KR100923540B1 - 5-Acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivatives and preparation thereof - Google Patents

Abstract

The present invention provides a novel 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivative or a pharmaceutically acceptable salt thereof, a method for preparing the compound, and an active ingredient, which show strong growth inhibition against various cancer cell lines. It relates to an anticancer agent composition.

Pyrazole derivatives, cancer diseases, cancer cell growth inhibition

Description

5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivatives and preparation method thereof {5-Acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivatives and preparation Technical}

The present invention provides a novel 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivative or a pharmaceutically acceptable salt thereof, and a method for preparing the compound and the compound, which exhibit strong growth inhibition against various cancer cell lines. It relates to an anticancer agent composition as a component.

Cancer is the process by which tumor cells caused by abnormal cell growth kill normal tissues and promote uncontrolled cell colonization, spreading to surrounding tissues, eventually other organs of the body, causing much pain and ultimately death to patients. It is a refractory disease. Cancer is on the rise worldwide, and in Korea, it accounts for 20% of all deaths. To date, cancer is classified into internal factors and external factors. Internal factors include genetic and immunological factors, and external factors include chemicals, radiation, and viral infections. The mechanism by which normal cells are transformed into cancer cells is not yet known, but more than 80% of them are considered to be caused by external factors. Cancer-causing genes are largely classified as blood and solid cancers due to the imbalance between oncogenes and tumor suppressor genes. Cancer occurs in all parts of the body, including lung cancer, stomach cancer, liver cancer, breast cancer, uterine cancer, esophageal cancer, prostate cancer, colon cancer, and skin cancer.

Cancer is treated by surgery, radiation therapy, and the use of chemotherapy. In particular, as the detection of cancer becomes possible early due to the development of diagnostic functions, the therapeutic effect by chemotherapeutic agents is increasing. Chemotherapeutic agents are broadly classified into antimetabolimics, alkylating agents, antimitotic drugs, and hormones. Metabolic antagonists include, for example, folate derivatives (methotrexate), purine derivatives (6-mercaptopurine, 6-thioguanine), and pyrimidine derivatives (5-fluorouracil, Cytarabine). As the alkylating agent, for example, nitrogen mustard compounds (chlororambucil, cyclophosphoamide), ethyleneimine compounds (thiotepa), alkylsulfonate compounds (busulfan), nitrosourea compounds (carmustine), triazene compounds (dicarbazine) There is. Anticancer drugs such as actinomycin D, doxorubicine, bleomycin, mitomycin, vegetable alkanoids (vincristine, vinblastine), taxol and the like. As hormone hormones, adrenal cortex hormones, progesterone, etc., and cisplatin, which is a platinum-containing anticancer agent, are used as the subsignal hormones.

Nevertheless, the development of anticancer drugs of the mechanism is still insufficient. Therefore, the use of anticancer agents suitable for the precise pathogenesis of various mechanisms is limited, and the problem of drug resistance remains a big problem to be solved. Therefore, in recent years, various studies have been conducted for the development of anticancer drugs with new mechanisms for the study of the cause of drug resistance and the treatment of cancers resistant to existing drugs.

Targets of anticancer agents known to date include protein kinase (mainly PKBa (Akt1), PKCb), aurora kinase (ARK1, ARK2, ARK3), cyclin dependent kinase (mainly CDK 2), glycogen synthesis kinase (mainly GSK-3β), Raf Serine / threonine kinase and threonine kinase and envelope cell growth factor receptor (EGFR), human envelope cell growth factor receptor (HER1, HER2, HER3, HER4), stem cell factor receptor (c-Kit), Rearraged during Transfection Receptor (RET), vascular endothelial growth factor (VEGF-1 (Flt1), VEGF-2 (KDR), VEGF-3 (Flt4)), platelet derived growth factor receptor (PDGFR), bcr-abl kinase, src kinase The same tyrosine kinase and the like are known. In addition, carbonic anhydrase, caspases 1, 2, 3, 8, 9, and tubulin are known targets for colon cancer.

The present inventors have found that the 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivatives newly designed and synthesized exhibit inhibitory activity against various tumor cells, thereby completing the present invention.

It is an object of the present invention to provide novel 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivatives or pharmaceutically acceptable salts thereof.

It is another object of the present invention to provide a method for preparing the novel compound.

In addition, the present invention has a further object to provide an anticancer agent and pharmaceutical composition containing the novel compound as an active ingredient, since the novel compound exhibits strong growth inhibitory action against various cancer cell lines.

In order to achieve the above object, the present invention is characterized by a 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof useful for cancer-related treatment.

In Chemical Formula 1,

R ₁ is a hydrogen atom, a C ₁ -C ₈ alkyl group, a C ₁ -C ₈ haloalkyl group, a phenyl group,-(CH ₂ ) _n -phenyl group, or heteroaryl containing 1 to 3 heteroatoms selected from sulfur, oxygen and nitrogen Group; R ₂ represents a hydrogen atom, a C ₁ -C ₈ alkyl group, a phenyl group, or a-(CH ₂ ) _n -phenyl group; R ₃ represents a C ₁ -C ₈ alkyl group, a phenyl group, a-(CH ₂ ) _n -phenyl group, or a heteroaryl group containing 1 to 3 heteroatoms selected from sulfur, oxygen and nitrogen; The phenyl ring of the aforementioned phenyl group or-(CH ₂ ) _n -phenyl group is 1 to 3 selected from halogen, nitro, C ₁ -C ₈ alkyl, C ₃ -C ₈ heterocycloalkyl, and C ₁ -C ₈ alkoxy. Substituents, n is an integer from 1 to 6.

In addition, the present invention is characterized in that the pharmaceutical composition for the treatment and prevention of cancer containing 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. It is done.

In addition, the present invention is characterized by an anticancer agent containing a 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

As a feature of the present invention, 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivatives are defined by Chemical Formula 1, and each substituent used in Chemical Formula 1 will be described in more detail as follows.

In the present invention, the term "halogen atom" means a fluorine, chlorine, bromine or iodine atom.

In the present invention, the alkyl group of C ₁ -C ₈ is methyl, ethyl, n -propyl, i -propyl, cyclopropyl, n -butyl, i -butyl, t -butyl, cyclobutyl, cyclopropylmethyl, aliphatic saturated hydrocarbon groups having 1 to 8 carbon atoms, including n -pentyl, i -pentyl, neopentyl, t -pentyl, cyclopentyl, cyclobutylmethyl, cyclohexyl, n -heptyl, n -octyl, etc. it means.

In the present invention, the "C ₁ -C ₈ haloalkyl group" means a C ₁ -C ₈ alkyl group substituted with one or more halogen atoms such as chloromethyl group, 3-chloropentyl group and trifluoromethyl group. do.

In the present invention, the term "C ₁ -C ₈ alkoxy group" includes methoxy, ethoxy, n -propoxy, i -propoxy, n -butoxy, i -butoxy, t -butoxy and the like. It means a hydroxyl group in which a hydrogen atom is substituted by a substituent selected from an alkyl group of C ₁ -C ₈ .

In the present invention, the "heteroaryl group" refers to pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxa Diazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, indolyl, isoindolyl, benzofuranyl, benzofur lazanyl, dibenzofuranyl, Isobenzofuranyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, dibenzothiophenyl, naphthyridyl, benzisothiazolyl, quinolinyl, isoquinolinyl It means a single ring, two rings, or three ring aromatic heterohydrocarbon group containing 1 to 3 heteroatoms selected from sulfur, oxygen and nitrogen, including quinoxalinyl, phthalazinyl, quinazolinyl, and the like.

In the present invention, the "C ₃ -C ₈ heterocycloalkyl group" is a single ring including 1 to 3 heteroatoms selected from sulfur, oxygen, and nitrogen, including piperazinyl, pyrazinyl, morpholinyl, and the like. , A bicyclic or tricyclic aliphatic heterohydrocarbon group.

In the 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivative represented by Chemical Formula 1 according to the present invention, more preferably, R ₁ is a hydrogen atom, a C ₁ -C ₆ alkyl group, C _1- C ₆ haloalkyl group, phenyl group,-(CH ₂ ) _n -phenyl group, furanyl group, thiophenyl group, or pyridyl group; R ₂ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a phenyl group, or a-(CH ₂ ) _n -phenyl group; R ₃ represents a C ₁ -C ₆ alkyl group, a phenyl group, a-(CH ₂ ) _n -phenyl group, a furanyl group, a thiophenyl group, or a pyridyl group; The phenyl ring of the aforementioned phenyl group or-(CH ₂ ) _n -phenyl group is 1 to 3 selected from halogen, nitro, C ₁ -C ₆ alkyl, C ₃ -C ₆ heterocycloalkyl, and C ₁ -C ₆ alkoxy. It may be substituted or unsubstituted with four substituents, n is a compound of an integer of 1 to 6.

In the 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivative represented by Formula 1 according to the present invention, particularly preferably, R ₁ represents a hydrogen atom, a methyl group, an ethyl group, an n -propyl group, i -Propyl group, n -butyl group, i -butyl group, t -butyl group, n -pentyl group, i -pentyl group, cyclohexyl group, phenyl group, benzyl group, phenethyl group, phenylpropyl group, furan-2-yl group , Furan-3-yl group, thiophen-2-yl group, thiophen-3-yl group, pyridin-2-yl group, pyridin-3-yl group, or pyridin-4-yl group; R ₂ is hydrogen atom, methyl group, ethyl group, n -propyl group, i -propyl group, n -butyl group, i -butyl group, t -butyl group, n -pentyl group, i -pentyl group, cyclohexyl group, phenyl group , Benzyl group, phenethyl group, or phenylpropyl group; R ₃ is methyl group, ethyl group, n -propyl group, i -propyl group, n -butyl group, i -butyl group, t -butyl group, n -pentyl group, i -pentyl group, cyclohexyl group, phenyl group, benzyl group , Phenethyl group, phenylpropyl group, or pyridyl group; The phenyl ring of the aforementioned phenyl group,-(CH ₂ ) _n -phenyl group or benzphenyl group is chloro, fluoro, bromo, nitro, methyl, ethyl, propyl, butyl, cyclohexyl, piperidyl, methoxy, It is a compound unsubstituted or substituted with 1 to 3 substituents selected from oxy, propoxy, and butoxy.

More specifically illustrating the 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivative represented by Formula 1 according to the present invention is as follows:

3- (3-chlorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 1)

5-benzoylhydrazinecarbonyl-3- (3-chlorophenyl) -4- (3-nitrophenyl) carboxylic mino-1 H- pyrazole (Compound No. 2)

3- (3-chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 3)

5-benzoylhydrazinecarbonyl-3- (3-chlorophenyl) -4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 4)

3- (3-chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 5)

3- (4-chlorophenyl) -4- (3-nitrophenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 6)

5-propanoylhydrazinecarbonyl-3- (4-chlorophenyl) -4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 7)

3- (4-chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 8)

5-benzoylhydrazinecarbonyl-3- (4-chlorophenyl) -4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 9)

5-benzoylhydrazinecarbonyl-3- (4-chlorophenyl) -4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 10)

5-nicotinoylhydrazinecarbonyl-3- (4-chlorophenyl) -4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 11)

3- (4-Chlorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxy amino-1 H- pyrazole (Compound No. 12)

3- (4-Chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 13)

4-phenylcarboxyamino-3- (4-chlorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 14)

4-phenylcarboxamido-5-benzoylhydrazinecarbonyl-3- (4-chlorophenyl) -1 H- pyrazole (Compound No. 15)

4-phenylcarboxyamino-3- (4-chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 16)

3- (2-chlorophenyl) -4- (3-nitrophenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 17)

3- (2-Chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 18)

3- (2-chlorophenyl) -4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 19)

3- (2-Chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 20)

3- (2-chlorophenyl) -4- (3-methylphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 21)

3- (2-chlorophenyl) -4- (3-phenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 22)

5-benzoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 23)

5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 24)

4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 25)

5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 26)

5-isonicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxyamino-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 27)

4- (3-methylphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 28)

3- (4-Chlorophenyl-4- (phenethyl) carboxyamino-5- (nicotinoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 29)

4-phenylcarboxyamino-5-nicotinoylhydrazinecarbonyl-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 30)

3- (furan-2-yl) -5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 31)

5-benzoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3- (furan-2-yl) -1 H- pyrazole (Compound No. 32)

5-nicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3- (furan-2-yl) -1 H- pyrazole (Compound No. 33)

3- (furan-2-yl) -4- (3-methoxyphenyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 34)

3- (furan-2-yl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino) -1 H- pyrazole (Compound No. 35)

4- (3-nitrophenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-3- (1-phenethyl) -1 H- pyrazole (Compound No. 36)

5-benzoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3- (1-phenethyl) -1 H- pyrazole (Compound No. 37)

4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-3- (1-phenethyl) -1 H- pyrazole (Compound No. 38)

4- (3-methoxyphenyl) carboxyamino-5-benzoylhydrazinecarbonyl-3- (1-phenethyl) -1 H- pyrazole (Compound No. 39)

3- (3-chlorophenyl) -4- (3-nitrophenyl) carboxyamino-5-propanoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 40)

5- (3-hydroxybenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3- (3-chlorophenyl) -1 H- pyrazole (Compound No. 41)

3- (4-Chlorophenyl) -4- (3-methoxyphenylacetamino) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 42)

3- (4-Chlorophenyl) -4- (3-methoxyphenylacetamino) -5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 43)

3- (4-chlorophenyl) -4- (3-methoxyphenylacetamino) -5-phenylacetylhydrazinecarbonyl-1 H- pyrazole (Compound No. 44)

3- (4-Chlorophenyl) -5-nicotinoylhydrazinecarbonyl-4-pentanecarboxyamino-1 H- pyrazole (Compound No. 45)

5-benzoylhydrazinecarbonyl-3- (4-chlorophenyl) -4-pentanecarboxyamino-1 H- pyrazole (Compound No. 46)

3-isobutyl-5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 47)

5-benzoylhydrazinecarbonyl-3-isobutyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 48)

3-isobutyl-5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino1 H- pyrazole (Compound No. 49)

3-isobutyl-4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 50)

3-isobutyl-4- (3-methoxyphenyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 51)

3-isobutyl-4- (3-methoxyphenyl) carboxyamino-5-isonicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 52)

3-propyl-4- (3-nitrophenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 53)

5-benzoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-propyl-1 H- pyrazole (Compound No. 54)

5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-propyl-1 H- pyrazole (Compound No. 55)

5-benzoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3-propyl-1 H- pyrazole (Compound No. 56)

5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3-propyl-1 H- pyrazole (Compound No. 57)

3- (4-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 58)

3- (4-fluorophenyl) -5-benzoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 59)

3- (4-fluorophenyl) -4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 60)

3- (4-fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 61)

3- (4-fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 62)

5-benzoylhydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 63)

5-isonicotinoylhydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 64)

4-phenylcarboxyamino-3- (4-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 65)

4- (3-nitrophenyl) carboxyamino-3- (3-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 66)

3- (3-fluorobenzyl) -4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 67)

5-benzoylhydrazinecarbonyl-3- (3-fluorophenyl) -4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 68)

3- (3-fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 69)

3- (3-fluorophenyl) -4- (3-methylphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 70)

3- (3-fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 71)

4-phenylcarboxyamino-3- (3-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 72)

4-phenylcarboxyamino-5-benzoylhydrazinecarbonyl-3- (3-fluorophenyl) -1 H- pyrazole (Compound No. 73)

3- (3-fluorophenyl) -4-phenylcarboxyamino-5-isonicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 74)

3- (2-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 75)

3- (2-fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 76)

3- (2-fluorophenyl) -4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 77)

3- (2-fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 78)

3- (2-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 79)

3- (2-fluorophenyl) -4- (3-methylphenyl) carboxyamino-5-isonicotinoylhydrazinecarbonyl) -1 H- pyrazole (Compound No. 80)

4-phenylcarboxyamino-3- (2-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 81)

4-phenylcarboxyamino-3- (2-fluorophenyl) -5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 82)

5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3- (thiophen-2-yl) -1 H- pyrazole (Compound No. 83)

4- (3-nitrophenyl) carboxyamino-3- (thiophen-2-yl) -5-phenylacetylhydrazinecarbonyl-1 H- pyrazole (Compound No. 84)

3- (thiophen-2-yl) -4- (3-nitrophenyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 85)

5- (3-hydroxybenzoyl) hydrazinecarbonyl-3- (thiophen-2-yl) -4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 86)

5-nicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3- (thiophen-2-yl) -1 H- pyrazole (Compound No. 87)

5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3- (thiophen-2-yl) -1 H- pyrazole (Compound No. 88)

4-butylcarboxyamino-5-nicotinoylhydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 89)

5-benzoylhydrazinecarbonyl-3- (4-fluorophenyl) -4-phenylacetylamino-1 H- pyrazole (Compound No. 90)

3- (4-fluorophenyl) -4- (3-methylphenyl) carboxyamino-5- (propanoylhydrazinecarbonyl) -1 H- pyrazole (Compound No. 91)

3- (4-fluorophenyl) -4- (3-methoxyphenylacetyl) amino-5-nicotinoylhydrazine carbonyl-1 H- pyrazole (Compound No. 92)

3- (4-fluorophenyl) -4- (3-methoxyphenylacetyl) amido-5-phenylacetylhydrazinecarbonyl-1 H- pyrazole (Compound No. 93)

3- (2-fluorophenyl) -4- (3-phenylpropyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 94)

3- (2-fluorophenyl) -4- (3-phenylpropyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 95)

5- (2-chlorobenzoyl) hydrazinecarbonyl-4- (2-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 96)

5- (4-chlorobenzoyl) hydrazinecarbonyl-4- (2-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 97)

5- (4-chlorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 98)

5- (2-chlorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 99)

5- (3-chlorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 100)

5- (4-chlorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 101)

5- (3-methoxybenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazol-2-yl}-(Compound No. 102)

5- (4-methoxybenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 103)

5- (3-fluorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 104)

5- (4-fluorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 105)

5- (3-methylbenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 106)

5- (4-Methylbenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 107)

3- (2-fluorophenyl) -4- (3-phenylpropyl) carboxyamino-5- (4-benzylacetyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 108)

4- (3-cyclohexylmethyl) carboxyamino-5- (4-phenacetyl) hydrazinecarbonyl-3- (3-fluorophenyl) -1 H- pyrazole (Compound No. 109)

5- (nicotinoyl) hydrazinecarbonyl4- (3-phenylethyl) carboxyamino-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 110)

5- (4-benzoyl) hydrazinecarbonyl-4- (3-phenylethyl) carboxyamino-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 111)

3- (4-fluorophenyl) -5- (4-phenacetyl) hydrazinecarbonyl-4- (3-phenylethyl) carboxyamino-1 H- pyrazole (Compound No. 112)

5- (4-trimethylphenylacetyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-phenylethyl) carboxyamino-1 H- pyrazole (Compound No. 113)

4- (3-methoxybenzyl) carboxyamino-5- (4-trimethylphenylacetyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 114)

4- (3-methoxybenzyl) carboxyamino-5- (4-methoxybenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 115)

4- (3-methoxybenzyl) carboxyamino-5- (4-trifluoromethylbenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 116)

4- (3-methoxybenzyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 117)

4- (3-methoxybenzyl) carboxyamino-5- (4-fluorobenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 118)

4- (3-methoxybenzyl) carboxyamino-5- (4-chlorobenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 119)

5- (benzoyl) hydrazinecarbonyl-4- (3-methoxybenzyl) carboxyamino-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 120)

3- (thiophen-2-yl) -5- (phenacetyl) hydrazinecarbonyl-4- (3-pentyl) carboxyamino-1 H- pyrazole (Compound No. 121)

5- (methylbenzoyl) hydrazinecarbonyl-3- (thiophen-2-yl) -4- (3-pentyl) carboxyamino-1 H- pyrazole (Compound No. 122)

5- (methoxybenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-fluorophenyl) carboxyamino-1 H- pyrazole (Compound No. 123)

5- (methylbenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-fluorophenyl) carboxyamino-1 H- pyrazole (Compound No. 124)

5- (benzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-fluorophenyl) carboxyamino-1 H- pyrazole (Compound No. 125)

5- (3-methylbenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-phenethyl) carboxyamino-1 H- pyrazole (Compound No. 126)

5- (3-methylbenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 127)

3- (4-Chlorophenyl-4- (phenethyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 128)

3- (4-Chlorophenyl-4- (phenethyl) carboxyamino-5-phenacetylhydrazinecarbonyl-1 H- pyrazole (Compound No. 129)

3- (4-chlorophenyl-4- (3-methoxyphenylacetyl) carboxyamino-5- (4-trimethylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 130)

3- (3-chlorophenyl-4- (3-methylphenylacetyl) carboxyamino-5- (nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 131)

3- (3-chlorophenyl-4- (3-methylphenylacetyl) carboxyamino-5- (benzoylhydrazine carbonyl-1 H- pyrazole (Compound No. 132)

3- (3-chlorophenyl-4-phenylcarboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 133)

3- (3-chlorophenyl) -4-phenylcarboxyamino-5-phenacetylhydrazinecarbonyl-1 H- pyrazole (Compound No. 134)

3- (4-cyclohexylphenyl) -4- (3-nitrophenyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 135)

3- (4-cyclohexylphenyl) -4- (3-methoxyphenyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 136)

3- (4-Chlorophenyl) -4- (cyclohexylacetylphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 137)

3- (4-Chlorophenyl) -4- (3-cyclohexylacetyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 138)

3- (4-Chlorophenyl) -4- (3-cyclohexylacetyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 139)

3- (4-chlorophenyl) -4- (3-phenacetyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 140)

3- (4-Chlorophenyl) -4- (3-cyclohexylacetyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 141)

3- (4-chlorophenyl) -4- (pentyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 142)

3- (4-chlorophenyl) -4- (3-methoxyphenylacetyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 143)

3- (3-chlorophenyl) -4- (phenyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 144)

3- (4-Chlorophenyl) -4- (benzyl) carboxyamino-5- (phenacetyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 145)

3- (phenylethyl) -4- (3-nitrophenyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 146)

3- (3-chlorophenyl) -4- (3-methylphenyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 147)

3- (phenylethyl) -4- (3-nitrophenyl) carboxyamino-5- (phenacetyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 148)

3- (phenylethyl) -4- (3-methoxyphenyl) carboxyamino-5- (methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 149)

3- (phenylethyl) -4- (3-methoxyphenyl) carboxyamino-5- (phenacetyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 150).

On the other hand, the present invention includes a method for preparing a 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivative represented by the formula (1), the preparation method comprises a manufacturing process as shown below:

Iii) converting the beta -diketone compound represented by Formula 2 to a diketo oxime compound represented by Formula 3,

Ii) converting the diketo oxime compound represented by the following formula (3) to the 4-nitroso-1 H -pyrazole compound represented by the following formula (4),

Iii) converting the 4-nitroso-1 H -pyrazole compound represented by the following formula (4) to an aminopyrazole ester compound represented by the following formula (5),

Iii) reacting the aminopyrazole ester compound represented by the following formula (5) with the acyl compound represented by the formula (6), and then hydrolyzing to convert into 4-acylamino-parazol-5-carboxylic acid represented by the following formula (7) process,

Iii) 5-acylhydrazinecarbonyl-3 represented by the following formula (1) by coupling a 4-acylamino-parazol-5-carboxylic acid represented by the following formula (7) with an acyl hydrazine compound represented by the formula (8): Process of conversion to 4-disubstituted pyrazole derivatives.

In Reaction Scheme 1, R ₁ , R ₂ , and R ₃ are each as defined in Chemical Formula 1, and L may be a halogen, alkoxy group, sulfonate group, or phosphate group as a general leaving group.

Referring to the manufacturing method according to the invention in more detail for each manufacturing process as follows. In addition, the β-diketone compound represented by the formula (2) used as a starting material in the production method according to the present invention can be prepared with reference to a method known in the literature (Proic et. Al., Synthesis 1991 , 195-198). For example, the ketone compound, sodium ethoxide and diethyl oxalate may be prepared by reacting under ethanol solvent conditions.

First, the β-diketone compound represented by Chemical Formula 2 is reacted with sodium nitrite to prepare a diketo oxime compound represented by Chemical Formula 3. The reaction solvent is carried out using acetic acid or a mixed solvent of water and acetic acid, the reaction temperature is preferably carried out in a temperature range of 0 ℃ to room temperature, preferably 0 ℃ to 20 ℃. When the reaction is complete, the reaction solution is added in the form of powder such as sodium carbonate, sodium bicarbonate, or in the form of an aqueous solution dissolved in water to adjust the pH of the solution to about 7 to remove acetic acid remaining in the reaction solution.

The diketo oxime compound represented by Chemical Formula 3 is reacted with hydrazine hydrate to prepare 4-nitroso-1 H -pyrazole compound represented by Chemical Formula 4. The reaction solvent is carried out using an alcohol solvent such as methanol, ethanol or a mixed solvent of water and alcohol, the reaction temperature is carried out in the temperature range of 0 ℃ to room temperature, preferably in the temperature range of 0 ℃ to 20 ℃ It is good.

Then, the 4-nitroso-1 H -pyrazole compound represented by Chemical Formula 4 is reduced to prepare an aminopyrazole ester compound represented by Chemical Formula 5. As the reducing agent, any conventional reducing agent can be used, and indium metal is preferably reacted under acidic conditions. At this time, it is also possible to use water, a normal organic solvent or a mixed solvent of water and an organic solvent as the reaction solvent. When the reaction is completed, the pH of the solution is adjusted to about 7 by adding a powder such as sodium carbonate, sodium bicarbonate, or in the form of an aqueous solution dissolved in water to remove the acid remaining in the reaction solution.

Then, after reacting the aminopyrazole ester compound represented by Chemical Formula 5 with the acyl compound represented by Chemical Formula 6, hydrolysis is performed to prepare 4-acylamino-parazol-5-carboxylic acid represented by Chemical Formula 7. do. The reaction can be carried out in the presence of an N, N -dimethylaminopyridine (dMAP) catalyst and an amine base. The amine base can use conventional organic bases, such as triethylamine and pyridine. The reaction temperature is preferably in the temperature range of -20 ℃ to room temperature, preferably in the temperature range of 0 ℃ to 20 ℃. The hydrolysis can be carried out by conventional acid hydrolysis or alkaline hydrolysis methods.

The 4-acylamino-parazol-5-carboxylic acid represented by Chemical Formula 7 and the acyl hydrazine compound represented by Chemical Formula 8 are coupled to each other to prepare a compound represented by Chemical Formula 1. Reagents such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), 1, 3-dicyclohexylcarbodiimide (dCC) may be used as the coupling reaction reagent. The reaction temperature is preferably in the temperature range of -20 ℃ to room temperature, preferably in the temperature range of 0 ℃ to 20 ℃.

On the other hand, the compound represented by the formula (1) according to the present invention has a growth inhibitory effect on various cancer cell lines can be used as an active ingredient of an anticancer agent. Therefore, the present invention includes the anticancer agent or the pharmaceutical composition for anticancer agent containing the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient as a scope. In order to measure the anticancer activity of the compounds according to the present invention, the degree of inhibition of activity against each anticancer cell line was measured, and in particular, the degree of activity inhibition against glycogen synthesis kinase 3β (GSK-3β) was measured. GSK-3β is a serine / threonine kinase and is known as an anticancer agent as a protease similar to cyclin - dependent kinase (CDK). In particular, it has been reported to exhibit anticancer activity by participating in the regulation of TRAIL (tNF-related apoptpsis inducing-ligand) or by regulating P53 - dependent apoptosis. ( molecular. Cancer, Therapeutics , 2003, 2 , 1215; Clin. Cancer. Res . 2005, 65 , 9012; 2005, 11 , 4580).

Pharmaceutically acceptable salts of the compounds represented by Formula 1 used in the preparation of the pharmaceutical composition according to the present invention may be prepared by conventional methods in the art, for example hydrochloric acid, bromic acid, sulfuric acid, Salts with inorganic acids such as sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, etc., formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gesty acid, fumaric acid, lactose Salts with organic acids such as ionic acid, salicylic acid, or acetylsalicylic acid (aspirin), glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline Salts with amino acids such as, salts with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and alkali metals such as sodium and potassium; Metal salts or salts with ammonium ions due to the reaction thereof.

