CN111138425A - Triazole derivative and preparation method and application thereof - Google Patents

Triazole derivative and preparation method and application thereof Download PDF

Info

Publication number
CN111138425A
CN111138425A CN202010008540.XA CN202010008540A CN111138425A CN 111138425 A CN111138425 A CN 111138425A CN 202010008540 A CN202010008540 A CN 202010008540A CN 111138425 A CN111138425 A CN 111138425A
Authority
CN
China
Prior art keywords
acid
arh
compound
reaction
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202010008540.XA
Other languages
Chinese (zh)
Inventor
朱启华
张杉
何光超
沈慧
王弈伟
顾书卉
孙泽人
徐云根
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
China Pharmaceutical University
Original Assignee
China Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by China Pharmaceutical University filed Critical China Pharmaceutical University
Priority to CN202010008540.XA priority Critical patent/CN111138425A/en
Publication of CN111138425A publication Critical patent/CN111138425A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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

Abstract

The invention discloses a triazole derivative shown as a formula I, or a stereoisomer, a hydrate, a solvate or a crystal thereof, application of a composition containing the triazole derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier in preparation of an IDO inhibitor, and application of a pharmaceutical composition containing the compounds in preparation of antitumor drugs.

Description

Triazole derivative and preparation method and application thereof
Technical Field
The invention relates to the field of medicinal chemistry, and relates to triazole derivatives, a preparation method thereof and application thereof in preparing antitumor drugs.
Background
The life health of human beings is seriously threatened by cancer, and the number of new 1810 ten thousand cancer cases and 960 ten thousand cancer cases dead are counted in 2018 data of cancer patients all over the world. In our country, the incidence of tumors is rising at a rate of 10% per year. The high incidence and mortality of cancer has led people to speak about "cancerous" color changes in life. Therefore, the development of effective antitumor drugs is imminent. In recent years, immunotherapy has achieved some breakthrough achievements in anti-tumor clinical trials, and has shown attractive prospects, so that immunotherapy becomes a popular field for new drug research and development.
Indoleamine-2, 3-dioxygenase (IDO) is a rate-limiting enzyme in the metabolism of extrahepatic tryptophan (tryptophan) and can catalyze the epoxidation and cleavage of indole in tryptophan molecules, so that the tryptophan is metabolized along the kynurenine pathway. There are three subtypes of IDO, IDO1, IDO2, and TDO. Research shows that IDO can regulate the body to perform anti-tumor immunity through mediating tryptophan depletion and metabolites thereof, participate in the formation of tumor microenvironment, promote the regeneration of tumor blood vessels, and is related to clinical staging, prognosis and metastasis of various malignant tumors, and is also related to Tumor Infiltrating Lymphocytes (TILs) and regulatory T cells (tregs). With the continuous and deep research of IDO in oncology and immunology, IDO becomes the most important small molecule regulatory target of anti-tumor immunotherapy.
Disclosure of Invention
The invention aims to provide anti-tumor candidate compounds containing triazole structures and having novel structures, a preparation method of the compounds and application of the compounds in preparing anti-tumor medicaments.
The purpose of the invention is realized by the following technical scheme:
a compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure BDA0002356256440000011
wherein:
x is selected from
Figure BDA0002356256440000021
R1、R2And R3Are respectively selected from H, F, Cl, Br and CH3、CHF2、CN、OCH3、NH2、NO2、OH、CF3But cannot satisfy R simultaneously1＝H、R2＝Br、R3＝F。
Preferably, the method comprises the following steps:
x is selected from
Figure BDA0002356256440000022
R1Is H, F, Cl, Br, CH3、OH、CF3；
R2Is H, Cl, Br, CH3、CN、CHF2、OH、CF3；
R3Is H, F, Cl, CH3、CHF2、OH、CF3；
But cannot satisfy R simultaneously1＝H、R2＝Br、R3＝F。
Further preferably:
x is selected from
Figure BDA0002356256440000023
When R is1Is H, F, R2Is H, Cl, CH3，R3Is H, F, Cl, CH3But cannot satisfy R simultaneously1＝H、R2＝H、R3＝CH3；
X is selected from
Figure BDA0002356256440000024
When R is1Is H, F, Br, R2Is H, Cl, CH3，R3Is H, F, CH3。
Still more preferably:
x is selected from
Figure BDA0002356256440000025
R1Is H, F, Br, CH3、OH；
R2Is Cl;
R3is H, F, Cl, CH3、CF3。
Most preferably:
x is selected from
Figure BDA0002356256440000026
R1Is H, R2Is Cl, R3Is H or F.
The above preferred or further preferred or more preferred radicals do not necessarily represent a simultaneous preference for these radicals, such as, in preference, R1May be preferred only, R2May not be preferred, of course R1And R2May also be preferred.
The compounds of the present invention are selected from the group consisting of I-1 to I-18:
Figure BDA0002356256440000027
Figure BDA0002356256440000031
Figure BDA0002356256440000041
Figure BDA0002356256440000051
Figure BDA0002356256440000061
the pharmaceutically acceptable salt is an acid addition salt (I & A) of a triazole derivative shown in a general formula (I), wherein the acid (A) for salt formation is as follows: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
Another object of the present invention is to provide a process for producing a triazole derivative represented by the general formula (I), which comprises: hydrolyzing the compound II to obtain a compound III, and preparing a compound I from the compound III and a compound IV through a click chemistry reaction:
Figure BDA0002356256440000062
wherein R is1、R2、R3And X is described in the general formula I.
In the process of preparing the compound III by hydrolyzing the compound II, the used alkali is sodium hydroxide, potassium carbonate, sodium carbonate or sodium acetate, preferably sodium hydroxide; the molar ratio of the compound II to the alkali is 1: 2-1: 5, preferably 1: 2.5-1: 3.5; the solvent is methanol, tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-dimethylformamide or a mixed solvent of at least one of the solvents and water, preferably a mixed solvent of tetrahydrofuran and water, and the volume ratio of tetrahydrofuran to water is 1: 1-1: 3.
The process of preparing the compound I by the Click reaction of the compound III and the compound IV uses copper sulfate, copper chloride, copper bromide, cuprous chloride, cuprous bromide, cuprous iodide or copper powder as a catalyst, and preferably cuprous iodide; the molar ratio of the compound III to the compound IV to the catalyst is 1:0.8: 0.1-1: 2:0.3, more preferably 1:1: 0.15-1: 1.5: 0.25; the solvent is tetrahydrofuran, 1, 4-dioxane, acetonitrile, ethanol, methanol, ethylene glycol dimethyl ether, dichloromethane, N-dimethylformamide, N-dimethylacetamide or a mixed solvent of at least one of the solvents and water, preferably a mixed solvent of acetonitrile and water, wherein the volume ratio of acetonitrile to water is 1: 4-1: 6.
Or preparing a compound V from the compound II through a click chemical reaction, and preparing a compound I from the compound V through hydrolysis:
Figure BDA0002356256440000071
wherein R is1、R2、R3And X is described in the general formula I.
Preparing a compound V by a Click reaction between a compound II and corresponding alkyne IV, wherein the used catalyst is copper sulfate, copper chloride, copper bromide, cuprous chloride, cuprous bromide, cuprous iodide or copper powder, and is preferably cuprous iodide; the molar ratio of the compound III to the compound IV to the catalyst is 1:0.8: 0.1-1: 2:0.3, more preferably 1:1: 0.15-1: 1.5: 0.25; the solvent is tetrahydrofuran, 1, 4-dioxane, acetonitrile, ethanol, methanol, ethylene glycol dimethyl ether, dichloromethane, N-dimethylformamide, N-dimethylacetamide or a mixed solvent of at least one of the solvents and water, preferably a mixed solvent of acetonitrile and water, wherein the volume ratio of acetonitrile to water is 1: 4-1: 6.
The compound V is hydrolyzed to prepare a compound I, and the used alkali is sodium hydroxide, potassium carbonate, sodium carbonate or sodium acetate, preferably sodium hydroxide; the solvent used is methanol, tetrahydrofuran, 1, 4-dioxane, acetonitrile, N-dimethylformamide or a mixed solvent of at least one of the above solvents and water, preferably a mixed solvent of methanol and water or a mixed solvent of tetrahydrofuran and water.
The compound IV is 3-butyne-2-alcohol or ethoxylated propiolic alcohol.
The invention also aims to provide a pharmaceutical composition which contains the triazole derivative shown in the general formula (I) or the pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
