CN114539237B - IDO inhibitor, preparation method, pharmaceutical composition and application - Google Patents
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Abstract
The invention discloses an IDO inhibitor, a preparation method, a pharmaceutical composition and application. The structure of the inhibitor is shown as a formula (I), and the inhibitor comprises an isomer, pharmaceutically acceptable salt or a mixture thereof. The IDO inhibitor and the pharmaceutical composition thereof have high-efficiency inhibition effect on IDO, and can be used as a medicament for treating inflammatory diseases such as rheumatoid arthritis and the like; the prepared medicine can exert medicine effect at molecular level and animal level, the anti-inflammatory activity is superior to that of naproxen, and the synthetic method of the compound is simple and convenient and easy to operate.
Description
Technical Field
The invention relates to an IDO inhibitor, a preparation method, a pharmaceutical composition and application thereof, in particular to an IDO inhibitor which can be prepared into medicines for treating inflammatory diseases such as rheumatoid arthritis and the like, a preparation method, a pharmaceutical composition and application thereof.
Background
Rheumatoid arthritis (Rheumatoid Arthritis, RA) is a chronic, inflammatory synovitis-based autoimmune disease, which clinically manifests itself mainly as nonspecific inflammation of the peripheral joints, with progressive destruction of the diseased joint and its surrounding tissues, with recurrent attacks of synovitis over time, causing destruction of intra-articular bone and cartilage, which in turn leads to joint dysfunction, even loss of function. And has a rising trend with increased aging, with the prevalence of the elderly population (age > 65 years) being highest and female being higher than male. A substantial proportion of RA patients see bone destruction, with almost no effort for severely joint destroyed patients.
Currently, the main drugs for treating RA include nonsteroidal anti-inflammatory drugs, glucocorticoids, immunosuppressants, biological agents, small molecule targeting drugs and the like, which effectively improve the disease condition of patients, but have respective limitations. Therefore, there is a great interest in finding new therapeutic approaches, in particular drugs acting on new targets.
Indoleamine 2,3-dioxygenase (IDO) is a key rate-limiting enzyme that mediates the Trp-Kyn pathway, and there are three subtypes, i.e., indoleamine 2,3-dioxygenase 1 (IDO 1), indoleamine 2,3-dioxygenase 2 (indoramine 2,3-dioxygenase 2, IDO 2), and Tryptophan 2,3-dioxygenase (trptophan 2,3-dioxygenase, TDO). In recent years, the effect of IDO2 on the aspects related to tumor and organism autoimmunity is gradually revealed, and researches show that IDO2 can directly act on B cells or mediate the pathological mechanism of autoimmune arthritis through the interaction between B-T cells, so that IDO2 becomes a potential target for treating RA, and no drug aiming at the IDO2 target is successfully marketed at present.
Disclosure of Invention
The invention aims to: aiming at the defects of weak inhibitory activity, low selectivity and the like of the existing compound on IDO2, the invention aims to provide an IDO inhibitor with excellent anti-inflammatory activity, a preparation method, a pharmaceutical composition and application.
The technical scheme is as follows: as a first aspect to which the present invention relates, the IDO inhibitors of the present invention have the structure of formula (I), comprising an isomer, a pharmaceutically acceptable salt thereof, or a mixture thereof:
wherein:
m is selected from 1,2 or 3; n is selected from 0, 1,2,3 or 4; x is selected from O or NH;
R 1 selected from five-membered or six-membered aromatic heterocyclic groups;
R 2 selected from H, F, cl, br, I, CF 3 、CHF 2 、CN、OCH 3 OH or CH 3 ，R 2 Is mono-substituted or poly-substituted.
Preferably, in the above structure:
m is selected from 1; n is selected from 1 or 2; x is selected from NH.
Preferably, in the above structure:
R 1 selected from:
wherein R is 3 Selected from H, F, cl, br, I, CF 3 、CHF 2 、CN、OCH 3 OH or CH 3 ，R 3 Is mono-substituted or poly-substituted; y is selected from NH or O.
Preferably, in the above structure:
R 2 selected from H, F, cl, br, CF 3 Or CN, R 2 Is monosubstituted or disubstituted.
Further preferably, in the above structure:
R 1 selected from:
wherein R is 3 Selected from H, F, cl, br, CF 3 CN or OCH 3 ，R 3 Is monosubstituted or disubstituted.
