CN114907317A - Pyrazole-vinyl-isonicotinic acid derivative and preparation method and application thereof - Google Patents

Pyrazole-vinyl-isonicotinic acid derivative and preparation method and application thereof Download PDF

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CN114907317A
CN114907317A CN202210621385.8A CN202210621385A CN114907317A CN 114907317 A CN114907317 A CN 114907317A CN 202210621385 A CN202210621385 A CN 202210621385A CN 114907317 A CN114907317 A CN 114907317A
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vinyl
isonicotinic acid
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黄利华
李冉
符运栋
黄明杰
宋亭谕
李远洋
高北岭
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Zhengzhou University
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Abstract

The invention discloses a pyrazole-vinyl-isonicotinic acid derivative, which has obvious biological inhibition activity on KDM5B, can be used for preparing and researching a novel KDM5B inhibitor, enriches the variety of isonicotinic acid derivatives and lays a foundation for developing KDM5B inhibition medicaments. 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 an inhibitory effect on KDM5B at a nanomolar level on an enzyme level, provides a lead compound structure for further researching an anti-cancer drug inhibiting KDM5B, and has a good application prospect.

Description

Pyrazole-vinyl-isonicotinic acid derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and relates to a pyrazole-vinyl-isonicotinic acid derivative, and a preparation method and application thereof.
Background
Cancer has developed into a public health problem seriously threatening the health of the global public, placing a heavy burden on the families and society, and its morbidity and mortality are still increasing. The cancer treatment comprises surgery, radiotherapy, chemotherapy, molecular targeted therapy, tumor immunotherapy, cell therapy and the like, wherein the molecular targeted therapy medicine can specifically inhibit tumor growth related regulatory factors or inhibit microenvironment and the like which are beneficial to the growth or survival of the cancer, so that the growth, invasion and metastasis of the tumor are inhibited or blocked, and the safety is higher than that of the traditional chemotherapy medicine. Therefore, designing and developing targeted anticancer therapeutic drugs with good effects and little side effects is urgent and necessary.
Methylation modification of histone is a reversible epigenetic process, mainly occurs on lysine and arginine residues of tail, and has wide biological functions. The existence of lysine specific demethylase 1 (LSD 1) is found for the first time in the subject group of professor of Populus at Harvard university, and the methylation of histone is confirmed to be a reversible process. Subsequently, there are a number of groups reporting the Jumonji C (JmjC) family of histone demethylases. With the continuous and intensive research, unknown problems in the process of methylation modification of histones are gradually uncovered. The expression regulation histone lysine demethylase KDM5B (lysine-specific demethylase 5B, KDM5B), also known as plu-1 or JARID1B, belongs to one member of JMJD (Jmjc-KDMs) subfamily, can remove H3K4Me2/3 methylation state, regulates the transcription and expression of genes, and is closely related to the occurrence and development of diseases such as cancer, immunity, chemotherapy multiple drug resistance and the like. According to related research reports, KDM5B is over-expressed in various solid tumors such as prostate, gastric cancer, breast cancer, ovarian cancer, liver cancer and the like and leukemia, and the over-expression level is related to the deterioration degree and poor prognosis of the cancer. A large number of evidences show that KDM5B is a potential oncogene, the reduction or knockout of the expression level of KDM5B can obviously inhibit the tumor biological activities such as tumor metastasis and invasion, and the like, and the antitumor drug targeting KDM5B provides a new opportunity for cancer treatment.
In recent years, through computer-aided technology (high-throughput virtual screening, HTS) and corresponding drug design means, a plurality of KDM5 inhibitors with different structural frameworks have been discovered, wherein part of the inhibitors (CPI-455, EPT103182) have already entered preclinical research, but no drugs are yet on the market at present, and most of the inhibitors are still in early research stage. Therefore, the development of KDM5B inhibitor with high efficiency, low toxicity, high selectivity and good pharmacokinetic parameters is of great significance.
Disclosure of Invention
In order to overcome the disadvantages of the prior art, one of the objects of the present invention is to provide a pyrazole-vinyl-isonicotinic acid derivative having a good inhibitory effect on HDM5B, its IC 50 On the micrometer scale, exhibit good inhibitory activity.
Another object of the present invention is to provide a process for producing a pyrazole-vinyl-isonicotinic acid derivative.
