydroxyethyl) terephthalic acid methyl ester to give the desired product, 2-chloro-4-hydrazinocarbonyl-N- (2-hydroxyethyl) benzamide (66% yield) )

Morphology: colorless solid

LC / MS: conditions 2, retention time 0.32 (min)

LC / MS (ESI ⁺ ) m / z; 258, 260 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 256, 258 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 9

Synthesis of 5- (2-cyanobutyryl) thiophene-2-carbohydrazide methyl 5- (2-cyanobutyryl) thiophene-2-carboxylate

To butyronitrile (957 μl, 11 mmol) in tetrahydrofuran was added lithium hexamethyldisilazide (12.5 ml of a 1M solution in tetrahydrofuran, 12.5 mmol) at -78 ° C and the resulting solution was stirred for 1 hour and was added dropwise to 5-methoxycarbonylthiophene -2-carbonyl chloride (1.02 g, 5 mmol) in tetrahydrofuran at -78 ° C for 30 minutes and the resulting reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated, the reaction solution was mixed with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride and a saturated solution of sodium chloride and purified by column chromatography on silica gel (eluent hexane / ethyl acetate = 3/1) to obtain the desired product, methyl 5- (2-cyanobutyryl) thiophene -2-carboxylate (yield 41%).

Morphology: yellow solid

LC / MS: conditions 3, retention time 2.45 (min)

LC / MS (ESI ⁺ ) m / z; 238 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 236 [M-1] ^-

5- (2-cyanobutyryl) thiophene-2-carbohydrazide

Methyl 5- (2-cyanobutyryl) thiophene-2-carboxylate (213 mg, 0.90 mmol) in methanol was stirred with 0.1 M potassium hydroxide in methanol (9.0 ml, 0.90 mmol) at room temperature for 10 minutes and then with hydrazine monohydrate (225 mg, 4.50 mg) at 80 ° C for 6 hours. After adding a saturated aqueous solution of sodium chloride, the reaction solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated to obtain the crude desired product.

Morphology: yellow solid

REFERENCE EXAMPLE OF SYNTHESIS 10

Synthesis of 5-hydrazinocarbonylthiophene-2-carboxylic acid methyl 2-picolylamide

The procedure of Synthesis Reference Example 1 was followed using methyl 5- (methyl-2-picolylamido) thiophene-2-carboxylate to give the desired product, 5-hydrazinocarbonylthiophen-2-carboxylic acid methyl 2-picolylamide (yield 77%).

Morphology: white solid

LC / MS: conditions 8, retention time 0.45 (min)

LC / MS (ESI ⁺ ) m / z; 291 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 289 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 11

Synthesis of 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-picolylamide

Methyl 5- (3-picolylcarbamoyl) thiophene-2-carboxylate (860 mg, 3.11 mmol) in ethanol (34 ml) was stirred with hydrazine monohydrate (1.57 ml, 31.1 mmol) at 85 ° C for 12 hours. The reaction solution was concentrated and stirred with diethyl ether at 0 ° C for 1 hour. The precipitated solid was isolated by filtration and washed with a liquid mixture of diethyl ether and ethanol and dried to obtain the desired product, 5-hydrazinocarbonylthiophen-2-carboxylic acid 3-picolylamide (yield 92%).

Morphology: white solid

LC / MS: conditions 1, retention time 0.23 (min)

LC / MS (ESI ⁺ ) m / z; 277 [M + 1] ⁺

LC / MS (ESI ^{+ -} ) m / z; 275 [M-1] ^-

REFERENCE EXAMPLE SYNTHESIS 12

Synthesis of 5-hydrazinocarbonylthiophene-2-carboxylic acid 4-picolylamide

The procedure for Synthesis Example 11 was followed using methyl 5- (4-picolylcarbamoyl) thiophene-2-carboxylate to give the desired product, 5-hydrazinocarbonylthiophen-2-carboxylic acid 4-picolylamide (81% yield).

Morphology: white solid

LC / MS: conditions 1, retention time 0.23 (min)

LC / MS (ESI ⁺ ) m / z; 277 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 275 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 13

Synthesis of (furan-2-ylmethyl) 5-hydrazinocarbonylthiophen-2-carboxylic acid amide

The procedure for Synthesis Example 11 was followed using methyl 5- (furan-2-ylmethylcarbamoyl) thiophene-2-carboxylate to give the desired product, (furan-2-ylmethyl) amide 5-hydrazinocarbonylthiophene-2-carboxylic acid (86% yield) .

Morphology: white solid

LC / MS: conditions 3, retention time 1.50 (min)

LC / MS (ESI ⁺ ) m / z; 266 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 264 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 14

Synthesis of methylamide 5-hydrazinocarbonylthiophene-2-carboxylic acid

The procedure for Synthesis Example 11 was followed using methyl 5- (methylcarbamoyl) thiophene-2-carboxylate to give the desired product, 5-hydrazinocarbonylthiophen-2-carboxylic acid methylamide (yield 83%).

Morphology: pale yellow solid

LC / MS: conditions 3, retention time 0.37 (min)

LC / MS (ESI ⁺ ) m / z; 200 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 198 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 15

Synthesis of 5-hydrazinocarbonylthiophene-2-carboxylic acid isopropylamide

The procedure for Synthesis Example 11 was followed using methyl 5- (isopropylcarbamoyl) thiophene-2-carboxylate to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid isopropylamide (yield 45%).

Morphology: white solid

LC / MS: conditions 2, retention time 1,07 (min)

LC / MS (ESI ⁺ ) m / z; 228 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 226 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 16

Synthesis of 5-hydrazinocarbonylthiophene-2-carboxylic acid 2-picolylamide

The procedure for Synthesis Example 11 was followed using methyl 5- (2-picolylcarbamoyl) thiophene-2-carboxylate to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid 2-picolylamide (81% yield).

Morphology: white solid

LC / MS: conditions 1, retention time 0.28 (min)

LC / MS (ESI ⁺ ) m / z; 277 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 275 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 17

Synthesis of (2-pyridin-4-yl) 5-hydrazinocarbonylthiophen-2-carboxylic acid ethylamide

Methyl 5- [2- (pyridin-4-yl) ethylcarbamoyl] thiophene-2-carboxylate (0.40 g, 1.4 mmol) was suspended in a liquid mixture of methanol (4.0 ml) and tetrahydrofuran (2.0 ml) and left at 55 ° C until conversion to a homogeneous amber-colored solution was confirmed. After adding an 80% solution of hydrazine monohydrate (0.17 ml, 2.8 mmol), the mixture was allowed to stand at 55 ° C for 24 hours. After adding an 80% solution of hydrazine monohydrate (0.17 ml, 2.8 mmol), the mixture was allowed to stand at 55 ° C for 4.5 hours, and then at room temperature for 14 hours. The precipitated solid was isolated by filtration and dried to obtain the desired product, (2-pyridin-4-yl) 5-hydrazinocarbonylthiophene-2-carboxylic acid ethylamide (82% yield).

Morphology: white solid

¹ H-NMR (DMSO-d ₆ ) δ: 2.86 (t, J = 7.0 Hz, 2H), 3.50 (dt, J = 5.5 and 7.0 Hz, 2H), 4, 52 (broad s, 2H), 7.26 (d, J = 6.0 Hz, 2H), 8.46 (d, J = 6.0 Hz, 2H), 8.72 (t, J = 5 5 Hz, 1H); 9.90 (br s, 1H).

REFERENCE EXAMPLE OF SYNTHESIS 18

Synthesis of 5- (hydrazinocarbonyl) -N - [(1-methyl-1H-pyrazol-5-yl) methyl] thiophene-2-carboxamide

Methyl 5- (1-methyl-1H-pyrazol-5-ylmethylcarbamoyl) thiophene-2-carboxylate (0.25 g, 0.90 mmol) in methanol (2.5 ml) was stirred with hydrazine monohydrate (0.17 ml, 3.6 mmol) at 70 ° C for 3.5 hours. The precipitated solid was isolated by filtration, washed with chloroform and dried to obtain the desired product, 5- (hydrazinocarbonyl) -N - [(1-methyl-1H-pyrazol-5-yl) methyl] thiophen-2-carboxamide (49% yield).

Morphology: white solid

LC / MS: conditions 2, retention time 0.40 (min)

LC / MS (ESI ⁺ ) m / z; 280 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 278 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 19

Synthesis of (5-methylisoxazol-3-ylmethyl) 5-hydrazinocarbonylthiophen-2-carboxylic acid amide

The procedure for Synthesis Example 18 was followed using methyl 5- (5-methylisoxazol-3-ylmethylcarbamoyl) thiophene-2-carboxylate to give the desired product (5-methylisoxazol-3-ylmethyl) 5-hydrazinocarbonylthiophene-2-carboxylic acid amide (yield 47%).

Morphology: white solid

LC / MS: conditions 2, retention time 1.00 (min)

LC / MS (ESI ⁺ ) m / z; 281 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 279 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 20

Synthesis of (5-methylpyrazin-2-ylmethyl) 5-hydrazinocarbonylthiophen-2-carboxylic acid amide

Methyl 5- (5-methylpyrazin-2-ylmethylcarbamoyl) thiophene-2-carboxylate (304 mg, 1.04 mmol) in methanol (3 ml) was stirred with hydrazine monohydrate at 60 ° C for 12 hours. After adding chloroform, the mixture was stirred at room temperature for 5 hours. The precipitated solid was isolated by filtration to obtain the desired product of 5-hydrazinocarbonylthiophene-2-carboxylic acid (5-methylpyrazin-2-ylmethyl) amide (yield 72%).