In addition, the pharmaceutical composition of the present invention is a conventional formulation in the pharmaceutical field by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient to the compound represented by the formula (1) or pharmaceutically acceptable salts thereof For example, it can be prepared by oral administration such as tablets, capsules, troches, solutions, suspensions, or parenteral administration, and can be used for the prevention and treatment of various types of tumors.

Excipients that may be used in the pharmaceutical compositions of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth rubber, arginine acid, sodium Alginate, methyl cellulose, sodium carboxymethyl cellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.

In addition, the dosage of the compound represented by Formula 1 according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, based on an adult patient weighing 70 kg In general, 0.01 mg to 5000 mg per day, and may be dividedly administered once to several times a day at regular intervals according to the judgment of a doctor or pharmacist.

[ Example ]

Hereinafter, the present invention will be described in detail with respect to the preparation method and efficacy of the compound according to the present invention through Examples and Experimental Examples. However, these Examples and Experimental Examples are only for helping the understanding of the present invention, the scope of the present invention is not limited to the Examples.

Example 1. 3- (3-Chlorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 1)

(1) Preparation of ( Z ) -ethyl 4- (3-chlorophenyl) -4-hydroxy-2-oxo-3-butanoate (Formula 2)

100 mL of ethanol was added to sodium ethoxide (28 mL, 75 mmol), and the temperature was lowered to 0 ° C., and 3'-chloroacetophenone (6.6 mL, 50 mmol) was added thereto. After 20 minutes, diethyl oxalate (6.9 mL, 50 mmol) was added, and after 20 minutes, the reaction mixture was heated to room temperature and stirred for about 20 hours. Since the product was formed as a solid and was not stirred well, a total of 100 mL of ethanol was added in 20 mL or 30 mL portions. The solvent was removed under reduced pressure, concentrated and then acidified with 1 N HCl at 0 ° C. Extraction with ether was followed by washing with saturated NaCl solution. The extracted organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure and dried to obtain the product (12.4 g, 98%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.88 (d, J = 7.82 Hz, 1 H), 7.59 (d, J = 8.00 Hz, 1H), 7.46 (t, J = 7.86 Hz, 1H), 7.04 (s, 1H), 4.42 (q, J = 7.14 Hz, 2H), 1.43 (t, J = 7.14 Hz, 3H)

(2) Preparation of ( Z ) -ethyl 4- (3-chlorophenyl) -3-hydroxyimino-2,4-dioxobutanoate (Formula 3)

60 mL of acetic acid was added to ( Z ) -ethyl-4- (3-chlorophenyl) -4-hydroxy-2-oxo-3-butanoate (5.98 g, 23.5 mmol), followed by distilled water to 10 to 12 ° C. A solution of NaNO ₂ (1.70 g, 24.7 mmol) dissolved in 15 mL was added. The mixture was stirred at 20 ° C. for 1 hour, and then ether was added thereto. The mixture was extracted with saturated NaHCO ₃ solution until pH ˜7 to remove acetic acid. The extracted organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Obtained the product (5.52 g, 83%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.86 (s, 1H), 7.73 (d, J = 7.73 Hz, 1H), 7.61 (d, J = 8.54 Hz, 1H), 7.48 (t, J = 7.86 Hz , 1H), 4.41 (q, J = 7.11 Hz, 2H), 1.39 (t, J = 7.11 Hz, 3H)

(3) Preparation of ethyl 3- (3-chlorophenyl) -4-nitroso-1 H- pyrazole-5-carboxylate (Formula 4)

55 mL of ethanol was added to ( Z ) -ethyl 4- (3-chlorophenyl) -3- (hydroxyimino) -2,4-dioxobutanoate (5.51 g, 19.4 mmol), and the mixture was cooled to 0 ° C. and hydrazine. Hydrate (1.19 mL, 19.6 mmol) was added. After 20 minutes, the mixture was stirred at room temperature for 3 hours, and ether was added thereto, concentrated under reduced pressure, and dried to obtain a residue product.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.00 (s, 1H), 7.88 (d, J = 8.87 Hz, 1H), 7.53 (d, J = 8.09 Hz, 1H), 7.44 (t, J = 7.76 Hz , 1H), 4.44 (q, J = 7.14 Hz, 2H), 1.42 (t, J = 7.14 Hz, 3H)

(4) Preparation of ethyl 4-amino-3- (3-chlorophenyl-1 H- pyrazole-5-carboxylate (Formula 5)

Aqueous THF solution (H ₂ O / THF = 3/1, v / v in ethyl 3- (3-chlorophenyl) -4-nitroso-1 H- pyrazole-5-carboxylic acid salt (2.57 g, 9.18 mmol) ) 46 mL were added, indium (4.22 g, 36.7 mmol) was added, followed by addition of concentrated hydrochloric acid (4.80 mL) (1.5 eq of indium) and stirred for 3 h. Solid NaHCO ₃ was added until the pH of the solution was 7, diluted with H ₂ O, extracted with ethyl acetate, the organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure. Column chromatography packed with neutral alumina (eluate: hexane / EA = 2/1 → 1/1) afforded the product.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.73 (s, 1H), 7.61 (d, J = 7.47 Hz, 1H), 7.43-7.32 (m, 2H), 5.06 (br, 2H), 4.43 (q, J = 7.12 Hz, 2H), 1.38 (t, J = 7.12 Hz, 3H)

(5) Preparation of ethyl 4- (3-nitrobenzamido) -3- (3-chlorophenyl) -1 H- pyrazole-5-carboxylate (Formula 6)

Ethyl 4-amino-3- (3-chlorophenyl) -1 H- pyrazole-5-carboxylic acid salt (493 mg, 1.86 mmol) and 5.0 mL of methylene chloride were added to a catalytic amount of DMAP, and the pyridine (165 was lowered to 0 ° C. μL, 2.04 mmol) was added. 3-nitrobenzoyl chloride (458 mg, 2.42 mmol) dissolved in methylene chloride was added, and after 30 minutes, the reaction mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with methylene chloride, and the organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure. Column chromatography (eluent: hexane / EA = 1/1 → MC / MeOH = 10/1) afforded the product (648 mg, 84%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.89 (s, 1H), 8.80 (s, 1H), 8.45 (d, J = 7.48 Hz, 1H), 8.30 (d, J = 7.35 Hz, 1H), 7.73 (t, J = 8.00 Hz, 1H), 7.63 (s, 1H), 7.52-7.50 (m, 1H), 7.34-7.33 (m, 2H), 4.33 (q, J = 6.79 Hz, 2H), 1.29 ( t, J = 6.74 Hz, 3H)

(6) Preparation of 4- (3-nitrobenzamido-3- (3-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (Formula 7)

To ethyl 4- (3-nitrobenzamido) -3- (3-chlorophenyl) -1 H- pyrazole-5-carboxylic acid salt (167 mg, 0.402 mmol) was added 3.2 mL (0.125 M) of ethanol, 2 N NaOH (604 μL, 1.21 mmol) was added and stirred at 70 ° C. for 3 hours. After heating to room temperature and acidified with 1 N HCl at 0 ℃, extracted with ether, the organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the product (156 mg, 100%).

¹ H NMR (300 MHz, CD ₃ OD) δ 8.82 (s, 1H), 8.47 (d, J = 8.24 Hz, 1H), 8.34 (d, J = 7.87 Hz, 1H), 7.80 (t, J = 8.00 Hz, 1H), 7.75 (s, 1H), 7.66 (d, J = 6.89 Hz, 1H), 7.45-7.37 (m, 2H)

(7) Preparation of 3- (3-chlorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 1)

4- (3-Nitrobenzamido) -3- (3-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (101 mg, 0.261 mmol), nicotinehydrazide (39.5 mg, 0.288 mmol), ethyl 9.0 mL of acetate was added and DCC (60.0 mg, 0.288 mmol) dissolved in ethyl acetate was added to 0 ° C. After 15 minutes, the mixture was allowed to rise to room temperature and stirred for 3 hours. Then, water was added and extracted with ethyl acetate. The extracted organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure, followed by column chromatography (eluate: MC / MeOH = 10/1 → 7/1 → MeOH) to obtain a product (90.6 mg, 69%).

¹ H NMR (500 MHz, DMSO) δ 9.06 (s, 1H), 8.83 (s, 1H), 8.73 (d, J = 4.92 Hz, 1H), 8.46 (d, J = 8.04 Hz, 1H), 8.37- 8.31 (m, 2H), 7.79 (t, J = 8.10 Hz, 1H), 7.73 (s, 1H), 7.63-7.56 (m, 2H), 7.50-7.45 (m, 2H); ¹³ C NMR (125 MHz, CD ₃ OD) δ 165.4, 164.8, 153.0, 149.1, 148.5, 136.2, 135.9, 134.7, 134.3, 131.6, 131.0, 129.2, 127.0, 126.7, 125.7, 124.3, 123.0

Example 2. 5-benzoylhydrazinecarbonyl-3- (3-chlorophenyl) -4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 2)

4- (3-nitrobenzamido) -3- (3-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (186.1 mg, 0.481 mmol), benzoichydrazide (73.7 mg, 0.529 mmol), 11.0 mL of ethyl acetate was added and DCC (110.3 mg, 0.529 mmol) dissolved in ethyl acetate was added to 0 ° C. After 15 minutes, the mixture was raised to room temperature, stirred for 4 hours, added with water, and extracted with ethyl acetate. The extracted organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure, followed by column chromatography (eluate: MC / MeOH = 10/1 → 7/1 → MeOH) to obtain a product (178.4 mg, 73%).

¹ H NMR (300 MHz, DMSO) δ 8.77 (s, 1H), 8.43 (d, J = 8.16 Hz, 2H), 7.89-7.81 (m, 3H) 7.77 (s, 1H), 7.66 (d, J = 7.33 Hz, 1H), 7.55-7.44 (m, 5H)

Example 3. 3- (3-Chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 3)

(1) Preparation of ethyl 4- (3-methoxybenzamido) -3- (3-chlorophenyl) -1 H- pyrazole-5-carboxylate (Formula 6)

Ethyl 4-amino-3- (3-chlorophenyl) -1 H- pyrazole-5-carboxylic acid salt (504.5 mg, 1.90 mmol) and 5.1 mL of methylene chloride were added to a catalytic amount of DMAP, followed by lowering to 0 ° C. to pyridine (169 μL, 2.09 mmol) was added. 3-methoxybenzoyl chloride (340 μL, 2.47 mmol) was added, and after 20 minutes, it was allowed to rise to room temperature and stirred for 3 hours. Water was added, followed by extraction with methylene chloride. The organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure, and then column chromatography (eluate: MC / MeOH = 15/1 → 10/1) was used to give the product (637 mg, 84%). Got.

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.66 (s, 1H), 7.64 (s, 1H), 7.52-7.48 (m, 3H), 7.41 (t, J = 7.70 Hz, 1H), 7.34-7.32 ( m, 2H), 7.12 (d, J = 8.13 Hz, 1H), 4.40 (q, J = 7.13 Hz, 2H), 1.36 (t, J = 7.13 Hz, 3H)

(2) Preparation of ethyl 4- (3-methoxybenzamido) -3- (3-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (Formula 7)

To ethyl 4- (3-methoxybenzamido) -3- (3-chlorophenyl) -1 H- pyrazole-5-carboxylic acid salt (381 mg, 0.953 mmol) was added 7.6 mL (0.125 M) of ethanol, 2 N NaOH (1.43 mL, 2.86 mmol) was added and stirred at 70 ° C for 2 h. The mixture was heated to room temperature, acidified with 1 N HCl at 0 ° C., extracted with ether, dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain a product (354 mg, 100%).

¹ H NMR (300 MHz, CD ₃ OD) δ 7.77 (s, 1H), 7.66 (d, J = 6.96 Hz, 1H), 7.55-7.50 (m, 2H), 7.46-7.38 (m, 3H), 7.16 (d, J = 8.15 Hz, 1H), 3.87 (s, 3H)

(3) Preparation of 3- (3-chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole

4- (3-methoxybenzamido) -3- (3-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (102.5 mg, 0.276 mmol), isicotinoylhydrazide (41.9 mg, 0.303 mmol) and 6.4 mL of ethyl acetate were added, and DCC (63.5 mg, 0.303 mmol) dissolved in ethyl acetate was added to 0 ° C. After 20 minutes, the mixture was allowed to rise to room temperature, stirred for 4 hours, added with water, and extracted with ethyl acetate. The extracted organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure, followed by column chromatography (eluate: MC / MeOH = 10/1 → MeOH) to obtain a product (128 mg, 95%).

¹ H NMR (300 MHz, CD ₃ OD) δ 9.07 (s, 1H), 8.73 (d, J = 4.94 Hz, 1H) 8.33 (d, J = 8.04 Hz, 1H), 7.73 (s, 1H), 7.62 -7.48 (m, 4H), 7.46-7.39 (m, 3H), 7.14 (d, J = 7.94 Hz, 1H), 3.86 (s, 3H); ¹³ C NMR (75 MHz, CD ₃ OD) δ 159.9, 151.7, 148.0, 136.0, 135.2, 134.4, 130.1, 129.4, 128.9, 128.4, 126.4, 124.8, 123.8, 119.5, 117.8, 112.4, 54.5

Example 4. 5-Benzoylhydrazinecarbonyl-3- (3-chlorophenyl) -4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 4)

4- (3-methoxybenzamido) -3- (3-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (200.1 mg, 0.538 mmol), benzoichydrazide (82.5 mg, 0.592 mmol) Was synthesized in the same manner as in Example 1.

Yield 55%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.93 (d, J = 7.09 Hz, 2H), 7.72 (s, 1H), 7.62-7.39 (m, 9H), 7.14 (d, J = 8.22 Hz, 1H ), 3.86 (s, 3 H)

Example 5. 3- (3-Chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 5)

4- (3-methoxybenzamido) -3- (3-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (117.9 mg, 0.317 mmol), isnicotinhydrazide (48.3 mg, 0.349 mmol) Was synthesized in the same manner as in Example 1.

Yield 69%; ¹ H NMR (300 MHz, CD ₃ OD) δ 8.73 (d, J = 5.86 Hz, 2H), 7.88 (d, J = 5.69 Hz, 2H), 7.73 (s, 1H), 7.62-7.39 (m, 6H ), 7.14 (d, J = 8.02 Hz, 1 H), 3.83 (m, 3 H); ¹³ C NMR (75 MHz, CD ₃ OD) δ 168.6, 159.9, 149.6, 149.5, 135.2, 134.4, 130.1, 129.4, 126.4, 124.8, 121.7, 119.5, 117.8, 112.5, 54.5

Example 6. 3- (4-Chlorophenyl) -4- (3-nitrophenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H -pyrazole (Compound No. 6)

4- (3-nitrobenzamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (306.5 mg, 0.793 mmol), nicotinhydrazide (119.8 mg, 0.872 mmol) was used Synthesis was carried out in the same manner as in Example 1.

Yield 73%; ¹ H NMR (300 MHz, CD ₃ OD) δ 9.06 (s, 1H), 8.83 (s, 1H), 8.73 (d, J = 4.92 Hz, 1H), 8.53 (d, J = 5.70 Hz, 1H), 8.34 (t, J = 8.20 Hz, 2H), 7.78 (t, J = 8.01 Hz, 1H), 7.67 (d, J = 8.54 Hz, 2H), 7.58 (dd, J = 4.96, 7.95 Hz, 1H), 7.49 (d, J = 8.57 Hz, 2H)

Example 7. 5-propanoylhydrazinecarbonyl-3- (4-chlorophenyl) -4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 7)

4- (3-Nitrobenzamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (318 mg, 0.822 mmol), propanoic hydrazide (125.7 mg, 0.904 mmol) It was synthesized in the same manner as in Example 1 using.

Yield 74%; ¹ H NMR (300 MHz, CD ₃ OD) δ 8.82 (s, 1H), 8.45 (d, J = 8.22 Hz, 1H), 8.38 (d, J = 7.71 Hz, 1H), 7.93 (d, J = 7.10 Hz, 2H), 7.78 (t, J = 8.02 Hz, 1H), 7.66 (d, J = 8.52 Hz, 2H), 7.56 (d, J = 7.21 Hz, 1H), 7.51-7.44 (m, 4H)

Example 8. 3- (4-Chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 8)

4- (3-nitrobenzamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (311.5 mg, 0.805 mmol), isnicotinhydrazide (121.8 mg, 0.886 mmol) Synthesis was carried out in the same manner as in Example 1 above.

Yield 43%; ¹ H NMR (300 MHz, CD ₃ OD) δ 8.83 (s, 1H), 8.73 (d, J = 6.10 Hz, 2H), 8.46 (d, J = 8.15 Hz, 1H), 8.36 (d, J = 7.74 Hz, 1H), 7.87 (d, J = 6.12 Hz, 2H), 7.78 (t, J = 8.06 Hz, 1H), 7.67 (d, J = 8.53 Hz, 2H), 7.49 (d, J = 8.51 Hz, 2H); ¹³ C NMR (75 MHz, CD ₃ OD) δ 149.6, 148.4, 133.3, 129.8, 128.8, 128.1, 126.0, 122.4, 121.8

Example 9. 5-benzoylhydrazinecarbonyl-3- (4-chlorophenyl) -4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 9)

(1) Preparation of ethyl 4- (3-methoxybenzamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylate

Ethyl 4-amino-3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid salt (831.7 mg, 3.13 mmol) and 8.3 mL of methylene chloride were added to a catalytic amount of DMAP, followed by lowering to 0 deg. μL, 3.44 mmol) was added. 3-methoxybenzoyl chloride (474 μL, 3.44 mmol) was added and the mixture was raised to room temperature after 30 minutes and stirred for 3.5 hours. After addition of water, the mixture was extracted with methylene chloride, and the organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure, followed by column chromatography (eluate: MC / MeOH = 20/1) to obtain a product (1.12 g, 89%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.70 (s, 1H), 7.57 (d, J = 8.44 Hz, 2H), 7.51-7.41 (m, 3H), 7.37 (d, J = 8.40 Hz, 2H) , 4.39 (q, J = 7.10 Hz, 2H), 3.86 (s, 3H), 1.34 (t, J = 7.10 Hz, 3H)

(2) Preparation of ethyl 4- (3-methoxybenzamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylate

To ethyl 4- (3-methoxybenzamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid salt (947 mg, 2.37 mmol) was added 18.9 mL (0.125 M) of ethanol. N NaOH (3.55 mL, 7.10 mmol) was added and stirred at 70 ° C for 2 h. After raising to room temperature, acidified with 1 N HCl at 0 ° C., extracted with ether, the organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain a product (880 mg, 100%).

¹ H NMR (300 MHz, CD ₃ OD) δ 7.71 (d, J = 8.61 Hz, 2H), 7.55-7.50 (m, 2H), 7.46-7.40 (m, 3H), 7.16 (d, J = 8.18 Hz , 1H), 3.87 (s, 3H)

(3) Preparation of 5-benzoylhydrazinecarbonyl-3- (4-chlorophenyl) -4- (3-nitrophenyl) carboxyamino-1 H- pyrazole

4- (3-methoxybenzamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (316 mg, 0.850 mmol), benzoichydrazide (128.4 mg, 0.935 mmol) It was synthesized in the same manner as in Example 1 using.

Yield 45%; ¹ H NMR (300 MHz, CD ₃ OD) δ 9.07 (s, 1H), 8.71 (d, J = 4.89 Hz, 1H), 8.33 (d, J = 8.10 Hz, 1H), 7.64 (d, J = 8.47 Hz, 2H), 7.59-7.51 (m, 3H), 7.47-7.39 (m, 3H), 7.14 (d, J = 8.20 Hz, 1H), 3.79 (s, 3H)

Example 10. 5-Benzoylhydrazinecarbonyl-3- (4-chlorophenyl) -4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 10)

4- (3-methoxybenzamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (325.3 mg, 0.875 mmol), benzoichydrazide (133.7 mg, 0.963 mmol) It was synthesized in the same manner as in Example 1 using.

Yield 90%; ¹ H NMR (300 MHz, CD ₃ OD) δ 8.33 (d, J = 8.61 Hz, 2H), 7.71 (d, J = 7.17 Hz, 2H), 7.60-7.43 (m, 5H), 7.37 (t, J = 7.83 Hz, 1H), 7.26 (d, J = 7.57 Hz, 2H), 7.04 (d, J = 8.61 Hz, 1H), 3.79 (s, 3H)

Example 11. 5-nicotinoylhydrazinecarbonyl-3- (4-chlorophenyl) -4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 11)

4- (3-methoxybenzamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (322.5 mg, 0.868 mmol), nicotinhydrazide (131 mg, 0.954 mmol) Synthesis was carried out in the same manner as in Example 1 above.

Yield 42%; ¹ H NMR (300 MHz, CD ₃ OD) δ 8.73 (d, J = 6.12 Hz, 2H), 7.87 (d, J = 6.12 Hz, 2H), 7.66 (d, J = 8.32 Hz, 2H), 7.56- 7.47 (m, 4H), 7.41 (t, J = 8.02 Hz, 1H), 7.15 (d, J = 8.53 Hz, 1H), 3.86 (s, 3H)

Example 12. 3- (4-Chlorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 12)

(1) Preparation of ethyl 4- (3-methylbenzamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylate

Example using ethyl 4-amino-3- (4-chlorophenyl) -1 H -pyrazole-5-carboxylic acid salt (804.5 mg, 3.03 mmol) and m-toluoylchloride (443.4 μL, 3.33 mmol) Synthesis was carried out in the same manner as in 1.

Yield 86%; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.64 (s, 1H), 7.73 (br, 2H), 7.57 (d, J = 8.55 Hz, 2H), 7.42-7.36 (m, 4H), 4.41 (q, J = 7.11 Hz, 2H), 2.44 (s, 3H), 1.37 (t, J = 7.11 Hz, 3H)

(2) Preparation of ethyl 4- (3-methylbenzamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (300 MHz, CD ₃ OD) δ 7.78-7.69 (m, 4H), 7.45-7.39 (m, 4H), 2.44 (s, 3H)

(3) Preparation of 3- (4-chlorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxyamino-1 H- pyrazole

4- (3-methylbenzamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (450.6 mg, 0.949 mmol), nicotinhydrazide (143.4 mg, 1.04 mmol) was used Synthesis was carried out in the same manner as in Example 1.

Yield 42%; ¹ H NMR (300 MHz, CD ₃ OD) δ 9.06 (s, 1H), 8.74 (d, J = 4.92 Hz, 1H), 8.33 (d, J = 8.03 Hz, 1H), 7.79 (s, 1H), 7.75 (d, J = 6.69 Hz, 1H), 7.66 (d, J = 8.31 Hz, 2H), 7.58 (dd, J = 4.95, 8.00 Hz, 1H), 7.47 (d, J = 8.47 Hz, 2H), 7.42-7.35 (m, 2H), 2.42 (s, 3H)

Example 13. 3- (4-Chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 13)

4- (3-methylbenzamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (339 mg, 0.953 mmol), isicotinhydrazide (144 mg, 1.05 mmol) Synthesis was carried out in the same manner as in Example 1 above.

Yield 42%; ¹ H NMR (300 MHz, CD ₃ OD) δ 8.73 (d, J = 6.16 Hz, 2H), 7.87 (d, J = 6.16 Hz, 2H), 7.79-7.74 (m, 2H), 7.66 (d, J = 8.41 Hz, 2H), 7.47 (d, J = 8.56 Hz, 2H), 7.40-7.38 (m, 2H), 2.42 (s, 3H)

Example 14 4-phenylcarboxyamino-3- (4-chlorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 14)

(1) Preparation of ethyl 4-benzamido-3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylate

Ethyl 4-amino-3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid salt (782 mg, 2.94 mmol), benzoyl chloride (379.3 μL, 3.24 mmol) as in Example 1 above Synthesized by the method.

Yield 80%; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.94 (d, J = 7.42 Hz, 2H), 7.62-7.49 (m, 5H), 7.37 (d, J = 8.38 Hz, 2H), 4.40 (q, J = 7.10 Hz, 2H), 1.36 (t, J = 7.10 Hz, 3H)

(2) Preparation of 4-benzamido-3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (300 MHz, CD ₃ OD) δ 7.96 (d, J = 7.06 Hz, 2H), 7.71 (d, J = 8.58 Hz, 2H), 7.59 (d, J = 7.24 Hz, 1H), 7.54- 7.50 (m, 2H), 7.44 (d, J = 8.60 Hz, 2H)

(3) Preparation of 4-phenylcarboxyamino-3- (4-chlorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (benzamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (261.5 mg, 0.765 mmol), nicotinhydrazide (115.5 mg, 0.842 mmol) Synthesis was carried out in the same manner as in Example 1.

¹ H NMR (300 MHz, CD ₃ OD) δ 9.07 (s, 1H), 8.73 (d, J = 4.95 Hz, 1H), 8.33 (d, J = 8.11 Hz, 1H), 7.67 (d, J = 7.07 Hz, 2H), 7.66 (d, J = 8.55 Hz, 2H), 7.60-7.56 (m, 2H), 7.53-7.46 (m, 4H)

Example 15. 4-phenylcarboxamido-5-benzoylhydrazinecarbonyl-3- (4-chlorophenyl) -1 H- pyrazole (Compound No. 15)

4- (benzamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (260.3 mg, 0.762 mmol), benzoichydrazide (116.7 mg, 0.838 mmol) Synthesis was carried out in the same manner as in Example 1.

Yield 80%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.98-7.91 (m, 4H), 7.66 (d, J = 8.51 Hz, 2H), 7.59 (t, J = 7.20 Hz, 2H), 7.52-7.46 (m , 6H)

Example 16. 4-phenylcarboxyamino-3- (4-chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 16)

4- (benzamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (263.3 mg, 0.770 mmol), isonicotinhydrazide (116.3 mg, 0.848 mmol) Synthesis was carried out in the same manner as in Example 1.

Yield 43%; ¹ H NMR (300 MHz, CD ₃ OD) δ 8.71-8.68 (m, 2H), 7.98 (d, J = 7.16 Hz, 2H), 7.89 (d, J = 5.77 Hz, 2H), 7.76 (d, J = 6.20 Hz, 1H), 7.66-7.45 (m, 6H).

Example 17. 3- (2-Chlorophenyl) -4- (3-nitrophenyl) carboxyamino-5-nicotinoyl hydrazinecarbonyl-1 H- pyrazole (Compound No. 17)

(1) Preparation of ( Z ) -ethyl 4- (2-chlorophenyl) -4-hydroxy-2-oxo-3-butanoate

100 mL of ethanol was added to sodium ethoxide (28 mL, 75 mmol), and the temperature was lowered to 0 ° C. and 2'-chloroacetophenone (6.7 mL, 50 mmol) was added thereto. After 20 minutes, diethyl oxalate (6.9 mL, 50 mmol) was added, and after 20 minutes, the mixture was stirred to room temperature overnight. The solvent was removed under reduced pressure, concentrated and then acidified with 1N HCl. Extracted with ether and washed with saturated NaCl solution. The extracted organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure and dried to obtain the product (9.83 g, 77%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.66 (d, J = 8.45 Hz, 1H), 7.55-7.41 (m, 3H), 6.98 (s, 1H), 4.40 (q, J = 7.13 Hz, 2H) , 1.41 (t, J = 7.13 Hz, 3H)

(2) Preparation of ( Z ) -ethyl 4- (2-chlorophenyl) -3-hydroxyimino-2,4-dioxobutanoate

97.6 mL of acetic acid was added to ( Z ) -ethyl4- (2-chlorophenyl) -4-hydroxy-2-oxo-3-butanoate (9.77 g, 38.4 mmol), and the mixture was diluted to 10 to 12 ° C and distilled water 24 A solution of NaNO ₂ (2.78 g, 40.3 mmol) dissolved in mL was added. The mixture was stirred at 20 ° C. for 1 hour, and then ether was added. The mixture was extracted with saturated NaHCO ₃ solution until pH ˜7 to remove acetic acid. The extracted organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to dry the product. (7.25 g, 67%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.86 (d, J = 7.77 Hz, 1H), 7.54-7.36 (m, 3H), 4.38 (q, J = 7.15 Hz, 2H), 1.38 (t, J = 7.19 Hz, 3H)

(3) Preparation of ethyl 3- (2-chlorophenyl) -4-nitroso-1 H- pyrazole-5-carboxylate

72 mL of ethanol was added to ( Z ) -ethyl4- (2-chlorophenyl) -3- (hydroxyimino) -2,4-dioxobutanoate (7.23 g, 25.5 mmol), and the mixture was cooled to 0 ° C. and hydrazine. Hydrate (2.01 mL, 25.7 mmol) was added. After 20 minutes, the mixture was stirred at room temperature for 3 hours, and ether was added thereto, concentrated under reduced pressure, and dried to obtain a residue product.

