CN109748911B - Triazole-containing IDO inhibitor, and preparation method and medical application thereof - Google Patents

Triazole-containing IDO inhibitor, and preparation method and medical application thereof Download PDF

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CN109748911B
CN109748911B CN201810007024.8A CN201810007024A CN109748911B CN 109748911 B CN109748911 B CN 109748911B CN 201810007024 A CN201810007024 A CN 201810007024A CN 109748911 B CN109748911 B CN 109748911B
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ethyl acetate
fluorophenyl
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CN109748911A (en
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徐云根
朱启华
贺新
何广卫
储昭兴
何光超
王俊杰
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Hefei Industrial Pharmaceutical Institute Co ltd
China Pharmaceutical University
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China Pharmaceutical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to an IDO inhibitor (I) containing a triazole group, a preparation method thereof and a medicinal composition containing the compounds.

Description

Triazole-containing IDO inhibitor, and preparation method and medical application thereof
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to an IDO inhibitor (I) containing a triazole group, a preparation method thereof, a medicinal composition containing the compounds and application thereof in treating malignant tumors.
Background
Cancer is a leading cause of morbidity and mortality worldwide. Recent data shows that over 160 million patients have been diagnosed with cancer in the united states in 2016, while nearly 60 million patients die due to cancer; the number of newly added cancer patients reaches 430 ten thousand in 2015 years in China, and the number of cancer deaths reaches 280 thousand. The high incidence and mortality of cancer has led people to speak about "cancerous" color changes in life. Particularly, as the aging problem of the population comes, the problem becomes more prominent, and therefore, the search for a new cancer treatment is urgent. After the 21 st century, with the continuous and deep research of oncology and immunology, the human immune system has become a hot field for the development of new drugs. In 2013, the journal of science lists tumor immunotherapy as the first place of ten scientific breakthroughs.
Indoleamine-2, 3-dioxygenase (IDO) is an important enzyme for decomposing tryptophan (tryptophan), and there are three subtypes of IDO, namely IDO1, IDO2 and TDO. IDO is expressed in a variety of tumor cells, mediating tumor-induced immunosuppression. This enzyme can locally degrade tryptophan, inactivate the tumor surveillance of the immune system and prevent tumor rejection. IDO affects immunosuppressive molecules associated with the body's immune system through a variety of pathways, ultimately leading to immune escape of tumor cells, which further translates into cancer. Therefore, the role of IDO in tumor immune escape is more and more emphasized, so that IDO becomes the most important small molecule regulatory target for anti-tumor immunotherapy.
Disclosure of Invention
The invention discloses an anti-tumor candidate compound with novel structure, high activity and small side effect. The compounds have good antitumor activity, and can be used together with other antitumor drugs, so that the effects of improving the curative effect of the existing antitumor drugs and reducing the dose and toxicity are achieved.
The invention discloses a compound of a general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention discloses compounds of general formula (I):
Figure BDA0001538964720000011
wherein R is1Is C3～C6Cycloalkyl group of, -COOCH3、-CONH2、-C(CH3)2NH2、-CH2N(CH3)2、-CH2N(CH2CH3)2、
Figure BDA0001538964720000021
Figure BDA0001538964720000022
Wherein
m＝0～3；
X＝CH2Or O;
R2is H, F, Cl, Br, CH3、OH、NH2、-N(CH3)2or-N (CH)2CH3)2；
R3Is H or CH3；
R4Is H, CH3、CH2CH3、CH2OH、CH2CH2OH、CH2CH2CH2OH、CH2CONH2、CH2CONHCH3、 CH2COOH or CH2COOCH3；
R5Is optionally substituted H, F, Cl, Br, CH3、CN、NO2、OH、OCH3、NH2、NHCH3、N(CH3)2、 COOH、COOCH3、COOCH2CH3、CONH2Or CONHCH3。
Wherein R is1Preferably represents cyclopropyl, 4-methoxyphenyl, 3-aminophenyl, CONH2、COOCH3、
Figure BDA0001538964720000023
Figure BDA0001538964720000024
Wherein m is 0-2, and X is CH2Or O, R2Preferably H, CH3OH or NH2，R3Is H or CH3，R4Preferably H, CH3、CH2CH2OH、CH2CH2CH2OH、CH2CONH2Or CH2CONHCH3。
R1More preferably represents CONH2Or
Figure BDA0001538964720000025
Wherein m is preferably 0 to 1, and X is CH2Or O, R2More preferably H, CH3OH or NH2，R3Is H or CH3，R4More preferably H, CH3、CH2CH2OH、CH2CH2CH2OH or CH2CONH2。
Preferred partial compounds of the invention are the following:
Figure BDA0001538964720000026
Figure BDA0001538964720000031
Figure BDA0001538964720000041
Figure BDA0001538964720000051
Figure BDA0001538964720000061
Figure BDA0001538964720000071
the compounds of the general formula according to the invention are preferably prepared by the following process:
Figure BDA0001538964720000072
wherein:
the compound II is hydrolyzed to prepare the compound III, and the used base is sodium hydroxide, potassium carbonate, sodium carbonate or sodium acetate, preferably sodium hydroxide. The solvent used is tetrahydrofuran, 1, 4-dioxane, acetonitrile or a mixed solvent of N, N-dimethylformamide and water, preferably a mixed solvent of tetrahydrofuran and water.
The process for preparing compound I by the Click reaction of compound III and corresponding alkyne derivative IV uses copper sulfate, cupric chloride, cupric bromide, cuprous chloride, cuprous bromide, cuprous iodide or copper powder as catalyst, preferably cuprous bromide. The solvent is tetrahydrofuran, 1, 4-dioxane, acetonitrile, ethanol, methanol, ethylene glycol dimethyl ether, dichloromethane, N-dimethylformamide or N, N-dimethylacetamide, or a mixed solvent of the above solvents and water, preferably a mixed solvent of acetonitrile and water.
The compounds of the invention are preferably prepared by the following process:
Figure BDA0001538964720000073
wherein:
the process for preparing compound V by the Click reaction of compound II and corresponding alkyne derivative IV uses copper sulfate, cupric chloride, cupric bromide, cuprous chloride, cuprous bromide, cuprous iodide or copper powder as catalyst, preferably cuprous bromide. The solvent is tetrahydrofuran, 1, 4-dioxane, acetonitrile, ethanol, methanol, ethylene glycol dimethyl ether, dichloromethane, N-dimethylformamide or N, N-dimethylacetamide, or a mixed solvent of the above solvents and water, preferably a mixed solvent of acetonitrile and water.
The base used in the preparation of compound I by hydrolysis of compound V is sodium hydroxide, potassium carbonate, sodium carbonate or sodium acetate, preferably sodium hydroxide. The solvent used is tetrahydrofuran, 1, 4-dioxane, acetonitrile or a mixed solvent of N, N-dimethylformamide and water, preferably a mixed solvent of tetrahydrofuran and water.