Morphology: white solid

LC / MS: conditions 3, retention time 0.69 (min)

LC / MS (ESI ⁺ ) m / z; 292 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 290 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 21

Synthesis of (isoxazol-5-ylmethyl) 5-hydrazinocarbonylthiophen-2-carboxylic acid amide

The procedure for Synthesis Example 18 was followed using methyl 5- (isoxazol-5-ylmethylcarbamoyl) thiophene-2-carboxylate to give the desired product (isoxazole-5-ylmethyl) amide 5-hydrazinocarbonylthiophene-2-carboxylic acid (46% yield).

Morphology: white solid

LC / MS: conditions 2, retention time 0.62 (min)

LC / MS (ESI ⁺ ) m / z; 267 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 265 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 22

Synthesis of (3-methoxyisoxazol-5-ylmethyl) 5-hydrazinocarbonylthiophen-2-carboxylic acid amide

The procedure for Synthesis Example 18 was followed using methyl 5- (3-methoxyisoxazol-5-ylmethylcarbamoyl) thiophene-2-carboxylate to give the desired product (3-methoxyisoxazol-5-ylmethyl) 5-hydrazinocarbonylthiophene-2-carboxylic acid amide (yield fifty%).

Morphology: colorless solid

LC / MS: conditions 2, retention time 1.25 (min)

LC / MS (ESI ⁺ ) m / z; 297 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 295 [M-1] ^-

REFERENCE EXAMPLE SYNTHESIS 23

Synthesis of (1,5-dimethyl-1H-pyrazol-3-ylmethyl) 5-hydrazinocarbonylthiophene-2-carboxylic acid amide

The procedure for Synthesis Example 18 was followed using methyl 5- (1,5-dimethyl-1H-pyrazol-3-ylmethylcarbamoyl) thiophene-2-carboxylate to give the desired product (1,5-dimethyl-1H-pyrazol-3-ylmethyl ) 5-hydrazinocarbonylthiophene-2-carboxylic acid amide (yield 59%).

Morphology: white solid

LC / MS: conditions 2, retention time 1.00 (min)

LC / MS (ESI ⁺ ) m / z; 294 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 292 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 24

Synthesis of (pyrazin-2-ylmethyl) 5-hydrazinocarbonylthiophen-2-carboxylic acid amide

The procedure for Synthesis Example 18 was followed using methyl 5- (pyrazin-2-ylmethylcarbamoyl) thiophene-2-carboxylate to give the desired product (pyrazin-2-ylmethyl) amide 5-hydrazinocarbonylthiophene-2-carboxylic acid ((82% yield) .

Morphology: white solid

LC / MS: conditions 2, retention time 0.37 (min)

LC / MS (ESI ⁺ ) m / z; 278 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 276 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 25

a) Synthesis of 4 - [{5- (methoxycarbonyl) thiophene-2-carboxamido} methyl] pyridine 1-oxide

5-Hydrazinocarbonylthiophene-2-carboxylic acid 4-picolylamide (0.20 g, 0.72 mmol) obtained in Reference Example Synthesis 12 in chloroform (4.0 ml) was mixed with 65% wt. m-chloroperbenzoic acid (0.21 g, 0.80 mmol) at room temperature for 9 hours, then the mixture was allowed to stand for 18 hours and concentrated to dryness under reduced pressure. Chloroform (30 ml) was added to the residue, a saturated aqueous solution of sodium hydrogen carbonate (3 ml) and water (7 ml) and the organic layer was separated. The aqueous layer was extracted with chloroform (10 ml × 2) and hot chloroform (10 ml × 1). The resulting organic layer was concentrated to obtain the desired crude product, 4 - [{5- (methoxycarbonyl) thiophen-2-carboxamido} methyl] pyridine 1-oxide (purity 80%, yield 62%).

Morphology: white solid

LC / MS: conditions 2, retention time of 1.77 (min)

LC / MS (ESI ⁺ ) m / z; 293 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 291 [M-1] ^-

b) Synthesis of 4 - [{5-hydrazinocarbonyl) thiophene-2-carboxamido} methyl] pyridine 1-oxide

4 - [{5- (Methoxycarbonyl) thiophene-2-carboxamido} methyl] pyridine 1-oxide (0.12 g, 0.34 mmol) obtained above, suspended in methanol (2.0 ml), was left at 60 ° C. After adding 80% solution of hydrazine monohydrate (0.082 ml, 1.4 mmol), the mixture was allowed to stand at 60 ° C for 3.5 hours, then at room temperature for 5.5 hours and at 0 ° C for 11.5 hours. The precipitated solid was isolated by filtration and dried to obtain the desired product, 4 - [{5-hydrazinocarbonyl) thiophene-2-carboxamido} methyl] pyridine 1-oxide (51% yield).

Morphology: pale yellow solid

LC / MS: conditions 2, retention time 0.37 (min)

LC / MS (ESI ⁺ ) m / z; 293 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 291 [M-1] ^-

¹ H-NMR (DMSO-d ₆ ) δ: 4.42 (br s, 2H), 4.51 (br s, 0.7H), 7.32 (d, J = 7.0 Hz, 2H ), 7.68 (d, J = 4.0 Hz, 1H), 7.75 (d, J = 7.0 Hz, 1H), 8.17 (d, J = 7.0 Hz, 2H), 9.25 (t, J = 6.0 Hz, 0.3H); 9.92 (br s, 0.3H).

REFERENCE EXAMPLE OF SYNTHESIS 26

Synthesis of 3- (pyridin-4-yl) propylamide 5-hydrazinocarbonylthiophene-2-carboxylic acid

An 80% solution of hydrazine monohydrate (0.17 ml, 2.8 mmol) was added to methyl 5- [3- (pyridin-4-yl) propylcarbamoyl] thiophene-2-carboxylate (0.28 g, 0.92 mmol) in methanol (10 ml) and the reaction solution was left at 50 ° C for 95 hours. After adding 80% hydrazine monohydrate solution (0.17 ml, 2.8 mmol), the mixture was allowed to stand at 55 ° C for another 14 hours and concentrated to dryness by evaporation of the solvent under reduced pressure. Methanol (2 ml) was added to the residue, and the resulting solution was placed in an ultrasonic treatment device. The precipitated solid was isolated by filtration and dried to obtain the desired product, 5- hydrazinocarbonylthiophene-2-carboxylic acid 3- (pyridin-4-yl) propylamide (yield 61%).

Morphology: white solid

¹ H-NMR (DMSO-d ₆ ) δ: 1.84 (tt, J = 7.5 and 6.5 Hz, 2H), 2.64 (t, J = 7.5 Hz, 2H), 3, 25 (dt, J = 5.5 And 6.5 Hz, 2H), 4.54 (br s, 1.6H), 7.26 (d, J = 6.0 Hz, 2H), 7.65 (d, J = 4.0 Hz, 1H), 7.67 (d, J = 4.0 Hz, 1H), 8.45 (d, J = 6.0 Hz, 2H), 8.65 (broad .t, J = 5.5 Hz, 0.9H), 9.90 (br s, 0.9H).

REFERENCE EXAMPLE OF SYNTHESIS 27

Synthesis of 5- (hydrazinocarbonyl) -N - [(1-methyl-1H-imidazol-5-yl) methyl] thiophene-2-carboxamide

The procedure for Synthesis Example 18 was followed using methyl 5- (1-methyl-1H-imidazol-5-ylmethylcarbamoyl) thiophene-2-carboxylate to give the desired product, 5- (hydrazinocarbonyl) -N - [(1-methyl-1H -imidazol-5-yl) methyl] thiophen-2-carboxamide (yield 70%).

Morphology: pale yellow solid

LC / MS: conditions 3, retention time 0.30 (min)

LC / MS (ESI ⁺ ) m / z; 280 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 278 [M-1] ^-

REFERENCE EXAMPLE OF SYNTHESIS 28

Synthesis of 5- (3-hydroxypyrrolidin-1-carbonyl) thiophene-2-carbohydrazide

The procedure for Synthesis Example 18 was followed using methyl 5- (3-hydroxypyrrolidin-1-carbonyl) thiophene-2-carboxylate to give the desired product, 5- (3-hydroxypyrrolidin-1-carbonyl) thiophene-2-carbohydrazide (yield 53 %).

Morphology: white solid

SYNTHESIS EXAMPLE 1

Synthesis of {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (4-isopropylpiperazine-1-carbonyl) thiophene-2-carboxylic acid hydrazide

{ 1- [5- (3,4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (4-isopropylpiperazine-1-carbonyl) thiophene-2-carboxylic acid hydrochloride

28 mg of 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (synthesized according to WO 2004/108683) and 29.7 mg of 5- (4-isopropylpiperazine-1-carbonyl) thiophene-2-carbohydrazide obtained in Reference Synthesis Example 1, in 2 ml of isopropyl alcohol was heated with 3 mg of p-toluenesulfonic acid monohydrate and 25 μl (1 eq) of a solution of 4M hydrogen chloride / dioxane at 105 ° C for 8 hours. The reaction solution was again heated with 2 ml of dimethylformamide at 105 ° C for 5 hours and cooled to room temperature. The precipitated solid was isolated by filtration and washed with 1 ml of isopropyl alcohol and 1 ml of chloroform, and the obtained crystals were dried to obtain the desired product (yield 54%).

