CN103408540B - 2-azoles ring substituted thiophene class PLK1 inhibitor and uses thereof and uses thereof - Google Patents

Abstract

The present invention relates to the field of medicinal chemistry, in particular to 2-azole ring substituted thiophene PLK1 inhibitors, their preparation methods, pharmaceutical compositions containing these compounds and their medical applications, especially as Polo-like kinase 1 (Polo-like (?kinase1, PLK1) inhibitors.

Description

2-oxazole ring substituted thiophene PLK1 inhibitors and their uses and uses

technical field

The present invention relates to the field of medicinal chemistry, in particular to 2-oxazole ring substituted thiophene PLK1 inhibitors, their preparation methods, pharmaceutical compositions containing these compounds and their medical applications, especially as Polo-like kinase 1 (Polo-like kinase 1 , use of a PLK1) inhibitor.

Background technique

Tumor is a kind of disease characterized by uncontrolled cell growth and proliferation. Abnormalities in cell proliferation, differentiation and apoptosis are all involved in the occurrence and development of tumors. Cell cycle disorder is the main mechanism of tumorigenesis. In the entire regulatory network of the cell cycle, various molecular abnormalities may cause tumors. The frequency of tumor cell division is faster than that of normal cells, and various proteins that regulate microtubule polymerization, centrosome duplication, spindle formation, and cytokinesis are often overexpressed and their activities are enhanced.

An important class of traditional anti-tumor chemotherapy drugs is to act on tubulin to polymerize or depolymerize tubulin, thereby achieving the purpose of interfering with tumor cell division and inhibiting tumor growth, such as vinblastine drugs widely used in clinical practice and paclitaxel drugs. However, tubulin also plays an extremely important role in normal cells and participates in synaptic signal transduction, so traditional tubulin disruptors have relatively large toxic and side effects, such as paclitaxel has obvious toxicity to the peripheral nervous system, and in addition Their ADME properties are also less than ideal. Therefore, people turn their attention to specific proteins that are overexpressed in tumor cells and can regulate the function of tubulin and affect the function of the spindle, such as KSP (kinesinspindleprotein), Aurora kinases, Polo-like kinases (polo-likekinases, PLKs) , CENPE (centromericproteinE), etc., hoping to specifically and efficiently affect the functions of microtubules and spindles in tumor cells, while not interfering with the morphology and function of tubulin in normal cells, thereby reducing the side effects of drugs.

Inhibition of disease-related protein kinases can be achieved through a variety of methods, but because synthetic antisense oligonucleotides are vulnerable to ribozyme attack and degradation, RNA interference technology has problems such as safety, stability and off-target effects, so Researchers began to try to chemical small molecule inhibitors from organically synthesized chemical small molecules or natural products. The conserved serine/threonine kinase PLK has received great attention, and it mainly focuses on the strategy of using the ATP pocket and PDB phosphopeptide binding domain as the binding domain of small molecule compounds, and many inhibitors have come out. Among them, kinase domain inhibitors mainly include dihydropteridones (BI2536, BI6727), benzylstyrene sulfones (ON01910), thiophenes (GSK461364), N-hetero-stilbenes (HMN-176, HMN- 214), 2-aminoaromatic heterocycles, 4,5-dihydro-1H-quinazoline[4,3-h]pyrazoles (NMS-P937), benzocaprolactams, benzodiazepines miscellaneous (RO3280, TAK-960), β-carbolines; PBD is far away from the catalytic region, which can avoid the accumulation of structural variation in the ATP region of tumor cells due to competition with ATP and lead to problems such as drug resistance and cross-action. This direction is currently It mainly includes small molecule inhibitors such as thymoquinone and some peptide or peptide-like inhibitors.

In recent years, the research on anti-tumor drugs has been advancing rapidly. A large number of new technologies such as the advancement of molecular biology and computer-aided drug design, as well as the development of automated high-speed drug screening systems have made it easier for humans to understand the mode of drug action, which is very useful for drug development. big help. As a mitosis-related kinase, PLK1 has received extensive attention, and it plays a vital role in the smooth progress of the cell cycle and the regulation of cycle-related checkpoints. Targeting PLK1 and finding anti-tumor drugs with definite curative effects from gene and protein levels will become a new breakthrough point in tumor treatment.

Contents of the invention

Based on the research of a large number of selective PLK1 small molecule inhibitors, and according to the crystal structure model of PLK1, the present invention designs and synthesizes a series of compounds with a new structure with 2-oxazole ring substituted for thiophene as the core.

The purpose of the present invention is to provide a class of small molecule organic compounds or pharmaceutically acceptable salts thereof with PLK1 inhibitory activity. It includes acid addition salts formed by compounds of general formula I with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, Pyruvate, acetic acid, maleic or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid. In addition, acid salts of inorganic bases are also included, such as: salts containing alkaline metal cations, alkaline earth metal cations, and ammonium cations.

Another object of the present invention is to provide the preparation method of the above compound.

Another object of the present invention is to provide a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide the medical application of the above-mentioned compound or its pharmaceutically acceptable salt and its pharmaceutical composition, especially in the prevention, delay or treatment of diseases mediated by PLK1 alone or both, especially Use in medicine for tumors.

To achieve the above object, the present invention provides a compound having a structure represented by general formula (I) or a pharmaceutically acceptable salt thereof:

Wherein, R ₁ represents -H, cyano group, amide group; R ₂ represents -H, cyano group, amide group.

Wherein, X represents O, N or -NH-; Y represents O, S or -CH-.

Wherein, R ₃ represents -H, methoxy or trifluoromethoxy.

Wherein, R ₄ and R ₅ independently represent hydrogen, piperidine-4-amino, 1-methylpiperidin-4-amino, 3-morpholinopropylamino, piperazinyl, 4-methylpiperazine-1 -yl, 4-(pyrrolidin-1-yl) butylamino, 3-diethylaminopropylamino, 3-methoxypropylamino; or independently

Compounds of general formula I are preferably compounds of the following structure:

5-{5-[4-(4-Methylpiperidin-1-yl)anilino]-1H-pyrazol-3-yl}thiophene-2-carbonitrile (I-1)

5-{5-[4-(N-aminopiperidin-1-ylamino)anilino]-1H-pyrazol-3-yl}thiophene-2-carbonitrile (I-2)

5-{5-[4-(3-(Diethylamino)propylamino)anilino]-1H-pyrazol-3-yl}thiophene-2-carbonitrile (I-3)

5-{5-[4-(3-morpholinopropylamino)anilino]-1H-pyrazol-3-yl}thiophene-2-carbonitrile (I-4)

5-{5-[2-Methoxy-4-(4-methylpiperidin-1-yl)anilino]-1H-pyrazol-3-yl}thiophene-2-carbonitrile (I-5)

5-{5-[2-Methoxy-4-(N-aminopiperidin-1-ylamino)anilino]-1H-pyrazol-3-yl}thiophene-2-carbonitrile (I-6)

5-{5-[2-methoxy-4-(3-(diethylamino)propylamino)anilino]-1H-pyrazol-3-yl}thiophene-2-carbonitrile (I-7)