Preparing a compound I.A by salifying a compound I, wherein a reactant (A) is hydrogen chloride, hydrogen bromide, sulfuric acid, phosphoric acid, carbonic acid, oxalic acid, citric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or ferulic acid; the solvent is preferably methanol, ethanol, dichloromethane, acetone, ethyl acetate, toluene or tetrahydrofuran, or a mixed solvent of any of the above.
It is another object of the present invention to provide a pharmaceutical composition comprising a pharmaceutically effective dose of the compound of the present invention or a salt thereof and a pharmaceutically acceptable carrier.
The compound can be added with pharmaceutically acceptable carriers to prepare common medicinal preparations, such as tablets, capsules, powder, syrup, liquid, suspending agents and injection, and common medicinal auxiliary materials such as spices, sweeteners, liquid or solid fillers or diluents and the like can be added.
The clinical administration mode of the compound of the invention can adopt oral administration, injection and other modes.
Typically, the compounds of the invention are administered to humans in a dosage range of 1mg to 1000mg per day. Dosages outside this range may also be used depending on the dosage form and the severity of the disease.
The pharmacological experiments and results of part of the compounds of the invention are as follows:
(1) detecting the activity of part of the target compound for inhibiting IDO1 at the enzyme level
Experimental methods
Establishing IDO1 enzyme activity inhibition molecule screening model, detecting inhibition IC of positive control drug Epacadostat on the model50The 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 IDO enzyme and 900. mu.M L-tryptophan were mixed at room temperature, and reaction buffer (20mM ascorbate, 3.5. mu.M methyl blue and 0.2mg/mL catalase in 50mM potassium phosphate buffer pH 6.5) was added to react at room temperature for 3 hours, followed by UV measurement on a microplate reader at a detection wavelength of 321 nM. Percent (%) enzyme activity (OD value dose well-OD value background)/(OD value control well-OD value background) × 100%, and IC was calculated by fitting with Prism GraphPad sofeware software50The value is obtained.
The results are shown in Table 1
TABLE 1 inhibition of IDO1 by some of the compounds of interest at the enzyme level
Figure BDA0001538964720000091
As can be seen from Table 1, the tested target compounds all had stronger inhibitory activity against IDO1 than the positive control drug Epacadostat at 100nM concentration, wherein the inhibitory activity of compounds I-3 and I-17 was significantly stronger than that of the positive control drug Epacadostat. We selected compounds with an inhibition greater than 50% to determine their IC's for IDO1 and IDO250(median inhibitory concentration), the results are shown in Table 2.
TABLE 2 inhibitory Activity of some of the target Compounds on IDO1 and IDO2 at the enzyme level
Figure BDA0001538964720000092
Figure BDA0001538964720000101
The results of the experiment show that the IC of the tested compound on IDO150The compounds are all smaller than the positive control drug Epacadostat, which shows that the compounds have stronger inhibitory activity to IDO1, wherein the inhibitory activity of the compound I-17 is strongest; IC of Compound on IDO250Are all smaller than the positive control drug Epacadostat, which shows that the compounds have stronger inhibitory activity to IDO2, wherein the inhibitory activity of the compound I-17 is strongest. From the above results, it is understood that the compound (I) of the present invention has a stronger inhibitory activity against IDO1 and a better inhibitory activity against IDO2 than the positive control drug Epacadostat, and therefore the balance of the inhibitory activity against IDO1 and IDO2 of the compound (I) of the present invention is better than that of the positive control drug Epacadostat.
(2) Detecting the inhibitory activity of a portion of the target compound against IDO1 in cells
5000-10000 HeLa cells were added to each well of a 96-well plate. After overnight growth, human IFN-. gamma.was added to each well (final concentration 10-50ng/mL) and the drug was added in different concentrations with 15. mu.g/mL L-tryptophan in a gradient to give a final volume of 200. mu.L per well. After 48 hours, 140. mu.L of the supernatant was added with 10. mu.L of trichloroacetic acid, mixed well and incubated at 50 ℃ for 30 minutes. The resulting mixture was centrifuged at 2500rpm for 10 minutes. mu.L of the supernatant was placed in a 96-well plate, and 100. mu.L of acetic acid containing 2% p-dimethylaminobenzaldehyde was added thereto. And measuring by a microplate reader at 480 nm. Detecting the OD value of each hole by using a microplate reader (the detection wavelength is 515 nm); recording the result; the inhibition rate was calculated according to the following formula: inhibition (%) - (OD control-OD administration)/OD control × 100%, and IC was calculated50The results are shown in Table 3.
TABLE 3 inhibitory Activity of some of the compounds of interest on INF-gamma induced IDO1 on Hela cells
Figure BDA0001538964720000102
The results of the experiment show that the tested compounds have IC to INF-gamma induced IDO1 of Hela cells50Are all smaller than the positive control drug Epacadostat, which indicates that the compound has stronger inhibitory activity to IDO 1.
(3) Inhibition experiment of Compound I-3 and Compound I-17 on growth of mouse colon cancer cell CT-26 xenograft tumor
Selecting CT-26 colon cancer cells grown to logarithmic phase by conventional culture, performing conventional digestion under aseptic condition, collecting cells, adjusting cell concentration to 5 × 10 with sterile physiological saline6. The left axilla of BALB/C mice sterilized with alcohol was inoculated subcutaneously 0.2mL each with a 1mL syringe, and the whole inoculation was completed within 1 hour. When the tumor volume reaches 100mm3About (about 7-14 days), BALB/C nude mice were randomly divided into 4 groups of 10 mice each. Each group was administered according to the experimental protocol set forth in Table 4, and model control group, compound I-3 group, compound I-17 group, and positive control group Epacadostat were administered twice daily for 28 days, and the body weight and the volume of transplanted tumors were measured every 3 days during the administration period, and after 30 days, mice were sacrificed, and tumor masses were surgically removed and weighed. The results of the experiment are shown in FIG. 1.
TABLE 4 inhibitory Activity of test Compounds on growth of mouse Colon cancer cells CT-26 xenograft tumors
Figure BDA0001538964720000111
The inhibitory effects of Compound I-3 and Compound I-17 on tumor growth are shown in FIG. 1.
The results in FIG. 1 show that the compound I-3 and the compound I-17 have stronger inhibiting effect on the growth of mouse colon cancer cell CT-26 xenograft tumor than the positive control drug Epacadostat.
