CN113999211B - Indazole skeleton derivative containing 1,2,3-triazole with specific activity of resisting prostate cancer - Google Patents
Indazole skeleton derivative containing 1,2,3-triazole with specific activity of resisting prostate cancer Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical chemistry, and discloses an indazole skeleton derivative containing 1,2,3 triazole with specific anti-prostate cancer activity, a synthesis method and application thereof. The preparation method is simple, mild in condition and high in yield. In vitro activity evaluation results show that the compound has specific antiproliferative activity on prostate cancer, does not show activity on breast cancer, liver cancer and gastric cancer, has obvious superiority compared with a positive compound 5-fluorouracil, shows better in vitro and in vivo safety, and has an application prospect in preparing prostate cancer medicaments. It has the following structural general formula:
Description
Technical Field
The invention relates to a novel indazole skeleton derivative containing 1,2,3-triazole and application thereof as a prostate cancer treatment drug, and belongs to the field of pharmaceutical chemistry.
Background
Prostate cancer is the second most common cancer in men worldwide, and has gradually become a major killer threatening the health of men in european and american countries. Chemotherapy plays an indispensable role in current clinical treatment. Therefore, the search, design and synthesis of the efficient and safe anti-tumor drug for treating the prostate cancer have important significance.
Different substituted indazole derivatives with different functional groups have received a great deal of attention in the past and in recent years because of their different biological properties, such as anti-inflammatory, antibacterial, anti-HIV, anti-arrhythmic, anti-fungal, anti-tumor etc. Currently, at least 43 indazole-based therapeutic agents have entered clinical use or clinical trials. The development of novel drugs based on indazole skeletons has important prospects in the future.
1,2,3-the triazolyl group is an attractive linker unit. A large number of molecules containing 1,2,3-triazole have various biological activities, such as anti-tumor, anti-HIV, anti-tuberculosis, antibacterial and the like. Since they are stable to metabolic degradation and can form hydrogen bonds, which facilitate binding of the biomolecule target and can improve solubility. In contrast to other nitrogen heterocycles, the 1,2,3-triazole ring is not protonated at physiological pH because of its poor basicity. Thus, 1,2,3-triazole can be used as a pharmacophore for small drug molecules.
1,2,3-triazole is used as a connecting unit to introduce an active group into indazole to synthesize a novel compound, the medicinal activity of the novel compound is researched, the development of an anti-prostate cancer medicament is attempted, and no relevant report of the compound is found at present.
Disclosure of Invention
The invention aims to provide an indazole skeleton derivative containing 1,2,3-triazole with good activity of resisting prostatic cancer or a salt thereof.
Another object of the present invention is to provide a method for synthesizing the same.
The invention further aims to provide application of the compound in preparing an anti-prostate cancer medicament.
In order to realize the purpose of the invention, the technical scheme is as follows:
the indazole skeleton derivative containing 1,2,3-triazole has the following structural general formula:
including pharmaceutically acceptable salts, esters, prodrugs or solvate thereof
n＝0,1,2
R 1 Selected from i or ii or iii or iv:
i：R 1 is hydrogen, straight-chain alkyl or isopropyl containing 1 to 3 carbon atoms;
ii：R 1 is phenyl or substituted phenyl, the substituent is mono-substituent, di-substituent or tri-substituent, the substituent is selected from F, cl, br or I, or straight chain or branched chain alkyl with 1-3 carbon atoms or hydroxyl, nitryl, methoxyl and tertiary butyl;
iii：R 1 is a single nitrogen or multi-nitrogen containing unsaturated five-membered or six-membered heterocyclic group; or substituted single-nitrogen or multi-nitrogen unsaturated five-membered or six-membered heterocyclic group, wherein the substituent is single substituent or double substituent, and the substituent is selected from F, cl, br or I, or straight chain or branched chain alkyl or hydroxyl with 1-3 carbon atoms, nitro, trifluoromethyl, acetamido, N, N-dimethylamino, methoxy and tert-butyl;
iv：R 1 is a five-membered or six-membered heterocyclic group containing single oxygen, single sulfur, nitrogen oxygen and nitrogen sulfur; or substituted five-membered or six-membered heterocyclic group containing mono-oxygen, mono-sulfur, nitrogen oxygen and nitrogen sulfur unsaturation, wherein the substituent is mono-substituent or di-substituent, and is selected from F, cl, br or I, or straight chain or branched chain alkyl or hydroxyl with 1-3 carbon atoms, nitro, trifluoromethyl, acetamido, N, N-dimethylamino, methoxy and hydroxyethyl;
R 2 selected from v or vi or vii or viii:
v：R 2 is hydrogenA linear alkyl or isopropyl group containing 1 to 3 carbon atoms;
vi：R 2 is phenyl or substituted phenyl, the substituent is mono-substituent, di-substituent or tri-substituent, the substituent is selected from F, cl, br or I, or straight chain or branched chain alkyl or hydroxyl with 1-3 carbon atoms, nitro, trifluoromethyl, acetamido, N, N-dimethylamino, methoxyl, tertiary butyl and nitrile group;
vii：R 2 is a single nitrogen or multi-nitrogen containing unsaturated five-membered or six-membered heterocyclic group; or substituted single-nitrogen or multi-nitrogen unsaturated five-membered or six-membered heterocyclic group, wherein the substituent is single substituent or double substituent, and the substituent is selected from F, cl, br or I, or straight chain or branched chain alkyl or hydroxyl with 1-3 carbon atoms, nitro, trifluoromethyl, acetamido, N, N-dimethylamino, methoxy and tert-butyl;
viii：R 2 is a five-membered or six-membered heterocyclic group containing single oxygen, single sulfur, nitrogen oxygen and nitrogen sulfur; or substituted five-membered or six-membered heterocyclic group containing mono-oxygen, mono-sulfur, nitrogen oxygen and nitrogen sulfur unsaturation, wherein the substituent is mono-substituent or di-substituent, and is selected from F, cl, br or I, or straight chain or branched chain alkyl or hydroxyl with 1-3 carbon atoms, nitro, trifluoromethyl, acetamido, N, N-dimethylamino, methoxy and hydroxyethyl;
the following substituent compounds are preferred:
n＝0,1
R 1 is selected from i:
i：R 1 is hydrogen, straight-chain alkyl or isopropyl containing 1 to 3 carbon atoms;
R 2 selected from vi
vi：R 2 Is phenyl or substituted phenyl, the substituent is mono-substituent or di-substituent, the substituent is selected from F, cl, br or I, or straight chain or branched chain alkyl or hydroxyl with 1-3 carbon atoms, nitro, trifluoromethyl, methoxyl, tertiary butyl and nitrile group;
more preferred are the following specific compounds:
the preparation method of the compound provided by the invention is realized through the following reaction route (taking 4-position side chain substitution as an example):
(1) Dissolving methyl 1H-indazole-4-carboxylate in an organic solvent, adding an iodo compound and an inorganic base, and refluxing to obtain an orange target 1.