More specifically, the IDO inhibitor is selected from any of the following compounds:
as a second aspect of the present invention, the above IDO inhibitor is prepared by:
the compound (II) and the compound (III) are subjected to substitution, cyclization, oxidation, reduction-coupling, azide, ring opening and cyclization reaction to obtain a compound (I);
wherein R is 1 、R 2 The definition of m, n and X is as described above.
Specifically, the compound II is reacted with substituted benzylamine III to prepare a compound IV, wherein the base is selected from triethylamine, pyridine, N-Diisopropylethylamine (DIPEA), 4-Dimethylaminopyridine (DMAP), potassium carbonate, sodium carbonate, cesium carbonate or sodium acetate, preferably sodium carbonate; the solvent is selected from methanol, ethanol, tetrahydrofuran or a mixed solvent of the solvent and water, preferably a mixed solvent of ethanol and water.
The compound V is prepared by reacting the compound IV with N, N' -Carbonyldiimidazole (CDI), wherein the solvent is selected from dichloromethane, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide or a mixed solvent of any two, and preferably ethyl acetate.
From compound V and hydrogen peroxide (H) 2 O 2 ) The reaction produces compound VI using an acid selected from hydrochloric acid, acetic acid or trifluoroacetic acid, preferably trifluoroacetic acid.
Preparing a compound VIII by reacting a compound VI with a compound VII, wherein the base is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably sodium hydroxide; the solvent is selected from dichloromethane, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide or mixed solvent of the above solvents and water, preferably mixed solvent of tetrahydrofuran and water.
Preparing compound IX from compound VIII using an azide reagent selected from sodium azide and azido trimethylsilane, preferably sodium azide; the solvent is selected from tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide or a mixed solvent composed of any two, preferably N, N-dimethylformamide.
Preparing a compound X from the compound IX by hydrolysis, wherein the base is selected from lithium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate, preferably sodium hydroxide; the solvent is selected from methanol, tetrahydrofuran, 1, 4-dioxane, acetonitrile or N, N-dimethylformamide and water, preferably methanol and water or tetrahydrofuran and water.
Preparing a compound I by reacting the compound X with a corresponding alkyne compound XI, wherein the catalyst is selected from copper sulfate/sodium ascorbate, copper chloride, copper bromide, cuprous chloride, cuprous bromide, cuprous iodide or copper powder, and preferably copper sulfate/sodium ascorbate; the inert gas used is selected from nitrogen or argon; the solvent is selected from tetrahydrofuran, 1, 4-dioxane, acetonitrile, ethanol, methanol, ethylene glycol dimethyl ether, dichloromethane, N-dimethylformamide, N-dimethylacetamide or a mixed solvent of the solvent and water, preferably a mixed solvent of tetrahydrofuran and water.
And (3) salifying the corresponding acid with the compound (I) prepared by the method to obtain the pharmaceutically acceptable salt of the IDO inhibitor.
As a third aspect to which the present invention relates, the pharmaceutical composition of the present invention comprises the IDO inhibitor described above and a pharmaceutically acceptable carrier.
The IDO inhibitor can be added with pharmaceutically acceptable carriers to prepare common medicinal preparations such as tablets, capsules, syrup, suspending agents or injection, and the preparations can be added with common medicinal auxiliary materials such as perfume, sweetener, liquid/solid filler, diluent and the like.
As a fourth aspect of the present invention, the IDO inhibitor and the pharmaceutical composition thereof are useful as IDO inhibitor drugs for the treatment of inflammatory diseases such as rheumatoid arthritis.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
(1) The IDO inhibitor and the pharmaceutical composition thereof can effectively inhibit IDO2 at nanomolar concentration level, and the inhibition rate is more than 40% optimally;
(2) The IDO inhibitor and the pharmaceutical composition thereof have wide application and can be used as a medicament for treating inflammatory diseases such as rheumatoid arthritis and the like; the medicine can exert medicine effect at molecular level and animal level, and under the same administration dosage, the anti-inflammatory activity is obviously better than that of naproxen;
(3) The preparation method of the compound is simple and convenient and is easy to operate.