Drawings
FIG. 1 is a graph showing the inhibitory effects of Compound I-3 and Compound I-17 on the growth of mouse colon carcinoma cells CT-26 xenograft tumors
Detailed Description
Example 1
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-1)
Preparation of 4- ((2-azidoethyl) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (III)
THF (2mL) and 3- {4- [ (2-azidoethyl) amino ] -1,2, 5-oxadiazol-3-yl } -4- (3-bromo-4-fluorophenyl) -1,2, 4-oxadiazol-5 (4H) -one (II) (411mg,1.0mmol) were placed in a 25mL three-necked flask and dissolved with stirring. Adding 2mol/L sodium hydroxide (1mL) dropwise at below 10 ℃, heating to 25 ℃ after dropping, keeping the temperature and reacting for about 2 hours, monitoring the completion of the reaction of the raw materials by TLC, evaporating the solvent under reduced pressure below 30 ℃, adding 5mL of water, extracting with ethyl acetate (5mL × 3) for three times, washing with water (5mL × 2) twice, washing with saturated saline (5mL), and evaporating under reduced pressure to obtain 0.39g of light brown oily substance (III).
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-1)
Acetonitrile (4mL), water (1mL) and oil III prepared in the previous step (0.39g,1.0mmol) were placed in a 25mL three-necked flask and dissolved with stirring. Phenylacetylene (IV-1) (250. mu.L, 2.3mmol) and cuprous bromide (15mg,0.1mmol) were added and the reaction stirred for about 5 hours. After TLC monitoring of the completion of the reaction of the raw materials, the solvent was evaporated under reduced pressure below 40 ℃, ethyl acetate (5mL) and water (5mL) were added, filtration was carried out, standing and layer separation was carried out, the aqueous layer was extracted three times with ethyl acetate (5 mL. times.3), the organic layers were combined, washed twice with water (5 mL. times.2) respectively, washed with saturated saline (5mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to dryness to give a light brown oily substance, and subjected to column chromatography separation (eluent: petroleum ether: ethyl acetate: 1: 2 to 1: 4) to give 250mg of a white solid, melting point: 208 ℃ and 210 ℃ and the yield of the two steps is 51.3 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.46(s,1H),8.94(s,1H),8.62(s,1H),7.85(d,J＝ 7.1Hz,2H),7.47(t,J＝7.3Hz,2H),7.35(t,J＝7.4Hz,1H),7.22-7.09(m,2H),6.75-6.70(m,1H), 6.46(d,J＝5.8Hz,1H),4.68(t,J＝5.7Hz,2H),3.78(t,J＝5.9Hz,2H).HRMS(ESI):m/z [M+H]+Calcd for C19H17BrFN8O2:487.0636；Found:487.0624.
Example 2
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4-cyclopropyl-1H-1, 2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-2)
Starting from III (0.39g,1.0mmol) and cyclopropylacetylene (IV-2) (250 μ L, 3.0mmol), the same procedure as I-1 was followed, and column chromatography was performed (eluent: petroleum ether: ethyl acetate 1: 2) to give 263mg of a white solid, melting point: 154 ℃ and 158 ℃ and the yield is 58.3 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.48(s,1H),8.93(s,1H),7.82(s,1H),7.24-7.08(m, 2H),6.78-6.69(m,1H),6.38(t,J＝5.7Hz,1H),4.52(t,J＝5.5Hz,2H),3.67(d,J＝5.7Hz,2H), 1.96-1.85(m,1H),0.88(d,J＝8.1Hz,2H),0.69(d,J＝4.6Hz,2H).13C NMR(75MHz,DMSO)δ 155.40,152.13,148.92,139.90,139.05,137.92,124.82,121.50,121.03,116.07,115.76,107.19, 106.90,47.51,44.06,7.58,6.50.
Example 3
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (1-hydroxyethyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-3)
THF (70mL) and 3- {4- [ (2-azidoethyl) amino ] -1,2, 5-oxadiazol-3-yl } -4- (3-bromo-4-fluorophenyl) -1,2, 4-oxadiazol-5 (4H) -one (II) (15g,36.5mmol) were charged to a 250mL reaction flask and dissolved with stirring. Controlling the temperature below 10 ℃, dropwise adding 2mol/L sodium hydroxide (66mL), heating to 25 ℃ after dropwise adding, keeping the temperature and reacting for about 3 hours, monitoring the complete reaction of the raw materials by TLC, evaporating the solvent under reduced pressure below 30 ℃, adding 20mL of water, extracting with ethyl acetate (75mL multiplied by 3) for three times, washing with water (50mL multiplied by 2) twice, washing with saturated saline (50mL), and evaporating under reduced pressure to obtain 14.07g of light brown oily substance (III).
Acetonitrile (100mL), water (20mL) and oil III (14.07g) prepared above were charged to a 250mL three-necked flask and dissolved with stirring. 3-butyn-2-ol (IV-3) (4mL, 50mmol) and cuprous bromide (0.53g,3.7mmol) were added and the reaction stirred for about 12 hours. After TLC monitoring of the completion of the reaction of the raw materials, the solvent was evaporated under reduced pressure below 40 ℃, ethyl acetate (75mL) and water (30mL) were added, filtration was carried out, standing and layering were carried out, the aqueous layer was extracted three times with ethyl acetate (50 mL. times.3), the organic layers were combined, washed twice with water (50 mL. times.2), washed with saturated saline (50mL), dried over anhydrous magnesium sulfate for 2 hours, filtration was carried out, the filtrate was evaporated under reduced pressure to dryness to obtain a light brown oily substance, and column chromatography was carried out (eluent: petroleum ether: ethyl acetate: 1: 2-1: 4) to obtain 9.30g of a white solid, melting point: 176 ℃ and 177 ℃, and the yield is 56.0 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):9.00(br,1H),7.95(s,1H),7.24-7.18(t,J＝8.7Hz, 1H),7.15-7.12(dd,J＝2.7,6.12Hz,1H)6.80-6.70(m,1H),6.44(t,J＝5.6Hz,1H),4.83(dd,J＝ 13.0,6.3Hz,1H),4.59(t,J＝6.0Hz,2H),3.71(d,J＝5.8Hz,2H),1.40(d,J＝6.5Hz,3H). HRMS(ESI):m/z[M+H]+Calcd for C15H17BrFN8O3:455.0586；Found:455.0576.
Example 4
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (p-tolyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-4)
Starting from III (0.39g,1.0mmol) and 4-methylphenylacetylene (IV-4) (250 μ L, 2.0mmol), separation by column chromatography (eluent: petroleum ether: ethyl acetate 1: 2) was carried out as I-1 to give 274mg of a white solid, melting point: 217 ℃ and 220 ℃ with a yield of 54.7 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.47(s,1H),8.94(s,1H),8.55(s,1H),7.74(d,J＝ 7.9Hz,2H),7.27(d,J＝7.5Hz,2H),7.22-7.09(m,2H),6.74-6.71(m,1H),6.47(t,J＝6.0Hz,1H), 4.66(t,J＝5.5Hz,2H),3.78(m,2H),2.34(s,3H).HRMS(ESI):m/z[M+H]+Calcd for C20H19BrFN8O2:501.0793；Found:501.0800.