R 1 Selected from i or ii or iii or iv.
The used inorganic base is one or two of potassium carbonate, sodium carbonate and cesium carbonate;
the organic solvent is one or two of acetonitrile and N, N-dimethylformamide;
among them, methyl 1H-indazole-4-carboxylate and iodo compound are commercially available.
(2) Dissolving the compound of the general formula 1 in an organic solvent, adding strong base for reflux reaction, and adjusting acid to obtain a white solid target 2.
A compound of the general formula 1: r is 1 Selected from i or ii or iii or iv.
The organic solvent is one or two of methanol or ethanol;
the strong base is one or two of sodium hydroxide or potassium hydroxide.
(3) Dissolving the compound of the general formula 2 in an organic solvent, adding an acid amine condensing agent and propargylamine to react at room temperature to obtain an off-white target 3.
The compounds of the general formula 2 used: r is 1 Selected from i or ii or iii or iv.
The organic solvent is one or two of dichloromethane or N, N-dimethylformamide;
the acid-amine condensing agent is one or two of EDCI/HOBT (1- (3-dimethylaminopropyl) -3-ethyl carbodiimide hydrochloride/1-hydroxybenzotriazole), HATU (N, N, N ', N' -tetramethyl-O- (7-azabenzotriazol-1-yl) urea hexafluorophosphate) and HBTU (benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate);
the starting propargylamine and the acid amine condensing agent are commercially available.
(4) Dissolving the compound of the general formula 3 and the compound of the general formula 7 in an organic solvent and water (V: V = 1:1), adding anhydrous copper sulfate and sodium ascorbate, and reacting at room temperature to obtain an off-white target 4.
A compound of the general formula 3: r 1 Selected from i or ii or iii or iv.
The organic solvent is one or two of dichloromethane or tetrahydrofuran;
a compound of the general formula 7: r is 2 Selected from v or vi or vii or viii; n =0,1,2
When n = 0:
dissolving aromatic amine in dilute hydrochloric acid, sequentially dropwise adding aqueous solutions of sodium nitrite and sodium azide, adjusting the pH of the system to be neutral after the reaction is completed, extracting with ethyl acetate, and drying an organic phase to obtain a compound of a general formula 7;
when n =1,2:
and (3) adding the bromine substituent and sodium azide into an organic solvent, refluxing overnight, and evaporating an organic phase extracted by the system to dryness to obtain the compound in the general formula 7.
The organic solvent is one or two of dimethyl sulfoxide and N, N-dimethylformamide;
the starting material, sodium azide, is commercially available.
The synthetic methods of the present invention include, but are not limited to, the addition or removal of an appropriate protecting group before or after the above steps to obtain the compounds of the present invention. In addition, it is also within the scope of the synthetic methods of the present invention to vary the order of the reaction steps to obtain the compounds of the present invention.
The compounds of the present invention are useful for treating or preventing prostate cancer diseases.
The amount of the present invention to be expressed in terms of treating or preventing prostate cancer disease is expressed as "therapeutically effective amount" and may vary depending on body weight, specific surface area or the compound of the present invention.
The effective amount of the present invention may be increased or decreased in proportion to the urgency of the condition.
The application of the compound and the pharmaceutically acceptable salt, ester, prodrug or solvent compound thereof: as an active ingredient, in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent, to form a pharmaceutical or veterinary composition for use in the manufacture of a biopharmaceutical product, therapeutic.
An "acceptable carrier" is an acceptable ingredient disclosed in the pharmaceutical field, and is a solid or liquid filler, excipient, solvent, diluent, etc., which helps transport, absorption and distribution of the drug to be tested in the body, and must not be harmful to the patient.
The preparation of the invention includes but is not limited to final sterilized injection, non-final sterilized injection, powder injection, tablet, granule, capsule, soluble powder and powder.
Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are within the scope of the present invention.
According to the invention, 1,2,3-triazole is used as a connecting unit to introduce active groups into the 4 position, the 5 position and the 6 position of indazole respectively, experiments show that the compounds show specific antiproliferative activity on prostate cancer, but have no activity on breast cancer, liver cancer and gastric cancer, and compared with a positive compound 5-fluorouracil, the compounds have remarkable superiority and show better in-vitro safety.
The invention has the innovation points and advantages that: an indazole skeleton derivative containing 1,2,3-triazole is designed and synthesized by skillfully combining an indazole parent nucleus and an active group 1,2,3-triazole, and the compound disclosed by the invention is subjected to antitumor activity evaluation, wherein the indazole skeleton derivative comprises prostate cancer cells (PC-3), breast cancer cells (MCF-7), liver cancer cells (HepG-2) and stomach cancer cells (MGC-803). The compounds of the present invention showed specific inhibitory activity against PC-3 (see Table 1). The antiproliferative activity of the compound 4-16 is more obvious than that of the contrast drug 5-fluorouracil. Furthermore, the antiproliferative activity of inventive compounds 4-16 against normal prostate cells WPYM-1 was four to five times that of PC-3 (see Table 2), indicating the superiority of inventive compounds 4-16. The synthesis method is simple, has high yield and is beneficial to production and implementation conversion. Opens up a new way for researching new anti-prostate cancer drugs and has important significance for developing anti-prostate cancer drugs with own intellectual property rights.
Detailed Description
The present invention will be further described with reference to the following examples. For example, substitution at the 4-position, substitution at the 5-and 6-positions requires replacement of the starting material with methyl 1H-indazole-5-carboxylate or methyl 1H-indazole-6-carboxylate, which are commercially available.