5-{5-[2-Methoxy-4-(3-morpholinopropylamino)anilino]-1H-pyrazol-3-yl}thiophene-2-carbonitrile (I-8)

5-{5-[4-(4-methylpiperidine-1carbonyl)anilino]-1H-pyrazol-3-yl}thiophene-2-carbonitrile (I-9)

4-{[3-(5-cyanothiophen-2-yl)-1H-pyrazol-5-yl]amino}-N-(1-methylpiperidin-4-yl)benzamide (I- 10)

4-{[3-(5-cyanothiophen-2-yl)-1H-pyrazol-5-yl]amino}-N-[3-(diethylamino)propyl]benzamide (I- 11)

4-{[3-(5-cyanothiophen-2-yl)-1H-pyrazol-5-yl]amino}-N-[3morpholinopropyl]benzamide (I-12)

5-{5-[4-(4-methylpiperidin-1-yl)anilino]-1H-pyrazol-3-yl}thiophene-2-carboxamide (I-13)

5-{5-[4-(1-Methylpiperidin-4-ylamino)anilino]-1H-pyrazol-3-yl}thiophene-2-carboxamide (I-14)

5-{5-[4-(3-(Diethylamino)propylamino)anilino]-1H-pyrazol-3-yl}thiophene-2-carboxamide (I-15)

5-{5-[4-(3-morpholinylamino)anilino]-1H-pyrazol-3-yl}thiophene-2-carboxamide (I-16)

5-{5-[2-Methoxy-4-(4-methylpiperazin-1-yl)anilino]-1H-pyrazol-3-yl}thiophene-2-carboxamide (I-17)

5-{5-[2-methoxy-4-(1-methylpiperidin-4-ylamino)anilino]-1H-pyrazol-3-yl}thiophene-2-carboxamide (I-18 )

5-{5-[2-Methoxy-4-(3-(diethylamino)propylamino)anilino]-1H-pyrazol-3-yl}thiophene-2-carboxamide (I-19)

5-{5-[2-Methoxy-4-(3-morpholinylamino)anilino]-1H-pyrazol-3-yl}thiophene-2-carboxamide (I-20)

5-{5-[4-(4-Methylpiperazine-1-carbonyl)anilino]-1H-pyrazol-3-yl}thiophene-2-carboxamide (I-21)

5-{5-[4-(1-Methylpiperidin-4-ylcarbamoyl)anilino]-1H-pyrazol-3-yl}thiophene-2-carboxamide (I-22)

5-{5-[4-(3-(Diethylamino)propylaminocarbonyl)anilino]-1H-pyrazol-3-yl}thiophene-2-carboxamide (I-23)

5-{5-[4-(3-Morpholinopropylaminocarbonyl)anilino]-1H-pyrazol-3-yl}thiophene-2-carboxamide (I-24)

5-{5-[4-(4-Methylpiperazin-1-yl)anilino]isoxazol-3-yl}thiophene-2-carbonitrile (I-25)

5-{5-[4-(1-Methylpiperidin-4-ylamino)anilino]isoxazol-3-yl}thiophene-2-carbonitrile (I-26)

5-{5-[4-(3-(Diethylamino)-4-ylamino)anilino]isoxazol-3-yl}thiophene-2-carbonitrile (I-27)

5-{5-[4-(3-morpholinylamino)anilino]isoxazol-3-yl}thiophene-2-carbonitrile (I-28)

5-{5-[4-(4-Methylpiperazine-1-carbonyl)anilino]isoxazol-3-yl}thiophene-2-carbonitrile (I-29)

4-[3-(5-cyanothiophen-2-yl)isoxazol-5-ylamino]-N-(1-methylpiperidin-4-yl)benzamide (I-30)

4-[3-(5-cyanothiophen-2-yl)isoxazol-5-ylamino]-N-[(3-diethylamino)propyl]benzamide (I-31)

4-[3-(5-cyanothiophen-2-yl)isoxazol-5-ylamino]-N-(3-morpholinopropyl)benzamide (I-32)

5-{5-[4-(4-Methylpiperazin-1-yl)anilino]isoxazol-3-yl}thiophene-2-carboxamide (I-33)

5-{5-[4-(1-Methylpiperidin-4-ylamino)anilino]isoxazol-3-yl}thiophene-2-carboxamide (I-34)

5-{5-[4-(3-(Diethylamino)-4-ylamino)anilino]isoxazol-3-yl}thiophene-2-carboxamide (I-35)

5-{5-[4-(3-morpholinylamino)anilino]isoxazol-3-yl}thiophene-2-carboxamide (I-36)

5-{5-[2-Methoxy-4-(4-methylpiperazin-1-yl)anilino]isoxazol-3-yl}thiophene-2-carboxamide (I-37)

5-{5-[2-Methoxy-4-(1-methylpiperidin-4-ylamino)anilino]isoxazol-3-yl}thiophene-2-carboxamide (I-38)

5-{5-[2-methoxy-4-(3-(diethylamino)-4-ylamino)anilino]isoxazol-3-yl}thiophene-2-carboxamide (I-39 )

5-{5-[2-Methoxy-4-(3-morpholinylamino)anilino]isoxazol-3-yl}thiophene-2-carboxamide (I-40)

5-{5-[4-(4-methylpiperazine-1-carbonyl)anilino]isoxazol-3-yl}thiophene-2-carboxamide (I-41)

5-{5-[4-(1-Methylpiperidin-4-ylcarbamoyl)anilino]isoxazol-3-yl}thiophene-2-carboxamide (I-42)

5-{5-[4-(3-(Diethylamino)propylcarbamoyl)anilino]isoxazol-3-yl}thiophene-2-carboxamide (I-43)

5-{5-[4-(3-morpholinopropylcarbamoyl)anilino]isoxazol-3-yl}thiophene-2-carboxamide (I-44)

5-{5-[2-Methoxy-4-(4-methylpiperazine-1-carbonyl)anilino]isoxazol-3-yl}thiophene-2-carboxamide (I-45)

5-{5-[[2-methoxy-4-(1-methylpiperidin-4-ylcarbamoyl)anilino]isoxazol-3-yl}thiophene-2-carboxamide (I- 46)

5-{5-[[2-methoxy-4-(3-(diethylamino)propylcarbamoyl)anilino]isoxazol-3-yl}thiophene-2-carboxamide (I- 47)

5-{5-[[2-methoxy-4-(3-morpholinopropylcarbamoyl)anilino]isoxazol-3-yl}thiophene-2-carboxamide (I-48)

5-{5-[4-(4-methylpiperazin-1-yl)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carbonitrile (I-49)

5-{5-[4-(1-methylpiperidin-4-ylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carbonitrile (I-50)

5-{5-[4-(3-(Diethylamino)propylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carbonitrile (I-51)

5-{5-[4-(3-morpholinopropylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carbonitrile (I-52)

5-{5-[4-(4-Methylpiperazin-1-yl)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carboxamide (I-53)