The pharmaceutical composition can be prepared into common pharmaceutical preparations, such as tablets, capsules, syrup and suspending agents, and common pharmaceutical excipients, such as spices, sweeteners, liquid or solid fillers or diluents, and the like can be added.
The invention also aims to provide application of the triazole derivative or the pharmaceutically acceptable salt thereof in preparing IDO inhibitor medicines, so that the triazole derivative or the pharmaceutically acceptable salt thereof can be used for treating tumor-related diseases.
The invention also aims to provide application of the triazole derivative or the pharmaceutically acceptable salt thereof in preparing a medicament for treating or preventing malignant tumors.
The malignant tumor is breast cancer and colon cancer.
The application of the stereoisomer, hydrate, solvate or crystal of the triazole derivative shown in the general formula (I) in IDO inhibitors or medicaments for treating tumor-related diseases is also within the protection scope of the invention.
The invention has the beneficial effects that:
pharmacodynamic experiments prove that the triazole derivative or the pharmaceutically acceptable salt thereof has the activity of an IDO inhibitor and has the effects of treating or preventing tumors and the like.
Detailed Description
The present application will be described in detail with reference to specific examples.
Example 1
4- ((2-azidoethyl) amino) -N- (4-chlorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (III-1)
Adding 3- (4- ((2-azidoethyl) amino) -1,2, 5-oxadiazol-3-yl) -4- (4-chlorophenyl) -1,2, 4-oxadiazol-5 (4H) -one (II-1,3.2g,9.40mmol) and tetrahydrofuran (20mL) to a 100mL three-necked flask, dropwise adding 2mol/L NaOH solution (14.1mL,28.20mmol) at 0 ℃, and after the addition, stirring at 40 ℃ for about 5 hours (TLC monitoring reaction); the reaction solution was transferred to a 100mL eggplant-shaped flask, THF was evaporated under reduced pressure, the residual aqueous phase was extracted once with dichloromethane (25mL), the aqueous phase was adjusted to pH 3 to 4 with concentrated hydrochloric acid, extracted with dichloromethane (25mL × 2), the organic layer was washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered under suction to obtain 2.16g of a pale yellow solid III-1 with a yield of 71.4%. m.p.106.0-108.0 deg.C.
1H NMR(300MHz,CDCl3),δ(ppm):7.55(d,J＝8.8Hz,2H,ArH),7.35(d,J＝8.8Hz,2H,ArH),5.61(s,1H,NH),3.71–3.56(m,4H,CH2CH2).
N- (4-chlorophenyl) -N' -hydroxy-4- ((2- (4- (1-hydroxyethyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-1)
4- ((2-azidoethyl) amino) -N- (4-chlorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (III-1,1.50g,4.65mmol) was placed in a 50mL Erica flask, and 3mL water and 18mL acetonitrile, respectively, were added. Adding 3-butyn-2-ol (V,436 mu L,5.58mmol) and cuprous iodide (177mg,0.93mmol) under ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol ═ 15: 1V/V); removing the solvent by reduced pressure distillation, adding methanol (20mL), stirring for 30min, carrying out suction filtration, removing the solvent by reduced pressure distillation to obtain a light brown solid, and carrying out column chromatography purification (eluent: petroleum ether: ethyl acetate ═ 2: 1-1: 4v/v) to obtain 470mg of pale yellow solid I-1, wherein the yield is 26.0%, and m.p.186.0-188.0 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.43(s,1H,NH),8.90(s,1H，OH),7.94(s,1H，ArH),7.24(d,J＝8.6Hz,2H，ArH),6.77(d,J＝8.6Hz,2H,ArH),6.39(t,J＝5.6Hz,1H,NH),5.27(d,J＝4.4Hz,1H,CH),4.88–4.76(m,1H,OH),4.59(t,J＝5.7Hz,2H,CH2),3.74–3.68(m,2H,CH2),1.40(d,J＝6.5Hz,3H,CH3).
13C NMR(75MHz,DMSO-d6),δ(ppm):155.47,152.55,139.97,139.36,139.16,128.08,125.59,121.97,121.56,61.58,47.54,44.07,23.75.
IR(cm-1):3566.33,3391.68,3130.59,3073.06,2920.06,2775.76,1634.72,1599.13,1560.54,1519.60,1494.27,1422.76,1148.37,1090.78,985.70,894.93,828.44.
Example 2
N- (4-chlorophenyl) -N' -hydroxy-4- ((2- (4- ((2-hydroxyethoxy) methyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-2)
4- ((2-azidoethyl) amino) -N- (4-chlorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (III-1,1.50g,4.65mmol) was placed in a 50mL Erica flask, and 3mL water and 18mL acetonitrile, respectively, were added. Adding ethoxylated propiolic alcohol (544 mu L,5.58mmol) and cuprous iodide (177mg,0.93mmol) under ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring and reacting for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol ═ 15:1 v/v); removing the solvent by reduced pressure distillation, adding methanol (20mL), stirring for 30min, performing suction filtration, removing the solvent by reduced pressure distillation to obtain a light brown solid, and performing column chromatography purification (eluent: petroleum ether: ethyl acetate: 2: 1-1: 4v/v) to obtain 290mg of white solid I-2, wherein the yield is 16.0%, and m.p.118.0-120.0 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.44(s,1H，NH),8.89(s,1H，OH),8.09(s,1H，ArH),7.25–7.20(m,2H,ArH),6.80–6.70(m,2H,ArH),6.40(s,1H，NH),4.62(s,1H,OH),4.58–4.50(m,4H,CH2CH2),4.75–4.65(m,2H,CH2),3.52–3.42(m,4H,CH2CH2).
13C NMR(75MHz,DMSO-d6)δ(ppm):155.56,144.17,140.10,139.45,139.27,128.19,125.74,124.22,122.08,71.57,63.57,60.22,47.74,44.17.
IR(cm-1):3302.86,2922.08,2871.00,1635.36,1595.70,1557.95,1490.48,1419.05,1448.56,1383.35,1296.60,1241.75,1149.33,1103.73,1088.06,1058.37,1030.32,1012.74,991.28,956.07,889.81.
Example 3
4- ((2-azidoethyl) amino) -N- (3-chlorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (III-2)
Adding 3- (4- ((2-azidoethyl) amino) -1,2, 5-oxadiazol-3-yl) -4- (3-chlorophenyl) -1,2, 4-oxadiazol-5 (4H) -one (II-2,2.16g,6.20mmol) and tetrahydrofuran (15mL) to a 50mL three-necked flask, adding 2mol/L NaOH solution (9.3mL,18.60mmol) dropwise at 0 ℃, and after the addition, stirring the reaction at 40 ℃ for about 5 hours (TLC monitoring reaction completion); the reaction solution was transferred to a 100mL eggplant-shaped flask, THF was evaporated under reduced pressure, the residual aqueous phase was extracted once with dichloromethane (25mL), the aqueous phase was adjusted to pH 3 to 4 with concentrated hydrochloric acid, extracted with dichloromethane (25mL × 2), the organic layer was washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered under suction to obtain 1.40g of a pale yellow solid III-2 with a yield of 72.4%. m.p.79.0-81.0 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.58(s,1H,NH),8.97(s,1H,OH),7.17(t,J＝8.0Hz,1H,ArH),6.94(d,J＝7.9Hz,1H,ArH),6.84(s,1H,ArH),6.67(d,J＝7.1Hz,1H,ArH),6.39(t,J＝5.1Hz,1H,NH),3.60–3.53(m,2H,CH2),3.49–3.41(m,2H,CH2).
N- (3-chlorophenyl) -N' -hydroxy-4- ((2- (4- (1-hydroxyethyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-3)
4- ((2-azidoethyl) amino) -N- (3-chlorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (III-2,0.5g,1.55mmol) was placed in a 50mL Erica flask, and 2mL of water and 12mL of acetonitrile, respectively, were added. Adding 3-butyn-2-ol (137 mu L,1.86mmol) and cuprous iodide (59mg,0.31mmol) under ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol ═ 15:1 v/v); removing the solvent by reduced pressure distillation, adding methanol (20mL), stirring for 30min, carrying out suction filtration, removing the solvent by reduced pressure distillation to obtain a light brown solid, and carrying out column chromatography purification (eluent: petroleum ether: ethyl acetate: 2: 1-1: 4v/v) to obtain 92.5mg of light yellow solid I-3, wherein the yield is 15.2%, and m.p.110.5-112.0 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.49(s,1H,NH),8.90(s,1H,OH),7.91(s,1H,ArH),7.17(t,J＝7.5Hz,1H,ArH),6.92(d,J＝7.7Hz,1H,ArH),6.84(d,J＝1.6Hz,1H，ArH),6.63(d,J＝8.1Hz,1H，ArH),6.33(t,J＝5.6Hz,1H,NH),5.19(s,1H,CH),4.84–4.78(m,1H,OH),4.56(t,J＝5.8Hz,2H,CH2),3.70(q,J＝5.4Hz,2H,CH2),1.38(d,J＝5.6Hz,3H,CH3).
13C NMR(75MHz,DMSO-d6),δ(ppm):155.41,142.01,140.09,138.88,132.58,129.71,121.70,121.59,121.10,119.50,118.41,61.56,47.57,44.09,23.73.
IR(cm-1):3361.57,3138.33,2978.41,2929.80,2797.23,1632.81,1597.91,1556.73,1518.69,1477.21,1433.42,1391.21,1369.16,1317.14,1269.88,1159.36,1143.16,1066.14,983.77,940.92,775.70.
Example 4
N- (3-chlorophenyl) -N' -hydroxy-4- ((2- (4- ((2-hydroxyethoxy) methyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-4)
4- ((2-azidoethyl) amino) -N- (3-chlorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (III-2,0.5g,1.55mmol) was placed in a 50mL Erica flask, and 2mL of water and 12mL of acetonitrile, respectively, were added. Adding ethoxylated propiolic alcohol (181 mu L,1.86mmol) and cuprous iodide (59mg,0.31mmol) under ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring and reacting for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol ═ 15:1 v/v); removing the solvent by reduced pressure distillation, adding methanol (20mL), stirring for 30min, performing suction filtration, removing the solvent by reduced pressure distillation to obtain a light brown solid, and performing column chromatography purification (eluent: petroleum ether: ethyl acetate: 2: 1-1: 4v/v) to obtain 100mg of white solid I-4, wherein the yield is 16.4%, and m.p.128.0-130.0 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.49(s,1H,NH),8.90(s,1H,OH),8.06(s,1H,ArH),7.17(t,J＝8.0Hz,1H,ArH),6.93(d,J＝8.0Hz,1H，ArH),6.88–6.80(m,1H,ArH),6.62(d,J＝8.0Hz,1H,ArH),6.35(t,J＝5.7Hz,1H,NH),4.62–4.59(m,2H,CH2),4.58(s,1H,OH),4.51(s,2H,CH2),3.70(q,J＝5.5Hz,2H,CH2),3.53–3.40(m,4H,CH2CH2).
