CN114907318B - Isonicotinic acid-pyrazole derivative and preparation method and application thereof - Google Patents

Isonicotinic acid-pyrazole derivative and preparation method and application thereof Download PDF

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CN114907318B
CN114907318B CN202210787475.4A CN202210787475A CN114907318B CN 114907318 B CN114907318 B CN 114907318B CN 202210787475 A CN202210787475 A CN 202210787475A CN 114907318 B CN114907318 B CN 114907318B
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isonicotinic acid
stirring
pyrazole derivatives
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CN114907318A (en
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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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    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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 which has a structural general formula

Description

Isonicotinic acid-pyrazole derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to an isonicotinic acid-pyrazole derivative, and a preparation method and application thereof.
Background
Malignant tumor is one of global serious public health problems, and is a disease caused by malignant proliferation and abnormal metastasis and invasion of cancer cells, which seriously threatens human health and life. According to the statistics of the world health organization international cancer research institute, nearly 1000 tens of thousands of patients die from cancer every year worldwide, and the morbidity and mortality are still increasing. In malignant disorders, epigenetic abnormalities occur frequently, and epigenetic mainly includes: DNA/RNA methylation, histone modification, nucleosome localization, non-coding RNA and chromatin three-dimensional structure, etc., wherein imbalance of histone modification affects cell vital activity, resulting in the occurrence of various cancers. The genome-wide chromatin state analysis finds that common deletions of H4K16ac, H3K4me3 and H4K20me3, and increases of H3K9me and H3K27me3 modification exist in the occurrence process of various cancers such as colorectal cancer, prostate cancer, breast cancer, gastric cancer and the like. Histone modification can regulate the expression of a plurality of genes, and the regulation can be reversed under certain conditions, thus providing a new opportunity for the treatment of tumors.
Histone lysine demethylases (Histone lysine demethylases, KDM) are divided into two groups: FAD-dependent monoamine oxidase (lysine-specific demethylase, LSD1; also known as KDM 1) and Fe (II)/alpha-ketoglutarate-dependent demethylase (jumonji C domain histone demethylase, JMJD). Histone lysine demethylase KDM5B (lysine-specific demethylase B, KDM 5B), also known as plur-1 or JARID1B, belongs to a member of the (JMjc-KDMS) subfamily of JMJD, which is capable of removing the H3K4Me2/3 methylation state, regulating transcription and expression of genes. Through research documents, the KDM5B has low expression level in normal tissues of adults, and has high expression in various solid tumors such as breast cancer, prostatic cancer, gastric cancer, lung cancer, oral cancer and the like and leukemia cells. Moreover, there is a great deal of evidence that KDM5B is closely related to tumor growth, angiogenesis, invasion, metastasis and tumor-related chemotherapy resistance, and has a certain carcinogenesis. Thus, KDM5B is considered a potential drug target for cancer treatment. At present, scientific researchers design a plurality of inhibitors by taking KDM5B as a drug target spot, but all have the problems of low selectivity, poor cell membrane permeability and the like. And there are no currently marketed inhibitors of KDM 5B. Therefore, development of KDM5B inhibitors with independent intellectual property, high efficiency, low toxicity, high selectivity and good pharmacokinetic parameters has very important significance.
Disclosure of Invention
In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide isonicotinic acid-pyrazole derivatives which have 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:
isonicotinic acid-pyrazole derivatives having the general structural formula I
Wherein R is 1 Is hydrogen, substituted phenyl, unsaturated six-membered heterocyclic ring, naphthyl; r is R 2 Is an unsaturated six-membered ring.
Further, the R 1 The substituent of the medium substituted phenyl is halogen, C1-C10 haloalkyl, nitro, p-sulfonyl, benzyloxy and C1-C10 alkoxy; the R is 2 The unsaturated six-membered ring in (2) 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 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) 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 for reaction to obtain a compound F;
(5) And (3) dissolving the compound F and lithium hydroxide monohydrate obtained in the step (4) in a mixed solution of tetrahydrofuran and water, and stirring and reacting to obtain a final product compound I.