(4) Preparation of ethyl 4-amino-3- (2-chlorophenyl-1 H- pyrazole-5-carboxylate

Water-soluble THF solution (H ₂ O / THF = 3/1, in residue ethyl 3- (2-chlorophenyl) -4-nitroso-1 H- pyrazole-5-carboxylic acid salt (8.99 g, 32.2 mmol) v / v) 160 mL was added, indium (14.8 g, 128.6 mmol) was added, followed by addition of concentrated hydrochloric acid (17 mL) (1.5 eq of indium) and stirred for 3 h. After adding until solid pH 7 with NaHCO ₃ , diluted with H ₂ O and extracted with ethyl acetate, the organic layer was dried over MgSO ₄ and filtered, and then concentrated under reduced pressure. Neutral alumina packed column chromatography (eluent: hexane / EA = 2/1 → 1/1 → EA) gave the product (3.32 g).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.53-7.48 (m, 2H), 7.40-7.35 (m, 2H), 4.43 (q, J = 7.14 Hz, 2H), 4.24 (br, 2H), 1.43 ( t, J = 7.14 Hz, 3H)

(5) Preparation of ethyl 4- (3-nitrobenzamido) -3- (2-chlorophenyl-1 H- pyrazole-5-carboxylate

Ethyl 4-amino-3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylic acid salt (723.7 mg, 2.72 mmol) was added 7.2 mL of methylene chloride to a catalytic amount of DMAP, and the pyridine (243 was lowered to 0 ° C. μL, 3.0 mmol) was added. 3-nitrobenzoyl chloride (567.8 mg, 3.0 mmol) dissolved in methylene chloride was added, and after 30 minutes, the reaction mixture was heated to room temperature and stirred for 3.5 hours. Water was added, followed by filtration and concentration under reduced pressure to give the product (900 mg, 80%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.41 (br, 1H), 8.73 (s, 1H), 8.63 (d, J = 4.24 Hz, 1H), 8.40 (d, J = 8.12 Hz, 1H), 8.20 (d, J = 7.68 Hz, 1H), 7.68 (t, J = 8.02 Hz, 1H), 7.56-7.53 (m, 1H), 7.50-7.47 (m, 1H), 7.43-7.38 (m, 1H), 4.49 (q, J = 7.11 Hz, 2H), 1.46 (t, J = 7.11 Hz, 3H)

(6) Preparation of ethyl 4- (3-nitrobenzamido) -3- (2-chlorophenyl-1 H- pyrazole-5-carboxylic acid

To ethyl 4- (3-nitrobenzamido) -3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylic acid salt (897.4 g, 2.16 mmol) was added 17.3 mL (0.125 M) of ethanol. N NaOH (3.25 mL, 6.49 mmol) was added and stirred at 70 ° C for 2 h. After heating up to room temperature and acidified with 1 N HCl at 0 ° C., extracted with ether, the organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain a product (836 g, 100%).

¹ H NMR (300 MHz, CD ₃ OD) δ 8.72 (s, 1H), 8.43 (d, J = 7.79 Hz, 1H), 8.24 (d, J = 7.66 Hz, 1H), 7.74 (t, J = 7.95 Hz, 1H), 7.56-7.50 (m, 2H), 7.45-7.39 (m, 2H)

(7) Preparation of 3- (2-chlorophenyl) -4- (3-nitrobenzamido) -5-nicotinoylhydrazinecarbonyl-1 H -pyrazole

4- (3-nitrobenzamido) -3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (306.4 mg, 0.792 mmol), nicotinhydrazide (119.5 mg, 0.872 mmol), ethyl 18.4 mL of acetate was added and methylene chloride (136.3 μL, 0.872 mmol) was added to 0 ° C. After 20 minutes, the mixture was stirred at room temperature for 4 hours, filtered, concentrated under reduced pressure, and water was added to give a product (209 mg, 52%).

¹ H NMR (300 MHz, CD ₃ OD) δ 9.08 (s, 1H), 8.75-8.72 (m, 2H), 8.41 (d, J = 8.48 Hz, 1H), 8.34 (d, J = 8.15 Hz, 1H ), 8.26 (d, J = 8.04 Hz, 1H), 7.74 (t, J = 8.02 Hz, 1H), 7.61-7.53 (m, 3H), 7.48-7.41 (m, 2H)

Example 18. 3- (2-Chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 18)

4- (3-nitrobenzamido) -3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (301 mg, 0.778 mmol), isnicotinhydrazide (117.7 mg, 0.856 mmol), 18.1 mL of ethyl acetate was added and methylene chloride (133.9 μL, 0.856 mmol) was added to 0 ° C. After 20 minutes, the mixture was allowed to rise to room temperature, stirred for 4 hours, added with water, and extracted with ethyl acetate. The extracted organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure, followed by column chromatography (eluate: MC / MeOH = 10/1 → 7/1 → MeOH) to obtain a product (246 mg, 63%).

¹ H NMR (300 MHz, CD ₃ OD) δ 8.72-8.68 (m, 3H), 8.42 (d, J = 8.15 Hz, 1H), 8.27 (d, J = 7.39 Hz, 1H), 7.90 (d, J = 6.07 Hz, 2H), 7.77-7.71 (m, 1H), 7.58-7.52 (m, 2H), 7.46-7.41 (m, 2H)

Example 19. 3- (2-Chlorophenyl) -4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 19)

(1) Preparation of ethyl 4- (3-methoxybenzamido) -3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylate

Ethyl 4-amino-3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylic acid salt (835.5 mg, 3.145 mmol) was added 8.3 mL of methylene chloride to a catalytic amount of DMAP, and the pyridine (280.3) was lowered to 0 deg. μL, 3.46 mmol) was added. 3-methoxybenzoyl chloride (476.1 μL, 3.46 mmol) was added, and after 30 minutes, it was allowed to rise to room temperature and stirred for 3.5 hours. After addition of water, the mixture was extracted with methylene chloride, and the organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure, and column chromatography (eluate: MC / MeOH = 17/1) gave a product (908 mg, 72%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.20 (br, 1H), 7.53-7.50 (m, 1H), 7.47-7.35 (m, 6H), 7.08 (d, J = 8.03 Hz, 1H), 4.47 ( q, J = 7.16 Hz, 2H), 3.83 (s, 3H), 1.44 (t, J = 7.16 Hz, 3H)

(2) Preparation of ethyl 4- (3-methoxybenzamido) -3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylic acid

To ethyl 4- (3-methoxybenzamido) -3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylic acid salt (895 mg, 2.24 mmol) was added 17.9 mL (0.125 M) of ethanol, 2 N NaOH (3.36 mL, 6.72 mmol) was added and stirred at 70 ° C for 2 h. After raising to room temperature, acidified with 1 N HCl at 0 ° C., extracted with ether, the organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain a product (832 mg, 100%).

¹ H NMR (300 MHz, CD ₃ OD) δ 7.52-7.49 (m, 2H), 7.44-7.37 (m, 5H), 7.11 (d, J = 7.79 Hz, 1H), 3.83 (s, 3H)

(3) Preparation of 3- (2-chlorophenyl) -4- (3-methoxyphenyl) carboxyamino) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (3-methoxybenzamido) -3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (306 mg, 0.823 mmol), nicotinhydrazide (124.5 mg, 0.905 mmol), 19.1 mL of ethyl acetate was added and methylene chloride (141.6 μL, 0.905 mmol) was added to 0 ° C. After 20 minutes, the reaction mixture was warmed to room temperature, stirred for 4 hours, filtered, concentrated under reduced pressure, and the product (232.9 mg, 58%) was obtained.

¹ H NMR (300 MHz, CD ₃ OD) δ 9.08 (s, 1H), 8.74 (d, J = 4.92 Hz, 1H), 8.35 (d, J = 8.00 Hz, 1H), 7.62-7.52 (m, 3H ), 7.46-7.34 (m, 5H), 7.10 (d, J = 8.08 Hz, 1H), 3.82 (s, 3H)

Example 20. 3- (2-Chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 20)

4- (3-methoxybenzamido) -3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (288.7 mg, 0.777 mmol), isnicotinhydrazide (117.5 mg, 0.854 mmol) Was used to give the product (205.5 mg, 54%).

¹ H NMR (300 MHz, CD ₃ OD) δ 8.74 (d, J = 6.16 Hz, 2H), 7.89 (d, J = 6.15 Hz, 2H), 7.57-7.51 (m, 2H), 7.45-7.34 (m , 5H), 7.10 (d, J = 8.05 Hz, 1H), 3.82 (s, 3H)

Example 21. 3- (2-Chlorophenyl) -4- (3-methylphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 21)

(1) Preparation of ethyl 4- (3-methylbenzamido) -3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylate

Ethyl 4-amino-3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylic acid salt (759.3 mg, 2.86 mmol) and 7.6 mL of methylene chloride were added to a catalytic amount of DMAP, followed by lowering to 0 ° C. and pyridine (254.8). μL, 3.14 mmol) was added. m -toluylchloride (418.5 μL, 3.14 mmol) was added, and after 30 minutes, it was allowed to rise to room temperature and stirred for 3.5 hours. After addition of water, the mixture was extracted with methylene chloride, and the organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure, and column chromatography (eluate: MC / MeOH = 17/1) gave a product (491.2 mg, 45%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.17 (br, 1H), 8.63 (d, J = 4.19 Hz, 1H), 7.82 (d, J = 7.52 Hz, 1H), 7.70-7.66 (m, 2H) , 7.44-7.33 (m, 4H), 4.47 (q, J = 7.12 Hz, 2H), 2.40 (s, 3H), 1.43 (t, J = 7.12 Hz, 3H)

(2) Preparation of 4- (3-methylbenzamido) -3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (300 MHz, CD ₃ OD) δ 7.67-7.62 (m, 2H), 7.52-7.36 (m, 6H), 2.39 (s, 3H)

(3) Preparation of 3- (2-chlorophenyl) -4- (3-methylphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (3-methylbenzamido) -3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (218.6 mg, 0.614 mmol), nicotinhydrazide (93.1 mg, 0.676 mmol) was used To obtain the product.

¹ H NMR (300 MHz, CD ₃ OD) δ 9.10 (s, 1H), 8.74 (t, J = 5.03 Hz, 1H), 8.36 (d, J = 6.03 Hz, 1H), 7.68-7.51 (m, 5H ), 7.45-7.36 (m, 4H), 2.39 (s, 3H)

Example 22. 3- (2-Chlorophenyl) -4- (3-phenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 22)

(1) Preparation of ethyl 4-benzamido-3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylate

Ethyl 4-amino-3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylic acid salt (832.8 mg, 3.13 mmol) and 8.3 mL of methylene chloride were added to the catalytic amount of DMAP, and the pyridine (279.4 was lowered to 0 deg. μL, 3.45 mmol) was added. Benzoyl chloride (403.9 μL, 3.45 mmol) was added, and after 30 minutes, it was allowed to rise to room temperature and stirred for 3.5 hours. Water was added, followed by extraction with methylene chloride. The organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure, and column chromatography (eluent: MC / MeOH = 17/1 → 10/1) gave the product (552.9 mg, 48%). Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.22 (br, 1H), 8.63 (d, J = 4.16 Hz, 1H), 7.87 (d, J = 7.27 Hz, 1H), 7.82 (t, J = 7.21 Hz , 1H), 7.52-7.27 (m, 6H), 4.47 (q, J = 7.17 Hz, 2H), 1.43 (t, J = 7.17 Hz, 3H)

(2) Preparation of 4-benzamido-3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (300 MHz, CD ₃ OD) δ 7.85 (d, J = 7.24 Hz, 1H), 7.53-7.38 (m, 8H)

(3) Preparation of 3- (2-chlorophenyl) -4- (3-phenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

The product was purified using 4- (benzamido) -3- (2-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (250.6 mg, 0.733 mmol), nicotinhydrazide (110.9 mg, 0.807 mmol). Prepared.

¹ H NMR (300 MHz, CD ₃ OD) δ 9.09 (s, 1H), 8.73 (d, J = 5.00 Hz, 1H), 8.35 (d, J = 7.97 Hz, 1H), 7.86 (d, J = 7.28 Hz, 1H), 7.62-7.38 (m, 9H)

Example 23. 5-Benzoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 23)

(1) Preparation of ( Z ) -ethyl 4-hydroxy-2-oxo-4- [4- (piperidin-1-yl) phenyl] -3-butanoate

130 mL of ethanol was added to sodium ethoxide (42 mL, 112.5 mmol), and cooled to 0 ° C. to 4-piperidinoacetophenone (15.7 g, 75 mmol). After 20 minutes, diethyl oxalate (10.8 mL, 78.8 mmol) was added, and after 20 minutes, the reaction mixture was heated to room temperature and stirred for about 72 hours. Since the product was formed as a solid, and the stirring was not good, a total of 130 mL ethanol was added in 20 or 30 mL portions. The solvent was prepared under reduced pressure, concentrated and acidified with 1N HCl. Washed with saturated NaCl solution extracted with ether. The extracted organic layer was dried over MgSO ₄ , filtered, concentrated under reduced pressure and dried to obtain the product (21.2 g, 93%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.94 (d, J = 9.05 Hz, 2H), 7.07 (br, 2H), 7.01 (s, 1H), 4.39 (q, J = 7.14 Hz, 2H), 3.45 (br, 4H), 1.80 (br, 4H), 1.72 (br, 2H), 1.41 (t, J = 7.14 Hz, 3H)

(2) Preparation of ( Z ) -ethyl 3-hydroxyimino-2,4-dioxo-4- [4- (piperidin-1-yl) phenyl] butanoate

94.3 mL of acetic acid was added to ( Z ) -ethyl 4-hydroxy-2-oxo-4- (4- (piperidin-1-yl) phenyl) -3-butanoate (11.25 g, 37.1 mmol), A solution of NaNO ₂ (2.69 g, 38.9 mmol) dissolved in 23 mL of distilled water was added to the solution at 10 to 12 ° C. The mixture was heated to 20 ° C. and stirred for 1 hour. Then, ether was added and extracted with saturated NaHCO ₃ solution until pH ˜7 to remove acetic acid. The extracted organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure and dried. (10.4 g, 85%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.72 (d, J = 9.10 Hz, 2H), 6.85 (d, J = 9.24 Hz, 2H), 4.40 (q, J = 7.14 Hz, 2H), 3.44 (br , 4H), 1.72 (br, 6H), 1.38 (t, J = 7.14 Hz, 3H)

(3) Preparation of ethyl 4-nitroso-3-([4- (piperidin-1-yl) phenyl] -1 H- pyrazole-5-carboxylate

( Z ) -Ethyl 3- (hydroxyimino) -2,4-dioxo-4- (4- (piperidin-1-yl) phenyl) butanoate (10.4 g, 31.3 mmol) in ethanol 88.7 mL Was added, and the hydrazine hydrate (2.36 mL, 31.6 mmol) was added to 0 ° C. After 20 minutes, the mixture was stirred at room temperature for 3 hours, ether was added thereto, concentrated under reduced pressure, and dried to obtain a product (8.32 g, 81%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 3.45 (br, 4H), 1.80 (br, 4H), 1.72 (br, 2H)

(4) Preparation of ethyl 4-amino-3- [4- (piperidin-1-yl) phenyl] -1 H- pyrazole-5-carboxylate

Aqueous THF solution (H ₂ O / THF) in ethyl 4-nitroso-3- (4- (piperidin-1-yl) phenyl) -1 H- pyrazole-5-carboxylic acid salt (8.32 g, 25.3 mmol) = 3/1, v / v) 126.7 mL were added, indium (11.6 g, 101 mmol) was added, followed by addition of concentrated hydrochloric acid (13.4 mL) (1.5 eq of indium) and stirred for 3 hours. After adding until solid pH 7 with NaHCO ₃ , diluted with H ₂ O and extracted with ethyl acetate, the organic layer was dried over MgSO ₄ and filtered, and then concentrated under reduced pressure. Column chromatography packed with neutral alumina (eluent: hexane / EA = 1/1 → 1/2 → EA) afforded the product (4.18 g, 52%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.56 (d, J = 8.77 Hz, 2H), 7.02 (d, J = 8.80 Hz, 2H), 4.42 (q, J = 7.13 Hz, 2H), 3.24 (t , J = 5.12 Hz, 4H), 1.73 (br, 4H), 1.63 (br, 2H), 1.42 (t, J = 7.13 Hz, 3H)

(5) Preparation of ethyl 4- (3-nitrobenzamido) -3-([4- (piperidin-1-yl) phenyl] -1 H- pyrazole-5-carboxylate

Ethyl 4-amino-3- (4- (piperidin-1-yl) phenyl) -1 H- pyrazole-5-carboxylic acid salt (908.5 mg, 2.89 mmol) was added 7.7 mL of methylene chloride to a catalytic amount of DMAP. Pyridine (257.6 μL, 3.18 mmol) was added to 0 ° C. 3-nitrobenzoyl chloride (712.3 mg, 3.76 mmol) dissolved in methylene chloride was added thereto, followed by stirring at room temperature for 30 minutes and stirring for 3.5 hours. After addition of water, filtration and concentration under reduced pressure afforded the product (1.24 g, 92%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.80 (s, 1H), 8.72 (br, 1H), 8.43 (d, J = 7.61 Hz, 1H), 8.30 (d, J = 6.35 Hz, 1H), 7.71 (t, J = 7.97 Hz, 1H), 7.47 (d, J = 8.22 Hz, 2H), 6.97 (d, J = 7.47 Hz, 2H), 4.32 (q, J = 7.00 Hz, 2H), 3.23 (br , 4H), 1.71 (br, 4H), 1.60 (br, 2H), 1.30 (t, J = 6.60 Hz, 3H)

(6) Preparation of ethyl 4- (3-nitrobenzamido) -3-([4- (piperidin-1-yl) phenyl] -1 H- pyrazole-5-carboxylic acid

¹ H NMR (300 MHz, CD ₃ OD) δ 8.83 (s, 1H), 8.46 (d, J = 8.15 Hz, 1H), 8.34 (d, J = 7.78 Hz, 1H), 7.79 (t, J = 8.01 Hz, 1H), 7.57 (d, J = 8.83 Hz, 2H), 7.03 (d, J = 8.90 Hz, 2H), 3.23 (br, 4H), 1.71 (br, 4H), 1.63 (br, 2H)

(7) Preparation of 5-benzoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole

4- (3-nitrobenzamido) -3- (4- (piperidin-1-yl) phenyl) -1 H- pyrazole-5-carboxylic acid (414.8 mg, 0.953 mmol), benzoichydrazide (143.7 mg, 1.05 mmol) was used to give the product (210.5 mg, 47%).

¹ H NMR (300 MHz, CD ₃ OD) δ 9.06 (s, 1H), 8.82 (s, 1H), 8.72 (d, J = 4.91 Hz, 1H), 8.44 (d, J = 7.77 Hz, 1H), 8.37-8.31 (m, 2H), 7.76 (t, J = 7.98 Hz, 1H), 7.59-7.52 (m, 3H), 6.99 (d, J = 8.80 Hz, 2H), 3.21 (br, 4H), 1.69 (br, 4H), 1.63 (br, 2H)

Example 24. 5-Isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 24)

4- (3-nitrobenzamido) -3- (4- (piperidin-1-yl) phenyl) -1 H- pyrazole-5-carboxylic acid (503.6 mg, 1.16 mmol), isnicotinhydrazide (174.5 mg, 1.27 mmol) was used to give the product (258.8 mg, 40%).

¹ H NMR (300 MHz, CD ₃ OD) δ 8.83 (s, 1H), 8.72 (d, J = 6.07 Hz, 2H), 8.45 (d, J = 8.19 Hz, 1H), 8.36 (d, J = 7.85 Hz, 1H), 7.87 (d, J = 6.10 Hz, 2H), 7.77 (t, J = 8.00 Hz, 1H), 7.54 (d, J = 8.73 Hz, 2H), 7.01 (d, J = 8.83 Hz, 2H), 3.22 (br, 4H), 1.70 (br, 4H), 1.63 (br, 2H)

Example 25. 4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 25)

(1) Preparation of ethyl 4- (3-methoxybenzamido) -3- (4- (piperidin-1-yl) phenyl) -1 H- pyrazole-5-carboxylic acid salt

Ethyl 4-amino-3- (4- (piperidin-1-yl) phenyl) -1 H- pyrazole-5-carboxylic acid salt (911.7 mg, 2.90 mmol) and 7.7 mL of methylene chloride were added to a catalytic amount of DMAP. Pyridine (258.5 μL, 3.19 mmol) was added to 0 ° C. 3-methoxybenzoyl chloride (518.9 μL, 3.77 mmol) was added, and after 20 minutes, it was allowed to rise to room temperature and stirred for 3.5 hours. After addition of water, the mixture was extracted with methylene chloride, and the organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure, followed by column chromatography (eluate: MC / MeOH = 15/1) to obtain a product (1.29 g, 99%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.59 (s, 1H), 7.52-7.50 (m, 4H), 7.40 (t, J = 8.12 Hz, 1H), 7.12-7.09 (m, 3H), 4.35 ( q, J = 7.12 Hz, 2H), 3.87 (s, 3H), 3.25 (br, 4H), 1.80 (br, 4H), 1.62 (br, 2H), 1.32 (t, J = 7.12 Hz, 3H)

(2) Preparation of 3-[(4-piperidin-1-yl) phenyl] -4- (3-methoxybenzamido) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (300 MHz, CD ₃ OD) δ 7.57-7.52 (m, 4H), 7.41 (t, J = 8.00 Hz, 1H), 7.14 (d, J = 8.16 Hz, 1H), 6.99 (d, J = 8.83 Hz, 2H), 3.86 (s, 3H), 3.21 (br, 4H), 1.70 (br, 4H), 1.62 (br, 2H)

(3) Preparation of 4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole

4- (3-methoxybenzamido) -3- (4- (piperidin-1-yl) phenyl) -1 H- pyrazole-5-carboxylic acid (440.2 mg, 1.05 mmol), nicotinhydrazide (158.2 mg, 1.15 mmol) was used to obtain the product.

¹ H NMR (300 MHz, CD ₃ OD) δ 9.07 (s, 1H), 8.73 (d, J = 4.91 Hz, 1H), 8.33 (d, J = 8.09 Hz, 1H), 7.60-7.54 (m, 5H ), 7.41 (t, J = 7.85 Hz, 1H), 7.14 (d, J = 7.87 Hz, 1H), 7.02 (d, J = 8.67 Hz, 2H), 3.86 (s, 3H), 3.23 (br, 4H ), 1.70 (br, 4H), 1.63 (br, 2H)

Example 26. 5-Isnicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound Number 26)

4- (3-methoxybenzamido) -3- (4- (piperidin-1-yl) phenyl) -1 H- pyrazole-5-carboxylic acid (430.4 mg, 1.02 mmol), isnicotinhydra Zide (154.7 mg, 1.13 mmol) was used to give the product.

¹ H NMR (300 MHz, CD ₃ OD) δ 8.72 (d, J = 6.14 Hz, 2H), 7.87 (d, J = 6.10 Hz, 2H), 7.56-7.52 (m, 4H), 7.41 (t, J = 8.02 Hz, 1H), 7.13 (d, J = 8.16 Hz, 1H), 7.01 (d, J = 8.76 Hz, 2H), 3.86 (s, 3H), 3.22 (br, 4H), 1.70 (br, 4H ), 1.63 (br, 2H)

Example 27. 5-Isonicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxyamino-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 27 )

(1) Preparation of ethyl 3- (4- (piperidin-1-yl) phenyl) -4- (3-methylbenzamido) -1 H- pyrazole-5-carboxylic acid salt

Ethyl 4-amino-3- (4- (piperidin-1-yl) phenyl) -1 H- pyrazole-5-carboxylic acid salt (1.15 g, 3.66 mmol) with m -toluoylchloride (535.7 μL, 4.02 mmol) was used to give the product (1.12 g, 71%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.59 (s, 1H), 7.79 (br, 2H), 7.50 (d, J = 8.57 Hz, 2H), 7.38-7.30 (m, 2H), 6.94 (d, J = 7.63 Hz, 2H), 4.18 (br, 2H), 3.19 (br, 4H), 2.43 (s, 3H), 1.71 (br, 4H), 1.59 (br, 2H), 1.18 (br, 3H)

(2) Preparation of 3-[(4-piperidin-1-yl) phenyl] -4- (3-methylphenyl) carboxyamino-1 H- pyrazole-5-carboxylic acid

¹ H NMR (300 MHz, CD ₃ OD) δ 7.79-7.74 (m, 2H), 7.56 (d, J = 8.80 Hz, 2H), 7.70-7.36 (m, 2H), 6.99 (d, J = 8.88 Hz , 2H), 3.20 (br, 4H), 2.43 (s, 3H), 1.70 (br, 4H), 1.62 (br, 2H)

(3) Preparation of 5-isonicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxyamino-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole

3-[(4-piperidin-1-yl) phenyl] -4- (3-methylbenzamido) -1 H- pyrazole-5-carboxylic acid (370 mg, 0.915 mmol), nicotinhydra Zide (138.1 mg, 1.01 mmol) was used to give the product (207.3 mg, 43%).

¹ H NMR (300 MHz, CD ₃ OD) δ 9.06 (s, 1H), 8.73 (d, J = 4.92 Hz, 1H), 8.33 (d, J = 8.07 Hz, 1H), 7.80-7.75 (m, 2H ), 7.60-7.54 (m, 3H), 7.39-7.35 (m, 2H), 7.02 (d, J = 8.93 Hz, 2H), 3.22 (br, 4H), 2.42 (s, 3H), 1.70 (br, 4H), 1.63 (br, 2H)

Example 28. 4- (3-methylphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 28)

4- (3-Methylbenzamido) -3- (4- (piperidin-1-yl) phenyl) -1 H- pyrazole-5-carboxylic acid (327 mg, 0.809 mmol), isnicotinhydrazide (122.2 mg, 0.889 mmol) was used to prepare the product.

¹ H NMR (300 MHz, CD ₃ OD) δ 8.72 (d, J = 6.10 Hz, 2H), 7.87 (d, J = 6.08 Hz, 2H), 7.80 (s, 1H), 7.76 (d, J = 6.31 Hz, 1H), 7.55 (d, J = 8.73 Hz, 2H), 7.40-7.35 (m, 2H), 7.01 (d, J = 8.75 Hz, 2H), 3.22 (br, 4H), 2.42 (s, 3H ), 1.70 (br, 4H), 1.63 (br, 2H)

Example 29. 3- (4-Chlorophenyl-4- (phenethyl) carboxyamino-5- (nicotinoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 29)

Yield 53%; ¹ H NMR (300 MHz, CD ₃ OD) δ 9.08 (s, 1H), 8.75 (d, J = 4.91 Hz, 1H), 8.35 (d, J = 8.03 Hz, 1H), 7.60 (dd, J = 4.99 , 7.99 Hz, 1H), 7.48 (d, J = 8.55 Hz, 2H), 7.39 (d, J = 8.48 Hz, 2H), 7.28-7.20 (m, 5H), 3.00 (t, J = 7.77 Hz, 2H ), 2.72 (t, J = 7.72 Hz, 2H)

Example 30. 4-phenylcarboxyamino-5-nicotinoylhydrazinecarbonyl-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 30)

(1) Preparation of ethyl 3-[(4-piperidin-1-yl) phenyl] -4-benzamido-1 H- pyrazole-5-carboxylate

Ethyl 4-amino-3- (4- (piperidin-1-yl) phenyl) -1 H- pyrazole-5-carboxylic acid salt (1.16 g, 3.69 mmol), benzoyl chloride (475.5 μL, 4.06 mmol) To give the product (975.3 mg, 63%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.64 (s, 1H), 8.00 (d, J = 7.11 Hz, 2H), 7.58-7.47 (m, 5H), 6.94 (d, J = 7.64 Hz, 2H) , 4.19 (br, 2H), 3.19 (br, 4H), 1.72 (br, 4H), 1.59 (br, 2H), 1.17 (br, 3H)

(2) Preparation of 3-[(4-piperidin-1-yl) phenyl] -4-benzamido-1 H- pyrazole-5-carboxylic acid

¹ H NMR (300 MHz, CD ₃ OD) δ 7.96 (d, J = 7.04 Hz, 2H), 7.60-7.51 (m, 5H), 7.02 (d, J = 8.93 Hz, 2H), 3.23 (br, 4H ), 1.71 (br, 4H), 1.63 (br, 2H)

(3) Preparation of 4-phenylcarboxyamino-5-nicotinoylhydrazinecarbonyl-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole

4- (benzamido) -3- (4- (piperidin-1-yl) phenyl) -1 H- pyrazole-5-carboxylic acid (349.3 mg, 0.895 mmol), nicotinhydrazide (135.3 mg, 0.984 mmol) to obtain the product.