Drawings
FIG. 1 is a graph showing the results of compound I-1 on carrageenan-induced swelling of the mouse feet;
FIG. 2 shows the carrageenan-induced inhibition effect of compound I-1 on foot swelling in mice.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
Example 1: synthesis of (Z) -N- ((1- (2- ((4- (N- (3-bromobenzyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) pyridine carboxamide (I-1)
Synthesis of (Z) -4-amino-N- (3-bromobenzyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (IV-1)
Raw material (Z) -4-amino-N' -hydroxy-1, 2, 5-oxadiazole-3-carboimidoyl chloride (II-1, 21.0g,129.7 mmol), 3-bromobenzylamine (III-1, 20.0g,108.1 mmol) and 95% ethanol (500 mL) were sequentially added to a 2L three-necked flask and stirred, and 200mLN was added to the reaction solutiona 2 CO 3 The solution (17.2 g,162.0 mmol) was heated to 60 ℃ and stirred for 5 hours, monitored by TLC (petroleum ether: ethyl acetate=5:1) and reacted completely; transferring the reaction solution into a 2L eggplant type bottle, evaporating ethanol under reduced pressure, adding 500mL of water, stirring at 25 ℃ for 1 hour, carrying out suction filtration, washing a filter cake with water (100X 3 mL), and drying at 45 ℃; the crude product obtained is refined by ethyl acetate/n-hexane (V: V=1:5), suction filtered and dried at 45℃to obtain 25.7g of pale yellow solid IV-1, yield 76.6%, m.p.100.0-102.0 ℃. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):10.86(s,1H),7.43–7.38(m,1H),7.40–7.36(m,1H),7.24(t,J＝7.6Hz,1H),7.22–7.17(m,1H),7.03(t,J＝7.2Hz,1H),6.28(s,2H),4.61(d,J＝7.2Hz,2H).
Synthesis of 3- (4-amino-1, 2, 5-oxadiazol-3-yl) -4- (3-bromobenzyl) -1,2, 4-oxadiazol-5 (4H) -one (V-1)
In a 1L three-necked flask, compound IV-1 (25.5 g,81.7 mmol) and ethyl acetate (300 mL) were added, CDI (20.0 g,122.5 mmol) was added under stirring, and after completion of the reaction at 50℃under stirring, the reaction was carried out for 6 hours, after TLC monitoring (Petroleum ether: ethyl acetate=5:1), water (300 mL) was added to wash, and the organic phase was washed with 2mol/L aqueous hydrochloric acid (100 mL. Times.2) and saturated sodium chloride solution (300 mL. Times.2) in this order, and dried over anhydrous sodium sulfate; suction filtration, decompression evaporation of the filtrate to remove the solvent, and recrystallization of the crude product with methanol gave 22.4g of off-white solid V-1 in a yield of 81.1%, m.p.152.0-154.0deg.C. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):7.66–7.61(m,1H,-ArH),7.55(dt,J＝7.2,1.9Hz,1H),7.43–7.32(m,2H),6.65(s,2H),5.13(s,2H).
Synthesis of 4- (3-bromobenzyl) -3- (4-nitro-1, 2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazol-5 (4H) -one (VI-1)
Into a 2L three-necked flask, compound V-1 (22.5 g,66.5 mmol) and trifluoroacetic acid (300 mL) were successively added, followed by stirring, cooling the reaction solution to 0℃and slowly dropwise adding 30% H 2 O 2 After the reaction was substantially completed by TLC monitoring (petroleum ether: ethyl acetate=10:1), the reaction was cooled to 0℃and quenched by slowly dropping 500mL of sodium sulfite solution (126.0 g,1.0 mol) and the internal temperature was maintained at not more than 5 ℃. Ethyl acetate (500 mL) was added to the reaction mixture to extract,the organic phase is washed with water (300 ml×3), dried over anhydrous sodium sulfate, suction filtered, the filtrate is distilled under reduced pressure to remove the solvent, and the crude product is purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate=25:1-5:1) to give 11.1g of yellow solid VI-1, yield 45.5%, m.p.99.0-100.0 ℃. 1 H-NMR(300MHz,CDCl 3 ),δ(ppm):7.52(dt,J＝7.5,1.8Hz,1H),7.46–7.41(m,1H),7.34–7.19(m,2H),5.08(s,2H).
