WO2006032173A1 - Aryl hydrazide compounds and usage in preparation of immunosuppressive agent theirof - Google Patents

Abstract

This invention relates to aryl hydrazide compounds of formula I, their geometric isomers, medical salts or hydrates, their preparation process and medical compositions containing the compounds. The invention also relates to usage of the said compounds in preparation of drugs for rejection of foreign organ transplants and prophylaxis and/or treatment of certain auto-immune diseases such as rheumatoid, psoriasis, multiple sclerosis and systemic erythema lupus: Formula (I).

Description

 Aromatic hydrazide compounds and use thereof for preparing immunosuppressive agents

 The present invention relates to an aroyl hydrazide compound, a geometric isomer thereof or a pharmaceutically acceptable salt or hydrate thereof, a process for producing the same, and a pharmaceutical composition containing the compound. The invention further relates to the use of said compounds for the manufacture of a medicament for the prevention of organ transplant rejection and for the prevention and/or treatment of certain autoimmune diseases such as rheumatoid, psoriasis, multiple sclerosis, systemic lupus erythematosus and the like. Background technique

 Recent studies have shown that CD4 plays a very important role in immune rejection and in some autoimmune diseases such as rheumatism, rheumatoid, psoriasis, and multiple sclerosis.

CD4 is a single-chain transmembrane glycoprotein expressed on Th cells. Human CD^ has a molecular weight of 55 kDa and consists of 435 amino acid residues with 374, 21 and 40 amino acid residues in the extracellular, transmembrane and cytosol, respectively. The extracellular domain is a member of IgSF. Two N-linked glycosylation sites share four IgSF domains (D1 ~ D4) (Whi te, RAH, Mason, DW, 1978, J. Exp. Med. 148, 664-673), wherein D1 and D3 are V-like regions, D3 has no disulfide bond, D2 and D4 are C ₂ -like regions, D2's di-bonds are formed in β-sheets, and characteristic hydrophobicity The membrane-permissive zone and a short cytoplasmic functional zone with a potential serine sulphate site. The three serines (Ser408, ser415, se431) in the cytoplasmic region may be PKC substrates, and the cytoplasmic region CxcpJI motif is a site that binds to P56 ^lek . The CD4 molecule is distributed as a glycoprotein on the surface of CD4+ cells along with the distribution of CD4+ T cells, which is different in various organs. In peripheral blood and lymphoid organs, CD4+ T cells are helper T cells (Th). Includes ThO, Thl and Th2 subpopulations. In the thymus, CD4-positive cells include CD4 single positive cells (Th) And CD4 CD8 double positive immature T cells. In addition, CD4 is also expressed in certain sputum cells, EBV-transformed sputum cells, and brain cells.

 In allogeneic transplant rejection, CD4+ T cells are involved in different types of rejection (Abbas A et al, ed. Ce l lular and Mo lecular Immunology, 3 rd ed., P 362-381, 1997. ) , its role in various types of rejection is also different (Janetway C, et al. P 115-162 Immunobiology, 4th ed.): In acute humoral rejection, anti-MHC antibodies and anti-endothelial cell surface molecules The binding of the antibody to the corresponding antigen-activated complement system leads to vascular damage, and in the presence of the mechanism of action of inflammatory CD4+ T cells, leads to vasculitis; in acute cellular rejection, inflammatory CD4+ T cells/macrophages The involvement of the effector mechanism leads to stromal cell damage; in chronic rejection, it is mainly chronic inflammation associated with inflammatory CD4+ T cells/macrophages, leading to interstitial fibrosis and intravascular hardening of the graft. It can be seen that CD4+ T cells are involved in various types of immune rejection reactions. The binding of CD4 to dimerization or oligomerization with MHC class I I molecules is a key condition for CD4+ T cell activation to participate in immune rejection - (Gould DS and Auchincloss H., Immunology Today, 1999 (20): 77-82. J. Thus, inhibition of CD4 dimerization or oligomerization of this active form or blocking of binding of CD4 to MHC class 11 molecules can prevent or inhibit allogeneic transplant rejection.

Autoimmune disease is a disease state caused by the immune response of the body's immune system to its own components (Zhu Y, Bao L, Zhu S, Chen Z, et al Exp Neuro l 2002 Sep; 177 (1): 314-20). Caused by an autoimmune response to autoantigens mediated by autoantibodies and/or autoreactive T lymphocytes. The activation of T cells requires dual signal stimulation, in which the formation of TCR and antigen peptide-MHC molecular complexes is one of the key signals. The binding of CD4 molecules to MHC class I I molecules is an important condition for their stability during the formation of this complex. CD4 inhibitors can be selective Inhibits the formation of active forms of CD4 molecules or blocks the binding of CD4 to MHC class I I molecules, thereby failing to form a stable TCR and antigen peptide-MHC molecular complex, one of the two-signal stimuli required for T cell activation. The key signal is incapable, so autoantibodies and/or autoreactive T lymphocyte-mediated immune responses to autoantigens cannot occur, so CD4 inhibitors can be applied to autoimmune diseases such as rheumatoid, psoriasis, multiple sclerosis, Prevention and treatment of systemic lupus erythematosus, etc. Since the above link is a common link between the autoantigen and the immune response elicited by the foreign antigen, CD4 inhibitors have an effect on both transplant rejection and autoimmune diseases. Summary of the invention

 The object of the present invention is to find and develop a compound capable of selectively inhibiting the formation of an active form of CD4 molecules or blocking the binding of a CD4 molecule to an MHC class I class I molecule to achieve immunosuppressive action.

 The present inventors have found through research that the compound represented by the general formula I can act on the CD4 molecule and thus has an immunosuppressive effect, and can be used for, but not limited to, anti-immunological rejection in organ transplantation and/or prevention and/or treatment of certain autoimmunity. Diseases such as rheumatoid, psoriasis, multiple sclerosis, systemic lupus erythematosus, etc.

 Accordingly, one aspect of the invention relates to an aroyl hydrazide compound of formula I, a geometric isomer thereof or a pharmaceutically acceptable salt or hydrate thereof:

 I

 among them:

 R1 is a hydrogen atom or a d-C^alkyl group;

^ and Ar ₂ are each independently selected from the group consisting of: 3-indenyl, 5-indenyl, 2-quinolinyl, 4-quinolinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 -pyrrolyl, 3- Pyrrolyl, 2-thienyl, 3-thienyl, pyrazolyl, 2-furyl, 3-furyl; the above group is unsubstituted or substituted by 1 or 2 substituents selected from the group consisting of: halogen, nitrate Base, hydroxy, trifluoromethyl, d-C _fi alkyl, d-Cs alkoxy, C-C ₆ alkoxy, amino, carboxy, phenyl, benzyl, phenylsulfonyl.

 Another aspect of the invention relates to a pharmaceutical composition comprising at least one compound of formula I or a geometric isomer thereof, or a pharmaceutically acceptable salt or hydrate thereof, and one or more pharmaceutically acceptable carriers or excipients.

 A further aspect of the invention relates to a process for the preparation of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof, which comprises reacting an aryl aldehyde or an aryl ketone with an aryl hydrazide in an alcohol or ether solvent.

 Another aspect of the invention relates to at least one compound of the formula I, or a geometric isomer thereof, or a pharmaceutically acceptable salt or hydrate thereof, for use in the manufacture of a medicament for the prevention and/or treatment of rejection or autoimmune diseases in organ transplantation use.

 According to a preferred embodiment of the invention, the compound of formula I has the definition wherein R1 is a hydrogen atom; A is a substituted or unsubstituted 3-indenyl or 5-indenyl group, said substituent being selected from methoxy Base, methyl, methoxyl, benzyl, phenyl;

2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl or 2-furyl.

According to another preferred embodiment of the invention, the compound of formula I has the definition wherein R1 is a hydrogen atom; k^j 2-quinolinyl or 4-quinolinyl; Ar ₂ is 2-pyridyl, 3-pyridyl , 4-pyridyl, 2-thienyl or 2-furyl.

According to another preferred embodiment of the invention, the compound of formula I has the definition wherein R1 is a hydrogen atom; A is 2-pyridyl, 3-pyridyl, 4-pyridyl; Ar ₂ is a 3-decyl group.

According to another preferred embodiment of the present invention, the compound of the formula I has the following definition, wherein R1 is a hydrogen atom; human is 2-thienyl, 4-mercaptothiophen-2-yl, 5-bromothiophen-2-yl, 2-pyrrolyl, 1-phenylsulfonylpyrrolidin-2-yl or 1-methylpyrrole-2- Base; Ar ₂ is 3-pyridyl or 4-pyridyl.

According to another preferred embodiment of the invention, the compound of formula I has the definition wherein R1 is a hydrogen atom; human is 1-phenyl-3,5-dimethylpyrazol-4-yl; Ar ₂ is 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl.

