CN114907318A - Isonicotinic acid-pyrazole derivative and preparation method and application thereof - Google Patents
Isonicotinic acid-pyrazole derivative and preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
The invention discloses an isonicotinic acid-pyrazole derivative with a general structural formula
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and relates to an isonicotinic acid-pyrazole derivative, and a preparation method and application thereof.
Background
Malignant tumor is one of the major public health problems in the world, is a disease caused by malignant proliferation and abnormal metastasis and invasion of cancer cells, and seriously threatens human health and life. According to the international cancer research organization of the world health organization, nearly 1000 million patients die from cancer every year worldwide, and the morbidity and mortality are still increasing. In malignant disorders, epigenetic abnormalities frequently occur, and epigenetic abnormalities mainly include: DNA/RNA methylation, histone modification, nucleosome localization, non-coding RNA and chromatin three-dimensional structure, etc., wherein imbalance of histone modification affects cell life activities, leading to the development of various cancers. The analysis of the whole genome chromatin state shows that the universal deletion of H4K16ac, H3K4me3 and H4K20me3, the increase of the modification of H3K9me and H3K27me3 and the like exist in the process of generating various cancers such as colorectal cancer, prostate cancer, breast cancer, gastric cancer and the like. Histone modification can regulate the expression of many genes, and the regulation can be reversed under certain conditions, so that a new opportunity is provided for treating tumors.
Histone lysine demethylases (KDMs) are divided into two groups: FAD-dependent monoamine oxidative demethylase (lysine-specific demethylase, LSD 1; also known as KDM1) and Fe (II)/α -ketoglutarate-dependent demethylase (jumonji C-domain histone demethylase, JMJD). Histone lysine demethylase KDM5B (lysine-specific demethylase 5B, KDM5B), also known as plu-1 or JARID1B, belongs to a member of JMJD (Jmjc-KDMs) subfamily, and can remove H3K4Me2/3 methylation state and regulate the transcription and expression of genes. Research literature shows that KDM5B has low expression level in adult normal tissues, and has high expression level in various solid tumors such as breast cancer, prostate cancer, gastric cancer, lung cancer, oral cancer and the like and leukemia cells. And a large amount of evidence shows that KDM5B is closely related to tumor growth, angiogenesis, invasion, metastasis and tumor-related chemotherapy drug resistance and has a certain carcinogenic effect. Therefore, KDM5B is considered a potential drug target for cancer therapy. At present, researchers design various inhibitors by taking KDM5B as a drug target, but the inhibitors have the problems of low selectivity, poor cell membrane permeability and the like. And no KDM5B inhibitor is currently on the market. Therefore, the development of the KDM5B inhibitor with independent intellectual property rights, 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 an isonicotinic acid-pyrazole derivative, which has a good inhibitory effect on HDM 5B.
The second object of the present invention is a process for the preparation of isonicotinic acid-pyrazole derivatives.
The invention also relates to the use of isonicotinic acid pyrazole derivatives.
One of the purposes of the invention is realized by adopting the following technical scheme:
an isonicotinic acid-pyrazole derivative with a general structural formula I
Wherein R is 1 Hydrogen, substituted phenyl, unsaturated six-membered heterocyclic ring, naphthyl; r 2 Is an unsaturated six-membered ring.
Further, said R 1 The substituent of the substituted phenyl is halogen, C1-C10 haloalkyl, nitro, p-sulfonyl, benzyloxy, C1-C10 alkoxy; the R is 2 The medium unsaturated six-membered ring is phenyl.
Further, the R1 and R2 are selected from one or more of the following groups:
the second purpose of the invention is realized by adopting the following technical scheme:
(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) first, Vilsmeier-Haack reagent was 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) dissolving the compound D and the triamino isonicotinic acid methyl ester obtained in the step (2) in N, N-dimethylformamide, uniformly stirring, adding zinc chloride and trimethylsilyl acetate, and stirring for reaction to obtain a compound E;
(4) mixing the compound E obtained in the step (3) with sodium triacetoxyborohydride, and stirring to react to obtain a compound F;
(5) and (3) dissolving the compound F obtained in the step (4) and lithium hydroxide monohydrate in a mixed solution of tetrahydrofuran and water, and stirring to react to obtain a final product, namely 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 in the step (1) is 1:1, and the ratio of the compound A to the ethanol is 1 g: 10-20 mL.