The invention also aims to provide application of the pyrazole-vinyl-isonicotinic acid derivative in preparing a medicament for inhibiting KDM 5B.
One of the purposes of the invention is realized by adopting the following technical scheme:
a pyrazole-vinyl-isonicotinic acid derivative with a structural general formula I
Figure BDA0003674794700000021
Wherein R is 1 Selected from phenyl, substituted phenyl, N-containing six-membered heterocyclic group, benzo dioxin radical;
R 2 selected from phenyl and substituted phenyl.
Furthermore, the substituent of the substituted phenyl is C1-C6 saturated alkyl, C1-C6 saturated alkoxy, halogen, nitro, C1-C6 saturated alkylsulfonyl and phenyl.
Further, said R 1 Is selected from
Figure BDA0003674794700000022
Figure BDA0003674794700000023
R 2 Is selected from
Figure BDA0003674794700000024
The second purpose of the invention is realized by adopting the following technical scheme:
a process for the preparation of pyrazole-vinyl-isonicotinic acid derivatives comprising the steps of:
Figure BDA0003674794700000031
(1) adding absolute ethyl alcohol into the compound A, then adding the compound B and a catalyst into the compound A, and stirring the mixture at room temperature to react to obtain a compound C;
(2) firstly, Vilsmeier-Haack reagent is prepared: dropwise adding phosphorus oxychloride into N, N-dimethylformamide under an ice bath condition, and stirring at room temperature to obtain a mixture; dissolving the compound C obtained in the step (1) in N, N-dimethylformamide, dropwise adding the mixture into the mixture under ice bath, and stirring for reaction to obtain a compound D;
(3) and (3) mixing the compound D obtained in the step (2) with 2-methylisonicotinic acid, N-dimethylformamide and a catalyst, and stirring to react to obtain a compound I.
Further, the catalyst in the step (1) is glacial acetic acid, the adding molar ratio of the compound A to the compound B is 1:1, and the adding ratio of the compound A to the absolute ethyl alcohol is 1 g: 10-20 mL.
Further, in the Vilsmeier-Haack reagent in the step (2), the adding molar ratio of the compound C to the phosphorus oxychloride and the N, N-dimethylformamide is 1:5: 10;
when the compound C is dissolved in N, N-dimethylformamide, the adding ratio of the compound C to the N, N-dimethylformamide is 1 g: 10 mL.
Further, the catalyst in the step (3) is trimethylchlorosilane;
the addition molar ratio of the compound D to 2-methylisonicotinic acid is 1: 1.
The third purpose of the invention is realized by adopting the following technical scheme:
use of a pyrazole-vinyl-isonicotinic acid derivative for the preparation of a medicament for inhibiting KDM 5B.
Furthermore, the derivative is used for preparing a medicine for treating tumors with high KDM5B expression.
Further, the tumor is gastric cancer, breast cancer or prostate cancer.
Compared with the prior art, the invention has the beneficial effects that:
the pyrazole-vinyl-isonicotinic acid derivative provided by the invention has obvious biological inhibition activity on KDM5B, can be used for preparing and researching a novel KDM5B inhibitor, enriches the variety of isonicotinic acid derivatives, and lays a foundation for developing KDM5B inhibition drugs. 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, the condition is mild and the yield is high. The compound has an inhibitory effect on KDM5B at a nanomolar level on an enzyme level, provides a lead compound structure for further researching an anti-cancer drug inhibiting KDM5B, and has a good application prospect.
Detailed Description
The present invention is further described below with reference to specific embodiments, and it should be noted that, without conflict, any combination between the embodiments or technical features described below may form a new embodiment.
Example 1
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-1, wherein R 1 Is composed of
Figure BDA0003674794700000041
R 2 Is composed of
Figure BDA0003674794700000042
The preparation process comprises the following steps:
Figure BDA0003674794700000043
(1) adding benzaldehyde (compound A, 1g, 8.32mmol) into a 50mL flask, adding 20mL of absolute ethanol, adding phenylhydrazine (compound B, 900.07mg, 8.32mmol) and glacial acetic acid (0.05mL, equivalent weight is 0.05), and reacting under reflux at room temperature for 1h under stirring; after the reaction is finished, most of the organic solvent is removed by reduced pressure rotary evaporation, a large amount of solid is separated out by slow temperature reduction, and the white solid (E) -1-phenyl-2- (1-phenylethylidene) hydrazine (compound C, 1.2g, 5.71mmol) is obtained by suction filtration, wherein the yield is 68%. The product was unstable and was then immediately sent to the next step.