 More preferably, the compounds listed in Table 1 below, or geometric isomers thereof, or pharmaceutically acceptable salts or hydrates thereof:

根据本发明， 式 I化合物可以按照以下方法制备:

According to the invention, the compounds of formula I can be prepared as follows:

 General method for the synthesis of compounds of formula I:

 The compound of the formula IV and the compound of the formula V are stirred in a solvent such as tetrahydrofuran, ethanol, methanol, isopropanol or diethyl ether at 0-100 Torr for 0.1-100 hours, filtered, purified and dried.

One of the starting materials of the above-mentioned reaction, the compound of the formula IV can be produced by the method described below. For example, when Α _Γι in the compound of formula IV is a substituted or unsubstituted fluorenyl group, ie a compound of formula IVa below, wherein R1 is as defined in formula I; R3, Methyl, d-C ₆ alkyl, benzyl, benzenesulfonyl

¹¹ IVa

 Toluene, tetrahydrofuran, diethyl ether or benzene can be used as a solvent, and anhydrous potassium carbonate, anhydrous sodium carbonate, triethylamine or pyridine is used as a deacidifying agent to make a compound of formula II (purchased from a reagent company) and R2-X (wherein R2 is a benzyl group, a decyloxy group, a methyl group. The reaction is carried out at 0 to 120 ° C for 0 to 100 hours to give a compound of the formula IVa of the compound of the formula IV.

Another starting compound of the formula V used in the above reaction can be produced by the method described below. For example, when Ar ₂ in the compound of the formula V is a substituted or unsubstituted fluorenyl group, that is, V is a compound of the formula Va below, wherein R 10 , R 11 , and R 12 are each independently selected from the group consisting of halogen, nitro, hydroxy, and tri Fluoromethyl, C "C ₆ alkyl, C -M oxy, d- alkoxy acyl, amino, carboxy, phenyl, benzyl, phenylsulfonyl,

Va The alcohol corresponding to R9-OH can be used as a solvent. Under the catalysis of sulfuric acid, hydrochloric acid or DCC, the compound of the formula VI (purchased from the reagent company) and the R9-0H wherein R9 is a ^-C ₆ alkyl group are at 0 to 120 °. The reaction of C is carried out for 1 to 100 hours to obtain VI I , and then the compound of the formula VI I is reacted with hydrazine hydrate at 0 to 150 ° C for 1-100 hours with hydrazine hydrate or tetrahydrofuran as a solvent to obtain a specific compound of the formula Va of the compound of the formula V.

In a similar manner, a compound of formula I wherein human and Ar ₂ are each other heterocyclic group can be prepared.

 According to the present invention, pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts thereof with inorganic or organic acids or base addition salts with bases. Wherein acid addition salts include, but are not limited to: hydrochloride, hydrobromide, hydroiodide, nitrate, citrate, hydrogen sulphate, phosphate, hydrogen phosphate, acetate, propionate, Butyrate, trimethylacetate, adipate, alginate, lactate, citrate, tartrate, succinate, maleate, fumarate, picrate, day Aspartate, gluconate, benzoate, methanesulfonate, ethanesulfonate, besylate, p-toluenesulfonate and pamoate; base addition salts include but are not limited to : ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, organic base salts such as dicyclohexylamine and guanidine-methyl-D-glucosamine salts, and amino acid salts such as arginine And lysine salts.

 According to the present invention, the pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, Intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or input, or by means of an explant reservoir. Among them, oral administration, intraperitoneal or intravenous administration and topical administration are preferred.

 When administered orally, the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions. Among them, carriers which are generally used for tablets include lactose and corn starch, and a lubricant such as magnesium stearate may also be added. Diluents commonly used in capsule preparations include lactose and dried corn starch.

-11- Replace ( ] ^6) Aqueous suspension formulations are usually prepared by admixing the active ingredient with a suitable emulsifier and suspension. If desired, some sweeteners, fragrances or colorants may be added to the above oral formulations.

 When administered rectally, the compounds of the invention will generally be in the form of a suppository prepared by admixing the drug with a suitable non-irritating excipient. The excipient exhibited a solid state at room temperature and melted at a rectal temperature to release the drug. Such excipients include cocoa butter, beeswax and polyethylene glycol.

 When applied topically, especially in the treatment of facial surfaces or organs easily accessible by topical application, such as eye, skin or lower intestinal neurological diseases, the compounds of the present invention can be formulated into different topical preparations according to different affected faces or organs. , the specific instructions are as follows:

 When applied topically to the eye, the compound of the present invention can be formulated into a micronized suspension or solution in a form of isotonic, sterile saline at a pH which may or may not be added with a preservative such as benzyl chloride. Alkoxide. In addition, for ophthalmic use, the compound can also be formulated into a cream form such as a vaseline cream.

 When applied topically to the skin, the compounds of the invention may be in the form of a suitable ointment, lotion or cream preparation wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers usable herein for ointment preparations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions or creams which may be used include, but are not limited to: Mineral oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.

 When the lower intestinal tract is administered topically, the compound of the present invention can be formulated into a rectal suppository preparation as described above or a suitable enema preparation, and a topical transdermal patch can also be used.

The compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile injectable aqueous or oily suspensions, or sterile injectable solutions. Among them, carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterilized non-volatile oil is also It can be used as a solvent or suspension medium, such as a monoglyceride or a diglyceride.

 In addition, the compounds of the invention may also be administered with other immunosuppressive drugs: These include, but are not limited to, cyclosporin A, steroid hormones, FK506, RPM, Lef lunomide, DSG, SKF 105685 MZ, RS61443 BQR, and the like.

 It should also be noted that the specific dosage and method of use of the compounds of the present invention for different patients depends on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the condition. The severity of the diagnosis and the subjective judgment of the doctor. The preferred dosage is from 0.01 to 300 mg/kg body weight per day. DRAWINGS

 Fig. 1 shows the results of immunosuppressive experiments using representative compounds of the present invention in HPB-Al l cell mixed lymphocyte culture.

 Fig. 1 shows the results of immunosuppressive experiments using representative compounds of the present invention in human peripheral blood mixed lymphocyte culture. detailed description

 The following examples are intended to describe the invention in further detail, but without restricting the invention.

 The melting point of the compound was determined by a RY-1 type melting point apparatus, and the thermometer was not corrected. ^ NMR was determined by an ARX-400 NMR instrument. Mass spectra were determined by a Micromass-ZabSpec MS instrument. All reactions were pretreated with a solvent that was not indicated.

 Example 1: N-(l-Benzylindole-3-yl)methylene-3-pyridineformylhydrazide

1. 1 1-Benzyl-3-oxanal

0. 72克(5mmol) of benzyl bromide, 0. 72g (5mmol) of benzyl bromide, and a solution of 0. 72g (5mmol) of bromobenzyl, Room The reaction was carried out for a period of 24 hours, and the mixture was stirred for 5 hours, and the mixture was stirred for 5 hr. .

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 5.53 (s, 2H),

7.21-7.35 (m,7H), 7.56 - 7.58 (dd, 1H, =6.2Hz, J ₂ =L7Hz),

8.11-8.13 (dd, 1H, J 6.2Hz, J ₂ =2.2Hz), 8.42 (s,lH), 9.95 (s, 1H).

 1.2 N-(l-benzyl 吲哚-3-yl)methylene-3-pyridinium hydrazide

 210 g of self-made 1-benzyl-3-nonanal was dissolved in 10 ml of hot anhydrous ethanol, and then 139 mg of 3-pyridine forminide (purchased from ACROS) was added and reacted at 50 ° C for two hours. The mixture was cooled to room temperature for 48 hours, and filtered to give the title compound as white crystals.肼280 亳, yield: 88.051⁄2, melting point: 188-191 °C.

EI -MS [M+]=354.3 (m/e) ₀ 'H-NMR (400MHz, DMS0-d6): δ (ppm) 5.48 (s,lH), 7.26 - 7.33 (m, 7H), 7.31 - 7.33 ( m, 2H), 8.1 (s, lH), 8.25 (d, 1H), 8.30 (d, 1H), 8.61 (s, 1H), 8.74 (d, 1H), 9.07 - 9.08 (d, 1H), 11.71 (s, 1H) ₍ , Elemental analysis calculated C 74.56% H 5.12% N 15.81% Found: C 74.51% H 5.13% N 15.99%. Prepared in the same manner as in Example 1.2, using different reactants (aromatic aldehyde) The following compounds were prepared by substituting 1-benzyl-3-nonanal and 3-pyridinecarboxhydrazide in 1.1: Example 2: N-(indol-3-yl)methylene- Formyl hydrazide

According to the method of Example 1.2, the aromatic aldehyde is 3-furfural, and the aromatic hydrazine is used. 3-Pyroformylhydrazide (available from ACROS) gave the title compound as an off-white solid, yield 74.24%, mp.

 EI-MS [M+]=264. l(m/e),

'H-NMR (400MHz, DMS0-d ₆ ) : δ (ppm) 11.6 - 11.7 (s, 1H) , 9.08 — 9.07 (s, lH), 8.75 - 8.74 (m, 1H) , 8.61 (ra, 1H) , 8.31 - 8.25 (m, 2H), 7.86 - 7.85 (s, lH), 7.58 - 7.56 (m, 1H), 7.46 - 7.44 (d, 1H, J = 7.7Hz), 7.22 - 7.16 (m, 2H) .