Further, the molar ratio of the compound C to the phosphorus oxychloride and the N, N-dimethylformamide in the step (2) is 1:5:10 respectively;
the molar ratio of the compound D to the triamino isonicotinic acid methyl ester, the zinc chloride and the trimethyl isonicotinic acid methyl ester in the step (3) is 1:1:0.2: 0.3;
the molar ratio of the compound E to the sodium triacetoxyborohydride in the step (4) is 1: 3;
the molar ratio of the compound F to the lithium hydroxide monohydrate in the step (5) is 1: 1.5; the volume ratio of the tetrahydrofuran to the water is 1: 0.8-1.
Further, the temperature of the stirring reaction in the step (3) is 100 ℃ and the time is 12 h.
Further, the stirring reaction temperature in the step (4) and the step (5) is room temperature.
The third purpose of the invention is realized by adopting the following technical scheme:
the use of said derivatives for the preparation of a medicament for inhibiting KDM 5B.
Further, the drug is an anti-tumor targeted drug.
Compared with the prior art, the invention has the beneficial effects that:
the isonicotinic acid-pyrazole 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 also provides a preparation method of the compound, which is prepared by taking the aromatic ring amine compound as a raw material through nucleophilic addition-elimination, Vilsmeier-Haack reaction and reductive amination, and has the advantages of simple preparation method, mild conditions and high yield. The invention also provides application of the compound, 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.
Examples 1 to 15 the compounds prepared have the general structural formula I
Example 1
An isonicotinic acid-pyrazole derivative I-1, 3- (((1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R is 1 Is H, R 2 Is composed of
The preparation process comprises the following steps:
(1) synthesis of intermediate Compound E (E) -3- (((1-phenyl-1H-pyrazol-4-yl) methylene) amino) methyl isonicotinate (methyl (E) -3- (((1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinate)
Taking compound D (1-phenyl-1H-pyrazole-4-carbaldehyde) (1g, 5.81mmol), adding methyl trimethylisonicotinate (889.65mg, 5.81mmol) and N, N-dimethylformamide (15mL) into a Schlenk tube, stirring uniformly, adding zinc chloride (158.29mg, 1.16mmol) and trimethylsilylacetate (2.30g, 17.42mmol), stirring at 100 ℃ for 12H, and directly feeding to the next step after TCL monitors that the reaction is finished.
(2) Preparation of intermediate F3- (((1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid methyl ester (methyl 3- (((1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinite)
Sodium triacetoxyborohydride (1.73g, 8.16mmol) was added to the Schlenk's tube at the end of the reaction in step (1) and stirred at room temperature for 72 h. After the reaction was completed, a large amount of water (200mL) was added first to wash off the unreduced imine, the mixture was sonicated thoroughly, extracted with dichloromethane (50 mL. times.3), the combined organic phases were washed with saturated brine (10 mL. times.3), anhydrous Na 2 SO 4 Drying and column chromatography gave compound F as a solid (677mg, 2.18mmol) in 67% yield.
(3) Preparation of Compound I-13- (((1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid)
Intermediate compound F (300mg, 973. mu. mol) and lithium hydroxide monohydrate (61.24mg, 1.46mmol) were weighed out and dissolved in a mixed solution of tetrahydrofuran (5ml) and water (5ml), and stirred at room temperature for 3 hours. After the reaction was completed, most of the organic solvent was distilled off under reduced pressure, then water (80ml) was added, diluted hydrochloric acid (6mol/L) was used to adjust to weak acidity, and a solid was precipitated and filtered to obtain a white solid (Compound I-1, 255mg, 827. mu. mol) with a yield of 85%.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d 6 ,ppm)δ13.40(s,1H,-COOH),8.54(s,1H,Ar-H),8.35(s,1H,Ar-H),7.87(d,J＝5.0Hz,1H,Ar-H),7.81(d,J＝7.7Hz,2H,Ar-H),7.77(s,1H,Ar-H),7.58(d,J＝5.0Hz,1H,Ar-H),7.49(t,J＝8.0Hz,2H,Ar-H),7.30(t,J＝7.4Hz,1H,Ar-H),4.48(s,2H,-CH 2 -). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ169.30,144.64,140.97,140.05,136.28,136.20,130.01,126.95,126.63,123.80,121.51,118.61,116.11,36.96.
example 2
An isonicotinic acid-pyrazole derivative I-2, 3- (((1,3-diphenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((1,3-diphenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R is 1 Is composed of
R 2 Is composed of
The preparation process comprises the following steps:
(1) synthesis of intermediate C (E) -1-phenyl-2- (1-phenylethylene) hydrazine ((E) -1-phenyl-2- (1-phenylethylidene) hydrazine)
Taking a compound A (benzaldehyde) (2g, 16.65mmol) and putting the compound A (benzaldehyde) into a 50mL flask, adding 20mL of absolute ethyl alcohol, then adding phenylhydrazine (1.80g, 16.65mmol) and glacial acetic acid (49.99mg, 0.83mmol), and carrying out reflux reaction for 1h under stirring at room temperature; 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 after slow temperature reduction, and the compound C white solid (2.73g,12.99mmol) is obtained by suction filtration, wherein the yield is 78%. The product was unstable and was quickly sent to the next step.
