CN114907317B - Pyrazole-vinyl-isonicotinic acid derivative and preparation method and application thereof - Google Patents

Abstract

The invention discloses a pyrazole-vinyl-isonicotinic acid derivative which has remarkable biological inhibition activity on KDM5B, can be used for preparing and researching and developing a novel KDM5B inhibitor, enriches the variety of isonicotinic acid derivatives, and lays a foundation for developing a drug for inhibiting KDM 5B. The invention takes basic compounds such as aromatic ring aldehydes and the like as raw materials, and is prepared by nucleophilic addition-elimination, vilsmeier-Haack reaction and Knoevenagel condensation reaction, and the preparation method is simple, mild in condition and high in yield. The compound has nanomolar inhibition on KDM5B on enzyme level, provides a lead compound structure for further researching anti-cancer drugs for inhibiting KDM5B, and has better application prospect.

Description

A pyrazole-vinyl-isonicotinic acid derivative and its preparation method and application

Technical Field

The invention belongs to the field of pharmaceutical chemistry and relates to a pyrazole-vinyl-isonicotinic acid derivative and a preparation method and application thereof.

Background Art

Cancer has developed into a public health problem that seriously threatens the health of the global population, bringing a heavy burden to families and society, and its morbidity and mortality rates are still increasing. Cancer treatment includes surgery, radiotherapy, chemotherapy, molecular targeted therapy, tumor immunotherapy, cell therapy, etc. Among them, molecular targeted therapy drugs can specifically inhibit regulatory factors related to tumor growth or inhibit the microenvironment that helps cancer growth or survival, thereby inhibiting or blocking tumor growth, invasion and metastasis, and are safer than traditional chemotherapy drugs. Therefore, it is urgent and necessary to design and develop targeted anti-cancer therapeutic drugs with good effects and few side effects.

The methylation modification of histones is a reversible epigenetic process, which mainly occurs on the lysine and arginine residues at the tail and has a wide range of biological functions. Professor Shi Yang's research group at Harvard University first discovered the existence of lysine specific demethylase 1 (LSD1), confirming that histone methylation is a reversible process. Afterwards, several research groups reported the Jumonji C (JmjC) family of histone demethylases. With the continuous deepening of research, unknown problems in the methylation modification process of histones have gradually been revealed. The epigenetic regulatory histone lysine demethylase KDM5B (lysine-specific demethylase 5B, KDM5B), also known as plu-1 or JARID1B, belongs to the JMJD (Jmjc-KDMs) subfamily. It can remove the H3K4Me2/3 methylation state, regulate gene transcription and expression, and is closely related to the occurrence and development of diseases such as cancer, immunity, and chemotherapy multidrug resistance. According to relevant research reports, KDM5B is overexpressed in a variety of solid tumors and leukemias, such as prostate, gastric cancer, breast cancer, ovarian cancer, and liver cancer, and the overexpression level is associated with the degree of cancer progression and poor prognosis. A large amount of evidence shows that KDM5B is a potential oncogene. Reducing the expression level or knocking out KDM5B can significantly inhibit tumor biological activities such as tumor metastasis and invasion. Anti-tumor drugs targeting KDM5B provide new opportunities for cancer treatment.

In recent years, through computer-aided technology (high-throughput virtual screening, HTS) combined with corresponding drug design methods, a variety of KDM5 inhibitors with different structural skeletons have been discovered, some of which (CPI-455, EPT103182) have entered preclinical research, but there are still no drugs on the market, and most inhibitors are still in the early research stage. Therefore, it is of great significance to develop KDM5B inhibitors with high efficiency, low toxicity, high selectivity and good pharmacokinetic parameters.

Summary of the invention

In order to overcome the shortcomings of the prior art, one of the purposes of the present invention is to provide a pyrazole-vinyl-isonicotinic acid derivative, which has a good inhibitory effect on HDM5B, and its IC ₅₀ is at the micron level, showing good inhibitory activity.

The second object of the present invention is to provide a method for preparing pyrazole-vinyl-isonicotinic acid derivatives.

The third object of the present invention is to provide the use of pyrazole-vinyl-isonicotinic acid derivatives in the preparation of drugs for inhibiting KDM5B.

One of the purposes of the present invention is achieved by the following technical solution:

A pyrazole-vinyl-isonicotinic acid derivative having the general structural formula I

Wherein, ^R1 is selected from phenyl, substituted phenyl, N-containing six-membered heterocyclic group, benzodioxinyl;

^R2 is selected from phenyl and substituted phenyl.

Furthermore, the substituent of the substituted phenyl group is a C1-C6 saturated alkyl group, a C1-C6 saturated alkoxy group, a halogen, a nitro group, a C1-C6 saturated alkylsulfonyl group, or a phenyl group.

Further, the R ¹ is selected from

R ² is selected from

The second object of the present invention is achieved by adopting the following technical solution:

The preparation method of pyrazole-vinyl-isonicotinic acid derivatives comprises the following steps:

(1) adding anhydrous ethanol to compound A, then adding compound B and a catalyst thereto, stirring at room temperature to react, to obtain compound C;

(2) First, prepare a Vilsmeier-Haack reagent: add phosphorus oxychloride dropwise to N,N-dimethylformamide under ice bath conditions, and stir at room temperature to obtain a mixture; dissolve the compound C obtained in step (1) in N,N-dimethylformamide, and add dropwise to the above mixture under ice bath conditions, and stir to react to obtain a compound D;

(3) Compound D obtained in step (2) is mixed with 2-methylisonicotinic acid, N,N-dimethylformamide and a catalyst, and stirred to react to obtain compound I.