13C NMR(75MHz,DMSO-d6),δ(ppm):155.40,144.05,142.00,140.13,138.80,132.58,129.72,124.11,121.09,119.48,118.37,71.48,63.48,60.11,47.59,44.10.
IR(cm-1):3345.21,3274.21,3133.39,2959.90,2922.28,2866.88,1628.75,1598.90,1561.00,1477.94,1431.68,1359.28,1315.79,1158.09,1097.83,1059.92,1007.13,993.76,945.74,778.81,682.87.
Example 5
4- ((2-azidoethyl) amino) -N- (2-fluorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (III-3)
Adding 3- (4- ((2-azidoethyl) amino) -1,2, 5-oxadiazol-3-yl) -4- (2-fluorophenyl) -1,2, 4-oxadiazol-5 (4H) -one (II-3,2.2g, 6.60mmol) and tetrahydrofuran (15mL) to a 50mL three-necked flask, dropwise adding 2mol/L NaOH solution (9.9mL,19.8mmol) at 0 ℃, and after the addition, stirring the reaction at 40 ℃ for about 5 hours (TLC monitoring reaction completion); the reaction solution was transferred to a 100mL eggplant-shaped flask, THF was evaporated under reduced pressure, the residual aqueous phase was extracted once with dichloromethane (25mL), the aqueous phase was adjusted to pH 3 to 4 with concentrated hydrochloric acid, extracted with dichloromethane (25mL × 2), the organic layer was washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered under suction to obtain 1.43g of a brown solid III-3 with a yield of 71.0%. m.p.88.5-90.0 deg.C.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.26(s,1H,NH),8.60(s,1H,OH),7.08(d,J＝5.0Hz,4H,ArH),6.37(t,J＝5.6Hz,1H,NH),3.61–3.51(m,2H,CH2),3.44(q,J＝5.4Hz,2H,CH2).
N- (2-fluorophenyl) -N' -hydroxy-4- ((2- (4- (1-hydroxyethyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-5)
4- ((2-azidoethyl) amino) -N- (2-fluorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (III-3,0.80g,2.61mmol) was placed in a 50mL Erica flask and 2mL water and 12mL acetonitrile, respectively, were added. Adding 3-butyn-2-ol (230 mu L,3.13mmol) and cuprous iodide (99mg,0.52mmol) in ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol: 15:1 v/v); removing the solvent by reduced pressure distillation, adding methanol (20mL), stirring for 30min, carrying out suction filtration, removing the solvent by reduced pressure distillation to obtain a light brown solid, and carrying out column chromatography purification (eluent: petroleum ether: ethyl acetate: 2: 1-1: 4v/v) to obtain 315mg of white solid I-5, wherein the yield is 32.1%, and m.p.158.0-159.0 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.20(s,1H,NH),8.59(s,1H,OH),7.89(s,1H,ArH),7.10–7.05(m,4H,ArH),6.34(t,J＝5.4Hz,1H,NH),5.25(d,J＝4.3Hz,1H,OH),4.85–4.74(m,1H,CH),4.56(t,J＝5.6Hz,2H,CH2),3.71–4.65(m,2H,CH2),1.37(d,J＝6.5Hz,3H,CH3).
13C NMR(75MHz,DMSO-d6),δ(ppm):155.21,152.53,140.74,139.51,125.87,125.22,125.12,124.19,121.56,115.56,115.30,61.56,47.51,44.06,23.72.
IR(cm-1):3379.12,3295.59,3144.23,2957.62,2867.29,2359.88,1644.42,1610.20,1570.08,1506.15,1452.98,1400.20,1318.76,1305.89,1265.03,1221.95,1167.23,1106.39,1064.01,983.38,906.46,813.62,750.50,738.60,568.36.
Example 6
Preparation of N- (2-fluorophenyl) -N' -hydroxy-4- ((2- (4- ((2-hydroxyethoxy) methyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-6)
4- ((2-azidoethyl) amino) -N- (2-fluorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (III-3,0.75g, 2.45mmol) was placed in a 50mL Erica flask and 2mL water and 12mL acetonitrile, respectively, were added. Adding ethoxylated propiolic alcohol (290 mu L and 2.94mmol) and cuprous iodide (93mg and 0.49mmol) in ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring and reacting for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol is 15:1 v/v); removing the solvent by reduced pressure distillation, adding methanol (20mL), stirring for 30min, performing suction filtration, removing the solvent by reduced pressure distillation to obtain a light brown solid, and performing column chromatography purification (eluent: petroleum ether: ethyl acetate ═ 2: 1-1: 4v/v) to obtain 275mg of white solid I-6, wherein the yield is 27.6%, and m.p.138.0-140.0 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.16(s,1H,NH),8.51(s,1H,OH),8.04(s,1H,ArH),7.12–7.07(m,2H,ArH),7.05–7.02(m,2H,ArH),6.33(t,J＝5.9Hz,1H,NH),4.62–4.58(m,2H,CH2),4.57(s,1H,OH),4.51(s,2H,CH2),3.70(q,J＝5.8Hz,2H,CH2),3.51–3.43(m,4H,CH2CH2).
13C NMR(75MHz,DMSO-d6),δ(ppm):155.20,144.04,140.74,125.85,125.24,125.14,124.18,124.13,124.09,115.55,115.28,71.46,63.46,60.11,47.61,44.04.
IR(cm-1):3422.65,3339.15,2928.98,2868.73,1636.80,1617.31,1563.66,1502.23,1465.40,1404.06,1363.83,1262.73,1142.39,1061.18,980.67,810.18,752.29.
Example 7
4- ((2-azidoethyl) amino) -N- (4-fluorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (III-4)
Adding 3- (4- ((2-azidoethyl) amino) -1,2, 5-oxadiazol-3-yl) -4- (4-fluorophenyl) -1,2, 4-oxadiazol-5 (4H) -one (II-4,2.60g, 7.80mmol) and tetrahydrofuran (20mL) to a 100mL three-necked flask, adding 2mol/LNaOH solution (11.7mL,23.4mmol) dropwise at 0 ℃, and after the addition, stirring the reaction at 40 ℃ for about 5 hours (TLC monitoring reaction completion); transferring the reaction solution to a 100mL eggplant-shaped bottle, evaporating THF under reduced pressure, extracting the residual water phase once by dichloromethane (25mL), adjusting the pH of the water phase to 3-4 by concentrated hydrochloric acid, extracting by dichloromethane (25mL multiplied by 2), washing the organic layer once by a saturated sodium chloride solution, drying by anhydrous sodium sulfate, and performing suction filtration to obtain 1.65g of gray solid III-4 with the yield of 72.9 percent and the m.p.103.0-105.0 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.31(s,1H NH),8.74(s,1H,OH),7.01(t,J＝8.8Hz,2H,ArH),6.89–6.73(m,2H,ArH),6.41(t,J＝5.3Hz,1H NH),3.60–3.49(m,2H,CH2),3.48–3.38(m,2H,CH2).
N- (4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (1-hydroxyethyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-7)
4- ((2-azidoethyl) amino) -N- (4-fluorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (III-4,0.75g,2.48mmol) was placed in a 50mL Erica flask and 3mL water and 18mL acetonitrile, respectively, were added. Adding 3-butyn-2-ol (220 mu L,2.98mmol) and cuprous iodide (95mg,0.50mmol) in ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol ═ 15:1 v/v); removing the solvent by reduced pressure distillation, adding methanol (20mL), stirring for 30min, performing suction filtration, removing the solvent by reduced pressure distillation to obtain a light brown solid, and performing column chromatography purification (eluent: petroleum ether: ethyl acetate: 2: 1-1: 4v/v) to obtain 250mg of pale yellow solid I-7, wherein the yield is 26.8%, and m.p.169.5-170.5 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.26(s,1H,NH),8.75(s,1H,OH),7.93(s,1H,ArH),7.04(t,J＝8.7Hz,2H,ArH),6.83–6.78(m,2H,ArH),6.41(t,J＝5.8Hz,1H,NH),5.27(d,J＝4.7Hz,1H,CH),4.89–4.76(m,1H,OH),4.58(t,J＝5.7Hz,2H,CH2),3.70(d,J＝5.8Hz,2H,CH2),1.40(d,J＝6.5Hz,3H,CH3).
13C NMR(75MHz,DMSO-d6),δ(ppm):155.53,152.55,139.76,136.58,123.05,122.95,121.54,114.98,114.68,61.58,47.53,44.05,23.75.
IR(cm-1):3381.82,3307.53,2960.89,2853.11,1641.18,1606.65,1566.19,1512.13,1220.43,1153.47,1105.73,1064.18,983.09,904.32,834.98,819.40,571.89.
Example 8
N- (4-fluorophenyl) -N' -hydroxy-4- ((2- (4- ((2-hydroxyethoxy) methyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-8)
4- ((2-azidoethyl) amino) -N- (4-fluorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (III-4,0.75g,2.45mmol) was placed in a 50mL Erica flask, and 3mL water and 18mL acetonitrile, respectively, were added. Adding ethoxylated propiolic alcohol (290 mu L and 2.94mmol) and cuprous iodide (93mg and 0.49mmol) in ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring and reacting for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol is 15:1 v/v); removing the solvent by distillation under reduced pressure, adding methanol (20mL), stirring for 30min, performing suction filtration, removing the solvent by distillation under reduced pressure to obtain a light brown solid, and performing column chromatography purification (eluent: petroleum ether: ethyl acetate ═ 2: 1-1: 4v/v) to obtain 165mg of white solid I-8, wherein the yield is 17.3%, and m.p.115.0-117.0 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.24(s,1H,NH),8.73(s,1H,OH),8.08(s,1H，ArH),7.10–7.00(m,2H,ArH),6.80–6.70(m,2H,ArH),6.41(s,1H，NH),4.68–4.58(m,4H,CH2CH2),4.52(s,1H,OH),3.74–3.66(m,2H,CH2),3.52–3.44(m,4H,CH2CH2).