5-{5-[4-(1-methylpiperidin-4-ylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carboxamide (I-54)

5-{5-[4-(3-(Diethylamino)propylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carboxamide (I-55)

5-{5-[4-(3-morpholinopropylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carboxamide (I-56)

5-{5-[3-(4-methylpiperazin-1-yl)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carbonitrile (I-57)

5-{5-[3-(1-methylpiperidin-4-ylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carbonitrile (I-58)

5-{5-[3-(3-(Diethylamino)propylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carbonitrile (I-59)

5-{5-[3-(3-morpholinopropylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carbonitrile (I-60)

5-{5-[3-(4-Methylpiperazin-1-yl)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carboxamide (I-61)

5-{5-[3-(1-methylpiperidin-4-ylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carboxamide (I-62)

5-{5-[3-(3-(Diethylamino)propylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carboxamide (I-63)

5-{5-[3-(3-morpholinopropylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carboxamide (I-64)

5-{5-[4-(4-methylpiperazin-1-yl)anilino]-1,3,4-thiadiazol-2-yl}thiophene-3-carbonitrile (I-65)

5-{5-[4-(1-methylpiperidin-1-ylamino)anilino]-1,3,4-thiadiazol-2-yl}thiophene-3-carbonitrile (I-66)

5-{5-[4-(3-(Diethylamino)propylamino)anilino]-1,3,4-thiadiazol-2-yl}thiophene-3-carbonitrile (I-67)

5-{5-[4-(3-morpholinopropylamino)anilino]-1,3,4-thiadiazol-2-yl}thiophene-3-carbonitrile (I-68)

5-{5-[4-(4-methylpiperazin-1-yl)anilino]-1,3,4-thiadiazol-2-yl}thiophene-3-carboxamide (I-69)

5-{5-[4-(1-methylpiperidin-1-ylamino)anilino]-1,3,4-thiadiazol-2-yl}thiophene-3-carboxamide (I-70)

5-{5-[4-(3-(Diethylamino)propylamino)anilino]-1,3,4-thiadiazol-2-yl}thiophene-3-carboxamide (I-71)

5-{5-[4-(3-morpholinopropylamino)anilino]-1,3,4-thiadiazol-2-yl}thiophene-3-carboxamide (I-72)

5-{5-[4-(4-methylpiperazine-1-carbonyl)anilino]-1,3,4-thiadiazol-2-yl}thiophene-3-carboxamide (I-73)

5-{5-[4-(1-methylpiperidin-4-ylcarbamoyl)anilino]-1,3,4-thiadiazol-2-yl}thiophene-3-carboxamide (I- 74)

5-{5-[4-(3-(Diethylamino)propylcarbamoyl)anilino]-1,3,4-thiadiazol-2-yl}thiophene-3-carboxamide (I- 75)

5-{5-[4-(3-morpholinopropylcarbamoyl)anilino]-1,3,4-thiadiazol-2-yl}thiophene-3-carboxamide (I-76)

The preparation method of some compounds of the present invention is as follows:

method one

ents and conditions:

(i) Br ₂ , AlCl ₃ , CCl ₄ , -30°C→rt; (ii) CuCN, reflux, 5h; (iii) 1-methylpiperazine, TEA, N,N-dimethylaniline, 3.5h; (iv) H ₂ , Pd/C, rt, overnight; (v) CSCl ₂ , DCM, NaHCO ₃ , H ₂ O, 0°C; (vi) NaH, THF, Reflux; (vii) NH ₂ NH _{2 ·} H ₂ O, EtOH, Reflux, 3h; (viii) NaOH, 30% H ₂ O ₂ , EtOH, DMSO, 80°C, 12h.

Method Two

Reagents and conditions:

(i) SOCl ₂ , MeOH, reflux, 2h; (ii) CuCN, reflux, 5h; (iii) NH ₂ NH _{2 ·} H ₂ O, EtOH, 50°C, 3h; (iv) 1-methylpiperazine, TEA, N _{( _ _ _} viii) Hg(OAc) ₂ , EtOH, reflux; (ix) NaOH, 30% H ₂ O ₂ , EtOH, DMSO, 80°C, 12h.

The compounds of the present invention can be prepared by the above-mentioned or similar preparation methods, and the corresponding raw materials can be selected according to the difference of the substituent and the position of the substituent.

The results of biological activity test show that the compound of general formula I and the pharmaceutically acceptable salt thereof provided by the present invention have PLK1 inhibitory effect, and at the same time have a certain inhibitory effect on the growth of tumor cell lines. The compounds of the present invention are useful in the treatment of various solid organ cancers, including melanoma, liver cancer, kidney cancer, lung cancer, prostate cancer, thyroid cancer, skin cancer, colorectal cancer, pancreatic cancer, ovarian cancer, breast cancer, testicular cancer, bone Cancer, brain cancer, esophageal cancer, gastrointestinal cancer, soft tissue tumor, blood cancer, lymphatic cancer, etc., among them, it may be a cancer mediated by PLK1, or a cancer that does not depend on the above-mentioned mechanism. Therefore, the present invention proposes that the compounds of the present invention and their pharmaceutically acceptable salts can be used in the preparation of anticancer drugs.

The pharmacological tests of some compounds are as follows:

1. PLK1 inhibitory activity test

IExperimental material

PLK1 (Invitrogen, USA), Z-lyteSer/Thr16Phospho-peptide (Invitrogen, USA), 5×kinasebuffer (Invitrogen, USA), ATP (Invitrogen, USA), DevelopmentReagentA (Invitrogen, USA), DevelopmentBuffer (Invitrogen, USA), StopReagent (Invitrogen, USA), 384-well black microplate (Corning, USA).

IIExperimental steps

Add 2.5 μL compound solution to each well, and then add 5 μL 2× substrate and 2× ATP mixed solution to each well. At the same time, add 5 μL buffer, 5 μL 2× substrate and 2×ATP mixture as 0% phosphorylation control, add 5 μL buffer, 5 μL 2× phosphopeptide solution (100% phosphorylation control) as 100% phosphorylation and 0% inhibition as control. Shake the plate for 30 seconds and incubate at room temperature (20-25°C) for 1 hour. Add 5 μL of DevelopmentSolution to each well, shake the plate for 30 seconds, and incubate at room temperature (20-25° C.) for 1 hour. Add 5 μL StopReagent to each well, shake the plate for 30 seconds, and stop the reaction. The wavelength of the excitation light is 400nm, and the plate is read at λem=445nm and 520nm respectively, and the inhibition rate is calculated (n=3).

Part III Experimental Results

2. In vitro tumor cell inhibitory activity test

Inhibitory activity of the compound of the present invention on tumor cell lines in vitro.

IExperimental material

96-well cell culture plate (Corning, USA), T25 cell culture flask (Corning, USA), T75 cell culture flask (Corning, USA), centrifuge tube (Corning, USA), pipette (Corning, USA) Dye (Invitrogen, USA), 3% SDS phosphate buffer (Invitrogen, USA), 384-well black-walled culture plate (Corning, USA), tip (Axygen, USA), Multidrop sampler (Thermo, USA), Janus liquid handling system (Perkinelmer, USA), Safire2 full-wavelength microplate reader (Tecan, Switzerland).