Further, the catalyst in the step (1) is glacial acetic acid; the 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 1g:10-20mL.
Further, the molar ratio of the compound C to phosphorus oxychloride and N, N-dimethylformamide in the step (2) is 1:5:10 respectively;
the molar ratio of the compound D to the methyl triamino isonicotinate, the zinc chloride and the methyl trimethyl isonicotinate 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 tetrahydrofuran to water is 1:0.8-1.
Further, the temperature of the stirring reaction in the step (3) is 100 ℃ for 12 hours.
Further, the temperature of the stirring reaction 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 application of the derivative in preparing a medicament for inhibiting KDM 5B.
Further, the drug is an anti-tumor targeting drug.
Compared with the prior art, the invention has the beneficial effects that:
the compound has remarkable biological inhibition activity on KDM5B, can be used for preparing and researching and developing novel KDM5B inhibitors, enriches the variety of isonicotinic acid derivatives, and lays a foundation for developing drugs for inhibiting KDM 5B. The invention also provides a preparation method of the compound, which takes aromatic ring amine compounds as raw materials, and the aromatic ring amine compounds are prepared through nucleophilic addition-elimination, vilsmeier-Haack reaction and reductive amination, and the preparation method is simple, mild in condition and high in yield. The invention also provides application of the compound, the compound has nanomolar inhibition effect on KDM5B on enzyme level, provides a structure of a lead compound for further researching anticancer 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.
The compounds prepared in examples 1 to 15 have the general structural formula I
Example 1
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 1 Is H, R 2 Is thatThe preparation process comprises the following steps:
(1) Synthesis of intermediate compound E (E) -3- (((1-phenyl-1H-pyrazol-4-yl) methylene) amino) isonicotinate methyl (E) -3- (((1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinate)
Compound D (1-phenyl-1H-pyrazole-4-carbaldehyde) (1 g,5.81 mmol) was taken in a Shi Laike tube, methyl trimethylisonicotinate (889.65 mg,5.81 mmol) and N, N-dimethylformamide (15 mL) were added, after stirring uniformly, zinc chloride (158.29 mg,1.16 mmol) and trimethylsilyl acetate (2.30 g,17.42 mmol) were added and stirred at 100deg.C for 12H, and the TCL monitoring reaction was ended and directly put into the next step.
(2) Preparation of intermediate F3- (((1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinate methyl (methyl 3- (((1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinate)
Sodium triacetoxyborohydride (1.73 g,8.16 mmol) was added to the Schlenk tube after the completion of the reaction in the step (1), and the mixture was stirred at room temperature for 72 hours. After the reaction, a large amount of water (200 mL) was added to wash out the unreduced imine, followed by sufficient sonication, extraction with methylene chloride (50 mL. Times.3), washing the combined organic phases with saturated brine (10 mL. Times.3), anhydrous Na 2 SO 4 Drying and column chromatography gave compound F as a solid (677 mg,2.18 mmol) in 67% yield.
(3) Preparation of Compound I-1 3- (((1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid)
Intermediate compound F (300 mg, 973. Mu. Mol) and lithium hydroxide monohydrate (61.24 mg,1.46 mmol) were weighed, dissolved in a mixed solution of tetrahydrofuran (5 ml) and water (5 ml), and stirred at room temperature for 3 hours. After the reaction, most of the organic solvent was distilled off under reduced pressure, then water (80 ml) was added, the mixture was adjusted to be weakly acidic with dilute hydrochloric acid (6 mol/L), and a solid was precipitated and suction-filtered to obtain a white solid (Compound I-1, 255mg, 827. Mu. Mol) in 85% yield.