Furthermore, the catalyst in step (1) is glacial acetic acid, the molar ratio of compound A to compound B is 1:1, and the ratio of compound A to anhydrous ethanol is 1 g: 10-20 mL.

Furthermore, in the step (2), the molar ratio of compound C to phosphorus oxychloride and N,N-dimethylformamide in the Vilsmeier-Haack reagent is 1:5:10;

When compound C is dissolved in N,N-dimethylformamide, the addition ratio of compound C to N,N-dimethylformamide is 1 g:10 mL.

Furthermore, the catalyst in step (3) is trimethylchlorosilane;

The added molar ratio of the compound D to 2-methylisonicotinic acid is 1:1.

The third object of the present invention is achieved by adopting the following technical solution:

Application of pyrazole-vinyl-isonicotinic acid derivatives in the preparation of drugs for inhibiting KDM5B.

Furthermore, the derivative is used to prepare a drug for treating tumors with high expression of KDM5B.

Furthermore, the tumor is gastric cancer, breast cancer or prostate cancer.

Compared with the prior art, the present invention has the following beneficial effects:

The present invention provides a pyrazole-vinyl-isonicotinic acid derivative, which has significant biological inhibitory activity on KDM5B, can be used to prepare and develop new KDM5B inhibitors, enrich the types of isonicotinic acid derivatives, and lay a foundation for the development of drugs that inhibit KDM5B. The present invention uses basic compounds such as aromatic ring aldehydes as raw materials, and is prepared by nucleophilic addition-elimination, Vilsmeier-Haack reaction, and Knoevenagel condensation reaction. The preparation method is simple, the conditions are mild, and the yield is high. This type of compound has a nanomolar inhibitory effect on KDM5B at the enzyme level, provides the structure of a lead compound for further research on anticancer drugs that inhibit KDM5B, and has good application prospects.

DETAILED DESCRIPTION

The present invention is further described below in conjunction with specific implementation methods. It should be noted that, under the premise of no conflict, the various embodiments or technical features described below can be arbitrarily combined to form a new embodiment.

Example 1

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-1, wherein R ¹ is

^R2 is

The preparation process is as follows:

(1) Benzaldehyde (Compound A, 1 g, 8.32 mmol) was placed in a 50 mL flask, and 20 mL of anhydrous ethanol was added, followed by phenylhydrazine (Compound B, 900.07 mg, 8.32 mmol) and glacial acetic acid (0.05 mL, equivalent to 0.05). The mixture was stirred at room temperature and refluxed for 1 h. After the reaction was completed, most of the organic solvent was removed by rotary evaporation under reduced pressure. A large amount of solid was precipitated by slow cooling. The solid was filtered to obtain a white solid (E)-1-phenyl-2-(1-phenylethylidene)hydrazine (Compound C, 1.2 g, 5.71 mmol). The yield was 68%. Since the product was unstable, it needed to be quickly transferred to the next step.

(2) First, prepare Vilsmeier-Haack reagent: Weigh N,N-dimethylformamide (4.17 g, 57.07 mmol) in a 100 mL flask, add phosphorus oxychloride (4.37 g, 28.53 mmol) dropwise under ice bath and stir at room temperature for 40 min (the molar ratio of compound C to phosphorus oxychloride and N,N-dimethylformamide is 1:5:10). Then, the compound C (1.2 g, 5.71 mmol) obtained in step (1) was weighed and dissolved in 5 mL of N,N-dimethylformamide, and then added dropwise to the prepared Vilsmeier-Haack reagent under ice bath, and reacted at 85° C. for 5 h under stirring. After the reaction was completed by TLC monitoring, 200 mL of ice water was added, and KOH alkaline aqueous solution was added to adjust the pH to neutral (pH 6-7), and the mixture was thoroughly sonicated and filtered to obtain a white solid 1,3-diphenyl-1H-pyrazole-4-carboxylic acid (compound D, 994 mg, 3.99 mmol) with a yield of 70%.

The analytical data of the product are as follows: ¹ H NMR (600 MHz, DMSO-d ₆ , ppm) δ 12.55 (s, 1H, -COOH), 9.07 (s, 1H, Ar-H), 8.02-7.95 (m, 2H, Ar-H), 7.87-7.80 (m, 2H, Ar-H), 7.54 (t, J = 8.0 Hz, 2H, Ar-H), 7.48-7.41 (m, 3H, Ar-H), 7.39 (t, J = 7.4 Hz, 1H, Ar-H).

(3) In a Shrek tube, 1,3-diphenyl-1H-pyrazole-4-carboxylic acid (Compound D, 900 mg, 3.68 mmol) prepared in step (2), 2-methylisonicotinic acid (497.11 mg, 3.68 mmol), trimethylsilyl chloride (3 mL, equivalent weight 0.05) and N,N-dimethylformamide (15 mL) were added and mixed, and the mixture was stirred at 120° C. for 24 h. After the reaction was completed, 100-200 mL of water was added, and the mixture was ultrasonicated, filtered and dried to obtain a crude product. The crude product was separated by silica gel column chromatography and eluted with dichloromethane/methanol (V:V=10:1) to obtain Compound I-1 (1.04 g, 2.87 mmol) ((E)-2-(2-(1,3-diphenyl-1H-pyrazol-4-yl)vinyl)isonicotinic acid) as a yellow solid with a yield of 78%.

