CN114907317B - 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 PDFInfo
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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
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
Cancer has developed into a public health problem that severely threatens the health of the general public, placing a heavy burden on the home and society, and its morbidity and mortality are still increasing. Cancer treatment comprises surgery, radiotherapy, chemotherapy, molecular targeted therapy, tumor immunotherapy, cell therapy and the like, wherein the molecular targeted therapy drug can specifically inhibit a regulatory factor related to tumor growth or inhibit microenvironment conducive to cancer growth or survival, and the like, so that tumor growth, invasion and metastasis are inhibited or blocked, and the safety is higher than that of the traditional chemotherapy drug. Therefore, the targeted anticancer therapeutic drug with good design and research and development effects and small side effects has urgency and necessity.
Methylation modification of histones is a reversible epigenetic process, mainly occurring on tail lysine and arginine residues, with a broad range of biological functions. The university of harvard Shi Yang professor task group discovered for the first time that lysine-specific demethylase 1 (lysine specific demethylase, lsd 1) was present, confirming that histone methylation is a reversible process. Later, there are several subject groups reporting the family of histone demethylases, jumonji C (JMjC). With the continuous and intensive research, the unknown problems in the methylation modification process of histones are gradually revealed. The apparent regulatory histone lysine demethylase KDM5B (lysine-specific demethylase B, KDM 5B), also called plu-1 or JARID1B, belongs to one member of the (JMjjc-KDMS) subfamily of JMJD, can remove the methylation state of H3K4Me2/3, 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 the related research report, 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 worsening degree of the cancer and the poor prognosis. A great deal of evidence shows that KDM5B is a potential oncogene, and the reduction or knockout of the expression level of KDM5B can obviously inhibit the tumor bioactivity such as tumor metastasis and invasion, and the anti-tumor drug targeting KDM5B provides a new opportunity for cancer treatment.
In recent years, KDM5 inhibitors of various structural frameworks have been discovered by computer-aided technology (high throughput virtual screening, HTS) in combination with corresponding drug design approaches, some of which (CPI-455, EPT 103182) have entered preclinical studies, but currently no drug is marketed, and most of which are still in early stages of research. Therefore, it is of great importance to develop KDM5B inhibitors with high potency, low toxicity, high selectivity and good pharmacokinetic parameters.
Disclosure of Invention
In order to overcome the deficiencies of the prior art, one of the objects of the present invention is to provide a pyrazole-vinyl-isonicotinic acid derivative which has a good inhibitory effect on HDM5B, IC 50 On the order of micrometers, shows good inhibitory activity.
It is a second object of the present invention to provide a process for the preparation of pyrazole-vinyl-isonicotinic acid derivatives.
The invention further aims to provide application of the pyrazole-vinyl-isonicotinic acid derivative in preparing medicines for inhibiting KDM 5B.
One of the purposes of the invention is realized by adopting the following technical scheme:
pyrazole-vinyl-isonicotinic acid derivative with structural formula I
Wherein R is 1 Selected from phenyl, substituted phenyl, N-containing six membered heterocyclyl, benzodioxinyl;
R 2 selected from phenyl and substituted phenyl.
Further, the substituent of the substituted phenyl is C1-C6 saturated alkyl, C1-C6 saturated alkoxy, halogen, nitro, C1-C6 saturated alkylsulfonyl and phenyl.
Further, the R 1 Selected from the group consisting of
R 2 Selected from the group consisting of
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:
(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 for reaction to obtain a compound C;
(2) First, vilsmeier-Haack reagent was prepared: dropwise adding phosphorus oxychloride into N, N-dimethylformamide under 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 N-dimethylformamide into the mixture in 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-methyliisonicotinic acid, N-dimethylformamide and a catalyst, and stirring for reaction 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 1g:10-20mL.
Further, the addition mole ratio of the compound C to phosphorus oxychloride and N, N-dimethylformamide in the Vilsmeier-Haack reagent in the step (2) 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 1g:10mL.
Further, the catalyst in the step (3) is trimethylchlorosilane;
the addition molar ratio of the compound D to the 2-methylisonicotinic acid is 1:1.