(2) Synthesis of intermediate D1,3-diphenyl-1H pyrazole-4-carboxylic acid (1,3-diphenyl-1H-pyrazole-4-carboxylic acid)
Vilsmeier-Haack reagent: preparation N, N-dimethylformamide (3.48g, 47.56mmol) is weighed into a 100ml flask, and phosphorus oxychloride (3.65g, 23.78mmol) is dropwise added under ice bath and stirred for 40min at room temperature; weighing an intermediate C (1.00g, 4.76mmol), dissolving in 5ml of N, N-dimethylformamide, dropwise adding into the prepared Vilsmeier-Haack reagent under ice bath, reacting at 85 ℃ for 5h 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 (pH:6-7), and performing ultrasonic suction filtration to obtain a compound D white solid (979.40mg, 3.95mmol) with the yield of 83%.
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) preparation of intermediate E (E) -methyl 3- (((1,3-diphenyl-1H-pyrazol-4-yl) methylene) amino) isonicotinate (methyl (E) -3- (((1,3-diphenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinate)
Intermediate compound D1,3-diphenyl-1H-pyrazole-4-carboxylic acid (979.40mg, 3.95mmol) was put in Schlenk's tube, methyl trimethylisonicotinate (889.65mg, 5.81mmol) and N, N-dimethylformamide (15mL) were added thereto, after stirring to uniform, zinc chloride (107.68g, 0.79mmol) and trimethylsilylacetate (1.57g, 11.85mmol) were added, and the mixture was stirred at 100 ℃ for 12 hours, and then the reaction was directly charged to the next step after completion of the reaction monitored by TCL.
(4) Preparation of intermediate F3- (((1,3-diphenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid methyl ester (methyl 3- (((1,3-diphenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinate)
Sodium triacetoxyborohydride (2.51g,11.85mmol) was added to the Schlenk's tube at the end of the reaction in step (3) and stirred at room temperature for 72 h. After the completion of the reaction, most of the organic solvent was distilled off under reduced pressure, then water (100mL) was added, sonication was carried out, extraction was carried out with methylene chloride (30 mL. times.3), and the combined organic phases were washed with saturated brine (10 mL. times.3) and anhydrous Na 2 SO 4 Drying and performing column chromatography to obtainCompound F was a solid (1.14g, 2.96mmol), 75% yield.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d 6 ,ppm)δ8.55(s,1H,Ar-H),8.18(d,J＝5.2Hz,1H,Ar-H),7.88(d,J＝8.1Hz,2H,Ar-H),7.79(d,J＝7.6Hz,2H,Ar-H),7.52(t,J＝7.8Hz,2H,Ar-H),7.46(t,J＝7.6Hz,2H,Ar-H),7.39(t,J＝7.3Hz,1H,-NH),7.35–7.29(m,2H,Ar-H),7.11(s,1H,Ar-H),6.93(d,J＝5.2Hz,1H,Ar-H),4.56(d,J＝4.8Hz,2H,-CH 2 -),3.84(s,3H,-CH 3 ).
(5) preparation of compound I-23- (((1,3-diphenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((1,3-diphenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid)
Intermediate F (500mg, 1.30mmol) and lithium hydroxide monohydrate (81.82mg, 1.95mmol) were weighed out, dissolved in a mixed solution of tetrahydrofuran (5ml) and water (5ml), and stirred at room temperature for 3 hours. After the reaction is finished, most of the organic solvent is firstly distilled off under reduced pressure, then water (50ml) is added, diluted hydrochloric acid (6mol/L) is used for adjusting the mixture to be weak acid, solid is separated out, and the mixture is filtered by suction to obtain compound I-2 white solid (414.70mg, 1.1mmol) with the yield of 90%.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d 6 ,ppm)δ13.44(s,1H,-COOH),8.63(s,1H,Ar-H),8.33(s,1H,Ar-H),7.89(d,J＝5.8Hz,3H,Ar-H),7.78(d,J＝7.4Hz,2H,Ar-H),7.60(d,J＝5.0Hz,1H,Ar-H),7.52(t,J＝7.9Hz,2H,Ar-H),7.47(t,J＝7.5Hz,2H,Ar-H),7.40(t,J＝7.3Hz,1H,Ar-H),7.33(t,J＝7.3Hz,1H,Ar-H),4.62(s,2H，-CH 2 -). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ168.12,149.71,143.59,138.74,134.97,134.82,132.07,128.98,128.29,128.11,127.51,126.68,125.73,122.93,117.58,117.50,115.48,36.67.