¹ H NMR (300 MHz, CD ₃ OD) δ 9.05 (s, 1H), 8.73 (d, J = 4.18 Hz, 1H), 8.32 (d, J = 8.17 Hz, 1H), 7.97 (d, J = 6.99 Hz, 2H), 7.60-7.44 (m, 6H), 7.02 (d, J = 8.93 Hz, 2H), 3.22 (br, 4H), 1.70 (br, 4H), 1.63 (br, 2H)

Example 31. 3- (furan-2-yl) -5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 31)

(1) Preparation of ( Z) -ethyl 4- (furan-2-yl) -4-hydroxy-2-oxo-3-butanoate

2-acetyl furan (5.57 mL, 55 mmol) and diethyl oxalate (7.9 mL, 57.8 mmol) were reacted by the method of Example 2 (2), to obtain a product (11.4 g, 99%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.70 (s, 1H), 7.36 (d, J = 3.60 Hz, 1H), 6.96 (s, 1H), 6.64 (d, J = 3.62 Hz, 1H), 4.41 (q, J = 7.14 Hz, 2H), 1.42 (t, J = 7.14 Hz, 3H)

(2) Preparation of ( Z ) -ethyl 4- (furan-2-yl) -3- (hydroxyimino) -2,4-dioxobutanoate

Using ( Z ) -ethyl 4- (furan-2-yl) -4-hydroxy-2-oxo-3-butanoate (11.4 g, 54.2 mmol) as in the method of (3) above Reaction gave the product (6.45 g, 50%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 7.68 (d, J = 3.78 Hz, 1H), 6.77 (d, J = 3.78 Hz, 1H), 4.39 (q, J = 7.13 Hz , 2H), 1.40 (t, J = 7.12 Hz, 3H)

(3) Preparation of ethyl 3- (furan-2-yl) -4-nitroso-1 H- pyrazole-5-carboxylic acid salt

( Z ) -Ethyl 4- (furan-2-yl) -3- (hydroxyimino) -2,4-dioxobutanoate (6.41 g, 26.8 mmol) was added hydrazine hydrate (2.05 mL, 27.1 mmol). The product (5.7 g, 91%) was obtained by reacting by the method of Example 4 (4).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.48 (s, 1H), 7.17 (d, J = 3.47 Hz, 1H), 6.53 (d, J = 3.47 Hz, 1H), 4.38q, J = 7.16 Hz, 2H), 1.39 (t, J = 7.13 Hz, 3H)

(4) Preparation of ethyl 4-amino-3- (furan-2-yl) -1 H- pyrazole-5-carboxylic acid salt

Prepared by reducing ethyl 3- (furan-2-yl) -4-nitroso-1 H- pyrazole-5-carboxylic acid salt (5.72 g, 24.3 mmol).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.51 (s, 1H), 6.68 (d, J = 3.37 Hz, 1H), 6.53 (d, J = 3.35 Hz, 1H), 4.64 (br, 2H), 4.42 (q, J = 7.13 Hz, 2H), 1.43 (t, J = 7.13 Hz, 3H)

(5) Preparation of ethyl 4- (3-nitrobenzamido) -3- (furan-2-yl) -1 H- pyrazole-5-carboxylic acid salt

Ethyl 4-amino-3- (furan-2-yl) -1 H- pyrazole-5-carboxylic acid salt (722.7 mg, 3.27 mmol), 3-nitrobenzoyl chloride (804.5 mg, 4.25 mmol) was prepared in Example 1 above. Reaction was carried out to give the product (878.3 mg, 73%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.85 (br, 2H), 8.47 (d, J = 8.11 Hz, 1H), 8.34 (d, J = 7.83 Hz, 1H), 7.76 (t, J = 7.87 Hz , 1H), 7.52 (s, 1H), 6.54 (s, 2H), 4.45 (q, J = 7.13 Hz, 2H), 1.43 (t, J = 7.15 Hz, 3H)

(6) Preparation of 4- (3-nitrobenzamido) -3- (furan-2-yl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (300 MHz, CD ₃ OD) δ 8.87 (s, 1H), 8.49 (d, J = 6.45 Hz, 1H), 8.39 (d, J = 7.17 Hz, 1H), 7.82 (t, J = 8.01 Hz, 1H), 7.61 (s, 1H), 6.72 (s, 1H), 6.56 (s, 1H)

(7) Preparation of 3- (furan-2-yl) -5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole

4- (3-nitrobenzamido) -3- (furan-2-yl) -1 H- pyrazole-5-carboxylic acid (232.9 mg, 0.681 mmol), nicotinhydrazide (103.3 mg, 0.749 mmol) The reaction was carried out in the same manner as in Example 1 to prepare a product.

¹ H NMR (300 MHz, CD ₃ OD) δ 9.06 (s, 1H), 8.89 (s, 1H), 8.74 (d, J = 4.98 Hz, 1H), 8.48 (d, J = 7.64 Hz, 1H), 8.42 (d, J = 7.54 Hz, 1H), 8.33 (d, J = 7.93 Hz, 1H), 7.81 (t, J = 7.95 Hz, 1H), 7.66 (s, 1H), 7.58 (dd, J = 4.99 , 7.89 Hz, 1H), 6.70 (d, J = 3.32 Hz, 1H), 6.59 (s, 1H)

Example 32. 5-Benzoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3- (furan-2-yl) -1 H- pyrazole (Compound No. 32)

4- (3-nitrobenzamido) -3- (furan-2-yl) -1 H- pyrazole-5-carboxylic acid (231 mg, 0.675 mmol), benzoichydrazide (103.4 mg, 0.742 mmol) The reaction was carried out in the same manner as in Example 1, to prepare a product.

¹ H NMR (300 MHz, CD ₃ OD) δ 8.88 (s, 1H), 8.47 (d, J = 7.72 Hz, 1H), 8.42 (d, J = 7.81 Hz, 1H), 7.92 (d, J = 7.10 Hz, 2H), 7.81 (t, J = 7.97 Hz, 1H), 7.65 (s, 1H), 7.58 (d, J = 7.34 Hz, 1H), 7.50 (t, J = 7.10 Hz, 2H), 6.70 ( d, J = 3.34 Hz, 1H), 6.58 (d, J = 3.39 Hz, 1H)

Example 33. 5-Nicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3- (furan-2-yl) -1 H- pyrazole (Compound No. 33)

(1) Preparation of ethyl 4- (3-methoxybenzamido) -3- (furan-2-yl) -1 H- pyrazole-5-carboxylic acid salt

Using ethyl 4-amino-3- (furan-2-yl) -1 H- pyrazole-5-carboxylic acid salt (693.4 mg, 3.13 mmol), 3-methoxybenzoyl chloride (560.9 μL, 4.08 mmol) Reaction was carried out in the same manner as in Example 1, to obtain a product (940.9 mg, 84%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.75 (s, 1H), 7.56-7.53 (m, 2H), 7.49 (s, 1H), 7.44 (t, J = 8.10 Hz, 1H), 7.14 (d, J = 7.65 Hz, 1H), 6.52 (s, 2H), 4.43 (q, J = 7.13 Hz, 2H), 3.90 (s, 3H), 1.40 (t, J = 7.13 Hz, 3H)

(2) Preparation of 4- (3-methoxybenzamido) -3- (furan-2-yl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (300 MHz, CD ₃ OD) δ 7.60-7.56 (m, 3H), 7.44 (t, J = 8.22 Hz, 1H), 7.17 (d, J = 8.19 Hz, 1H), 6.64 (d, J = 3.26 Hz, 1H), 6.53 (d, J = 3.31 Hz, 1H), 3.88 (s, 3H)

(3) Preparation of 5-nicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3- (furan-2-yl) -1 H- pyrazole

4- (3-methoxybenzamido) -3- (furan-2-yl) -1 H- pyrazole-5-carboxylic acid (280.5 mg, 0.857 mmol), nicotinhydrazide (129.3 mg, 0.943 mmol) Reaction was carried out by the method of Example 1 using to prepare a product.

¹ H NMR (300 MHz, CD ₃ OD) δ 9.07 (s, 1H), 8.73 (d, J = 4.86 Hz, 1H), 8.33 (d, J = 7.98 Hz, 1H), 7.65 (s, 1H), 7.61-7.58 (m, 3H), 7.44 (t, J = 7.94 Hz, 1H), 7.16 (d, J = 6.65 Hz, 1H), 6.65 (t, J = 3.19, 1H), 6.58 (s, 1H) , 3.88 (s, 3 H)

Example 34. 3- (furan-2-yl) -4- (3-methoxyphenyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 34)

4- (3-methoxybenzamido) -3- (furan-2-yl) -1 H- pyrazole-5-carboxylic acid (249.2 mg, 0.761 mmol), benzoichydrazide (131.3 mg, 0.944 mmol , 20 mL of ethyl acetate was reacted in the same manner as in Example 1 to prepare a product.

¹ H NMR (300 MHz, CD ₃ OD) δ 7.92 (d, J = 7.33 Hz, 2H), 7.64-7.57 (m, 4H), 7.52-7.41 (m, 3H), 7.16 (d, J = 8.26 Hz , 1H), 6.65 (d, J = 3.24 Hz, 1H), 6.58 (s, 1H), 3.88 (s, 3H)

Example 35. 3- (furan-2-yl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino) -1 H- pyrazole (Compound No. 35)

4- (3-methoxybenzamido) -3- (furan-2-yl) -1 H- pyrazole-5-carboxylic acid (250.2 mg, 0.764 mmol), isnicotinhydrazide (130.1 mg, 0.948 mmol The reaction was carried out in the same manner as in Example 1 above, to prepare a product.

¹ H NMR (300 MHz, CD ₃ OD) δ 8.73 (d, J = 6.06 Hz, 2H), 7.87 (d, J = 5.99 Hz, 2H), 7.65-7.58 (m, 3H), 7.44 (t, J = 7.68 Hz, 1H), 7.18-7.15 (m, 1H), 6.66 (d, J = 3.02 Hz, 1H), 6.58 (s, 1H), 3.88 (s, 3H)

Example 36. 4- (3-Nitrophenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-3- (1-phenethyl) -1 H- pyrazole (Compound No. 36)

(1) ( Z ) -ethyl 4-hydroxy-2-oxo-6-phenylhex-3-enoate

4'-benzylacetone (7.66 mL, 50 mmol) and diethyl oxalate (7.2 mL, 52.5 mmol) were reacted by the method of Example (2) to obtain the product (10.4 g, 83%). .

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.34-7.20 (m, 5H), 6.38 (s, 1H), 4.36 (q, J = 7.13 Hz, 2H), 3.00 (t, J = 6.98 Hz, 2H) , 2.84 (t, J = 6.85 Hz, 2H), 1.39 (t, J = 7.13 Hz, 3H)

(2) Preparation of ( Z ) -ethyl3- (hydroxyimino) -2,4-dioxo-6-phenylhexane salt

( Z ) -Ethyl 4-hydroxy-2-oxo-6-phenylhex-3-enoate (11.5 g, 46.4 mmol) was used for the reaction of the method of Example 1 (3) to give the product (8.39 g , 65%)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.34-7.18 (m, 5H), 4.38 (q, J = 7.15 Hz, 2H), 2.99 (t, J = 7.57 Hz, 2H), 2.71 (t, J = 7.38 Hz, 2H), 1.37 (t, J = 7.18 Hz, 3H)

(3) Preparation of ethyl 4-nitroso-3-phenethyl-1 H- pyrazole-5-carboxylic acid salt

Example 1 using ( Z ) -ethyl 3- (hydroxyimino) -2,4-dioxo-6-phenylhexanoate (8.39 g, 30.3 mmol) and hydrazine hydrate (2.3 mL, 30.6 mmol) It reacted by the method (4) of to obtain the residue product (11.7 g).

(4) Preparation of ethyl 4-amino-3-phenethyl-1 H- pyrazole-5-carboxylic acid salt

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.33-7.19 (m, 5H), 4.37 (q, J = 7.13 Hz, 2H), 2.99 (t, J = 7.13 Hz, 2H), 2.88 (t, J = 7.82 Hz, 2H), 1.39 (t, J = 7.13, 3H)

(5) Preparation of ethyl 4- (3-nitrobenzamido) -3-phenethyl-1 H- pyrazole-5-carboxylic acid salt

By the method of Example 1 above using ethyl 4-amino-3-phenethyl-1 H- pyrazole-5-carboxylic acid salt (804.3 mg, 3.10 mmol) and 3-nitrobenzoyl chloride (764.3 mg, 4.03 mmol) Reaction gave the product (1.08 g, 85%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.75 (s, 1H), 8.46 (d, J = 8.13 Hz, 1H), 8.25 (d, J = 7.82 Hz, 1H), 7.74 (t, J = 7.89 Hz , 1H), 7.27-7.18 (m, 5H), 4.44 (q, J = 7.07 Hz, 2H), 3.34 (t, J = 6.66 Hz, 2H), 3.06 (t, J = 6.95 Hz, 2H), 1.42 (t, J = 7.08, 3H)

(6) Preparation of 4- (3-nitrobenzamido) -3-phenethyl-1 H- pyrazole-5-carboxylic acid

¹ H NMR (300 MHz, CD ₃ OD) δ 8.82 (s, 1H), 8.47 (d, J = 8.06 Hz, 1H), 8.35 (d, J = 7.50 Hz, 1H), 7.80 (t, J = 7.91 Hz, 1H), 7.24-7.13 (m, 5H), 3.07 (t, J = 7.10 Hz, 2H), 2.95 (t, J = 7.09 Hz, 2H)

(7) Preparation of 4- (3-nitrophenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-3- (1-phenethyl) -1 H- pyrazole

This example using 4- (3-nitrobenzamido) -3-phenethyl-1 H- pyrazole-5-carboxylic acid (230.5 mg, 0.606 mmol) and nicotinhydrazide (91.5 mg, 0.667 mmol) Reaction was carried out in the manner of 1 to prepare a product.

¹ H NMR (300 MHz, CD ₃ OD) δ 9.06 (s, 1H), 8.82 (s, 1H), 8.73 (d, J = 4.90 Hz, 1H), 8.46 (d, J = 7.91 Hz, 1H), 8.34 (d, J = 8.10 Hz, 2H), 7.79 (t, J = 7.99 Hz, 1H), 7.58 (dd, J = 4.96, 7.93 Hz, 1H), 7.26-7.15 (m, 5H), 3.10 (t , J = 7.05 Hz, 2H), 2.98 (t, J = 7.14 Hz, 2H)

Example 37. 5-Benzoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3- (1-phenethyl) -1 H- pyrazole (Compound No. 37)

The above practice using 4- (3-nitrobenzamido) -3-phenethyl-1 H- pyrazole-5-carboxylic acid (231.7 mg, 0.609 mmol), benzoichydrazide (93.3 mg, 0.670 mmol) Reaction was carried out by the method of Example 1 to prepare a product.

¹ H NMR (300 MHz, CD ₃ OD) δ 8.82 (s, 1H), 8.46 (d, J = 8.23 Hz, 1H), 8.36 (d, J = 7.72 Hz, 1H), 7.92 (d, J = 7.04 Hz, 2H), 7.79 (t, J = 8.03 Hz, 1H), 7.58 (d, J = 7.36 Hz, 1H), 7.50 (t, J = 7.64 Hz, 2H), 7.26-7.13 (m, 5H), 3.10 (t, J = 7.39 Hz, 2H), 2.98 (t, J = 7.18 Hz, 2H)

Example 38. 4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-3- (1-phenethyl) -1 H- pyrazole (Compound No. 38)

(1) Preparation of ethyl 4- (3-methoxybenzamido) -3-phenethyl-1 H- pyrazole-5-carboxylic acid salt

Example 1 above using ethyl 4-amino-3-phenethyl-1 H- pyrazole-5-carboxylic acid salt (798.5 mg, 3.08 mmol), and 3-methoxybenzoyl chloride (551.0 μL, 4.00 mmol) Reaction was carried out to give the product (959 mg, 79%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 7.50-7.40 (m, 3H), 7.27-7.12 (m, 5H), 4.43 (q, J = 7.07 Hz, 2H), 3.90 ( s, 3H), 3.37 (t, J = 7.55 Hz, 2H), 3.07 (t, J = 7.54 Hz, 2H), 1.41 (t, J = 7.04, 3H)

(2) Preparation of 4- (3-methoxybenzamido) -3-phenethyl-1 H- pyrazole-5-carboxylic acid

¹ H NMR (300 MHz, CD ₃ OD) δ 7.55-7.52 (m, 2H), 7.44 (t, J = 8.08 Hz, 1H), 7.26-7.15 (m, 6H), 3.88 (s, 3H), 3.01 (d, J = 7.35 Hz, 2H), 2.96 (t, J = 7.04 Hz, 2H)

(3) Preparation of 4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-3- (1-phenethyl) -1 H- pyrazole

The above procedure was used with 4- (3-methoxybenzamido) -3-phenethyl-1 H- pyrazole-5-carboxylic acid (183.8 mg, 0.503 mmol), nicotinhydrazide (75.9 mg, 0.553 mmol) Reaction was carried out in the same manner as in Example 1, to obtain a product (153.1 mg, 63%).

¹ H NMR (300 MHz, CD ₃ OD) δ 9.06 (s, 1H), 8.74 (d, J = 4.94 Hz, 1H), 8.33 (d, J = 8.17 Hz, 1H), 7.61-7.52 (m, 3H ), 7.43 (t, J = 8.02 Hz, 1H), 7.27-7.13 (m, 6H), 3.88 (s, 3H), 3.12 (t, J = 7.90 Hz, 2H), 2.97 (t, J = 7.89 Hz , 2H)

Example 39. 4- (3-methoxyphenyl) carboxyamino-5-benzoylhydrazinecarbonyl-3- (1-phenethyl) -1 H- pyrazole (Compound No. 39)

Using 4- (3-methoxybenzamido) -3-phenethyl-1 H- pyrazole-5-carboxylic acid (185.1 mg, 0.507 mmol) and benzoichydrazide (76.1 mg, 0.557 mmol) Reaction was carried out by the method of Example 1 to obtain the product (148.2 mg, 61%).

¹ H NMR (300 MHz, CD ₃ OD) δ 7.92 (d, J = 7.08 Hz, 2H), 7.62-7.40 (m, 6H), 7.26-7.13 (m, 6H), 3.88 (s, 3H), 3.12 (t, J = 8.19 Hz, 2H), 2.96 (t, J = 7.93 Hz, 2H)

Example 40. 3- (3-Chlorophenyl) -4- (3-nitrophenyl) carboxyamino-5-propanoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 40)

4- (3-nitrobenzamido) -3- (3-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (167.7 mg, 0.434 mmol) and butyrohydrazide (48.9 mg, 0.477 mmol) Was reacted in the same manner as in Example 1 to obtain the product (154.1 mg, 76%).

¹ H NMR (300 MHz, CD ₃ OD) δ 8.82 (s, 1H), 8.47 (d, J = 7.56 Hz, 1H), 8.35 (d, J = 7.81 Hz, 1H), 7.79 (t, J = 8.00 Hz, 1H), 7.70 (s, 1H), 7.60 (d, J = 7.74 Hz, 1H), 7.47-7.42 (m, 2H), 2.28 (t, J = 7.55 Hz, 2H), 1.76-1.65 (m , 2H), 1.00 (t, J = 7.41 Hz, 3H)

Example 41. 5- (3-hydroxybenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3- (3-chlorophenyl) -1 H- pyrazole (Compound No. 41)

4- (3-nitrobenzamido) -3- (3-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (138.8 mg, 0.359 mmol), 3-hydroxybenzoichydrazide (61.5 mg, 0.395 mmol) was reacted in the same manner as in Example 1, to obtain a product (126.6 mg, 68%).

¹ H NMR (300 MHz, CD ₃ OD) δ 8.82 (s, 1H), 8.46 (d, J = 8.11 Hz, 1H), 8.36 (d, J = 7.84 Hz, 1H), 7.79 (t, J = 8.00 Hz, 1H), 7.72 (s, 1H), 7.61 (d, J = 6.83 Hz, 1H), 7.48-7.40 (m, 2H), 7.38-7.26 (m, 3H), 6.99 (d, J = 7.89 Hz , 1H)

Example 42. 3- (4-Chlorophenyl) -4- (3-methoxyphenylacetamino) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 42)

(1) Preparation of ethyl 4- (2- (3-methoxyphenyl) acetamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid salt

Using ethyl 4-amino-3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid salt (752.5 mg, 2.83 mmol) and 3-methoxyphenylacetyl chloride (585.8 μL, 3.68 mmol) Reaction was carried out by the method of Example 1 to give the product (960 mg, 82%).

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.44-7.37 (m, 3H), 7.33-7.29 (m, 2H), 6.96-6.86 (m, 3H), 4.36 (q, J = 7.16 Hz, 2H), 3.84 (s, 3H), 3.70 (s, 2H), 1.37 (t, J = 7.14 Hz, 3H)

(2) Preparation of 4- (2- (3-methoxyphenyl) acetamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (300 MHz, CD ₃ OD) δ 7.45 (d, J = 8.57 Hz, 2H), 7.25 (d, J = 8.44 Hz, 2H), 6.96 (br, 2H), 6.90-6.84 (m, 1H ), 3.80 (s, 3H), 3.66 (s, 2H)

(3) Preparation of 3- (4-chlorophenyl) -4- (3-methoxyphenylacetamino) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (2- (3-methoxyphenyl) acetamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (181.1 mg, 0.469 mmol), nicotinhydrazide (70.9 mg , 0.516 mmol), and 10.9 mL of ethyl acetate were reacted by the method of Example 1, to obtain a product (118.3 mg, 50%).

¹ H NMR (300 MHz, CD ₃ OD) δ 9.09 (s, 1H), 8.76 (d, J = 3.58 Hz, 1H), 8.35 (d, J = 8.02 Hz, 1H), 7.61 (dd, J = 4.82 , 7.66 Hz, 1H), 7.41 (t, J = 8.37 Hz, 2H), 7.30-7.23 (m, 3H), 6.96 (br, 2H), 6.87 (d, J = 7.92 Hz, 1H), 3.78 (s , 3H), 3.67 (s, 2H)

Example 43. 3- (4-Chlorophenyl) -4- (3-methoxyphenylacetamino) -5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 43)

4- (2- (3-methoxyphenyl) acetamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (183.0 mg, 0.474 mmol), benzoichydrazide (71.3 mg, 0.522 mmol) was reacted by the method of Example 1 to obtain a product (138.5 mg, 58%).

¹ H NMR (300 MHz, CD ₃ OD) δ 7.95 (d, J = 7.25 Hz, 2H), 7.61 (d, J = 7.02 Hz, 1H), 7.55-7.50 (m, 2H), 7.41 (d, J = 8.54 Hz, 2H), 7.30-7.23 (m, 3H), 6.96-6.93 (m, 2H), 6.87 (d, J = 6.97 Hz, 1H), 3.77 (s, 3H), 3.67 (s, 2H)

Example 44. 3- (4-Chlorophenyl) -4- (3-methoxyphenylacetamino) -5-phenylacetylhydrazinecarbonyl-1 H- pyrazole (Compound No. 44)

4- (2- (3-methoxyphenyl) acetamido) -3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid (181.1 mg, 0.469 mmol) and phenylacetylhydrazide (79.1 mg, 0.516 mmol) was reacted by the method of Example 1, to obtain a product (96.7 mg, 40%).

¹ H NMR (300 MHz, CD ₃ OD) δ 7.41-7.29 (m, 6H), 7.28-7.22 (m, 4H), 6.94 (br, 2H), 6.87 (d, J = 8.25 Hz, 1H), 3.78 (s, 3H), 3.65 (s, 4H)

Example 45. 3- (4-Chlorophenyl) -5-nicotinoylhydrazinecarbonyl-4-pentanecarboxyamino-1 H- pyrazole (Compound No. 45)

(1) Preparation of ethyl 3- (4-chlorophenyl) -4- (pentaneamido) -1 H- pyrazole-5-carboxylic acid salt

Example 1 above using ethyl 4-amino-3- (4-chlorophenyl) -1 H- pyrazole-5-carboxylic acid salt (771.9 mg, 2.91 mmol) and valeryl chloride (467 μL, 3.78 mmol) Reaction was carried out to give the product (888 mg, 87%).

¹ H NMR (300 MHz, CD ₃ OD) δ 7.64 (d, J = 8.65 Hz, 2H), 7.46 (d, J = 8.69 Hz, 2H), 4.37 (q, J = 7.13 Hz, 2H), 2.41 ( t, J = 7.38 Hz, 2H), 1.74-1.62 (m, 2H), 1.45-1.41 (m, 2H), 1.39 (t, J = 7.13 Hz, 3H), 0.97 (t, J = 7.37 Hz, 3H )

(2) Preparation of 3- (4-chlorophenyl) -4- (pentaneamido) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (300 MHz, CD ₃ OD) δ 7.64 (d, J = 8.11 Hz, 2H), 7.44 (d, J = 8.15 Hz, 2H), 2.39 (t, J = 7.26 Hz, 2H), 1.71- 1.64 (m, 2H), 1.45-1.36 (m, 2H), 0.96 (t, J = 7.27 Hz, 3H)

(3) Preparation of 3- (4-chlorophenyl) -5-nicotinoylhydrazinecarbonyl-4-pentanecarboxylic cyano-1 H- pyrazole

The above was carried out using 3- (4-chlorophenyl) -4- (pentaneamido) -1 H- pyrazole-5-carboxylic acid (171.6 mg, 0.533 mmol), nicotinehydrazide (74.2 mg, 0.540 mmol) Reaction was carried out by the method of Example 1 to obtain the product (109.1 mg, 46%).

¹ H NMR (300 MHz, CD ₃ OD) δ 9.08 (s, 1H), 8.75 (d, J = 4.90 Hz, 1H), 8.35 (d, J = 8.17 Hz, 1H), 7.62-7.58 (m, 3H ), 7.49 (d, J = 7.87 Hz, 2H), 2.41 (t, J = 7.51 Hz, 2H), 1.72-1.62 (m, 2H), 1.43-1.35 (m, 2H), 0.95 (t, J = 7.33 Hz, 3H)

Example 46. 5-Benzoylhydrazinecarbonyl-3- (4-chlorophenyl) -4-pentanecarboxyamino-1 H- pyrazole (Compound No. 46)

Using 3- (4-chlorophenyl) -4- (pentaneamido) -1 H- pyrazole-5-carboxylic acid (171 mg, 0.532 mmol), benzoichydrazide (73.2 mg, 0.538 mmol) Reaction was carried out in the same manner as in Example 1, to obtain a product (92.7 mg, 40%).