The third purpose of the invention is realized by adopting the following technical scheme:
use of pyrazole-vinyl-isonicotinic acid derivatives for the preparation of a medicament for inhibiting KDM 5B.
Further, the derivative is used for preparing medicines 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 invention provides a pyrazole-vinyl-isonicotinic acid derivative which has obvious 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.
Detailed Description
The present invention will be further described with reference to the following specific embodiments, and it should be noted that, on the premise of no conflict, new embodiments may be formed by any combination of the embodiments or technical features described below.
Example 1
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-1, wherein R 1 Is that
R 2 Is->
The preparation process is as follows:
(1) Benzaldehyde (compound A,1g,8.32 mmol) is taken in a 50mL flask, 20mL of absolute ethyl alcohol is added, phenylhydrazine (compound B,900.07mg,8.32 mmol) and glacial acetic acid (0.05 mL, equivalent weight is 0.05) are added, and reflux reaction is carried out for 1h under stirring at room temperature; after the reaction, most of the organic solvent was removed by rotary evaporation under reduced pressure, a large amount of solid was precipitated by slow cooling, and the mixture was suction-filtered to obtain (E) -1-phenyl-2- (1-phenylethynyl) hydrazine (compound C,1.2g,5.71 mmol) as a white solid, with a yield of 68%. Because the product is unstable, it needs to be rapidly taken to the next step.
(2) First, vilsmeier-Haack reagent was prepared: preparation N, N-dimethylformamide (4.17 g,57.07 mmol) was weighed into a 100mL flask, phosphorus oxychloride (4.37 g,28.53 mmol) was added dropwise under ice bath and stirred at room temperature for 40min (molar ratio of addition of compound C to phosphorus oxychloride to N, N-dimethylformamide was 1:5:10). Then, compound C (1.2 g,5.71 mmol) obtained in the step (1) is weighed and dissolved in 5mL of N, N-dimethylformamide, the obtained compound C is dropwise added into the prepared Vilsmeier-Haack reagent in an ice bath, the reaction is carried out for 5H under the condition of stirring at 85 ℃, 200mL of ice water is added after the TLC monitoring reaction is finished, KOH alkaline aqueous solution is added to adjust the pH to be neutral (pH is 6-7), and white solid 1, 3-diphenyl-1H-pyrazole-4-carboxylic acid (compound D,994mg,3.99 mmol) is obtained through full ultrasonic filtration and suction filtration, and the yield is 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) 1, 3-diphenyl-1H-pyrazole-4-carboxylic acid (compound D,900mg,3.68 mmol) prepared in the step (2), 2-methyliisonicotinic acid (497.11 mg,3.68 mmol), trimethylchlorosilane (3 mL, equivalent of 0.05) solvent N, N-dimethylformamide (15 mL) were added to the Schlenk tube and mixed, stirred at 120℃for 24 hours, after completion of the TCL monitoring reaction, water was added first for 100-200mL, followed by ultrasonic filtration, suction filtration and drying to obtain a crude product, which was separated by silica gel column chromatography, and dichloromethane/methanol (V: V=10:1) was eluted 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 in 78% yield.
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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-2, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-pyridinecarboxaldehyde to give 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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-3, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 3-pyridinecarboxaldehyde to give 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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-4, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-methylbenzaldehyde to give 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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-5, wherein R 1 Is that
R 2 Is->
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 2-fluorobenzaldehyde to give 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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-6, wherein R 1 Is that
R 2 Is that
Its preparation process is as followsThe following steps:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 3-fluorobenzaldehyde to give 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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-7, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-fluorobenzaldehyde to give 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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-8, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-chlorobenzaldehyde to give 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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-9, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-bromobenzaldehyde to give 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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-10, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the 4-methoxybenzaldehyde of example 1, step (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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-11, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-nitrobenzaldehyde to give 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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-12, wherein R 1 Is that
R 2 Is that
The preparation process is as follows: />
This embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 1-methyl-4 (methylsulfonyl) benzaldehyde to give 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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-13, wherein R 1 Is that
R 2 Is->
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-phenylbenzaldehyde to give 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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-14, wherein R 1 Is that
R 2 Is->
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 1- (benzyloxy) -4-methylbenzaldehyde to give 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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-15, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 2, 4-difluorobenzaldehyde to give 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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-16, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 2, 5-difluorobenzaldehyde to give compound (E) -2- (2- (3- (2, 6-difluorophenyl) -1-phenyl-1H-pyrazol-4-yl) vinyl) isonicotinic acid as a yellow solid in 72% yield.