Example 5
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (3-aminophenyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-5)
Column chromatography was performed using III (0.39g,1.0mmol) and 3-aminophenylacetylene (IV-5) (250 μ L, 2.2mmol) as starting materials in the same manner as I-1 (eluent: petroleum ether: ethyl acetate: 1: 2-1: 4) to give 300mg of a white solid, melting point: 202 ℃ and 206 ℃, and the yield is 59.8 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.47(s,1H),8.94(s,1H),8.44(s,1H),7.20-7.05 (m,4H),6.94(d,J＝7.6Hz,1H),6.75-6.70(m,1H),6.53(d,J＝6.9Hz,1H),6.45(t,J＝5.6Hz, 1H),5.21(s,2H),4.64(d,J＝5.5Hz,2H),3.77(d,J＝5.4Hz,2H).HRMS(ESI):m/z[M+H]+ Calcd for C19H18BrFN9O2:502.0745；Found:502.0760.
Example 6
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (4-methoxyphenyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-6)
Starting from III (0.39g,1.0mmol) and 4-methoxyphenylacetylene (IV-6) (250 μ L, 1.9mmol), separation is performed by column chromatography as in I-1 (eluent: petroleum ether: ethyl acetate 1: 2) to give 232mg of a white solid, melting point: 225 ℃ and 227 ℃ with a yield of 44.9 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.47(s,1H),8.92(s,1H),8.48(s,1H),7.77(d,J＝ 8.7Hz,2H),7.22-7.10(m,2H),7.03(d,J＝8.7Hz,2H),6.76-6.71(m,1H),6.46(t,J＝5.8Hz,1H), 4.65(t,J＝5.6Hz,2H),3.78(m,5H).HRMS(ESI):m/z[M+H]+Calcd for C20H19BrFN8O3: 517.0742；Found:517.0754.
Example 7
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (4-tert-butylphenyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-7)
Starting from III (0.39g,1.0mmol) and 4-tert-butylphenyl acetylene (IV-7) (250 μ L, 1.4mmol), separation is carried out by column chromatography using I-1 (eluent: petroleum ether: ethyl acetate 1: 2) to give 165mg of a white solid, melting point: 210 ℃ and 212 ℃, and the yield is 30.4 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.48(s,1H),8.92(s,1H),7.86(s,1H),7.78(d,J＝ 8.7Hz,2H),7.20(t,J＝8.8Hz,1H),7.15(t,J＝2.6Hz,6.0Hz,1H),7.04(d,J＝8.7Hz,1H), 6.83-6.70(m,1H),6.39(t,J＝5.9Hz,1H),4.55(t,J＝5.9Hz,2H),3.71(q,J＝5.9Hz,11.5Hz, 2H),1.27(s,9H).HRMS(ESI):m/z[M+H]+Calcd for C17H21BrFN8O2:467.0949；Found: 467.0954.
Example 8
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (2-hydroxyethyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-8)
Using III (0.39g,1.0mmol) and 3-butyn-1-ol (IV-8) (250 μ L, 3.3mmol) as starting materials, the same procedure as I-1 was followed, and column chromatography was performed (eluent: petroleum ether: ethyl acetate 1: 2-1: 4) to give 186mg of white solid, melting point: 175 ℃ and 177 ℃, and the yield is 40.9 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.48(s,1H),8,92(s,1H),7.88(s,1H),7.20(t,J＝ 8.8Hz,1H),7.15(dd,J＝2.6,6.0Hz,1H),6.77-6.73(m,1H),6.38(t,J＝5.7Hz,1H),4.74(t,J＝5.2Hz,1H),4.57(t,J＝5.8Hz,2H),3.70(q,J＝5.4Hz,11.2Hz,2H),3.62(q,J＝7.0Hz,12.4Hz, 2H),2.78(t,J＝6.9Hz,2H).HRMS(ESI):m/z[M+H]+Calcd for C15H16BrFN8O3:456.0580； Found:456.0575.
Example 9
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (2-hydroxypropyl-2-yl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-9)
Using III (0.39g,1.0mmol) and 2-methyl-3-butyn-2-ol (IV-9) (250 μ L, 2.6mmol) as starting materials, the same procedure as I-1 was followed, and column chromatography was performed (eluent: petroleum ether: ethyl acetate: 1: 2-1: 4) to give 172mg of a white solid, melting point: 182 ℃ and 183 ℃, and the yield is 36.7 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.50(s,1H),8.92(s,1H),7.90(s,1H),7.20(t,J＝ 8.8Hz,1H),7.15(dd,J＝2.6,6.0Hz,1H),6.78-6.74(m,1H),6.39(t,J＝5.8Hz,1H),5.13(s,1H), 4.58(t,J＝5.8Hz,2H),3.72(q,J＝5.9,11.6Hz,2H),1.46(s,6H).HRMS(ESI):m/z[M+H]+ Calcd for C16H18BrFN8O3:469.0745；Found:469.0745.
Example 10
Preparation of N- (3-bromo-4-fluorophenyl) -4- ((2- (4- ((2-ethylamino) methyl) -1H-1,2, 3-triazole-1-yl) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-formamidine (I-10)
Column chromatography was performed using III (0.39g,1.0mmol) and N, N-diethylpropargylamine (IV-10) (250 μ L, 2.2mmol) as starting materials in the same manner as in I-1 (eluent: petroleum ether: ethyl acetate: 1: 2-1: 4) to give 195mg of a white solid, melting point: 161 ℃ and 163 ℃ with a yield of 39.3 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.52(s,1H),8.87(s,1H),7.94(s,1H),7.19(t,J＝ 8.7Hz,1H),7.12(dd,J＝2.1,5.6Hz,1H),6.80-6.68(m,1H),6.30(t,J＝5.5Hz,1H),4.58(t,J＝ 5.4Hz,2H),3.71(q,J＝5.8,11.2Hz,2H),3.65(s,2H),2.39(q,J＝6.9,13.9Hz,4H),0.97(t,J＝6.9Hz,6H).
Example 11
Preparation of N- (3-bromo-4-fluorophenyl) -4- ((2- (4- (2- (dimethylamino) methyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-formamidine (I-11)
Using III (0.39g,1.0mmol) and N, N-dimethyl-3-butyn-1-amine (IV-11) (250 μ L, 2.2mmol) as starting materials, the same procedure as I-1 was followed, and column chromatography was performed (eluent: petroleum ether: ethyl acetate 1: 2-1: 4) to give 181mg of a white solid, melting point: 184 ℃ and 188 ℃, and the yield is 37.6 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.58(s,1H),8.85(s,1H),7.95(s,1H),7.22-7.07 (m,2H),6.73(dd,J＝7.9,3.8Hz,1H),6.29(t,J＝5.9Hz,1H),4.58(t,J＝5.6Hz,2H),3.69(d,J ＝5.6Hz,2H),3.46(s,2H),2.11(s,6H).