example 3
An isonicotinic acid-pyrazole derivative I-3, 3- (((1-phenyl-3- (pyridine-3-yl) -1H-pyrazole-4-yl) methyl) amino) isonicotinic acid (3- (((1-phenyl-3- (pyridine-3-yl) -1H-pyrazole-4-yl) methyl) amino) isonicotinic acid), wherein R is 1 Is composed of
R 2 Is composed of
The preparation process comprises the following steps:
this example differs from example 2 as follows: the benzaldehyde in step (1) was adjusted to 2-pyridinecarboxaldehyde, and the procedure was otherwise the same as in example 2.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d 6 )δ8.97(s,1H,Ar-H),8.62(s,1H,Ar-H),8.56(d,J＝3.6Hz,1H,Ar-H),8.16(d,J＝8.5Hz,2H,Ar-H),7.88(d,J＝7.6Hz,2H,Ar-H),7.79(d,J＝4.4Hz,1H,Ar-H),7.57(d,J＝4.4Hz,1H,Ar-H),7.49(dt,J＝12.6,7.2Hz,3H,Ar-H),7.32(t,J＝7.1Hz,1H,Ar-H),4.47(s,2H,-CH 2 -). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ170.12,149.33,148.42,148.11,144.87,139.72,136.64,135.00,134.31,130.03,129.47,129.13,126.93,124.93,124.25,119.88,118.77,37.78.
example 4
An isonicotinic acid-pyrazole derivative I-4, 3- (((3- (2-fluorophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((3- (2-fluorophenyl) -1-phenyl-1H-pyrazoyl-4-yl) methyl) amino) isonicotinic acid), wherein R is 1 Is composed of
R 2 Is composed of
The preparation process comprises the following steps:
this example differs from example 2 as follows: the benzaldehyde in the step (1) was adjusted to 2-fluorobenzaldehyde, and the procedure was otherwise the same as in example 2.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d6,ppm)δ13.30(s,1H,-COOH),8.65(s,1H,Ar-H),8.19(s,1H,Ar-H),7.87(d,J＝6.9Hz,2H,Ar-H),7.83(s,1H,Ar-H),7.66(s,-NH),7.59(s,1H,Ar-H),7.51(s,4H,Ar-H),7.32(d,J＝8.1Hz,2H,Ar-H),7.30(d,J＝7.0Hz,1H,Ar-H),4.47(s,2H,-CH2-). 13 C NMR(100MHz,DMSO-d6,ppm)δ169.16,161.19,158.74,146.52,144.53,139.76,136.16,135.97,131.73(d,J＝3.2Hz),131.15(d,J＝8.3Hz),130.06,128.50,126.95,125.09(d,J＝3.3Hz),123.76,120.89(d,J＝14.9Hz),120.28,118.73,116.38(d,J＝21.9Hz),116.19,37.37(d,J＝5.2Hz). 19 F NMR(565MHz,DMSO-d 6 ,ppm)δ-115.14.
example 5
An isonicotinic acid-pyrazole derivative I-5, 3- (((3- (3-fluorophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((3- (3-fluorophenyl) -1-phenyl-1H-pyrazoyl-4-yl) methyl) amino) isonicotinic acid), wherein R is 1 Is composed of
R 2 Is composed of
The preparation process comprises the following steps:
this example differs from example 2 as follows: the benzaldehyde in the step (1) was adjusted to 3-fluorobenzaldehyde, and the procedure was repeated as in example 2.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d 6 )δ13.38(s,1H,-COOH),8.65(s,1H,Ar-H),8.34(s,1H,Ar-H),7.89(t,J＝6.4Hz,3H,Ar-H),7.72(s,1H,-NH),7.62(d,J＝7.6Hz,1H,Ar-H),7.58(d,J＝5.1Hz,2H,Ar-H),7.54–7.48(m,3H,Ar-H),7.34(t,J＝7.3Hz,1H,Ar-H),7.24(t,J＝7.6Hz,1H,Ar-H),4.66(s,2H，-CH 2 -). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ169.29,164.02,161.60,149.46,149.43,144.55,139.70,136.50,136.30,135.48(d,J＝8.3Hz),131.22(d,J＝8.5Hz),130.07,129.66,127.00,123.79,118.89,118.78,116.35,115.34(d,J＝21.0Hz),114.28(d,J＝22.6Hz),37.58. 19 F NMR(565MHz,DMSO-d 6 ,ppm)δ-112.72.