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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-17, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to biphenyl formaldehyde to give 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, giving the compound I-18, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 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 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 77% yield.
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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-19, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-fluorobenzaldehyde and phenylhydrazine was adjusted to 4-fluorobenzylhydrazine to give the 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
Pyrazole-vinyl-isonicotinic acid derivative, and preparation method thereofI-20 wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-fluorobenzaldehyde and phenylhydrazine was adjusted to 4-chlorophenylhydrazine to give 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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-21, wherein R 1 Is that
R 2 Is that
The preparation process is as follows: />
This embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-fluorobenzaldehyde and phenylhydrazine was adjusted to 4-bromophenylhydrazine to give 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
Pyrazole-vinyl-isonicotinic acid derivatives, giving the compound I-22, wherein R 1 Is that
R 2 Is that
The preparation process is as follows:
this embodiment differs from embodiment 1 in that: the benzaldehyde in step (1) of example 1 was adjusted to 4-fluorobenzaldehyde and phenylhydrazine was adjusted to 4-methoxyphenylhydrazine to give 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
KDM5B inhibition Activity assay
Detection of 1.1KDM5B Activity inhibition
(1) 1 XAssaybuffer is configured.
(2) Concentration gradient configuration of the compound: the initial concentration of the test compound was 25 μm, diluted 3-fold, and divided into 10 concentrations, each concentration being a single well test. The initial concentration of the positive control compound CPI-455 test was 1. Mu.M, diluted 3-fold, and equally divided into 10 concentrations, each concentration was set up for the multiplex well test. The solution was diluted to a corresponding 1000-fold final concentration in 384-well Source plates and then transferred with Echo550 to the 384-well reaction plates for assay. Min and Max wells were shifted to 10nL of 100% DMSO.
(3) A2 Xenzyme solution was prepared from the 1 Xreaction solution.
(4) A2X substrate mixed solution was prepared from the 1X reaction solution.
(5) Add 5. Mu.L of 2 Xenzyme solution to each well; mu.L of 1 Xreaction solution was added to Min wells, centrifuged at 1000rpm for 1Min and incubated at room temperature for 15 Min.
(6) mu.L of the 2 Xsubstrate mixed 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 30min.
(7) mu.L of the detection solution was added to each well, centrifuged at 1000rpm for 1min, and incubated at room temperature for 60 min.
(8) Signal Intiness (665 nm)/Intiness (615 nm) was read using EnVision.
The data analysis was performed according to the following formula:
fitting dose-response curve: the X axis is the log value of the concentration, the Y axis is the percent inhibition rate, and the analysis software GraphPad Prism5 log (inhibitor) vs. response-Variable slope fit quantitative response curve is adopted, so that the IC of the compound on protein binding inhibition is obtained 50 Values.
1.2 experimental results
The experimental results are shown in the following table:
TABLE 1
As can be seen from Table 1, the compounds of the general formula I have a remarkable inhibitory activity on histone demethylase KDM5B, and the compounds I-1, I-3, I-5, I-6, I-7, I-9, I-10, I-19, I-22 have IC 50 <10 mu M of IC in which compounds I-7, I-10 50 Down to nanomolar levels. Surface the compound with the structural general formula I has remarkable inhibition activity on histone demethylase 5B.
The above embodiments are only preferred embodiments of the present invention, and the scope of the present invention is not limited thereto, but any insubstantial changes and substitutions made by those skilled in the art on the basis of the present invention are intended to be within the scope of the present invention as claimed.