¹ H NMR (600MHz, DMSO-d ₆ , ppm) δ13.67(s,1H,-COOH),9.12(s,1H,Ar-H),8.73(d,J＝4.7Hz,1H,Ar-H ),7.95(d,J＝7.8Hz,2H,Ar-H),7.79(s,1H,Ar-H),7.71(s,1H,Ar-H),7.68(d,J＝16.7Hz,2H ,Ar-H),7.70(d,J＝15.9Hz,1 H,-CH＝C-),7.68(d,J＝16.7Hz,2H,Ar-H),7.64(d,J＝4.5Hz,1H,Ar-H),7.57(dd,J＝11.4,7.2 Hz,4H,Ar-H),7.49(t,J＝7.3Hz,1H,Ar-H),7.38(t,J＝7.3Hz,1H,Ar-H),7.33(d,J＝15.9Hz, 1H,-CH＝C-) ¹³ C NMR (100MHz, DMSO-d ₆ , ppm) δ166.16,156.09,151.43,150.60,139.19,138.91,132.56,129.61,128.78,128.35,128.25,127.46,126.84,126.68 ,122.83,120.81,120.75,118.96,118.45 .

Example 2

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-2, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this example and Example 1 is that the benzaldehyde in step (1) of Example 1 is adjusted to 4-pyridinecarboxaldehyde to obtain compound (E)-2-(2-(1-phenyl-3-(pyridin-4-yl)-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 64%.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ9.23 (s, 1H, Ar-H), 8.85 (d, J = 6.3Hz, 2H, Ar-H), 8.77 (d, J = 4.9Hz ,1H,Ar-H),8.00(s,1H,Ar-H),7.98(s,1H,Ar-H),7.97(s,1H,Ar-H),7.96(s,1H,Ar-H ),7.89(s,1H,Ar-H),7.77(d,J＝15.9Hz,1H,-C＝CH-),7.68(dd,J＝4.9,1.4Hz,1H,Ar-H),7.60 (t,J＝8.0Hz,2H,Ar-H),7.46–7.39(m,1H,-C＝CH-,1H,Ar-H). ¹³ CNMR (100MHz, DMSO-d ₆ ) δ166.58,156.23,151.02,147.78,147.68,143.51,139.56,139.34,130.19,129.68,128.56,127.84,123.72,122.30,121 .68,121.57,120.80,119.27,34.46.

Example 3

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-3, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this example and Example 1 is that the benzaldehyde in step (1) of Example 1 is adjusted to 3-pyridinecarboxaldehyde to obtain compound (E)-2-(2-(1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 68%.

¹ H NMR (600MHz, DMSO-d ₆ , ppm) δ9.21 (s, 1H, Ar-H), 9.04 (s, 1H, Ar-H), 8.80 (d, J = 4.6Hz, 1H, Ar- H),8.75(d,J＝4.8Hz,1H,Ar-H),8.40(d,J＝7.5Hz,1H,Ar-H),7.98(d,J＝7.9Hz,2H,Ar-H) ,7.89(s,1H,Ar-H ),7.85–7.79(m,1H,Ar-H),7.70(d,J＝16.1Hz,1H,-CH＝C-),7.68(d,J＝5.0Hz,1H,Ar-H),7.59 (t,J＝7.8Hz,2H,Ar-H),7.41(t,J＝7.3Hz,1H,Ar-H),7.37(d,J＝15.9Hz,1H,-CH＝C-). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm) δ166.45,155.98,150.38,147.48,146.18,145.45,139.98,139.38,130.39,130.17,128.39,128.18,127.66,126.06 ,123.09,121.69,120.08,119.15.

Example 4

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-4, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this example and Example 1 is that the benzaldehyde in step (1) of Example 1 is adjusted to 4-methylbenzaldehyde to obtain compound (E)-2-(2-(1-phenyl-3-(methylphenyl)-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 63%.

¹ H NMR (600MHz, DMSO-d ₆ , ppm) δ13.71(s,1H,-COOH),9.11(s,1H,Ar-H),8.73(d,J＝4.9Hz,1H,Ar-H ),7.94(d,J＝8.0Hz,2H,Ar-H),7.82(s,1H,Ar-H),7.69(d,J＝16.0Hz,1H,-CH＝C-),7.66(d ,J＝4.9Hz,1H,Ar-H),7.57(dd,J＝18.5,7.9Hz,4H,Ar-H),7.37(t,J＝7.3Hz,3H,Ar-H),7.32(d ,J＝15.9Hz,1H,-CH＝C-),2.40(s,3H,-CH ₃ ). ¹³ C NMR (100MHz, DMSO-d ₆ ,ppm) δ165.93,155.63,151.56,149.78,139.57,139.18,137.81,129.61,129.35,128.17,126.93,126.66,126.37,123.92,121 .04,120.98,118.79,118.44,20.86.

Example 5

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-5, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this example and Example 1 is that the benzaldehyde in step (1) of Example 1 is adjusted to 2-fluorobenzaldehyde to obtain compound (E)-2-(2-(3-(2-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 71%.

¹ H NMR (600MHz, DMSO-d ₆ , ppm) δ13.65(s,1H,-COOH),9.17(s,1H,Ar-H),8.67(d,J＝4.9Hz,1H,Ar-H ),7.91(d,J＝7.7Hz,2H,Ar-H),7.71(s,1H,Ar-H),7.69–7.64(m,1H,Ar-H),7.62(dd,J＝4.9, 1.3Hz,1H,Ar-H),7.57(t,J＝8.0Hz,2H,Ar-H),7.40(t,J＝7.4Hz,1H,Ar-H),7.37–7.31(m,1H, -C＝CH-,1H,Ar-H),7.16(d,J＝16.0Hz,1H,-C＝CH-). ¹³ C NMR(100MHz,DMSO-d ₆ )δ166.70,160.65(dd,J＝248.6,6.7Hz),156.21,151.04,141.02,139.83,139.50,132.43(t,J＝10.2Hz),130.20,127.71,127.53 ,127.20,122.38,121.58,121.50,121.29,119.05,112.67(d,J＝13.2Hz),112.60,112.54,110.16(t,J＝20.0Hz).