¹ H NMR (300 MHz, CD ₃ OD) δ 7.95-7.91 (m, 2H), 7.59-7.54 (m, 3H), 7.52-7.46 (m, 4H), 2.44-2.37 (m, 2H), 1.70- 1.64 (m, 2H), 1.43-1.36 (m, 2H), 0.95 (t, J = 7.20 Hz, 3H)

Example 47. 3-Isobutyl-5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 47)

(1) Preparation of ( Z ) -ethyl 4-hydroxy-6-methyl-2-oxo-3-heptanoate

4-methyl-2-pentanone (12.5 mL, 100 mmol) was reacted with diethyl oxalate by the method of Example 1 (2) to obtain a product (17.6 g, 87.699 mmol, 87.7%).

¹ H NMR (CD ₃ OD, 300 MHz) δ 6.37 (s, 1 H), 4.33 (q, J = 7.1 Hz, 2H), 2.41 (d, J = 7.1 Hz, 2H), 2.19-2.12 (m, 1H), 1.35 (t, J = 7.1 Hz, 3H), 0.98 (d, J = 6.6 Hz, 6H)

(2) Preparation of ( E ) -ethyl 3- (hydroxyimino) -6-methyl-2,4-dioxoheptanoate

( Z ) -Ethyl 4-hydroxy-6-methyl-2-oxo-3-heptanoate (17.6 g, 87.699 mmol) was reacted by the method of Example (3) above to give the product (11.8 g (58.7%) was obtained

¹ H NMR (CDCl ₃ , 300 MHz) δ 4.38 (q, J = 7.1 Hz, 2H), 2.71 (d, J = 7.0 Hz, 2H), 2.28-2.19 (m, 1H), 1.38 (t, J = 7.1 Hz, 3H), 0.99 (d, J = 6.6 Hz, 6H)

(3) Preparation of ethyl 3-isobutyl-4-nitroso-1 H- pyrazole-5-carboxylic acid salt

Example 1 using ( E ) -ethyl 3- (hydroxyimino) -6-methyl-2,4-dioxoheptanoate (4.9 g, 21.668 mmol) and hydrazine hydrate (1.18 mL, 21.668 mmol) Was reacted by the method of (4) to obtain the product (4.8 g, 98.9%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 4.58 (q, J = 7.1 Hz, 2H), 2.74 (d, J = 7.2 Hz, 2H), 2.25-1.89 (m, 1H), 1.48 (t, J = 7.1 Hz, 3H), 0.95 (d, J = 6.7 Hz, 6H)

(4) Preparation of ethyl 4-amino-3-isobutyl-1 H- pyrazole-5-carboxylic acid salt

¹ H NMR (CD ₃ OD, 300 MHz) δ 4.36 (q, J = 7.1 Hz, 2H), 2.47 (br, 2H), 2.03-1.94 (m, 1H), 1.39 (t, J = 7.1 Hz, 3H ), 0.94 (d, J = 6.6 Hz, 6H)

(5) Preparation of ethyl 4- (3-nitrobenzamido) -3-isobutyl-1 H- pyrazole-5-carboxylic acid salt

By the method of Example 1 above using ethyl 4-amino-3-isobutyl-1 H- pyrazole-5-carboxylic acid salt (508.5 mg, 2.406 mmol), 3-nitrobenzoylchloride (580.7 mg, 3.129 mmol) Reaction to give the product (810.5 mg, 3.4%)

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.85 (s, 1H), 8.48 (d, J = 9.5 Hz, 1H), 8.37 (d, J = 7.7 Hz, 1H), 7.82 (t, J = 7.9 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.60 (d, J = 7.1 Hz, 2H), 2.02-1.91 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 0.93 (d, J = 6.6 Hz, 6H)

(6) Preparation of 4- (3-nitrobenzamido) -3-isobutyl-1 H- pyrazole-5-carboxylic acid

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.83 (s, 1H), 8.47 (d, J = 7.9 Hz, 1H), 8.36 (d, J = 8.0 Hz, 1H), 7.80 (t, J = 6.9 Hz, 1H), 2.61 (d, J = 7.2 Hz, 2H), 2.02-1.95 (m, 1H), 0.94 (d, J = 6.5 Hz, 6H)

(7) Preparation of 3-isobutyl-5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole

This example using 4- (3-nitrobenzamido) -3-isobutyl-1 H- pyrazole-5-carboxylic acid (195.2 mg, 0.587 mmol) and nicotinhydrazide (84.6 mg, 0.616 mmol) Reaction was carried out in the manner of 1 to obtain the product (168.6 mg, 62.5%).

¹ H NMR (CD ₃ OD, 300 MHz) δ 9.06 (s, 1H), 8.84 (s, 1H), 8.72 (d, J = 4.9 Hz, 1H), 8.46 (d, J = 9.6 Hz, 1H), 8.39-8.32 (m, 2H), 7.79 (t, J = 7.9 Hz, 1H), 7.58 (dd, J = 5.1, 7.9 Hz, 1H), 2.69 (d, J = 7.2 Hz, 2H), 2.05-1.94 (m, 1H), 0.95 (d, J = 6.6 Hz, 6H)

Example 48. 5-Benzoylhydrazinecarbonyl-3-isobutyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 48)

The above practice using 4- (3-nitrobenzamido) -3-isobutyl-1 H- pyrazole-5-carboxylic acid (82.8 mg, 0.249 mmol) and benzoichydrazide (35.6 mg, 0.262 mmol) The reaction was carried out in the same manner as in Example 1, to obtain a product (52.5 mg, 46.8%).

¹ H NMR (CD ₃ OD, 300 MHz) δ 08.83 (s, 1H), 8.45 (d, J = 7.4 Hz, 1H), 8.37 (d, J = 6.7 Hz, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.79 (t, J = 7.9 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.52-7.47 (m, 2H), 2.68 (d, J = 6.8 Hz, 2H), 2.09-1.96 (m, 1H), 0.95 (d, J = 6.6 Hz, 6H)

Example 49. 3-Isobutyl-5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino 1 H- pyrazole (Compound No. 49)

The above was carried out with 4- (3-nitrobenzamido) -3-isobutyl-1 H- pyrazole-5-carboxylic acid (201.3 mg, 0.606 mmol) and isnicotinhydrazide (87.2 mg, 0.636 mmol). The reaction was carried out in the same manner as in Example 1, to obtain 94.8 mg (34.7%) of a product.

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.85 (s, 1H), 8.64 (br, 2H), 8.47-8.39 (m, 2H), 7.89 (br, 2H), 7.80 (t, J = 7.3 Hz , 1H), 2.68 (d, J = 5.9 Hz, 2H), 2.04-1.91 (m, 1H), 0.94 (d, J = 6.3 Hz, 6H)

Example 50. 3-Isobutyl-4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 50)

(1) Preparation of ethyl 4- (3-methoxybenzamido) -3-isobutyl-1 H- pyrazole-5-carboxylic acid salt

The method of Example 1 above using ethyl 4-amino-3-isobutyl-1 H- pyrazole-5-carboxylic acid salt (1.3 g, 6.122 mmol), 3-methoxybenzoylchloride (1.08 mL, 7.958 mmol) Reaction to give the product (2 g, 92%).

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.56-7.52 (m, 2H), 7.44 (t, J = 8.1 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 2.61 (d, J = 7.02 Hz, 2H), 2.01-1.97 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 0.93 (d , J = 6.6 Hz, 6H)

(2) Preparation of 4- (3-methoxybenzamido) -3-isobutyl-1 H- pyrazole-5-carboxylic acid

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.52 (br, 2H), 7.43 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 3.88 (s, 3H), 2.62 (d, J = 7.2 Hz, 2H), 2.03-1.94 (m, 1H), 0.93 (d, J = 6.6 Hz, 6H)

(3) Preparation of 3-isobutyl-4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

The above was carried out using 4- (3-methoxybenzamido) -3-isobutyl-1 H- pyrazole-5-carboxylic acid (410.9 mg, 1.295 mmol) and nicotinhydrazide (186.5 mg, 1.359 mmol) Reaction was carried out by the method of Example 1 to obtain 301 mg (53.3%) of product.

¹ H NMR (CD ₃ OD, 300 MHz): d 9.07 (s, 1H), 8.72 (s, 1H), 8.32 (d, J = 6.4 Hz, 1H), 7.62-7.52 (m, 3H), 7.39 ( t, J = 6.5 Hz, 1H), 7.13 (br, 1H), 3.86 (s, 3H), 2.70 (d, J = 6.1 Hz, 2H), 2.04-1.97 (m, 1H), 0.93 (d, J = 8.1 Hz, 6H)

Example 51. 3-Isobutyl-4- (3-methoxyphenyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 51)

Using 4- (3-methoxybenzamido) -3-isobutyl-1 H- pyrazole-5-carboxylic acid (415.2 mg, 1.308 mmol) and benzoichydrazide (187.1 mg, 1.374 mmol) Reaction was carried out in the same manner as in Example 1 to obtain 302.1 mg (53%) of product.

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.92 (d, J = 8.1 Hz, 2H), 7.62-7.47 (m, 5H), 7.42 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 3.87 (s, 3H), 2.71 (d, J = 7.2 Hz, 2H), 2.04-1.93 (m, 1H), 0.94 (d, J = 6.6 Hz, 6H)

Example 52. 3-Isobutyl-4- (3-methoxyphenyl) carboxyamino-5-isonicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 52)

Using 4- (3-methoxybenzamido) -3-isobutyl-1 H- pyrazole-5-carboxylic acid (455.4 mg, 1.435 mmol) and isnicotinhydrazide (206.6 mg, 1.507 mmol) Reaction was carried out by the method of Example 1 to obtain the product (333.3 mg, 53.2%).

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.73 (d, J = 6.1 Hz, 2H), 7.87 (d, J = 5.4 Hz, 2H), 7.56-7.53 (m, 2H), 7.42 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 9.9 Hz, 1H), 3.87 (s, 3H), 2.71 (d, J = 7.0 Hz, 2H), 2.04-1.95 (m, 1H), 0.94 (d , J = 6.6 Hz, 6H)

Example 53. 3-propyl-4- (3-nitrophenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 53)

(1) Preparation of ( Z ) -ethyl 4-hydroxy-2-oxo-3-heptanoate

2-pentanone (11.5 mL, 107.41 mmol) and diethyloxalate (14.5 mL, 107.41 mmol) were reacted by the method of Example 1 (2) above to give a product (15.4 g, 82.702 mmol, 76.8%). Got.

¹ H NMR (CDCl ₃ , 300 MHz) δ 6.38 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 2.48 (t, J = 7.4 Hz, 2H), 1.77-1.65 (m, 2H) , 1.39 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H)

(2) Preparation of ( E ) -ethyl 3- (hydroxyimino) -2,4-dioxoheptanoate

( Z ) -ethyl 4-hydroxy-2-oxo-3-heptanoate (15.4 g, 82.702 mmol) was reacted by the method of Example 1 (3) above to give the product (12 g, 55.759 mmol, 67.5%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 4.38 (q, J = 7.1 Hz, 2H), 2.82 (t, J = 7.3 Hz, 2H), 1.77-1.65 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H)

(3) Preparation of ethyl 4-nitroso-3 - proyl-1 H- pyrazole-5-carboxylic acid salt

(4) of Example 1, using ( E ) -ethyl 3- (hydroxyimino) -2,4-dioxoheptanoate (10.6 g, 49.347 mmol) and hydrazine hydrate (2.7 mL, 49.347 mmol) Reaction was carried out to give the product (9.4 g, 90.3%).

(4) Preparation of ethyl 4-amino-3 - proyl-1 H- pyrazole-5-carboxylic acid salt

¹ H NMR (CDCl ₃ , 300 MHz) δ 4.39 (q, J = 7.1 Hz, 2H), 3.94 (s, 2H), 2.55 (t, J = 7.6 Hz, 2H), 1.76-1.66 (m, 2H) , 1.39 (t, J = 7.1 Hz, 3H), 0.99 (t, J = 7.3 Hz, 3H)

(5) Preparation of ethyl 4- (3-nitrophenyl) carboxyamino-3 - proyl-1 H- pyrazole-5-carboxylic acid salt

In the method of Example 1 above using ethyl 4-amino-3-proyl-1 H- pyrazole-5-carboxylic acid salt (1.7 g, 8.644 mmol), 3-nitrobenzoylchloride (2.1 g, 11.234 mmol) Reaction gave a product (3 g, 90.5%).

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.85 (s, 1H), 8.48 (d, J = 8.2 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H), 7.82 (t, J = 8.0 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H), 1.77-1.64 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.4 Hz, 3H)

(6) Preparation of 4- (3-nitrobenzamido) -3 - proyl-1 H- pyrazole-5-carboxylic acid

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.84 (s, 1H), 8.47 (d, J = 7.7 Hz, 1H), 8.36 (d, J = 738 Hz, 1H), 7.80 (t, J = 7.9 Hz, 1H), 2.70 (t, J = 7.5 Hz, 2H), 1.77-1.65 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H)

(7) Preparation of 3-propyl-4- (3-nitrophenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

This example using 4- (3-nitrobenzamido) -3-proyl-1 H- pyrazole-5-carboxylic acid (453.3 mg, 1.368 mmol) and nicotinhydrazide (196.9 mg, 1.436 mmol) Reaction was carried out in the manner of 1 to give the product (60.7%) as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 9.06 (s, 1H), 8.84 (s, 1H), 8.73 (d, J = 4.1 Hz, 1H), 8.46 (d, J = 8.3 Hz, 1H), 8.38 (d, J = 7.8 Hz, 1H), 8.32 (d, J = 8.1 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.58 (t, J = 6.3 Hz, 1H), 2.76 ( t, J = 7.4 Hz, 2H), 1.77-1.65 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H)

Example 54. 5-Benzoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-propyl-1 H- pyrazole (Compound No. 54)

The above procedure was used with 4- (3-nitrobenzamido) -3-proyl-1 H- pyrazole-5-carboxylic acid (657.9 mg, 1.985 mmol) and benzoichydrazide (283.8 mg, 2.085 mmol). Reaction was carried out in the same manner as in Example 1, to obtain 487.8 mg (56.3%) of a product as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.84 (s, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.38 (d, J = 7.7 Hz, 1H), 7.92 (d, J = 7.8 Hz, 2H), 7.79 (t, J = 8.0 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.50 (t, J = 7.4 Hz, 2H), 2.76 (t, J = 7.6 Hz, 2H), 1.79-1.66 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H)

Example 55. 5-Isnicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-propyl-1 H- pyrazole (Compound No. 55)

The above was carried out using 4- (3-nitrobenzamido) -3-proyl-1 H- pyrazole-5-carboxylic acid (650.9 mg, 1.964 mmol) and isnicotinhydrazide (282.9 mg, 2.063 mmol). Reaction by the method of Example 1 gave the product (327.7 mg, 38.1%) as a light yellow solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.84 (s, 1H), 8.73 (d, J = 6.1 Hz, 2H), 8.45 (d, J = 8.2 Hz, 1H), 8.37 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 6.1 Hz, 2H), 7.79 (t, J = 8.0 Hz, 1H), 2.75 (t, J = 7.5 Hz, 2H), 1.79-1.66 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H)

Example 56. 5-Benzoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3-propyl-1 H- pyrazole (Compound No. 56)

4- (3-methoxybenzamido) -3-proyl-1 H- pyrazole-5-carboxylic acid (508.4 mg, 1.676 mmol) and benzoichydrazide (239.6 mg, 1.759 mmol) Reaction by the method of Example 1 gave the product (249 mg, 35.3%) as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.92 (d, J = 7.2 Hz, 2H), 7.62-7.48 (m, 5H), 7.42 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 3.87 (s, 3H), 2.78 (t, J = 7.6 Hz, 2H), 1.77-1.65 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H)

Example 57. 5-Isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3-propyl-1 H- pyrazole (Compound No. 57)

Using 4- (3-methoxybenzamido) -3-proyl-1 H- pyrazole-5-carboxylic acid (499 mg, 1.645 mmol) and isnicotinhydrazide (236.9 mg, 1.727 mmol) Reaction by the method of Example 1 gave the product (364.1 mg, 952.4%) as a yellow solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.70 (d, J = 6.1 Hz, 2H), 7.89 (d, J = 5.6 Hz, 2H), 7.58-7.54 (m, 2H) 7.42 (t, J = 7.1 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 3.87 (s, 3H), 2.77 (t, J = 7.0 Hz, 2H), 1.77-1.65 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H)

Example 58. 3- (4-Fluorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 58)

(1) Preparation of ( Z ) -ethyl 4- (4-fluorophenyl) -4-hydroxy-2-oxo-3-butanoate

4'-fluoroacetophenone (7.6 mL, 62.969 mmol) and diethyloxalate (8.5 mL, 62.969 mmol) were reacted in the same manner as in Example 1 (2) to give the product (12.6 g, 52.895 mmol, 84.4%) was obtained as a yellow solid.

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.05 (dd, J = 5.3, 8.9 Hz, 2H), 7.20 (t, J = 8.6 Hz, 2H), 7.06 (s, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H)

(2) Preparation of ( E ) -ethyl 4- (4-fluorophenyl) -3- (hydroxyimino) -2,4-dioxobutanoate

By the method of Example 1 (4) above using ( Z ) -ethyl 4- (4-fluorophenyl) -4-hydroxy-2-oxo-3-butanoate (11 g, 46.259 mmol) Reaction gave the product (11.2 g, 90.5%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.90 (dd, J = 5.3, 8.9 Hz, 2H), 7.20 (t, J = 8.6 Hz, 2H), 4.40 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H)

(3) Preparation of ethyl 3- (4-fluorophenyl) -4-nitroso-1 H- pyrazole-5-carboxylic acid salt

( E ) -Ethyl 4- (4-fluorophenyl) -3- (hydroxyimino) -2,4-dioxobutanoate (11.2 g, 41.741 mmol) and hydrazine hydrate (2.3 mL, 41.741 mmol) Was reacted by the method of Example 4 (4) to give the product (10.9 g, 100%) as a sticky green solid.

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.01 (dd, J = 5.2, 8.9 Hz, 2H), 7.17 (t, J = 8.7 Hz, 2H), 4.51 (q, J = 7.2 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H)

(4) Preparation of ethyl 4-amino-3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

Ethyl 3- (4-fluorophenyl) -4-nitroso-1 H- pyrazole-5-carboxylic acid salt (11.1 g, 42.199 mmol) was reduced to give the product (5.3 g, 52.8%) as a light yellow solid. .

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.69 (dd, J = 5.4, 8.8 Hz, 2H), 7.17 (t, J = 8.8 Hz, 2H), 4.43 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H)

(5) Preparation of ethyl 4- (3-nitrobenzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

This was done using ethyl 4-amino-3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt (849.4 mg, 3.408 mmol) and 3-nitrobenzoylchloride (822.1 mg, 4.430 mmol). Reaction was carried out by the method of Example 1 to obtain the product (1.3 g, 95%) as a white solid.

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.78 (s, 1H), 8.45 (d, J = 7.1 Hz, 1H), 8.28 (d, J = 7.6 Hz, 1H), 7.73 (t, J = 8.0 Hz , 1H), 7.59 (dd, J = 5.4, 8.7 Hz, 2H), 7.13 (t, J = 8.6 Hz, 2H), 4.44 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz , 3H)

(6) Preparation of 4- (3-nitrobenzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.83 (s, 1H), 8.47 (d, J = 6.7 Hz, 1H), 8.34 (d, J = 7.8 Hz, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.73 (dd, J = 5.4, 8.7 Hz, 2H), 7.18 (t, J = 8.8 Hz, 2H)

(7) Preparation of 3- (4-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole

4- (3-nitrobenzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (323 mg, 0.872 mmol) and nicotinhydrazide (125.6 mg, 0.916 mmol) Reaction was carried out in the same manner as in Example 1 to obtain the product (148.3 mg, 34.7%) as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 9.06 (s, 1H), 8.82 (s, 1H), 8.72 (br, 1H), 8.45 (d, J = 7.9 Hz, 1H), 8.35 (t, J = 8.0 Hz, 2H), 7.81-7.69 (m, 3H), 7.58 (t, J = 6.5 Hz, 1H), 7.23 (t, J = 7.7 Hz, 2H)

Example 59. 3- (4-Fluorophenyl) -5-benzoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 59)

4- (3-nitrobenzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (382.3 mg, 1.032 mmol) and benzoichydrazide (147.6 mg, 1.084 mmol) Was reacted in the same manner as in Example 1 to obtain a product (34.4 mL, 331.1 mg, 65.7%).

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.82 (s, 1H), 8.45 (d, J = 8.2 Hz, 1H), 8.35 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 7.3 Hz, 2H), 7.77 (t, J = 8.0 Hz, 1H), 7.70 (dd, J = 5.4, 8.5 Hz, 2H), 7.59 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.21 (t, J = 8.7 Hz, 2H)

Example 60. 3- (4-Fluorophenyl) -4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 60)

(1) Preparation of ethyl 4- (3-methoxybenzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

Using ethyl 4-amino-3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt (1 g, 4.045 mmol) and 3-methoxybenzoylchloride (0.77 mL, 5.663 mmol) Reaction by the method of Example 1 gave the product (1.14 g, 73.7%) as a white solid.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.60 (dd, J = 5.3, 8.2 Hz, 2H), 7.50-7.48 (m, 2H), 7.41 (t, J = 7.8 Hz, 1H), 7.11 (t, J = 8.5 Hz, 3H), 4.43 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H)

(2) Preparation of 4- (3-methoxybenzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.73 (dd, J = 5.4, 8.8 Hz, 2H), 7.55-7.50 (m, 2H), 7.42 (t, J = 7.9 Hz, 1H), 7.18 (t , J = 8.8 Hz, 3H), 3.87 (s, 3H)

(3) Preparation of 3- (4-fluorophenyl) -4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (3-methoxybenzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (323.5 mg, 0.910 mmol) and nicotinhydrazide (131.1 mg, 0.956 mmol) Reaction was carried out in the same manner as in Example 1 using to obtain the product (277.7 mg, 64.3%) as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 9.06 (s, 1H), 8.73 (d, J = 4.8 Hz, 1H), 8.33 (d, J = 7.9 Hz, 1H), 7.69 (br, 2H), 7.60-7.50 (m, 3H), 7.40 (t, J = 7.9 Hz, 1H), 7.21 (t, J = 8.6 Hz, 2H), 7.13 (d, J = 7.0 Hz, 1H), 3.85 (s, 3H )

Example 61. 3- (4-Fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 61)

4- (3-methoxybenzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (319.5 mg, 0.899 mmol) and isnicotinhydrazide (129.5 mg, 0.944 mmol) ) Was reacted in the same manner as in Example 1, to obtain a product (201.2 mg, 47.2%) as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.73 (d, J = 6.0 Hz, 2H), 7.87 (d, J = 6.1 Hz, 2H), 7.70 (dd, J = 5.4, 8.5 Hz, 2H), 7.55-7.51 (m, 2H), 7.41 (t, J = 7.9 Hz, 1H), 7.22 (t, J = 8.7 Hz, 2H), 7.14 (d, J = 8.1 Hz, 1H), 3.86 (s, 3H )

Example 62. 3- (4-Fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 62)

(1) Preparation of ethyl 4- (3-methylbenzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

This was done using ethyl 4-amino-3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt (1.1 g, 4.342 mmol) and m-toluoylchloride (0.69 mL, 5.210 mmol). Reaction was carried out by the method of Example 1 to give the product (1.4 g, 90.4%) as a white solid.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.75 (br, 2H), 7.61 (dd, J = 5.5, 8.8 Hz, 2H), 7.39 (d, J = 4.9 Hz, 2H), 7.08 (t, J = 8.7 Hz, 2H), 4.36 (q, J = 7.0 Hz, 2H), 2.43 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H)

(2) Preparation of 4- (3-methylbenzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.78-7.71 (m, 4H), 7.41 (br, 2H), 7.39 (t, J = 7.0 Hz, 2H), 2.44 (s, 3H)

(3) Preparation of 3- (4-fluorophenyl) -4- (3-methoxyphenyl) carboxyamino-5-isonicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (3-methylbenzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (303.2 mg, 0.894 mmol) and nicotinhydrazide (128.7 mg, 0.938 mmol) Was reacted in the same manner as in Example 1, to obtain a product (314.3 mg, 76.7%).

¹ H NMR (CD ₃ OD, 300 MHz) δ 9.07 (s, 1H), 8.74 (d, J = 4.5 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 7.78-7.67 (m, 4H ), 7.58 (dd, J = 5.0, 8.0 Hz, 1H), 7.40-7.35 (m, 2H), 7.21 (t, J = 8.7 Hz, 2H), 2.42 (s, 3H)

Example 63. 5-Benzoylhydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 63)

4- (3-methylbenzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (312.9 mg, 0.922 mmol) and benzoichydrazide (131.8 mg, 0.968 mmol) Reaction was carried out in the same manner as in Example 1 using to obtain the product (317.9 mg, 0.695 mmol, 75.4%) as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.93 (d, J = 8.3 Hz, 2H), 7.79 (s, 1H), 7.76-7.67 (m, 3H), 7.59 (t, J = 7.3 Hz, 1H ), 7.50 (t, J = 7.6 Hz, 2H), 7.40-7.35 (m, 2H), 7.21 (t, J = 8.8 Hz, 2H), 2.42 (s, 3H)

Example 64. 5-Isnicotinoylhydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 64)

4- (3-methylbenzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (357 mg, 1.052 mmol) and isnicotinhydrazide (151.5 mg, 1.105 mmol) Reaction was carried out in the same manner as in Example 1 using to obtain the product (482.3 mg, 1.0521 mmol, 100%) as a yellow solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.73 (d, J = 4.4 Hz, 2H), 7.87 (d, J = 4.2 Hz, 2H), 7.78-7.70 (m, 4H), 7.40 (br, 2H ), 7.21 (t, J = 8.2 Hz, 2H), 2.42 (s, 3H)

Example 65. 4-phenylcarboxyamino-3- (4-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 65)

(1) Preparation of ethyl 4- (benzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

Example 1 above using ethyl 4-amino-3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt (1.0 g, 4.151 mmol), benzoylchloride (0.58 mL, 4.981 mmol) Reaction was carried out to give the product (1.2 g, 3.396 mmol, 81.3%) as a white solid.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.39 (d, J = 7.5 Hz, 2H), 7.63-7.56 (m, 3H), 7.51 (t, J = 7.3 Hz, 2H), 7.11 (t, J = 8.7 Hz, 2H), 4.43 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H)

(2) Preparation of 4- (benzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.96 (d, J = 7.6 Hz, 2H), 7.74 (dd, J = 5.4, 8.7 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.52 (t, J = 7.4 Hz, 2H), 7.18 (t, J = 8.8 Hz, 2H)

(3) Preparation of 4-phenylcarboxyamino-3- (4-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (benzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (311.2 mg, 0.957 mmol) and nicotinhydrazide (137.8 mg, 1.005 mmol) were prepared in the above examples. Reaction in the preparation of 1 afforded the product (286 mg, 0.644 mmol, 67.3%) as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 9.07 (s, 1H), 8.73 (d, J = 4.9 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 7.1 Hz, 2H), 7.71 (dd, J = 5.2, 8.5 Hz, 2H), 7.60-7.56 (m, 2H), 7.50 (t, J = 7.3 Hz, 2H), 7.21 (t, J = 8.8 Hz, 2H )

Example 66. 4- (3-Nitrophenyl) carboxyamino-3- (3-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 66)

(1) Preparation of ( Z ) -ethyl 4- (3-fluorophenyl) -4-hydroxy-2-oxo-3-butanoate

3'-fluoroacetophenone (7.2 mL, 58.772 mmol) and diethyloxalate (7.9 mL, 58.772 mmol) were reacted in the same manner as in Example 1 (2) to give the product (12.6 g, 52.895 mmol, 90.5%) as a yellow solid

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.79 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 9.4 Hz, 1H), 7.56-7.47 (m, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.05 (s, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H)

(2) Preparation of ( E ) -ethyl 4- (3-fluorophenyl) -3- (hydroxyimino) -2,4-dioxobutanoate

( Z ) -Ethyl 4- (3-fluorophenyl) -4-hydroxy-2-oxo-3-butanoate (12 g, 50.389 mmol) by the method of Example (4) above Reaction gave the product (9.4 g, 69.6%).