13C NMR(75MHz,DMSO-d6),δ(ppm):155.46,144.07,139.83,136.54,124.09,123.10,122.99,114.98,114.68,71.38,63.37,60.08,47.65,43.99.
IR(cm-1):3375.55,2926.51,1631.36,1599.90,1560.85,1510.51,1216.48,1154.00,1098.47,1058.66,975.30,832.89,816.46.
Example 9
4- ((2-azidoethyl) amino) -N' -hydroxy-N- (m-tolyl) -1,2, 5-oxadiazole-3-carboxamidine (III-5)
Adding 3- (4- ((2-azidoethyl) amino) -1,2, 5-oxadiazol-3-yl) -4- (2-methylphenyl) -1,2, 4-oxadiazol-5 (4H) -one (II-5,3.60g, 7.92mmol) and tetrahydrofuran (25mL) into a 100mL three-necked flask, dropwise adding 2mol/L NaOH solution (11.9mL,23.8mmol) at 0 ℃, after the addition, stirring the reaction at 40 ℃ for about 5 hours (TLC monitoring reaction completion); transferring the reaction solution into a 100mL eggplant-shaped bottle, evaporating THF under reduced pressure, extracting the residual water phase once by dichloromethane (25mL), adjusting the pH of the water phase to 3-4 by concentrated hydrochloric acid, extracting by dichloromethane (25mL multiplied by 2), washing the organic layer once by a saturated sodium chloride solution, drying by anhydrous sodium sulfate, and performing suction filtration to obtain 1.65g of light yellow solid III-5, wherein the yield is 58.4 percent and the m.p.84.5-86.5 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.23(s,1H,NH),8.25(s,1H,OH),7.25(d,J＝3.6Hz,1H,ArH),7.16–7.08(m,2H,ArH),6.90–6.81(m,1H,ArH),6.56(t,J＝5.2Hz,1H,NH),3.65(d,J＝5.4Hz,2H,CH2),3.58–3.50(m,2H,CH2),2.32(s,3H,CH3).
N- (2-methylphenyl) -N' -hydroxy-4- ((2- (4- (1-hydroxyethyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-9)
4- ((2-azidoethyl) amino) -N' -hydroxy-N- (o-tolyl) -1,2, 5-oxadiazole-3-carboxamidine (III-5,1.0g,3.31mmol) was charged to a 100mL eggplant-shaped flask, and 4mL of water and 24mL of acetonitrile solution were added, respectively. Adding 3-butyn-2-ol (292 mu L,3.97mmol) and cuprous iodide (125mg,0.66mmol) in ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol ═ 15:1 v/v); removing the solvent by reduced pressure distillation, adding methanol (20mL), stirring for 30min, performing suction filtration, removing the solvent by reduced pressure distillation to obtain a light brown solid, and performing column chromatography purification (eluent: petroleum ether: ethyl acetate: 2: 1-1: 4v/v) to obtain 175mg of light yellow solid I-9, wherein the yield is 14.2%, and m.p.142.0-144.0 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.00(s,1H,NH),8.04(s,1H,OH),7.88(s,1H,ArH),7.12(d,J＝4.4Hz,1H,ArH),6.99(d,J＝5.1Hz,2H,ArH),6.71(d,J＝6.8Hz,1H,ArH),6.36(t,J＝5.1Hz,1H,NH),5.20(s,1H,CH),4.82–4.76(m,1H,OH),4.55(t,J＝5.1Hz,2H,CH2),3.69–3.66(m,2H,CH2),2.17(s,3H,CH3),1.38(d,J＝6.4Hz,3H,CH3).
13C NMR(75MHz,DMSO-d6),δ(ppm):155.41,152.50,141.58,139.59,138.77,132.87,130.08,125.86,125.35,124.69,121.54,61.58,47.55,43.98,23.68,17.71.
IR(cm-1):3416.85,3392.19,3320.92,2925.22,2853.02,1639.52,1604.67,1562.72,1522.39,1495.54,1458.45,1228.36,1168.48,1155.99,1104.51,1066.61,985.58,829.80,750.98,570.45,464.20.
Example 10
N- (2-methylphenyl) -N' -hydroxy-4- ((2- (4- ((2-hydroxyethoxy) methyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-10)
4- ((2-azidoethyl) amino) -N' -hydroxy-N- (o-tolyl) -1,2, 5-oxadiazole-3-carboxamidine (III-5,0.75g,2.45mmol) was charged to a 50mL eggplant-shaped flask, and 3mL of water and 18mL of acetonitrile solution were added, respectively. Adding ethoxylated propiolic alcohol (290 mu L and 2.94mmol) and cuprous iodide (93mg and 0.49mmol) in ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring and reacting for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol is 15:1 v/v); removing the solvent by reduced pressure distillation, adding methanol (20mL), stirring for 30min, performing suction filtration, removing the solvent by reduced pressure distillation to obtain a light brown solid, and performing column chromatography purification (eluent: petroleum ether: ethyl acetate: 2: 1-1: 4v/v) to obtain 200mg of white solid I-8, wherein the yield is 20.6%, and m.p.102.0-104.0 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.00(s,1H,NH),8.04(s,2H,ArH),7.17–7.08(m,1H,OH),7.05–6.92(m,2H,ArH),6.75–6.67(m,1H,ArH),6.38(t,J＝5.8Hz,1H,NH),4.60(s,1H,OH),4.57–4.53(m,2H,CH2),4.51(s,2H,CH2),3.69(q,J＝5.8Hz,2H,CH2),3.53–3.47(m,2H,CH2),3.45–3.43(m,2H,CH2),2.17(s,3H，CH3).
13C NMR(75MHz,DMSO-d6),δ(ppm):155.43,144.02,141.48,139.67,138.80,132.87,130.08,125.83,125.32,124.64,124.07,71.48,63.48,60.11,47.57,44.01,17.74.
IR(cm-1):3551.51,3432.36,3393.50,3358.33,1626.90,1557.99,1511.42,1429.35,1384.59,1371.27,1150.68,1103.45,1091.19,1057.57,1039.92,974.58,955.86,756.10.
Example 11
4- ((2-azidoethyl) amino) -N' -hydroxy-N- (m-tolyl) -1,2, 5-oxadiazole-3-carboxamidine (III-6)
Adding 3- (4- ((2-azidoethyl) amino) -1,2, 5-oxadiazol-3-yl) -4- (3-methylphenyl) -1,2, 4-oxadiazol-5 (4H) -one (II-6,3.60g, 7.92mmol) and tetrahydrofuran (25mL) into a 100mL three-necked flask, dropwise adding 2mol/L NaOH solution (11.4mL,23.7mmol) at 0 ℃, after the addition, stirring the reaction at 40 ℃ for about 5 hours (TLC monitoring reaction completion); transferring the reaction solution into a 100mL eggplant-shaped bottle, evaporating THF under reduced pressure, extracting the residual water phase once by using dichloromethane (25mL), adjusting the pH of the water phase to 3-4 by using concentrated hydrochloric acid, extracting by using dichloromethane (25mL multiplied by 2), washing the organic layer once by using a saturated sodium chloride solution, drying the organic layer by using anhydrous sodium sulfate, and performing suction filtration to obtain 1.40g of light yellow solid III-6, wherein the yield is 58.4 percent and the m.p.84.5-86.5 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.23(s,1H,NH),8.25(s,1H,OH),7.25(d,J＝3.6Hz,1H,ArH),7.16–7.08(m,2H,ArH),6.90–6.81(m,1H,ArH),6.56(t,J＝5.2Hz,1H,NH),3.65(d,J＝5.4Hz,2H,CH2),3.58–3.50(m,2H,CH2),2.32(s,3H,CH3).
N' -hydroxy-4- ((2- (4- (1-hydroxyethyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -N- (m-methyl) -1,2, 5-oxadiazole-3-carboxamidine (I-11)
4- ((2-azidoethyl) amino) -N' -hydroxy-N- (m-tolyl) -1,2, 5-oxadiazole-3-carboxamidine (III-6,0.80g,2.64mmol) was charged to a 100mL eggplant-shaped flask, and 3mL of water and 18mL of an acetonitrile solution were added, respectively. Adding 3-butyn-2-ol (235 mu L,3.2mmol) and cuprous iodide (101mg,0.53mmol) in ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol ═ 15:1 v/v); removing the solvent by reduced pressure distillation, adding methanol (20mL), stirring for 30min, performing suction filtration, removing the solvent by reduced pressure distillation to obtain a light brown solid, and performing column chromatography purification (eluent: petroleum ether: ethyl acetate: 2: 1-1: 4v/v) to obtain 475mg of pale yellow solid I-11 with the yield of 48.3% and m.p.172.0-174.0 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.21(s,1H,NH),8.56(s,1H，OH),7.89(s,1H，ArH),7.03(t,J＝7.7Hz,1H，ArH),6.73(d,J＝7.0Hz,1H，ArH),6.61(s,1H，ArH),6.50(d,J＝7.9Hz,1H，ArH),6.34(t,J＝5.7Hz,1H,NH),5.20(s,1H，OH),4.84–4.78(m,1H，CH),4.55(t,J＝5.6Hz,2H,CH2),3.76–3.61(m,2H,CH2),2.19(s,3H,CH3),1.37(d,J＝6.5Hz,3H,CH3).
13C NMR(75MHz,DMSO-d6),δ(ppm):155.51,152.54,140.18,140.13,139.67,137.45,128.09,122.72,121.53,121.33,117.91,61.58,47.51,44.05,23.74,20.99.
IR(cm-1):3415.34,3371.63,3152.89,3051.38,2976.73,2919.14,2773.72,1629.97,1610.80,1558.29,1508.93,1489.30,1434.51,1370.51,1268.11,1153.42,1115.56,1069.22,979.75,947.69,824.11,693.89,484.69.
Example 12
N' -hydroxy-4- ((2-hydroxyethoxy) methyl) -1H-,2, 3-triazol-1-yl) ethyl) amino) -N- (m-methyl) -1,2, 5-oxadiazole-3-carboxamidine (I-12)
4- ((2-azidoethyl) amino) -N' -hydroxy-N- (m-tolyl) -1,2, 5-oxadiazole-3-carboxamidine (III-6,0.60g,1.98mmol) was charged to a 50mL eggplant-shaped flask, and 2mL of water and 12mL of an acetonitrile solution were added, respectively. Adding ethoxylated propiolic alcohol (230 mu L,2.37mmol) and cuprous iodide (74mg,0.39mmol) under ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring and reacting for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol ═ 15:1 v/v); removing the solvent by reduced pressure distillation, adding methanol (20mL), stirring for 30min, performing suction filtration, removing the solvent by reduced pressure distillation to obtain a light brown solid, and performing column chromatography purification (eluent: petroleum ether: ethyl acetate: 2: 1-1: 4v/v) to obtain 197mg of white solid I-2, wherein the yield is 24.7%, and the m.p.133.5-135.5 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.24(s,1H,NH),8.63(s,1H,OH),8.06(s,1H,ArH),7.01(t,J＝7.7Hz,1H,ArH),6.71(d,J＝7.0Hz,1H,ArH),6.59(s,1H，ArH),6.46(d,J＝6.8Hz,1H，ArH),6.38(t,J＝5.3Hz,1H,NH),4.67–4.60(m,1H，OH),4.60–4.53(m,2H,CH2),4.49(s,2H,CH2),3.69–3.64(m,2H,CH2),4.48–4.40(m,4H,CH2CH2),2.17(s,3H,CH3).
13C NMR(75MHz,DMSO-d6),δ(ppm):155.49,140.16,139.57,137.46,128.09,124.11,122.70,121.27,117.85,71.48,63.48,60.09,47.55,44.05,20.99.