 Elemental analysis calculated: C 68.17%, H 4.58% N 21.20% found: C 68.41%, H 4.53%, N' 21.00%. Example 3: N-(Indol-3-yl)methylene-2-thiophene ruthenate

 The aromatic aldehyde used in the procedure of Example 1.2 is 3-decanoic acid, and the aroyl hydrazide is 2-thiophene hydrazide to give the title compound as an off-white solid.

75.09%, melting point: 264-266° (:.

 EI-MS [M+]=269.0 (m/e),

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 7.13 a 7.25 (m, 3H), 7.43 - 7.47 (t,lH, J=7.6Hz), 7.82— 7.89 (m, 2H) , 8.08 - 8.09 (d, 1H, J=3.1Ηζ), 8.25 - 8.27 (d, 1H, J=7.8Hz), 8.59 (s,lH), 11.45 - 11.68 (m, 2H) .

Elemental analysis calculated: C 62.44% H4.12% N 15.60°/. Sll. 91% Found: C 62.12% H4.12% N 15.67% S 11.11.92%. Example 4: N-(5-methoxyindol-3-yl)methylene-2-thiophenate oxime. The aromatic aldehyde used was 5-methoxy-3-furfural according to the procedure of Example 1.2. (Laboratory), the aroyl hydrazide was 2-thiophene hydrazide (available from ACROS), the title compound was obtained as an off-white solid, yield 57.04%, melting point: 192-195 °C.

 EI -MS [M+]= 299.1 (m/e) ,

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 3.80 (s, 3H), 6.48 - 6.86 (d, lH, J = 8.6 Hz), 7.21 (s, lH), 7.33 - 7.36 (dd , IH, J!=9.1Hz, J ₂ =4.1Hz), 7.78 - 7.79 (m, IH), 7.81(s,lH), 7.83 - 7, 84 (m,lH), 8.10-8.11 (d, IH ), 8.30 (s, IH), 11.4 (s, lH), 11.5 (s, lH). Example 5: N-(5-methoxyindol-3-yl)methylene-4-pyridinecarboxhydrazide The aromatic aldehyde used was 5-methoxy-3-oxime according to the procedure of Example 1.2. The aldehyde, the aroyl hydrazide used was 4-pyridine hydrazide (available from ACROS), the title compound was obtained as an off-white solid, yield: 88.59%, m.p.: 246-248.

 EI -MS [M+]=294. l(m/e),

^-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 3.80 (s, 3H), 6.85 -

6.87 (dd, IH, = .8Hz, J ₂ =2.8Hz), 7.34 - 7.36 (d, 1H, J=8.8Hz),

7.80 ― 7.84 (m, 4H) , 8.61 (d, IH, J=l.9 Hz), 8.77 - 8.78 (dd, 2H, J!=6.1Hz, J ₂ =1.4Hz), 11.51 (s,lH) , 11.73 (s, IH)

 Elemental analysis calculated: C 65.30% H 4.79% N 19.04% Found: C 65.34% H 4.77% N 19.01%. Example 6: N-(5-decyloxy-3-yl)methylene-3-pyridinecarbonylhydrazide The aromatic aldehyde used was 5-methoxy-3-oxime according to the procedure of Example 1.2. The aldehyde hydrazide used in the aldehyde is 3-pyridyl hydrazide (Beijing Fangcai Pharmaceutical Chemical Development Co., Ltd.) to give the title compound as a white solid, yield: 90.97%, melting point: 242-244. C.

EI -MS [M+]= 294.1 (m/e), 'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 3.81 (s, 3H) , 6.86 a 6.88 (dd, 1H, Jx=8.8Hz, J ₂ =2.5Hz), 7.35 a 7.37 (d, 1HJ=8.5Hz), 7.54 - 7.58 (m, 1H), 7.81 (s,lH), 7.87 (s,lH), 8.26 - 8.29 (m, 1H, ) , 8.61(s,lH), 8.74 - 8.76 ( Dd, 1H, Jx = 4.7 Hz, J ₂ = 1.6 Hz), 9.09 (s, lH), 11.5 - 11.7 (s, 1H).

 Elemental analysis calculated: C 65.30% H 4.79% N 19.04% Found: C 65.09% H 4.78% N 18.77%. Example 7: N-(1-phenyl-3,5-dimethylpyrazol-4-yl)methylene-3-pyridylformylhydrazide

 According to the method of Example 1.2, the aromatic aldehyde used was 1-phenyl-3,5-dimethyl-4-pyrazolecarboxaldehyde (purchased from ACR0S), and the aroylhydrazide used was 3-picolinylhydrazide. The title compound was obtained as a white solid. ield::::::::::::::::::::::::::::::::::::::: . C.

 EI -MS [M+]=319.2(m/e),

J₂=2.0Hz)， 8.48 (s，lH)， 8.75 ― 8.76 (dd, 1H, J!=4.8Hz, J₂=l.4Hz) , 9.05 - 9.06 (d, 1H, J=1.4Hz), 11.73 (s，lH)。 'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 2.48 (s, 3H) , 2.49 (s, 3H), 7.44 ― 7.48 (m, 1H) , 7.50 - 7.59 (ra, 5H) , 8.23 - 8.25 (dt, lH,

J ₂ =2.0 Hz), 8.48 (s,lH), 8.75 ― 8.76 (dd, 1H, J!=4.8Hz, J ₂ =l.4Hz), 9.05 - 9.06 (d, 1H, J=1.4Hz), 11.73 (s, lH).

Elemental analysis calculated: C 67.70% H 5.37% N 21.93% Found: C 67.47% H 5.36% N21.97%. Example 8: N-(l-methylindol-3-yl)methylene-4-pyridinecarboxhydrazide The aromatic aldehyde used was 1-methyl-3-furfural according to the procedure of Example 1.2. Purchased from ACROS), the aroyl hydrazide was 4-picolinylhydrazide, the title compound was obtained as a pale yellow-green solid, yield: 80.94%, m.p.: 265-268.

 EI- MS [Μ+]=278· 2(m/e),

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 3.84 (s, 3H) , 7.20 - 7.24 (td, 1H, J!=8.0Hz, J ₂ =l.2Hz), 7.27 - 7.31 ( Td, 1H, J^.0Hz J ₂ =l.2Hz), 7.51 -7.53 (d, 1H, J=8.0Hz) , 7.82 - 7.84 (m, 2H) , 7.88 (s,lH), 8.28— 8.30 ( d, 1H, J=8.0Hz), 8.60 (s,lH), 8.77 - 8.79 (m, 2H), 11.75 (s,lH).

 Elemental analysis calculated: C 69.05% H 5.07% N 20.13% Found: C 68.59% H 5.04% N 19.91%. Example 9: N-(indol-3-yl)methylene-2-furoylhydrazide

 The aromatic aldehyde used was 3-furfural according to the method of Example 1.2, and the aroyl hydrazide was 2-furoyl hydrazide (available from ACROS) to give the title compound as a white solid. Melting point: 274- 276 °C.

 EI- MS [M+]=253. l(ra/e),

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 6.69-6.70 (m, 1H), 7.15-7.25 (m, 3H), 7.43 - 7.45 (d, 1H, J=8.0Hz), 7.82 (d, 1H, J=l.8Hz), 7.92 (s,lH), 8.26-8.28 (d, 1H, J=8.0Hz), 8.61 (s,lH), 11.52 (s, 1H), 11.61 (s , lH).

Elemental analysis calculated: C 66.40% H 4.38% N 16.59% Found: C 66.37% H 4.30% N 16.38%. Example 10: N-(2-methylindole-3-yl)methylene-4-pyridinecarboxhydrazide The aromatic aldehyde used was 2-methyl-3-nonanal according to the procedure of Example 1.2. Used in ACROS), the aroyl hydrazide used is 4-picolinyl hydrazide to give the title compound. It is an off-white solid, yield: 88.12%, m.p.: 268-270.

 EI -MS [M+]=278.2 (m/e),

^{! H-NMR (400MHz, DMS0} -d 6): δ (ppm) 2.52 (s, 3H), 7.08 - 7.15 (m, 1H), 7.32 - 7.34 (dd, 1H, J: = 6.2Hz, J 2 = L.7Hz), 7.56 - 7.58 (dd, 1H, =T.1 J ₂ =5.6 Hz), 8.20 - 8.27 (m, 2H), 8.67 (s, 1H) , 8.74 - 8.76 (dd, 1H, =4.8 Hz J ₂ =l.7 Hz) , 9.07- 9.08 (d,lH, J=2.2 Hz) , 11.52 (s.lH), 11.61 (s,lH),

 Elemental analysis calculated: C 69.05% H 5.07% N 20.13% Found: C 69.01% H 5.04% N 19.97%. Example 11: N-(2-methylindole-3-yl)methylene-2-thiophene hydrazide. According to the method of Example 1.2, the aromatic aldehyde used was 2-methyl-3-nonanal. The aroyl hydrazide used was 2-thirazolylhydrazide (available from ACR0S) to give the title compound as a pale yellowish white solid, yield: 41.36%, melting point: 230-232 °C.