Morphology: colorless solid

LC / MS: conditions 5, retention time 3.80 (min)

LC / MS (ESI ⁺ ) m / z; 565, 567 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 563, 565 [M-1] ^-

5- (4-Isopropylpiperazine-1-carbonyl) thiophene-2-carboxylic acid {1- [5- (3,4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazide

5- (4-Isopropylpiperazine-1-carbonyl) thiophene-2-carboxylic acid {1- [5- (3,4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazide. hydrochloride (14 mg, 0.025 mmol) was suspended in methanol (2.7 ml) and a solution of 0.1 M potassium hydroxide in methanol (0.24 ml) and methanol (5.4 ml) were added. The suspension was heated at 50 ° C and concentrated to dryness under reduced pressure to obtain the desired product (yield 100%).

Morphology: light brown solid

SYNTHESIS EXAMPLE 2

Synthesis of Potassium Salt {1- [5- (3,4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (morpholine-4-carbonyl) thiophen-2-carboxylic acid hydrazide

5- (morpholine-4-carbonyl) thiophene-2-carboxylic acid {1- [5- (3,4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazide

28 mg of 2- (3,4-Dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and 26 mg of 5- (morpholine-4-carbonyl) thiophene-2-carbohydrazide obtained in Reference Synthesis Example 2 were heated in isopropyl alcohol with 3 mg p-toluenesulfonic acid monohydrate at 105 ° C for 18 hours and cooled to room temperature. The precipitated solid was isolated by filtration and washed with 1 ml of isopropyl alcohol, and the obtained crystals were dried to obtain the desired product (yield 86%).

Morphology: pale yellow solid

LC / MS: conditions 5, retention time 4,89 (min)

LC / MS (ESI ⁺ ) m / z; 524, 526 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 522, 524 [M-1] ^-

Potassium salt of {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (morpholine-4-carbonyl) thiophen-2-carboxylic acid hydrazide

5- (Morpholine-4-carbonyl) thiophene-2-carboxylic acid {1- [5- (3,4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazide (20 mg, 0.038 mmol) was suspended in methanol (2.4 ml) and a solution of 0.1 M potassium hydroxide in methanol (0.38 ml) was added, followed by methanol (5.6 ml). The suspension was heated at 50 ° C and concentrated to dryness under reduced pressure to obtain the desired product (yield 100%).

SYNTHESIS EXAMPLE 3

Synthesis of Potassium salt of 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene-2-carboxylic acid diethylamide

5 - [(2- {1- [5- (3,4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene-2-carboxylic acid diethylamide

The synthesis was carried out in the same manner as in Synthesis Example 2 using 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and 5-hydrazinocarbonylthiophene-2-carboxylic acid diethylamide obtained in Reference Synthesis Example 3 (yield 76 %).

Morphology: pale yellow solid

LC / MS: conditions 5, retention time 5.82 (min)

LC / MS (ESI ⁺ ) m / z; 510, 512 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 508, 510 [M-1] ^-

Potassium salt of diethylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2, using 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene- diethylamide 2-carboxylic acid (100% yield).

Morphology: orange solid

SYNTHESIS EXAMPLE 4

Synthesis of Potassium Salt {1- [5- (3,4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (pyrrolidin-1-carbonyl) thiophen-2-carboxylic acid hydrazide

5- (Pyrrolidine-1-carbonyl) thiophene-2-carboxylic acid {1- [5- (3,4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazide

The synthesis was carried out in the same manner as in synthesis example 2, using 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonyl) thiophene and 5- (pyrrolidine-1-carbonyl) thiophene-2-carbohydrazide obtained in reference synthesis example 4 (yield 94%).

Morphology: pale yellow solid

LC / MS: conditions 5, retention time 5.34 (min)

LC / MS (ESI ⁺ ) m / z; 508, 510 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 506, 508 [M-1] ^-

Potassium salt of {1- [5- {3, 4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (pyrrolidine-1-carbonyl) thiophen-2-carboxylic acid hydrazide

The synthesis was carried out in the same manner as in Synthesis Example 2 using {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (pyrrolidine-1-carbonyl) thiophen-2 hydrazide -carboxylic acid (100% yield).

Morphology: orange solid

SYNTHESIS EXAMPLE 5

Synthesis of Potassium salt of 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene-2-carboxylic acid salt

5 - [(2- {1- [5- (3,4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene-2-carboxylic acid dimethylamide

The synthesis was carried out in the same manner as in Synthesis Example 2 using 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and 5-hydrazinocarbonylthiophene-2-carboxylic acid dimethylamide obtained in Reference Synthesis Example 5 (yield 65 %).

Morphology: colorless solid

LC / MS: conditions 5, retention time 4.93 (min)

LC / MS (ESI ⁺ ) m / z; 482, 484 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 480, 482 [M-1] ^-

Potassium salt of dimethylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

The synthesis was carried out in the same manner as in Synthesis Example 2 using 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene- dimethylamide 2-carboxylic acid (100% yield).

Morphology: orange solid

SYNTHESIS EXAMPLE 6

Synthesis of Potassium salt of 2-methoxyethylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

5 - [(2- {1- [5- (3,4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene) hydrazino) carbonyl] thiophene-2-carboxylic acid 2-methoxyethylamide

The synthesis was carried out in the same manner as in Synthesis Example 2 using 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and 5-hydrazinocarbonylthiophene-2-carboxylic acid 2-methoxyethylamide obtained in Reference Synthesis Example 6 ( yield 80%).

Morphology: pale yellow solid

LC / MS: conditions 7, retention time 3,15 (min)

LC / MS (ESI ⁺ ) m / z; 512, 514 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 510, 512 [M-1] ^-

Potassium salt of 2-methoxyethylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 2 using 2-methoxyethylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene-2-carboxylic acid (100% yield).

Morphology: orange solid

SYNTHESIS EXAMPLE 7

Synthesis of Potassium Salt of 3-pyridylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] -thiophene-2-carboxylic acid

3-Pyridylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

28 mg of 2- (3,4-Dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and 26 mg of 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-pyridylamide were dissolved in 2 ml of dimethyl sulfoxide and heated at 100 ° C for 18 hours and the solvent evaporated. Recrystallization from chloroform diethyl ether gave the desired product (yield 94%).

Morphology: pale yellow solid

LC / MS: conditions 2, retention time 4,02 (min)

LC / MS (ESI ⁺ ) m / z; 531, 533 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 529, 531 [M-1] ^-

Potassium salt of 3-pyridylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

The synthesis was carried out in the same manner as in Synthesis Example 2 using 3-pyridylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene-2-carboxylic acid (yield 76%).

Morphology: orange solid

SYNTHESIS EXAMPLE 8

Synthesis of 5 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene-2-carboxylic acid diethylamide

The synthesis was carried out in the same manner as in Synthesis Example 2 using 2- (4-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene (synthesized in accordance with WO 2004/108683) and 5-hydrazinocarbonylthiophene-2-carboxylic acid diethylamide obtained in reference synthesis example 3 (yield 67%).

Morphology: pale yellow solid

LC / MS: conditions 6, retention time 3.82 (min)

LC / MS (ESI ^- ) m / z; 508 [M-1] ^-

SYNTHESIS EXAMPLE 9

Synthesis of Potassium Salt {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (4-isopropylpiperazine-1-carbonyl) thiophene-2-carboxylic acid hydrazide

5- (4-Isopropylpiperazine-1-carbonyl) thiophene-2-carboxylic acid {1- [5- (4-Trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazide

The synthesis was carried out in the same manner as in synthesis example 7 using 2- (4-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene and 5- (4-isopropylpiperazine-1-carbonyl) thiophene-2-carbohydrazide obtained in the reference example synthesis 1 (yield 55%).

Morphology: yellow solid

LC / MS: conditions 3, retention time 2,49 (min)

LC / MS (ESI ⁺ ) m / z; 565 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 563 [M-1] ^-

Potassium salt of {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (4-Isopropylpiperazine-1-carbonyl) thiophene-2-carboxylic acid hydrazide

The synthesis was carried out in the same manner as in Synthesis Example 2 using {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazide 5- (4-isopropylpiperazin-1-carbonyl) thiophen-2 -carboxylic acid (100% yield).

Morphology: red solid

SYNTHESIS EXAMPLE 10

Synthesis of Potassium Salt {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (pyrrolidin-1-carbonyl) thiophen-2-carboxylic acid hydrazide

5- (Pyrrolidine-1-carbonyl) thiophene-2-carboxylic acid {1- [5- (4-Trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazide

The synthesis was carried out in the same manner as in synthesis example 2 using 2- (4-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene and 5- (pyrrolidine-1-carbonyl) thiophene-2-carbohydrazide obtained in reference synthesis example 4 (yield 82%).

Morphology: pale yellow solid

LC / MS: conditions 8, retention time 5.10 (min)

LC / MS (ESI ⁺ ) m / z; 508 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 506 [M-1] ^-

Potassium salt of {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (pyrrolidin-1-carbonyl) thiophen-2-carboxylic acid hydrazide

The synthesis was carried out in the same manner as in Synthesis Example 2 using {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (pyrrolidine-1-carbonyl) thiophene-2-carbonic hydrazide acid (100% yield).