Example 6

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-6, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this example and Example 1 is that the benzaldehyde in step (1) of Example 1 is adjusted to 3-fluorobenzaldehyde to obtain compound (E)-2-(2-(3-(3-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 61%.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ9.16 (s, 1H), 8.68 (d, J = 4.9Hz, 1H), 7.94 (d, J = 7.7Hz, 2H), 7.74 (s, 1H),7.67–7.62(m,2H),7.58(t,J＝8.0Hz,3H),7.46(d,J＝9.9Hz,1H),7.44–7.42(m,1H),7.42–7.36(m ,2H),7.24(d,J＝16.0Hz,1H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ166.93,159.92(d,J＝246.9Hz),156.32,150.93,147.22,139.62,132.32,132.29,131.56(d,J＝8.1Hz),130.15,127.61,127.34,126.98,125.32( d,J＝3.4 Hz), 122.92 (d, J = 3.5Hz), 121.45, 121.27, 120.76 (t, J = 7.5Hz), 119.00, 116.70, 116.48.

Example 7

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-7, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this example and Example 1 is that the benzaldehyde in step (1) of Example 1 is adjusted to 4-fluorobenzaldehyde to obtain compound (E)-2-(2-(3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 65%.

¹ H NMR (600MHz, DMSO--d ₆ ,ppm) δ13.69(s,1H,-COOH),9.11(s,1H,Ar-H),8.72(d,J＝4.9Hz,1H,Ar- H),7.95(s,1H,Ar-H),7.94(s,1H,Ar-H),7.79(s,1H,Ar-H),7.74(q,J＝8.4,5.6Hz,2H,Ar -H),7. 65(d,J＝8.4Hz,1H,Ar-H),7.63(s,1H,Ar-H),7.57(t,J＝7.9Hz,2H,Ar-H),7.41(d,J＝8.8 Hz,1H,-CH＝C-),7.38(q,J＝8.9,5.4Hz,2H,Ar-H),7.32(d,J＝15.9Hz,1H,-CH＝C-). ¹³ C NMR (150MHz, DMSO-d ₆ , ppm) δ166.16,162.95,161.33,155.94,150.47,150.36,139.09,130.26,130.20,129.55,128.99,128.97,127.69,126.89 ,126.66,122.49,120.82,120.70,118.87 ,118.40,115.77,115.63.

Example 8

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-8, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this example and Example 1 is that the benzaldehyde in step (1) of Example 1 is adjusted to 4-chlorobenzaldehyde to obtain compound (E)-2-(2-(3-(4-chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 65%.

¹ H NMR (600MHz, DMSO-d ₆ , ppm) δ13.66(s,1H,-COOH),9.14(s,1H,Ar-H),8.74(s,1H,Ar-H),8.50(s ,1H,Ar-H),7.95(d,J＝7.1Hz,2H,Ar-H),7.81(s,1H,Ar-H),7.73(d,J＝7.2Hz,2H,Ar-H) ,7.64(m,1H-CH＝C-1H and Ar-H 2H),7.57(s,2H,Ar-H),7.39(s,1H,Ar-H),7.34(d,J＝15.9Hz, 1H,-CH＝C-). ¹³ C NMR (100MHz, DMSO-d ₆ ,ppm)δ166.64,156.49,151.08,150.60,139.58,139.43,133.65,131.88,130.40,130.14,129.39,128.34,127.63,127.31,122.99,121.42,121. 35,119.54,118.98.

Example 9

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-9, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this example and Example 1 is that the benzaldehyde in step (1) of Example 1 is adjusted to 4-bromobenzaldehyde to obtain compound (E)-2-(2-(3-(4-bromophenyl)-1-phenyl-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 77%.

¹ H NMR (600MHz, DMSO-d ₆ , ppm) δ9.12 (s, 1H), Ar-H, 8.71 (d, J = 4.4Hz, 1H, Ar-H), 7.95 (d, J = 7.7Hz ,2H,Ar-H),7.81(s,1H,Ar-H),7.76(d,J＝8.0Hz,2H,Ar-H),7.70–7.61(m,4H),7.57(t,J＝ 7.5Hz, 2H, Ar-H), 7.38 (t, J＝7.1Hz, 1H, Ar-H), 7.32 (d, J＝15.9Hz, 1H, -CH＝C-). ¹³ C NMR (100MHz, DMSO-d ₆ ,ppm)δ167.01,156.33,150.92,150.62,140.66,139.59,132.30,132.26,130.67,130.13,128.54,127.56,127.29,122.74,122.28,121.53,121. 43,119.57,118.98.

Example 10

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-10, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this embodiment and embodiment 1 is that: 4-methoxybenzaldehyde in step (1) of embodiment 1 is used to obtain compound (E)-2-(2-(3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 66%.