 EI -MS [M+]=283.2 (m/e),

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 2.53 (s,3H), 7.08 - 7.13 (m,2H), 7.21 -7.23 (m, 1H) , 7.32 - 7.34 (d, 1H, J=8.0Hz) , 7.82 - 7.83 (d, 1H, J=4.8Hz), 7.87 - 7.88 (d, 1H, J=2.8Hz), 8.09 (s,lH), 8.19 - 8.20 (d, 1H, J =7.2 Hz), 8.42 (s, lH), 8.65 (s, 1H).

Elemental analysis calculated: C 63.58% H 4.62% N 14.83% Found: C 63.59% H 4.66% N 14.78%. Example 12: N-(2-methylindol-3-yl)methylene-2-furoylhydrazide. According to the method of Example 1.2, the aromatic aldehyde used was 2-methyl-3-nonanal. The aroyl hydrazide is 2-furoyl hydrazide to give the title compound as a pale yellow solid. Yield: 56.18%, melting point: 131-134 °C.

 EI -MS [M+]=267.2 (m/e),

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 2.50 (s, 3H) , 6.68 - 6.69 (m, 1H), 7.07 - 7.14 (m, 2H) , 7.22 - 7.23 (d, 1H, J = 3.2 Hz), 7.31 - 7.33 (d, 1H, J = 6.8 Hz), 7.91 (s, 1H), 8.17 - 8.19 (d, 1H, J = 6.8 Hz), 8.69 (s, lH).

 Elemental analysis calculated: C 67.41% H 4.90% N 15.72% Found: C 67.13% H 4.94% N 15.70%. Example 13: N-(quinolin-2-yl)methylene-2-thiophene hydrazide

 According to the method of Example 1.2, the aromatic aldehyde used was 2-quinolinecarboxaldehyde, and the aryl hydrazide was 2-thiophene hydrazide to give the title compound as a light brown solid.

47.45%, melting point: 225-227 °C.

 EI -MS [M+]=281.2(m/e),

 'H-NMR (400MHz, DMSO-dfi): δ (ppm) 7.27 - 7.29 (t, 1H, J=4.0Hz), 7.64 - 7.68 (t, 1H, J-8.0Hz) , 7.80 ― 7.84 (t, lH, J=8.0 Hz), 7.95 - 8.60 (m, 7H), 12.23 (s, lH).

Elemental analysis Calcd: C 63.81% H 4.28% N 14.88% Found: N- (indol-3-yl) methylene-2-picolinate: 14 C 63.93% H 3.96% N 14.86% 0 Example肼

 According to the method of Example 1.2, the aromatic aldehyde used was 3-furfural, and the aroyl hydrazide was 2-pyridine formyl hydrazide (available from Tokyo Chemical Industry Co., Ltd.) to obtain the title compound as an off-white solid. : 77.27%, melting point: 226-228 °C.

 EI -MS [M+]=264.2 (m/e),

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 7.15 - 7.23 (m, 2H), 7.44-7.46 (dd, IH, J yield 7.7Hz, J ₂ =0.8Hz), 7.65 - 7.66 (m, IH),

, 8.12 — 8.14 (dd, IH =7.7Hz， J₂=0.8Hz) , 8.31 — 8.33 (dd, IH

J₂ =0.8Hz)，7.79 - 7.08 (s,lH), 8.05 -8.07 (td, IH,

, 8.12 — 8.14 (dd, IH = 7.7Hz, J ₂ =0.8Hz), 8.31 — 8.33 (dd, IH

J ₂ =0.8Hz),

8.78 (d, IH, J=l.1 Hz), 11.61 (s,lH), 11.83 (s,lH).

 Elemental analysis calculated: C 68.17% H 4.58% N 21.20% Found: C 68.04% H 4.23% N 21.26%. Example 15: N-(5-methoxyindol-3-yl)methylene-2-pyridinecarboxhydrazide. The aromatic aldehyde used was 5-nonyloxy 3-furfural according to the method of Example 1.2. The aroyl hydrazide was used as the 2-pyridine hydrazide to give the title compound as an off-white solid, yield 44.22%, m.p.: 135 - 138.

 EI -MS [M+]=294.3 (m/e),

8.70 - 8.71 (dd, IH J!=4.7Hz, J₂=0.8Hz) , 8.76 (s，lH), 11.49 (s, IH)， 11.82 (s， IH)。 'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 3.81 (s,3H), 6.85 - 6.88 (d, IH, J!=8.8Hz, J ₂ =2.5Hz), 7.34 - 7.36 (d , IH, J=8.8Hz) , 7.65 - 7.66 (m,lH), 7.74 (s,lH), 7.87- 7.88 (d, 1H, J=2.4Hz), 8.05 - 8.07 (td, IH, J!= 7.7Hz, J ₂ =1.4Hz), 8.12 -8.14 (dd, IH,

8.70 - 8.71 (dd, IH J!=4.7Hz, J ₂ =0.8Hz), 8.76 (s,lH), 11.49 (s, IH), 11.82 (s, IH).

 Elemental analysis calculated: C 65.30% H 4.79% N 19.04% Found: C 64.78% H 4.83% N 18.92° Example 16: N-(quinolin-4-yl)methylene-4-pyridinecarbonylhydrazide

 According to the method of Example 1.2, the aromatic aldehyde used was 4-quinolinecarboxaldehyde, and the aryl hydrazide was 4-pyridyl hydrazide to give the title compound as a white solid.

60.38%, melting point: 236-238°C ₀ EI-MS [M+] =276. 2 (m/e) ,

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 7. 76 - 7. 79 (m, 1H) ,

7. 84 - 7. 90 (m, 4H), 8. 12 - 8. 14 (d, 1H, J=8. 3Hz), 8. 77 - 8. 79 (d, 1H, J=8. 0Hz) , 8. 84 - 8. 85 (dd, 2H, Ja=6. lHz, J ₂ =l. 4Hz), 9. 02 - 9. 03 (d, 1H, J=4. 7Hz) , 9. 11 ( s,lH) , 12. 46 (s, 1H).

 Elemental analysis calculated: C 69. 55% H 4. 38% N 20. 28% Found: C 69. 22% H 4. 27% N 20. 00%. Example 17: N-(quinolin-4-yl)indenyl-2-thiophene hydrazide

 According to the method of the embodiment 1. 2, the aromatic aldehyde used is 4-quinolaldehyde, and the aroyl hydrazide is 2-thiophene hydrazide to give the title compound as a white solid.

37. 95%, melting point: 200-202 °C.

 EI-MS [M+] =281. 0 (m/e) ,

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 7. 28 (s,lH) , 7. 73 -

8. 13 (m, 6H), 8. 38 (s, lH), 8. 75- 8. 77 (m, 1H), 8. 93 — 9. 07 (m, 2H) .

 Elemental analysis calculated: C 64. 04% H 3. 94% N 14. 94% Found: C 63. 91% H 3. 73% N 14. 85%. Example 18: N-(quinolin-4-yl)methylene-2-furoyl hydrazide

 According to the method of Example 1. 2, the aromatic aldehyde used was 4-quinolinylaldehyde, and the aroyl hydrazide was 2-furoyl hydrazide to give the title compound as a white solid.

71. 70%, melting point: 226-228. C.

 EI-MS [M+] =265. 0 (m/e) ,

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 6. 76 - 6. 77 (m, 1H) , 7. 75 - 7. 77 (t, 1H, J=7. 4Hz) , 7 83 - 7. 87 (m, 2H), 8. 02 (s, 1H), 8.11 - 8.13 (d, 1H, J = 6.8 Hz), 8.70 - 8.72 (d, 1H, J = 7.1 Hz), 8.99 - 9.01 (d, 1H, J-4.7Hz), 9.14 (s, lH), 12.24 (s, 1H).

 Elemental analysis calculated: C 67.92% H 4.18% N 15.84% Found: C 67.74% H 4.09% N 15.48%. Example 19: N-(quinolin-4-yl)methylene-3-lipoformylhydrazide

 The aromatic aldehyde used was 4-quinolinylfurfural, and the aryl hydrazide was used as the 3-pyridine hydrazide to give the title compound as a white solid.

71.26%, melting point: 185-187 °C.

EI -MS [M+]=276.0 (m/e) _o

^-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 7.62 ― 7.65(m,lH), 7.75― 7.89 (m, 3H), 8.12 - 8.14 (d, 1H, J=8.3Hz), 8.32 - 8.34 (d, 1H, J=8.0Hz), 8.78 ― 8.83 (m, 2H), 9.01 - 9.02 (d, 1H, J=4.4Hz), 9.09 (s,lH), 9.14 (d, 1H, J= L.4Hz), 12.41(s,lH).

 Elemental analysis calculated: C 69.55% H 4.38% N 20.28% Found: C 69.37% H 4.31% N 20.22%. Example 20: N-(pyrrol-2-yl)indenyl-4-pyridylhydrazide

 The aromatic aldehyde used was the 2-pyrrolidine (available from ACROS), and the aroyl hydrazide was 4-pyridyl hydrazide. The title compound was obtained as a yellow solid. Yield: 77.88%. Melting point: 226-229° (.