IR(cm-1):3549.51,3413.78,3333.34,3138.55,2909.42,2867.05,2360.14,2341.37,1628.56,1608.37,1560.71,1489.92,1450.15,1431.71,1358.13,1329.50,1315.41,1179.69,1150.85,1098.49,1061.38,1039.05,1008.91,986.13,974.04,946.06,823.40,778.31,695.00,602.62,574.61.
Example 13
4- ((2-azidoethyl) amino) -N' -hydroxy-N- (p-methylphenyl) -1,2, 5-oxadiazole-3-carboxamidine (III-7)
Adding 3- (4- ((2-azidoethyl) amino) -1,2, 5-oxadiazol-3-yl) -4- (4-methylphenyl) -1,2, 4-oxadiazol-5 (4H) -one (II-7,2.10g, 6.41mmol) and tetrahydrofuran (20mL) into a 100mL three-necked flask, dropwise adding 2mol/L NaOH solution (9.6mL,19.2mmol) at 0 ℃, and after the addition, stirring the reaction at 40 ℃ for about 5 hours (TLC monitoring reaction completion); the reaction solution was transferred to a 100mL eggplant-shaped flask, THF was evaporated under reduced pressure, the residual aqueous phase was extracted once with dichloromethane (25mL), the aqueous phase was adjusted to pH 3 to 4 with concentrated hydrochloric acid, extracted with dichloromethane (25mL × 2), the organic layer was washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered under suction to obtain 1.26g of a pale yellow solid III-7 with a yield of 64.3%. m.p.82.0-84.0 deg.C.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.22(s,1H,NH),8.60(s,1H,OH),6.97(d,J＝8.1Hz,2H,ArH),6.68(d,J＝8.2Hz,2H,ArH),6.41(t,J＝5.5Hz,1H,NH),3.54(t,J＝5.3Hz,2H,CH2),3.42(q,J＝5.4Hz,2H,CH2),2.20(s,3H,CH3).
N- (4-methylphenyl) -N' -hydroxy-4- ((2- (4- (1-hydroxyethyl) -1H-,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-13)
4- ((2-azidoethyl) amino) -N' -hydroxy-N- (p-methylphenyl) -1,2, 5-oxadiazole-3-carboxamidine (III-7,0.75g,2.48mmol) was charged to a 100mL eggplant-shaped flask, and 3mL of water and 18mL of acetonitrile, respectively, were added. Adding 3-butyn-2-ol (220 mu L,2.98mmol) and cuprous iodide (94mg,0.50mmol) in ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol ═ 15:1 v/v); removing the solvent by distillation under reduced pressure, adding methanol (20mL), stirring for 30min, suction filtering, removing the solvent by distillation under reduced pressure to obtain a light brown solid, and purifying by column chromatography (eluent: petroleum ether: ethyl acetate: 2: 1-1: 4v/v) to obtain 247mg of pale yellow solid I-11 with the yield of 25.6% and m.p.156.0-158.0 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.15(s,1H,NH),8.60(s,1H,OH),7.90(s,1H,ArH),6.96(d,J＝7.7Hz,2H,ArH),6.64(d,J＝7.4Hz,2H,ArH),6.38(s,1H,NH),5.24(s,1H,CH),4.82–4.78(m,1H,OH),4.54(t,J＝4.9Hz,2H,CH2),3.68–3.62(m,2H,CH2),2.19(s,3H,CH3),1.37(d,J＝6.2Hz,3H,CH3).
13C NMR(75MHz,DMSO-d6),δ(ppm):155.57,152.54,140.00,139.90,137.60,131.16,128.76,121.54,121.33,61.59,47.53,44.04,23.74,20.26.
IR(cm-1):3577.32,3372.38,3330.20,3129.93,2979.47,2932.31,2776.86,1624.51,1555.45,1519.69,1431.25,1371.99,1321.40,1288.16,1265.73,1162.45,1145.35,1085.01,1064.87,1033.82,980.12,950.78,897.92,870.68,842.82,821.24,801.14,750.04,639.57,574.06,497.83.
Example 14
N- (4-methylphenyl) -N' -hydroxy-4- ((2- (4- ((2-hydroxyethoxy) methyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-14)
4- ((2-azidoethyl) amino) -N' -hydroxy-N- (p-methylphenyl) -1,2, 5-oxadiazole-3-carboxamidine (III-7,0.80g,2.64mmol) was charged to a 50mL eggplant-shaped flask, and 2mL and 12mL of acetonitrile solution of water were added, respectively. Adding ethoxylated propiolic alcohol (315 mu L,3.17mmol) and cuprous iodide (101mg,0.53mmol) under ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring and reacting for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol ═ 15:1 v/v); removing the solvent by reduced pressure distillation, adding methanol (20mL), stirring for 30min, performing suction filtration, removing the solvent by reduced pressure distillation to obtain a light brown solid, and performing column chromatography purification (eluent: petroleum ether: ethyl acetate: 2: 1-1: 4v/v) to obtain 290mg of white solid I-14, wherein the yield is 27.2%, and m.p.138.0-141.5 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.16(s,1H,NH),8.60(s,1H,OH),8.07(s,1H,ArH),7.05–6.95(m,2H,ArH),6.75–6.65(m,2H,ArH),6.41(s,1H,NH),4.59–4.57(m,4H,CH2CH2),4.52(s,1H,OH),3.70–3.67(m,2H,CH2),3.49–3.45(m,4H,CH2CH2),2.21(s,3H,CH3).
13C NMR(75MHz,DMSO-d6),δ(ppm):155.53,144.04,140.00,139.89,137.57,131.23,128.77,124.05,121.31,71.46,63.46,60.11,47.62,44.01,20.24.
IR(cm-1):3392.64,2923.52,2866.02,1631.30,1560.51,1516.81,1458.23,1399.09,1310.93,1241.43,1145.53,1108.91,1058.46,973.56,898.48,815.25.
Example 15
4- ((2-azidoethyl) amino) -N' -hydroxy-N- (2-bromophenyl) -1,2, 5-oxadiazole-3-carboxamidine (III-8)
Adding 3- (4- ((2-azidoethyl) amino) -1,2, 5-oxadiazol-3-yl) -4- (2-bromophenyl) -1,2, 4-oxadiazol-5 (4H) -one (II-8,2.20g, 5.30mmol) and tetrahydrofuran (20mL) to a 100mL three-necked flask, dropwise adding 2mol/L NaOH solution (8.0mL,15.9mmol) at 0 ℃, after the addition, stirring the reaction at 40 ℃ for about 5 hours (TLC monitoring reaction completion); the reaction solution was transferred to a 100mL eggplant-shaped flask, THF was evaporated under reduced pressure, the residual aqueous phase was extracted once with dichloromethane (25mL), the aqueous phase was adjusted to pH 3 to 4 with concentrated hydrochloric acid, extracted with dichloromethane (25mL × 2), the organic layer was washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered under suction to obtain 1.57g of a pale yellow solid III-4 with a yield of 79.8%. m.p.97.5-98.5 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.33(s,1H,NH),8.35(s,1H,OH),7.54(d,J＝7.9Hz,1H,ArH),7.26(t,J＝7.5Hz,1H,ArH),7.04(t,J＝7.1Hz,2H,ArH),6.38(t,J＝5.4Hz,1H,NH),3.60–3.53(m,2H,CH2),3.48–3.41(m,2H,CH2).
N- (2-bromophenyl) -N' -hydroxy-4- ((2- (4- (1-hydroxyethyl) -1H-,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-15)
4- ((2-azidoethyl) amino) -N' -hydroxy-N- (2-bromophenyl) -1,2, 5-oxadiazole-3-carboxamidine (III-8,0.5g,1.36mmol) was charged to a 50mL eggplant-shaped flask, and 2mL of water and 12mL of acetonitrile solution were added, respectively. Adding 3-butyn-2-ol (120 mu L,1.63mmol) and cuprous iodide (52mg,0.27mmol) in ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol ═ 15:1 v/v); removing the solvent by reduced pressure distillation, adding methanol (20mL), stirring for 30min, performing suction filtration, removing the solvent by reduced pressure distillation to obtain a light brown solid, and performing column chromatography purification (eluent: petroleum ether: ethyl acetate: 2: 1-1: 4v/v) to obtain 110mg of light yellow solid I-15, wherein the yield is 18.4%, and m.p.162.0-164.0 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.25(s,1H,NH),8.33(s,1H,OH),7.88(s,1H,ArH),7.51(d,J＝7.2Hz,1H,ArH),7.24(t,J＝7.0Hz,1H,ArH),7.11–6.94(m,2H,ArH),6.32(t,J＝5.3Hz,1H,NH),5.25(s,1H,CH),4.82–4.72(s,1H,OH),3.57–3.53(m,2H,CH2),3.73–3.63(m,2H,CH2),1.35(d,J＝6.4Hz,3H,CH3).
13C NMR(75MHz,DMSO-d6),δ(ppm):155.27,152.56,140.58,139.40,138.53,132.45,127.90,126.56,126.03,121.58,118.97,61.58,47.46,44.03,23.76.
IR(cm-1):3412.95,3324.59,2772.96,1637.34,1606.93,1561.80,1500.06,1458.58,1447.89,1435.97,1394.29,1302.59,1290.61,1226.54,1157.25,1132.55,1106.69,1084.05,1027.96,978.17,906.03,866.77,745.51,738.12,588.69.
Example 16
N- (2-bromophenyl) -N' -hydroxy-4- ((2- (4- ((2-hydroxyethoxy) methyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-16)
4- ((2-azidoethyl) amino) -N' -hydroxy-N- (2-bromophenyl) -1,2, 5-oxadiazole-3-carboxamidine (III-8,0.5g,1.36mmol) was charged to a 50mL eggplant-shaped flask, and 2mL of water and 12mL of acetonitrile solution were added, respectively. Adding ethoxylated propiolic alcohol (160 mu L,1.63mmol) and cuprous iodide (52mg,0.27mmol) under ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring and reacting for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol ═ 15:1 v/v); removing the solvent by reduced pressure distillation, adding methanol (20mL), stirring for 30min, performing suction filtration, removing the solvent by reduced pressure distillation to obtain a light brown solid, and performing column chromatography purification (eluent: petroleum ether: ethyl acetate: 2: 1-1: 4v/v) to obtain 100mg of white solid I-16, wherein the yield is 16.8%, and m.p.130.0-132.0 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.24(s,1H,NH),8.26(s,1H,OH),8.05(s,1H,ArH),7.52(d,J＝7.8Hz,1H,ArH),7.26(t,J＝7.1Hz,1H,ArH),7.02(t,J＝7.5Hz,2H,ArH),6.33(t,J＝5.9Hz,1H,NH),4.64–4.60(m,2H,CH2),4.58(s,1H,OH),4.51(s,2H,CH2),3.71(q,5.7Hz,2H,CH2),3.51–4.48(m,2H,CH2),3.45–3.43(m,2H,CH2).
13C NMR(75MHz,DMSO-d6),δ(ppm):155.51,144.32,140.78,139.67,138.74,132.69,128.13,126.64,126.22,124.32,119.06,71.74,63.75,60.38,47.84,44.27.
IR(cm-1):3415.49,3370.20,3332.79,2923.18,2863.16,1638.00,1602.70,1561.00,1513.86,1475.96,1458.60,1387.95,1308.12,1154.06,1107.88,1068.50,1027.42,1017.61,982.17,903.50,756.02,568.56.
Example 17