¹ H NMR (600MHz, DMSO-d ₆ , ppm) δ13.65 (s, 1H, -COOH), 9.09 (s, 1H, Ar-H), 8.72 (d, J = 4.9Hz, 1H, Ar-H ),7.93(d,J＝7.9Hz,2H,Ar-H),7.78(s,1H,Ar-H),7.66(d,J＝15.9Hz,1H,-CH＝C-),7.63(d ,J=2. 5Hz,2H,Ar-H),7.62(s,1H,Ar-H),7.56(t,J＝7.9Hz,2H,Ar-H),7.36(t,J＝7.4Hz,1H,Ar-H ),7.31(d,J＝15.9Hz,1H,-CH＝C-),7.12(d,J＝8.6Hz,2H,Ar-H),3.84(s,3H,-OCH ₃ ). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm) δ166.69,159.91,156.64,151.80,151.08,139.71,139.45,130.09,130.01,127.71,127.17,127.03,125.40,12 3.51,121.27,121.22,119.23, 118.84,114.74,55.70.

Embodiment 11

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-11, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this example and Example 1 is that the benzaldehyde in step (1) of Example 1 is adjusted to 4-nitrobenzaldehyde to obtain compound (E)-2-(2-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 78%.

¹ H NMR (600MHz, DMSO-d ₆ , ppm) δ9.20 (s, 1H, Ar-H), 8.71 (d, J = 4.1Hz, 1H, Ar-H), 8.41 (d, J = 8.4Hz ,2H,Ar-H),8.01(d,J＝8.4Hz,2H,Ar-H),7.98(d,J＝7.9Hz,2H,Ar-H),7.85(s,1H,Ar-H) ,7.69(d,J＝16.0Hz,1H,-CH＝C-),7.66(d,J＝4.3Hz,1H,Ar-H),7.59(t,J＝7.6Hz,2H,Ar-H) ,7.41(t,J＝7.3Hz,1H,Ar-H),7.37(d,J＝15.9Hz,1H,-CH＝C-). ¹³ CNMR (100MHz, DMSO-d ₆ , ppm) δ155.61,150.32,148.90,147.04,139.06,138.97,129.67,129.07,128.96,127.60,127.11,124.10,121.68,121.25 ,121.07,119.78,118.66.

Example 12

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-12, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this example and Example 1 is that the benzaldehyde in step (1) of Example 1 is adjusted to 1-methyl-4-(methylsulfonyl)benzaldehyde to obtain compound (E)-2-(2-(3-(4-(methylsulfonyl)phenyl)-1-phenyl-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 69%.

¹ H NMR (600 MHz, DMSO-d ₆ ,ppm)δ9.20(s,1H,Ar-H),8.76(d,J＝4.2Hz,1H,Ar-H),8.11(d,J＝7.6Hz,2H,Ar-H),8.01(d,J＝7.7Hz,2H,Ar-H),7.98(d,J＝7.5Hz,2H,Ar-H),7.94(s,1H,Ar-H ),7.77(d,J＝15.9Hz,1H,-CH＝C-),7.72(d,J＝3.2Hz,1H,Ar-H),7.59(t,J＝6.8Hz,2H,Ar-H),7.42(s,1H,Ar-H),7.40(d,J＝10.0Hz,1H,-CH＝C-),3.31(s,3H,-CH ₃ ) ^.13C NMR (100MHz, DMSO-d ₆ ,ppm) δ166.23,155.48,150.14,149.58,140.83,140.70,139.45,137.80,130.17,129.42,128.19,128.06,127.60,127.17,124 .43,122.10,121.90,119.83,119.16,44.01.

Example 13

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-13, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this example and Example 1 is that the benzaldehyde in step (1) of Example 1 is adjusted to 4-phenylbenzaldehyde to obtain compound (E)-2-(2-(3-([1,1'-diphenyl]-4-yl)-1-phenyl-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 59%.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ9.16 (s, 1H), 8.75 (d, J = 4.9Hz, 1H), 7.98 (d, J = 8.0Hz, 2H), 7.90 (s, 1H),7.87(d,J＝8.2Hz,2H),7.84–7.76(m,5H),7.70(d,J＝4.5Hz,1H),7.58(t,J＝7.7Hz,2H),7.51( t,J＝7.5Hz,2H),7.44–7.36(m,3H). ¹³ C NMR (100MHz, DMSO-d ₆ )δ165.93,155.57,151.01,149.76,140.00,139.64,139.48,139.15,131.56,129.64,129.00,128.74,127.68,127.13,127.03,126.78,126.66,1 23.84,121.19,121.07,119.02,118.50.

Embodiment 14

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-14, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this example and Example 1 is that the benzaldehyde in step (1) of Example 1 is adjusted to 1-(benzyloxy)-4-methylbenzaldehyde to obtain compound (E)-2-(2-(3-(4-(benzyloxy)phenyl)-1-phenyl-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 62%.

¹ H NMR (600MHz, DMSO-d ₆ , ppm) δ9.10 (s, 1H, Ar-H), 8.75 (d, J = 4.4Hz, 1H, Ar-H), 7.94 (d, J = 7.6Hz ,2H,Ar-H),7.90(s,1H,Ar-H),7.73(d,J＝16.2Hz,1H,-CH＝C-and 1H, Ar-H), 7.64 (d, J＝7.9Hz, 2H, Ar-H), 7.56 (t, J＝7.2Hz, 2H, Ar-H), 7.50 (d, J＝7.0Hz, 2H, Ar-H),7.42(t,J＝7.1Hz,2H,Ar-H),7.40–7.35(m,2H,Ar-H),7.33(d,J＝16.1Hz,1H,-CH＝C- ), 7.20 (d, J = 8.0Hz, 2H, Ar-H), 5.20 (s, 2H, -CH ₂ -). ¹³ C NMR (100MHz, DMSO-d ₆ ,ppm)δ166.01,159.08,155.12,151.95,148.60,141.44,139.60,137.41,130.11,128.94,128.37,128.22,127.70,127.20,126.41,125.41,124. 90,122.30,121.88,118.99,118.93,115.60,69.79.