Synthesis of 4- (3-bromobenzyl) -3- (4- ((2-bromoethyl) amino) -1,2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazol-5 (4H) -one (VIII-1)
To a 250mL three-necked flask, compound VI-1 (11.1 g,30.1 mmol) and THF (100 mL) were added, stirred and dissolved, cooled to 0-5 ℃, and then bromoethylamine hydrogen bromide salt (VII-1, 12.3g,60.2 mmol) was slowly added, and then 2mol/L sodium hydroxide solution (45 mL,90.0 mmol) was slowly added dropwise, and the reaction was maintained at 0-5℃for 1.5 hours, after TLC monitoring (petroleum ether: ethyl acetate=10:1) was essentially complete, the reaction solution was transferred to a 500mL eggplant-type flask, the solvent was distilled off under reduced pressure, ethyl acetate (120 mL) was added and extracted with water (120 mL), and the organic phase was washed with saturated sodium chloride solution (100 mL. Times.2) and dried over anhydrous sodium sulfate; suction filtration, reduced pressure evaporation of the filtrate, solvent removal, purification of the crude product by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=50:1-15:1) gave 7.4g of yellow oil VIII-1, yield 54.9%. 1 H-NMR(300MHz,CDCl 3 ),δ(ppm):7.64(t,J＝1.9Hz,1H),7.52–7.49(m,1H),7.45–7.41(m,1H),7.32–7.26(m,1H),5.80(t,J＝6.0Hz,1H),5.27(s,2H),3.86(q,J＝6.0Hz,2H),3.66(t,J＝6.0Hz,2H).
Synthesis of 3- (4- ((2-azidoethyl) amino) -1,2, 5-oxadiazol-3-yl) -4- (3-bromobenzyl) -1,2, 4-oxadiazol-5 (4H) -one (IX-1)
To a 250mL three-necked flask, compound VIII-1 (7.4 g,16.63 mmol) and DMF (50 mL) were added, stirred and dissolved, cooled to 0-5 ℃, sodium azide (1.3 g,20.0 mmol) was slowly added, after the addition was completed, the reaction was completed at 50℃for 4 hours, after TLC monitoring (Petroleum ether: ethyl acetate=10:1) was completed, cooled to 0-5℃water (60 mL) was slowly added dropwise, solid was separated out, suction filtration was performed, the filter cake was washed with water (15 mL. Times.3), the filtrate was treated with sodium hypochlorite solution, and dried at 40℃to obtain 5.5g of pale yellow solid IX-1, yield 81.1%, m.p.80.0-81.0℃。 1 H-NMR(300MHz,CDCl 3 ),δ(ppm):7.63–7.58(m,1H),7.50–7.46(m,1H),7.42–7.38(m,1H),7.24(t,J＝7.9Hz,1H),5.64(t,J＝6.4Hz,1H),5.24(s,2H),3.68–3.60(m,4H).
Synthesis of (Z) -4- ((2-azidoethyl) amino) -N- (3-bromobenzyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (X-1)
To a 100mL three-necked flask, compound IX-1 (5.50 g,13.5 mmol) and THF (40 mL) were added, and the mixture was stirred and dissolved and cooled to 0 to 5℃and then 2mol/L sodium hydroxide solution (20 mL,40.0 mmol) was slowly added dropwise thereto, and after completion of the dropwise reaction, the mixture was stirred at 50℃for 4 hours, and after completion of the reaction, TLC monitoring (Petroleum ether: ethyl acetate=5:1) was conducted, the reaction solution was transferred to a 250mL eggplant-type flask, the solvent was distilled off under reduced pressure, and the residue was added with water (50 mL), extracted with methylene chloride (40 mL. Times.3), and the organic layers were combined, washed with saturated sodium chloride solution (50 mL. Times.2), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to give 4.40g of yellow oily substance X-1 in 85.7% yield. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):10.94(s,1H),7.44(t,J＝1.7Hz,1H),7.41(m,1H),7.27(t,J＝7.6Hz,1H),7.23–7.18(m,1H),7.14(t,J＝7.2Hz,1H),6.47(t,J＝5.9Hz,1H),4.63(d,J＝7.2Hz,2H,3.55(q,J＝5.8Hz,2H),3.43(t,J＝5.8Hz,2H).