(2) Firstly, Vilsmeier-Haack reagent is prepared: preparation N, N-dimethylformamide (4.17g, 57.07mmol) was weighed into a 100mL flask, and phosphorus oxychloride (4.37g, 28.53mmol) was added dropwise under ice bath and stirred at room temperature for 40min (the molar ratio of compound C to phosphorus oxychloride, N-dimethylformamide added was 1:5: 10). Then weighing the compound C (1.2g, 5.71mmol) obtained in the step (1) and dissolving the compound C in 5mL of N, N-dimethylformamide, dropwise adding the compound C into the Vilsmeier-Haack reagent prepared in the ice bath, reacting for 5H at 85 ℃ under stirring, monitoring by TLC after the reaction is completed, then adding 200mL of ice water, adding KOH alkaline aqueous solution to adjust the pH to be neutral (the pH is 6-7), fully performing ultrasonic treatment and performing suction filtration to obtain a white solid 1, 3-diphenyl-1H-pyrazole-4-carboxylic acid (a compound D, 994mg, 3.99mmol) with the yield of 70%.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d 6 ,ppm)δ12.55(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＝8.0Hz,2H,Ar-H),7.48–7.41(m,3H,Ar-H),7.39(t,J＝7.4Hz,1H,Ar-H).
(3) adding 1, 3-diphenyl-1H-pyrazole-4-carboxylic acid (compound D, 900mg, 3.68mmol) prepared in the step (2), 2-methylisonicotinic acid (497.11mg, 3.68mmol) and trimethylchlorosilane (3mL, equivalent weight of 0.05) solvent N, N-dimethylformamide (15mL) into a Schlenk tube, mixing at 120 ℃ for 24 hours, monitoring the reaction by TCL, firstly adding 100mL of water, carrying out ultrasonic treatment, carrying out suction filtration and drying to obtain a crude product, carrying out silica gel column chromatography separation on the crude product, eluting by dichloromethane/methanol (V: 10:1) to obtain compound I-1 (1.04g, 2.87mmol) ((E) -2- (2- (1, 3-diphenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid), yellow solid, yield 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,1H,-CH＝C-),7.68(d,J＝16.7Hz,2H,Ar-H),7.64(d,J＝4.5Hz,1H,Ar-H),7.57(dd,J＝11.4,7.2Hz,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
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-2, wherein R 1 Is composed of
Figure BDA0003674794700000051
R 2 Is composed of
Figure BDA0003674794700000052
The preparation process comprises the following steps:
this example differs from example 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-pyridinecarboxaldehyde to give the compound (E) -2- (2- (1-phenyl-3- (pyridin-4-yl) -1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 64% yield.
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 C NMR(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
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-3, wherein R 1 Is composed of
Figure BDA0003674794700000053
R 2 Is composed of
Figure BDA0003674794700000054
The preparation process comprises the following steps:
this example differs from example 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 3-pyridinecarboxaldehyde to give the compound (E) -2- (2- (1-phenyl-3- (pyridin-3-yl) -1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 68% yield.
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
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-4, wherein R 1 Is composed of
Figure BDA0003674794700000061
R 2 Is composed of
Figure BDA0003674794700000062
The preparation process comprises the following steps:
this example differs from example 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-methylbenzaldehyde to give the compound (E) -2- (2- (1-phenyl-3- (tolyl) -1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 63% yield.
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
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-5, wherein R 1 Is composed of
Figure BDA0003674794700000063
R 2 Is composed of
Figure BDA0003674794700000064
The preparation process comprises the following steps:
the present example differs from example 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 2-fluorobenzaldehyde to give the compound (E) -2- (2- (3- (2-fluorophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 71% yield.
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
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-6, wherein R 1 Is composed of
Figure BDA0003674794700000071
R 2 Is composed of
Figure BDA0003674794700000072
The preparation process comprises the following steps:
this example differs from example 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 3-fluorobenzaldehyde to give the compound (E) -2- (2- (3- (3-fluorophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 61% yield.