IIExperimental steps

Cells were treated with test compound for 24-72 hours before detection, Add it to the cell culture medium according to the ten-fold dilution ratio, and incubate for 1-4 hours in the dark at 5% CO ₂ and 37°C. Fluorescence values were detected by a full-wavelength microplate reader (Safire2, Switzerland), with instrument settings: excitation light wavelength (excitaion) = 540 nm, emission light wavelength (emission) = 585 nm. Prism5.0 (GraphpadSoftware, USA) statistical analysis software was used to calculate the inhibitory rate and _IC50 value of the compound.

The activity data of some compounds on the human leukemia cell line HL60 is shown in the following table:

(The compound codes in the table correspond to the preceding compound codes)

detailed description

The melting point was measured with a b-shaped melting point tube, the medium was methyl silicone oil, and the thermometer was not calibrated; ¹ HNMR was completed with a JEOLFX90Q Fourier transform nuclear magnetic resonance instrument, a BRUKERACF-300 nuclear magnetic resonance instrument and a BRUKERAM-500 nuclear magnetic resonance instrument (TMS internal standard) ; MS was determined by Nicolet2000 Fourier transform mass spectrometer and MAT-212 mass spectrometer.

Example 1

2-Acetyl-4-bromothiophene (M-1)

Add 3.00g (23.81mmol) of 2-acetylthiophene, 9.53g (71.43mmol) of anhydrous aluminum chloride and 80ml of carbon tetrachloride into a 250ml single-necked bottle, cool to -40°C, and slowly add liquid bromine dropwise after stabilizing for 10min 3.81g (23.81mmol) of carbon tetrachloride solution (20ml), after 0.5h of dripping, stirred at room temperature. After 12h, TLC showed that no starting material remained. The reaction system was poured into a mixture of saturated NaOH solution and crushed ice, extracted with ethyl acetate (75ml×3), the organic phases were combined, washed twice with saturated brine, and dried over anhydrous MgSO ₄ . The column layer (PE:EA=500:1) was concentrated under reduced pressure to obtain 2.74 g of light yellow oily liquid with a yield of 72.6%.

¹ HNMR (300MHzDMSO-d ₆ ) δ: 7.65 (1H, d, ArH), 6.91 (1H, d, ArH), 2.57 (3H, s, -COC H ₃ ).MS[M+H] ⁺ 205.2, 207.1 .

Example 2

2-Acetyl-4-cyanothiophene (M-2)

Add M-10.5g (2.45mmol), cuprous cyanide 0.66g (3.68mmol), potassium iodide 0.04g (0.245mmol) and anhydrous DMF10ml into a 100ml pressure tube. The temperature was raised to 190° C. under the protection of an inert gas. After 3 hours, TLC showed that there was no remaining raw material. The reaction system was poured into a mixture of ammonia water and crushed ice, extracted with ethyl acetate (20ml×3), the organic phases were combined, washed twice with saturated brine, dried over anhydrous MgSO ₄ , concentrated under reduced pressure and column chromatography (PE: EA=100:1), 0.23 g of light yellow solid was obtained, yield 62.2%. mp.112～114℃ (literature mp.111～113℃).

Example 3

1-Methyl-4-(4-nitrophenyl)piperidine (M-3)

Add 1.41g (10.00mmol) of p-fluoronitrobenzene, 1.01g (10.00mmol) of 1-methylpiperazine, 1.01g (10.00mmol) of triethylamine and 25ml of anhydrous DMF into a 50ml single-necked bottle, react at room temperature for 24h Post-TLC showed no starting material remaining. The solvent was evaporated under reduced pressure, ice water was added, the pH was adjusted to 8 with saturated sodium carbonate solution, extracted with ethyl acetate (40ml×3), the organic phases were combined, washed twice with saturated brine, and dried over anhydrous MgSO ₄ . After concentration under reduced pressure, column chromatography (PE:EA=1:1) gave 1.38 g of orange-yellow needle-like crystals, yield 85.3%, mp.35-38°C.

MS[M+H] ⁺ 222.3.

Example 4

4-(4-Methylpiperidine)aniline (M-4)

Add 0.60g (0.27mmol) of M-3, 0.46g (1.34mmol) of ammonium chloride and 25ml of 70% ethanol into a 50ml single-necked bottle, stir evenly, add 0.46g (0.80mmol) of reduced iron powder in batches, and heat to reflux. After 5 h, TLC showed that no starting material remained. Suction filtration while hot, evaporate the filtrate under reduced pressure, add water, extract with ethyl acetate (15ml×3), combine the organic phases, wash twice with saturated brine, and dry over anhydrous MgSO ₄ . After concentration under reduced pressure, column chromatography (PE:EA=1:1) gave 0.47 g of a light brown liquid with a yield of 91.1%.

MS[M+H] ⁺ 192.3.

Example 5

1-(4-thiocyanophenyl)-4-methylpiperidine (M-5)

Add 1.20g (14.28mmol) of sodium bicarbonate and 10ml of water into a 50ml single-necked bottle, stir for 10min under ice bath conditions, then slowly add 0.40g (2.65mmol) of M-4 in dichloromethane solution (10ml) into the single-necked bottle , and finally 0.58g (3.97mmol) of thiophosgene in dichloromethane solution (10ml) was slowly dropped into a single-necked bottle for 0.5h, and after 4h, TLC showed that no raw material remained. Extracted with dichloromethane (20ml×7), combined the organic phases, washed twice with saturated brine, and dried over anhydrous MgSO ₄ . Concentrate under reduced pressure to remove the solvent, then recrystallize from petroleum ether to obtain 0.34 g of white solid, yield 87.3%, mp.73-75°C.

MS[M+H] ⁺ 234.1, MS[MH] ^- 232.2.

Example 6

3-(4-cyanothiophen-2-yl)-N-(4-(4-methylpiperidin-1-yl)phenyl)-3-oxopropanesulfamide (M-6)

Under the condition of ice bath, add M-50.54g (2.65mmol), sodium hydride 0.16g (3.98mmol) and anhydrous tetrahydrofuran 25ml into a 100ml single-necked bottle, after stirring for 10min, slowly drop into M-5 (2.65mmol) Tetrahydrofuran solution (5ml) was reacted at room temperature. After 3 h, TLC showed that no starting material remained. The solvent was distilled off under reduced pressure, ice water was added, and the pH was adjusted to 7-8 with glacial acetic acid. A solid precipitated, filtered with suction, and dried to obtain 0.8 g of an orange-yellow solid, yield 69.1%, mp.121-125°C.