Example 1: preparation of the derivatives (1-1) shown by the Compounds of formula 1
And (2) dropwise adding iodoisopropane into the uniformly stirred acetonitrile solution of methyl 1H-indazole-4-carboxylate and cesium carbonate, refluxing and stirring for 4-6 hours, monitoring the reaction by TLC, cooling to room temperature after the reaction is completed, performing suction filtration, evaporating the filtrate to dryness, and performing column chromatography to obtain colorless transparent liquid, wherein the yield is 66%.
Example 2: preparation of the derivative (2-1) shown by the Compound of formula 2
Dissolving 1-isopropyl-1H-indazole-4-carboxylic acid methyl ester in anhydrous methanol, slowly adding sodium hydroxide, refluxing and stirring for 1-2 hours, cooling to room temperature, distilling under reduced pressure to remove the solvent, adding a proper amount of water into the system, adjusting the pH value to 3-4 by hydrochloric acid, separating out a large amount of white solids, and performing suction filtration to obtain the white solids, wherein the yield is as follows: 85 percent.
Example 3: preparation of the derivative (3-1) shown by the Compound of formula 3
1-isopropyl-1H-indazole-4-carboxylic acid and HATU were added to anhydrous dichloromethane at room temperature and stirred well, followed by propargylamine and stirred at room temperature overnight. Evaporating to dryness to obtain a crude product, and concentrating the crude product to obtain a white solid with the yield of 87%.
Example 4: preparation of the derivative (7-1) shown by the Compound of formula 7
Dissolving aniline in 10 wt% aqueous solution of hydrochloric acid at room temperature, stirring, adding dropwise aqueous solution of sodium nitrite, reacting for one hour, adding dropwise aqueous solution of sodium azide, and stirring at room temperature for 1-2 hours. Slowly adding sodium bicarbonate into the system to make the system alkalescent, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness to obtain brown oily liquid, and obtaining the yield: and 63 percent.
Example 5: preparation of the derivative (7-2) shown by the Compound of formula 7
Dissolving 2,4-dimethylaniline in 10% hydrochloric acid aqueous solution at room temperature, stirring uniformly, dropwise adding sodium nitrite aqueous solution, reacting for one hour, dropwise adding sodium azide aqueous solution, and stirring for 1-2 hours at room temperature. Slowly adding sodium bicarbonate into the system to make the system alkalescent, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness to obtain brown oily liquid, and obtaining the yield: 82 percent.
Example 6: preparation of the derivative (7-3) shown by the Compound of formula 7
Dissolving 3,4-dimethylaniline in 10% hydrochloric acid aqueous solution at room temperature, stirring uniformly, dropwise adding sodium nitrite aqueous solution, reacting for one hour, dropwise adding sodium azide aqueous solution, and stirring at room temperature for 1-2 hours. Slowly adding sodium bicarbonate into the system to make the system weakly alkaline, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and evaporating to obtain brown oily liquid, wherein the yield is as follows: 81 percent.
Example 7: preparation of the derivative (7-4) shown by the Compound of formula 7
Dissolving 4-iodoaniline in 10 wt% hydrochloric acid water solution at room temperature, stirring, dripping sodium nitrite water solution, reacting for one hour, dripping sodium azide water solution, and stirring at room temperature for 1-2 hours. Slowly adding sodium bicarbonate into the system to make the system alkalescent, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness to obtain brown oily liquid, and obtaining the yield: 87 percent.
Example 8: preparation of the derivative (7-5) shown by the Compound of formula 7
Dissolving 4-fluoroaniline in 10% hydrochloric acid aqueous solution by mass percent at room temperature, uniformly stirring, dropwise adding sodium nitrite aqueous solution, reacting for one hour, dropwise adding sodium azide aqueous solution, and stirring for 1-2 hours at room temperature. Slowly adding sodium bicarbonate into the system to make the system alkalescent, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness to obtain brown oily liquid, and obtaining the yield: 38 percent.
Example 9: preparation of the derivative (7-6) shown by the Compound of formula 7
Dissolving 3-bromoaniline in 10% hydrochloric acid aqueous solution by mass percentage at room temperature, uniformly stirring, dropwise adding sodium nitrite aqueous solution, reacting for one hour, dropwise adding sodium azide aqueous solution, and stirring for 1-2 hours at room temperature. Slowly adding sodium bicarbonate into the system to make the system alkalescent, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness to obtain brown oily liquid, and obtaining the yield: 56 percent.
Example 10: preparation of the derivatives (7-7) shown by the Compounds of formula 7
Dissolving 3-fluoroaniline in 10% hydrochloric acid aqueous solution by mass percent at room temperature, uniformly stirring, dropwise adding sodium nitrite aqueous solution, reacting for one hour, dropwise adding sodium azide aqueous solution, and stirring for 1-2 hours at room temperature. Slowly adding sodium bicarbonate into the system to make the system weakly alkaline, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, and evaporating to obtain brown oily liquid, wherein the yield is as follows: 78 percent.
Example 11: preparation of the derivatives (7-8) shown by the Compounds of formula 7
Dissolving 4-nitroaniline in 10% hydrochloric acid aqueous solution at room temperature, uniformly stirring, dropwise adding sodium nitrite aqueous solution, reacting for one hour, dropwise adding sodium azide aqueous solution, and stirring for 1-2 hours at room temperature.
Slowly adding sodium bicarbonate into the system to make the system alkalescent, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness to obtain brown oily liquid, and obtaining the yield: 77 percent.
Example 12: preparation of derivatives (7-9) shown by Compounds of formula 7
Dissolving 4-methylaniline in 10% hydrochloric acid aqueous solution at room temperature, uniformly stirring, dropwise adding sodium nitrite aqueous solution, reacting for one hour, dropwise adding sodium azide aqueous solution, and stirring for 1-2 hours at room temperature.
Slowly adding sodium bicarbonate into the system to make the system alkalescent, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness to obtain brown oily liquid, and obtaining the yield: 79 percent.
Example 13: preparation of derivatives (7-10) shown by Compounds of formula 7
Dissolving 3-methylaniline in 10% hydrochloric acid aqueous solution at room temperature, uniformly stirring, dropwise adding sodium nitrite aqueous solution, reacting for one hour, dropwise adding sodium azide aqueous solution, and stirring for 1-2 hours at room temperature.