 EI-MS [M+]=214.0 (m/e) ,

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 6.15 ― 6.16 (t, 1H, J=3.0Hz) , 6.52 - 6.53 (dd, 1H 6Hz, J ₂ =l.1Hz) , 6.94 ( s,lH), 7.79 - 7.80 (dd, 2H J^.4Hz, J ₂ =l.6Hz) , 8.29 (s,lH), 8. 75 - 8. 76 (dd, 2H Jx=4. 4Hz, J ₂ =1. 6Hz), 11. 60 (s, 1H), 11. 78 (s, 1H) .

 Elemental analysis calculated: C 61. 67% H 4. 71% N 26. 15% Found: C 61. 66% H 4. 67% N 25. 76%. Example 21: N-(3-methylthiophen-2-yl)methylene-3-pyridinecarbonylhydrazide The aromatic aldehyde used was 3-methyl-2-thiophenecarboxaldehyde according to the method of Example 1. The aroyl hydrazide was used as the pyridine hydrazide, and the title compound was obtained as a pale yellowish white solid. Yield: 61. 25%, melting point: 214-215 °C.

 EI -MS [M+] =244. 9 (m/e) ,

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 2. 49 (s, 3H), 6. 84 (s, 1H) , 7. 27 (s, lH), 7. 53 - 7. 56 (m, 1H), 8. 20 - 8. 22 (d, 1H, J=7. 2Hz) , 8. 57 (s,lH), 8. 74 (d, 1H, J=3. 3Hz), 9. 03 (s, lH), 11. 91 (s, lH).

 Elemental analysis calculated: C 58. 76% H 4. 52% N 17. 13% Found: C 58. 83% H 4. 54% N 16.97%. Example 22: N-(l-methylpyrrole-2-yl)methylene-3-pyridinecarboxhydrazide The aromatic aldehyde used was 1-methyl-2-pyrrolidine according to the method of Example 1. 2. The aroyl hydrazide was used in the form of a pyridine hydrazide. The title compound was obtained as a yellow solid. Yield: 52. 63%, melting point: 155-158.

 EI -MS [M+] =228. 1 (m/e) ,

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 3. 87 (s, 3H) , 6. 11 -6. 13 (t, 1H, J=3. 0Hz), 6. 53 - 6 . 55 (m, 1H), 6. 99 (s, 1H) , 7. 54 - 7. 58 (m,lH), 8. 21 -8. 24 (dt, 1H 0Hz,: T ₂ =l. 6Hz ), 8. 36 (s,lH) , 8. 74 - 8. 76 (dd, 1H , 7Hz, J ₂ =l. 6Hz), 9. 04 (d, 1H, J=l. 6) , 11.71 (s, lH).

 Elemental analysis calculated: C 63.15% H 5.30% N 24.55% Found: C 62.88% H 5.27% N 24.19%. Example 23: N-(l-Phenylsulfonyl-2-yl)methylene-3-pyridinecarbonyl hydrazide

 The aromatic aldehyde used was 1-benzenesulfonyl-2-pyrrolecarboxaldehyde (available from ALDRICH), and the aroylhydrazide was 3-picolinylhydrazide. The title compound was obtained as a brown solid. , Yield: 53.67%, Melting point: 215-217Ό.

 EI -MS [M+]=354.0 (ra/e),

'H-NMR (400MHz, DMS0-d ₆ ) : δ (ppm) 6.49 - 6.51 (t, 1H, J=3.4Hz), 6.92 - 6.93 (d, 1H, J=2.2), 7.57 - 7.71(m, 4H) , 7.77 - 7.81 (t, lH, J = 7.3 Hz), 7.97 - 7.99 (d, 2H, J = 7.6 Hz), 8.25 - 8.27 (d, 1H, J = 7.9 Hz), 8,78 - 8.79 (dd, 1H, J=4.5Hz, J ₂ =l.1Hz), 8.94 (s,lH), 9.07 - 9.08 (d, 1H, J=2.0Hz), 12.14 (s, 1H).

 Elemental analysis calculated: C 57.62% H 3.98% N 15.81% Found: C 57.41% H 3.92% N 15.66%. Example 24: N-(4-bromothien-2-yl)methylene-3-pyridinecarboxhydrazide The aromatic aldehyde used was 4-bromo-2-thiophenecarboxaldehyde (purchased from ACROS) according to the procedure of Example 1.2. The aroyl hydrazide was used as the 3-pyridine hydrazide to give the title compound as a brown solid. Yield: 68.18%, mp.

 EI -MS [M+]=308.9 (m/e),

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 7.29 - 7.30 (d, 1H, J=4.0Hz), 7.36 - 7.37 (d, 1H, J=4.0Hz), 7.56 - 7.59 (dd , 1H, =7.9Hz, J ₂ =4.8Hz), 8.21— 8.24 (dt, 1H, 8Hz, J ₂ =2.0Hz), 8. 58 (s, lH) , 8. 76— 8. 77 (dd, 1H, 8Hz, J ₂ -l. 7Hz), 9. 03 -

9. 04 (d, 1H, J=l. 7Hz), 12. 07 (s, 1H).

 Elemental analysis calculated: C 42. 60% H 2. 60% N 13. 55% Found: C 42. 88% H 2. 48% N 13. 44%. Example 25: N-(pyridin-3-yl)methylene-3-indole hydrazide

 25. Synthesis of 1 3-methyl decanoate

 克克下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下下Step reaction).

 25. 2 Synthesis of 3-indole hydrazide

 6克的溶液。 Methyl 3- decanoate 0. The compound was obtained as a pale yellow solid. Ethyl acetate: petroleum ether = 1 : 1 thin layer chromatography was used as a single spot and used directly in the next step.

 25. Synthesis of 3 N-(pyridin-3-yl)methylene-3-indole

321克(3. 0mmol) 3-pyridinecarboxaldehyde (purchased from the self-made 3 - decanoate 肼 0. 413 g (2.5 ol) heated to 50 ° C, completely dissolved in anhydrous ethanol, added 0. 321 g (3.0 mmol) 3-pyridine formaldehyde (purchased from ACR0S company, stirring, N ₂ protection reaction, while allowing the reaction system to naturally cool, after the reaction to room temperature for 24 hours, allowed to stand, filtered, to obtain a white solid 360 grams. Yield: 75. 76%, m.p.: 261-263 °C.

 EI -MS [M+] =264. l (ra/e) ,

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 7. 17 - 7. 26 (m, 2H), 7. 38 7. 42 (m, 1H), 7. 51 - 7. 49 ( d, 1H, J=7. 8Hz), 7. 88 -7. 91 (td, 1H, J!=7. 6Hz, J ₂ =l. 7Hz) , 7. 97 - 7. 99 (d, 1H, J=7. 8Hz), 8.21 - 8.34 (m, 3H), 8.61 - 9.62 (m, 1H), 11.64 (s, lH), 11.81 (s, lH).

 Elemental analysis calculated: C 68.17% H 4.58% N 21.20% Real i ^ value: C 68.07% H 4.55% N 20.99%. Example 26: N-(pyridin-4-yl)methylene-3-indolylhydrazide

 The aromatic aldehyde used was 4-pyridinecarboxaldehyde (available from ACROS) and the title compound was obtained as an off-white solid. Yield: 54.55. %, Melting point: 302-303. C.

 EI-MS [M+]=264.2 (m/e),

'H-NMR (400MHz, DMSO-d ₆ ) : δ (ppm) 7.14 - 7.23 (m, 2H) , 7.48 - 7.50 (d, 1H, J = 7.8Hz), 7.65 - 7.66 (d, 2H, J= 5.1 Hz), 8.19 - 8.29 (m, 3H,), 8.64 - 8.65 (d, 2H, J = 5.1 Hz), 11.67 (s, lH), 11.80 (s, lH).

 Elemental analysis calculated: C 68.17% H 4.58% N 21.20% Real' value: C 67.77% H 4.51% N 21.02%. Example 27: N-(5-bromothien-2-yl)methylene-3-indoleyl. According to the method of Example 25.3, the aromatic aldehyde used was 5-bromothiophen-2- aldehyde (purchased from ACR0S). Company), the aroyl hydrazide is 3-indole hydrazide, the title compound is obtained as an off-white solid, yield: 75.76%, melting point: 214-216 °C.

 EI-MS [M+]=264 (m/e),

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 7.15 - 7.21 (m, 2H) , 7.46 -7.49 (m, 2H) , 7.74- (s,lH), 8.19 (s,2H), 8.52 (s, lH), 11.50 (s, lH), 11.79 (s, 1H). Example 28: N-(pyridin-4-yl)ethylidene-3-hydrazide hydrazide The aromatic aldehyde used was 4-acetylpyridine (purchased from ACROS), using the method of Example 25.3. The aroylhydrazide is 3-indole hydrazide, which is the title compound, which is an off-white solid, yield: 79.14%, m.p.: 287-288.