example 6
An isonicotinic acid-pyrazole derivative I-6, 3- (((3- (4-fluorophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((3- (4-fluorophenyl) -1-phenyl-1H-pyrazoyl-4-yl) methyl) amino) isonicotinic acid), wherein R is 1 Is composed of
R 2 Is composed of
The preparation process comprises the following steps:
this example differs from example 2 as follows: the benzaldehyde in the step (1) was adjusted to 4-fluorobenzaldehyde, and the procedure was repeated as in example 2.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d 6 )δ13.30(s,1H,-COOH),8.66(s,1H,Ar-H),8.19(s,1H,Ar-H),7.87(d,J＝7.8Hz,2H,Ar-H),7.82(d,J＝5.0Hz,1H,Ar-H),7.67(s,1H,-NH),7.59(td,J＝7.5,1.5Hz,1H,Ar-H),7.54–7.47(m,4H,Ar-H),7.36–7.31(m,2H,Ar-H),7.31–7.28(m,1H,Ar-H),4.47(s,2H,Ar-H). 13 C NMR(100MHz,DMSO-d6,ppm)δ169.26,159.89,150.68,144.62,139.79,136.25,135.99,134.43,130.28,130.05,129.50,126.84,123.93,120.09,118.71,118.54,116.49,114.51,112.83,55.42,37.73. 19 F NMR(565MHz,DMSO-d 6 ,ppm)δ-113.90.
example 7
An isonicotinic acid-pyrazole derivative I-7, 3- (((3- (4-chlorophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((3- (4-chlorophenyl) -1-phenyl-1H-pyrazoyl-4-yl) methyl) amino) isonicotinic acid), wherein R is 1 Is composed of
R 2 Is composed of
The preparation process comprises the following steps:
this example differs from example 2 as follows: the benzaldehyde in the step (1) was adjusted to 4-chlorobenzaldehyde, and the procedure was otherwise the same as in example 2.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d 6 ,ppm)δ13.45(s,1H,-COOH),8.63(s,1H,Ar-H),8.33(s,1H,Ar-H),7.94–7.85(m,3H,Ar-H),7.81(s,1H,Ar-H),7.80(s,1H,Ar-H),7.62(d,J＝5.6Hz,1H,Ar-H),7.56–7.48(m,4H,Ar-H),7.33(t,J＝7.1Hz,1H,Ar-H),4.64(s,2H,-CH 2 -). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ168.60,149.43,145.40,139.71,133.27,132.01,131.25,130.06,129.47,129.23,126.96,125.47,119.76,118.75,118.45,37.87.
example 8
An isonicotinic acid-pyrazole derivative I-8, 3- (((3- (4-bromophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((3- (4-bromophenyl) -1-phenyl-1H-pyrazoyl-4-yl) methyl) amino) isonicotinic acid), wherein R is 1 Is composed of
R 2 Is composed of
The preparation process comprises the following steps:
this example differs from example 2 as follows: the benzaldehyde in the step (1) was adjusted to 4-bromobenzaldehyde, and the procedure was otherwise the same as in example 2.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d6,ppm)δ13.40(s,1H,-COOH),8.63(s,1H,Ar-H),8.32(s,1H,Ar-H),7.89(d,J＝7.7Hz,3H,Ar-H),7.74(d,J＝8.2Hz,2H,Ar-H),7.66(d,J＝8.2Hz,2H,Ar-H),7.59(d,J＝4.9Hz,1H,Ar-H),7.52(t,J＝7.7Hz,2H,Ar-H),7.33(t,J＝7.3Hz,1H,Ar-H),4.63(s,2H，-CH2-). 13 C NMR(100MHz,DMSO-d6,ppm)δ169.10,149.59,144.69,139.76,135.61,132.38,132.15,130.09,129.73,129.59,126.98,124.25,121.92,118.75,37.71.
example 9
An isonicotinic acid-pyrazole derivative I-9, 3- (((1-phenyl-3- (4- (trifluoromethyl) phenyl) -1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((1-phenyl-3- (4- (trifluoromethyl) phenyl) -1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R is 1 Is composed of
R 2 Is composed of
The preparation process comprises the following steps:
this example differs from example 2 as follows: the benzaldehyde in the step (1) was adjusted to 4-trifluoromethylbenzaldehyde, and the rest was the same as in example 2.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d 6 ,ppm)δ13.44(s,1H,-COOH),8.67(s,1H,Ar-H),8.34(s,1H,Ar-H),8.01(d,J＝8.1Hz,2H,Ar-H),7.90(t,J＝7.4Hz,3H,Ar-H),7.82(d,J＝8.1Hz,2H,Ar-H),7.75(s,1H,-NH),7.60(d,J＝5.0Hz,1H,Ar-H),7.53(t,J＝7.8Hz,2H,Ar-H),7.35(t,J＝7.3Hz,1H,Ar-H),4.69(s,2H，-CH 2 -). 19 F NMR(565MHz,DMSO-d 6 ,ppm)δ-60.97.