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＝3.4Hz),122.92(d,J＝3.5Hz),121.45,121.27,120.76(t,J＝7.5Hz),119.00,116.70,116.48.
Example 7
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-7, wherein R 1 Is composed of
Figure BDA0003674794700000073
R 2 Is composed of
Figure BDA0003674794700000074
The preparation process comprises the following steps:
this example differs from example 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-fluorobenzaldehyde to give the compound (E) -2- (2- (3- (4-fluorophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 65% yield.
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＝8.8Hz,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
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-8, wherein R 1 Is composed of
Figure BDA0003674794700000075
R 2 Is composed of
Figure BDA0003674794700000076
The preparation process comprises the following steps:
this example differs from example 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-chlorobenzaldehyde to give the compound (E) -2- (2- (3- (4-chlorophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 65% yield.
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
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-9, wherein R 1 Is composed of
Figure BDA0003674794700000081
R 2 Is composed of
Figure BDA0003674794700000082
The preparation process comprises the following steps:
the present example differs from example 1 in that: the benzaldehyde from step (1) of example 1 was adjusted to 4-bromobenzaldehyde to give the compound (E) -2- (2- (3- (4-bromophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 77% yield.
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
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-10, wherein R 1 Is composed of
Figure BDA0003674794700000083
R 2 Is composed of
Figure BDA0003674794700000084
The preparation process comprises the following steps:
this example differs from example 1 in that: the 4-methoxybenzaldehyde in step (1) of example 1 gave the compound (E) -2- (2- (3- (4-methoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 66% yield.
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)δ166.69,159.91,156.64,151.80,151.08,139.71,139.45,130.09,130.01,127.71,127.17,127.03,125.40,123.51,121.27,121.22,119.23,118.84,114.74,55.70.
Example 11
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-11, wherein R 1 Is composed of
Figure BDA0003674794700000091
R 2 Is composed of
Figure BDA0003674794700000092
The preparation process comprises the following steps:
this example differs from example 1 in that: the benzaldehyde from step (1) of example 1 was adjusted to 4-nitrobenzaldehyde to give the compound (E) -2- (2- (3- (4-nitrophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 78% yield.
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 C NMR(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
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-12, wherein R 1 Is composed of
Figure BDA0003674794700000093
R 2 Is composed of
Figure BDA0003674794700000094
The preparation process comprises the following steps:
the present example differs from example 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 1-methyl-4 (methylsulfonyl) benzaldehyde to give the compound (E) -2- (2- (3- (4- (methylsulfonyl) phenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 69% yield.
1 H NMR(600MHz,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 ). 13 C 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
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-13, wherein R 1 Is composed of
Figure BDA0003674794700000101
R 2 Is composed of
Figure BDA0003674794700000102
The preparation process comprises the following steps:
this example differs from example 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-phenylbenzaldehyde to give the compound (E) -2- (2- (3- ([1,1' -diphenyl ] -4-yl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 59% yield.
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 )δ165.93,155.57,151.01,149.76,140.00,139.64,139.48,139.15,131.56,129.64,129.00,128.74,127.68,127.13,127.03,126.78,126.66,123.84,121.19,121.07,119.02,118.50.
Example 14
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-14, wherein R 1 Is composed of
Figure BDA0003674794700000103
R 2 Is composed of
Figure BDA0003674794700000104
The preparation process comprises the following steps:
this example differs from example 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 1- (benzyloxy) -4-methylbenzaldehyde to give the compound (E) -2- (2- (3- (4- (benzyloxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 62% yield.
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.
Example 15
A pyrazole-vinyl-isonicotinic acid derivative to give a compound I-15, wherein R 1 Is composed of
Figure BDA0003674794700000111
R 2 Is composed of
Figure BDA0003674794700000112
The preparation process comprises the following steps:
this example differs from example 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 2, 4-difluorobenzaldehyde to give the compound (E) -2- (2- (3- (2, 4-difluorophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 64% yield.
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
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-16, wherein R 1 Is composed of
Figure BDA0003674794700000113
R 2 Is composed of
Figure BDA0003674794700000114
The preparation process comprises the following steps:
this example differs from example 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 2, 5-difluorobenzaldehyde to give the compound (E) -2- (2- (3- (2, 6-difluorophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 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 )δ166.84,162.77(d,J＝243.8Hz)156.40,151.01,150.43,150.41,140.11,139.58,135.38(d,J＝8.2Hz),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).