 EI-MS [M+]=278.2 (ra/e),

^J H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 2.37 (s, 3H), 7.16 - 7.20 (m, 2H) , 7.47 ― 7.49 (d, 1H, J=7.6Hz) , 7.74 - 7.76 (d, 2H, J=5.9Hz), 8.20 -8.22 (d, 1H, J=7.6Hz), 8.33 - 8. 34 (d, 1H, J=2.8Hz) , 8.63 - 8.65 (d, 2H, J =5.9 Hz), 10.44 (s, 1H), 11.82 (s, lH).

 Elemental analysis calculated: C 69.05% H 5.07% N 20.13°/. Found: C 68.91% H 5.01% N 20.11%. Example 29: N-(pyridin-3-yl)methylene-3-indole hydrazide

The aromatic aldehyde used was 3-pyridinecarboxaldehyde (available from ACROS) and the title compound was obtained as a white solid. Yield: 60.61%. , Melting point: 273-274 °C EI-MS [M+]=264.2 (m/e), 'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 7.14 -

7.22 (m, 2H), 7.47 - 7.50 (m, 2H), 8.12 - 8.14 (d, 1H, J = 7.8),

8.20 - 8.36 (m,3H), 8.59 - 8.60 (dd, 1H, Ji=4.8Hz, J ₂ =1.7Hz), 8.87 (d, 1H, J=1.4Hz), 11.57 (S,1H), 11.77 ( S, 1H).

 Elemental analysis calculated: C 68.17% H 4.58% N 21.20% Found: C 67.79% H 4.45% N 21.03%. Example 30 N-(pyrrol-2-yl)methylene-3-pyridineformylhydrazide

Add 0.47 g (3 leg. 1) 2-pyrrolidine (purchased from ACR0S) to 15ML To the ethanol, 0.415 g (3 mmol) of nicotinic acid hydrazide was added, and the reaction was carried out for 48 hours at room temperature under N ₂ protection, filtered, dried and purified with anhydrous ethanol to give 400 g of white solid. Yield: 57.72%, melting point: 231- 233"C.

 EI -MS 231. Km/ e),

'H-NMR (400MHz,. DMS0-d ₆ ): δ (ppm) 6.15 ― 6.16 (q, lH, J=3.1Hz), 6.52 ((S,1H), 6.93 (d, 1H, J=l. 1Hz), 7.55 - 7.57 (m, 1H) , 8.22 - 8.24 (m, 1H) , 8.27 (s, 1H), 8.74 - 8.75 (dd, 1H, J!=5.0Hz, J ₂ =3.4Hz) , 9.04 - 9.05 (d, 1H, J=l.6), 11.58 (s,lH), 11.65 (s,lH).

Elemental analysis calculated: C 61.67% H 4.71% N 26.15% Found: C 61.45% H 4.65% N 25.79%. Example 31: N-(l-benzylindol-3-yl)methylene-3-pyridinecarboxhydrazide The aromatic aldehyde used was 1-benzyl-3-indolylaldehyde according to the method of Example 1.2. The aroyl hydrazide used was 3-pyridinecarbonyl hydrazide to give the title compound as a pale yellow white solid, yield: 87.88%, melting point: 188-191 °C ₀

 EI-MS [M+]=354.3 (m/e) ,

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 5.48 (s,lH), 7.26 - 7.33(m, 7H), 7.31 - 7.33 (m, 2H), 8.1 (s,lH), 8.25 (d, 1H, J=2.0Hz), 8.30 (d, 1H, J=1.2Hz), 8.61 (s,lH), 8.74 (d, 1H, J=l.8Hz), 9.07 — 9.08 (d, 1H , J=l.5Hz), 11.71 (s, 1H).

Elemental analysis calculated: C 74.56% H 5.12% N 15.81%, found: C 74.51% H 5.13% N 15.99%. Example 32: N-(l-methoxyxyindol-3-yl)methylene-2-thiophene hydrazide Synthesis of 32.1 1-methoxyacyl-3-furfural

 1.45 g (0. Olmol) 3-furfural was dissolved in 25 ml of anhydrous tetrahydrofuran, and 1.10 g of triethylamine was added thereto, and stirred, and 1.10 g (0. Olmol) of methyl chloroformate was added dropwise, and the mixture was stirred for 1 hour. After refluxing for 2 hours, the solvent was evaporated, washed with water and then filtered, and filtered, and the obtained solid thin layer chromatography was a single spot and weighed 1.72 g. (Directly used in the next step).

 32.2 N-(l-methoxyxoindol-3-yl)methylene-2-thiophene hydrazide hydrazide according to the method of Example 1.2, the aromatic aldehyde used is 1-methoxyacyl-3-indolecarboxaldehyde, The aroyl hydrazide was 2-thirazolylhydrazide (available from ACR0S) to give the title compound as a white solid, yield: 76.45%, m.p.: 185-187.

 EI-MS [M+]=327.2 (m/e),

'H-NMR (400MHz, DMS0-d ₆ ) : δ (ppm) 4.04 (s, 3H) , 7.23 -7.25 (t, 1H, J=3.9Hz), 7.37 - 7.41 (m, IH) , 7.43 - 7.47 (m, IH) 7.86 ― 7.87 (d, IH, J=4.0Hz), 7.94 (s, IH), 8.15 ― 8.17 (d, IH, J=8.2Hz), 8.23 (s, IH) , 8.43 - 8.45 (d, IH, J = 7.3 Hz), 8.60 (s, lH), 11.92 (s, IH).

 Elemental analysis calculated: C 58.70% H 4.00% N 12.84% Found: C 58.95% H 3.90% N 12.81 °/. . Example 33: N-(l-methoxyxoindol-3-yl)indenyl-3-indolehydrazide The aromatic aldehyde used was 1-methoxyxo-3-indole according to the procedure of Example 1.2. The title compound was obtained as a white solid, yield: 48.61%, m.p.: 195-197.

 EI-MS [M+]=360.3 (m/e),

^-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 4.04 (s,3H), 7.13 - 7.22 (m, 2H), 7.36 - 7.39 (t, 1H, J=7.6Hz) , 7.42 - 7.49 ( m, 2H) , 8.14 - 8.24 (m, 4H), 8.45 (s,lH), 8.50 (s,lH), 11.34 (s, IH) , 11.70 (s, lH).

 Elemental analysis calculated: C 66.66% H 4.48% N 15.55% Found: C 66.18% H 4.53% N 15.26%. Example 34: N-(l-methoxyxyin-3-yl)hydrazono-3-pyridinecarbonyl hydrazide

 The aromatic aldehyde used was 1-methoxycarbonyl-3-indenecarbaldehyde, and the aroyl hydrazide was 3-pyridyl hydrazide to give the title compound as a white solid, yield: 50.72%. Melting point: 168-169 ° C.

 EI-MS [M+]=322.2 (m/e),

^{! H-NMR (400MHz, DMS0} -d 6): δ (ppm) 4.15 (s, 3H), 7.38 a

7.47 (m, 2H), 7.55 - 7.59 (m, lH), 8.14 - 8.16 (d, 1H, J = 8.1 Hz),

8.24 (s,lH), 8.26 ― 8.28 (d, 1H, J=7.9Hz), 8.46 - 8.48 (d, 1H, J=7.6Hz), 8.62 (s, 1H), 8.74 - 8.78 (dd, 1H, J=5.0Hz),

9.10 (s, lH), 11.90 (s, lH).

 Elemental analysis calculated: C 63.35% H 4.38% N 17.38% Found: C 62.99% H 4.37% N 17.22%. Example 35: N-(Pyridin-2-yl)methylene-3-indole hydrazide

 The aromatic aldehyde used was 2-pyridinecarboxaldehyde, and the aryl hydrazide was used as the 3-pyridine hydrazide to give the title compound as a white solid.

75.76%, Melting point: 260-261°C _o

 EI-MS [M+]=264.2 (m/e),

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 7.14 - 7.22 (m, 2H), 7.38 - 7.41 (m,lH), 7.48 - 7.50 (m,lH), 7.88 (m, 1H) , 7.95 a 7.97 (d, 1H, J=7.8Hz), 8.20 ― 8.334 (m, 3H) , 8.60 - 8.62 (d, 1H, J=4.2Hz), 11.59 (s,lH), 11.79 (s, 1H).

 Elemental analysis calculated: C 68.17% H 4.58% N 21.20% Found: C 67.70% H 4.57% N 21.26%. Example 36: N-(Thien-2-yl)methylene-3-indole hydrazide

 The aromatic aldehyde used was 2-thiophenecarboxaldehyde (available from ACROS) and the title compound was obtained as an off-white solid. Yield: 84.76%. Melting point: 263-264°C

 EI -MS [M+]=269.2 (m/e),

aH-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 7.12 - 7.21 (m, 2H),

7.46 — 7.50 (m, 2H) , 7.63— 7.65 (m, lH), 7.87 – 7.88 (m.1H),

8.21 - 8.37 (m, 3H), 11.26 (s, lH), 11.70 (s, 1H).