Morphology: red solid

SYNTHESIS EXAMPLE 11

Synthesis of Potassium Salt 2-chloro-4- (2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazinocarbonyl) -N- (2-hydroxyethyl) benzamide

2-chloro-4- (2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazinocarbonyl) -N- (2-hydroxyethyl) benzamide

To 2- (3,4-Dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (40 mg, 0.14 mmol) and 2-chloro-4-hydrazinocarbonyl-N- (2-hydroxyethyl) benzamide (43 mg, 0, 17 mmol) obtained in Synthesis Reference Example 8, in dimethylformamide (0.7 ml) was added concentrated hydrochloric acid (12 μl, 0.14 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 1 day and stirred with 2 -chloro-4-hydrazinocarbonyl-N- (2-hydroxyethyl) benzamide (18 mg, 0.07 mmol) for 1 day. After adding water, the resulting crystals were isolated by filtration and dried. Chloroform was added and the resulting crystals were isolated by filtration to obtain the desired product (yield 83%).

Morphology: pale green solid

LC / MS: conditions 3, retention time 3,42 (min)

LC / MS (ESI ⁺ ) m / z; 526, 528 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 524, 526 [M-1] ^-

Potassium salt of 2-chloro-4- (2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazinocarbonyl) -N- (2-hydroxyethyl) benzamide

The synthesis was carried out in the same manner as in Synthesis Example 2 using 2-chloro-4- (2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazinocarbonyl) -N - (2-hydroxyethyl) benzamide (yield 77%).

Morphology: red solid

SYNTHESIS EXAMPLE 12

Synthesis of the Potassium Salt of methyl 2-picolylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] -thiophene-2-carboxylic acid methyl-2-picolylamide

The synthesis was carried out in the same manner as in synthesis example 7, using 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and 5-hydrazinocarbonylthiophene-2-carboxylic acid methyl-2-picolylamide obtained in Reference Synthesis Example 10 (yield 66%).

Morphology: pale yellow solid

LC / MS: conditions 3, retention time 3/57 (min)

LC / MS (ESI ⁺ ) m / z; 559, 561 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 557, 559 [M-1] ^-

Potassium salt of methyl 2-picolylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

The synthesis was carried out in the same manner as in Synthesis Example 2 using methyl 2-picolylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] -thiophene-2-carboxylic acid (100% yield).

Morphology: red solid

SYNTHESIS EXAMPLE 13

Synthesis of Potassium Salt of methyl 2-picolylamide 5 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

Methyl-2-picolylamide 5 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

The synthesis was carried out in the same manner as in Synthesis Example 7 using 2- (4-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene and 5-hydrazinocarbonylthiophene-2-carboxylic acid methyl-2-picolylamide obtained in Reference Synthesis Example 10.

Morphology: pale green solid

Potassium salt of methyl 2-picolylamide 5 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

The synthesis was carried out in the same manner as in Synthesis Example 2 using methyl 2-picolylamide 5 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) -carbonyl ] thiophene-2-carboxylic acid (yield 100%).

Morphology: orange solid

SYNTHESIS EXAMPLE 14

Synthesis of Potassium Salt of {1- [5- (3,4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (2-cyanobutyryl) thiophen-2-carboxylic acid hydrazide

5- (2-Cyanobutyryl) thiophene-2-carboxylic acid {1- [5- (3,4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene}

The synthesis was carried out in the same manner as in synthesis example 7 using 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and 5- (2-cyanobutyryl) thiophene-2-carbohydrazide obtained in reference synthesis example 9 (yield 36%).

Morphology: yellow solid

LC / MS: conditions 3, retention time 3,45 (min)

LC / MS (ESI ⁺ ) m / z; 506, 508 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 504, 506 [M-1] ^-

Potassium salt of {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (2-cyanobutyryl) thiophene-2-carboxylic acid hydrazide

The synthesis was carried out in the same manner as in Synthesis Example 2 using {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (2-cyanobutyryl) thiophene-2-carboxylic hydrazide acid (75% yield).

Morphology: red solid

SYNTHESIS EXAMPLE 15

Synthesis of Potassium Salt {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (2-cyanobutyryl) thiophene-2-carboxylic acid hydrazide

5- (2-Cyanobutyryl) thiophen-2-carboxylic acid {1- [5- (4-Trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazide

The synthesis was carried out in the same manner as in synthesis example 7, using 2- (4-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene and 5- (2-cyanobutyryl) thiophene-2-carbohydrazide obtained in Reference Synthesis Example 9 (yield 53%).

Morphology: yellow solid

LC / MS: conditions 3, retention time 3.82 (min)

LC / MS (ESI ⁺ ) m / z; 506 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 504 [M-1] ^-

Potassium salt of 1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (2-cyanobutyryl) thiophen-2-carboxylic acid hydrazide

The synthesis was carried out in the same manner as in Synthesis Example 2 using {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (2-cyanobutyryl) thiophen-2-carboxylic acid hydrazide ( yield 91%).

Morphology: red solid

SYNTHESIS EXAMPLE 16

Synthesis of Potassium Salt of {1- [5- (4-Bromophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (2-cyanobutyryl) thiophen-2-carboxylic acid hydrazide

{1- [5- (4-Bromophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (2-cyanobutyryl) thiophen-2-carboxylic acid hydrazide

The synthesis was carried out in the same manner as in synthesis example 7, using 2- (4-bromophenyl) -3-hydroxy-4-methylcarbonylthiophene (synthesized in accordance with WO2004 / 108684) and 5- (2-cyanobutyryl) thiophene-2-carbohydrazide obtained in Reference example synthesis 9 (yield 51%).

Morphology: yellow solid

LC / MS: conditions 3, retention time 3.85 (min)

LC / MS (ESI ⁺ ) m / z; 516, 518 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 514, 516 [M-1] ^-

Potassium salt of {1- [5- (4-bromophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (2-cyanobutyryl) thiophen-2-carboxylic acid hydrazide

The synthesis was carried out in the same manner as in Synthesis Example 2 using {1- [5- (4-bromophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (2-cyanobutyryl) thiophene-2-carboxylic acid hydrazide ( yield 91%).

Morphology: red solid

SYNTHESIS EXAMPLE 17

Synthesis of 3-picolylamide 5 - [(2- {1- [5- (4-bromophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

2- (4-Bromophenyl) -3-hydroxy-4-methylcarbonylthiophene (50.5 mg, 0.17 mmol) (synthesized according to WO 2004/108683) and 5-hydrazinocarbonylthiophen-2-carboxylic acid 3-picolylamide obtained in reference synthesis example 11, was dissolved in dimethyl sulfoxide (4.0 ml) and heated at 110 ° C. for 24 hours. The solvent was evaporated and the residue was washed with methanol and water to obtain the desired product (81% yield).

Morphology: pale yellow solid

LC / MS: conditions 6, retention time 4,15 (min)

LC / MS (ESI ⁺ ) m / z; 555, 557 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 553, 555 [M-1] ^-

SYNTHESIS EXAMPLE 18

Synthesis of 4-picolylamide 5 - [(2- {1- [5- (4-bromophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

The synthesis was carried out in the same manner as in Synthesis Example 17 using 2- (4-bromophenyl) -3-hydroxyl-4-methylcarbonylthiophene and 5-hydrazinocarbonylthiophene-2-carboxylic acid 4-picolylamide obtained in Synthesis Reference Example 12 (yield 72 %).

Morphology: pale yellow solid

LC / MS: conditions 6, retention time 4.03 (min)

LC / MS (ESI ⁺ ) m / z; 555, 557 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 553, 555 [M-1] ^-

SYNTHESIS EXAMPLE 19

Synthesis of furan-2-ylmethylamide 5 - [(2- {1- [5- (4-bromophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

2- (4-Bromophenyl) -3-hydroxy-4-methylcarbonylthiophene (50.1 mg, 0.17 mmol) and (furan-2-ylmethyl) 5-hydrazinocarbonylthiophene-2-carboxylic acid amide (45.0 mg, 0 , 17 mmol) obtained in Reference Example Synthesis 13 in 2-propanol (4.0 ml) was heated with p-toluenesulfonic acid monohydrate (6 mg) at 100 ° C. for 7.5 hours and cooled to room temperature. The precipitated solid was isolated by filtration, washed with 2-propanol (1 ml) and dried to obtain the desired product (yield 72%).

Morphology: pale yellow solid

LC / MS: conditions 6, retention time 4.98 (min)

LC / MS (ESI ⁺ ) m / z; 544, 546 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 542, 544 [M-1] ^-

SYNTHESIS EXAMPLE 20

Synthesis of methylamide 5 - [(2- {1- [5- (4-bromophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 19, using 2- (4-bromophenyl) -3-hydroxy-4-methylcarbonylthiophene and 5-hydrazinocarbonylthiophene-2-carboxylic acid methylamide obtained in reference synthesis synthesis 14 (yield 65%) .

Morphology: pale yellow solid

LC / MS: conditions 6, retention time 4.67 (min)

LC / MS (ESI ⁺ ) m / z; 478, 480 [M + 1] ⁺

LC / MS (ESI) ^- m / z; 476, 478 [M-1] ^-

SYNTHESIS EXAMPLE 21

Synthesis of isopropylamide 5 - [(2- {1- [5- (4-bromophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

The synthesis was carried out in the same manner as in Synthesis Example 19, using 2- (4-bromophenyl) -3-hydroxy-4-methylcarbonylthiophene and 5-hydrazinocarbonylthiophene-2-carboxylic acid isopropylamide obtained in Synthesis Reference Example 15 (70% yield) .