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
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 1 Is thatR 2 Is->The preparation process comprises the following steps:
(1) Synthesis of intermediate C (E) -1-phenyl-2- (1-phenylethynyl) hydrazine
Compound a (benzaldehyde) (2 g,16.65 mmol) was taken in a 50mL flask, 20mL of absolute ethanol was added thereto, phenylhydrazine (1.80 g,16.65 mmol) and glacial acetic acid (49.99 mg,0.83 mmol) were then added thereto, and the mixture was stirred at room temperature and then refluxed for 1 hour; after the reaction, most of the organic solvent was removed by rotary evaporation under reduced pressure, and a large amount of solid was precipitated by slow cooling, and the compound C was obtained as a white solid (2.73 g,12.99 mmol) in 78% yield by suction filtration. The product was unstable and was taken on to the next step rapidly.
(2) Synthesis of intermediate D1,3-diphenyl 1H pyrazole-4-carboxylic acid (1, 3-diphenyl-1H-pyrazole-4-carboxilic acid)
Vilsmeier-Haack reagent: preparation N, N-dimethylformamide (3.48 g,47.56 mmol) was weighed into a 100ml flask, phosphorus oxychloride (3.65 g,23.78 mmol) was added dropwise under ice bath and stirred at room temperature for 40min; intermediate C (1.00 g,4.76 mmol) was weighed and dissolved in 5ml of N, N-dimethylformamide, dropwise added to the prepared Vilsmeier-Haack reagent under ice bath, reacted for 5h at 85℃under stirring, after TLC monitoring the reaction was completed, 200ml of ice water was then added, pH was adjusted to neutral (pH: 6-7) by adding KOH aqueous alkaline solution, and compound D was obtained as a white solid (979.40 mg,3.95 mmol) by ultrasonic suction filtration in 83% yield.
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) -3- (((1, 3-diphenyl-1H-pyrazol-4-yl) methylene) amino) isonicotinic acid methyl ester (methyl (E) -3- (((1, 3-diphenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinate)
Intermediate compound D1, 3-diphenyl-1H-pyrazole-4-carboxilic acid (979.40 mg,3.95 mmol) was taken in Shi Laike tube, methyl trimethylisonicotinate (889.65 mg,5.81 mmol) and N, N-dimethylformamide (15 mL) were added, zinc chloride (107.68 g,0.79 mmol) and trimethylsilyl acetate (1.57 g,11.85 mmol) were added after stirring, stirring was carried out at 100℃for 12H, and the reaction was directly put into the next step after TCL monitoring.
(4) Preparation of intermediate F3- (((1, 3-diphenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinate methyl (methyl 3- (((1, 3-diphenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinate)
Sodium triacetoxyborohydride (2.51 g,11.85 mmol) was added to the Schlenk tube after the completion of the reaction in step (3), and the mixture was stirred at room temperature for 72 hours. After the completion of the reaction, most of the organic solvent was distilled off under reduced pressure, then water (100 mL) was added, followed by sonication, extraction with methylene chloride (30 mL. Times.3), washing the combined organic phases with saturated brine (10 mL. Times.3), anhydrous Na 2 SO 4 Drying and column chromatography gave compound F as a solid (1.14 g,2.96 mmol) in 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-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)
Intermediate F (500 mg,1.30 mmol) and lithium hydroxide monohydrate (81.82 mg,1.95 mmol) were weighed and dissolved in a mixed solution of tetrahydrofuran (5 ml) and water (5 ml), and stirred at room temperature for 3 hours. After the reaction, most of the organic solvent was distilled off under reduced pressure, then water (50 ml) was added, the mixture was adjusted to be weakly acidic with dilute hydrochloric acid (6 mol/L), and a solid was precipitated and suction-filtered to give Compound I-2 as a white solid (414.70 mg,1.1 mmol) in 90% yield.