Claims (9)
1. A pyrazole-vinyl-isonicotinic acid derivative is characterized by having a structural general formula I
Wherein when R is 1 Selected from phenyl, substituted phenyl,
R in the case of benzodioxin group 2 Selected from phenyl, substituted phenyl;
when R is 1 Selected from the group consisting of
When R is 2 Selected from the group consisting of substitutionA phenyl group;
the substituent of the substituted phenyl is C1-C6 saturated alkyl, C1-C6 saturated alkoxy, halogen, nitro, C1-C6 saturated alkylsulfonyl and phenyl.
2. The pyrazole-vinyl-isonicotinic acid derivative according to claim 1, wherein R 1 Selected from the group consisting of
R 2 Selected from the group consisting of
3. Process for the preparation of pyrazole-vinyl-isonicotinic acid derivatives according to any of claims 1 to 2, characterized in that it comprises the following steps:
(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 for reaction to obtain a compound C;
(2) First, vilsmeier-Haack reagent was prepared: dropwise adding phosphorus oxychloride into N, N-dimethylformamide under 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 N-dimethylformamide into the mixture in 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-methyliisonicotinic acid, N-dimethylformamide and a catalyst, and stirring for reaction to obtain a compound I.
4. The method for producing pyrazole-vinyl-isonicotinic acid derivative according to claim 3, wherein the catalyst in the step (1) is glacial acetic acid, the addition molar ratio of the compound A to the compound B is 1:1, and the addition ratio of the compound A to the absolute ethyl alcohol is 1g:10-20mL.
5. The method for producing pyrazole-vinyl-isonicotinic acid derivative according to claim 3, wherein the addition molar ratio of compound C to phosphorus oxychloride, N-dimethylformamide in the Vilsmeier-Haack reagent of step (2) 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 1g:10mL.
6. The process for the preparation of pyrazole-vinyl-isonicotinic acid derivatives according to claim 3, wherein the catalyst in step (3) is trimethylchlorosilane;
the addition molar ratio of the compound D to the 2-methylisonicotinic acid is 1:1.
7. Use of a pyrazole-vinyl-isonicotinic acid derivative according to any of claims 1 to 2, for the preparation of a medicament for inhibiting KDM 5B.
8. The use according to claim 7, wherein said derivative is used for the preparation of a medicament for the treatment of tumors in which KDM5B is highly expressed.
9. The use of claim 8, wherein the tumor is gastric cancer, breast cancer or prostate cancer.
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| CN104981458A (en) * | 2012-10-02 | 2015-10-14 | Epi生物医疗有限公司 | Inhibitors of histone demethylases |
| CN107074807A (en) * | 2014-08-27 | 2017-08-18 | 吉利德科学公司 | Composition and method for inhibition of histone demethylase |
| WO2018149986A1 (en) * | 2017-02-16 | 2018-08-23 | Oryzon Genomics, S.A. | 2-(bicyclo-heteroaryl)-isonicotinic derivatives as histone demethylase inhibitors |
| CN112979613A (en) * | 2019-12-16 | 2021-06-18 | 四川大学华西医院 | 2- (1H-pyrazol-3-yl) pyridine derivative and preparation method and application thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104981458A (en) * | 2012-10-02 | 2015-10-14 | Epi生物医疗有限公司 | Inhibitors of histone demethylases |
| CN107074807A (en) * | 2014-08-27 | 2017-08-18 | 吉利德科学公司 | Composition and method for inhibition of histone demethylase |
| WO2018149986A1 (en) * | 2017-02-16 | 2018-08-23 | Oryzon Genomics, S.A. | 2-(bicyclo-heteroaryl)-isonicotinic derivatives as histone demethylase inhibitors |
| CN112979613A (en) * | 2019-12-16 | 2021-06-18 | 四川大学华西医院 | 2- (1H-pyrazol-3-yl) pyridine derivative and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
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| Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3‑Amino-4-pyridine Carboxylate Derivatives;Susan M. Westaway等;《J. Med. Chem.》;第59卷;第1357-1369页 * |
| 组蛋白赖氨酸去甲基化酶抑制剂研究进展;杨波等;《药学学报》;第52卷(第7期);第1102-1109页 * |
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