Synthesis of (Z) -N- ((1- (2- ((4- (N- (3-bromobenzyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) pyridine carboxamide (I-1)
To a 100mL three-necked flask, compound X-1 (2.20 g,5.77 mmol), N- (propyl-2-yn-1-yl) -pyridine carboxamide (XI-1, 1.10g,6.92 mmol) and acetonitrile (24 mL) were sequentially added, stirred and dissolved, 6mL of an aqueous solution of copper sulfate (183mg, 1.15 mmol)/sodium ascorbate (445 mg,2.30 mmol) prepared at present was added dropwise to the reaction solution, the reaction was evacuated under nitrogen protection, stirred at 25℃for 8 hours, TLC was monitored (dichloromethane: methanol=25:1) and the reaction solution was transferred to a 50mL eggplant type flask, the solvent was distilled off under reduced pressure, and the crude product obtained was purified by flash silica gel column chromatography (eluent: dichloromethane: methanol=1:0 to 50:1) and purified by N-hexane/ethyl acetate (V: V=1:1), and dried at 40℃to obtain 1.55g of white solid I-1, yield 49.7%, m.p.127.0 to 128.0 ℃. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):10.86(s,1H),9.27(t,J＝6.0Hz,1H),8.67(d,J＝4.7Hz,1H),8.10–7.97(m,3H),7.65–7.61(m,1H),7.43–7.39(m,2H),7.27(t,J＝7.6Hz,1H),7.19(d,J＝7.7Hz,1H),7.11(t,J＝7.2Hz,1H),6.44(t,J＝5.9Hz,1H),4.59–4.52(m,6H),3.67(q,J＝6.1Hz,2H).
Example 2: synthesis of (Z) -N- ((1- (2- ((4- (N- (3-bromobenzyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) -1H-pyrrole-2-carboxamide (I-2)
Using compound X-1 (0.10 g,0.26 mmol), N- (propyl-2-yn-1-yl) -1H-pyrrole-2-carboxamide (XI-2, 45mg,0.31 mmol) and copper sulfate (8 mg,0.05 mmol)/sodium ascorbate (20 mg,0.10 mmol) as starting materials, the same procedure as for I-1 gave 60mg of white solid I-2 in 43.8% yield, m.p.156.0-158.0 ℃. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):11.46(s,1H),10.85(s,1H),8.52(s,1H),7.96(s,1H),7.49–7.38(m,2H),7.28(t,J＝7.6Hz,1H),7.21(d,J＝7.8Hz,1H),7.08(t,J＝7.1Hz,1H),6.88–6.81(m,2H),6.43(s,1H),6.10(s,1H),4.66–4.53(m,4H),4.48(d,J＝5.7Hz,2H),3.68(d,J＝6.1Hz,2H).
Example 3: synthesis of (Z) -N- ((1- (2- ((4- (N- (3-chlorobenzyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) -1H-pyrrole-2-carboxamide (I-3)
Synthesis of (Z) -4-amino-N- (3-chlorobenzyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (IV-2)
In the form of compound II-1 (6.9 g,42.5 mol), 3-chlorobenzylamine (III-2, 5.0g,35.4 mmol) and Na 2 CO 3 (5.6 g,53.1 mmol) was used as starting material, and the same procedure was followed as for IV-1 to give 4.8g of off-white solid IV-2 in a yield of 50.7%, m.p.106.0-108.0deg.C. 1 H-NMR(400MHz,DMSO-d 6 ),δ(ppm):10.84(s,1H,),7.31(t,J＝7.7Hz,1H),7.29–7.23(m,2H),7.15(d,J＝7.6Hz,1H),7.04(t,J＝7.2Hz,1H),6.29(s,2H),4.62(d,J＝7.2Hz,2H).
Synthesis of 3- (4-amino-1, 2, 5-oxadiazol-3-yl) -4- (3-chlorobenzyl) -1,2, 4-oxadiazol-5 (4H) -one (V-2)
Starting with compound IV-2 (4.5 g,16.8 mmol) and CDI (4.0 g,25.2 mol), the same procedure as V-1 gave 4.0g of white solid V-2 in 82.2% yield, m.p.134.0-136.0deg.C. 1 H-NMR(300MHz,CDCl 3 ),δ(ppm):7.49(s),7.42–7.32(m,3H),5.28(s,2H),5.17(s,2H).
Synthesis of 4- (3-chlorobenzyl) -3- (4-nitro-1, 2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazol-5 (4H) -one (VI-2)
As compound V-2 (3.7 g,12.6 mmol), trifluoroacetic acid (57 mL) and 30% H 2 O 2 The solution (19 mL) was used as a starting material, and the same procedure as VI-1 was followed to give 1.9g of VI-2 as a pale yellow solid in a yield of 47.7%, m.p.84.0-86.0deg.C. 1 H-NMR(300MHz,CDCl 3 ),δ(ppm):7.43(dd,J＝6.8,2.2Hz,1H),7.29–7.21(m,1H),7.17(t,J＝8.5Hz,1H),5.10(s,2H).