example 10
An isonicotinic acid-pyrazole derivative I-10, 3- (((3- (4-nitrophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((3- (4-nitrophenyl) -1-phenyl-1H-pyrazoyl-4-yl) methyl) amino) isonicotinic acid), wherein R is 1 Is composed of
R 2 Is composed of
The preparation process comprises the following steps:
this example differs from example 2 as follows: the benzaldehyde in step (1) was adjusted to 4-nitrobenzaldehyde, and the procedure was repeated as in example 2.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d 6 ,ppm)δ13.44(s,1H,-COOH),8.70(s,1H,Ar-H),8.36–8.29(m,3H,Ar-H),8.08(d,J＝8.7Hz,2H,Ar-H),7.91(dd,J＝11.9,6.5Hz,3H,Ar-H),7.79(s,1H,-NH),7.61(d,J＝5.0Hz,1H,Ar-H),7.54(t,J＝7.8Hz,2H,Ar-H),7.37(t,J＝7.3Hz,1H,Ar-H),4.74(s,2H,-CH 2 -). 13 C NMR(100MHz,DMSO-d6,ppm)δ168.99,148.52,147.35,144.67,139.71,139.65,136.00,135.79,130.08,130.00,128.67,127.30,124.35,124.09,119.78,119.04,117.18,37.77. 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ168.99,148.52,147.35,144.67,139.71,139.65,136.00,135.79,130.08,130.00,128.67,127.30,124.35,124.09,119.78,119.04,117.18,37.77.
example 11
An isonicotinic acid-pyrazole derivative I-11, 3- (((3- (4- (methylsulfonyl) phenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((3- (4- (methylsulfonyl) phenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R is 1 Is composed of
R 2 Is composed of
The preparation process comprises the following steps:
this example differs from example 2 as follows: the benzaldehyde in the step (1) was adjusted to 1-methyl-4 (methylsulfonyl) benzaldehyde, and the rest was the same as in example 2.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d 6 ,ppm)δ8.67(s,1H,Ar-H),8.37(s,1H,Ar-H),8.05(t,J＝8.1Hz,2H,Ar-H),8.00(d,J＝8.4Hz,2H,Ar-H),7.93(d,J＝4.9Hz,1H,Ar-H),7.91(d,J＝7.9Hz,2H,Ar-H),7.72(d,J＝4.9Hz,1H,Ar-H),7.53(t,J＝7.9Hz,2H,Ar-H),7.36(t,J＝7.4Hz,1H,Ar-H),4.73(s,2H,-CH 2 -),3.26(s,3H,-CH 3 ). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ168.75,148.92,145.11,140.42,139.62,138.03,134.28,130.10,129.78,128.38,127.90,127.21,124.94,119.30,118.90,118.15,44.05,37.80.
example 12
An isonicotinic acid-pyrazole derivative I-12, 3- (((3- (4- (benzyloxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((3- (4- (benzyloxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R is 1 Is composed of
R 2 Is composed of
The preparation process comprises the following steps:
this example differs from example 2 as follows: the benzaldehyde in step (1) was adjusted to 1- (benzyloxy) -4-methylbenzaldehyde, and the procedure in example 2 was repeated.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d 6 ,ppm)δ13.39(s,1H,-COOH),8.59(s,1H,Ar-H),8.32(s,1H,Ar-H),7.91–7.85(m,3H,Ar-H),7.71(d,J＝8.6Hz,2H,Ar-H),7.59(d,J＝5.0Hz,1H,Ar-H),7.50(t,J＝7.9Hz,2H,Ar-H),7.47(d,J＝7.4Hz,2H,Ar-H),7.40(t,J＝7.5Hz,2H,Ar-H),7.34(t,J＝7.5Hz,1H,Ar-H),7.31(t,J＝7.4Hz,1H,Ar-H),7.10(d,J＝8.7Hz,2H,Ar-H),5.15(s,2H,-CH 2 -),4.58(s,2H,-CH 2 -). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ169.34,158.79,150.62,144.62,139.84,137.44,136.35,136.16,130.02,129.24,129.04,128.92,128.33,128.20,126.63,125.81,123.86,118.53,118.13,116.36,115.48,69.73,37.82.