 Elemental analysis calculated: C 62.44% H 4.12% N 15.60% Found: C 62.11% H 4.07% N 15.60%. Example 37: N-(l-methoxyxyin-3-yl)methylene-4-pyridinecarbonyl hydrazide

The aromatic aldehyde used was 1-methoxyxy-3-indolaldehyde, and the aroyl hydrazide was 4-pyridine hydrazide. The title compound was obtained as white solid. Yield: 28.57% , Melting point: 190-193°C _o

 EI -MS [M+]=322.2 (m/e)

^-NMR (400MHz, DMS0-d ₆ ) : δ (ppm) 4.04 (s,3H), 7.38 -

8.15 — 8.17 (d, 1H, J=8.1), 8.28 - 8.30 (s,lH)， 8.45 -8.47 (d, 1H, J=7.6),7.48 (m, 2H), 7.84 -7.86 (dd, 2H,

8.15 — 8.17 (d, 1H, J=8.1), 8.28 - 8.30 (s,lH), 8.45 -8.47 (d, 1H, J=7.6),

8.63 (s,lH), 8.78 - 8.80 (dd, 2H, =6.0, J ₂ =l.4) , 12.11 (s,lH). Elemental analysis calculated: C 63.35% H 4.38% N 17.38% Found: C 63.20% H 4.31% N 17.33%. Example 38: N-(l-benzylindol-3-yl)methylene-4-pyridinecarboxhydrazide The aromatic aldehyde used was 1-benzyl-3-indenecarbaldehyde according to the method of Example 1.2. The aroyl hydrazide used was 4-picolinyl hydrazide to give the title compound as an off-white solid. Yield: 72.19%, melting: 238-240.

 EI -MS [M+]=354.2 (m/e),

^: H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 5.48 (s,lH), 7.16

7.33 (m,8H), 7.52 ― 7.54 (d, 1H, J=7.32Hz), 7.82 ― 7.84 (d, 2H, J=6.0Hz) , 8.29 — 8.31 (d, 1H, J=7.0Hz) , 8.63 (s,lH),

8.77― 8.78 (m, 2H), 11.77 (s, 1H). Elemental analysis calculated: C 74.56% H 5.12% N 15.81% Found: C 74.21% H 5.14% N 15.81%. Example 39: N-(Indolyl-5-yl)methylene-4-pyridinecarboxhydrazide

 The aromatic aldehyde used was 5-indene-formaldehyde (available from ALDRICH), and the aroyl hydrazide was 4-picolinylhydrazide. The title compound was obtained as a yellow-white solid. Yield: 62.50 %, Melting point: 264-265 ° C.

EI -MS [M+]=264.2 (m/e), ^-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 6.52 (s,lH), 7.40 (s,lH), 7.46 - 7.48 (d, 1H, J-8.6Hz), 7.60 (d, 1H, J=1.2Hz), 7.82 - 7.87 (m, 3H), 8.52 (s,lH), 8.77 a 8.78(m, 2H), 11.34 (s,lH ), 11.87 (s, 1H).

Elemental analysis calculated: C 68.17% H 4.58% N 21.20% Found: C 67.86% H 4.58% N 20.88%. Example 40: N-(l-Benzylindole-3-yl)methylene-2-thiophenehydrazide The aromatic aldehyde used was 1-benzyl-3-nonanal, and the aroyl hydrazide was 2-thiophene hydrazide. The title compound was obtained as a pale yellow solid. Yield: 58.80% , Melting point: 185-188 ° C.

 EI-MS [M+]=359.2 (m/e),

^: H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 5.48 (s, 2H), 7.16 - 7.34 (m, 8H) , 7.51 - 7.53 (m, 1H), 7.83 - 7.84 (d, 1H, J=5.0Hz), 7.89 - 7.90 (d, 1H, J=3.4Hz), 8.04 (s,lH), 8.27 - 8.29 (d, 1H, J=7.6Hz), 8.60 (s,lH), 11.6 ( s, 1H ).

Elemental analysis calculated value: C 70.17°/. H 4.77% N 11.69% Found: C 69.83% H 4.84% N 11.88% ₀ Example 41: N-(quinolin-2-yl)methylene-4-pyridinylhydrazide

 The aromatic aldehyde used was 2-quinolinecarboxaldehyde, and the aryl hydrazide was 4-pyridyl hydrazide. The title compound was obtained as a pale yellow solid, yield 38.65. , melting point: 187-190 ° C.

 EI-MS [M+]=276.2 (m/e),

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 7.65 - 7.69 (t,lH, J=8.0Hz), 7.80 ― 7.84 (m,lH,), 7.87 a 7.88 (dd, 2H L= 6.0Hz, J ₂ =l.6Hz), 8.03— 8, 05 (d, 1H, J=8.0Hz), 8.07—8.09 (d, 1H, J=8.5Hz), 8.14 - 8.17 (d, 1H, J =8.8Hz) , 8.45 - 8.47 (d, 1H, J=8.8Hz), 8.64 (s,lH), 8.83 - 8.84 (dd, 2H ,

J ₂ = l.6 Hz), 12.45 (S, 1H).

Elemental analysis calculated: C 69.55% H 4.38% N 20.28% Found: C 69.54% H 4.31% N 19.95%. Example 42: N-(pyridin-4-yl)methylene-2-thiophene hydrazide The aromatic aldehyde used was 4-pyridinecarboxaldehyde (available from ACROS), and the aroylhydrazide was 2-thiophene hydrazide. The title compound was obtained as an off-white solid. Yield 7.93. 183-185° ( .

 EI-MS [M+]=231.8(m/e),

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 7.25 ― 7.26 (m, 1H), 7.69 - 7.73 (d, 2H) , 7.95 - 8.10 (m, 2H) , 8.42 (s,lH) , 8.67 ― 8.68 (d, 2H) , 12.15 (s, lH).

 Elemental analysis calculated: C 57.13% H 3.92% N 18.17% Found: C 57.03% H 3.81% N 18.16%. Example 43: N-(2-phenylindole-3-yl)methylene-2-pyridinecarboxhydrazide The aromatic aldehyde used was 2-phenyl-3-furfural according to the procedure of Example 1.2. Purchased from

ALDRICH), the aroyl hydrazide is 2-picolinylhydrazide, the title compound is obtained as a yellow solid, yield: 73.53%, m.p.: 234 - 237.

 EI-MS [M+]=340.2 (m/e),

'H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 7.17-7.28 (m,2H), 7.44 - 7.46 (d, 1H, J=7.8Hz), 7.50 - 7.53 (t, 1H, J= 7.6 Hz) , 7.58 - 7.66 (m, 3H), 7.70 - 7.72 (s, lH), 7.72 - 7.74 (m, 1H) , 8.02 - 8.07 (td, 1Ή, L-7.6HZ, J ₂ = l.7Hz ), 8.12 -8.14 (d, 1H, J=7.6Hz), 8.50 - 8.53 (d, 1H, J=7.6Hz), 8.68 - 8.70 (d, 1H, J=4.2Hz), 8.99 (s,lH) , 11.78 (s, lH), 12.05 (s, 1H).

 Elemental analysis calculated: C 74.10% H 4.74% N 16.46% Found: C 73.80% H 4.79% N 16.49%. Example 44: N-(Indolyl-5-yl)methylene-2-thiophene hydrazide

According to the method of Example 1.2, the aromatic aldehyde used is 5-furfural, and the aromatic hydrazide is 2- The thiophene hydrazide gave the title compound as a light red-white solid, yield 53.90%, mp.

 EI -MS [M+] = 269. l(m/e),

^J H-NMR (400MHz, DMS0-d ₆ ): δ (ppm) 6.51 (s,lH), 7.21 - 7.23 (t, 1H, J=4.8Hz) , 7.39 -7.40 (t, 1H, J=2.8Hz ), 7.48 ― 7.50 (ra, 1H), 7.60 - 8.50 (m, 5H), 11.30 (s, lH), 11.58 (s, 1H).

 Elemental analysis 弇 value: C 62.44% H 4.12% N 15.60% Found: C 62.32% H 4.11% N 15.60%. Example 45: Cell line (HPB-ALL cells) mixed lymphocyte culture (MTT method) The immunosuppressive effect of aroyl hydrazide compounds was investigated.

The normal passaged HPB-ALL cells were resuspended in 10% FCS 1640 medium (purchased from GIBC0) at a concentration of 5 X 107 ral, seeded in a 96-well flat bottom plate, 50 μl/well; normal passage The Daudi cells were resuspended in 1040 FCS in 1640 medium at a concentration of 2 x 107 ml. After irradiation with 30 Gy of "CO ray, inoculate the same 96-well flat bottom plate, 50 μl/well; The compound of the present invention to be screened by gradient dilution (Ιμιη, ΙΟμπι and ΙΟΟμιη) was added to each well, 10 μM/well, solvent control and positive control, cultured in a cell culture incubator at 5% CO ₂ , 37 ° C. For 48 hours, add MTT (5mg/ml) 10 μl per well, shake for 3 ~ 5 minutes, then set 5% C0 ₂ , continue to culture for 4-6 hours in 37 °C cell culture incubator, add 0.01N hydrochloric acid per well. 10% SDS 100μ 1, after shaking for 3 ~ 5 minutes, placed in a 5% C0 ₂ , 37 ° C cell culture incubator to continue to culture overnight, the next day on the enzyme-linked instrument to determine the optical density value of 570nm. According to the optical density value of the drug The inhibition rate of cell proliferation.