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
Isonicotinic acid-pyrazole derivatives i-3, 3- (((1-phenyl-3- (pyridin-3-yl) -1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((1-phenyl-3- (pyridin-3-yl) -1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R 1 Is thatR 2 Is->The preparation process comprises the following steps:
this embodiment differs from embodiment 2 in that: the benzaldehyde in the step (1) was adjusted to 2-pyridylaldehyde, 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 )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
Isonicotinic acid-pyrazole derivatives i-4, 3- (((3- (2-fluorophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((2-fluorophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R 1 Is thatR 2 Is->The preparation process comprises the following steps:
this embodiment differs from embodiment 2 in that: the benzaldehyde in the step (1) was adjusted to 2-fluorobenzaldehyde, and the rest was 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
Isonicotinic acid-pyrazole derivatives i-5, 3- (((3- (3-fluorophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((3-fluorophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R 1 Is thatR 2 Is->The preparation process comprises the following steps:
this embodiment differs from embodiment 2 in that: the benzaldehyde in the step (1) was adjusted to 3-fluorobenzaldehyde, 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 )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
Isonicotinic acid-pyrazole derivatives i-6, 3- (((3- (4-fluorophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((4-fluorophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R 1 Is thatR 2 Is->The preparation process comprises the following steps:
this embodiment differs from embodiment 2 in that: the benzaldehyde in the step (1) was adjusted to 4-fluorobenzaldehyde, 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 )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
Isonicotinic acid-pyrazole derivatives I-7, 3- (((3- (4-chlorophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((3- (4-chlorophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R 1 Is thatR 2 Is->The preparation process comprises the following steps:
this embodiment differs from embodiment 2 in that: the benzaldehyde in the step (1) was adjusted to 4-chlorobenzaldehyde, 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)δ13.45(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
Isonicotinic acid-pyrazole derivatives I-8, 3- (((3- (4-bromophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((4-bromophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R 1 Is thatR 2 Is->The preparation process comprises the following steps:
this embodiment differs from embodiment 2 in that: the benzaldehyde in the step (1) was adjusted to 4-bromobenzaldehyde, and the rest was 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
Isonicotinic acid-pyrazole derivatives 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 1 Is thatR 2 Is->The preparation process comprises the following steps:
this embodiment differs from embodiment 2 in that: 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
Isonicotinic acid-pyrazole derivatives i-10, 3- (((3- (4-nitrophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((4-nitrophenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R 1 Is thatR 2 Is->The preparation process comprises the following steps:
this embodiment differs from embodiment 2 in that: the benzaldehyde in the step (1) was adjusted to 4-nitrobenzaldehyde, 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),8.70(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
Isonicotinic acid-pyrazole derivatives i-11, 3- (((3- (4- (methylsulfonyl) phenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((4- (methyl) phenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R 1 Is thatR 2 Is->The preparation process comprisesThe method comprises the following steps:
this embodiment differs from embodiment 2 in that: 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
Isonicotinic acid-pyrazole derivatives I-12, 3- (((3- (4- (benzyloxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((4- (benzoyl) phenyl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R 1 Is thatR 2 Is->The preparation process comprises the following steps:
this embodiment differs from embodiment 2 in that: the benzaldehyde in the step (1) was adjusted to 1- (benzyloxy) -4-methylbenzaldehyde, 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)δ13.39(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
Isonicotinic acid-pyrazole derivatives I-13, 3- (((3- (naphthalen-2-yl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid (3- (((3- (naphthalen-2-yl) -1-phenyl-1H-pyrazol-4-yl) methyl) amino) isonicotinic acid), wherein R 1 Is thatR 2 Is->The preparation process comprises the following steps:
this embodiment differs from embodiment 2 in that: the benzaldehyde in the step (1) was adjusted to biphenyl formaldehyde, 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
Isonicotinic acid-pyrazole derivatives 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 1 Is thatR 2 Is->The preparation process comprises the following steps: />
This embodiment differs from embodiment 2 in that: the benzaldehyde in the step (1) was adjusted to 3-methoxybenzaldehyde, 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 )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
Isonicotinic acid-pyrazole derivatives 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 1 Is thatR 2 Is->The preparation process comprises the following steps:
this embodiment differs from embodiment 2 in that: the benzaldehyde in the step (1) was adjusted to 4-methoxybenzaldehyde, 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),8.59(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
KDM5B inhibition Activity assay
1. The experimental method comprises the following steps:
(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.