Morphology: white solid

LC / MS: conditions 2, retention time 4,50 (min)

LC / MS (ESI ⁺ ) m / z; 506, 508 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 504, 506 [M-1] ^-

SYNTHESIS EXAMPLE 22

Synthesis of 2-picolylamide 5 - [(2- {1- [4-hydroxy-5- (4-trifluoromethoxyphenyl) thiophen-3-yl] ethylidene} hydrazino) -carbonyl] thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 17 using 3-hydroxy-2- (4-trifluoromethoxyphenyl) -4-methylcarbonylthiophene (synthesized in accordance with WO 2004/108683) and 5-hydrazinocarbonylthiophene-2-carboxylic acid 2-picolylamide obtained in reference synthesis example 16 (yield 76%).

Morphology: pale yellow solid

LC / MS: conditions 2, retention time 3.92 (min)

LC / MS (ESI ⁺ ) m / z; 561 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 559 [M-1] ^-

SYNTHESIS EXAMPLE 23

Synthesis of 5 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene-2-carboxylic acid isopropylamide

The synthesis was carried out in the same manner as in synthesis example 19, using 2- (4-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene (synthesized in accordance with WO 2004/108683) and 5-hydrazinocarbonylthiophene-2-carboxylic acid isopropylamide obtained in the reference synthesis example 15 (yield 83%).

Morphology: light gray solid

LC / MS: conditions 3, retention time 3,65 (min)

LC / MS (ESI ⁺ ) m / z; 496 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 494 [M-1] ^-

SYNTHESIS EXAMPLE 24

Synthesis of 4-picolylamide 5 - [(2- {1- [5- (4-chlorophenyl) -4-hydroxythiophen-3-yl] ethylidene) hydraeino) carbonyl] thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in Synthesis Example 17 using 2- (4-chlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (synthesized in accordance with WO 2004/108683) and 5-hydrazinocarbonylthiophene-2-carboxylic acid 4-picolylamide obtained in reference synthesis example 12 (yield 69%).

Morphology: light brown solid

LC / MS: conditions 3, retention time 2.55 (min)

LC / MS (ESI ⁺ ) m / z; 511, 513 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 509, 511 [M-1] ^-

SYNTHESIS EXAMPLE 25

Synthesis of 2-picolylamide 5 - [(2- {1- [5- (4-chlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

The synthesis was carried out in the same manner as in Synthesis Example 17 using 2- (4-chlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and 5-hydrazinocarbonylthiophene-2-carboxylic acid 2-picolylamide obtained in Synthesis Reference Example 16 (yield 68 %).

Morphology: yellow solid

LC / MS: conditions 3, retention time 3.10 (min)

LC / MS (ESI ⁺ ) m / z; 511, 513 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 509, 511 [M-1] ^-

SYNTHESIS EXAMPLE 26

Synthesis of 3-picolylamide 5 - [(2- {1- [5- (4-chlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 17 using 2- (4-chlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-picolylamide obtained in reference synthesis example 11 (yield 50 %).

Morphology: yellow solid

LC / MS: conditions 3, retention time 2.72 (min)

LC / MS (ESI ⁺ ) m / z; 511, 513 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 509, 511 [M-1] ^-

SYNTHESIS EXAMPLE 27

Synthesis of methylamide 5 - [(2- {1- [5- (4-chlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in Synthesis Example 19, using 2- (4-chlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and 5-hydrazinocarbonylthiophen-2-carboxylic acid methylamide obtained in Synthesis Reference Example 14 (82% yield) .

Morphology: pale yellow solid

LC / MS: conditions 6, retention time 4.62 (min)

LC / MS (ESI ⁺ ) m / z; 434, 436 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 432, 434 [M-1] ^-

SYNTHESIS EXAMPLE 28

Synthesis of 5 - [(2- {1- [5- (3,4-dimethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene-2-carboxylic acid isopropylamide

The synthesis was carried out in the same manner as in synthesis example 19 using 2- (3,4-dimethylphenyl) -3-hydroxy-4-methylcarbonylthiophene (synthesized in accordance with WO 2004/108683) and 5-hydrazinocarbonylthiophene-2-carboxylic acid isopropylamide obtained in the reference synthesis example 15 (yield 71%).

Morphology: pale yellow solid

LC / MS: conditions 2, retention time 4.40 (min)

LC / MS (ESI ⁺ ) m / z; 456 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 454 [M-1] ^-

SYNTHESIS EXAMPLE 29

Synthesis of 2-picolylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

The synthesis was carried out in the same manner as in Synthesis Example 17 using 2- (3,4-dichlorophenyl-3-hydroxy-4-methylcarbonylthiophene (synthesized in accordance with WO 2004/108683) and 5-hydrazinocarbonylthiophene-2-carbonic 2-picolylamide acid obtained in reference synthesis example 16 (yield 65%).

Morphology: yellow solid

LC / MS: conditions 3, retention time 3.30 (min)

LC / MS (ESI ⁺ ) m / z; 545, 547 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 543, 545 [M-1] ^-

SYNTHESIS EXAMPLE 30

Synthesis of 4-picolylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 17, using 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and 4-picolylamide 5-hydrazinocarbonylthiophene-2-carboxylic acid obtained in reference synthesis example 12 ( yield 51%).

Morphology: pale yellow solid

LC / MS: conditions 2, retention time 3.25 (min)

LC / MS (ESI ⁺ ) m / z; 545, 547 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 543, 545 [M-1] ^-

SYNTHESIS EXAMPLE 31

Synthesis of 2- (pyridin-4-yl) ethylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carbon acid

2- (3,4-Dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (0.11 g, 0.38 mmol) and (2-pyridin-4-yl) 5-hydrazinocarbonylthiophen-2-carboxylic acid ethylamide (0, 10 g, 0.34 mmol) obtained in Synthesis Reference Example 17 was suspended in N, N-dimethylformamide (2.0 ml) and the mixture was allowed to stand at 100 ° C. for 5 hours and then at room temperature for 20 hours. . Water (0.20 ml) was added with stirring, and the precipitated solid was isolated by filtration, washed with chloroform and dried to obtain the desired product, 2- (pyridin-4-yl) ethylamide 5 - [(2- {1- [5- (3 , 4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) -carbonyl] thiophene-2-carboxylic acid (66% yield).

Morphology: white solid

LC / MS: conditions 3, retention time 2.67 (min)

LC / MS (ESI ⁺ ) m / z; 559, 561 [M + 1] ⁺

SYNTHESIS EXAMPLE 32

Synthesis of (1-methyl-1H-pyrazol-5-ylmethyl) amide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] - thiophene-2-carboxylic acid

2- (3,4-Dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (50 mg, 0.17 mmol) and 5- (hydrazinocarbonyl) -N - [(1-methyl-1H-pyrozol-5-yl) methyl ] thiophene-2-carboxamide (49 mg, 0.17 mmol) obtained in Reference Example Synthesis 18 was dissolved in N, N-dimethylformamide (0.50 ml) and heated at 70 ° C. for 24 hours and cooled to room temperature temperature. After adding water, the precipitated crystals were isolated by filtration, washed with water and chloroform, and dried to obtain the desired product (yield 76%).

Morphology: pale yellow solid

LC / MS: conditions 3, retention time 3.60 (min)

LC / MS (ESI ⁺ ) m / z; 548, 550 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 546, 548 [M-1] ^-

SYNTHESIS EXAMPLE 33

Synthesis of (5-methylisoxazol-3-ylmethyl) amide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2- carboxylic acid

The synthesis was carried out in the same manner as in Synthesis Example 32 using 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and (5-methylisoxazol-3-ylmethyl) 5-hydrazinocarbonylthiophene-2-carboxylic acid amide, obtained in the reference synthesis example 19 (yield 67%).

Morphology: yellow solid

LC / MS: conditions 3, retention time 3.77 (min)

LC / MS (ESI ⁺ ) m / z; 549, 551 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 547, 549 [M-1] ^-

SYNTHESIS EXAMPLE 34

Synthesis of (5-methylpyrazin-2-ylmethyl) amide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] -thiophen-2- carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 17, using 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and (5-methylpyrazin-2-ylmethyl) amide 5-hydrazinocarbonylthiophene-2-carboxylic acid, obtained in Reference example synthesis 20 (yield 74%).

Morphology: pale yellow solid

LC / MS: conditions 3, retention time 3.62 (min)

LC / MS (ESI ⁺ ) m / z; 560, 562 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 558, 560 [M-1] ^-

SYNTHESIS EXAMPLE 35

Synthesis of (isoxazol-5-ylmethyl) amide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 19, using 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and (isoxazol-5-ylmethyl) 5-hydrazinocarbonylthiophene-2-carboxylic acid amide obtained in Reference example synthesis 19 (yield 74%).

Morphology: pale yellow solid

LC / MS: conditions 3, retention time 3,69 (min)

LC / MS (ESI ⁺ ) m / z; 535, 537 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 533, 535 [M-1] ^-

SYNTHESIS EXAMPLE 36

Synthesis of (3-methoxyisoxazol-5-ylmethyl) amide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2- carboxylic acid

The synthesis was carried out in the same manner as in synthesis synthesis example 19 using 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and (3-methoxyisoxazol-5-ylmethyl) amide 5-hydrazinocarbonylthiophene-2-carboxylic acid obtained in Reference example synthesis 22 (yield 52%).