The inhibition rate of the drug on cell proliferation (%) = (average 0D of the solvent control group - the average 0D value of the administration group) / the average 0D value of the model control group. The results are shown in Figure 1. The results show that the compounds of the present invention exhibit better immunosuppressive effects. Example 46: Mixed lymphocyte culture of human peripheral blood (PBMC- MLR) investigated the immunosuppressive effects of the aromatic hydrazide compound ⁽³ H- TdR)

Take two human (blood donors and recipients) peripheral blood (taken from 301 hospital), dilute with sterile saline, and separate with human lymphocyte separation solution. Lymphocyte separation solution: diluted human peripheral Blood "1: 2, centrifugation, 2000 rpm, 20 minutes, draw the middle white membrane layer, the mononuclear cell (PBMC) layer, wash with 5 volumes of sterile physiological saline, centrifuge, 2000 rpm, 10 minutes, the precipitation After the hook, it was washed with sterile physiological saline, centrifuged, and centrifuged at 1500 rpm for 10 minutes. The pellet was resuspended in 1640 medium containing 10% human AB serum, adjusted to a concentration of 1 X 10 Vml, and one of them was used as a reaction cell. In a 96-well U-shaped plate, 100 μM/well; another part was used as a stimulating cell, irradiated with 30 Gy of CO ray, and seeded in the same 96-well U-shaped plate, 100 μM/well, while The compound of the present invention was added to each well by gradient dilution (Ιμιη, ΙΟμιη and ΙΟΟμπι), and the solvent control and the positive control were cultured in a 5% CO ₂ , 37 ° C cell culture chamber for 5 days, and then added - TdR (purchased in Beijing Atomic Energy). research 1 μ(η/well, continued culture for 12-16 hours, cells were collected, and ³ H-TdR incorporation rate (cpm) was determined. Then, the inhibition rate of the compound of the present invention was calculated. The results are shown in Fig. 2. The compounds of the invention are shown to exhibit good immunosuppressive effects.

Claims

Rights request A compound of formula I, or a geometric isomer thereof, or a pharmaceutically acceptable salt or hydrate thereof:

 among them: R1 is a hydrogen atom or a dC ₆ alkyl group; ^ and Ar ₂ are each independently selected from the group consisting of: 3-indenyl, 5-indenyl, 2-quinolinyl, 4-quinolinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2 -pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, pyrazolyl, 2-furyl, 3-furyl; the above groups are unsubstituted or substituted by 1 or 2 selected from Base substitution: halogen, nitro, hydroxy, trifluoromethyl, d-C ₆ alkyl, C-C ₆ alkoxy, d-Ce alkoxy, amino, carboxy, phenyl, benzyl, phenylsulfonyl . 2. A compound according to claim 1 wherein:  R1 is a hydrogen atom;  A is a substituted or unsubstituted 3-indenyl group or a 5-indenyl group, and the substituent is selected from the group consisting of a methoxy group, a methyl group, a methoxy group, a benzyl group, a phenyl group; Ar ₂ is a fixed base ¹¹ pyrazoline, 3-pyridyl, 4-pyridyl, 2-thienyl or 2-furyl. 3. A compound according to claim 1 wherein: R1 is a hydrogen atom; A is 2-leaf base or 4-leaf base; Ar ₂ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl or 2-furyl. 4. The compound of claim 1 wherein:  R1 is a hydrogen atom;  ^ is 2-pyridyl, 3-pyridyl, 4-pyridyl; Ar ₂ is a 3-indenyl group. 5. The compound of claim 1 wherein:  R1 is a hydrogen atom,  Is 2-thienyl, 4-methylthiophen-2-yl, 5-bromothiophen-2-yl, 2-pyrrolyl, 1-phenylsulfonylpyrrolidin-2-yl or 1-methylpyrrole-2-yl . Ar ₂ is a 3-pyridyl group or a 4-pyridyl group. 6. The compound of claim 1 wherein:  R1 is a hydrogen atom,  ^ is 1-phenyl-3,5-dimethylpyrazole-4-yl, Ar ₂ is 2-biting pyrazolyl group, 3-pyridyl, 4-pyrazolyl group given ^11, 2-Haji. 7. A compound according to claim 1 selected from the group consisting of the following compounds or geometric isomers thereof, or a pharmaceutically acceptable salt or hydrate thereof:  N-(indol-3-yl)methylene-3-pyridinylhydrazide,  N-(吲哚-3-yl)methylene-2-thiophene hydrazide,  N-(5-methoxyindol-3-yl)methylene-2-thiophenehydrazide, N-(5-decyloxy-3-yl)methylene-4-pyridinecarboxhydrazide, N-(5-methoxyindol-3-yl)methylene-3-pyridineformylhydrazide,  N-(l-phenyl-3,5-dimethylpyrazol-4-yl)methylene-3-pyridine N-(1-methylindol-3-yl)methylene-4-pyridinecarboxhydrazide,  N-(indol-3-yl)methylene-2-furoyl hydrazide,  N-(2-methylindole-3-yl)methylene-4-pyridineformylhydrazide,  N-(2-methylindol-3-yl)methylene-2-thiophene hydrazide,  N-(2-methylindole-3-yl)methylene-2-furoylhydrazide,  N-(quinolin-2-yl)methylene-2-thiophene hydrazide,  N-(indol-3-yl)methylene-2-pyridineformylhydrazide,  N-(5-methoxyindol-3-yl)methylene-2-pyridineformylhydrazide,  N-(quinolin-4-yl)methylene-4-pyridineformylhydrazide,  N-(quinolin-4-yl)methylene-2-thiophene hydrazide,  N-(quinolin-4-yl)methylene-2-furoylhydrazide,  N-(quinoline-4-yl)methylene-3-pyridine formyl hydrazide,  N-(pyrrol-2-yl)methylene-4-pyridineformylhydrazide,  N-(pyrrol-2-yl)methylene-3-pyridine formyl hydrazide,  N-(3-methylthiophen-2-yl)methylene-3-pyridine forminide,  N-(1-methylpyrrol-2-yl)methylene-3-pyridineformylhydrazide,  N-(1-benzenesulfonylpyrrole-2-yl)methylene-3-pyridineformylhydrazide, N-(4-bromothiophen-2-yl)methylene 3-pyridinium hydrazide,  N-(pyridin-3-yl)methylene-3-indole hydrazide,  N-(pyridin-4-yl)methylene-3-mercaptohydrazide,  N-(pyridin-4-yl)ethylidene-3-mercaptohydrazide,  N-(pyridin-3-yl)methylene-3-mercaptohydrazide,  N-(l-benzylindol-3-yl)methylene-3-pyridineformylhydrazide, N-(1-decyloxyindol-3-yl)methylene-2-thiophene hydrazide, N-(l-methoxyxyin-3-yl)methylene-3-hydrazyl hydrazide,  N-(l-methoxyxoindol-3-yl)methylene-3-pyridineformylhydrazide,  N-(pyridin-2-yl)methylene- 3-oxime formyl hydrazide,  N-(thiophen-2-yl)methylene-3-carboyl formyl hydrazide,  N-(pyridin-4-yl)methylene-1-methoxyxy-3-oxohydrazide,  N-(1-benzylindol-3-yl)methylene-4-pyridinylhydrazide,  N-(吲哚-5-yl)methylene-4-pyridylhydrazide,  N-(1-benzylindol-3-yl)methylene-2-thiophene hydrazide,  N-(2-phenylindol-3-yl)methylene-4-pyridineformylhydrazide,  N-(2-phenylindole-3-yl)methylene-2-pyridinecarbazide,  N-(1-phenyl-3,5-dimethylpy-4-yl)arylene-3-oxohydrazide, N-(吲哚-5-yl)methylene-2-thiophene hydrazide,  N-(quinolin-2-yl)methylene-4-pyridylhydrazide, and  N-(pyridin-4-yl)methylene-2-thioformylhydrazide. 8. A method of preparing a compound of formula I, the method comprising  The aryl aldehyde or aryl ketone of the formula IV is reacted with an aryl hydrazide of the formula V in a hydrazine or ether solvent at 0 to 100 ° C,

Wherein, the definition of human and Ar _{2 is} the same as claim 1. 9. A compound as claimed in any one of claims 1 to 7, or a geometric isomer thereof, or a pharmaceutically acceptable salt or hydrate thereof, for use in the preparation of a medicament for the prevention or treatment of rejection and/or autoimmune diseases in organ transplantation the use of. 10. The use of claim 9, wherein the autoimmune disease is multiple sclerosis, lupus erythematosus syndrome, psoriasis or rheumatoid.