4- ((2-azidoethyl) amino) -N' -hydroxy-4- (3-chloro-4-fluorophenyl) -1,2, 5-oxadiazole-3-carboxamidine (III-9)
Adding 3- (4- ((2-azidoethyl) amino) -1,2, 5-oxadiazol-3-yl) -4- (3-chloro-4-fluorophenyl) -1,2, 4-oxadiazol-5 (4H) -one (II-9,2.10g, 5.10mmol) and tetrahydrofuran (20mL) to a 100mL three-necked flask, dropwise adding 2mol/L NaOH solution (7.8mL,15.3mmol) at 0 ℃, and after completion of addition, stirring the reaction at 40 ℃ for about 5 hours (TLC monitoring reaction completion); the reaction solution was transferred to a 100mL eggplant-shaped flask, THF was evaporated under reduced pressure, the residual aqueous phase was extracted once with dichloromethane (25mL), the aqueous phase was adjusted to pH 3 to 4 with concentrated hydrochloric acid, extracted with dichloromethane (25mL × 2), the organic layer was washed once with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered under suction to obtain 1.52g of a pale yellow solid III-4 with a yield of 86.3%. m.p.82.0-84.5 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.53(s,1H,NH),8.93(s,1H,OH),7.22(t,J＝9.0Hz,1H，ArH),7.00(dd,J＝6.1,2.1Hz,1H，ArH),6.80–6.67(m,1H，ArH),6.40(t,J＝5.4Hz,1H,NH),3.56(d,J＝5.3Hz,2H,CH2),3.45(q,J＝5.0Hz,2H,CH2).
N- (4-fluoro-3-chlorophenyl) -N' -hydroxy-4- ((2- (4- (1-hydroxyethyl) -1H-,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-17)
4- ((2-azidoethyl) amino) -N' -hydroxy-4- (3-chloro-4-fluorophenyl) -1,2, 5-oxadiazole-3-carboxamidine (III-9,0.80g,2.35mmol) was charged to a 50mL eggplant-shaped flask, and 3mL of water and 18mL of acetonitrile solution were added, respectively. Adding 3-butyn-2-ol (207 mu L,2.82mmol) and cuprous iodide (90mg,0.47mmol) in ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol ═ 15:1 v/v); removing the solvent by reduced pressure distillation, adding methanol (20mL), stirring for 30min, performing suction filtration, removing the solvent by reduced pressure distillation to obtain a light brown solid, and performing column chromatography purification (eluent: petroleum ether: ethyl acetate: 2: 1-1: 4v/v) to obtain 325mg of pale yellow solid I-17 with the yield of 34.7% and m.p.176.5-178.0 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.47(s,1H,NH),8.92(s,1H,OH),7.92(s,1H,ArH),7.21(t,J＝9.0Hz,1H,ArH),7.03–6.93(m,1H,ArH),6.70–6.66(m,1H,ArH),6.35(t,J＝5.4Hz,1H,NH),5.25(d,J＝4.6Hz,1H,OH),4.84–4.72(m,1H,CH),4.56(t,J＝5.6Hz,2H,CH2),3.68(q,J＝5.4Hz,2H,CH2),1.37(d,J＝6.4Hz,3H,CH3).
13C NMR(75MHz,DMSO-d6),δ(ppm):155.44,139.88,139.09,137.71,137.67,122.05,121.58,120.85,120.75,116.31,116.03,61.57,47.53,44.10,23.75.
IR(cm-1):3597.67,3328.84,3147.49,2983.53,2919.30,2360.36,1634.78,1608.52,1561.34,1497.24,1433.62,1377.90,1322.13,1261.38,1224.53,1162.00,1144.52,1107.52,1057.92,982.45,948.59,906.70,864.52,835.77,816.94,575.92.
Example 18
N- (4-fluoro-3-chlorophenyl) -N' -hydroxy-4- ((2- (4- ((2-hydroxyethoxy) methyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-18)
4- ((2-azidoethyl) amino) -N' -hydroxy-4- (3-chloro-4-fluorophenyl) -1,2, 5-oxadiazole-3-carboxamidine (III-9,0.80g,2.35mmol) was charged to a 50mL eggplant-shaped flask, and 3mL of water and 18mL of acetonitrile solution were added, respectively. Adding ethoxylated propiolic alcohol (280 mu L,2.82mmol) and cuprous iodide (90mg,0.47mmol) under ice bath, keeping the temperature and stirring for 0.5h, then transferring to a room temperature environment to continue stirring and reacting for about 8h, and monitoring the reaction by TLC until the reaction is complete (a developing agent: dichloromethane: methanol ═ 15:1 v/v); the solvent was removed by distillation under reduced pressure, methanol (20mL) was added and stirred for 30min, suction filtration was performed, the solvent was removed by distillation under reduced pressure to give a light brown solid, which was purified by column chromatography (eluent: petroleum ether: ethyl acetate ═ 2:1 to 1:4v/v) to give 285mg of white solid I-18 in 27.5% yield, m.p.92.5-94.5 ℃.
1H NMR(300MHz,DMSO-d6),δ(ppm):11.46(s,1H,NH),8.91(s,1H,OH),8.09(s,1H,ArH),7.29–7.11(m,1H,ArH),7.05–6.95(m,1H,ArH),6.68(s,1H,ArH),6.37(s,1H,NH),4.65–4.62(m,2H,CH2),4.53–4.49(m,2H,CH2),4.48(s,1H,OH),3.72–3.68(m,2H,CH2),3.48–3.38(m,4H,CH2CH2).
13C NMR(75MHz,DMSO-d6),δ(ppm):146.92,131.40,130.56,129.20,115.61,113.54,112.32,112.23,107.80,107.51,105.99,62.97,54.97,51.59,39.09,35.59.
IR(cm-1):3409.58,3330.90,3153.58,2922.63,2360.09,2341.51,1653,13,1636.78,1607.19,1567.89,1500.49,1454.69,1388.28,1303.65,1261.75,1223.37,1143.21,1105.35,1057.73,1031.40,937.22,892.75,856.98,815.32,793.63,563.92.
Example 19
Firstly, detecting the activity of target compounds for inhibiting IDO1 and IDO2 at enzyme level
(1) Experimental methods
Firstly, an IDO1/2 enzyme activity inhibition molecule screening model is established, and the inhibition IC of a positive control drug Epacadostat on the model is detected50The values, the inhibition rate and the results are similar to those reported in various literatures, and the construction success of the screening model is shown. The IDO enzyme may catalyze the epoxylytic cleavage of pyrrole to tryptophan to produce N '-formylkynurenine (N' -formylkynurenine). 40nM of IDO1/IDO2 enzyme, 900. mu.M of L-tryptophan and the test compound were mixed at room temperature, and a reaction buffer (50mM potassium phosphate buffer (pH6.5), 20mM vitamin C, 3.5mM methylene blue and 0.2mg/mL catalase) was added to react at room temperature for 3 hours, followed by measurement on a microplate reader at a detection wavelength of 321 nM.
Percent (%) enzyme activity (OD value-OD value background for dosed wells)/(OD value-OD value background for control wells) × 100%;
the enzyme activity inhibition (%) was 1-enzyme activity percentage (%).
A: the enzyme activity inhibition rate (%) is more than or equal to 80 percent; b: 80% > the enzyme activity inhibition rate (%) > is more than or equal to 40%; c: the enzyme activity inhibition ratio (%) < 40%.
(2) Test results
The inhibition rates of IDO1 and IDO2 at the enzyme level for some of the compounds of interest of the present invention are shown in table 1. The results show that under the concentration of 500nM, the four compounds I-3, I-4, I-17 and I-18 have better effect of inhibiting IDO1 enzyme, and are equivalent to the positive drug Epacadostat; at a concentration of 1. mu.M, the four compounds I-3, I-4, I-17 and I-18 had better inhibitory effects on the IDO2 enzyme than the positive drug Epacadostat.
TABLE 1 inhibitory Activity of Compounds on IDO1 and IDO2 at the enzyme level
Figure BDA0002356256440000221
Figure BDA0002356256440000231
Second, investigation of inhibitory Activity of part of target Compounds on tumor cell proliferation
(1) Test cells
Breast cancer cell MDA-MB-231, colon cancer cell HCT 116.
(2) Experimental methods
The cells were subcultured for 10-15 passages in a medium composed of penicillin (final concentration 100U/mL), streptomycin (final concentration 100. mu.g/mL) and 10% FBS-containing RPMI1640 medium, and when the cells fused to 90%, the old medium was discarded, the cells were washed twice with 2mL of PBS, PBS was discarded, 2mL of a mixed digest of 0.25% trypsin and 0.53mM EDTA was added, the mixture was observed under a microscope, and when the cells became round, 5mL of complete medium was added, and the cells were collected. Centrifuging at 800rpm and 4 deg.C for 5min, discarding supernatant, suspending cells with complete culture medium, culturing in bottles, and changing the culture medium every other day.
Cells in logarithmic growth phase were taken at 100. mu.L/well (about 5X 10)3One) was inoculated in a 96-well plate, test compounds were added to final concentrations of 100, 50, 25, 12.5, 6.25, 3.125, 1.562, 0.781 μmol/L after cells adhered to the wall, and an equal volume of culture medium was added to the control group. Adding 20 mu L/hole MTT solution after 72h, incubating in an incubator at 37 ℃ for 4h, then discarding the supernatant, adding 150 mu L/hole DMSO, oscillating on a cell oscillator for 10min, measuring the light absorption value at 570nm by using an enzyme-labeling instrument after the crystal is fully dissolved, and calculating the cell survival rate according to the formula:
cell viability (%) - (absorbance in experimental group/absorbance in control group) × 100%.
(3) Test results
TABLE 2 data on the in vitro anti-MDA-MB-231 wild-type breast cancer cell activity of some of the compounds of interest
Figure BDA0002356256440000232
TABLE 3 in vitro data on the activity of some target compounds against HCT116 colon cancer cells
Figure BDA0002356256440000233
Figure BDA0002356256440000241
In vitro anti-proliferative activity investigation results show that the target compounds I-3, I-4, I-17 and I-18 have weak proliferation inhibition effects on MDA-MB-231 wild type breast cancer cells and colon cancer cells HCT116, are equivalent to positive drug Epacadostat, and indicate that the cytotoxicity is low.