Morphology: pale yellow solid

LC / MS: conditions 3, retention time 3.75 (min)

LC / MS (ESI ⁺ ) m / z; 565, 567 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 563, 565 [M-1] ^-

SYNTHESIS EXAMPLE 37

Synthesis of (1,5-dimethyl-1H-pyrazol-3-ylmethyl) amide 5- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidenehydrazinocarbonyl} thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in Synthesis Example 17 using 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and (1,5-dimethyl-1H-pyrazol-3-ylmethyl) amide 5-hydrazinocarbonylthiophene -2-carboxylic acid obtained in reference synthesis example 23 (yield 86%).

Morphology: yellow solid

LC / MS: conditions 3, retention time 3,65 (min)

LC / MS (ESI ⁺ ) m / z; 562, 564 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 560, 562 [M-1] ^-

SYNTHESIS EXAMPLE 38

Synthesis of (pyrazin-2-ylmethyl) amide 5- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidenehydrazinocarbonyl} thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 17 using 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene and (pyrazin-2-ylmethyl) amide 5-hydrazinocarbonylthiophene-2-carboxylic acid, obtained in Reference example synthesis 24 (yield 88%).

Morphology: pale yellow solid

LC / MS: conditions 3, retention time 3,57 (min)

LC / MS (ESI ⁺ ) m / z; 546, 548 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 544, 546 [M-1] ^-

SYNTHESIS EXAMPLE 39

Synthesis of 4 - [{5- (2- [1- {5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl} ethylidene] hydrazinocarbonyl) thiophene-2-carboxamido} methyl] pyridine 1-oxide

2- (3,4-Dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (32 mg, 0.11 mmol) and 4 - [{5-hydrazinocarbonyl) thiophene-2-carboxamido} methyl] pyridine 1-oxide (30 mg , 0.10 mmol) obtained in Reference Synthesis Example 25 was suspended in N, N-dimethylformamide (0.60 ml) and stirred at 80 ° C. for 90 hours. After adding 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (26 mg, 0.091 mmol), the suspension was stirred at 80 ° C for 24 hours, left at room temperature for 5 hours and concentrated to dryness, s obtaining a yellow crude paste (91 mg). The paste was suspended in chloroform (2.0 ml) and insoluble materials were isolated by filtration and dried to obtain the desired product, 4 - [{5- (2- [1- {5- (3,4-dichlorophenyl) -4-hydroxythiophen-3 -yl} ethylidene] hydrazinocarbonyl) thiophene-2-carboxamido} methyl] pyridine 1-oxide (yield 52%).

Morphology: pale yellow solid

LC / MS: conditions 3, retention time 3.29 (min)

LC / MS (ESI ⁺ ) m / z; 561, 563 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 559, 561 [M-1] ^-

SYNTHESIS EXAMPLE 40

Synthesis of 3- (pyridin-4-yl) propylamide 5- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidenehydrazinocarbonyl} thiophene-2-carboxylic acid

2- (3,4-Dichlorophenyl) -3-hydroxy-4-methylcarbonylthiophene (42 mg, 0.14 mmol) and 3- (pyridin-4-yl) 5-hydrazinocarbonylthiophene-2-carboxylic acid propylamide (40 mg, 0 , 13 mmol) obtained in Reference Synthesis Example 26 was dissolved in N, N-dimethylformamide (1.0 ml) and the mixture was allowed to stand at 70 ° C. for 16 hours and then at room temperature for 24 hours. Water (0.36 ml) was added with stirring, and the precipitated solid was isolated by filtration to obtain the desired product, 3- (pyridin-4-yl) propylamide 5- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophene -3-yl] ethylidenehydrazinocarbonyl} thiophene-2-carboxylic acid (95% yield).

Morphology: pale yellow solid

LC / MS: conditions 2, retention time 3,31 (min)

LC / MS (ESI ⁺ ) m / z; 573, 575 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 571, 573 [M-1] ^-

SYNTHESIS EXAMPLE 41

Synthesis of (1-methyl-1H-imidazol-5-ylmethyl) amide 5- {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidenehydrazinocarbonyl} thiophene-2-carboxylic acid

The synthesis was carried out in the same manner as in synthesis example 17, using 2- (4-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonylthiophene and (1-methyl-1H-imidazol-5-ylmethyl) amide 5-hydrazinocarbonylthiophene-2-carboxylic acid obtained in reference synthesis example 27 (yield 39%).

Morphology: pale yellow solid

LC / MS: conditions 2, retention time 3,02 (min)

LC / MS (ESI ⁺ ) m / z; 548 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 546 [M-1] ^-

SYNTHESIS EXAMPLE 42

Synthesis of {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (3-hydroxypyrrolidin-1-carbonyl) thiophen-2-carboxylic acid hydrazide

The synthesis was carried out in the same manner as in Synthesis Example 2 using 2- (3,4-dichlorophenyl) -3-hydroxy-4-methylcarbonyl) thiophene and 5- (3-hydroxypyrrolidin-1-carbonyl) thiophene-2-carbohydrazide, obtained in Reference synthesis example 28 (yield 97%).

Morphology: yellow solid

LC / MS: conditions 6, retention time 3.47 (min)

LC / MS (ESI ⁺ ) m / z; 524, 526 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 522, 524 [M-1] ^-

SYNTHESIS EXAMPLE 43

Synthesis of {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (3-hydroxypyrrolidin-1-carbonyl) thiophen-2-carboxylic acid hydrazide

The synthesis was carried out in the same manner as in synthesis example 2, using 2- (4-trifluoromethylphenyl) -3-hydroxy-4-methylcarbonyl) thiophene and 5- (3-hydroxypyrrolidin-1-carbonyl) thiophene-2-carbohydrazide obtained in Reference synthesis example 28 (yield 84%).

Morphology: pale yellow solid

LC / MS: conditions 6, retention time 3.34 (min)

LC / MS (ESI ⁺ ) m / z; 524, 525 [M + 1] ⁺

LC / MS (ESI ^- ) m / z; 522, 523 [M-1] ^-

The structures of the compounds obtained in the reference synthesis examples and in the synthesis examples are presented below.

TEST EXAMPLE 1

Stimulation of proliferation of thrombopoietin-dependent cell line

The ability of the compounds of the synthesis examples of the present invention to interact with a thrombopoietin receptor (TPO) was evaluated using the UT7 / EPO-mpl human leukemia cell line.

(1) Cells and cell culture

UT7 / EPO-mpl is a stably transformed cell line obtained by introducing into the human leukemia cell line a UT7 / EPO vector that induces expression of the human thrombopoietin receptor (c-mp1) under the control of the cytomegalovirus early promoter by the method of Takatoku et al. (J. Biol. Chem., 272: 7259-7263 (1997)). The proliferation of this cell line is stimulated by thrombopoietin, while its maternal cell line UT7 / EPO does not show any response to thrombopoietin. These two cell lines were subcultured in IMDM (GIBCO) containing 10% fetal bovine serum (Thermo Electron or BioWest) using a CO ₂ incubator (5% CO ₂ , 37 ° C).

(2) Analysis of cell proliferation

The subcultured cells described above were washed twice with PBS and suspended in IMDM containing 10% fetal bovine serum at a cell density of 6 × 10 ⁴ cells / ml. The cell suspension was transferred into 96-well culture plates (CORNING) in 100 μl aliquots. Then, either thrombopoietin (Pepro Tech EC) or the compounds of Synthesis Examples dissolved in dimethyl sulfoxide was diluted 83-fold with IMDM containing 10% fetal bovine serum and added to the above cell suspension in 20 μl aliquots. The cell suspension was incubated in a CO ₂ incubator (5% CO ₂ , 37 ° C) for 4 days. Cell proliferation was evaluated using a WST-8 reagent (Kishida Chemical Co., Ltd.) in accordance with the manufacturer's instructions. A 10 μl aliquot of a solution of a 5 mM WST-8 reagent was added to each well of the culture plate, and the plate was incubated at 37 ° C for 4 hours. The formation of formazan pigment was detected by measuring absorbance at 450 nm using a reader for 96-well microplates (Nihon Molecular Devices, Spectramax 190). The compounds of the Synthesis Examples of the present invention stimulated the proliferation of thrombopoietin-responsive UT7 / EPO-mpl cells in a concentration-dependent manner, while no effect of the compounds of the Synthesis Examples on the proliferation of UT7 / EPO, the mother cell line, was observed. These results show that the compounds of the synthesis examples of the present invention selectively act on the thrombopoietin receptor as activators thereof.

The compounds of synthesis examples 1-43 (in free forms) were tested to determine the concentration of each compound, which provides a growth rate corresponding to 50% of the growth of the human leukemia cell line UT7 / EPO-mpl observed in the presence of 10 ng / ml TPO (EC ₅₀ ) All compounds of Synthesis Examples 1-43 showed an EC ₅₀ value of about 10 ng / ml or lower.