Example 12
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (2-hydroxypropyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-12)
Using III (0.39g,1.0mmol) and 4-pentyn-2-ol (IV-12) (250 μ L, 2.6mmol) as starting materials, the same procedure as I-1 was followed, and column chromatography was performed (eluent: petroleum ether: ethyl acetate 1: 2-1: 4) to give 205mg of white solid, melting point: 151 ℃ and 153 ℃ and the yield is 43.7 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.45(br,1H),8.88(s,1H),7.85(s,1H),7.20(t,J＝ 8.7Hz,1H),7.15(dd,J＝2.2,5.7Hz,1H),6.78-6.75(m,1H),6.36(t,J＝5.6Hz,1H),4.65(s,1H), 4.57(d,J＝5.6Hz,2H),3.87(q,J＝5.3Hz,11.5Hz,1H),3.71(q,J＝5.3Hz,11.0Hz,2H),2.69 (m,2H),1.06(d,J＝5.9Hz,3H).
Example 13
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (6-hydroxyhexyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-13)
Using III (0.39g,1.0mmol) and 5-hexyn-1-ol (IV-13) (250 μ L, 2.3mmol) as starting materials, the same procedure as I-1 was followed, and column chromatography was performed (eluent: petroleum ether: ethyl acetate 1: 2-1: 4) to give 190mg of white solid, melting point: 153 ℃ and 155 ℃, and the yield is 39.3 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.50(br,1H),8.91(s,1H),7.86(s,1H),7.20(t,J ＝8.9Hz,1H),714(dd,J＝2.6,5.9Hz,1H),6.78-6.73(m,1H),6.38(t,J＝5.8Hz,1H),4.55(t,J＝5.7Hz,2H),3.70(q,J＝5.6,11.3Hz,2H),3.44(t,J＝5.9Hz,4H),2.65(t,J＝7.6Hz,2H), 1.78-1.71(m,2H).
Example 14
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4-isobutyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-14)
Starting from III (0.39g,1.0mmol) and 3, 3-dimethyl-1-butyne (IV-14) (250 μ L, 2mmol), the same procedure as I-1 was followed, with column chromatography (eluent: petroleum ether: ethyl acetate 1: 2) to give 188mg of a white solid, melting point: 154 ℃ and 158 ℃ and the yield is 40.2 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.44(s,1H),8.88(s,1H),8.09(s,1H),7.16(dd,J ＝20.8,6.2Hz,2H),6.76(s,1H),6.36(s,1H),4.61(s,2H),4.44(s,2H),3.72(d,J＝4.5Hz,2H), 3.25(s,3H).
Example 15
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4-methoxymethyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-15)
Starting from III (0.39g,1.0mmol) and 3-methoxy-1-propyne (IV-15) (250 μ L, 3.0mmol), column chromatography was performed as in I-1 (eluent: petroleum ether: ethyl acetate 1: 2) to give 225mg of white solid, melting point: 159 ℃ and 161 ℃ with a yield of 49.5 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.44(s,1H),8.88(s,1H),8.09(s,1H),7.18(t,J＝ 8.6Hz,1H),7.14-712(m,1H),6.85-6.66(m,1H),6.36(s,1H),4.61(s,2H),4.44(s,2H),3.72(d,J ＝4.5Hz,2H),3.25(s,3H).
Example 16
Preparation of 1- (2- ((4- (N- (3-bromo-4-fluorophenyl) -N' -hydroxycarbamimidoyl) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-1,2, 3-triazole-4-carboxylate (I-16)
Column chromatography was performed using III (0.39g,1.0mmol) and methyl propiolate (IV-16) (250 μ L, 2.8mmol) as starting materials in the same manner as in I-1 (eluent: petroleum ether: ethyl acetate: 1: 2 to 1: 4) to obtain 155mg of a white solid with a yield of 33.0%.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.42(s,1H),8.89(s,1H),8.81(s,1H),7.30-7.03 (m,2H),6.74-6.70(m,1H),6.40(t,J＝5.1Hz,1H),4.70(s,2H),3.85(s,3H),3.78(s,2H).
Example 17
Preparation of N- (3-bromo-4-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-17)
THF (70mL) and 3- {4- [ (2-azidoethyl) amino ] -1,2, 5-oxadiazol-3-yl } -4- (3-bromo-4-fluorophenyl) -1,2, 4-oxadiazol-5 (4H) -one (15g,36.5mmol) were charged into a 250mL three-necked flask and dissolved with stirring. Sodium hydroxide (66mL) is added dropwise at an internal temperature of below 10 ℃, the temperature is raised to 25 ℃ after dropping, the reaction is kept for about 3 hours, TLC monitors that the raw materials are completely reacted, the solvent is evaporated at a temperature of below 30 ℃ under reduced pressure, 20mL of water is added, ethyl acetate (75mL × 3) is extracted for three times, water (50mL × 2) is washed twice, saturated saline (50mL) is washed, and the mixture is concentrated under reduced pressure to be dry to obtain 14.31g of light brown oily matter (III).
Acetonitrile (100mL), water (20mL) and oil III (14.31g) prepared above were charged to a 250mL three-necked flask and dissolved with stirring. 2- (prop-2-yn-1-yloxy) ethanol (IV-17) (4.9mL, 50mmol) and cuprous bromide (0.53g,3.7mmol) were added and the reaction stirred for about 16 hours. After TLC monitoring of the completion of the reaction of the raw materials, the solvent was evaporated under reduced pressure below 40 ℃, ethyl acetate (75mL) and water (30mL) were added, filtration was carried out, standing and layering were carried out, the aqueous layer was extracted three times with ethyl acetate (75 mL. times.3), the organic layers were combined, washed twice with water (50 mL. times.2), washed with saturated saline (50mL), dried over anhydrous magnesium sulfate for 2 hours, filtration was carried out, the filtrate was evaporated under reduced pressure to dryness to obtain a light brown oily substance, and column chromatography was carried out (eluent: petroleum ether: ethyl acetate: 1: 2-1: 4) to obtain 10.76g of a white solid, melting point: 125 ℃ and 126 ℃, and the yield is 60.8 percent.