Slowly adding sodium bicarbonate into the system to make the system alkalescent, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness to obtain brown oily liquid, and obtaining the yield: 59 percent.
Example 14: preparation of the derivatives (7-11) shown by the Compounds of formula 7
Dissolving 2-methylaniline in 10 wt% hydrochloric acid aqueous solution at room temperature, stirring uniformly, dropwise adding sodium nitrite aqueous solution, reacting for one hour, dropwise adding sodium azide aqueous solution, and stirring for 1-2 hours at room temperature.
Slowly adding sodium bicarbonate into the system to make the system alkalescent, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness to obtain brown oily liquid, and obtaining the yield: and 69 percent.
Example 15: preparation of the derivatives (7-12) shown by the Compounds of formula 7
Dissolving 2-fluoroaniline in 10% hydrochloric acid aqueous solution at room temperature, stirring uniformly, dropwise adding sodium nitrite aqueous solution, reacting for one hour, dropwise adding sodium azide aqueous solution, and stirring for 1-2 hours at room temperature. Slowly adding sodium bicarbonate into the system to make the system alkalescent, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness to obtain brown oily liquid, and obtaining the yield: 61 percent.
Example 16: preparation of the derivatives (7-13) shown by the Compounds of formula 7
Dissolving 4-trifluoromethylaniline in 10% hydrochloric acid aqueous solution by mass at room temperature, stirring uniformly, dropwise adding sodium nitrite aqueous solution, reacting for one hour, dropwise adding sodium azide aqueous solution, and stirring for 1-2 hours at room temperature. Slowly adding sodium bicarbonate into the system to make the system alkalescent, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness to obtain brown oily liquid, and obtaining the yield: 80 percent.
Example 17: preparation of derivatives (7-14) shown by Compounds of formula 7
Dissolving 4-ethylaniline in 10% hydrochloric acid aqueous solution by mass at room temperature, uniformly stirring, dropwise adding sodium nitrite aqueous solution, reacting for one hour, dropwise adding sodium azide aqueous solution, and stirring for 1-2 hours at room temperature. Slowly adding sodium bicarbonate into the system to make the system alkalescent, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness to obtain brown oily liquid, and obtaining the yield: and 64 percent.
Example 18: preparation of the derivatives (7-15) shown by the Compounds of formula 7
Dissolving 4-methoxyaniline in 10% hydrochloric acid aqueous solution by mass at room temperature, stirring uniformly, dropwise adding sodium nitrite aqueous solution, reacting for one hour, dropwise adding sodium azide aqueous solution, and stirring for 1-2 hours at room temperature. Slowly adding sodium bicarbonate into the system to make the system alkalescent, extracting with ethyl acetate, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness to obtain brown oily liquid, and obtaining the yield: 73 percent.
Example 19: preparation of the derivatives (7-16) shown by the Compounds of formula 7
Adding benzyl bromide and sodium azide into dimethyl sulfoxide, stirring at 80 ℃ for 8 hours, standing the system, cooling to room temperature, extracting with dichloromethane and saturated saline solution, drying an organic phase with anhydrous sodium sulfate, and evaporating to obtain a brown oily liquid with the yield of 80%.
Example 20: preparation of derivatives (7-17) shown by Compounds of formula 7
Adding 4-trifluoromethyl benzyl bromide and sodium azide into dimethyl sulfoxide, stirring at 80 ℃ for 8 hours, standing the system, cooling to room temperature, extracting with dichloromethane and saturated saline solution, drying an organic phase with anhydrous sodium sulfate, and evaporating to obtain a brown oily liquid with the yield of 67%.
Example 21: preparation of derivatives (7-18) shown by Compounds of formula 7
Adding 4-cyanobenzylbromide and sodium azide into dimethyl sulfoxide, stirring for 8 hours at the temperature of 80 ℃, standing and cooling the system to room temperature, extracting with dichloromethane and saturated saline water, drying an organic phase with anhydrous sodium sulfate, and evaporating to obtain a brown oily liquid with the yield of 85%.
Example 23: preparation of derivatives (7-19) shown by Compounds of formula 7
Adding 4-methoxybenzyl bromide and sodium azide into dimethyl sulfoxide, stirring for 8 hours at the temperature of 80 ℃, standing the system, cooling to room temperature, extracting with dichloromethane and saturated saline water, drying an organic phase with anhydrous sodium sulfate, and evaporating to obtain a brown oily liquid with the yield of 81%.
Example 24: preparation of the derivatives (7-20) shown by the Compounds of formula 7
Adding 4-tert-butyl benzyl bromide and sodium azide into dimethyl sulfoxide, stirring at 80 ℃ for 8 hours, standing the system, cooling to room temperature, extracting with dichloromethane and saturated saline solution, drying an organic phase with anhydrous sodium sulfate, and evaporating to obtain a brown oily liquid with the yield of 98%.
Example 25: preparation of the derivative (4-1) shown by the Compound of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding azidobenzene after 0.5 hour, and reacting at room temperature for 6-8 hours. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 68 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.14(t,J＝5.6Hz,1H),8.73(s,1H),8.43(s,1H),7.94–7.87(m,3H),7.66(d,J＝7.1Hz,1H),7.59(t,J＝7.9Hz,2H),7.51–7.42(m,2H),5.05(dt,J＝13.1,6.6Hz,1H),4.68(d,J＝5.6Hz,2H),1.48(d,J＝6.6Hz,6H). 13 C NMR(101MHz,DMSO)δ166.74,146.77,139.24,137.16,133.21,130.34,129.01,127.75,125.58,121.97,121.60,120.42,113.32,73.32,49.85,35.26,22.57.HR-MS(ESI),calcd.C 20 H 20 N 6 O,[M+H] + m/z:361.1777,found:361.1782.