Example 7

5-{5-[4-(4-Methylpiperidin-1-yl)anilino]-1H-pyrazol-3-yl}thiophene-2-carbonitrile (I-1)

Add 0.25g (0.57mmol) of M-6, 40mg (0.68mmol) of hydrazine hydrate and 25ml of absolute ethanol to a 100ml single-necked bottle, and react under reflux. After 6h, TLC shows that there is no remaining raw material. Evaporate the solvent under reduced pressure, add water, adjust the pH to 9-10 with triethylamine solution, extract with ethyl acetate (40ml×3), combine the organic phases, wash twice with saturated brine, dry over anhydrous _MgSO4 , and After concentration under pressure, column chromatography (DCM:MeOH=20:1) gave 90 mg of light yellow solid, yield 37.8%, mp.137-139°C.

¹ H-NMR (300MHzDMSO-d ₆ ) δ: 12.39-12.15 (1H, d, -NH-, Pyrazole), 8.10-8.03 (1H, d, -NH-), 7.22 (3H, s, ArH), 6.85 -6.82 (3H, br.s, ArH), 6.12-5.99 (1H, d, Pyrazo-le), 3.31-2.43 (8H, m, piperazine), 2.21 (3H, m, -N-CH3).MS[ M+H] ⁺ 365.1, MS[MH] ^- 363.2.

Example 8

5-{5-[4-(N-aminopiperidin-1-ylamino)anilino]-1H-pyrazol-3-yl}thiophene-2-carbonitrile (I-2)

The preparation method was similar to (I-1), and 100 mg of the sample was obtained with a yield of 33.5%. mp: 134-136°C.

¹ H-NMR (300MHzDMSO-d ₆ ) δ: 12.66-12.34 (1H, d, -NH-, Pyrazole), 8.21-8.13 (1H, d, -NH-), 7.30 (3H, s, ArH), 7.02 -6.91 (3H, br.s, ArH), 6.80-6.71 (1H, d, -N H -CH-), 6.29-6.27 (1H, dPyrazole), 3.72-3.74 (1H, m, -CH-N H -), 2.73-2.72 (2H, d, piperidin), 2.19-2.06 (3H, s, -NC H ₃ ), 2.06-2.05 (2H, d, piperidin), 1.90-1.87 (2H, m, piperidin), 1.49-1.48 (2H, m, piperidin). MS[M+H] ⁺ 379.1, 401.3.

Example 9

5-{5-[4-(3-(Diethylamino)propylamino)anilino]-1H-pyrazol-3-yl}thiophene-2-carbonitrile (I-3)

The preparation method was similar to (I-1), and 28 mg of the sample was obtained with a yield of 23.2%. mp: 139-142°C.

¹ H-NMR (300MHzDMSO-d ₆ ) δ: 12.46-12.44 (1H, d, -NH-, Pyrazole), 9.21-9.13 (1H, d, -NH-), 7.51 (3H, s, ArH), 6.72 -6.41 (3H, br.s, ArH), 6.30-6.29 (1H, m, -N H -CH ₂ -), 6.21-6.20 (1H, d, Pyrazole), 3.12-3.04 (2H, m, -C H ₂ -NH-), 2.53-2.52 (6H, m, -CH ₂ -N-), 1.65-1.56 ( 2H , m, -CH ₂ -CH ₂ -CH ₂ ), 0.98-0.93 (6H, t, _-CH2 - CH3 ₎ . MS [M+H] ⁺ 395.4, MS [MH] ^- 393.2.

Example 10

5-{5-[4-(3-morpholinopropylamino)anilino]-1H-pyrazol-3-yl}thiophene-2-carbonitrile (I-4)

The preparation method was similar to (I-1), and 61 mg of the sample was obtained with a yield of 33.4%. mp: 142-145°C.

¹ H-NMR (300MHzDMSO-d ₆ ) δ: 12.36-12.32 (1H, d, -NH-, Pyrazole), 9.61-9.53 (1H, d, -NH-), 7.61 (3H, s, ArH), 7.02 -6.91 (3H, br.s, ArH), 6.43-6.39 (1H, m, -N H -CH ₂ -), 6.31-6.26 (1H, d, Pyrazole), 3.78-3.74 (4H, m, -C H ₂ -OC H ₂ -), 3.33-3.21 (2H, m, -CH ₂ -NH- ), 2.35-2.30 (6H, m, -CH ₂ -N-), 1.73-1.66 ( 2H , m , _-CH2 - _CH2 - CH2 ₎ . MS[M+H] ⁺ 409.2, MS[MH] ^- 407.3.

Example 11

Methyl 4-bromo-2-thiophenecarboxylate (M-7)

Add 2.07g (10mmol) of 4-bromo-2-thiophenecarboxylic acid, 1.19g (10mmol) of thionyl chloride and 25ml of absolute ethanol into a 100ml single-necked bottle, and react under reflux. After 6h, TLC shows that no raw materials remain. Distill the solvent off under reduced pressure, add ice water, adjust the pH to 9-10 with saturated sodium carbonate solution, extract with ethyl acetate (40ml×3), combine the organic phases, wash twice with saturated brine, and dry over anhydrous _MgSO4 . Obtained 2.02 g of light yellow oily liquid with a yield of 91.4%.

MS[M+H] ⁺ 221.02, 223.13.

Example 12

Methyl 4-cyano-2-thiophenecarboxylate (M-8)

Add 2.21g (10mmol) of M-7, 5.3g (30mmol) of cuprous cyanide, 0.16g (1mmol) of potassium iodide and 6ml of anhydrous DMF into a 60ml pressure-resistant tube. The temperature was raised to 190° C. under the protection of an inert gas. After 4 hours, TLC showed that there was no remaining raw material. The reaction system was poured into a mixture of ammonia water and crushed ice, extracted with ethyl acetate (20ml×3), the organic phases were combined, washed twice with saturated brine, dried over anhydrous MgSO ₄ , concentrated under reduced pressure and column chromatography (PE: EA=80:1), 0.95 g of white solid was obtained, and the yield was 56.8%.

MS[M+H] ⁺ 168.11, MS[MH] ^- 166.20.

Example 13

4-Nitrino-2-thienylhydrazide (M-9)

Add 1.67g (10mmol) of M-8, 1.19g (10mmol) of hydrazine hydrate and 25ml of absolute ethanol to a 100ml single-necked bottle, and react at 45°C. After 10h, TLC shows that no raw materials remain. The solvent was distilled off under reduced pressure and recrystallized from 95% ethanol to obtain 1.45 g of white crystals with a yield of 86.8%.

MS[M+H] ⁺ 168.21, MS[MH] ^- 166.30.

Example 14

2-(4-cyanothiophene-2-carbonyl)-N-[4-(4-methylpiperidin-1-yl)phenyl]thiosemicarbazide (M-10)

Add 0.17g (1mmol) of M-9 (1mmol), 0.26g (1.1mmol) of M-5, 0.79mg (0.01mmol) of pyridine and 10ml of absolute ethanol to a 50ml single-necked bottle, and react under reflux. After 1h, TLC shows that no raw materials remain. The solvent was distilled off under reduced pressure and recrystallized from 95% ethanol to obtain 0.21 g of a light yellow solid with a yield of 52.5%.

MS[M+H] ⁺ 401.14, MS[MH] ^- 399.06.