1H NMR(300MHz,MeOD)δ(ppm):7.94(s,1H),7.08(m,2H),6.83(s,1H),4.65(d,J＝ 11.2Hz,4H),3.80(s,2H),3.66(s,2H),3.57(s,2H).HRMS(ESI):m/z[M+H]+Calcd for C16H19BrFN8O4:485.0695；Found:485.0692
Example 18
Preparation of N- (3-bromo-4-fluorophenyl) -4- ((2- (4-butyl-1H-1, 2, 3-triazol-1-yl) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-formamidine (I-18)
Starting from III (0.39g,1.0mmol) and 1-hexyne (IV-18) (250 μ L, 2.2mmol), separation is performed by column chromatography as in I-1 (eluent: petroleum ether: ethyl acetate 1: 2) to give 165mg of a white solid, melting point: 204 ℃ and 208 ℃, and the yield is 35.3 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):7.79(s,1H),7.30(t,J＝8.8Hz,1H),7.18(dd,J＝ 6.3,2.4Hz,1H),7.05(s,2H),6.94-6.84(m,2H),4.54(t,J＝5.6Hz,2H),3.68(q,J＝5.8,11.3Hz, 2H),2.53(d,J＝7.4Hz,2H),1.46(dt,J＝15.1,7.4Hz,2H),1.28–1.21(m,2H),0.83(t,J＝7.3 Hz,3H).
Example 19
Preparation of 4- ((2- (4- (aminomethyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -N- (3-bromo-4-fluorophenyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-formamidine (I-19)
Using III (0.39g,1.0mmol) and propargylamine (IV-19) (250 μ L, 3.6mmol) as starting materials, the same procedure as I-1 was followed, and column chromatography was performed (eluent: petroleum ether: ethyl acetate: 1: 2-1: 4) to give 185mg of white solid, melting point: 167 ℃ and 172 ℃, and the yield is 42.0 percent.
MS(ESI):m/z[M+H]+439.1，441.1。
Example 20
Preparation of 2- (1- (1- (2- ((4- (N- (3-bromo-4-fluorophenyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-1,2, 3-triazol-4-yl) ethoxy) acetamide (I-20)
(Z)-2-(1-(1-(2-((4-(N-(3-bromo-4-fluorophenyl)-N'-hydroxycarbamimidoyl)-1,2,5-oxadiazol-3-yl)a mino)ethyl)-1H-1,2,3-triazol-4-yl)ethoxy)acetamide
Using III (0.39g,1.0mmol) and 2- (but-3-yn-2-yloxy) acetamide (IV-20) (250 μ L, 2.0mmol) as starting materials, the same procedure as I-1 was followed, and column chromatography was performed (eluent: petroleum ether: ethyl acetate 1: 2-1: 4) to give 154 mg of a white solid, melting point: 164 ℃ and 168 ℃, and the yield is 30.0 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.50(s,1H),8.91(s,1H),8.15(s,1H),7.36(s,1H), 7.20(t,J＝8.8Hz,1H),7.15(q,J＝2.6,6.0Hz,1H),6.78-6.72(m,1H),6.40(t,J＝5.8Hz,1H), 4.69(q,J＝6.4,12.9Hz,1H),4.61(t,J＝5.6Hz,2H),3.78(d,J＝3.0Hz,2H),3.74(d,J＝5.7Hz, 2H),1.50(d,J＝6.5Hz,3H).
Example 21
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- ((2-hydroxyethoxy) ethyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-21)
Starting from III (0.39g,1.0mmol) and 2- (but-3-yn-2-yloxy) ethanol (IV-21) (250 μ L, 2.0mmol), column chromatography was performed as in I-1 (eluent: petroleum ether: ethyl acetate 1: 2-1: 4) to give 205mg of a white solid, melting point: 144 ℃ and 148 ℃ with the yield of 41.1 percent.
1H NMR(300MHz,MeOD)δ(ppm):8.15(s,1H),7.16(dd,J＝2.6,6.0Hz,1H),7.08(t,J＝ 8.6Hz,1H),6.87-6.82(m,1H),4.75-4.69(m,3H),4.19-4.12(m,2H),3.84(t,J＝5.6Hz,2H), 3.67-3.52(m,2H),1.53(d,J＝6.6Hz,3H).
Example 22
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (2- (2-hydroxyethoxy) propyl-2-yl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-22)
Using III (0.39g,1.0mmol) and 2- ((2-methylbut-3-yn-2-yl) oxy) ethanol (IV-22) (250 μ L, 2.0mmol) as starting materials, the same procedure as I-1 was followed, and column chromatography was performed (eluent: petroleum ether: ethyl acetate ═ 1: 2 to 1: 4) to give 225mg of a white solid, melting point: 143 ℃ and 145 ℃ in a yield of 43.8 percent.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.48(s,1H),8.92(s,1H),8.08(s,1H),7.21(m, 2H),6.80(s,1H),6.41(s,1H),4.63(s,2H),4.52(s,1H),3.77(s,2H),3.42(s,2H),3.21(s,2H), 1.53(s,6H).
Example 23
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (1-hydroxycyclohexyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-23)
Column chromatography was performed using III (0.39g,1.0mmol) and 1-ethynylcyclohexyl-1-ol (IV-23) (248mg, 2.0mmol) as starting materials in the same manner as I-1 (eluent: petroleum ether: ethyl acetate: 1: 2-1: 4) to give 310mg of a white solid in 60.9% yield.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.48(s,1H),8.92(s,1H),7.90(s,1H),7.24-7.09(m, 2H),6.74(d,J＝9.1Hz,1H),6.38(t,J＝5.5Hz,1H),4.87(s,1H),4.57(t,J＝5.5Hz,2H),3.71(d, J＝5.4Hz,2H),1.86(t,J＝10.9Hz,2H),1.56(dd,J＝70.7,16.7Hz,8H).13C NMR(75MHz, DMSO)δ155.59,152.11,139.82,139.11,137.94,124.81,121.70,116.09,115.77,107.16,106.97, 67.95,47.63,44.10,37.74,25.20,21.63.
Example 24
Preparation of N- (3-bromo-4-fluorophenyl) -4- ((2- (4- (bromomethyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -N' -hydroxy-1, 2, 5-oxadiazole-3-formamidine (I-24)
I-15(0.455g and 1.0mmol) is dissolved in 5ml of dichloromethane, the mixture is cooled to-80 ℃, boron tribromide (195 mu L and 2.0mmol) is dripped, the mixture is dripped to-10 ℃ for reaction for 1 hour, the mixture is further heated to room temperature for reaction for half an hour, ice water destroys the boron tribromide, an organic phase is washed by water and then dichloromethane is removed by evaporation to obtain a crude product, and the crude product is separated by column chromatography (an eluent: petroleum ether: ethyl acetate: 2: 1-1: 2) to obtain 210mg of white solid with the yield of 41.7 percent.