example 26: preparation of the derivative (4-2) shown by the Compound of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding 1-azide-2,4-xylene after 0.5 hour, and reacting at room temperature for 6-8 hours. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 52 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.12(t,J＝5.4Hz,1H),8.42(s,1H),8.33(s,1H),7.89(d,J＝8.4Hz,1H),7.65(d,J＝7.1Hz,1H),7.45(m,J＝8.2,7.4Hz,1H),7.33–7.25(m,2H),7.19(d,J＝8.0Hz,1H),5.04(m,J＝13.1,6.5Hz,1H),4.69(d,J＝5.5Hz,2H),2.36(s,3H),2.12(s,3H),1.48(d,J＝6.6Hz,6H). 13 C NMR(101MHz,DMSO)δ166.75,139.75,139.22,134.47,133.19,132.21,127.84,126.19,125.59,125.05,121.96,120.41,113.17,49.86,35.24,22.56,21.08,17.84.HR-MS(ESI),calcd.C 22 H 24 N 6 O,[M+H] + m/z:389.2090,found:389.2088.
example 27: preparation of the derivative (4-3) shown by the Compound of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding 1-azide-3,4-xylene after 0.5 hour, and reacting at room temperature for 6-8 hours. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 76 percent. CoreMagnetic data: 1 H NMR(400MHz,CDCl 3 )δ8.50(t,1H),8.05(d,J＝23.9Hz,1H),7.58(d,J＝8.4Hz,1H),7.52(d,J＝7.4Hz,2H),7.45–7.34(m,2H),7.29(s,1H),7.25(d,J＝8.2Hz,1H),4.87(t,J＝5.9Hz,3H),2.32(d,J＝7.6Hz,6H),1.60(d,J＝6.7Hz,6H). 13 C NMR(101MHz,CDCl 3 )δ167.28,139.07,138.40,137.69,134.84,132.84,130.66,127.49,125.25,121.80,120.85,119.81,117.88,112.48,50.46,35.29,22.18,19.92,19.50.HR-MS(ESI),calcd.C 22 H 24 N 6 O,[M+H] + m/z:389.2090,found:389.2088.
example 28: preparation of the derivatives (4-4) shown by the Compounds of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding 1-azido-4-iodobenzene after 0.5 hour, and reacting at room temperature for 6-8 hours. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 73 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.14(t,J＝5.5Hz,1H),8.75(s,1H),8.42(s,1H),7.92(m,J＝18.7,8.6Hz,3H),7.76(d,J＝8.7Hz,2H),7.66(d,J＝7.1Hz,1H),7.52–7.38(m,1H),5.05(m,J＝13.1,6.6Hz,1H),4.67(d,J＝5.5Hz,2H),1.48(d,J＝6.6Hz,6H). 13 C NMR(101MHz,DMSO)δ166.74,147.00,139.23,139.03,136.80,133.29,127.71,125.59,122.31,121.96,121.53,120.44,113.24,94.63,49.86,35.24,22.57.HR-MS(ESI),calcd.C 20 H 19 IN 6 O,[M+H] + m/z:487.0743,found:487.0740.
example 29: preparation of the derivatives (4-5) shown by the Compounds of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding 1-azido-4-fluorobenzene after 0.5 hour, and reacting at room temperature for 6-8 hours. Extracting the system with dichloromethane, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness, and recrystallizing the crude product with dichloromethane and petroleum ether to obtain the targetCompound, yield 75%. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.14(t,J＝5.6Hz,1H),8.72(s,1H),8.43(s,1H),8.02–7.92(m,2H),7.89(d,J＝8.5Hz,1H),7.66(d,J＝7.1Hz,1H),7.45(m,J＝8.8,4.9,2.4Hz,3H),5.13–4.96(m,1H),4.67(d,J＝5.6Hz,2H),1.48(d,J＝6.6Hz,6H). 13 C NMR(101MHz,DMSO)δ166.74,162.01(d,J＝245.6Hz),146.84,139.23,133.71,133.30,127.73,125.59,122.76(d,J＝8.8Hz),121.91,120.44,117.16(d,J＝23.2Hz),113.23,49.85,35.24,22.57.HR-MS(ESI),calcd.C20H19FN6O,[M+H] + m/z:379.1682,found:379.1678.
example 30: preparation of the derivative (4-6) shown by the Compound of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding 1-azido-3-bromobenzene after 0.5 hour, and reacting at room temperature for 6-8 hours. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 58 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.15(t,J＝5.6Hz,1H),8.83(s,1H),8.43(s,1H),8.20(t,J＝1.8Hz,1H),7.99(m,J＝8.1,1.2Hz,1H),7.90(d,J＝8.4Hz,1H),7.68(t,J＝6.7Hz,2H),7.55(t,J＝8.1Hz,1H),7.49–7.40(m,1H),5.05(m,J＝13.1,6.6Hz,1H),4.68(d,J＝5.6Hz,2H),1.49(d,J＝6.6Hz,6H). 13 C NMR(101MHz,DMSO)δ166.74,147.06,139.24,138.26,133.31,132.30,131.74,127.71,125.59,122.91,121.97,121.77,120.46,119.36,113.25,49.86,35.24,22.57.HR-MS(ESI),calcd.C 20 H 19 BrN 6 O,[M+H] + m/z:439.0882,found:439.0878.
example 31: preparation of the derivatives (4-7) shown by the Compounds of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding 1-azido-3-fluorobenzene after 0.5 hour, and reacting at room temperature for 6-8 hours. Extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, evaporating to dryness, and coarseThe product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 80 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.15(t,J＝5.6Hz,1H),8.80(s,1H),8.40(d,J＝19.5Hz,1H),7.91–7.82(m,3H),7.67–7.59(m,2H),7.47–7.43(m,1H),7.34(m,J＝8.5,1.9Hz,1H),5.08–5.02(m,1H),4.67(d,J＝5.6Hz,2H),1.48(d,J＝6.6Hz,6H). 13 C NMR(101MHz,DMSO)δ166.74,162.91(d,J＝244.9Hz),147.04,139.24,138.38,133.21,132.30(d,J＝9.2Hz),127.71,127.34,125.59,122,120.40,116.29(d,J＝3.0Hz),115.71(d,J＝20.9Hz),113.33,108.00,107.73,49.85,35.23,22.57.HR-MS(ESI),calcd.C20H19FN6O,[M+H]+m/z:379.1682,found:379.1685.