Embodiment 15

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-15, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this embodiment and embodiment 1 is that the benzaldehyde in step (1) of embodiment 1 is adjusted to 2,4-difluorobenzaldehyde to obtain compound (E)-2-(2-(3-(2,4-difluorophenyl)-1-phenyl-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 64%.

¹ H NMR (400MHz, DMSO-d ₆ , ppm) δ9.15 (s, 1H, Ar-H), 8.66 (d, J = 4.9Hz, 1H, Ar-H), 7.94 (s, 1H, Ar- H),7.92(s,1H,Ar-H),7.75(s,1H,Ar-H),7.69(td,J＝8.5,6.7Hz,1H,Ar-H),7.62(dd,J＝4.9 ,1. 4Hz,1H,Ar-H),7.57(t,J＝8.0Hz,2H,Ar-H),7.54–7.48(m,1H,Ar-H),7.45–7.36(m,1H,-C＝CH -,1H,Ar-H),7.29(td,J＝8.4,2.1Hz,1H),7.22(d,J＝16.0Hz,1H,-C＝CH-). ¹³ C NMR (100MHz, DMSO-d ₆ )δ167.22,162.89(dd,J＝304.0,12.3Hz),160.42(dd,J＝305.3,12.3Hz),161.38(d,J＝12.6Hz),158.90(d,J＝12.5Hz),156.18,150.79 ,146.34,141.47,139.59,133.50(dd,J=9. 9,4.6Hz),130.15,127.91,127.37,127.07,122.56(d,J＝3.0Hz),121.57,121.37,120.78,119.02,117.40(q,J＝15.3,3.7Hz),112.64(dd,J＝ 21.4, 3.5Hz), 105.17 (t, J = 26.1Hz).

Example 16

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-16, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this embodiment and embodiment 1 is that the benzaldehyde in step (1) of embodiment 1 is adjusted to 2,5-difluorobenzaldehyde to obtain compound (E)-2-(2-(3-(2,6-difluorophenyl)-1-phenyl-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 72%.

¹ H NMR (600MHz, DMSO-d ₆ , ppm) δ13.72(s,1H,-COOH),9.13(s,1H,Ar-H),8.73(d,J＝4.9Hz,1H,Ar-H ),7.96(d,J＝7.7Hz,2H,Ar-H),7.81(s,1H,Ar-H),7.68(d,J＝15.9Hz,1H,-C＝CH-),7.65(dd ,J＝4.9,1.3Hz,1H,Ar-H), 7.64–7.59(m,1H,Ar-H),7.57(t,J＝8.0Hz,2H,Ar-H),7.55(d,J＝7.7Hz,1H,-C＝CH-),7.53–7.50 (m,1H,Ar-H),7.39(t,J＝7.4Hz,1H,Ar-H),7.34(d,J＝4.5Hz,1H,Ar-H),7.33–7.31(m,1H, Ar-H). ¹³ C NMR (101MHz, DMSO-d ₆ ) δ 166.84, 162.77 (d, J = 243.8 Hz) 156.40, 151.01, 150.43, 150.41, 140.11, 139.58, 135.38 (d, J = 8.2 Hz), 131.39 (d, J = 8.5Hz),130.12,128.54,127.58,127.34,124.84(d,J＝2.6Hz),122.78,121.48,121.40,119.64,119.03,115.67(d,J＝21.0Hz),115.19(d,J＝22.3Hz ).

Embodiment 17

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-17, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this example and Example 1 is that the benzaldehyde in step (1) of Example 1 is adjusted to biphenylaldehyde to obtain compound (E)-2-(2-(3-(naphthalen-2-yl)-1-phenyl-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 65%.

¹ H NMR (600MHz, DMSO-d ₆ , ppm) δ9.18 (s, 1H, Ar-H), 8.69 (d, J = 4.5Hz, 1H, Ar-H), 8.24 (s, 1H, Ar- H),8.10(d,J＝8.4Hz,1H,Ar-H),8.06(s,1H,Ar-H),8.00(d,J＝8.4Hz,3H,Ar-H),7.87(d, J＝8.2Hz,1H, Ar-H),7.80(s,1H,Ar-H),7.76(d,J＝16.0Hz,1H,-C＝CH-),7.63(d,J＝4.6Hz,1H,Ar-H), 7.59(t,J＝7.2Hz,4H,Ar-H),7.42–7.38(m,1H,Ar-H),7.36(d,J＝15.9Hz,1H,-C＝CH-). ¹³ C NMR (101MHz, DMSO-d ₆ ) δ166.88,156.49,151.83,150.96,139.71,133.42,133.08,130.60,130.13,128.80,128.71,128.27,128.15,127.72,127 .48,127.21,127.10,127.05,126.69,123.21 ,121.42,121.36,119.81,118.98,60.23,56.50,21.22,19.02,14.54.

Embodiment 18

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-18, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this embodiment and embodiment 1 is that the benzaldehyde in step (1) of embodiment 1 is adjusted to 2,3-dihydrobenzo[b][1,4]dioxin-6-carbaldehyde to obtain compound (E)-2-(2-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-phenyl-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 77%.