example 13
An isonicotinic acid-pyrazole derivative I-13, 3- (((3- (naphthalene-2-yl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((3- (naphthalene-2-yl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R is 1 Is composed of
R 2 Is composed of
The preparation process comprises the following steps:
this example differs from example 2 as follows: the benzaldehyde in the step (1) was adjusted to biphenylcarbaldehyde, and the rest was the same as in example 2.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d6)δ8.67(s,1H,Ar-H),8.34(s,1H,Ar-H),8.28(s,1H,Ar-H),8.03–7.99(m,2H,Ar-H),7.94(t,J＝6.9Hz,3H,Ar-H),7.88(dd,J＝8.6,5.6Hz,2H,Ar-H),7.59(d,J＝5.0Hz,1H,Ar-H),7.56–7.51(m,4H,Ar-H),7.34(t,J＝7.4Hz,1H,Ar-H),4.70(s,2H，-CH2-). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ169.48,150.72,139.89,136.54,133.49,132.96,130.73,130.08,129.48,128.68,128.61,128.03,126.87,126.79,126.70,125.87,119.62,118.70,38.02.
example 14
An isonicotinic acid-pyrazole derivative I-14, 3- (((3- (2-methoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((3- (2-methoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R is 1 Is composed of
R 2 Is composed of
The preparation process comprises the following steps:
this example differs from example 2 as follows: the procedure in example 2 was repeated except that benzaldehyde in step (1) was changed to 3-methoxybenzaldehyde.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d 6 )δ13.47(s,1H,-COOH),8.63(s,1H,Ar-H),8.35(s,1H,Ar-H),7.90(s,2H,Ar-H),7.89(s,1H,Ar-H),7.72(s,1H,Ar-H),7.61(d,J＝5.0Hz,1H,Ar-H),7.52(t,J＝7.8Hz,2H,Ar-H),7.40–7.31(m,3H,Ar-H),7.30(s,1H,Ar-H),6.96(d,J＝7.4Hz,1H,Ar-H),4.61(s,2H,-CH 2 -),3.73(s,3H,-CH 3 ). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ169.26,159.89,150.68,144.62,139.79,136.25,135.99,134.43,130.28,130.05,129.50,126.84,123.93,120.09,118.71,118.54,116.49,114.51,112.83,55.42,37.73.
example 15
An isonicotinic acid-pyrazole derivative I-15, 3- (((3- (3-methoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((3- (3-methoxyphenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R is 1 Is composed of
R 2 Is composed of
The preparation process comprises the following steps:
this example differs from example 2 as follows: the procedure of example 2 was repeated except that the benzaldehyde in step (1) was changed to 4-methoxybenzaldehyde.
Analytical data for the product are as follows: 1 H NMR(600MHz,DMSO-d 6 ,ppm)δ13.44(s,1H,-COOH),8.59(s,1H,Ar-H),8.33(s,1H,Ar-H),7.90(d,J＝6.7Hz,1H,Ar-H),7.87(d,J＝7.1Hz,2H,Ar-H),7.70(d,J＝11.2Hz,2H,Ar-H),7.62(d,J＝7.7Hz,1H,Ar-H),7.50(t,J＝7.2Hz,2H,Ar-H),7.31(t,J＝7.4Hz,1H,Ar-H),7.02(d,J＝10.9Hz,2H,Ar-H),4.58(s,2H,-CH 2 -),3.79(s,3H,-CH 3 ). 13 C NMR(100MHz,DMSO-d 6 ,ppm)δ169.26,159.89,150.68,144.62,139.79,136.25,135.99,134.43,130.28,130.05,129.50,126.84,123.93,120.09,118.71,118.54,116.49,114.51,112.83,55.42,37.73.
experimental example 1
Assay for KDM5B inhibitory Activity
1. The experimental method comprises the following steps:
(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 at room temperature for 60 min.
(8) The signals Intensity (665nm)/Intensity (615nm) were read using EnVision.
Fitting a dose-response curve: the X axis is the log value of the concentration, the Y axis is the percentage inhibition rate, and the analysis software GraphPad Prism5 log (inhibitor) vs. s.response-Variable slope is adopted to fit a dose-effect curve, thereby obtaining the IC of the compound for inhibiting the protein combination 50 The value is obtained.
2. The experimental results are as follows:
the results of the experiment are shown in table 1 below:
TABLE 1
Test results show that the compound of the general formula I has obvious inhibitory activity on histone demethylase KDM5B, and most of compounds IC 50 <100 nM. The compound with the structural general formula I prepared by the invention has obvious inhibition activity on histone demethylase 5B.
The above embodiments are only preferred embodiments of the present invention, and the scope of the present invention should not be limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are intended to be covered by the claims.
Claims (10)
1. An isonicotinic acid-pyrazole derivative is characterized by having a structural general formula I
Wherein R is 1 Hydrogen, substituted phenyl, unsaturated six-membered heterocyclic ring, naphthyl;
R 2 is an unsaturated six-membered ring.