Synthesis of 3- (4- ((2-bromoethyl) amino-1, 2, 5-oxadiazol-3-yl) -4- (3-chlorobenzyl) -1,2, 4-oxadiazol-5 (4H) -one (VIII-2)
Using compound VI-2 (1.0 g,3.1 mmol), VII-1 (1.2 g,6.1 mmol) and 2mol/L sodium hydroxide solution (4.6 mL,9.2 mmol) as starting material, the same procedure as for VIII-1 gave 490mg of off-white solid VIII-2 in 39.6% yield, m.p.64.0-66.0deg.C. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):7.51(s,1H),7.44–7.40(m,2H),7.38–7.33(m,1H),6.83(t,J＝5.6Hz,1H),5.14(s,2H),3.71–3.68(m,4H).
Synthesis of 3- (4- ((2-azidoethyl) amino-1, 2, 5-oxadiazol-3-yl) -4- (3-chlorobenzyl) -1,2, 4-oxadiazol-5 (4H) -one (IX-2)
Starting with compound VIII-2 (450 mg,1.12 mmol) and sodium azide (80 mg,1.23 mmol), the same procedure as IX-1 gave 368mg of oil IX-2 in 90.8% yield. 1 H-NMR(300MHz,CDCl 3 ),δ(ppm):7.48(s,1H),7.41–7.36(m,1H),7.36–7.31(m,2H),5.65(t,J＝4.9Hz,1H),5.27(s,2H),3.67–3.59(m,4H).
Synthesis of (Z) -4- ((2-azidoethyl) amino) -N- (3-chlorobenzyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (X-2)
Starting from compound IX (320 mg,0.88 mmol) and 2mol/L sodium hydroxide solution (1.3 mL,2.64 mmol), the same procedure was followed as for X-1 to give 206mg of oil X-2 in 69.7% yield. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):10.92(s,1H),7.33(t,J＝7.6Hz,1H),7.30–7.26(m,2H),7.18–7.09(m,2H),6.46(t,J＝5.9Hz,1H),4.64(d,J＝7.2Hz,2H),3.56(t,J＝5.7Hz,2H),3.43(q,J＝5.8Hz,2H).
Synthesis of (Z) -N- ((1- (2- ((4- (N- (3-chlorobenzyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) -1H-pyrrole-2-carboxamide (I-3)
Using compound X-2 (0.10 g,0.29 mmol), XI-2 (52 mg,0.35 mmol) and copper sulfate (9 mg,0.06 mmol)/sodium ascorbate (22 mg,0.11 mmol) as raw materials, the same procedure as for I-1 gave 72mg of off-white solid I-3 in 51.4% yield, m.p.220.0-222.0 ℃. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):11.46(s,1H),10.85(s,1H),8.52(t,J＝5.8Hz,1H),7.96(s,1H),7.36–7.26(m,3H),7.17(d,J＝7.3Hz,1H),7.08(t,J＝7.2Hz,1H),6.88–6.78(m,2H),6.43(t,J＝5.9Hz,1H),6.10(q,J＝2.6Hz,1H),4.64–4.52(m,4H),4.48(d,J＝5.8Hz,2H),3.68(q,J＝6.0Hz,2H).
Example 4: synthesis of (Z) -N- ((1- (2- ((4- (N- (3-bromo-4-fluorobenzyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) -1H-pyrrole-2-carboxamide (I-4)
Synthesis of (Z) -4-amino-N- (3-bromo-4-fluorobenzyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (IV-3)
In the form of compound II-1 (4.7 g,29.36 mol), 3-bromo-4-fluorobenzylamine (III-3, 5.0g,24.4 mmol) and Na 2 CO 3 (3.9 g,36.6 mmol) was used as a starting material, the same procedure was used as in IV-1, and purification by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=20:1-5:1) gave 5.5g of oily substance IV-3 in 68.8% yield. 1 H-NMR(300MHz,DMSO-d 6 +D2O),δ(ppm):7.70–7.60(m,1H,-ArH),7.45–7.38(m,2H),6.60(s,2H),5.11(s,2H).
Synthesis of 3- (4-amino-1, 2, 5-oxadiazol-3-yl) -4- (3-bromo-4-fluorobenzyl) -1,2, 4-oxadiazol-5 (4H) -one (V-3)
Using compound IV-3 (5.0 g,15.1 mmol) and CDI (3.7 g,22.7 mol) as starting materials, the same procedure was followed as for V-1 to give 4.3g of white solid V-3 in 80.5% yield, m.p.144.0-146.0deg.C. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):7.79(d,J＝6.5Hz,1H),7.45(s,1H),7.39(t,J＝8.6Hz,1H),6.64(s,2H),5.11(s,2H).