Example 15

5-{5-[4-(4-methylpiperazin-1-yl)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carbonitrile (I-49)

Add 0.4g (1mmol) of M-100, 0.35g (1.1mmol) of mercuric acetate and 15ml of absolute ethanol to a 50ml single-necked bottle, and react under reflux. After 3h, TLC shows that there are no raw materials remaining, and filter while hot. The solvent was distilled off under reduced pressure, and column chromatography (DCM:MeOH:TEA=40:2:1) gave 95 mg of a white solid with a yield of 25.9%. mp: 255-257°C.

¹ H-NMR (300MHzDMSO-d ₆ ) δ: 10.50 (1H, s, -NH-), 8.77-8.76 (1H, d, J=1.23, Thiophene), 7.97-7.96 (1H, d, J=1.23, Thiophene), 7.46-7.43 (2H, d, Benzene), 6.97-6.94 (2H, d, Benzene), 3.09-3.06 (4H, m, -NC H ₂ -), 2.51-2.46 (4H, m, -C H ₂ -N-CH ₃ ), 2.24 (3H, s, -NC H ₃ ). MS [M+H] ⁺ 367.2.

Example 16

5-{5-[4-(1-methylpiperidin-4-ylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carbonitrile (I-50)

The preparation method was similar to (I-49), and 61 mg of the sample was obtained with a yield of 23.4%. mp: 250-251°C.

¹ H-NMR (300MHzDMSO-d ₆ ) δ: 10.52 (1H, s, -NH-), 8.75-8.73 (1H, d, J=1.44, Thiophene), 8.07-8.05 (1H, d, J=1.44, Thiophene), 7.36-7.33 (2H, d, Benzene), 7.08-7.04 (2H, d, Benzene), 6.81-6.79 (1H, m, - N H-CH-), 3.11-3.10 (1H, m, piperidine ), 2.63-2.61 (2H, m, piperidine), 2.21 (3H, m, piperidine), 2.04-2.03 (2H, m, piperidine), 1.90-1.89 (2H, m, piperidine), 1.51-1.49 (2H, m.piperidine).MS[M+H] ⁺ 381.1.

Example 17

5-{5-[4-(3-(Diethylamino)propylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carbonitrile (I-51)

The preparation method was similar to (I-49), and 43 mg of the sample was obtained with a yield of 15.4%. mp: 259-261°C.

¹ H-NMR (300MHzDMSO-d ₆ ) δ: 10.65 (1H, s, -NH-), 8.45-8.44 (1H, d, J=1.46, Thiophene), 8.11-8.07 (1H, d, J=1.46, Thiophene), 7.38-7.35 (2H, d, Benzene), 7.10-7.08 (2H, d, Benzene), 6.71-6.69 (1H, m, - N H-CH ₂ -), 3.35-3.32 (2H, m, -NH-CH2-), 3.03-3.00 (6H, m, _-CH2 -N-), 1.63-1.61 ( 2H , m, _{-CH2 -} CH2 _- CH2- ₎ , 1.00-0.98 (6H, m, -CH ₂ -CH ₃ ). MS [M+ H ] ⁺ 397.4.

Example 18

5-{5-[4-(3-morpholinopropylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carbonitrile (I-52)

The preparation method was similar to (I-49), and 37 mg of the sample was obtained with a yield of 19.3%. mp: 259-262°C.

¹ H-NMR (300MHzDMSO-d ₆ ) δ: 10.65 (1H, s, -NH-), 8.43-8.42 (1H, d, J=1.45, Thiophene), 8.13-8.12 (1H, d, J=1.45, Thiophene), 7.36-7.34 (2H, d, Benzene), 7.10-7.07 (2H, d, Benzene), 6.43-6.42 (1H, m, - N H-CH ₂ -), 3.65-3.63 (4H, m, Morpholine), 3.35-3.32 (2H, m, -NH- CH ₂ -), 2.46-2.43 (6H, m, -CH ₂ -N-), 1.63-1.61 ( 2H , m, -CH ₂ -C H ₂ -CH ₂ -).MS[M+H] ⁺ 411.4.

Example 19

5-{5-[4-(4-Methylpiperazin-1-yl)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carboxamide (I-53)

Add 0.37g (1mmol) of I-49, 0.35g (1.1mmol) of 30% H ₂ O ₂ and 15ml of anhydrous ethanol to a 50ml single-necked bottle, and react under reflux. After 3 hours, TLC shows that no raw materials remain, and filter while hot. The solvent was distilled off under reduced pressure, and column chromatography (DCM:MeOH:TEA=40:2:1) gave 95 mg of a white solid with a yield of 25.9%. mp: 270-272°C.

¹ H-NMR (300MHzDMSO-d ₆ ) δ: 10.50 (1H, s, -NH-), 8.37-8.36 (1H, d, J=1.43, Thiophene), 7.94-7.92 (1H, s, -CON H ₂ -), 7.77-7.76 (1H, d, J=1.43, Thiophene), 7.36-7.33 (2H, d, Benzene), 6.98-6.96 (2H, d, Benzene), 6.84-6.82 (1H, s, -CON H ₂ -), 3.09-3.06 (4H, m, -NC H ₂ -), 2.51-2.46 (4H, m, -CH ₂ -N- CH ₃ ), 2.24 (3H, s, -NC H ₃ ) .MS[M+H] ⁺ 385.2.

Example 20

5-{5-[4-(1-methylpiperidin-4-ylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carboxamide (I-54)

The preparation method was similar to (I-53), and 57 mg of the sample was obtained with a yield of 25.3%. mp: 269-270°C.

¹ H-NMR (300MHzDMSO-d ₆ ) δ: 10.5 (1H, s, -NH-), 8.81-8.80 (1H, d, J=1.43, Thiophene), 7.84-7.82 (1H, s, -CON H ₂ -), 7.78-7.77 (1H, d, J=1.43, Thiophene), 7.46-7.43 (2H, d, Benzene), 7.18-7.16 (2H, d, Benzene), 6.91-6.89 (1H, s, -CON H ₂ -), 6.36-6.34 (1H, m, -N H -), 3.11-3.10 (1H, m, piperidine), 2.63-2.61 (2H, m, piperidine), 2.21 (3H, m, piperidine), 2.04-2.03 (2H, m, piperidine), 1.90-1.89 (2H, m, piperidine), 1.51-1.49 (2H, m. piperidine). MS[M+H] ⁺ 399.2.

Example 21

5-{5-[4-(3-(Diethylamino)propylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carboxamide (I-55)

The preparation method was similar to (I-53), and 23 mg of the sample was obtained with a yield of 14.3%. mp: 265-267°C.