example 32: preparation of the derivatives (4-8) shown by the Compounds of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding 1-azido-4-nitrobenzene after 0.5 hour, and reacting at room temperature for 6-8 hours. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 50 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.18(t,J＝5.7Hz,1H),8.96(s,1H),8.44(d,J＝9.3Hz,3H),8.26(d,J＝9.2Hz,2H),7.90(d,J＝8.5Hz,1H),7.67(d,J＝7.1Hz,1H),7.46(m,J＝8.3,7.3Hz,1H),5.05(m,J＝13.1,6.6Hz,1H),4.69(d,J＝5.6Hz,2H),1.48(d,J＝6.6Hz,6H). 13 C NMR(101MHz,DMSO)δ166.77,147.57,147.08,141.38,139.24,133.30,127.66,126.04,125.59,122.01,120.95,120.46,113.29,49.86,35.21,22.58.HR-MS(ESI),calcd.C 20 H 19 N 7 O 3 ,[M+H] + m/z:406.1627,found:406.1618.
example 33: preparation of the derivatives (4-9) shown by the Compounds of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding 1-azido-4-methylbenzene after 0.5 hour, and reacting at room temperature for 6-8 hours. The system was extracted with dichloromethaneDrying the organic phase by using anhydrous sodium sulfate, evaporating to dryness, and recrystallizing the crude product by using dichloromethane and petroleum ether to obtain the target compound with the yield of 44%. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.13(t,J＝5.5Hz,1H),8.68(s,1H),8.43(s,1H),7.90(d,J＝8.4Hz,1H),7.80(d,J＝8.4Hz,2H),7.67(d,J＝7.1Hz,1H),7.50–7.42(m,1H),7.38(d,J＝8.3Hz,2H),5.11–5.00(m,1H),4.67(d,J＝5.5Hz,2H),2.38(s,3H),1.49(d,J＝6.6Hz,6H). 13 C NMR(101MHz,DMSO)δ166.73,146.64,139.24,138.59,134.93,133.30,130.68,127.75,125.59,121.97,121.47,120.37,113.22,49.85,35.27,22.57,21.03.HR-MS(ESI),calcd.C 21 H 22 N 6 O,[M+H] + m/z:375.1933,found:375.1932.
example 34: preparation of the derivatives (4-10) shown by the Compounds of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding 1-azido-3-methylbenzene after 0.5 hour, and reacting at room temperature for 6-8 hours. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 39 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.14(t,J＝5.5Hz,1H),8.70(s,1H),8.43(s,1H),7.90(d,J＝8.5Hz,1H),7.77(s,1H),7.69(dd,J＝17.3,7.6Hz,2H),7.51–7.41(m,2H),7.29(d,J＝7.6Hz,1H),5.05(m,J＝13.2,6.6Hz,1H),4.67(d,J＝5.6Hz,2H),2.41(s,3H),1.49(d,J＝6.6Hz,6H). 13 C NMR(101MHz,DMSO)δ166.73,146.72,140.09,139.24,137.12,133.30,130.13,129.58,127.74,125.59,121.98,121.51,120.80,120.45,117.47,113.23,49.85,35.27,22.57,21.37.HR-MS(ESI),calcd.C 21 H 22 N 6 O,[M+H] + m/z:375.1933,found:375.1928.
example 35: preparation of the derivative (4-11) shown by the Compound of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, stirring uniformly, adding 1 after 0.5 hourAnd reacting the mixture for 6 to 8 hours at room temperature. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 39 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.14(t,J＝5.5Hz,1H),8.70(s,1H),8.43(s,1H),7.90(d,J＝8.5Hz,1H),7.77(s,1H),7.69(dd,J＝17.3,7.6Hz,2H),7.51–7.41(m,2H),7.29(d,J＝7.6Hz,1H),5.05(m,J＝13.2,6.6Hz,1H),4.67(d,J＝5.6Hz,2H),2.41(s,3H),1.49(d,J＝6.6Hz,6H). 13 C NMR(101MHz,DMSO)δ166.73,146.72,140.09,139.24,137.12,133.30,130.13,129.58,127.74,125.59,121.98,121.51,120.80,120.45,117.47,113.23,49.85,35.27,22.57,21.37.HR-MS(ESI),calcd.C 21 H 22 N 6 O,[M+H] + m/z:375.1933,found:375.1928.
example 36: preparation of the derivatives (4-12) shown by the Compounds of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding 1-azido-2-fluorobenzene after 0.5 hour, and reacting at room temperature for 6-8 hours. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 49 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.16(t,J＝6.0Hz,1H),8.45(m,J＝43.0,4.8Hz,2H),7.93–7.79(m,2H),7.68–7.29(m,5H),5.05(m,J＝13.1,6.6Hz,1H),4.69(d,J＝5.7Hz,2H),1.48(d,J＝6.6Hz,6H).13C NMR(101MHz,DMSO)δ166.79,154.25(d,J＝252.6Hz),149.88,146.27,139.23,133.23,131.62(d,J＝8.0Hz),127.75,126.36,126.03,125.50,124.91(d,J＝2.5Hz),121.93,120.41,117.61(d,J＝19.4Hz),113.24,49.81,35.13,22.58.HR-MS(ESI),calcd.C20H19FN6O,[M+H]+m/z:379.1682,found:379.1679.
example 37: preparation of the derivatives (4-13) shown by the Compounds of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, stirring uniformly,after 0.5 hour, 1-azido-4-trifluoromethylbenzene is added and reacted for 6 to 8 hours at room temperature. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 45 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.17(t,J＝5.6Hz,1H),8.90(s,1H),8.43(s,1H),8.20(d,J＝8.5Hz,2H),7.98(d,J＝8.6Hz,2H),7.90(d,J＝8.5Hz,1H),7.67(d,J＝7.1Hz,1H),7.46(m,J＝8.4,7.2Hz,1H),5.05(m,J＝13.2,6.6Hz,1H),4.69(d,J＝5.6Hz,2H),1.49(d,J＝6.6Hz,6H). 13 C NMR(101MHz,DMSO)δ166.77,147.27,139.24,133.30,127.77(q,J＝32Hz),125.68(d,J＝3.0Hz),123.22(q,J＝268Hz),120.87,120.45,113.26,49.85,35.22,22.57.HR-MS(ESI),calcd.C 21 H 19 F 3 N 6 O,[M+H] + m/z:429.1650,found:429.1645.