¹ H NMR (600 MHz, DMSO-d ₆ ,ppm)δ13.75(s,1H,-COOH),9.07(s,1H,Ar-H),8.73(d,J＝4.5Hz,1H,Ar-H),7.93(d,J＝7.8Hz,2H,Ar-H),7.78(s,1H,Ar-H),7.65(m,1H,-CH＝C-,1H,Ar-H),7. 56(t,J＝7.6Hz,2H,Ar-H),7.36(t,J＝7.2Hz,1H,Ar-H),7.31(d,J＝15.9Hz,1H,-CH＝C-),7.16(d,J＝8.0Hz,2H,Ar-H),7.03(d,J＝7.9Hz,1H,Ar-H),4.32(s,4H, -CH ₂ ). ¹³ C NMR (100MHz, DMSO-d ₆ , ppm) δ166.76,156.55,151.41,151.06,144.24,143.94,139.79,139.68,130.09,127.87,127.19,127.07,126.21,123.31,121 .77,121.33,119.26,118.86,117.94,117.16,64.67,64.62.

Embodiment 19

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-19, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this embodiment and embodiment 1 is that the benzaldehyde in step (1) of embodiment 1 is adjusted to 4-fluorobenzaldehyde, and the phenylhydrazine is adjusted to 4-fluorophenylhydrazine to obtain compound (E)-2-(2-(1,3-di(4-fluorophenyl)-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 64%.

¹ H NMR (600MHz, DMSO-d ₆ , ppm) δ13.69(s,1H,-COOH),9.10(s,1H,Ar-H),8.72(d,J＝4.7Hz,1H,Ar-H ),7.98(q,J＝8.4,4.5Hz,2H,Ar-H),7.79(s,1H,Ar-H),7.76–7.70(m,2H,Ar-H),7.65(s,1H, Ar-H),7.63(d,J＝9.8Hz,1H,-CH＝C-),7.48–7.35(m,4H,Ar-H),7.30(d,J＝15.9Hz,1H,-CH＝ C-). ¹³ C NMR (100MHz, DMSO-d ₆ ,ppm)δ166.27,162.57(d,J＝170.6Hz),160.98,159.30,155.96,150.48(d,J＝9.2Hz),139.31,135.74(d,J＝2.5Hz),130.32,130.24,128.94(d ,J＝3.1Hz),127.76,127.15,122.48,120.90,120.78,120.55,120.46,118.95,116.48,116.25,115.87,115.66.

Embodiment 20

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-20, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this embodiment and embodiment 1 is that the benzaldehyde in step (1) in embodiment 1 is adjusted to 4-fluorobenzaldehyde, and the phenylhydrazine is adjusted to 4-chlorophenylhydrazine to obtain compound (E)-2-(2-(1-(4-chlorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 69%.

¹ H NMR (600MHz, DMSO-d ₆ , ppm) δ13.72 (s, 1H), 9.14 (s, 1H), 8.72 (d, J = 4.7Hz, 1H), 7.97 (d, J = 8.7Hz, 2H),7.80(s,1H),7.77–7.71(m,2H),7.67–7.60(m,4H),7.40(t,J＝8.7Hz,2H),7.31(d,J＝15.9Hz,1H ). ¹³ C NMR (100MHz, DMSO-d ₆ ,ppm)δ166.71,163.96,161.51,156.42,151.15,151.05,139.64,138.42,131.26,130.83,130.75,130.02,129.33,129.30,128.41,127.55,122. 86,121.43,121.31,120.47,119.70,116.38,116.16.

Embodiment 21

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-21, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this embodiment and embodiment 1 is that the benzaldehyde in step (1) in embodiment 1 is adjusted to 4-fluorobenzaldehyde, and the phenylhydrazine is adjusted to 4-bromophenylhydrazine to obtain compound (E)-2-(2-(1-(4-bromophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 75%.

¹ H NMR (600MHz, DMSO-d ₆ , ppm) δ9.14 (s, 1H, Ar-H), 8.69 (d, J = 4.3Hz, 1H, Ar-H), 7.91 (d, J = 8.4Hz ,2H,Ar-H),7.79(s,1H,Ar-H),7.78–7.70(m,4H,Ar-H),7.63(s,1H,Ar-H),7.61(d,J＝15.8 Hz,1H,-CH＝C-),7.39(t,J＝8.5Hz,2H,Ar-H),7.29(d,J＝15.8Hz,1H,-CH＝C-). ¹³ C NMR (100MHz ,DMSO-d ₆ ,ppm)δ167.14,163.95,161.51,156.21,151.15,150.85,141.12,138.82,132.92,130.83,130.74,129.34,129.31,128.64,127.47,122.57,121. 58,121.44,120.76,119.78,119.49,116.38,116.17.

Example 22

R²为

其制备过程如下：A pyrazole-vinyl-isonicotinic acid derivative, to obtain compound Ⅰ-22, wherein R ¹ is

^R2 is

The preparation process is as follows:

The difference between this embodiment and embodiment 1 is that the benzaldehyde in step (1) in embodiment 1 is adjusted to 4-fluorobenzaldehyde, and the phenylhydrazine is adjusted to 4-methoxyphenylhydrazine to obtain compound (E)-2-(2-(3-(4-fluorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-4-yl)vinyl)isonicotinic acid as a yellow solid with a yield of 67%.

¹ H NMR (600MHz, DMSO-d6, ppm) δ8.98 (s, 1H, Ar-H), 8.60 (d, J = 3.9Hz, 1H, Ar-H), 7.85 (d, J = 8.4Hz, 2H,Ar-H),7.78(s,1H,Ar-H),7.71(d,J＝5.8Hz,2H,Ar-H),7.61(d,J＝3.8Hz,1H,Ar-H), 7.58(d,J＝16.1Hz,1H,-C＝CH-),7.38(t,J＝8.4Hz,2H,Ar-H),7.24(d,J＝15.9Hz,1H,-C＝CH- ),7.11(d,J＝8.4Hz,2H,Ar-H),3.82(s,3H,-CH3). ¹³ C NMR(100MHz,DMSO-d6,ppm)δ163.81,161.37,158.45,155.99,150.40,150.36,133.31,130.77,130.69,129.74,129.71,128.44,127.06,122.39,121.76 ,121.61,120.52,119.11,116.33,116.12, 115.15,55.95.