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.65-7.57 (m, 2H), 7.54-7.48 (m, 1H), 7.38 (t, J = 8.6 Hz, 1H), 4.43 (q, J = 6.8 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H)

(3) Preparation of ethyl 3- (3-fluorophenyl) -4-nitroso-1 H- pyrazole-5-carboxylic acid salt

( E ) -Ethyl 4- (3-fluorophenyl) -3- (hydroxyimino) -2,4-dioxobutanoate (8.3 g, 62.1 mL, 31.023 mmol) and hydrazine hydrate (1.7 mL, 31.023 mmol) to give the product (8.17 g, 100%).

(4) Preparation of ethyl 4-amino-3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

Ethyl 3- (3-fluorophenyl) -4-nitroso-1 H- pyrazole-5-carboxylic acid salt (9.18 g, 34.876 mmol) was reduced to give the product (4.7 g, 18.857 mmol, 53.8%) as a yellow solid. Got it.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.53-7.40 (m, 3H), 7.07 (t, J = 8.3 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H), 4.32 (br, 2H) , 1.44 (t, J = 7.1 Hz, 3H)

(5) Preparation of ethyl 4- (3-nitrobenzamido) -3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

This was done using ethyl 4-amino-3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt (900.1 mg, 3.611 mmol), 3-nitrobenzoylchloride (871.2 mg, 4.695 mmol). Reaction was carried out by the method of Example 1 to obtain the product (1.3 g, 90.1%) as a white solid.

¹ H NMR (CDCl ₃ , 300 MHz) δ 8.79 (s, 1H), 8.45 (d, J = 7.2 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.73 (t, J = 8.3 Hz , 1H), 7.42-7.32 (m, 3H), 7.10 (t, J = 8.9 Hz, 1H), 4.42 (q, J = 7.5 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H)

(6) Preparation of 4- (3-nitrobenzamido) -3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.84 (s, 1H), 8.48 (d, J = 8.2 Hz, 1H), 8.35 (d, J = 7.8 Hz, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.49-7.41 (m, 2H), 7.13 (t, J = 8.4 Hz, 1H)

(7) Preparation of 4- (3-nitrophenyl) carboxyamino-3- (3-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (3-nitrobenzamido) -3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (374 mg, 1.010 mmol) and nicotinhydrazide (145.4 mg, 1.061 mmol) The reaction of the preparation of Example 1 gave the product (224.6 mg, 45.4%) as a white solid.

¹ H NMR (dMSO, 300 MHz): d 9.02 (s, 1H), 8.78 (s, 1H), 8.73 (d, J = 4.4 Hz, 1H), 8.45-8.38 (m, 2H), 8.21 (d, J = 8.2 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.55-7.51 (m, 4H), 7.25 (t, J = 7.8 Hz, 1H)

Example 67. 3- (3-fluorobenzyl) -4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 67)

(1) Preparation of ethyl 4- (3-methoxy-3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

Ethyl 4-amino-3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt (1 g, 4.012 mmol), 0.442 mmol) and 3-methoxybenzoylchloride (0.77 mL, 5.663 mmol) Was reacted by the method of Example 1 to obtain a product.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.52-7.33 (m, 6H), 7.14-7.03 (m, 2H), 4.40 (q, J = 6.9 Hz, 2H), 3.86 (s, 3H), 1.35 ( t, J = 7.1 Hz, 3H)

(2) Preparation of 4- (3-methoxybenzamido) -3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.60-7.41 (m, 6H), 7.18-7.09 (m, 2H), 3.87 (s, 3H)

(3) Preparation of 3- (3-fluorobenzyl) -4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (3-methoxybenzamido) -3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (391.4 mg, 1.102 mmol) and nicotinhydrazide (158.6 mg, 1.157 mmol) Reaction was carried out in the same manner as in Example 1 to obtain the product (283 mg, 54.2%) as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 9.07 (s, 1H), 8.37 (d, J = 4.3 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 7.60-7.39 (m, 7H ), 7.15 (d, J = 8.1 Hz, 2H), 3.86 (s, 3H)

Example 68. 5-Benzoylhydrazinecarbonyl-3- (3-fluorophenyl) -4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 68)

4- (3-methoxybenzamido) -3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (393.5 mg, 1.108 mmol) and benzoichydrazide (158.3 mg, 1.163 mmol) ) Was reacted in the same manner as in Example 1, to obtain a product (278.8 mg, 0.589 mmol, 53.2%) as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.92 (d, J = 7.7 Hz, 2H), 7.65-7.39 (m, 9H), 7.19-7.13 (m, 2H), 3.86 (s, 3H)

Example 69. 3- (3-fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 69)

4- (3-methoxybenzamido) -3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (397.1 mg, 1.118 mmol) and isnicotinhydrazide (160.9 mg, 1.174 mmol) ) Was reacted in the same manner as in Example 1, to obtain a product (446.2 mg, 0.940 mmol, 84.2%) as a yellow solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.73 (d, J = 5.2 Hz, 2H), 7.87 (d, J = 5.6 Hz, 2H), 7.56-7.39 (m, 6H), 7.16 (br, 2H ), 3.86 (s, 3 H)

Example 70. 3- (3-Fluorophenyl) -4- (3-methylphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 70)

(1) Preparation of ethyl 4- (3-methylbenzamido) -3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

This was done using ethyl 4-amino-3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt (1 g, 4.012 mmol) and m-toluoylchloride (0.64 mL, 4.850 mmol). Reaction was carried out by the method of Example 1 to obtain the product (1.4 g, 91.9%) as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.75 (br, 2H), 7.43-7.34 (m, 5H), 7.06 (t, J = 8.0 Hz, 1H), 4.38 (q, J = 7.0 Hz, 2H ), 2.44 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H)

(2) Preparation of 4- (3-methylbenzamido) -3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.79-7.74 (m, 2H), 7.55 (d, J = 5.9 Hz, 1H), 7.49-7.40 (m, 4H), 7.12 (t, J = 7.9 Hz , 1H), 2.44 (s, 3H)

(3) Preparation of 3- (3-fluorophenyl) -4- (3-methylphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (3-methylbenzamido) -3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (368.5 mg, 1.086 mmol) and nicotinhydrazide (156.4 mg, 1.140 mmol) Reaction was carried out in the same manner as in Example 1 to obtain the product (420.7 mg, 84.5%) as a yellow solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 9.07 (s, 1H), 8.73 (d, J = 4.9 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 7.80 (s, 1H), 7.76 (d, J = 6.3 Hz, 1H), 7.58 (dd, J = 4.9, 8.1 Hz, 1H), 7.51-7.36 (m, 5H), 7.16 (t, J = 7.8 Hz, 1H), 2.43 (s , 3H)

Example 71. 3- (3-fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 71)

4- (3-methylbenzamido) -3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (371.5 mg, 1.095 mmol) and isnicotinhydrazide (157.7 mg, 1.149 mmol) Reaction was carried out in the same manner as in Example 1 above to obtain the product (194.8 mg, 38.8%) as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.72 (d, J = 4.5 Hz, 2H), 7.88 (d, J = 4.8 Hz, 2H), 7.80-7.75 (m, 2H), 7.49-7.39 (m , 5H), 7.15 (t, J = 6.6 Hz, 1H), 2.43 (s, 3H)

Example 72. 4-phenylcarboxyamino-3- (3-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 72)

(1) Preparation of ethyl 4- (benzamido) -3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

Ethyl 4-amino-3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt (996.4 mg, 3.998 mmol), DMAP (53.7 mg, 0.439 mmol), benzoylchloride (0.56 mL, 4.797 mmol ) Was reacted in the same manner as in Example 1, to obtain a product (87.2%) as a white solid.

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.97 (d, J = 7.0 Hz, 2H), 7.62-7.43 (m, 4H), 7.38-7.30 (m, 2H), 7.04 (t, J = 8.4 Hz, 1H), 4.32 (q, J = 7.0 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H)

(2) Preparation of 4- (benzamido) -3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid

Hydrolysis of ethyl 4- (benzamido) -3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt (1.23 g, 27.9 mL, 3.487 mmol) to give the product (1.1 g, 93.9% ) Was obtained as a yellow solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.97 (d, J = 8.2 Hz, 2H), 7.63-7.41 (m, 6H), 7.12 (t, J = 7.6 Hz, 1H)

(3) Preparation of 4-phenylcarboxyamino-3- (3-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (benzamido) -3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (357.1 mg, 1.098 mmol) and nicotinhydrazide (158.1 mg, 1.153 mmol) Reaction by the method of Example 1 gave the product (479.9 mg, 1.079 mmol, 98.4%) as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 9.07 (s, 1H), 8.73 (d, J = 3.2 Hz, 1H), 8.33 (d, J = 7.7 Hz, 1H), 7.97 (d, J = 7.2 Hz, 2H), 7.60-7.43 (m, 7H), 7.16 (t, J = 7.4 Hz, 1H)

Example 73. 4-phenylcarboxyamino-5-benzoylhydrazinecarbonyl-3- (3-fluorophenyl) -1 H- pyrazole (Compound No. 73)

4- (benzamido) -3- (3-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (354.9 mg, 1.091 mmol) and benzoichydrazide (155.9 mg, 1.146 mmol) Reaction was carried out by the method of Example 1, to obtain the product (410.6 mg, 84.9%) as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.95 (dd, J = 7.1, 14.7 Hz, 4H), 7.59 (t, J = 6.7 Hz, 2H), 7.54-7.42 (m, 7H), 7.16 (t , J = 7.8 Hz, 1H)

Example 74. 3- (3-Fluorophenyl) -4-phenylcarboxyamino-5-isonicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 74)

5-carboxylic acid (288.5 mg, 0.887 mmol) and isonicotinhydrazide (127.7 mg, 0.931 mmol) were reacted in the same manner as in Example 1 to obtain the product (314.3 mg, 9.7%) as a white solid.

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.71 (d, J = 6.0 Hz, 2H), 7.98 (d, J = 7.7 Hz, 2H), 7.89 (d, J = 6.5 Hz, 2H), 7.65- 7.39 (m, 6H), 7.16 (t, J = 7.4 Hz, 1H)

Example 75. 3- (2-Fluorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 75)

(1) Preparation of ( Z ) -ethyl 4- (2-fluorophenyl) -4-hydroxy-2-oxo-3-butanoate

Reaction was carried out by the method of Example 1 (1) to prepare a product.

Yield 93.2%; ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.01 (t, J = 8.9 Hz, 1H), 7.64-7.54 (m, 1H), 7.33 (t, J = 6.8 Hz, 1H), 7.21 (d, J = 11.5 Hz, 1H), 7.14 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H)

(2) Preparation of ( E ) -ethyl 4- (2-fluorophenyl) -3- (hydroxyimino) -2,4-dioxobutanoate

Reaction was carried out by the method of Example 2 (2) to prepare a product.

Yield 77.9%; ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.00 (t, J = 7.6 Hz, 1H), 7.69-7.55 (m, 1H), 7.33 (t, J = 8.2 Hz, 1H), 7.17 (dd, J = 8.3, 11.1 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H)

(3) Preparation of ethyl 3- (2-fluorophenyl) -4-nitroso-1 H- pyrazole-5-carboxylic acid salt

Reaction was carried out by the method of Example 3 (3) to prepare a product.

Yield 100%; ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.76 (t, J = 7.2 Hz, 1H), 7.40-7.37 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H)

(4) Preparation of ethyl 4-amino-3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

Yield 58.1%; ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.66 (t, J = 7.6 Hz, 1H), 7.41-7.33 (m, 1H), 7.25-7.16 (m, 2H), 4.43 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H)

(5) Preparation of ethyl 4- (3-nitrobenzamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

Yield 92.1%; ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.77 (s, 1H), 8.42 (d, J = 8.3 Hz, 1H), 8.24 (d, J = 7.1 Hz, 1H), 7.99 (t, J = 6.3 Hz , 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.63 (t, J = 7.1 Hz, 1H), 7.42 (d, J = 6.8 Hz, 1H), 7.15 (t, J = 8.8 Hz, 1H ), 4.47 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H)

(6) Preparation of 4- (3-nitrobenzamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.76 (s, 1H), 8.45 (d, J = 7.7 Hz, 1H), 8.28 (d, J = 7.5 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.63 (t, J = 6.9 Hz, 1H), 7.45 (q, J = 7.1 Hz, 1H), 7.30-7.18 (m, 2H)

(7) Preparation of 3- (2-fluorophenyl) -4- (3-nitrophenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (3-nitrobenzamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (351.4 mg, 0.949 mmol) and nicotinhydrazide (136.7 mg, 0.996 mmol) The reaction was carried out in the same manner as in Example 1 to prepare a product.

Yield 38.3%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 9.07 (s, 1H), 8.75 (d, J = 10.5 Hz, 2H), 8.43 (d, J = 8.4 Hz, 1H), 8.32 (t, J = 8.5 Hz, 2H), 7.76 (t, J = 8.1 Hz, 1H), 7.67-7.57 (m, 2H), 7.49 (br, 1H), 7.32-7.23 (m, 2H)

Example 76. 3- (2-Fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 76)

4- (3-nitrobenzamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (360 mg, 0.972 mmol) and isnicotinhydrazide (139.9 mg, 1.021 mmol) The reaction was carried out in the same manner as in Example 1, to prepare a product.

¹ H NMR (CD ₃ OD, 300 MHz) δ 8.77 (s, 1H), 8.73-8.68 (m, 2H), 8.44 (d, J = 8.1 Hz, 1H), 8.31 (d, J = 7.6 Hz, 1H ), 7.89 (d, J = 5.9 Hz, 2H), 7.79-7.75 (m, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 6.7 Hz, 1H), 7.32-7.22 (m, 2H)

Example 77. 3- (2-Fluorophenyl) -4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 77)

(1) Preparation of ethyl 4- (3-methoxybenzamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

Yield 81.2%; ¹ H NMR (CDCl ₃ , 300 MHz) δ 9.07 (s, 1H), 7.60 (t, J = 6.5 Hz, 1H), 7.50-7.36 (m, 4H), 7.24-7.09 (m, 2H), 4.46 ( q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H)

(2) Preparation of 4- (3-methoxybenzamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid

Yield 95.3%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.62 (t, J = 6.9 Hz, 1H), 7.49-7.37 (m, 4H), 7.28-7.11 (m, 3H), 3.85 (s, 3H)

(3) Preparation of 3- (2-fluorophenyl) -4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (3-methoxybenzamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (425.6 mg, 1.198 mmol) and nicotinhydrazide (172.5 mg, 1.258 mmol) The reaction was carried out in the same manner as in Example 1, to prepare a product.

Yield 76.4%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 9.08 (s, 1H), 8.74 (d, J = 4.9 Hz, 1H), 8.35 (d, J = 8.3 Hz, 1H), 7.66-7.57 (m, 2H ), 7.50-7.36 (m, 4H), 7.31-7.21 (m, 2H), 7.12 (d, J = 8.5 Hz, 1H), 3.84 (s, 3H)

Example 78. 3- (2-Fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 78)

4- (3-methoxybenzamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (414.3 mg, 1.166 mmol) and isnicotinhydrazide (167.9 mg, 1.224 mmol) ) Was reacted by the method of Example 1 to prepare a product.

Yield 50.1%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 8.73 (d, J = 4.5 Hz, 2H), 7.89 (d, J = 4.6 Hz, 2H), 7.63 (br, 1H), 7.50-7.36 (m, 4H ), 7.30-7.21 (m, 2H), 7.12 (d, J = 6.2 Hz, 1H), 3.84 (s, 3H)

Example 79. 3- (2-Fluorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 79)

(1) Preparation of ethyl 4- (3-methylbenzamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

Yield 91.4%; ¹ H NMR (CDCl ₃ , 300 MHz) δ 9.05 (s, 1H), 7.73 (br, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.38-7.35 (m, 2H), 7.24-7.11 ( m, 2H), 4.44 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H)

(2) Preparation of 4- (3-methylbenzamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid

Yield 82.4%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.85-7.60 (m, 3H), 7.39 (br, 3H), 7.25-7.20 (m, 2H), 2.42 (s, 3H)

(3) Preparation of 3- (2-fluorophenyl) -4- (3-methylphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (3-methylbenzamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (374.8 mg, 1.105 mmol) and nicotinhydrazide (159.1 mg, 1.159 mmol) The reaction was carried out in the same manner as in Example 1 to prepare a product.

Yield 60.3%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 9.08 (s, 1H), 8.73 (d, J = 4.9 Hz, 1H), 8.35 (d, J = 8.1 Hz, 1H), 7.73-7.57 (m, 4H ), 7.46 (q, J = 6.6 Hz, 1H), 7.40-7.33 (m, 2H), 7.30-7.20 (m, 2H), 2.41 (s, 3H)

Example 80. 3- (2-Fluorophenyl) -4- (3-methylphenyl) carboxyamino-5-isonicotinoylhydrazinecarbonyl) -1 H- pyrazole (Compound No. 80)

4- (3-methylbenzamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (331.5 mg, 0.977 mmol) and isnicotinhydrazide (140.7 mg, 1.026 mmol) The reaction was carried out in the same manner as in Example 1, to prepare a product.

Yield 49.9%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 8.73 (d, J = 4.9 Hz, 2H), 7.89 (d, J = 4.7 Hz, 2H), 7.76-7.61 (m, 3H), 7.44-7.20 (m , 5H), 2.41 (s, 3H)

Example 81. 4-phenylcarboxyamino-3- (2-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 81)

(1) Preparation of ethyl 4- (benzamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

Yield 92.4%; ¹ H NMR (CDCl ₃ , 300 MHz) δ 9.09 (s, 1H), 7.92 (d, J = 7.1 Hz, 2H), 7.62-7.46 (m, 3H), 7.38 (q, J = 7.0 Hz, 1H) , 7.23-7.10 (m, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H)

(2) Preparation of 4- (benzamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.90 (d, J = 7.2 Hz, 2H), 7.65-7.56 (m, 2H), 7.52-7.41 (m, 3H), 7.25 (t, J = 7.0 Hz , 1H), 7.19 (d, J = 8.8 Hz, 1H)

(3) Preparation of 4-phenylcarboxyamino-3- (2-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (benzamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (230.7 mg, 0.709 mmol) and nicotinhydrazide (102.1 mg, 0.745 mmol) Reaction was carried out by the method of Example 1 to prepare a product.

Yield 70.7%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 9.09 (s, 1H), 8.74 (d, J = 5.0 Hz, 1H), 8.35 (d, J = 7.7 Hz, 1H), 7.91 (d, J = 8.6 Hz, 2H), 7.66-7.55 (m, 3H), 7.46 (t, J = 7.5 Hz, 3H), 7.32-7.21 (m, 2H)

Example 82. 4-phenylcarboxyamino-3- (2-fluorophenyl) -5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 82)

4- (benzamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (223.5 mg, 0.687 mmol) and benzoichydrazide (98.9 mg, 0.721 mmol) Reaction was carried out by the method of Example 1 to prepare a product.

Yield 51.1%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 8.74 (d, J = 4.6 Hz, 2H), 7.90 (br, 4H), 7.63-7.46 (m, 5H), 7.35-7.20 (m, 2H)

Example 83. 5-Nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3- (thiophen-2-yl) -1 H- pyrazole (Compound No. 83)

(1) Preparation of ( Z ) -ethyl 4-hydroxy-2-oxo-4- (thiophen-2-yl) -3-butanoate

Yield 90.6%; ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.87 (d, J = 3.8 Hz, 1H), 7.76 (d, J = 4.9 Hz, 1H), 7.21 (t, J = 4.4 Hz, 1H), 6.94 (s , 1H), 4.41 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.13 Hz, 3H)

(2) ( E ) -ethyl 3- (hydroxyimino) -2,4-dioxo-4- (thiophen-2-yl) butanoate

Yield 66.2%; ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.16 (d, J = 4.0 Hz, 1H), 7.64 (d, J = 4.0 Hz, 1H), 7.20 (t, J = 4.3 Hz, 1H), 4.43 (q , J = 6.1 Hz, 2H), 1.41 (t, J = 6.5 Hz, 3H)

(3) Preparation of ethyl 4-amino-3- (thiophen-2-yl) -1 H- pyrazole-5-carboxylic acid salt

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.35 (br, 2H), 7.15 (t, J = 8.7 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz , 3H)

(4) Preparation of ethyl 4- (3-nitrobenzamido) -3- (thiophen-2-yl) -1 H- pyrazole-5-carboxylic acid salt

Yield 93.2%; ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.82 (s, 1H), 8.46-8.25 (m, 3H), 7.74 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 4.6 Hz, 1H) , 7.11 (t, J = 7.9 Hz, 1H), 4.38 (q, J = 8.4 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H)

(5) Preparation of 4- (3-nitrobenzamido) -3- (thiophen-2-yl) -1 H- pyrazole-5-carboxylic acid

Yield 91.4%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 8.88 (s, 1H), 8.49 (d, J = 8.2 Hz, 1H), 8.40 (d, J = 7.5 Hz, 1H), 7.82 (t, J = 8.0 Hz, 1H), 7.48 (br, 2H), 7.11 (t, J = 4.3 Hz, 1H)

(6) Preparation of 5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3- (thiophen-2-yl) -1 H- pyrazole

4- (3-nitrobenzamido) -3- (thiophen-2-yl) -1 H- pyrazole-5-carboxylic acid (221.8 mg, 0.619 mmol) and nicotinhydrazide (89.1 mg, 0.649 mmol) The reaction was carried out in the same manner as in Example 1, to prepare a product.

Yield 40.6%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 9.06 (s, 1H), 8.88 (s, 1H), 8.73 (d, J = 4.6 Hz, 1H), 8.47 (d, J = 8.1 Hz, 1H), 8.40 (d, J = 7.5 Hz, 1H), 8.33 (d, J = 7.7 Hz, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.59-7.52 (m, 3H), 7.16 (t, J = 4.1 Hz, 1H)

Example 84. 4- (3-nitrophenyl) carboxyamino-3- (thiophen-2-yl) -5-phenylacetylhydrazinecarbonyl-1 H- pyrazole (Compound No. 84)

4- (3-nitrobenzamido) -3- (thiophen-2-yl) -1 H- pyrazole-5-carboxylic acid (223.7 mg, 0.624 mmol) and phenylacetylhydrazide (98.4 mg, 0.656 mmol ) Was reacted by the method of Example 1 to prepare a product.

Yield 58.8%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 8.87 (s, 1H), 8.48 (d, J = 7.2 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.53-7.49 (m, 2H), 7.35-7.23 (m, 5H), 7.14 (br, 1H), 3.62 (s, 2H)

Example 85. 3- (thiophen-2-yl) -4- (3-nitrophenyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 85)

4- (3-nitrobenzamido) -3- (thiophen-2-yl) -1 H- pyrazole-5-carboxylic acid (196 mg, 0.547 mmol) and benzoichydrazide (78.2 mg, 0.574 mmol ) Was reacted by the method of Example 1 to prepare a product.

Yield 53.3%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 8.87 (s, 1H), 8.47 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 7.7 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.80 (t, J = 8.0 Hz, 1H), 7.61-7.47 (m, 5H), 7.16 (t, J = 4.3 Hz, 1H)

Example 86. 5- (3-hydroxybenzoyl) hydrazinecarbonyl-3- (thiophen-2-yl) -4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 86)

4- (3-nitrobenzamido) -3- (thiophen-2-yl) -1 H- pyrazole-5-carboxylic acid (220 mg, 0.614 mmol) and 3-hydroxybenzoichydrazide (98.1 mg, 0.645 mmol) was reacted in the same manner as in Example 1, to prepare a product.

Yield 40.3%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 8.88 (br, 1H), 8.55-8.40 (m, 2H), 7.81 (t, J = 8.0 Hz, 1H), 7.58-7.51 (m, 2H), 7.46 -7.26 (m, 3H), 7.16 (br, 1H), 7.01 (t, J = 7.7 Hz, 1H)

Example 87. 5-Nicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3- (thiophen-2-yl) -1 H- pyrazole (Compound No. 87)

(1) Preparation of ethyl 4- (3-methoxybenzamido) -3- (thiophen-2-yl) -1 H- pyrazole-5-carboxylic acid salt

¹ H NMR (CDCl ₃ , 300 MHz) δ 7.55-7.05 (m, 7H), 4.30 (br, 2H), 3.88 (s, 3H), 1.25 (br, 3H)

(2) Preparation of 4- (3-methoxybenzamido) -3- (thiophen-2-yl) -1 H- pyrazole-5-carboxylic acid

Yield 92.7%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.58-7.43 (m, 5H), 7.16 (br, 2H), 3.87 (s, 3H)

(3) Preparation of 5-nicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3- (thiophen-2-yl) -1 H- pyrazole

4- (3-methoxybenzamido) -3- (thiophen-2-yl) -1 H- pyrazole-5-carboxylic acid (238.6 mg, 0.695 mmol) and nicotinhydrazide (100.1 mg, 0.729 mmol Reaction was carried out by the method of Example 1 using the above) to prepare a product.

¹ H NMR (CD ₃ OD, 300 MHz) δ 9.06 (s, 1H), 8.72 (s, 1H), 8.32 (d, J = 6.3 Hz, 1H), 7.57-7.40 (m, 6H), 7.15 (br , 2H), 3.87 (s, 3H)

Example 88. 5-Isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3- (thiophen-2-yl) -1 H- pyrazole (Compound No. 88)

4- (3-methoxybenzamido) -3- (thiophen-2-yl) -1 H- pyrazole-5-carboxylic acid (265.9 mg, 0.774 mmol) and isnicotinhydrazide (111.5 mg, 0.813 mmol) was reacted in the same manner as in Example 1 to obtain a product.

Yield 53.3%; ¹ H NMR (dMSO, 300 MHz): d 10.73 (s, 1 H), 7.78 (d, J = 4.9 Hz, 1 H), 7.69-7.66 (m, 3 H), 7.62 (s, 1 H), 7.52 (t, J = 7.7 Hz, 2H), 7.23 (br, 3H), 3.87 (s, 3H)

Example 89. 4-Butylcarboxyamino-5-nicotinoylhydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 89)

(1) Preparation of ethyl 3- (4-fluorophenyl) -4- (pentaneamido) -1 H- pyrazole-5-carboxylic acid salt

Yield 45.6%; ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.73 (s, 1H), 7.56 (br, 1H), 7.08 (t, J = 8.1 Hz, 2H), 4.36 (q, J = 6.5 Hz, 2H), 2.40 (t, J = 7.0 Hz, 2H), 1.72-1.63 (m, 2H), 1.44-1.26 (m, 5H), 0.95 (t, J = 7.2 Hz, 3H)

(2) Preparation of 3- (4-fluorophenyl) -4- (pentaneamido) -1 H- pyrazole-5-carboxylic acid

Yield 96.7%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.69-7.65 (m, 2H), 7.18 (t, J = 8.8 Hz, 2H), 2.39 (t, J = 7.4 Hz, 2H), 1.72-1.63 (m , 2H), 1.47-1.37 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H)

(3) Preparation of 4-butanecarboxyamino-5-nicotinoylhydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole

3- (4-fluorophenyl) -4- (pentaneamido) -1 H- pyrazole-5-carboxylic acid (212.8 mg, 0.697 mmol) and nicotinhydrazide (100.4 mg, 0.732 mmol) Reaction was carried out by the method of Example 1 to prepare a product.

¹ H NMR (CD ₃ OD, 300 MHz) δ 9.08 (s, 1H), 8.74 (d, J = 4.3 Hz, 1H), 8.35 (d, J = 7.9 Hz, 1H), 7.66-7.57 (m, 3H ), 7.22 (t, J = 8.6 Hz, 2H), 2.41 (t, J = 7.3 Hz, 2H), 1.72-1.65 (m, 2H), 1.41-1.36 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H)

Example 90. 5-Benzoylhydrazinecarbonyl-3- (4-fluorophenyl) -4-phenylacetylamino-1 H- pyrazole (Compound No. 90)

(1) Preparation of ethyl 4- (2-phenylacetamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

Yield 67.9%; ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.44-7.36 (m, 7H), 7.05 (t, J = 8.4 Hz, 2H), 4.37 (q, J = 6.4 Hz, 2H), 3.73 (s, 2H) , 1.38 (t, J = 7.1 Hz, 3H)

(2) Preparation of 4- (2-phenylacetamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid

Yield 83.8%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.51-7.46 (m, 2H), 7.37-7.30 (m, 5H), 6.97 (t, J = 8.8 Hz, 2H), 3.69 (s, 2H)

(3) Preparation of 5-benzoylhydrazinecarbonyl-3- (4-fluorophenyl) -4-phenylacetylamido-1 H- pyrazole

4- (2-phenylacetamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (164.4 mg, 0.485 mmol) and benzoichydrazide (69.3 mg, 0.509 mmol) Reaction was carried out by the method of Example 1 using to prepare a product.