¹ H-NMR (300MHzDMSO-d ₆ ) δ: 10.65 (1H, s, -NH-), 8.45-8.44 (1H, d, J=1.46, Thiophene), 8.11-8.07 (1H, d, J=1.46, Thiophene), 7.88-7.85 (1H, s, -CON H ₂ -), 7.38-7.35 (2H, d, Benzene), 7.10-7.08 (2H, d, Benzene), 6.91-6.89 (1H, s, -CON H ₂ -), 6.70-6.65 (1H, m, -N H-CH ₂ -), 3.33-3.31 (2H, m, -NH- CH ₂ -), 3.01-3.00 (6H, m, -CH ₂ -N-), 1.60-1.56 ( 2H , m, -CH ₂ -CH ₂ -CH ₂ -), 1.00-0.95 (6H, m, -CH ₂ -CH ₃ ).MS[M+ H ] ⁺ 415.4.

Example 22

5-{5-[4-(3-morpholinopropylamino)anilino]-1,3,4-oxadiazol-2-yl}thiophene-3-carboxamide (I-56)

The preparation method was similar to (I-53), and 23 mg of the sample was obtained with a yield of 14.3%. mp: 263-264°C.

¹ H-NMR (300MHzDMSO-d ₆ ) δ: 10.52 (1H, s, -NH-), 8.81-8.78 (1H, d, J=1.45, Thiophene), 8.13-7.92 (2H, m, Thiophene and-CON H ₂ -), 7.36-7.34 (2H, d, Benzene), 7.10-7.04 (3H, m, Benzene and-CON H ₂ -), 6.40-6.39 (1H, m, -N H-CH ₂ -), 3.60- 3.58 (4H, m, Morpholine), 3.35-3.33 (2H, m, -NH- CH ₂ -), 2.47-2.45 (6H, m, -CH ₂ -N-), 1.63-1.61 ( 2H , m , _-CH2 - CH2 _- CH2-). MS[M+H] ⁺ 429.4, MS[MH] ^- 427.2.

Claims (6)

1. the compound of general formula (I) or its pharmaceutically acceptable salt:

Wherein, R₁Expression-H, cyano group, amide groups; R₂Expression-H, cyano group, amide groups;

Wherein, X represents O, N or-NH-; Y represents O, S ,-CH₂-；

Wherein, R₃Expression-H, trifluoromethoxy or methoxyl group;

Wherein, R₄、R₅Represent independently hydrogen, piperidines-4-amino, 1-methyl piperidine-4-amino, morpholinyl the third amino, piperazineBase, 4-methylpiperazine-1-yl, 4-(pyrrolidin-1-yl) fourth amino, 3-lignocaine the third amino, 3-methoxy propyl amino; Or solelyOn the spot represent

2. the compound of claim 1, its structure is selected from:

5-{5-[4-(4-methyl piperidine-1-yl) anilino-]-1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-1)

5-{5-[4-(N-amino piperidine-1-base amino) anilino-]-1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-2)

5-{5-[4-(3-(diethylamino) Propylamino) anilino-]-1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-3)

5-{5-[4-(morpholinyl Propylamino) anilino-]-1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-4)

5-{5-[2-methoxyl group-4-(4-methyl piperidine-1-yl) anilino-]-1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-5)

5-{5-[2-methoxyl group-4-(N-amino piperidine-1-base amino) anilino-]-1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-6)

5-{5-[2-methoxyl group-4-(3-(diethylamino) Propylamino) anilino-]-1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-7)

5-{5-[2-methoxyl group-4-(morpholinyl Propylamino) anilino-]-1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-8)

5-{5-[4-(4-methyl piperidine-1 carbonyl) anilino-]-1H-pyrazole-3-yl } thiophene-2-formonitrile HCN (I-9)

4-{[3-(5-cyano-thiophene-2-yl)-1H-pyrazoles-5-yl] amino }-N-(1-methyl piperidine-4-yl) benzamide (I-10)

4-{[3-(5-cyano-thiophene-2-yl)-1H-pyrazoles-5-yl] amino }-N-[3-(diethylamino) propyl group] benzamide (I-11)

4-{[3-(5-cyano-thiophene-2-yl)-1H-pyrazoles-5-yl] amino }-N-[3 morpholinyl propyl] benzamide (I-12)

5-{5-[4-(4-methyl piperidine-1-yl) anilino-]-1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-13)

5-{5-[4-(1-methyl piperidine-4-base amino) anilino-]-1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-14)

5-{5-[4-(3-(diethylamino) Propylamino) anilino-]-1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-15)

5-{5-[4-(morpholinyl amino) anilino-]-1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-16)

5-{5-[2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino-]-1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-17)

5-{5-[2-methoxyl group-4-(1-methyl piperidine-4-base amino) anilino-]-1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-18)

5-{5-[2-methoxyl group-4-(3-(diethylamino) Propylamino) anilino-]-1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-19)

5-{5-[2-methoxyl group-4-(morpholinyl amino) anilino-]-1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-20)

5-{5-[4-(4-methyl piperazine-1-carbonyl) anilino-]-1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-21)

5-{5-[4-(1-methyl piperidine-4-base carbamyl) anilino-]-1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-22)

5-{5-[4-(3-(diethylamino) Propylamino carbonyl) anilino-]-1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-23)

5-{5-[4-(morpholinyl Propylamino carbonyl) anilino-]-1H-pyrazole-3-yl } thiophene-2-carboxamide derivatives (I-24)

5-{5-[4-(4-methylpiperazine-1-yl) anilino-] isoxazole-3-yl } thiophene-2-formonitrile HCN (I-25)

5-{5-[4-(1-methyl piperidine-4-base amino) anilino-] isoxazole-3-yl } thiophene-2-formonitrile HCN (I-26)

5-{5-[4-(3-(diethylamino)-4-base amino) anilino-] isoxazole-3-yl } thiophene-2-formonitrile HCN (I-27)

5-{5-[4-(morpholinyl amino) anilino-] isoxazole-3-yl } thiophene-2-formonitrile HCN (I-28)

5-{5-[4-(4-methyl piperazine-1-carbonyl) anilino-] isoxazole-3-yl } thiophene-2-formonitrile HCN (I-29)

4-[3-(5-cyano-thiophene-2-yl) isoxazole-5-base amino]-N-(1-methyl piperidine-4-yl) benzamide (I-30)

4-[3-(5-cyano-thiophene-2-yl) isoxazole-5-base amino]-N-[(3-diethylamino) propyl group] benzamide (I-31)

4-[3-(5-cyano-thiophene-2-yl) isoxazole-5-base amino]-N-(morpholinyl propyl group) benzamide (I-32)

5-{5-[4-(4-methylpiperazine-1-yl) anilino-] isoxazole-3-yl } thiophene-2-carboxamide derivatives (I-33)

5-{5-[4-(1-methyl piperidine-4-base amino) anilino-] isoxazole-3-yl } thiophene-2-carboxamide derivatives (I-34)

5-{5-[4-(3-(diethylamino)-4-base amino) anilino-] isoxazole-3-yl } thiophene-2-carboxamide derivatives (I-35)

5-{5-[4-(morpholinyl amino) anilino-] isoxazole-3-yl } thiophene-2-carboxamide derivatives (I-36)

5-{5-[2-methoxyl group-4-(4-methylpiperazine-1-yl) anilino-] isoxazole-3-yl } thiophene-2-carboxamide derivatives (I-37)