Synthesis of 4- (3-bromo-4-fluorobenzyl) -3- (4-nitro-1, 2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazol-5 (4H) -one (VI-3)
In the form of compound V-3 (4.0 g,11.2 mmol), trifluoroacetic acid (50 mL) and 30% H 2 O 2 The solution (17 mL) was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate=40:1-10:1) using the same procedure as VI-1 to give 1.7g of VI-3 as an oil in 40.6% yield. 1 H-NMR(300MHz,CDCl 3 ),δ(ppm):7.59–7.52(m,1H),7.37–7.32(m,1H),7.21–7.18(m,1H),5.17(s,2H).
Synthesis of 4- (3-bromo-4-fluorobenzyl) -3- (4- ((2-bromoethyl) amino) -1,2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazol-5 (4H) -one (VIII-3)
Using compound VI-3 (1.5 g,3.9 mmol), VII-1 (1.6 g,7.8 mmol) and 2mol/L sodium hydroxide solution (VII-1, 5.9mL,11.7 mmol) as starting materials, the same procedure as VIII-1 was followed by purification by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=30:1-5:1) to give 1.0g of oily VIII-3 in 61.2% yield. 1 H-NMR(300MHz,CDCl 3 ),δ(ppm):7.74(dd,J＝6.4,2.2Hz,1H),7.50–7.45(m,1H),7.15–7.10(m,1H),5.79(t,J＝6.0Hz,1H),5.25(s,2H),3.86(q,J＝6.0Hz,2H),3.67(t,J＝5.9Hz,2H).
Synthesis of 3- (4- ((2-azidoethyl) amino) -1,2, 5-oxadiazol-3-yl) -4- (3-bromo-4-fluorobenzyl) -1,2, 4-oxadiazol-5 (4H) -one (IX-3)
Starting with compound VIII-3 (0.9 g,1.94 mmol) and sodium azide (138 mg,2.13 mmol), the same procedure as IX-1 gave 707mg of oil IX-3 in 85.8% yield. 1 H-NMR(300MHz,CDCl 3 ),δ(ppm):7.71(dd,J＝6.4,2.2Hz,1H),7.51–7.42(m,1H),7.12(t,J＝8.4Hz,1H),5.70(t,J＝6.5Hz,1H),5.23(s,2H),3.65–3.58(m,4H).
Synthesis of (Z) -4- ((2-azidoethyl) amino) -N- (3-bromo-4-fluorobenzyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (X-3)
Starting with compound IX-3 (650 mg,1.40 mmol) and 2mol/L sodium hydroxide solution (2.1 mL,4.20 mmol), the same procedure was followed as for IX-1, and purification by silica gel column chromatography (eluent: petroleum ether: ethyl acetate=15:1-3:1) afforded 321mg of oily IX-3 in 57.6% yield. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):10.94(s,1H),7.56(dd,J＝6.8,2.0Hz,1H),7.32(t,J＝8.6Hz,1H),7.26–7.23(m,1H),7.14(t,J＝7.2Hz,1H),6.45(t,J＝5.9Hz,1H),4.60(d,J＝7.2Hz,2H),3.55(t,J＝5.7Hz,2H),3.43(q,J＝5.8Hz,2H).
Synthesis of (Z) -N- ((1- (2- ((4- (N- (3-bromo-4-fluorobenzyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) -1H-pyrrole-2-carboxamide (I-4)
Using compound X-3 (0.10 g,0.25 mmol), XI-2 (44 mg,0.30 mmol) and copper sulfate (7 mg,0.05 mmol)/sodium ascorbate (20 mg,0.10 mmol) as starting materials, the same procedure as for I-1 gave 73mg of off-white solid I-4 in 53.2% yield, m.p.174.0-176.0deg.C. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):11.46(s,1H),10.86(s,1H),8.53(t,J＝5.9Hz,1H),7.96(s,1H),7.56(dd,J＝6.8,2.1Hz,1H),7.32(t,J＝8.6Hz,1H),7.28–7.20(m,1H),7.09(t,J＝7.2Hz,1H),6.87–6.80(m,2H),6.42(t,J＝5.9Hz,1H),6.09(q,J＝2.7Hz,1H),4.56–4.45(m,4H),4.46(d,J＝5.8Hz,2H),3.67(q,J＝6.1Hz,2H).