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.
2. Experimental results:
the experimental results are shown in table 1 below:
TABLE 1
/>
The test result shows that the compound in the general formula I has obvious inhibition activity on histone demethylase KDM5B, and most of the compounds IC 50 <100nM. 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 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 (11)

1. Isonicotinic acid-pyrazole derivatives of the general structural formula I
Wherein R is 1 Is substituted phenyl, unsaturated six-membered heterocyclic ring and naphthyl; the substituent of the substituted phenyl is selected from halogen, C1-C10 haloalkyl, nitro and benzyloxy;
R 2 is an unsaturated six-membered ring.
2. Isonicotinic acid-pyrazole derivatives according to claim 1, characterized in that R 1 Is pyridyl, naphthyl or substituted phenyl; wherein the substituent of the substituted phenyl is selected from halogen, C1-C6 haloalkyl, nitro and benzyloxy;
the R is 2 The unsaturated six-membered ring in (2) is phenyl.
3. An isonicotinic acid-pyrazole derivative is characterized by having a structural general formula I
Wherein R is 1 、R 2 One or more selected from the following groups:
4. a 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 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) Dissolving the compound D, 3-aminoisonicotinic 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 for reaction to obtain a compound F;
(5) And (3) dissolving the compound F and lithium hydroxide monohydrate obtained in the step (4) in a mixed solution of tetrahydrofuran and water, and stirring and reacting to obtain a final product compound I.
5. The method of preparing isonicotinic acid-pyrazole derivatives according to claim 4, wherein the catalyst of step (1) is glacial acetic acid;
the 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 1g:10-20mL.
6. The method for producing isonicotinic acid-pyrazole derivatives according to claim 4, wherein the molar ratio of the compound C to phosphorus oxychloride and N, N-dimethylformamide in the step (2) is 1:5:10, respectively;
the molar ratio of the compound D to the methyl triamino isonicotinate, the zinc chloride and the methyl trimethyl isonicotinate 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 tetrahydrofuran to water is 1:0.8-1.
7. The process for producing isonicotinic acid-pyrazole derivatives according to claim 4, wherein the stirring reaction in the step (3) is carried out at a temperature of 100℃for a period of 12 hours.
8. The method for producing isonicotinic acid-pyrazole derivatives according to claim 4, wherein the stirring reaction temperature in the step (4) and the step (5) is room temperature.
9. Use of isonicotinic acid-pyrazole derivatives according to any of claims 1 to 3, for the preparation of a medicament for inhibiting KDM 5B.
10. The application of isonicotinic acid-pyrazole derivatives is characterized in that the derivatives are used for preparing medicines for inhibiting KDM5B, the derivatives have the following structural formula I,
wherein R is 1 Is hydrogen, substituted phenyl, unsaturated six-membered heterocyclic ring, naphthyl;
the substituent of the substituted phenyl is selected from halogen, C1-C10 haloalkyl, nitro and benzyloxy;
R 2 is an unsaturated six-membered ring.
11. The use of isonicotinic acid-pyrazole derivatives according to claim 10, characterized in that the medicament is an antitumor targeting medicament.
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Citations (3)

* Cited by examiner, † Cited by third party
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
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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017205814A1 (en) * 2016-05-27 2017-11-30 Arkansas State University-Jonesboro Antimicrobial agents and the method of synthesizing the antimicrobial agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
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
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 (1)

* Cited by examiner, † Cited by third party
Title
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.》.2016,第59卷第1370-1387页. *

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