2. The isonicotinic acid-pyrazole derivative of claim 1 wherein R is 1 Is a hydrogen atom; a pyridyl group; differently substituted phenyl, wherein the substituents include halogen, haloalkyl, nitro, p-sulfonyl, benzyloxy; the amount of naphthalene,
the R is 2 The medium unsaturated six-membered ring is phenyl.
3. The isonicotinic acid-pyrazole derivative according to claim 1 wherein R1, R2 are selected from one or more of the following groups:
4. the process for the preparation of isonicotinic acid-pyrazole derivatives according to any of claims 1 to 3, 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 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) dissolving the compound D and the triamino isonicotinic acid methyl ester obtained in the step (2) in N, N-dimethylformamide, uniformly stirring, adding zinc chloride and trimethylsilyl acetate, and stirring for reaction to obtain a compound E;
(4) mixing the compound E obtained in the step (3) with sodium triacetoxyborohydride, and stirring to react to obtain a compound F;
(5) and (3) dissolving the compound F obtained in the step (4) and lithium hydroxide monohydrate in a mixed solution of tetrahydrofuran and water, and stirring to react to obtain a final product, namely a compound I.
5. The method of preparing the isonicotinic acid-pyrazole derivative according to claim 4, wherein the catalyst of step (1) is glacial acetic acid;
the adding molar ratio of the compound A to the compound B in the step (1) is 1:1, and the ratio of the compound A to the ethanol is 1 g: 10-20 mL.
6. The method for preparing the isonicotinic acid-pyrazole derivative according to claim 4, wherein the molar ratio of the compound C to the phosphorus oxychloride and the N, N-dimethylformamide in the step (2) is 1:5: 10;
the molar ratio of the compound D to the triamino isonicotinic acid methyl ester, the zinc chloride and the trimethyl isonicotinic acid methyl ester in the step (3) is 1:1:0.2: 0.3;
the molar ratio of the compound E to the sodium triacetoxyborohydride in the step (4) is 1: 3;
the molar ratio of the compound F to the lithium hydroxide monohydrate in the step (5) is 1: 1.5; the volume ratio of the tetrahydrofuran to the water is 1: 0.8-1.
7. The method for preparing the isonicotinic acid-pyrazole derivative according to claim 4, wherein the stirring reaction in step (3) is carried out at a temperature of 100 ℃ for 12 hours.
8. The method for preparing the isonicotinic acid-pyrazole derivative according to claim 4, wherein the stirring reaction in step (4) and step (5) is carried out at room temperature.
9. Use of the isonicotinic acid-pyrazole derivative according to any of claims 1 to 3 for the preparation of a medicament for inhibiting KDM 5B.
10. The use of the isonicotinic acid-pyrazole derivative according to claim 9, wherein the medicament is an anti-tumor targeting medicament.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013143597A1 (en) * | 2012-03-29 | 2013-10-03 | Glaxo Group Limited | Demethylase enzymes inhibitors |
| CN105026372A (en) * | 2012-12-21 | 2015-11-04 | 昆蒂赛尔制药公司 | Histone demethylase inhibitors |
| US20170340609A1 (en) * | 2016-05-27 | 2017-11-30 | Arkansas State University - Jonesboro | Antimicrobial agents and the method of synthesizing the antimicrobial agents |
| 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 |
|---|---|---|---|---|
| WO2013143597A1 (en) * | 2012-03-29 | 2013-10-03 | Glaxo Group Limited | Demethylase enzymes inhibitors |
| CN105026372A (en) * | 2012-12-21 | 2015-11-04 | 昆蒂赛尔制药公司 | Histone demethylase inhibitors |
| US20170340609A1 (en) * | 2016-05-27 | 2017-11-30 | Arkansas State University - Jonesboro | Antimicrobial agents and the method of synthesizing the antimicrobial agents |
| 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 (3)
| Title |
|---|
| SUSAN M. WESTAWAY等: "Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 1. 3‑Amino-4-pyridine Carboxylate Derivatives", vol. 59, pages 1357 - 1369 * |
| SUSAN M. WESTAWAY等: "Cell Penetrant Inhibitors of the KDM4 and KDM5 Families of Histone Lysine Demethylases. 2. Pyrido[3, 4‑d]pyrimidin-4(3H)‑one Derivatives", 《J. MED. CHEM.》, vol. 59, pages 1370 - 1387, XP055719291, DOI: 10.1021/acs.jmedchem.5b01538 * |
| 杨 波等: "组蛋白赖氨酸去甲基化酶抑制剂研究进展", vol. 52, no. 7, pages 1102 - 109 * |
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