Yield 45%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.95 (d, J = 7.2 Hz, 2H), 7.61 (d, J = 7.3 Hz, 1H), 7.54 (d, J = 7.7 Hz, 2H), 7.46 ( br, 2H), 7.37-7.29 (m, 5H), 7.03 (t, J = 8.7 Hz, 2H), 3.70 (s, 2H)

Example 91. 3- (4-Fluorophenyl) -4- (3-methylphenyl) carboxyamino-5- (propanoylhydrazinecarbonyl) -1 H- pyrazole (Compound No. 91)

4- (3-methylbenzamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (255.2 mg, 0.752 mmol) and butyrichydrazide (80.7 mg, 0.789 mmol) Reaction was carried out by the method of Example 1 using to prepare a product.

Yield 54.2%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.77-7.65 (m, 4H), 7.38 (br, 2H), 7.19 (t, J = 8.6 Hz, 2H), 2.43 (s, 3H), 2.29 (t , J = 7.4 Hz, 2H), 1.74-1.67 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H)

Example 92. 3- (4-Fluorophenyl) -4- (3-methoxyphenylacetyl) amino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 92)

(1) Preparation of ethyl 4- (2- (3-methoxyphenyl) acetamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

Yield 57.9%; ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.44-7.40 (m, 2H), 7.32 (t, J = 6.0 Hz, 1H), 7.02 (t, J = 6.5 Hz, 2H), 6.94-6.88 (m, 3H), 4.33 (q, J = 5.2 Hz, 2H), 3.80 (s, 3H), 3.68 (s, 2H), 1.32 (t, J = 9.2 Hz, 3H)

(2) Preparation of 4- (2- (3-methoxyphenyl) acetamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.49 (dd, J = 5.4, 8.6 Hz, 2H), 7.26 (t, J = 8.1 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 6.96 (t, J = 5.0 Hz, 2H), 6.86 (t, J = 6.9 Hz, 2H), 3.79 (s, 3H), 3.66 (s, 1H), 3.58 (s, 1H)

(3) Preparation of 3- (4-fluorophenyl) -4- (3-methoxyphenylacetyl) amino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (2- (3-methoxyphenyl) acetamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (197.5 mg, 0.535 mmol) and nicotinhydrazide (77 mg, 0.561 mmol) was reacted in the same manner as in Example 1, to prepare a product.

¹ H NMR (CD ₃ OD, 300 MHz) δ 9.09 (s, 1H), 8.76 (d, J = 6.4 Hz, 1H), 8.36 (d, J = 8.1 Hz, 1H), 7.61 (dd, J = 4.6 , 7.5 Hz, 1H), 7.49-7.44 (m, 2H), 7.25 (t, J = 8.1 Hz, 1H), 7.04 (t, J = 8.7 Hz, 2H), 6.96 (br, 2H), 6.86 (d , J = 9.1 Hz, 1H), 3.77 (s, 3H), 3.67 (s, 2H)

Example 93. 3- (4-Fluorophenyl) -4- (3-methoxyphenylacetyl) amido-5-phenylacetylhydrazinecarbonyl-1 H- pyrazole (Compound No. 93)

4- (2- (3-methoxyphenyl) acetamido) -3- (4-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (208.8 mg, 0.566 mmol) and phenylacetylhydrazide ( 84.3 mg, 0.562 mmol) was reacted in the same manner as in Example 1, to prepare a product.

Yield 43.2%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.49-7.25 (m, 8H), 7.01-6.86 (m, 5H), 3.78 (s, 3H), 3.66 (s, 4H)

Example 94. 3- (2-Fluorophenyl) -4- (3-phenylpropyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 94)

(1) Preparation of ethyl 4- (3-phenylpropylamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid salt

Yield 69.6%; ¹ H NMR (CDCl ₃ , 300 MHz) δ 8.07 (s, 1H), 7.48 (t, J = 7.3 Hz, 1H), 7.23-7.11 (m, 7H), 4.42 (q, J = 7.1 Hz, 2H) , 3.00 (t, J = 7.6 Hz, 2H), 2.70 (t, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H)

(2) Preparation of 4- (3-phenylpropylamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid

Yield 97.7%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.51-7.41 (m, 2H), 7.28-7.15 (m, 7H), 2.93 (t, J = 7.8 Hz, 2H), 2.64 (t, J = 7.8 Hz , 2H)

(3) Preparation of 3- (2-fluorophenyl) -4- (3-phenylpropyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole

4- (3-phenylpropylamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (183.1 mg, 0.518 mmol) and nicotinhydrazide (74.6 mg, 0.544 mmol) The reaction was carried out in the same manner as in Example 1 to prepare a product as a white solid.

Yield 46%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 9.09 (s, 1H), 8.75 (d, J = 6.5 Hz, 1H), 8.35 (d, J = 8.2 Hz, 1H), 7.60 (dd, J = 5.2 , 7.6 Hz, 1H), 7.48 (t, J = 6.9 Hz, 2H), 7.25-7.14 (m, 7H), 2.95 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 7.8 Hz, 2H )

Example 95. 3- (2-Fluorophenyl) -4- (3-phenylpropyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 95)

4- (3-phenylpropylamido) -3- (2-fluorophenyl) -1 H- pyrazole-5-carboxylic acid (183.4 mg, 0.519 mmol) and benzoichydrazide (74.2 mg, 0.545 mmol) The reaction was carried out in the same manner as in Example 1, to prepare a product.

Yield 51.3%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.95 (d, J = 8.5 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.55-7.43 (m, 4H), 7.26-7.16 (m , 7H), 2.95 (t, J = 7.7 Hz, 2H), 2.67 (t, J = 8.0 Hz, 2H)

Example 96. 5- (2-Chlorobenzoyl) hydrazinecarbonyl-4- (2-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 96)

(1) Preparation of 2,4-dioxo-4-phenyl-butyric acid ethyl ester

Yield 79%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 15.31 (s, 1H), 8.01 (d, J = 7.07 Hz, 2H), 7.62 (t, J = 7.45 Hz, 1H), 7.51 (t, J = 7.58 Hz 2H), 7.09 (s, 1H), 4.40 (q, J = 7.07 Hz, 2H), 1.42 (t, J = 7.07 Hz, 3H)

(2) Preparation of 3-hydroxyimino-2,4-dioxo-4-phenyl-butyric acid ethyl ester

Yield 61%; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.52 (d, J = 2.26 Hz, 1H), 8.03 (d, J = 7.91 Hz, 1H), 7.71 (d, J = 7.16 Hz, 1H), 7.75-7.48 (m, 3H), 4.38 (q, J = 7.10 Hz, 2H), 1.39 (t, J = 7.10 Hz, 3H)

(3) Preparation of 4-nitroso-5-phenyl-2 H- pyrazole-3-carboxylic acid ethyl ester

Yield 86%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.76-7.25 (m, 5H), 4.46-4.37 (m, 2H) 1.43-1.37 (m, 3H)

(4) Preparation of 4-amino-5-phenyl-2 H- pyrazole-3-carboxylic acid ethyl ester

Yield 52%; ¹ H NMR (300 MHz, CDCl ₃ ) δ 10.48 (s, 1H), 7.72-7.69 (m, 2H) 7.50-7.45 (m, 2H), 7.39-7.34 (m, 1H), 4.43 (q, J = 7.13 Hz, 2H), 4.32 (s, 2H) 1.43 (t, J = 7.12 Hz, 3H)

Preparation of 4- (2-nitro-benzoylamino) -5-phenyl-2 H- pyrazole-3-carboxylic acid ethyl ester

Yield 64%; ¹ H NMR (400 MHz, MeOD) δ 8.10 (d, J = 8.08 Hz, 1H), 7.94 (s, 1H), 7.86-7.78 (m, 3H), 7.75-7.69 (m, 1H), 7.47 (d , J = 7.07 Hz, 2H), 7.41 (s, 1H) 4.41 (q, J = 7.16 Hz, 2H) 1.37 (t, J = 7.07 Hz, 3H)

(5) Preparation of 4- (3-nitro-benzoylamino) -5-phenyl-2 H- pyrazole-3-carboxylic acid ethyl ester

Yield 80%; ¹ H NMR (400 MHz, MeOD) δ 8.84 (s, 1H), 8.51-8.45 (m, 1H), 8.35 (d, J = 7.54 Hz, 1H), 7.81 (t, J = 8.10 Hz, 1H), 7.73-7.68 (m, 2H), 7.49-7.40 (m, 3H), 4.34 (q, J = 7.16 Hz, 2H), 1.27 (t, J = 7.16 Hz, 3H)

(6) Preparation of 4- (2-nitro-benzoylamino) -5-phenyl-2 H- pyrazole-3-carboxylic acid

Yield 98%; ¹ H NMR (400 MHz, MeOD) δ 8.09 (d, J = 8.03 Hz, 1H), 7.91 (s, 1H), 7.83-7.71 (m, 3H), 7.73-7.67 (m, 1H), 7.49-7.45 (m, 2H), 7.40 (s, 1H)

(7) Preparation of 4- (3-nitro-benzoylamino) -5-phenyl-2 H- pyrazole-3-carboxylic acid

Yield 84%; ¹ H NMR (400 MHz, MeOD) δ 8.83 (s, 1H) 8.48-8.44 (m, 1H), 8.33 (d, J = 7.83 Hz 1H), 7.78 (t, J = 7.96 Hz, 1H), 7.72- 7.68 (m, 2H), 7.48-7.37 (m, 3H)

(8) Preparation of 5- (2-chlorobenzoyl) hydrazinecarbonyl-4- (2-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.88 (s, 1H), 10.35 (s, 1H), 10.24 (s, 1H) 10.18 (s, 1H), 8.05 (t, J = 8.59 Hz, 2H ), 7.86 (t, J = 7.50 Hz 1H), 7.82 (d, J = 7.74 Hz, 2H), 7.73 (t, J = 7.63 Hz, 1H), 7.55-7.41 (m, 7H)

Example 97. 5- (4-Chlorobenzoyl) hydrazinecarbonyl-4- (2-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 97)

Yield 72%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.88 (s, 1H), 10.53 (s, 1H), 10.21 (s, 1H), 10.15 (s, 1H), 8.03 (d, J = 8.08 Hz, 2H), 7.94 (d, J = 8.05 Hz 2H), 7.86-7.81 (m, 3H), 7.70 (t, J = 7.60 Hz, 1H), 7.59 (d, J = 8.59 Hz, 2H) 7.49 (t, J = 7.22 Hz, 2H), 7.43 (m, 1H)

Example 98. 5- (4-Chlorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 98)

Yield-%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ -------------------------------

Example 99. 5- (2-Chlorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 99)

Yield 54%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.88 (s, 1H), 10.28 (s, 2H), 10.23 (s, 1H), 8.80 (s, 1H), 8.45-8.38 (m, 2H), 7.83 t, J = 8.08 Hz, 1H), 7.69 (d, J = 7.33 Hz, 2H), 7.53-7.43 (m, 5H), 7.43-7.37 (m, 2H)

Example 100. 5- (3-Chlorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 100)

Yield 57%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.87 (s, 1H), 10.50 (s, 1H), 10.24 (s, 2H), 8.77 (s, H), 8.42-8.36 (m, 2H), 7.91-7.89 (m, 1H), 7.85-7.79 (m, 2H), 7.70 (d, J = 7.56 Hz, 2H), 7.65-7.63 (m, 1H), 7.53 (t, J = 7.88 Hz, 1H) , 7.49-7.45 (m, 2H), 7.40-7.37 (m, 1H)

Example 101. 5- (4-Chlorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 101)

Yield 57%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.88 (s, 1H), 10.48 (s, 1H), 10.24 (s, 1H), 10.19 (s, 1H), 8.77 (s, 1H), 8.44- 8.35 (m, 2H), 7.89 (d, J = 8.59 Hz, 2H), 7.81 (t, J = 7.96 Hz, 1H), 7.70 (d, J = 7.33 Hz, 2H), 7.56 (d, J = 8.34 Hz, 2H), 7.48-7.44 (m, 2H), 7.40-7.38 (m, 1H)

Example 102. 5- (3-methoxybenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 102)

Yield 46%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.86 (s, 1H), 10.35 (s, 1H), 10.24 (s, 1H), 10.15 (s, 1H), 8.77 (s, 1H), 8.42- 8.36 (m, 2H), 7.81 (t, J = 7.96 Hz 1H), 7.69 (d, J = 7.83 Hz, 2H), 7.47-7.42 (m, 3H), 7.43-7.36 (m, 3H), 7.12- 7.09 (m, 1 H), 3.78 (s, 3 H)

Example 103. 5- (4-methoxybenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 103)

Yield 53%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.86 (s, 1H), 10.23 (s, 2H), 10.08 (s, 1H), 8.77 (s, 1H), 8.42-8.36 (m, 2H), 7.86 (d, J = 8.84 Hz, 2H), 7.81 (t, J = 8.04 Hz, 1H), 7.70 (d, J = 7.83 Hz, 2H), 7.46-7.44 (m, 2H), 7.40-7.38 (m , 1H), 7.00 (d, J = 9.09 Hz, 2H), 3.80 (s, 3H)

Example 104. 5- (3-fluorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 104)

Yield 68%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.88 (s, 1H), 10.48 (s, 1H), 10.25 (s, 2H), 8.77 (s, 1H), 8.42 (d, J = 8.16 Hz 1H ), 8.37 (d, J = 7.71 Hz 1H), 7.82 (t, J = 7.96 Hz, 1 H), 7.76-7.65 (m, 4H), 7.58-7.51 (m, 1H), 7.49-7.46 (m, 2H) ), 7.45-7.40 (m, 2H)

Example 105. 5- (4-Fluorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 105)

Yield 81%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.88 (s, 1H), 10.41 (s, 1H), 10.25 (s, 1H), 10.18 (s, 1H), 8.77 (s, 1H), 8.42 ( dd, J = 8.34, 1.52 Hz, 1H), 8.38 (d, J = 7.58 Hz 1H), 7.98-7.94 (m, 2H), 7.82 (t, J = 7.96 Hz, 1H), 7.70 (d, J = 7.33, 2H), 7.48 (t, J = 7.33 Hz, 2H), 7.41-7.38 (m, 1H)

Example 106. 5- (3-Methylbenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 106)

Yield 84%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.87 (s, 1H), 10.32 (s, 1H), 10.25 (s, 1H), 10.14 (s, 1H), 8.78 (s, 1H), 8.43- 8.37 (m, 2H), 7.82 (t, J = 7.83 Hz, 1H), 7.71-7.67 (m, 4H), 7.49-7.46 (m, 2H), 7.41-7.34 (m, 3H), 2.35 (s, 3H)

Example 107. 5- (4-Methylbenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 107)

Yield 71%; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.85 (s, 1H), 10.29 (s, 1H), 10.24 (s, 1H), 10.11 (s, 1H), 8.77 (s, 1H), 8.43- 8.37 (m, 2H), 7.84-7.78 (m, 3H), 7.70 (d, J = 7.83 Hz, 2H), 7.49-7.45 (m, 2H), 7.41-7.37 (m, 1H), 7.28 (d, J = 8.34 Hz, 2H), 2.35 (s, 3H)

Example 108. 3- (2-Fluorophenyl) -4- (3-phenylpropyl) carboxyamino-5- (4-benzylacetyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 108)

Yield 61.8%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.50-7.40 (m, 3H), 7.38 (s, 1H), 7.33 (t, J = 7.9 Hz, 2H), 7.28-7.14 (m, 8H), 3.66 (s, 2H), 2.93 (t, J = 7.9 Hz, 2H), 2.66 (t, J = 7.8 Hz, 2H)

Example 109. 4- (3-Cyclohexylmethyl) carboxyamino-5- (4-phenacetyl) hydrazinecarbonyl-3- (3-fluorophenyl) -1 H- pyrazole (Compound No. 109)

Yield 44.6%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.57-7.21 (m, 8H), 7.16 (t, J = 7.7 Hz, 1H), 3.64 (s, 2H), 2.27 (d, J = 7.0 Hz, 2H ), 1.82-1.69 (m, 6H), 1.40 (d, J = 6.9 Hz, 1H), 1.35-1.16 (m, 2H), 1.12-0.99 (m, 1H), 0.83 (d, J = 6.6 Hz, 1H)

Example 110. 5- (Nicotinoyl) hydrazinecarbonyl4- (3-phenylethyl) carboxyamino-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 110)

Yield 38.4%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 9.08 (s, 1H), 8.75 (d, J = 6.5 Hz, 1H), 8.35 (d, J = 7.9 Hz, 1H), 7.60 (dd, J = 5.1 , 7.7 Hz, 1H), 7.53 (dd, J = 5.3, 8.8 Hz, 2H), 7.30-7.23 (m, 4H), 7.13 (t, J = 8.8 Hz, 3H), 3.00 (t, J = 7.6 Hz , 2H), 2.73 (t, J = 7.6 Hz, 2H)

Example 111. 5- (4-benzoyl) hydrazinecarbonyl-4- (3-phenylethyl) carboxyamino-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 111)

Yield 68.9%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.94 (d, J = 7.1 Hz, 2H), 7.61 (t, J = 7.3 Hz, 1H), 7.52 (t, J = 6.6 Hz, 4H), 7.26 ( br, 4H), 7.22-7.19 (m, 1H), 7.13 (t, J = 8.8 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 2.73 (t, J = 7.1 Hz, 2H)

Example 112. 3- (4-Fluorophenyl) -5- (4-phenacetyl) hydrazinecarbonyl-4- (3-phenylethyl) carboxyamino-1 H- pyrazole (Compound No. 112)

Yield 59.7%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.49 (dd, J = 5.3, 8.8 Hz, 2H), 7.38 (t, J = 7.7 Hz, 2H), 7.32-7.17 (m, 8H), 7.12 (t , J = 8.8 Hz, 2H), 3.65 (s, 2H), 2.99 (t, J = 7.6 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H)

Example 113. 5- (4-Trimethylphenylacetyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-phenylethyl) carboxyamino-1 H- pyrazole (Compound No. 113)

Yield 68.0%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.88 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 7.52 (dd, J = 5.3, 8.8 Hz, 2H), 7.30-7.18 (m, 5H), 7.13 (t, J = 8.8 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 2.73 (t, J = 7.6 Hz, 2H), 1.37 (s, 9H )

Example 114. 4- (3-methoxybenzyl) carboxyamino-5- (4-trimethylphenylacetyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 114)

Yield 33.4%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.89 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.46 (dd, J = 5.3, 8.7 Hz, 2H), 7.25 (t, J = 8.0 Hz, 1H), 7.03 (t, J = 8.8 Hz, 2H), 6.96-6.93 (m, 2H), 6.86 (d, J = 9.1 Hz, 1H), 3.77 (s, 3H ), 3.67 (s, 2H), 1.38 (s, 9H)

Example 115. 4- (3-methoxybenzyl) carboxyamino-5- (4-methoxybenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 115)

Yield 37.9%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.53-7.40 (m, 5H), 7.25 (t, J = 7.9 Hz, 1H), 7.16 (d, J = 6.3 Hz, 1H), 7.03 (t, J = 8.8 Hz, 2H), 6.96-6.93 (m, 2H), 6.86 (d, J = 7.4 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.67 (s, 2H)

Example 116 4- (3-methoxybenzyl) carboxyamino-5- (4-trifluoromethylbenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 116 )

Yield 35.0%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 8.11 (d, J = 8.1 Hz, 2H), 7.85 (d, J = 8.3 Hz, 2H), 7.45 (dd, J = 9.3, 14.2 Hz, 2H), 7.25 (t, J = 8.0 Hz, 1H), 7.04 (t, J = 8.8 Hz, 2H), 6.96-6.93 (m, 2H), 6.86 (d, J = 8.3 Hz, 1H), 3.77 (s, 3H ), 3.67 (s, 2 H)

Example 117. 4- (3-methoxybenzyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 117)

Yield 35.2%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.77 (s, 1H), 7.73 (d, J = 6.8 Hz, 1H), 7.48-7.38 (m, 4H), 7.25 (t, J = 7.9 Hz, 1H ), 7.03 (t, J = 8.8 Hz, 2H), 6.96-6.93 (m, 2H), 6.86 (d, J = 7.4 Hz, 1H), 3.77 (s, 3H), 3.67 (s, 2H), 2.44 (s, 3H)

Example 118. 4- (3-methoxybenzyl) carboxyamino-5- (4-fluorobenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 118)

Yield 25.6%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 8.01 (dd, J = 5.4, 8.8 Hz, 2H), 7.46 (dd, J = 5.3, 8.7 Hz, 2H), 7.29-7.22 (m, 3H), 7.03 (t, J = 8.8 Hz, 2H), 6.96-6.93 (m, 2H), 6.86 (d, J = 8.1 Hz, 1H), 3.77 (s, 3H), 3.67 (s, 2H)

Example 119. 4- (3-methoxybenzyl) carboxyamino-5- (4-chlorobenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 119)

Yield 41.7%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.93 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H), 7.45 (dd, J = 5.4, 8.7 Hz, 2H), 7.25 (t, J = 8.0 Hz, 1H), 7.03 (t, J = 8.8 Hz, 2H), 6.95-6.93 (m, 2H), 6.86 (d, J = 7.0 Hz, 1H), 3.77 (s, 3H) , 3.67 (s, 2 H)

Example 120. 5- (benzoyl) hydrazinecarbonyl-4- (3-methoxybenzyl) carboxyamino-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 120)

Yield 37.4%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.94 (d, J = 8.5 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.4 Hz, 2H), 7.48- 7.43 (m, 2H), 7.25 (t, J = 7.9 Hz, 1H), 7.03 (t, J = 8.8 Hz, 2H), 6.96-6.93 (m, 2H), 6.86 (d, J = 7.3 Hz, 1H ), 3.77 (s, 3H), 3.67 (s, 2H)

Example 121. 3- (thiophen-2-yl) -5- (phenacetyl) hydrazinecarbonyl-4- (3-pentyl) carboxyamino-1 H- pyrazole (Compound No. 121)

Yield 50.5%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.54 (d, J = 4.8 Hz, 1H), 7.43 (d, J = 4.7 Hz, 1H), 7.40-7.23 (m, 5H), 7.14 (dd, J = 3.7, 5.1 Hz, 1H), 3.64 (s, 2H), 2.45 (t, J = 7.6 Hz, 2H), 1.77-1.67 (m, 2H), 1.51-1.38 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H)

Example 122. 5- (Methylbenzoyl) hydrazinecarbonyl-3- (thiophen-2-yl) -4- (3-pentyl) carboxyamino-1 H- pyrazole (Compound No. 122)

Yield 38.0%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.76 (s, 1H), 7.72 (d, J = 7.1 Hz, 1H), 7.55 (d, J = 4.6 Hz, 1H), 7.46 (d, J = 4.6 Hz, 1H), 7.41-7.36 (m, 2H), 7.15 (dd, J = 3.7, 5.0 Hz, 1H), 2.49-2.43 (m, 5H), 1.78-1.68 (m, 2H), 1.51-1.39 ( m, 2H), 0.97 (t, J = 7.3 Hz, 3H)

Example 123. 5- (methoxybenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-fluorophenyl) carboxyamino-1 H- pyrazole (Compound No. 123)

Yield 62.3%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.79 (d, J = 7.8 Hz, 1H), 7.71-7.67 (m, 3H), 7.56-7.48 (m, 3H), 7.43-7.29 (m, 2H) , 7.21 (t, J = 8.8 Hz, 2H), 7.14 (d, J = 8.2 Hz, 1H), 3.86 (s, 3H)

Example 124. 5- (Methylbenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-fluorophenyl) carboxyamino-1 H- pyrazole (Compound No. 124)

Yield 56.6%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.80-7.66 (m, 6H), 7.56-7.49 (m, 1H), 7.43-7.29 (m, 3H), 7.21 (t, J = 8.8 Hz, 2H) , 2.42 (s, 3 H)

Example 125. 5- (benzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-fluorophenyl) carboxyamino-1 H- pyrazole (Compound No. 125)

Yield 56.0%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.92 (d, J = 7.2 Hz, 2H), 7.79 (d, J = 7.5 Hz, 1H), 7.72-7.67 (m, 3H), 7.59 (t, J = 7.3 Hz, 1H), 7.55-7.47 (m, 3H), 7.33 (t, J = 8.5 Hz, 1H), 7.21 (t, J = 8.8 Hz, 2H)

Example 126. 5- (3-Methylbenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-phenethyl) carboxyamino-1 H- pyrazole (Compound No. 126)

Yield 55.6%; ¹ H NMR (CD ₃ OD, 300 MHz) δ 7.77 (s, 1H), 7.73 (d, J = 7.0 Hz, 1H), 7.52 (dd, J = 5.4, 8.7 Hz, 2H), 7.44-7.37 (m , 2H), 7.33-7.18 (m, 5H), 7.13 (t, J = 8.8 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 2.73 (t, J = 7.6 Hz, 2H), 2.43 (s, 3H)

Example 127. 5- (3-Methylbenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 127)

¹ H NMR (CD ₃ OD, 300 MHz) δ 7.79-7.69 (m, 4H), 7.50-7.35 (m, 7H), 7.16 (t, J = 7.4 Hz, 1H), 2.42 (s, 6H)

Example 128. 3- (4-Chlorophenyl-4- (phenethyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 128)

Yield 48.9%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.94 (d, J = 7.21 Hz, 2H), 7.60 (d, J = 7.32 Hz, 1H), 7.54-7.46 (m, 4H), 7.39 (d, J = 8.50 Hz, 2H), 7.28-7.20 (m, 5H), 3.00 (t, J = 7.39 Hz, 2H), 2.74 (t, J = 7.27 Hz, 2H)

Example 129. 3- (4-Chlorophenyl-4- (phenethyl) carboxyamino-5-phenacetylhydrazinecarbonyl-1 H- pyrazole (Compound No. 129)

Yield 48.9%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.47-7.20 (m, 14H), 3.65 (s, 2H), 2.99 (t, J = 7.21 Hz, 2H), 2.72 (t, J = 7.20 Hz, 2H )

Example 130. 3- (4-Chlorophenyl-4- (3-methoxyphenylacetyl) carboxyamino-5- (4-trimethylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 130)

Yield 58.9%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.88 (d, J = 8.43 Hz, 2H), 7.57 (d, J = 8.47 Hz, 2H), 7.40 (d, J = 8.49 Hz, 2H), 7.29- 7.23 (m, 3H), 6.96 (br, 2H), 6.87 (d, J = 8.96 Hz, 1H), 3.77 (s, 3H), 3.67 (s, 2H), 1.38 (s, 9H)

Example 131. 3- (3-Chlorophenyl-4- (3-methylphenylacetyl) carboxyamino-5- (nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 131)

Yield 37.6%; ¹ H NMR (300 MHz, CD ₃ OD) δ 9.07 (s, 1H), 8.73 (d, J = 4.87 Hz, 1H), 8.33 (d, J = 8.00 Hz, 1H), 7.79-7.73 (m, 3H ), 7.62-7.56 (m, 2H), 7.47-7.36 (m, 4H), 2.42 (s, 3H)

Example 132. 3- (3-chlorophenyl-4- (3-methylphenylacetyl) carboxyamino-5- (benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 132)

Yield 48.4%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.93 (d, J = 7.13 Hz, 2H), 7.79-7.73 (m, 3H), 7.59 (t, J = 7.25 Hz, 2H), 7.53-7.38 (m , 6H), 2.43 (s, 3H)

Example 133. 3- (3-Chlorophenyl-4-phenylcarboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 133)

Yield 62.6%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.98-7.91 (m, 4H), 7.73 (s, 1H), 7.62-7.57 (m, 3H), 7.53-7.48 (m, 4H), 7.45-7.40 ( m, 2H)

Example 134. 3- (3-Chlorophenyl) -4-phenylcarboxyamino-5-phenacetylhydrazinecarbonyl-1 H- pyrazole (Compound No. 134)