example 38: preparation of the derivatives (4-14) shown by the Compounds of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding 1-azido-4-ethylbenzene after 0.5 hour, and reacting for 6-8 hours at room temperature. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 42 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.13(t,J＝5.6Hz,1H),8.68(s,1H),8.43(s,1H),7.89(d,J＝8.5Hz,1H),7.81(d,J＝8.5Hz,2H),7.66(d,J＝7.0Hz,1H),7.48–7.39(m,3H),5.04(m,J＝13.0,6.5Hz,1H),4.67(d,J＝5.6Hz,2H),2.70–2.65(m,2H),1.48(d,J＝6.6Hz,6H),1.21(t,J＝7.6Hz,3H). 13 C NMR(101MHz,DMSO)δ166.73,146.63,144.81,139.24,135.11,133.30,129.54,127.76,125.59,121.97,121.52,120.43,113.22,49.85,35.26,28.13,22.57,15.93.HR-MS(ESI),calcd.C 22 H 24 N 6 O,[M+H] + m/z:389.2090,found:389.2086.
example 39: preparation of the derivatives (4-15) shown by the Compounds of formula 4
1-isopropyl-N- (prop-2-yn-1-yl) -1H-indazole-4-carboxamide is added at room temperature toAnd (3) adding anhydrous copper sulfate and sodium ascorbate slowly into a mixed solution of tetrahydrofuran and water, uniformly stirring, adding 1-azido-4-methoxybenzene after 0.5 hour, and reacting at room temperature for 6-8 hours. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 49 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.11(t,J＝5.6Hz,1H),8.62(s,1H),8.42(s,1H),7.89(d,J＝8.5Hz,1H),7.85–7.77(m,2H),7.65(d,J＝7.1Hz,1H),7.45(dd,J＝8.3,7.3Hz,1H),7.12(d,J＝9.0Hz,2H),5.05(dt,J＝13.2,6.6Hz,1H),4.65(d,J＝5.6Hz,2H),3.82(s,3H),1.48(d,J＝6.6Hz,6H). 13 C NMR(101MHz,DMSO)δ166.71,159.61,146.50,139.23,133.29,127.76,125.59,122.02,121.57,120.43,115.31,113.22,56.01,49.85,35.27,22.58.HR-MS(ESI),calcd.C 21 H 22 N 6 O 2 ,[M+H] + m/z:391.1882,found:391.1878.
example 40: preparation of the derivatives (4-16) shown by the Compounds of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, then slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding (azidomethyl) benzene after 0.5 hour, and reacting at room temperature for 6-8 hours. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 47 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.06(t,J＝5.1Hz,1H),8.38(s,1H),8.07(s,1H),7.88(d,J＝8.4Hz,1H),7.60(d,J＝7.1Hz,1H),7.43(t,J＝7.8Hz,1H),7.38–7.29(m,5H),5.57(s,2H),5.04(dt,J＝12.6,6.3Hz,1H),4.56(d,J＝5.4Hz,2H),1.48(d,J＝6.4Hz,6H). 13 C NMR(101MHz,DMSO)δ166.67,145.94,139.23,136.67,133.23,129.19,128.50,127.77,125.59,123.54,121.93,120.30,113.20,53.16,49.85,35.29,22.57.HR-MS(ESI),calcd.C 21 H 22 N 6 O,[M+H] + m/z:375.1933,found:375.1935.
example 41: preparation of the derivatives (4-17) shown by the Compounds of formula 4
Reacting 1-isopropyl at room temperatureAdding the base-N- (prop-2-alkyne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water, slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding 1- (azidomethyl) -4- (trifluoromethyl) benzene after 0.5 hour, and reacting at room temperature for 6-8 hours. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 45 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.07(t,J＝5.5Hz,1H),8.38(s,1H),8.14(s,1H),7.88(d,J＝8.4Hz,1H),7.74(d,J＝8.0Hz,2H),7.60(d,J＝7.1Hz,1H),7.50(d,J＝8.1Hz,2H),7.46–7.39(m,1H),5.71(s,2H),5.05(m,J＝12.6,6.3Hz,1H),4.57(d,J＝5.6Hz,2H),1.48(d,J＝6.3Hz,6H). 13 C NMR(101MHz,DMSO)δ166.70,146.08,141.35,139.22,133.22,129.07(q,J＝32Hz),127.77,126.13(q,J＝4.0Hz),125.59,123.67(q,J＝270Hz),120.30,115.15,113.21,52.49,49.85,35.28,22.56.HR-MS(ESI),calcd.C 22 H 21 F 3 N 6 O,[M+H] + m/z:443.1807,found:443.1811.
example 42: preparation of the derivatives (4-18) shown by the Compounds of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding 1- (azidomethyl) -4- (nitrile group) benzene after 0.5 hour, and reacting at room temperature for 6-8 hours. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 45 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.08(t,J＝5.5Hz,1H),8.38(s,1H),8.14(s,1H),7.87(m,J＝15.5,8.3Hz,3H),7.60(d,J＝7.1Hz,1H),7.45(d,J＝8.1Hz,3H),5.70(s,2H),5.04(m,J＝13.1,6.5Hz,1H),4.57(d,J＝5.5Hz,2H),1.48(d,J＝6.5Hz,6H). 13 C NMR(101MHz,DMSO)δ166.70,146.11,142.15,139.22,133.18,129.15,127.75,125.59,123.98,121.92,120.31,119.02,113.22,111.34,52.53,49.85,35.29,22.57.HR-MS(ESI),calcd.C 22 H 21 N 7 O,[M+H] + m/z:400.1886,found:400.1891.
example 43: preparation of the derivatives (4-19) shown by the Compounds of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding 1- (azidomethyl) -4- (methoxyl) benzene after 0.5 hour, and reacting at room temperature for 6-8 hours. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 43 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.05(t,J＝5.7Hz,1H),8.38(s,1H),8.01(s,1H),7.88(d,J＝8.4Hz,1H),7.59(d,J＝7.1Hz,1H),7.43(m,J＝8.2,7.4Hz,1H),7.30(d,J＝8.6Hz,2H),6.91(d,J＝8.6Hz,2H),5.48(s,2H),5.05(m,J＝13.1,6.4Hz,1H),4.54(d,J＝5.7Hz,2H),3.72(s,3H),1.48(d,J＝6.6Hz,6H). 13 C NMR(101MHz,DMSO)δ166.65,159.56,145.88,139.22,133.23,130.10,128.56,127.77,125.58,123.17,121.92,120.29,114.54,113.19,55.58,52.72,49.85,35.28,22.57.HR-MS(ESI),calcd.C 22 H 24 N 6 O 2 ,[M+H] + m/z:405.2039,found:405.2034.