MS(ESI):m/z[M+Na]+525.0,527.0,529.0。
Example 25
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (1-hydroxypropyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-25)
Column chromatography was performed using III (0.39g,1.0mmol) and 1-pentyn-3-ol (IV-25) (250 μ L, 2.7mmol) as starting materials in the same manner as I-1 (eluent: petroleum ether: ethyl acetate: 1: 2-1: 4) to give 150mg of a white solid in 32.0% yield.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.48(s,1H),8.92(s,1H),7.91(d,J＝11.7Hz,1H), 7.24-7.09(m,2H),6.80–6.68(m,1H),6.37(t,J＝5.6Hz,1H),5.23(s,1H),4.59(s,3H),3.71(d, J＝5.5Hz,2H),1.71(ddd,J＝20.5,13.5,6.7Hz,2H),0.84(t,J＝7.3Hz,3H).13C NMR(75MHz, DMSO)δ155.44,152.12,144.03,139.85,139.10,137.93,124.82,121.99,121.52,116.08,115.77, 107.18,106.89,66.87,47.61,44.11,30.13,9.79.
Example 26
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (3-hydroxypropyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-26)
Column chromatography was performed using III (0.39g,1.0mmol) and 4-pentyn-1-ol (IV-26) (250 μ L, 2.7mmol) as starting materials in the same manner as I-1 (eluent: petroleum ether: ethyl acetate: 1: 2-1: 4) to give 175mg of a white solid in 37.3% yield.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.48(s,1H),8.92(s,1H),7.84(s,1H),7.23-7.09(m, 2H),6.81-6.69(m,1H),6.38(t,J＝5.8Hz,1H),4.54(dd,J＝10.6,5.1Hz,3H),3.69(d,J＝5.5Hz, 2H),3.43(d,J＝5.2Hz,2H),2.64(t,J＝7.6Hz,2H),1.78–1.67(m,2H).13C NMR(75MHz, DMSO)δ155.41,152.01,146.76,139.89,139.06,137.92,124.81,122.10,121.51,116.08,115.78, 107.19,106.90,59.99,47.50,44.10,32.23,21.63.
Example 27
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (2-hydroxybutyl-2-yl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-27)
Column chromatography was performed using III (0.39g,1.0mmol) and 3-methyl-1-pentyn-3-ol (IV-27) (250 μ L, 2.2mmol) as starting materials as in I-1 (eluent: petroleum ether: ethyl acetate: 1: 2-1: 4) to give 180mg of a white solid in 37.3% yield.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.51(s,1H),8.95(s,1H),7.89(s,1H),7.28-7.12(m, 2H),6.81-6.71(m,1H),6.41(t,J＝5.6Hz,1H),4.97(s,1H),4.59(d,J＝5.6Hz,2H),3.74(d,J＝ 5.7Hz,2H),1.75(q,J＝6.9Hz,2H),1.44(s,3H),0.74(t,J＝7.3Hz,3H).13C NMR(75MHz, DMSO)δ155.92,155.16,152.59,140.29,139.59,138.42,125.28,122.05,116.57,116.26,107.65, 70.23,48.12,44.58,35.90,28.67,8.74.
Example 28
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (2-hydroxy-4-methylpentyl-2-yl) -1H-1,2, 3-triazole-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-28)
Using III (0.39g,1.0mmol) and 3, 5-dimethyl-1-hexyn-3-ol (IV-28) (250 μ L, 1.7mmol) as starting materials, the same procedure was followed as in I-1, and column chromatography was performed (eluent: petroleum ether: ethyl acetate 1: 2-1: 4) to give 180mg of a white solid in 35.2% yield.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.49(s,1H),8.93(s,1H),7.86(s,1H),7.26-7.10(m, 2H),6.82-6.69(m,1H),6.37(s,1H),4.93(s,1H),4.59(s,2H),3.72(d,J＝5.0Hz,2H),1.67(dd,J ＝13.4,6.8Hz,2H),1.61-1.52(m,1H),1.44(s,3H),0.80(d,J＝6.2Hz,3H),0.69(d,J＝6.2Hz, 3H).13C NMR(75MHz,DMSO-d6)δ(ppm):155.42,152.10,139.78,139.11,137.91,124.78, 121.49,121.35,116.08,115.77,114.50,107.16,106.87,70.01,51.36,47.60,44.11,29.66,24.39, 24.19,23.75.
Example 29
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (2-aminopropyl-2-yl) -1H-1,2, 3-triazole-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-29)
Column chromatography was performed using III (0.39g,1.0mmol) and 2-methyl-3-butyn-2-amine (IV-29) (250 μ L, 2.4mmol) as starting materials in the same manner as in I-1 (eluent: petroleum ether: ethyl acetate: 1: 2 to 1: 4) to give 305mg of a white solid with a yield of 65.2%.
1H NMR(300MHz,DMSO-d6)δ(ppm):8.85(s,1H),8.01(s,1H),7.24-7.06(m,2H),6.76(d, J＝8.5Hz,1H),6.16(t,J＝5.5Hz,1H),4.59(s,2H),3.67(d,J＝5.3Hz,2H),1.43(s,6H).
Example 30
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (3-hydroxyphenyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine (I-30)
Column chromatography was performed using III (0.39g,1.0mmol) and 3-hydroxyphenylacetylene (IV-30) (232mg, 2.0mmol) as starting materials in the same manner as in I-1 (eluent: petroleum ether: ethyl acetate: 1-1: 4) to give 325mg of a white solid with a yield of 64.6%.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.45(s,1H),9.56(s,1H),8.92(s,1H),8.53(s,1H), 7.29-7.11(m,5H),6.73(s,2H),6.44(d,J＝5.9Hz,1H),4.65(s,2H),3.77(d,J＝5.5Hz,2H).13C NMR(75MHz,DMSO-d6)δ(ppm):157.71,155.45,152.16,146.36,139.92,139.03,137.91, 131.93,129.92,124.82,121.67,121.50,116.06,115.76,114.82,111.80,107.20,106.91,47.78, 44.04.
Example 31
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- (carbamoyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-carboxamidine (I-31)
Column chromatography was performed using III (0.39g,1.0mmol) and propiolamide (IV-31) (138mg, 2.0mmol) as starting materials as in I-1 (eluent: petroleum ether: ethyl acetate: 1 to 1: 2) to give 160mg of a white solid with a yield of 35.2%.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.45(s,1H),8.92(s,1H),8.55(s,1H),7.87(s,1H), 7.50(s,1H),7.20(t,J＝8.7Hz,1H),7.13(d,J＝5.9Hz,1H),6.74–6.66(m,1H),6.42(t,J＝5.7 Hz,1H),4.67(t,J＝5.1Hz,2H),3.75(dd,J＝10.8,5.7Hz,2H).13C NMR(75MHz,DMSO-d6)δ (ppm):161.55,155.43,152.17,142.85,139.88,138.99,137.89,126.87,124.83,121.50,115.83, 107.22,47.99,43.98.