Example 17
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-17, wherein R 1 Is composed of
Figure BDA0003674794700000121
R 2 Is composed of
Figure BDA0003674794700000122
The preparation process comprises the following steps:
this example differs from example 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to biphenylcarboxaldehyde to give the compound (E) -2- (2- (3- (naphthalen-2-yl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 65% yield.
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.
Example 18
Pyrazole-vinyl-isonicotinic acid derivatives, to give compounds I-18, which are useful as herbicidesIn R 1 Is composed of
Figure BDA0003674794700000123
R 2 Is composed of
Figure BDA0003674794700000124
The preparation process comprises the following steps:
this example differs from example 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-carbaldehyde to give the 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 in a yield of 77%.
1 H NMR(600MHz,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.
Example 19
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-19, wherein R 1 Is composed of
Figure BDA0003674794700000126
R 2 Is composed of
Figure BDA0003674794700000125
The preparation process comprises the following steps:
the present example differs from example 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-fluorobenzaldehyde and the phenylhydrazine was adjusted to 4-fluorophenylhydrazine to obtain compound (E) -2- (2- (1, 3-bis (4-fluorophenyl) -1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 64% yield.
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.
Example 20
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-20, wherein R 1 Is composed of
Figure BDA0003674794700000131
R 2 Is composed of
Figure BDA0003674794700000132
The preparation process comprises the following steps:
this example differs from example 1 in that: the benzaldehyde in step (1) in example 1 was adjusted to 4-fluorobenzaldehyde and phenylhydrazine was adjusted to 4-chlorophenylhydrazine to obtain the compound (E) -2- (2- (1- (4-chlorophenyl) -3- (4-fluorophenyl) -1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 69% yield.
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.
Example 21
A pyrazole-vinyl-isonicotinic acid derivative to give compound I-21, wherein R 1 Is composed of
Figure BDA0003674794700000133
R 2 Is composed of
Figure BDA0003674794700000134
The preparation process comprises the following steps:
this example differs from example 1 in that: the benzaldehyde in step (1) in example 1 was adjusted to 4-fluorobenzaldehyde and phenylhydrazine was adjusted to 4-bromophenylhydrazine to give the compound (E) -2- (2- (1- (4-bromophenyl) -3- (4-fluorophenyl) -1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 75% yield.
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＝15.8Hz,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
A pyrazole-vinyl-isonicotinic acid derivative to give a compound I-22, wherein R 1 Is composed of
Figure BDA0003674794700000141
R 2 Is composed of
Figure BDA0003674794700000142
The preparation process comprises the following steps:
this example differs from example 1 in that: the benzaldehyde in step (1) in example 1 was adjusted to 4-fluorobenzaldehyde and phenylhydrazine was adjusted to 4-methoxyphenylhydrazine to give the compound (E) -2- (2- (3- (4-fluorophenyl) -1- (4-methoxyphenyl) -1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 67% yield.
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
Assay for KDM5B inhibitory Activity
1.1 detection of inhibitory Effect of KDM5B Activity
(1) Configure 1 × Assaybuffer.
(2) Compound concentration gradient configuration: the test compound was tested at an initial concentration of 25 μ M, diluted 3-fold, and divided into 10 concentrations, each concentration being tested in a single well. The positive control compound CPI-455 was tested at an initial concentration of 1 μ M, diluted 3-fold, and equally divided into 10 concentrations, each concentration setting for a duplicate well test. Diluted to a solution of the corresponding 1000-fold final concentration in 384-well Source plates, and then 10nL was transferred to 384-well reaction plates using Echo550 for assay. Transfer 10nL of 100% DMSO in Min and Max wells.
(3) A2 Xenzyme solution was prepared from the 1 Xreaction solution.
(4) A2 Xsubstrate mixed solution was prepared from the 1 Xreaction solution.
(5) Add 5. mu.L of 2 Xenzyme solution to each well; mu.L of the 1 × reaction solution was added to Min wells, centrifuged at 1000rpm for 1Min, and incubated at room temperature for 15 Min.
(6) mu.L of a 2 Xsubstrate mix solution was added to each well of the reaction plate and the reaction was initiated, centrifuged at 1000rpm for 1min and incubated at room temperature for 30 min.