example 44: preparation of the derivatives (4-20) shown by the Compounds of formula 4
Adding 1-isopropyl-N- (prop-2-yne-1-yl) -1H-indazole-4-formamide into a mixed solution of tetrahydrofuran and water at room temperature, slowly adding anhydrous copper sulfate and sodium ascorbate, uniformly stirring, adding 1- (azidomethyl) -4- (tert-butyl) benzene after 0.5 hour, and reacting at room temperature for 6-8 hours. The system is extracted by dichloromethane, the organic phase is dried by anhydrous sodium sulfate and evaporated to dryness, and the crude product is recrystallized by dichloromethane and petroleum ether to obtain the target compound with the yield of 43 percent. Nuclear magnetic data: 1 H NMR(400MHz,DMSO)δ9.06(t,J＝5.7Hz,1H),8.37(s,1H),8.05(s,1H),7.88(d,J＝8.5Hz,1H),7.59(d,J＝7.1Hz,1H),7.43(m,J＝8.3,7.3Hz,1H),7.37(d,J＝8.3Hz,2H),7.25(d,J＝8.3Hz,2H),5.52(s,2H),5.04(m,J＝13.2,6.6Hz,1H),4.55(d,J＝5.7Hz,2H),1.48(d,J＝6.6Hz,6H),1.24(s,9H). 13 C NMR(101MHz,DMSO)δ166.67,151.04,139.22,133.71,133.22,128.26,127.80,125.95,125.58,123.42,121.92,120.29,113.18,52.88,49.84,35.28,34.75,31.51,22.57.HR-MS(ESI),calcd.C 25 H 30 N 6 O,[M+H] + m/z:431.2559,found:431.2552.
example 45: evaluation of in vitro antitumor Activity of Compounds of the present invention
Weighing 1-2 mg of sample, placing the sample in a 1.5mL EP tube, preparing the solution into 10mmol/L solution by DMSO, storing the solution at 4 ℃, and diluting the solution by a culture medium according to the concentration required by the experiment. Taking cells in logarithmic growth phase, digesting, counting, adjusting cell density with culture medium at 3 × 10 3 Inoculating each well to a 96-well plate, culturing for 8-12h after cells adhere to the wall by using 100 mu L of culture medium per well, discarding the culture medium, adding the medicine diluted by the culture medium, namely adding the sample to be detected into the 96-well plate at the concentrations of 80.0, 40.0, 20.0 and 10.0,5.00,2.50,1.25,0.625 mu mol/L, setting 3 multiple wells per concentration, and setting a blank control group and a positive medicine control group. Adding 20 μ L of thiazole blue (MTT) solution (5 mg/mL) into each well for 72h, incubating at 37 deg.C for 4h, removing liquid, adding 150 μ L of DMSO, shaking, detecting absorbance value at 490nm with microplate reader, and calculating IC with SPSS21.0 statistical software 50 The value is obtained.
In vitro antiproliferative activity of the compounds of Table 1 on four human cancer cells
a Anti-tumor activity was assayed by exposure for 72h to substances and expressed as concentration required to inhibit tumor cells proliferation by 50％(IC 50 ).Dataare presented as the mean±SDs of three independent experiments. b Used as a positive control.
The analysis of Table 1 shows that the series of compounds have good activity on PC-3 cells in four cancer cells and almost no activity on the rest three cancer cells, and although the compound 8a has stronger antiproliferative activity on PC-3 and greatly improves the antiproliferative activity on other three cancer cell lines when the benzene ring is replaced by the unsubstituted benzyl group, the improvement is not obvious compared with PC-3, and the antiproliferative activity is far lower than that of PC-3, so that the series of compounds show obvious specificity. And we have found that the activity of the 4-position substitution is not very different from that of the 5-and 6-positions in most cases, but the optimum active compound is clearly better than that of the 5-and 6-positions, e.g. compound 4-16IC 50 =4.42 ± 0.06 μmol/L is clearly superior to compound 5-16IC 50 =6.21 ± 0.84 μmol/L and compound 6-16IC 50 =6.43 ± 0.80 μmol/L. Therefore, 4-16 can be used as a preferred compound for the next evaluation of activity against normal prostate cells.
TABLE 2 in vitro antiproliferative Activity of Compounds 4-16 on prostate stromal cells
a Anti-tumor activity was assayed by exposure for 72h to substances and expressed as concentration required to inhibit tumor cells proliferation by 50％(IC50).Data are presented as the mean±SDs of three independent experiments. b Used as a positive control.
As shown in Table 2, it can be seen that compound 4-16 has certain antiproliferative activity on WPYM-1, has an IC50 value of 20.34. + -. 0.97. Mu. Mol/L, but is much weaker than the antiproliferative activity on PC-3, has activity of only about one fourth of that of PC-3, and that 4-16 has good safety on normal prostate stromal cells. In conclusion, 4-16 can be used as a lead compound for further research and development, and has an application prospect in preparation of prostate cancer drugs.
4-16 can be used as active ingredient or combined with other medicines, and can be prepared into pharmaceutical preparations for resisting prostate cancer according to conventional pharmaceutical methods and process requirements after being mixed with pharmaceutically acceptable auxiliary and/or additive ingredients.
Representative compound characterization data:
Claims (4)
1. the indazole skeleton derivative containing 1,2,3 triazole or salt thereof is characterized by being selected from one of the following compounds:
2. the indazole skeleton derivative or salt thereof containing 1,2,3 triazole according to claim 1, which is characterized by being selected from the following compounds:
3. the use of an indazole backbone derivative according to claim 1 or 2, containing 1,2,3 triazole, or salts thereof, as an active ingredient for the preparation of a medicament for the treatment of prostate.
4. The application of the indazole skeleton derivative containing 1,2,3 triazole or salts thereof according to claim 3, wherein the indazole skeleton derivative or the salts thereof is prepared into injections, powder injections, tablets, granules, capsules, soluble powder or powder.
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