5-{5-[2-methoxyl group-4-(1-methyl piperidine-4-base amino) anilino-] isoxazole-3-yl } thiophene-2-carboxamide derivatives (I-38)

5-{5-[2-methoxyl group-4-(3-(diethylamino)-4-base amino) anilino-] isoxazole-3-yl } thiophene-2-carboxamide derivatives (I-39)

5-{5-[2-methoxyl group-4-(morpholinyl amino) anilino-] isoxazole-3-yl } thiophene-2-carboxamide derivatives (I-40)

5-{5-[4-(4-methyl piperazine-1-carbonyl) anilino-] isoxazole-3-yl } thiophene-2-carboxamide derivatives (I-41)

5-{5-[4-(1-methyl piperidine-4-base carbamyl) anilino-] isoxazole-3-yl } thiophene-2-carboxamide derivatives (I-42)

5-{5-[4-(3-(diethylamino) propyl group carbamyl) anilino-] isoxazole-3-yl } thiophene-2-carboxamide derivatives (I-43)

5-{5-[4-(morpholinyl propyl group carbamyl) anilino-] isoxazole-3-yl } thiophene-2-carboxamide derivatives (I-44)

5-{5-[2-methoxyl group-4-(4-methyl piperazine-1-carbonyl) anilino-] isoxazole-3-yl } thiophene-2-carboxamide derivatives (I-45)

5-{5-[[2-methoxyl group-4-(1-methyl piperidine-4-base carbamyl) anilino-] isoxazole-3-yl } thiophene-2-carboxamide derivatives (I-46)

5-{5-[[2-methoxyl group-4-(3-(diethylamino) propyl group carbamyl) anilino-] isoxazole-3-yl } thiophene-2-carboxamide derivatives (I-47)

5-{5-[[2-methoxyl group-4-(morpholinyl propyl group carbamyl) anilino-] isoxazole-3-yl } thiophene-2-carboxamide derivatives (I-48)

5-{5-[4-(4-methylpiperazine-1-yl) anilino-]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-49)

5-{5-[4-(1-methyl piperidine-4-base amino) anilino-]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-50)

5-{5-[4-(3-(diethylamino) propyl group amino) anilino-]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-51)

5-{5-[4-(morpholinyl propyl group amino) anilino-]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-52)

5-{5-[4-(4-methylpiperazine-1-yl) anilino-]-1,3,4-oxadiazole-2-yl } thiophene-3-formamide (I-53)

5-{5-[4-(1-methyl piperidine-4-base amino) anilino-]-1,3,4-oxadiazole-2-yl } thiophene-3-formamide (I-54)

5-{5-[4-(3-(diethylamino) propyl group amino) anilino-]-1,3,4-oxadiazole-2-yl } thiophene-3-formamide (I-55)

5-{5-[4-(morpholinyl propyl group amino) anilino-]-1,3,4-oxadiazole-2-yl } thiophene-3-formamide (I-56)

5-{5-[3-(4-methylpiperazine-1-yl) anilino-]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-57)

5-{5-[3-(1-methyl piperidine-4-base amino) anilino-]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-58)

5-{5-[3-(3-(diethylamino) propyl group amino) anilino-]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-59)

5-{5-[3-(morpholinyl propyl group amino) anilino-]-1,3,4-oxadiazole-2-yl } thiophene-3-formonitrile HCN (I-60)

5-{5-[3-(4-methylpiperazine-1-yl) anilino-]-1,3,4-oxadiazole-2-yl } thiophene-3-formamide (I-61)

5-{5-[3-(1-methyl piperidine-4-base amino) anilino-]-1,3,4-oxadiazole-2-yl } thiophene-3-formamide (I-62)

5-{5-[3-(3-(diethylamino) propyl group amino) anilino-]-1,3,4-oxadiazole-2-yl } thiophene-3-formamide (I-63)

5-{5-[3-(morpholinyl propyl group amino) anilino-]-1,3,4-oxadiazole-2-yl } thiophene-3-formamide (I-64)

5-{5-[4-(4-methylpiperazine-1-yl) anilino-]-1,3,4-thiadiazoles-2-yl } thiophene-3-formonitrile HCN (I-65)

5-{5-[4-(1-methyl piperidine-1-base amino) anilino-]-1,3,4-thiadiazoles-2-yl } thiophene-3-formonitrile HCN (I-66)

5-{5-[4-(3-(diethylamino) propyl group amino) anilino-]-1,3,4-thiadiazoles-2-yl } thiophene-3-formonitrile HCN (I-67)

5-{5-[4-(morpholinyl propyl group amino) anilino-]-1,3,4-thiadiazoles-2-yl } thiophene-3-formonitrile HCN (I-68)

5-{5-[4-(4-methylpiperazine-1-yl) anilino-]-1,3,4-thiadiazoles-2-yl } thiophene-3-formamide (I-69)

5-{5-[4-(1-methyl piperidine-1-base amino) anilino-]-1,3,4-thiadiazoles-2-yl } thiophene-3-formamide (I-70)

5-{5-[4-(3-(diethylamino) propyl group amino) anilino-]-1,3,4-thiadiazoles-2-yl } thiophene-3-formamide (I-71)

5-{5-[4-(morpholinyl propyl group amino) anilino-]-1,3,4-thiadiazoles-2-yl } thiophene-3-formamide (I-72)

5-{5-[4-(4-methyl piperazine-1-carbonyl) anilino-]-1,3,4-thiadiazoles-2-yl } thiophene-3-formamide (I-73)

5-{5-[4-(1-methyl piperidine-4-base carbamyl) anilino-]-1,3,4-thiadiazoles-2-yl } thiophene-3-formamide (I-74)

5-{5-[4-(3-(diethylamino) propyl group carbamyl) anilino-]-1,3,4-thiadiazoles-2-yl } thiophene-3-formamide (I-75)

5-{5-[4-(morpholinyl propyl group carbamyl) anilino-]-1,3,4-thiadiazoles-2-yl } thiophene-3-formamide (I-76).

3. pharmaceutically acceptable salt of the compound of claim 1, wherein pharmaceutically acceptable salt comprise general formula (I) compound with underThe acid-addition salts that row acid forms: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-methyl benzenesulfonic acid, naphthalene sulfonic acids, citric acid,Tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or benzene sulfonic acid, butanedioic acid, fumaric acid, salicylic acid, phenylacetic acid or apricotBenevolence acid.

4. a pharmaceutical composition, described pharmaceutical composition is made up of general formula (I) compound and pharmaceutically acceptable carrier.

5. the compound of the general formula of claim 1 (I) or its pharmaceutically acceptable salt are swashing for the preparation of prevention or treatment and Polo samplePurposes in the medicine of the relevant disease of enzyme 1 inhibitor.

6. the purposes of claim 5, wherein the disease relevant with Polo sample kinases 1 inhibitor be melanoma, liver cancer, kidney,Acute leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, cutaneum carcinoma, colorectal cancer, cancer of pancreas, oophoroma,Breast cancer, RAEB, the cancer of the esophagus, gastrointestinal cancer or celiothelioma.