Yield 41.5%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.96 (d, J = 7.04 Hz, 2H), 7.70 (s, 1H), 7.59 (d, J = 7.24 Hz, 2H), 7.52 (t, J = 7.67 Hz, 2H), 7.43-7.23 (m, 7H), 3.63 (s, 2H)

Example 135. 3- (4-cyclohexylphenyl) -4- (3-nitrophenyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 135)

Yield 41.8%; ¹ H NMR (300 MHz, CD ₃ OD) δ 8.83 (s, 1H), 8.44 (d, J = 8.20 Hz, 1H), 8.36 (d, J = 7.94 Hz, 1H), 7.92 (d, J = 7.15 Hz, 2H), 7.77 (t, J = 7.90 Hz, 1H), 7.61-7.53 (m, 3H), 7.51-7.45 (m, 2H), 7.32 (d, J = 8.23 Hz, 2H), 2.55 (br , 1H), 1.87-1.75 (m, 5H), 1.53-1.23 (m, 5H)

Example 136. 3- (4-Cyclohexylphenyl) -4- (3-methoxyphenyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 136)

Yield 18%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.96 (d, J = 6.93 Hz, 1H), 7.79 (d, J = 6.87 Hz, 1H), 7.60-7.38 (m, 8H), 7.24 (d, J = 8.03 Hz, 1H), 7.16 (br, 2H), 3.86 (s, 3H), 2.52 (br, 1H), 1.93-1.75 (m, 5H), 1.45-1.25 (m, 5H)

Example 137. 3- (4-Chlorophenyl) -4- (cyclohexylacetylphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 137)

Yield 56%; ¹ H NMR (300 MHz, CD ₃ OD) δ 9.08 (s, 1H), 8.75 (d, J = 4.79 Hz, 1H), 8.34 (d, J = 7.93 Hz, 1H), 7.62-7.59 (m, 2H ), 7.47 (d, J = 8.55 Hz, 2H), 7.41 (d, J = 8.00 Hz, 1H), 2.28-2.24 (m, 2H), 1.82-1.69 (m, 6H), 1.27-1.23 (m, 3H), 1.06-0.99 (m, 2H)

Example 138. 3- (4-Chlorophenyl) -4- (3-cyclohexylacetyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 138)

Yield 53.1%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.93 (d, J = 8.59 Hz, 2H), 7.61-7.58 (m, 3H), 7.54-7.46 (m, 4H), 2.28-2.24 (m, 2H) , 1.82-1.69 (m, 6H), 1.31-1.21 (m, 3H), 1.10-0.99 (m, 2H)

Example 139 3- (4-Chlorophenyl) -4- (3-cyclohexylacetyl) carboxyamino-5-nicotinylhydrazinecarbonyl-1 H- pyrazole (Compound No. 139)

Yield 35%; ¹ H NMR (300 MHz, CD ₃ OD) δ 9.09 (s, 1H), 8.76 (d, J = 4.95 Hz, 1H), 8.36 (d, J = 7.97 Hz, 1H), 7.61 (dd, J = 4.95 , 7.58 Hz, 1H), 7.43-7.27 (m, 9H), 3.70 (s, 2H)

Example 140. 3- (4-Chlorophenyl) -4- (3-phenacetyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 140)

Yield 50%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.95 (d, J = 7.03 Hz, 2H), 7.62 (t, J = 7.39 Hz, 1H), 7.55-7.50 (m, 2H), 7.42-7.26 (m , 9H), 3.70 (s, 2H)

Example 141. 3- (4-Chlorophenyl) -4- (3-cyclohexylacetyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 141)

Yield 39.2%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.58 (d, J = 8.57 Hz, 2H), 7.47 (d, J = 8.58 Hz, 2H), 7.39-7.23 (m, 4H), 3.65 (s, 2H ), 2.40 (t, J = 7.38 Hz, 2H), 1.66 (q, J = 7.31 Hz, 2H), 1.45-1.33 (m, 2H), 0.95 (t, J = 7.33 Hz, 3H)

Example 142 3- (4-chlorophenyl) -4- (pentyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 142)

Yield 37.4%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.77 (s, 1H), 7.72 (d, J = 6.80 Hz, 1H), 7.61 (d, J = 8.46 Hz, 2H), 7.50-7.36 (m, 4H ), 2.43 (s, 3H), 2.41 (t, J = 7.77 Hz, 2H), 1.67 (q, J = 7.80 Hz, 2H), 1.45-1.35 (m, 2H), 0.95 (t, J = 7.32 Hz , 3H)

Example 143. 3- (4-Chlorophenyl) -4- (3-methoxyphenylacetyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 143)

Yield 54.1%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.77 (s, 1H), 7.73 (d, J = 6.98 Hz, 1H), 7.42-7.39 (m, 4H), 7.30-7.23 (m, 3H), 6.96 (br, 2H), 6.87 (d, J = 8.32 Hz, 1H), 3.77 (s, 3H), 3.67 (s, 2H), 2.44 (s, 3H)

Example 144. 3- (3-Chlorophenyl) -4- (phenyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 144)

Yield 65.7%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.97 (d, J = 7.16 Hz, 2H), 7.75-7.70 (m, 3H), 7.59 (t, J = 7.28 Hz, 2H), 7.54-7.49 (m , 2H), 7.47-7.35 (m, 4H), 2.42 (s, 3H)

Example 145. 3- (4-Chlorophenyl) -4- (benzyl) carboxyamino-5- (phenacetyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 145)

Yield 50.3%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.41-7.24 (m, 14H), 3.69 (s, 2H), 3.66 (s, 2H)

Example 146. 3- (phenylethyl) -4- (3-nitrophenyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 146)

Yield 34.8%; ¹ H NMR (300 MHz, CD ₃ OD) δ 8.81 (s, 1H), 8.46 (d, J = 8.24 Hz, 1H), 8.36 (d, J = 8.12 Hz, 1H), 7.79 (t, J = 8.01 Hz, 1H), 7.74 (s, 1H), 7.70 (d, J = 7.06 Hz, 1H), 7.43-7.35 (m, 2H), 7.26-7.12 (m, 5H), 3.10 (t, J = 7.40 Hz , 2H), 2.98 (t, J = 7.35 Hz, 2H), 2.42 (s, 3H)

Example 147. 3- (3-Chlorophenyl) -4- (3-methylphenyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 147)

Yield 22.6%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.79-7.70 (m, 5H), 7.61 (d, J = 6.85 Hz, 1H), 7.47-7.36 (m, 6H), 2.43 (s, 3H), 2.42 (s, 3H)

Example 148. 3- (phenylethyl) -4- (3-nitrophenyl) carboxyamino-5- (phenacetyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 148)

Yield 23.9%; ¹ H NMR (300 MHz, CD ₃ OD) δ 8.81 (s, 1H), 8.47 (d, J = 8.15 Hz, 1H), 8.35 (d, J = 7.90 Hz, 1H), 7.80 (t, J = 8.04 Hz, 1H), 7.37-7.14 (m, 10H), 3.63 (s, 2H), 3.07 (t, J = 7.14 Hz, 2H), 2.95 (t, J = 7.30 Hz, 2H)

Example 149. 3- (phenylethyl) -4- (3-methoxyphenyl) carboxyamino-5- (methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 149)

Yield 38.7%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.75 (s, 1H), 7.71 (d, J = 7.00 Hz, 1H), 7.56-7.52 (m, 2H), 7.45-7.35 (m, 3H), 7.26 -7.13 (m, 6H), 3.88 (s, 3H), 3.12 (t, J = 8.29 Hz, 2H), 2.96 (t, J = 8.08 Hz, 2H), 2.42 (s, 3H)

Example 150. 3- (phenylethyl) -4- (3-methoxyphenyl) carboxyamino-5- (phenacetyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 150)

Yield 68.5%; ¹ H NMR (300 MHz, CD ₃ OD) δ 7.75-7.52 (m, 2H), 7.43 (t, J = 8.08 Hz, 1H), 7.38-7.11 (m, 11H), 3.88 (s, 3H), 3.63 (s, 2H), 3.09 (t, J = 7.58 Hz, 2H), 2.94 (t, J = 7.93 Hz, 2H)

Formulation Example

On the other hand, the novel compound represented by Formula 1 according to the present invention can be formulated in various forms according to the purpose. The following illustrates some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

Formulation 1: tablet (direct pressure)

After sifting 5.0 mg of active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to form a tablet.

Formulation 2: Tablet (Wet Granulation)

After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

Formulation 3: Powders and Capsules

5.0 mg of the active ingredient was sieved, followed by mixing with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. No. solid the mixture using a suitable device. Filled in 5 gelatin capsules.

Formulation 4: Injection

Injectables were prepared by containing 100 mg as the active ingredient, followed by 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water.

[ Experimental Example ]

1. Anticancer Drug Screening Test

1) Cancer Cell Culture

Cancer cells to measure anticancer activity against test compounds A-549 (Human lung carcinoma), HT-29 (Human colon adenocarcinoma), DU145 (Human prostate cancer), SK-MEL-2 (Human malignant melanoma), and SK-OV-3 (Human ovary malignant ascites) were used. . These cancer cells were all human tumor cells and were cultured by the Korean Cell Line Bank. The culture medium was RPMI 1640 medium containing 10% fetal calf serum, and cultured in a constant temperature and humidity incubator (37 ℃, 5% CO ₂₎ . Cells were passaged once every 3 days using 0.25% trypsin - 1 mM EDTA.

2) Anticancer activity measurement

In 1989, the US National Cancer Institute used the sulforhodamine B assay method, which was developed to measure the in vitro anticancer activity of drugs.

In order to use the passaged cells for experiments, the cells were separated from the implant using trypsin-CDTA solution, and the cells in culture were placed in 96 well microplates with 5 × 10 ³ cells per well (dU145, SK-MEL-2, HT-29, 7 × 10 ³ (sK-OV-3) and 3 × 10 ³ (A-549) were aliquoted and incubated for 24 hours in a CO ₂ incubator. The medium was removed, and 100 μl of the test compound solution diluted to 4-fold concentration was incubated for 48 hours. 100 μl of formalin solution was added to fix the cells, and then washed five times with distilled water and dried at room temperature. 100 μl of 0.4% SRB solution was added thereto, and the mixture was left at room temperature for 30 minutes, washed five times with 1% acetic acid, and dried at room temperature. 200 mM of 10 mM Tisma base pH 10.3 for each well was completely dissolved and the absorbance was measured at 520 nm.

In order to calculate the efficacy of the test compound on cancer cells, GI ₅₀ was calculated according to Equation 1 or 2 below.

In Equation 1, T ₀ is the number of cells before adding the test compound, and T ₂ is the number of cells after incubation for 48 hours after adding the test compound.

In Equation 2, T ₀ is the number of cells before adding the test compound, T ₂ is the number of cells after incubation for 48 hours after adding the test compound, and C is 48 hours incubating the control group without adding the test compound. The number of cells after one.

Also, from the values calculated by Equation 1, the degree of inhibition (% inhibition) of each test compound by inhibiting the growth of cancer cells was determined by using data regression by the Lotus program. IC ₅₀ values were calculated from the% inhibition concentrations and are shown in Table 1 below.

As confirmed in Table 1 above, the 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivative represented by Formula 1 according to the present invention shows cytotoxicity against various cancer cells.

Since 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivatives represented by Formula 1 according to the present invention or pharmaceutically acceptable salts thereof exhibit excellent inhibitory activity against various cancer cells, anticancer agents and auxiliaries thereof Useful as

Claims (8)

delete 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivatives represented by Formula 1 below or a pharmaceutically acceptable salt thereof: [Formula 1]

In Chemical Formula 1, R ₁ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a phenyl group, a-(CH ₂ ) _n -phenyl group, a furanyl group, a thiophenyl group, or a pyridyl group; R ₂ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a phenyl group, or a-(CH ₂ ) _n -phenyl group; R ₃ represents a C ₁ -C ₆ alkyl group, a phenyl group, a-(CH ₂ ) _n -phenyl group, a furanyl group, a thiophenyl group, or a pyridyl group; The phenyl ring of the aforementioned phenyl group or-(CH ₂ ) _n -phenyl group is 1 to 3 selected from halogen, nitro, C ₁ -C ₆ alkyl, C ₃ -C ₆ heterocycloalkyl, and C ₁ -C ₆ alkoxy. And unsubstituted with n substituents, n is an integer from 1 to 6. The method of claim 2, R ₁ is a hydrogen atom, a methyl group, an ethyl group, n -propyl group, i -propyl group, n -butyl group, i -butyl group, t -butyl group, n -pentyl group, i -pentyl group, cyclohexyl group, Phenyl group, benzyl group, phenethyl group, phenylpropyl group, furan-2-yl group, furan-3-yl group, thiophen-2-yl group, thiophen-3-yl group, pyridin-2-yl group, pyridin-3-yl group, Or a pyridin-4-yl group; R ₂ is hydrogen atom, methyl group, ethyl group, n -propyl group, i -propyl group, n -butyl group, i -butyl group, t -butyl group, n -pentyl group, i -pentyl group, cyclohexyl group, phenyl group , Benzyl group, phenethyl group, or phenylpropyl group; R ₃ is methyl group, ethyl group, n -propyl group, i -propyl group, n -butyl group, i -butyl group, t -butyl group, n -pentyl group, i -pentyl group, cyclohexyl group, phenyl group, benzyl group , Phenethyl group, phenylpropyl group, or pyridyl group; The phenyl ring of the aforementioned phenyl group or-(CH ₂ ) _n -phenyl group is chloro, fluoro, bromo, nitro, methyl, ethyl, propyl, butyl, cyclohexyl, piperidyl, methoxy, ethoxy, pro A compound substituted or unsubstituted with 1 to 3 substituents selected from foxy, and butoxy. The method of claim 2, 3- (3-chlorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 1) 5-benzoylhydrazinecarbonyl-3- (3-chlorophenyl) -4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 2) 3- (3-chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 3) 5-benzoylhydrazinecarbonyl-3- (3-chlorophenyl) -4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 4) 3- (3-chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 5) 3- (4-chlorophenyl) -4- (3-nitrophenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 6) 5-propanoylhydrazinecarbonyl-3- (4-chlorophenyl) -4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 7) 3- (4-chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 8) 5-benzoylhydrazinecarbonyl-3- (4-chlorophenyl) -4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 9) 5-benzoylhydrazinecarbonyl-3- (4-chlorophenyl) -4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 10) 5-nicotinoylhydrazinecarbonyl-3- (4-chlorophenyl) -4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 11) 3- (4-Chlorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 12) 3- (4-Chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 13) 4-phenylcarboxyamino-3- (4-chlorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 14) 4-phenylcarboxamido-5-benzoylhydrazinecarbonyl-3- (4-chlorophenyl) -1 H- pyrazole (Compound No. 15) 4-phenylcarboxyamino-3- (4-chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 16) 3- (2-chlorophenyl) -4- (3-nitrophenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 17) 3- (2-Chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 18) 3- (2-chlorophenyl) -4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 19) 3- (2-Chlorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 20) 3- (2-Chlorophenyl) -4- ( 3 -methylphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 21) 3- (2-chlorophenyl) -4- (3-phenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 22) 5-benzoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 23) 5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 24) 4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 25) 5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 26) 5-isonicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxyamino-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 27) 4- (3-methylphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 28) 3- (4-Chlorophenyl-4- (phenethyl) carboxyamino-5- (nicotinoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 29) 4-phenylcarboxyamino-5-nicotinoylhydrazinecarbonyl-3-[(4-piperidin-1-yl) phenyl] -1 H- pyrazole (Compound No. 30) 3- (furan-2-yl) -5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 31) 5-benzoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3- (furan-2-yl) -1 H- pyrazole (Compound No. 32) 5-nicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3- (furan-2-yl) -1 H- pyrazole (Compound No. 33) 3- (furan-2-yl) -4- (3-methoxyphenyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 34) 3- (furan-2-yl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino) -1 H- pyrazole (Compound No. 35) 4- (3-nitrophenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-3- (1-phenethyl) -1 H- pyrazole (Compound No. 36) 5-benzoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3- (1-phenethyl) -1 H- pyrazole (Compound No. 37) 4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-3- (1-phenethyl) -1 H- pyrazole (Compound No. 38) 4- (3-methoxyphenyl) carboxyamino-5-benzoylhydrazinecarbonyl-3- (1-phenethyl) -1 H- pyrazole (Compound No. 39) 3- (3-chlorophenyl) -4- (3-nitrophenyl) carboxyamino-5-propanoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 40) 5- (3-hydroxybenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3- (3-chlorophenyl) -1 H- pyrazole (Compound No. 41) 3- (4-chlorophenyl) -4- (3-methoxyphenylacetamino) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 42) 3- (4-Chlorophenyl) -4- (3-methoxyphenylacetamino) -5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 43) 3- (4-chlorophenyl) -4- (3-methoxyphenylacetamino) -5-phenylacetylhydrazinecarbonyl-1 H- pyrazole (Compound No. 44) 3- (4-Chlorophenyl) -5-nicotinoylhydrazinecarbonyl-4-pentanecarboxyamino-1 H- pyrazole (Compound No. 45) 5-benzoylhydrazinecarbonyl-3- (4-chlorophenyl) -4-pentanecarboxyamino-1 H- pyrazole (Compound No. 46) 3-isobutyl-5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 47) 5-benzoylhydrazinecarbonyl-3-isobutyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 48) 3-isobutyl-5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino1 H- pyrazole (Compound No. 49) 3-isobutyl-4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 50) 3-isobutyl-4- (3-methoxyphenyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 51) 3-isobutyl-4- (3-methoxyphenyl) carboxyamino-5-isonicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 52) 3-propyl-4- (3-nitrophenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 53) 5-benzoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-propyl-1 H- pyrazole (Compound No. 54) 5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-propyl-1 H- pyrazole (Compound No. 55) 5-benzoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3-propyl-1 H- pyrazole (Compound No. 56) 5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3-propyl-1 H- pyrazole (Compound No. 57) 3- (4-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 58) 3- (4-fluorophenyl) -5-benzoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 59) 3- (4-fluorophenyl) -4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 60) 3- (4-fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 61) 3- (4-fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 62) 5-benzoylhydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 63) 5-isonicotinoylhydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 64) 4-phenylcarboxyamino-3- (4-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 65) 4- (3-nitrophenyl) carboxyamino-3- (3-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 66) 3- (3-fluorobenzyl) -4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 67) 5-benzoylhydrazinecarbonyl-3- (3-fluorophenyl) -4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 68) 3- (3-fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 69) 3- (3-fluorophenyl) -4- (3-methylphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 70) 3- (3-fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 71) 4-phenylcarboxyamino-3- (3-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 72) 4-phenylcarboxyamino-5-benzoylhydrazinecarbonyl-3- (3-fluorophenyl) -1 H- pyrazole (Compound No. 73) 3- (3-fluorophenyl) -4-phenylcarboxyamino-5-isonicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 74) 3- (2-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 75) 3- (2-fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 76) 3- (2-fluorophenyl) -4- (3-methoxyphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 77) 3- (2-fluorophenyl) -5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-1 H- pyrazole (Compound No. 78) 3- (2-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 79) 3- (2-fluorophenyl) -4- (3-methylphenyl) carboxyamino-5-isonicotinoylhydrazinecarbonyl) -1 H- pyrazole (Compound No. 80) 4-phenylcarboxyamino-3- (2-fluorophenyl) -5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 81) 4-phenylcarboxyamino-3- (2-fluorophenyl) -5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 82) 5-nicotinoylhydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3- (thiophen-2-yl) -1 H- pyrazole (Compound No. 83) 4- (3-nitrophenyl) carboxyamino-3- (thiophen-2-yl) -5-phenylacetylhydrazinecarbonyl-1 H- pyrazole (Compound No. 84) 3- (thiophen-2-yl) -4- (3-nitrophenyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 85) 5- (3-hydroxybenzoyl) hydrazinecarbonyl-3- (thiophen-2-yl) -4- (3-nitrophenyl) carboxyamino-1 H- pyrazole (Compound No. 86) 5-nicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3- (thiophen-2-yl) -1 H- pyrazole (Compound No. 87) 5-isonicotinoylhydrazinecarbonyl-4- (3-methoxyphenyl) carboxyamino-3- (thiophen-2-yl) -1 H- pyrazole (Compound No. 88) 4-butylcarboxyamino-5-nicotinoylhydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 89) 5-benzoylhydrazinecarbonyl-3- (4-fluorophenyl) -4-phenylacetylamino-1 H- pyrazole (Compound No. 90) 3- (4-fluorophenyl) -4- (3-methylphenyl) carboxyamino-5- (propanoylhydrazinecarbonyl) -1 H- pyrazole (Compound No. 91) 3- (4-fluorophenyl) -4- (3-methoxyphenylacetyl) amino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 92) 3- (4-fluorophenyl) -4- (3-methoxyphenylacetyl) amido-5-phenylacetylhydrazinecarbonyl-1 H- pyrazole (Compound No. 93) 3- (2-fluorophenyl) -4- (3-phenylpropyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 94) 3- (2-fluorophenyl) -4- (3-phenylpropyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 95) 5- (2-chlorobenzoyl) hydrazinecarbonyl-4- (2-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 96) 5- (4-chlorobenzoyl) hydrazinecarbonyl-4- (2-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 97) 5- (4-chlorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 98) 5- (2-chlorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 99) 5- (3-chlorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 100) 5- (4-chlorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 101) 5- (3-methoxybenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazol-2-yl}-(Compound No. 102) 5- (4-methoxybenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 103) 5- (3-fluorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 104) 5- (4-fluorobenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 105) 5- (3-methylbenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 106) 5- (4-Methylbenzoyl) hydrazinecarbonyl-4- (3-nitrophenyl) carboxyamino-3-phenyl-1 H- pyrazole (Compound No. 107) 3- (2-fluorophenyl) -4- (3-phenylpropyl) carboxyamino-5- (4-benzylacetyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 108) 4- (3-cyclohexylmethyl) carboxyamino-5- (4-phenacetyl) hydrazinecarbonyl-3- (3-fluorophenyl) -1 H- pyrazole (Compound No. 109) 5- (nicotinoyl) hydrazinecarbonyl4- (3-phenylethyl) carboxyamino-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 110) 5- (4-benzoyl) hydrazinecarbonyl-4- (3-phenylethyl) carboxyamino-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 111) 3- (4-fluorophenyl) -5- (4-phenacetyl) hydrazinecarbonyl-4- (3-phenylethyl) carboxyamino-1 H- pyrazole (Compound No. 112) 5- (4-trimethylphenylacetyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-phenylethyl) carboxyamino-1 H- pyrazole (Compound No. 113) 4- (3-methoxybenzyl) carboxyamino-5- (4-trimethylphenylacetyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 114) 4- (3-methoxybenzyl) carboxyamino-5- (4-methoxybenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 115) 4- (3-methoxybenzyl) carboxyamino-5- (4-trifluoromethylbenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 116) 4- (3-methoxybenzyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 117) 4- (3-methoxybenzyl) carboxyamino-5- (4-fluorobenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 118) 4- (3-methoxybenzyl) carboxyamino-5- (4-chlorobenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 119) 5- (benzoyl) hydrazinecarbonyl-4- (3-methoxybenzyl) carboxyamino-3- (4-fluorophenyl) -1 H- pyrazole (Compound No. 120) 3- (thiophen-2-yl) -5- (phenacetyl) hydrazinecarbonyl-4- (3-pentyl) carboxyamino-1 H- pyrazole (Compound No. 121) 5- (methylbenzoyl) hydrazinecarbonyl-3- (thiophen-2-yl) -4- (3-pentyl) carboxyamino-1 H- pyrazole (Compound No. 122) 5- (methoxybenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-fluorophenyl) carboxyamino-1 H- pyrazole (Compound No. 123) 5- (methylbenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-fluorophenyl) carboxyamino-1 H- pyrazole (Compound No. 124) 5- (benzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-fluorophenyl) carboxyamino-1 H- pyrazole (Compound No. 125) 5- (3-methylbenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-phenethyl) carboxyamino-1 H- pyrazole (Compound No. 126) 5- (3-methylbenzoyl) hydrazinecarbonyl-3- (4-fluorophenyl) -4- (3-methylphenyl) carboxyamino-1 H- pyrazole (Compound No. 127) 3- (4-Chlorophenyl-4- (phenethyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 128) 3- (4-Chlorophenyl-4- (phenethyl) carboxyamino-5-phenacetylhydrazinecarbonyl-1 H- pyrazole (Compound No. 129) 3- (4-chlorophenyl-4- (3-methoxyphenylacetyl) carboxyamino-5- (4-trimethylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 130) 3- (3-chlorophenyl-4- (3-methylphenylacetyl) carboxyamino-5- (nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 131) 3- (3-chlorophenyl-4- (3-methylphenylacetyl) carboxyamino-5- (benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 132) 3- (3-chlorophenyl-4-phenylcarboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 133) 3- (3-chlorophenyl) -4-phenylcarboxyamino-5-phenacetylhydrazinecarbonyl-1 H- pyrazole (Compound No. 134) 3- (4-cyclohexylphenyl) -4- (3-nitrophenyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 135) 3- (4-cyclohexylphenyl) -4- (3-methoxyphenyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 136) 3- (4-Chlorophenyl) -4- (cyclohexylacetylphenyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 137) 3- (4-Chlorophenyl) -4- (3-cyclohexylacetyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 138) 3- (4-Chlorophenyl) -4- (3-cyclohexylacetyl) carboxyamino-5-nicotinoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 139) 3- (4-chlorophenyl) -4- (3-phenacetyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 140) 3- (4-Chlorophenyl) -4- (3-cyclohexylacetyl) carboxyamino-5-benzoylhydrazinecarbonyl-1 H- pyrazole (Compound No. 141) 3- (4-chlorophenyl) -4- (pentyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 142) 3- (4-chlorophenyl) -4- (3-methoxyphenylacetyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 143) 3- (3-chlorophenyl) -4- (phenyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 144) 3- (4-Chlorophenyl) -4- (benzyl) carboxyamino-5- (phenacetyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 145) 3- (phenylethyl) -4- (3-nitrophenyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 146) 3- (3-chlorophenyl) -4- (3-methylphenyl) carboxyamino-5- (3-methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 147) 3- (phenylethyl) -4- (3-nitrophenyl) carboxyamino-5- (phenacetyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 148) 3- (phenylethyl) -4- (3-methoxyphenyl) carboxyamino-5- (methylbenzoyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 149) 3- (phenylethyl) -4- (3-methoxyphenyl) carboxyamino-5- (phenacetyl) hydrazinecarbonyl-1 H- pyrazole (Compound No. 150) The compound characterized in that it is selected from. The anti-cancer drug composition according to any one of claims 2 to 4, wherein the 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivative or a pharmaceutically acceptable salt thereof is contained as an active ingredient. An anticancer agent characterized in that the 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivative of any one of claims 2 to 4 or a pharmaceutically acceptable salt thereof is contained as an active ingredient. After the reaction of the aminopyrazole ester compound represented by the formula (5) and the acyl compound represented by the formula (6), and hydrolyzed to convert to 4-acylamino-parazol-5-carboxylic acid represented by the formula (7), And To 4-acylamino-parazol-5-carboxylic acid represented by the following formula (7) and the acyl hydrazine compound represented by the formula (8) by coupling reaction, 5-acylhydrazinecarbonyl-3,4- represented by the formula (1) Process of conversion to di-substituted pyrazole derivatives Process for preparing 5-acylhydrazinecarbonyl-3,4-disubstituted pyrazole derivatives comprising:

In the above scheme, R ₁ , R ₂ , and R ₃ are each as defined in claim 2, and L is a leaving group selected from halogen, alkoxy group, sulfonate group, and phosphate group. According to claim 7, wherein the compound represented by the formula (5) Reacting a diketo oxime compound represented by the following formula (3) with a hydrazine hydrate to convert it into a 4-nitroso-1 H -pyrazole compound represented by the following formula (4), and To convert the 4-nitroso-1 H -pyrazole compound represented by the formula (4) to the aminopyrazole ester compound represented by the formula (5) Manufacturing method characterized in that prepared by performing a process comprising:

In the above scheme, R ₁ is as defined in claim 2 above.