TEST EXAMPLE 2

Each of the compounds of the synthesis examples was suspended in a 99/1 liquid mixture of a 0.5% methyl cellulose / polyoxyethylene sorbitan monooleate solution and orally administered to 7-week-old male Sprague-Dawley rats (Japan SLC, Inc.) at a dose of 10 mg / kg / 10 ml via a gastric tube . From 0.5 to 2 hours after the administration of the compounds, blood was periodically taken from the cervical vein using heparin as an anticoagulant. Blood was centrifuged at 3500 min ^-1 for 10 minutes to obtain plasma. Plasma was added to the assay system to evaluate the proliferation of the thrombopoietin-dependent UT7 / EPO-mpl cell line in Test Example 1 at a final concentration of 0.1 to 3%, and cell proliferation was evaluated. The concentration of each compound in the plasma was calculated based on cell proliferation in the presence of plasma, by comparing with the standard cell proliferation curve versus the concentration of the compound obtained for each compound or determined by LC / MS (Agilent Technologies, Agilent 1100 series LC / MS D) . Each of the compounds of synthesis examples 1-16, 31 and 38 (the compounds of synthesis examples 31 and 38 were tested in the form of potassium salts) reached a maximum blood concentration (Cmax) of about 300 ng / ml 0.5-2 hours after oral administration to rats .

TEST EXAMPLE 3

Megakaryocyte colony stimulation activity

The effect of the compounds of synthesis examples 1-43 of the present invention and reference synthesis examples 29 and 30 on the proliferation, differentiation and maturation of megakaryocyte cells was determined by colony formation of megakaryocytes using human bone marrow cells (see table 7). 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% (vol./about.) Compounds of Examples of synthesis dissolved in dimethyl sulfoxide. After dehydration and fixation, the cells were stained with antiglycoprotein IIb / IIIa antibody in accordance with the manufacturer's instructions. Colonies consisting of at least 8 stained megakaryocyte cells in each well were counted under a microscope. The number of megakaryocyte colonies in at least 2 wells was averaged.

The results show that the compounds of the present invention have excellent activity in stimulating megakaryocyte colonies and increasing platelet count through such activity.

Table 7 Compound No. The number of colonies of megakaryocytes The concentration of the drug (mcg / ml) 0.1 0.3 one Synthesis Example 1 154 Synthesis Example 2 239 Synthesis Example 3 348 Synthesis Example 4 84 148 Synthesis Example 5 274 Synthesis Example 6 115 151 Synthesis Example 8 147 227 Synthesis Example 10 105 208 Synthesis Example 13 61 Synthesis Example 17 146 Synthesis Example 18 125 Synthesis Example 19 171 Synthesis Example 20 185 Synthesis Example 21 85 Synthesis Example 22 96 Synthesis Example 23 134 Synthesis Example 24 164 Synthesis Example 25 118 Synthesis Example 26 182 Synthesis Example 27 201 Synthesis Example 28 105 Synthesis Example 29 62 Synthesis Example 30 145 271 Synthesis Example 31 70 136 Synthesis Example 32 55 Synthesis Example 33 53 Synthesis Example 34 fifty Synthesis Example 35 135 153 Synthesis Example 36 102 135 Synthesis Example 37 81 Synthesis Example 38 66 Synthesis Example 39 86 Synthesis Example 40 70 Synthesis Example 41 41 Synthesis Example 42 90 Synthesis Example 43 109 Reference Synthesis Example 29 2 31 Reference Synthesis Example 30 12 34 87

FORMULATION EXAMPLE 1

The preparation is obtained in the form of granules containing the following ingredients

Ingredients The compound of formula (I) 10 mg Lactose 700 mg Corn starch 274 mg HPC-L 16 mg 1000 mg

The compound of formula (I) and lactose are passed through a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve. They are mixed in a V-type mixer. The powder mixture is mixed with an aqueous solution of low viscosity hydroxypropyl cellulose (HPC-L), granulated (extrusion granulation, extruder head size 0.5-1 mm) and dried. The obtained dry granules are passed through a vibrating sieve (12/60 mesh) to obtain a granular preparation.

FORMULATION EXAMPLE 2

An encapsulating powder is prepared containing the following ingredients

Ingredients The compound of formula (I) 10 mg Lactose 79 mg Corn starch 10 mg Magnesium stearate 1 mg 100 mg

The compound of formula (I) and lactose are passed through a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve. They are mixed in a V-type mixer. 10% powder is placed in hard gelatin capsules No. 5, 100 mg each.

FORMULATION EXAMPLE 3

Get the drug in the form of granules for encapsulation, containing the following ingredients

Ingredients The compound of formula (I) 15 mg Lactose 90 mg Corn starch 42 mg HPC-L 3 mg 150 mg

The compound of formula (I) and lactose are passed through a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve. The components are mixed in a V-type mixer. The powder mixture is mixed with an aqueous solution of low viscosity hydroxypropyl cellulose (HPC-L), granulated and dried. The resulting dry granules are passed through a vibrating sieve (12/60 mesh). Granules are placed in hard capsules No. 4, 150 mg each.

FORMULATION EXAMPLE 4

The preparation is obtained in the form of tablets containing the following ingredients

Ingredients The compound of formula (I) 10 mg Lactose 90 mg Microcrystalline cellulose 30 mg Magnesium stearate 5 mg CMC-Na 15 mg 150 mg

The compound of formula (I), lactose, microcrystalline cellulose and CMC-Na (sodium carboxymethyl cellulose) are passed through a 60 mesh sieve and mixed. The powder mixture is mixed with magnesium stearate to obtain a free-flowing powder mixture. The powder mixture is directly pressed into 150 mg tablets.

FORMULATION EXAMPLE 5

An intravenous preparation is prepared as follows:

The compound of formula (I) 100 mg Saturated Fatty Acid Glyceride 1000 ml

Solutions containing the above compositions are usually administered to the patient intravenously at a rate of 1 ml per 1 minute.

Industrial applicability

Compounds of the present invention, which have an affinity for a thrombopoietin receptor and act as thrombopoietin receptor agonists, are useful as agents for preventing, treating or improving the condition of diseases in which activation of a thrombopoietin receptor is effective, especially as drugs for treating hematological disorders, accompanied by an abnormal platelet count, and as medications for the treatment of diseases, the treatment or prevention of s can be carried out by stimulating differentiation and proliferation of vascular endothelial cells and endothelial progenitor cells, and are useful as medicaments.

Claims (33)

1. The compound represented by formula (I):

wherein R ¹ represents a phenyl group (said phenyl group is substituted by one or more C ₁ - ₆ alkyl groups, one C ₁ - ₃ alkyl group (said C ₁ - ₃ alkyl group substituted with one or more halogen atoms), a C _1-3 alkoxy group (said C ₁ - ₃ alkoxy group is substituted with one or more halogen atoms) or one or more halogen atoms),
R ² represents a C _1-3 alkyl group,
R ³ represents a phenyl group (said phenyl group is substituted by one or more substituents selected from the group consisting of halogen atoms and the group (C = O) R ^{5 '} , (where R ^5' represents NR ^{6 '} R ^7' , ( where R ^{6 '} represents a hydrogen atom, and R ^7' represents a C _1-6 alkyl group substituted by a hydroxyl group))),
thienyl group (said thienyl group is substituted by one or more substituents selected from the group consisting of hydrogen atoms and the group (C = O) R ⁵ , (where R ⁵ represents NR ⁶ R ⁷ , (where R ⁶ represents a hydrogen atom or C _1-3 alkyl group, and R ⁷ represents a C _1-6 alkyl group (said C _1-6 alkyl group may be substituted with one or more hydroxyl groups, one C _1-3 alkoxy group or a 5-6 membered aromatic heterocyclic group, comprising 1-2 heteroatoms selected from oxygen or nitrogen (g a 5-6 membered aromatic heterocyclic group may be substituted with one or more C _1-3 alkyl groups, one or more C _1-3 alkoxy groups, and in the case of a 5-6 membered aromatic heterocyclic group containing one nitrogen atom, there may be in the form of N-oxides)), a pyridyl group, or NR ⁶ R ⁷ represents, in general, a nitrogen-containing heterocyclyl group, which is a 5-6 membered heteromonocyclic group that includes one or two nitrogen atoms and may further include one oxygen atom (at azannaya nitrogen-containing heterocyclyl group may be substituted with one or more hydrogen atoms, one or more C _1-6 alkyl groups, one or more hydroxyl groups)) or a C _1-6 alkyl group (said C _1-6 alkyl group may be substituted with one or several halogen atoms and is substituted by one cyano group))), and
R ⁴ represents a hydrogen atom or a pharmaceutically acceptable salt of said compound. 2. The compound according to claim 1, where R ² represents a methyl group, and R ⁴ represents a hydrogen atom,
or a pharmaceutically acceptable salt of said compound. 3. The compound according to claim 2, where R ¹ represents a 3,4-dimethylphenyl group, 4-tert-butylphenyl group, 4-trifluoromethylphenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 4-fluorophenyl group, 3,4 a dichlorophenyl group, a 4-bromophenyl group or a 4-trifluoromethoxyphenyl group,
or a pharmaceutically acceptable salt of said compound. 4. The compound according to claim 3, where R ³ is represented by formula (II):

(where R ⁶ is a methyl group or an ethyl group, and R ^{7 is a} C _1-6 alkyl group (said C _1-6 alkyl group may be substituted with one or more methoxy groups)), or a pharmaceutically acceptable salt of said compound. 5. The compound according to claim 3, where R ³ is represented by formula (II):