(7) Add 10. mu.L of assay to each well, centrifuge at 1000rpm for 1min, and incubate for 60 min at room temperature.
(8) The signals Intensity (665nm)/Intensity (615nm) were read using EnVision.
Data analysis was performed according to the following formula:
Figure BDA0003674794700000151
fitting a dose-response curve: the X axis isLog values of concentration, Y-axis percent inhibition, Log (inhibitor) vs. s. response-Variable slope of GraphPad Prism5 were used to fit dose-response curves to derive IC for inhibition of protein binding by compounds 50 The value is obtained.
1.2 results of the experiment
The results are shown in the following table:
Figure BDA0003674794700000152
TABLE 1
Figure BDA0003674794700000153
Figure BDA0003674794700000161
Figure BDA0003674794700000171
As can be seen from Table 1, the compounds having the general structural formula I have significant inhibitory activity on histone demethylase KDM5B, and the IC of the compounds I-1, I-3, I-5, I-6, I-7, I-9, I-10, I-19 and I-22 50 <10 μ M, in which compounds I-7, IC of I-10 50 Down to nanomolar scale. The compound with the structural general formula I has obvious inhibition activity on histone demethylase 5B.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.

Claims (10)

1. A pyrazole-vinyl-isonicotinic acid derivative is characterized by having a structural general formula I
Figure FDA0003674794690000011
Wherein R is 1 Selected from phenyl, substituted phenyl, N-containing six-membered heterocyclic group, benzo dioxin radical;
R 2 selected from phenyl and substituted phenyl.
2. The pyrazole-vinyl-isonicotinic acid derivative of claim 1 wherein the substituents of said substituted phenyl are C1-C6 saturated alkyl, C1-C6 saturated alkoxy, halogen, nitro, C1-C6 saturated alkylsulfonyl, phenyl.
3. The pyrazole-vinyl-isonicotinic acid derivative of claim 2 wherein R is 1 Is selected from
Figure FDA0003674794690000012
Figure FDA0003674794690000013
R 2 Is selected from
Figure FDA0003674794690000014
4. A process for the preparation of pyrazole-vinyl-isonicotinic acid derivatives according to any of claims 1 to 3, characterized in that it comprises the following steps:
Figure FDA0003674794690000015
(1) adding absolute ethyl alcohol into the compound A, then adding the compound B and a catalyst into the compound A, and stirring the mixture at room temperature to react to obtain a compound C;
(2) firstly, Vilsmeier-Haack reagent is prepared: dropwise adding phosphorus oxychloride into N, N-dimethylformamide under an ice bath condition, and stirring at room temperature to obtain a mixture; dissolving the compound C obtained in the step (1) in N, N-dimethylformamide, dropwise adding the mixture into the mixture in an ice bath, and stirring for reaction to obtain a compound D;
(3) and (3) mixing the compound D obtained in the step (2) with 2-methylisonicotinic acid, N-dimethylformamide and a catalyst, and stirring to react to obtain a compound I.
5. The process for preparing pyrazole-vinyl-isonicotinic acid derivatives according to claim 4, wherein the catalyst of 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 absolute ethanol is 1 g: 10-20 mL.
6. The process for preparing pyrazole-vinyl-isonicotinic acid derivatives as claimed in claim 4, wherein in the step (2), the Vilsmeier-Haack reagent is added with phosphorus oxychloride and N, N-dimethylformamide in a molar ratio of 1:5: 10;
when the compound C is dissolved in N, N-dimethylformamide, the adding ratio of the compound C to the N, N-dimethylformamide is 1 g: 10 mL.
7. The process for preparing a pyrazole-vinyl-isonicotinic acid derivative according to claim 4, wherein the catalyst in step (3) is trimethylchlorosilane;
the addition molar ratio of the compound D to 2-methylisonicotinic acid is 1: 1.
8. Use of a pyrazole-vinyl-isonicotinic acid derivative according to any of claims 1 to 3, characterized in that it is used for the preparation of a medicament for inhibiting KDM 5B.
9. The use according to claim 8, wherein said derivative is used for the preparation of a medicament for the treatment of tumors that highly express KDM 5B.
10. The use of claim 8, wherein the tumor is a gastric cancer, a breast cancer or a prostate cancer.
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