Example 32
Preparation of N- (3-bromo-4-fluorophenyl) -N' -hydroxy-4- ((2- (4- ((2-hydroxyethoxy) methyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazole-3-formamidine hydrochloride (I-17A)
I-17(4.84g,10.0mmol) was added to 20ml of acetone and dissolved with stirring. A saturated solution of ethyl acetate in hydrogen chloride was added dropwise to a pH of 1-2 in an ice-water bath to precipitate a large amount of solid, which was washed with acetone to give 5.05g of a white solid with a yield of 97.1%.
1H NMR(300MHz,DMSO-d6)δ(ppm):11.48(s,1H),8.91(s,1H),8.11(s,1H),7.24-7.09(m, 2H),6.75(s,1H),6.39(s,1H),5.10(s,2H),4.61(t,J＝5.3Hz,2H),4.52(s,2H),3.71(d,J＝4.4 Hz,2H),3.48(dd,J＝9.6,3.9Hz,4H).
Example 33
Preparation of N- (3-bromo-4-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-17)
4- (3-bromo-4-fluorophenyl) -3- (4- ((2- (4- ((2-hydroxyethoxy) methyl) -1H-1,2, 3-triazol-1-yl) ethyl) amino) -1,2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazol-5 (4H) -one (preparation of V-17)
Acetonitrile (12mL), water (3mL) and 3- {4- [ (2-azidoethyl) amino ] -1,2, 5-oxadiazol-3-yl } -4- (3-bromo-4-fluorophenyl) -1,2, 4-oxadiazol-5 (4H) -one (II) (1.3g,3.2mmol) were charged into a 50mL three-necked flask, dissolved with stirring, 2- (prop-2-yn-1-yloxy) ethanol (IV-17) (750. mu.L, 6.0mmol) and cuprous bromide (45mg,0.31mmol) were added, the reaction was stirred for about 12 hours until TLC monitored that the starting material had reacted completely, the solvent was evaporated under reduced pressure at 40 ℃ below, ethyl acetate (15mL) and water (5mL) were added, filtration was carried out, the aqueous phase was extracted three times with ethyl acetate (15 mL. times.3), the combined organic phases were washed twice with water (15mL × 2), washed with saturated brine (15mL), dried over anhydrous magnesium sulfate, filtered, the filtrate was evaporated to dryness under reduced pressure to give a tan solid, which was separated by column chromatography (eluent: petroleum ether: ethyl acetate: 3: 1) to give 915mg of a white solid (V-17) in 56.6% yield.
1H NMR(300MHz,DMSO-d6)δ(ppm):8.09(s,2H),7.71-7.57(m,2H),6.73(s,1H), 4.62-4.52(m,5H),3.76(s,2H),3.48(d,J＝7.9Hz,4H).
Preparation of N- (3-bromo-4-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-17)
Adding THF (6mL) and V-17(915mg, 1.79mmol) prepared in the previous step into a 50mL three-necked flask, stirring for dissolving, dropwise adding 2mol/L sodium hydroxide (3mL) at the temperature of below 10 ℃, keeping the temperature to 25 ℃ for reaction for about 2 hours after dropping, monitoring the reaction completion of raw materials by TLC, evaporating the solvent at the temperature of below 30 ℃ under reduced pressure, adding 6mL of water, extracting with ethyl acetate (15mL × 3) for three times, combining organic layers, washing with water (15mL × 2) twice, washing with saturated saline (15mL), concentrating under reduced pressure to dryness, and performing column chromatography on residues (eluent: petroleum ether: ethyl acetate ═ 1: 2-1: 4) to obtain 765mg of white solid with the yield of 88.1% melting point: 125 ℃ and 126 ℃, and the total yield of the two steps is 49.9 percent.

Claims (7)

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0003387475120000011
wherein R is1Is cyclopropyl, -COOCH3、-CONH2、-CH2N(CH2CH3)2、
Figure FDA0003387475120000012
Wherein m is 0-1;
X＝CH2or O;
R2is H, CH3OH or NH2；
R3Is H or CH3；
R4Is H, CH3Or CH2CH2OH。
2. A process for preparing a compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising:
Figure FDA0003387475120000013
wherein R is1Is as defined in claim 1.
3. A process for preparing a compound of claim 1, or a pharmaceutically acceptable salt thereof, comprising:
Figure FDA0003387475120000014
wherein R is1Is as defined in claim 1.
4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is an acid addition salt of the compound of general formula (I) according to claim 1 with: 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.
5. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
6. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for an IDO inhibitor.
7. The use according to claim 6, wherein the IDO inhibitor is used for the treatment or prevention of a tumor.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106866648A (en) * 2017-01-03 2017-06-20 中国药科大学 Phthalimide class indoleamine 2, the inhibitor of 3 dioxygenase 1 and application thereof
WO2017106062A1 (en) * 2015-12-15 2017-06-22 Merck Sharp & Dohme Corp. Novel compounds as indoleamine 2,3-dioxygenase inhibitors
CN106883224A (en) * 2017-01-03 2017-06-23 中国药科大学 Nitrogen-containing benzoheterocycle class indoleamine 2, the inhibitor of 3 dioxygenase 1 and application thereof
CN107304191A (en) * 2016-04-20 2017-10-31 上海翰森生物医药科技有限公司 Indoleamine 2,3 dioxygenase inhibitors and preparation method and application

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL2559690T3 (en) * 2005-05-10 2016-09-30 Modulators of indoleamine 2,3-dioxygenase and methods of using the same
CN106967004B (en) * 2017-03-29 2019-09-17 中国药科大学 IDO1 and IDO2 double inhibitor, its preparation method and its medical usage containing urea groups

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017106062A1 (en) * 2015-12-15 2017-06-22 Merck Sharp & Dohme Corp. Novel compounds as indoleamine 2,3-dioxygenase inhibitors
CN107304191A (en) * 2016-04-20 2017-10-31 上海翰森生物医药科技有限公司 Indoleamine 2,3 dioxygenase inhibitors and preparation method and application
CN106866648A (en) * 2017-01-03 2017-06-20 中国药科大学 Phthalimide class indoleamine 2, the inhibitor of 3 dioxygenase 1 and application thereof
CN106883224A (en) * 2017-01-03 2017-06-23 中国药科大学 Nitrogen-containing benzoheterocycle class indoleamine 2, the inhibitor of 3 dioxygenase 1 and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"吲哚胺 2，3-双加氧酶 1(IDO1) 抑制剂的研究进展";鲁凯强等;《广州化工》;20170731;第45卷(第14期);第15-16页 *

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