(where R ⁶ represents a methyl group or ethyl group, and R ⁷ represents a C _1-3 alkyl group (said C _1-3 alkyl group is substituted by one or more phenyl groups or one or more pyridyl groups)), or a pharmaceutically acceptable salt the specified connection. 6. The compound according to claim 3, where R ³ is represented by formula (II):

(where R ⁶ represents a hydrogen atom and R ⁷ represents a C _1-6 alkyl group (said C _1-6 alkyl group is substituted by one or more methoxy groups) or a pyridyl group), or a pharmaceutically acceptable salt of said compound. 7. The compound according to claim 3, where R ³ is represented by formula (II):

(where the group NR ⁶ R ⁷ is generally represented by formula (III):

(where R ⁹ represents a C _1-3 alkyl group)), or a pharmaceutically acceptable salt of the compound. 8. The compound according to claim 3, where R ³ is represented by formula (IV):

(where R ⁶ represents a hydrogen atom, R ⁷ represents a C _1-3 alkyl group (said C _1-3 alkyl group may be substituted with one or more hydroxyl groups), and R ⁸ represents a chlorine atom),
or a pharmaceutically acceptable salt of said compound. 9. The compound according to claim 3, where R ³ is represented by formula (V):

(where R ¹⁰ represents a hydrogen atom or a C _1-3 alkyl group), or a pharmaceutically acceptable salt of said compound. 10. The compound according to claim 3, where R ³ is represented by formula (II):

(where R ⁶ represents a hydrogen atom and R ⁷ represents an isopropyl group, methyl group, ethyl group or normal propyl group (said methyl group, said ethyl group and said normal propyl group are unsubstituted or substituted by one or more pyridyl groups, one or several pyridyl-N-oxide groups, one or more furyl groups, one or more pyrazinyl groups, one or more imidazolyl groups, one or more pyrazolyl groups or one or more isoxazolyl groups (said pyridyl groups, said pyridyl-N-oxide groups, said furyl groups, said pyrazinyl groups, said imidazolyl groups, said pyrazolyl groups and said isoxazolyl groups may be substituted by one or more methyl groups, one or more methoxy groups))), or a pharmaceutically acceptable salt of said compound. 11. The compound according to any one of claims 4 to 10, where R ¹ represents a 3,4-dimethylphenyl group,
or a pharmaceutically acceptable salt of said compound. 12. The compound according to any one of claims 4 to 10, where R ¹ represents a 3, 4-dichlorophenyl group,
or a pharmaceutically acceptable salt of said compound. 13. The compound according to any one of claims 4 to 10, where R ¹ represents a 4-chlorophenyl group,
or a pharmaceutically acceptable salt of said compound. 14. The compound according to any one of claims 4 to 10, where R ¹ represents a 4-trifluoromethylphenyl group,
or a pharmaceutically acceptable salt of said compound. 15. The compound according to any one of claims 4 to 10, where R ¹ represents a 4-bromophenyl group,
or a pharmaceutically acceptable salt of said compound. 16. The compound according to any one of claims 4 to 10, where R ¹ represents a 4-trifluoromethoxyphenyl group,
or a pharmaceutically acceptable salt of said compound. 17. A thrombopoietin receptor activator containing a compound according to any one of claims 1-16, or a pharmaceutically acceptable salt of such a compound, as an active ingredient. 18. An agent for preventing, treating, or improving the condition of diseases in which thrombopoietin receptor activation is effective, which comprises the thrombopoietin receptor activator of claim 17 as an active ingredient. 19. An agent for increasing platelet count comprising a thrombopoietin receptor activator according to claim 17 as an active ingredient. 20. A medicament for preventing or treating diseases in which activation of a thrombopoietin receptor is effective, comprising a compound according to any one of claims 1-16, or a pharmaceutically acceptable salt of such a compound as an active ingredient. 21. The compound or its pharmaceutically acceptable salt, which is:
(i) {1- [5- (3,4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (4-isopropylpiperazine-1-carbonyl) thiophene-2-carboxylic acid hydrazide;
(ii) {1- [5- (3,4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (morpholine-4-carbonyl) thiophen-2-carboxylic acid hydrazide;
(iii) {1- [5- (3,4-Dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (pyrrolidin-1-carbonyl) thiophen-2-carboxylic acid hydrazide;
(iv) 2-methoxyethylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-
hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid;
(v) {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} -hydrazide 5- (pyrrolidine-1-carbonyl) thiophen-2-carboxylic acid;
(vi) 5 - [(2- {1- [5- (4-bromophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene-2-carboxylic acid;
(vii) methyl-2-picolylamide 5 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) -carbonyl] thiophen-2-carboxylic acid;
(viii) 4-picolylamide 5 - [(2- {1- [5- (4-bromophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid;
(ix) furan-2-ylmethylamide 5 - [(2- {1- [5- (4-bromophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid;
(xi) 5 - [(2- {1- [5- (4-bromophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene-2-carboxylic acid isopropylamide;
(xii) 2-picolylamide 5 - [(2- {1- [4-hydroxy-5- (4-trifluoromethoxyphenyl) thiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene-2-carboxylic acid;
(xiii) 5 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene-2-carboxylic acid isopropylamide;
(xiv) 4-picolylamide 5 - [(2- {1- [5- (4-chlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene-2-carboxylic acid;
(xv) 2-picolylamide 5 - [(2- {1- [5- (4-chlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid;
(xvi) 3-picolylamide 5 - [(2- {1- [5- (4-chlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene-2-carboxylic acid;
(xvii) 5 - [(2- {1- [5- (3,4-dimethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) -carbonyl] thiophene-2-carboxylic acid isopropylamide;
(xviii) 2-picolylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid;
(xix) 4-picolylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carboxylic acid;
(xx) 2- (pyridin-4-yl) ethylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2 β-carboxylic acid;
(xxi) (1-methyl-1H-pyrazol-5-ylmethyl) amide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl ] thiophene-2-carboxylic acid;
(xxii) (5-methylisoxazol-3-ylmethyl) amide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen- 2-carboxylic acid;
(xxiii) (5-methylpyrazin-2-ylmethyl) amide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen- 2-carboxylic acid;
(xxiv) (isoxazol-5-ylmethyl) amide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) -carbonyl] thiophen-2- carboxylic acid;
(xxv) (3-methoxyisoxazol-5-ylmethyl) amide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen- 2-carboxylic acid;
(xxvi) (1,5-dimethyl-1H-pyrazol-3-ylmethyl) amide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino ) -carbonyl] thiophene-2-carboxylic acid;
(xxvii) (pyrazin-2-ylmethyl) amide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carbon acids;
(xxviii) 4-picolyl-1-oxide amide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen-2-carbon acids;
(xxix) 3- (pyridin-4-yl) propylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen- 2-carboxylic acid;
(xxx) [(1-methyl-1H-imidazol-5-yl) methyl] amide 5 - [(2- {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) -carbonyl] thiophene-2-carboxylic acid;
(xxi) {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} -hydrazide 5- (3-hydroxypyrrolidin-1-carbonyl) thiophene-2-carboxylic acid;
(xxxii) {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} 5- (3-hydroxypyrrolidin-1-carbonyl) thiophen-2-carboxylic acid hydrazide. 22. The compound of claim 21, which is 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophene- 2-carboxylic acid or a pharmaceutically acceptable salt thereof. 23. The compound according to item 21, which is {1- [5- (4-trifluoromethylphenyl) -4-hydroxythiophen-3-yl] ethylidene} -hydrazide 5- (3-hydroxypyrrolidin-1-carbonyl) thiophen-2- carboxylic acid or a pharmaceutically acceptable salt thereof. 24. The compound according to item 21, which is 4 - picolylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino) carbonyl] thiophen- 2-carboxylic acid or a pharmaceutically acceptable salt thereof. 25. The compound according to item 21, which is 2- (pyridin-4-yl) ethylamide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene } hydrazino) carbonyl] thiophene-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 26. The compound according to item 21, which is (isoxazol-5-ylmethyl) amide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino ) -carbonyl] thiophene-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 27. The compound according to item 21, which is a (3-methoxyisoxazol-5-ylmethyl) amide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene } hydrazino) -carbonyl] thiophene-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 28. The compound according to item 21, which is a (pyrazin-2-ylmethyl) amide 5 - [(2- {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} hydrazino ) carbonyl] thiophene-2-carboxylic acid or a pharmaceutically acceptable salt thereof. 29. The compound according to item 21, which is {1- [5- (3,4-dichlorophenyl) -4-hydroxythiophen-3-yl] ethylidene} -hydrazide 5- (3-hydroxypyrrolidin-1-carbonyl) thiophene 2-carboxylic acid or a pharmaceutically acceptable salt thereof. 30. A thrombopoietin receptor activator containing a compound according to any one of claims 21 to 29, or a pharmaceutically acceptable salt of such a compound, as an active ingredient. 31. An agent for preventing, treating, or improving the condition of diseases in which activation of a thrombopoietin receptor is effective, which comprises the thrombopoietin receptor activator of claim 30 as an active ingredient. 32. An agent for increasing platelet count comprising a thrombopoietin receptor activator according to claim 30 as an active ingredient. 33. A medicament for preventing or treating diseases in which activation of a thrombopoietin receptor is effective, comprising a compound according to any one of claims 21 to 29 or a pharmaceutically acceptable salt of such a compound as an active ingredient.