Experimental Example 1

KDM5B inhibitory activity assay

1.1 Detection of KDM5B activity inhibition

(1) Configure 1×Assay buffer.

(2) Compound concentration gradient configuration: The starting concentration of the test compound was 25 μM, which was diluted 3 times and divided into 10 concentrations, each of which was tested in a single well. The starting concentration of the positive control compound CPI-455 was 1 μM, which was diluted 3 times and divided into 10 concentrations, each of which was tested in duplicate wells. The solution was diluted to a corresponding 1000-fold final concentration in a 384-well Source plate, and then 10 nL was transferred to a 384-well reaction plate for testing using Echo550. 10 nL of 100% DMSO was transferred to the Min and Max wells.

(3) Prepare 2× enzyme solution using 1× reaction solution.

(4) Use 1× reaction solution to prepare 2× substrate mixed solution.

(5) Add 5 μL of 2× enzyme solution to each well; add 5 μL of 1× reaction solution to the Min well, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 15 min.

(6) Add 5 μL of 2× substrate mixed solution to each well of the reaction plate to start the reaction, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 30 min.

(7) Add 10 μL of the test solution to each well, centrifuge at 1000 rpm for 1 min, and incubate at room temperature for 60 min.

(8) Use EnVision to read the signal Intensity (665nm)/Intensity (615nm).

Data analysis was performed according to the following formula:

Fitting the dose-effect curve: The X-axis is the log value of the concentration, and the Y-axis is the percentage inhibition rate. The log (inhibitor) vs. response-Variable slope of the analysis software GraphPadPrism5 was used to fit the dose-effect curve to obtain the IC ₅₀ value of the compound's inhibition of protein binding.

1.2 Experimental Results

The experimental results are shown in the following table:

Table 1

As shown in Table 1, the compounds with the general structural formula I have significant inhibitory activity against histone demethylase KDM5B, and the IC ₅₀ of compounds I-1, I-3, I-5, I-6, I-7, I-9, I-10, I-19, and I-22 are <10 μM, and the IC ₅₀ of compounds I-7 and I-10 are as low as nanomolar level. It is shown that the compounds with the general structural formula I in the present invention have significant inhibitory activity against histone demethylase 5B.

The above-mentioned embodiments are only preferred embodiments of the present invention and cannot be used to limit the scope of protection of the present invention. Any non-substantial changes and substitutions made by technicians in this field on the basis of the present invention shall fall within the scope of protection required by the present invention.

Claims (9)

1. A pyrazole-vinyl-isonicotinic acid derivative, characterized in that it has the general structural formula I

Wherein, when R ¹ is selected from phenyl, substituted phenyl,

When benzodioxinyl, R ² is selected from phenyl, substituted phenyl; When ^R1 is selected from

When, R ² is selected from substituted phenyl; The substituents of the substituted phenyl group are C1-C6 saturated alkyl, C1-C6 saturated alkoxy, halogen, nitro, C1-C6 saturated alkanesulfonyl, and phenyl. 2. The pyrazole-vinyl-isonicotinic acid derivative as claimed in claim 1, wherein said R ^is selected from

^R2 is selected from

3. The preparation method of the pyrazole-vinyl-isonicotinic acid derivative according to any one of claims 1 to 2, characterized in that, comprising the following steps:

(1) adding absolute ethanol to compound A, then adding compound B and a catalyst therein, stirring and reacting at room temperature to obtain compound C; (2) First prepare the Vilsmeier-Haack reagent: add phosphorus oxychloride dropwise to N,N-dimethylformamide under ice bath conditions, stir at room temperature to obtain the mixture; dissolve the compound C obtained in step (1) in N, Add N-dimethylformamide dropwise to the above mixture under ice bath, stir and react to prepare Compound D; (3) Mix compound D obtained in step (2) with 2-methylisonicotinic acid, N,N-dimethylformamide, and a catalyst, and react with stirring to obtain compound I. 4. the preparation method of pyrazole-vinyl-isonicotinic acid derivative as claimed in claim 3 is characterized in that, the catalyzer of described step (1) is glacial acetic acid, and the addition molar ratio of compound A, compound B is 1:1, the ratio of compound A to absolute ethanol is 1g:10-20mL. 5. the preparation method of pyrazole-vinyl-isonicotinic acid derivative as claimed in claim 3, is characterized in that, compound C and phosphorus oxychloride, N,N in described step (2) Vilsmeier-Haack reagent - The addition molar ratio of dimethylformamide is 1:5:10; When compound C is dissolved in N,N-dimethylformamide, the addition ratio of compound C and N,N-dimethylformamide is 1g:10mL. 6. the preparation method of pyrazole-vinyl-isonicotinic acid derivative as claimed in claim 3, is characterized in that, the catalyst in described step (3) is trimethylchlorosilane; The molar ratio of compound D to 2-methylisonicotinic acid is 1:1. 7. The application of the pyrazole-vinyl-isonicotinic acid derivative according to any one of claims 1 to 2, characterized in that the derivative is used to prepare a drug for inhibiting KDM5B. 8 . The application according to claim 7 , wherein the derivative is used to prepare a medicament for treating tumors with high expression of KDM5B. 9. The use according to claim 8, wherein the tumor is gastric cancer, breast cancer or prostate cancer.