Claims (10)

1. Triazole derivative shown in general formula I or pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or crystal thereof:
Figure FDA0002356256430000011
wherein:
x is selected from
Figure FDA0002356256430000012
R1、R2And R3Are respectively selected from H, F, Cl, Br and CH3、CHF2、CN、OCH3、NH2、NO2、OH、CF3But cannot satisfy R simultaneously1＝H、R2＝Br、R3＝F。
2. The triazole derivative according to claim 1, wherein:
x is selected from
Figure FDA0002356256430000013
R1Is H, F, Cl, Br, CH3、OH、CF3；
R2Is H, Cl, Br, CH3、CN、CHF2、OH、CF3；
R3Is H, F, Cl, CH3、CHF2、OH、CF3；
But cannot satisfy R simultaneously1＝H、R2＝Br、R3＝F。
3. The triazole derivative according to claim 2, wherein:
x is selected from
Figure FDA0002356256430000014
When R is1Is H, F, R2Is H, Cl, CH3，R3Is H, F, Cl, CH3But cannot satisfy R simultaneously1＝H、R2＝H、R3＝CH3；
X is selected from
Figure FDA0002356256430000015
When R is1Is H, F, Br, R2Is H, Cl, CH3，R3Is H, F, CH3。
4. The triazole derivative according to claim 2, wherein:
x is selected from
Figure FDA0002356256430000016
R1Is H, F, Br, CH3、OH；
R2Is Cl;
R3is H, F, Cl, CH3、CF3。
5. The triazole according to any one of claims 1 to 4A derivative characterized by: x is selected from
Figure FDA0002356256430000021
Figure FDA0002356256430000022
R1Is H, R2Is Cl, R3Is H or F.
6. The triazole derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein: the pharmaceutically acceptable salt is an acid addition salt of the triazole derivative shown in the general formula (I); wherein, the acids that can be used for salt formation are: hydrogen chloride, hydrogen bromide, sulfuric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid.
7. A process for producing a triazole derivative according to claim 1, which comprises: hydrolyzing the compound II to obtain a compound III, and preparing a compound I from the compound III and a compound IV through a click chemistry reaction:
Figure FDA0002356256430000023
wherein R is1、R2、R3X is as described in claim 1;
or preparing a compound V from the compound II through a click chemical reaction, and preparing a compound I from the compound V through hydrolysis:
Figure FDA0002356256430000024
wherein R is1、R2、R3X is as described in claim 1.
8. A pharmaceutical composition characterized by: comprises triazole derivatives shown in general formula I in claim 1 or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers.
9. Use of the triazole-based derivative or a pharmaceutically acceptable salt thereof according to claim 1 for the preparation of an IDO inhibitor drug.
10. Use of the triazole derivative of claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing malignant tumor.
CN202010008540.XA 2020-01-06 2020-01-06 Triazole derivative and preparation method and application thereof Pending CN111138425A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010008540.XA CN111138425A (en) 2020-01-06 2020-01-06 Triazole derivative and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010008540.XA CN111138425A (en) 2020-01-06 2020-01-06 Triazole derivative and preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN111138425A true CN111138425A (en) 2020-05-12

Family

ID=70523671

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010008540.XA Pending CN111138425A (en) 2020-01-06 2020-01-06 Triazole derivative and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN111138425A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115745982A (en) * 2022-11-07 2023-03-07 中国药科大学 Oxadiazole compound and preparation method and application thereof
WO2023077049A1 (en) * 2021-10-29 2023-05-04 Trevena, Inc. Methods of preparing 6-membered aza-heterocyclic containing delta-opioid receptor modulating compounds
US11912713B2 (en) 2017-02-17 2024-02-27 Trevena, Inc. 7-membered aza-heterocyclic containing delta-opioid receptor modulating compounds, methods of using and making the same

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101212967A (en) * 2005-05-10 2008-07-02 因塞特公司 Modulators of indoleamine 2,3-dioxygenase and methods of using the same
CN105646389A (en) * 2016-01-28 2016-06-08 中国科学院上海有机化学研究所 Sulfamate serving as indoleamine-2, 3-dioxygenase inhibitor and preparation method and application thereof
CN107176933A (en) * 2016-03-09 2017-09-19 中国科学院上海有机化学研究所 A kind of indoles amine -2,3- dioxygenase inhibitors containing N-alkylation and arylation sulphoxide imine
WO2018044663A1 (en) * 2016-08-29 2018-03-08 Merck Sharp & Dohme Corp. Novel substituted n'-hydroxycarbamimidoyl-1,2,5-oxadiazole compounds as indoleamine 2,3-dioxygenase (ido) inhibitors
CN107954999A (en) * 2016-10-17 2018-04-24 上海医药集团股份有限公司 Han oxadiazole rings compound, preparation method, intermediate, composition and application
CN108863976A (en) * 2017-09-11 2018-11-23 郑州泰基鸿诺医药股份有限公司 Compound and its application as IDO regulator
CN109111438A (en) * 2017-06-26 2019-01-01 正大天晴药业集团股份有限公司 amidine compound for IDO inhibitor
CN109574950A (en) * 2017-09-28 2019-04-05 上海翔锦生物科技有限公司 1,2,5- furodiazole derivative and application thereof
CN109748911A (en) * 2017-11-06 2019-05-14 中国药科大学 A kind of IDO inhibitor containing triazole, preparation method and its medical usage
CN109897011A (en) * 2017-12-08 2019-06-18 上海华汇拓医药科技有限公司 A kind of IDO inhibitor and its application
CN110143955A (en) * 2018-02-11 2019-08-20 中国科学院上海药物研究所 Oxadiazole derivatives, synthetic method and its application containing heterocyclic side chain
CN110204537A (en) * 2019-07-10 2019-09-06 盛世泰科生物医药技术(苏州)有限公司 A kind of 1,2,5- oxadiazole derivatives of the inhibitor as indoleamine 2,3-dioxygenase
CN110407765A (en) * 2018-04-28 2019-11-05 上海挚盟医药科技有限公司 1,2,5- furodiazole derivative, preparation method and its application in medicine

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101212967A (en) * 2005-05-10 2008-07-02 因塞特公司 Modulators of indoleamine 2,3-dioxygenase and methods of using the same
CN105646389A (en) * 2016-01-28 2016-06-08 中国科学院上海有机化学研究所 Sulfamate serving as indoleamine-2, 3-dioxygenase inhibitor and preparation method and application thereof
CN107176933A (en) * 2016-03-09 2017-09-19 中国科学院上海有机化学研究所 A kind of indoles amine -2,3- dioxygenase inhibitors containing N-alkylation and arylation sulphoxide imine
WO2018044663A1 (en) * 2016-08-29 2018-03-08 Merck Sharp & Dohme Corp. Novel substituted n'-hydroxycarbamimidoyl-1,2,5-oxadiazole compounds as indoleamine 2,3-dioxygenase (ido) inhibitors
CN107954999A (en) * 2016-10-17 2018-04-24 上海医药集团股份有限公司 Han oxadiazole rings compound, preparation method, intermediate, composition and application
CN109111438A (en) * 2017-06-26 2019-01-01 正大天晴药业集团股份有限公司 amidine compound for IDO inhibitor
CN108863976A (en) * 2017-09-11 2018-11-23 郑州泰基鸿诺医药股份有限公司 Compound and its application as IDO regulator
CN109574950A (en) * 2017-09-28 2019-04-05 上海翔锦生物科技有限公司 1,2,5- furodiazole derivative and application thereof
CN109748911A (en) * 2017-11-06 2019-05-14 中国药科大学 A kind of IDO inhibitor containing triazole, preparation method and its medical usage
CN109897011A (en) * 2017-12-08 2019-06-18 上海华汇拓医药科技有限公司 A kind of IDO inhibitor and its application
CN110143955A (en) * 2018-02-11 2019-08-20 中国科学院上海药物研究所 Oxadiazole derivatives, synthetic method and its application containing heterocyclic side chain
CN110407765A (en) * 2018-04-28 2019-11-05 上海挚盟医药科技有限公司 1,2,5- furodiazole derivative, preparation method and its application in medicine
CN110204537A (en) * 2019-07-10 2019-09-06 盛世泰科生物医药技术(苏州)有限公司 A kind of 1,2,5- oxadiazole derivatives of the inhibitor as indoleamine 2,3-dioxygenase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
池肇春主编 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11912713B2 (en) 2017-02-17 2024-02-27 Trevena, Inc. 7-membered aza-heterocyclic containing delta-opioid receptor modulating compounds, methods of using and making the same
WO2023077049A1 (en) * 2021-10-29 2023-05-04 Trevena, Inc. Methods of preparing 6-membered aza-heterocyclic containing delta-opioid receptor modulating compounds
CN115745982A (en) * 2022-11-07 2023-03-07 中国药科大学 Oxadiazole compound and preparation method and application thereof

Similar Documents

Publication Publication Date Title
CN106928245B (en) A kind of Quinolizinone type compounds and its preparation method and application
CN111138425A (en) Triazole derivative and preparation method and application thereof
CN105566276B (en) Benzo-hexatomic ring derivative as DPP-4 inhibitor and application thereof
CN111423416A (en) Inhibitors of RET
EP3495354A1 (en) Ido1 inhibitor and preparation method and application thereof
CN109071567B (en) Anti-influenza small molecule compound and preparation method and application thereof
EP3162801B1 (en) Salt of halogen-substituted heterocyclic compound
WO2020143653A1 (en) Preparation method for glucopyranosyl derivative and intermediate thereof
CN106660970B (en) Quinazoline derivatives
WO2021175079A1 (en) P-phenylenediamine lsd1 inhibitor and preparation method therefor
CN110770234A (en) Substituted aryl ether compound, preparation method thereof, medicinal composition and application thereof
WO2020221006A1 (en) Bet inhibitor, and preparation method and use thereof
CN112174940A (en) 3- (6, 7-bis (2-methoxyethoxy) -quinazoline-4-amido) phenyl-1H-triazole derivative
CN112010819A (en) Benzamide-containing benzo-hexahydric heterocyclic derivative and application thereof in antitumor drugs
CN111655685B (en) Thiophene derivative and use thereof
WO2015018182A1 (en) Phenylacetic acid derivative and antitumor use thereof
CN111454229A (en) Dihydronaphthoisoxazole derivative and application thereof in antitumor drugs
CN115160277B (en) Apigenin derivative and application thereof
CN114901639B (en) HBV inhibitors and uses thereof
CN113527275A (en) SKLB1039 compound and preparation method and application thereof
CN106883224A (en) Nitrogen-containing benzoheterocycle class indoleamine 2, the inhibitor of 3 dioxygenase 1 and application thereof
CN109422739B (en) Deuterated indoleamine 2, 3-dioxygenase inhibitor and application thereof
CN113105459A (en) Triazolopyrimidine derivative and preparation method and application thereof
CN109020890B (en) Preparation and application of saturated aliphatic cyclo-pyrazole derivatives
CN114728943A (en) Compounds as BCR-ABL inhibitors

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20200512

RJ01 Rejection of invention patent application after publication