Example 5: synthesis of (Z) -N- ((1- (2- ((4- (N- (3-bromobenzyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) furan-2-carboxamide (I-5)
Using compound X-1 (0.10 g,0.25 mmol), N- (propyl-2-yn-1-yl) furan-2-carboxamide (XI-3, 70mg,01.47 mmol) and copper sulfate (7 mg,0.05 mmol)/sodium ascorbate (20 mg,0.10 mmol) as starting materials, the same procedure as for I-1 gave 95mg of off-white solid I-5 in 45.9% yield and m.p.194.0-196.0 ℃. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):10.85(s,1H),8.92(t,J＝5.9Hz,1H),7.99(s,1H),7.86(s,1H),7.44–7.39(m,2H),7.27(t,J＝7.6Hz,1H),7.20(d,J＝7.7Hz,1H),7.15(d,J＝3.5Hz,1H),7.10(t,J＝7.2Hz,1H),6.65(dd,J＝3.5,1.8Hz,1H),6.43(t,J＝5.9Hz,1H),4.64–4.54(m,4H),4.47(d,J＝5.9Hz,2H),3.68(q,J＝6.0Hz,2H).
Example 6: synthesis of (Z) - (1- (2- ((4- (N- (3-bromobenzyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) -1H-pyrrole-2-carboxylate (I-6)
Using Compound X-1 (0.15 g,0.39 mmol), propyl-2-yn-1-yl-1H-pyrrole-2-carboxamide (XI-4, 70mg,0.47 mmol) and copper sulfate (13 mg,0.08 mmol)/sodium ascorbate (30 mg,0.15 mmol) as raw materials, the same procedure was followed as in I-1, giving 87mg of off-white solid I-6 in 42.0% yield, m.p.>250℃。 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):11.95(s,1H),10.84(s,1H),8.21(s,1H),7.44–7.38(m,2H),7.27(t,J＝7.6Hz,1H),7.20(d,J＝7.7Hz,1H),7.10(t,J＝7.2Hz,1H),7.05(q,J＝2.5Hz,1H),6.81–6.78(m,1H),6.46(t,J＝5.9Hz,1H),6.21–6.17(m,1H),5.31(s,2H),4.67–4.52(m,4H),3.71(q,J＝5.9Hz,2H).
Example 7: synthesis of (Z) -N- ((1- (2- ((4- (N- (3-bromobenzyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) isonicotinamide (I-7)
Using compound X-1 (0.15 g,0.39 mmol), N- (propyl-2-yn-1-yl) isonicotinamide (XI-5, 75mg,0.47 mmol) and copper sulfate (13 mg,0.08 mmol)/sodium ascorbate (30 mg,0.15 mmol) as starting materials, the same procedure as for I-1 gave 97mg of off-white solid I-7 in 45.7% yield, m.p.147.0-149.0 ℃. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):10.84(s,1H),9.36(t,J＝5.7Hz,1H),8.79–8.71(m,2H),8.03(s,1H),7.84–7.75(m,2H),7.47–7.36(m,2H),7.33–7.16(m,2H),7.08(t,J＝7.2Hz,1H),6.44(t,J＝5.9Hz,1H),4.63–4.50(m,6H),3.69(q,J＝6.0Hz,2H).
Example 8: synthesis of (Z) -N- ((1- (2- ((4- (N- (3-bromobenzyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-1,2, 3-triazol-4-yl) ethyl) pyridine carboxamide (I-8)
Using compound X-1 (0.15 g,0.39 mmol), N- (butyl-3-yn-1-yl) pyridine carboxamide (XI-6, 81mg,0.47 mmol) and copper sulfate (12 mg,0.08 mmol)/sodium ascorbate (30 mg,0.15 mmol) as raw materials, the same procedure as for I-1 gave 110mg of off-white solid I-8 in 50.6% yield. m.p.127-129 ℃. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):10.84(s,1H),8.97(t,J＝6.0Hz,1H),8.65(d,J＝4.8,1H),8.08–7.98(m,2H),7.92(s,1H),7.64–7.59(m 1H),7.46–7.38(m,2H),7.27(t,J＝7.6Hz,1H),7.20(d,J＝7.8Hz,1H),7.07(t,J＝7.2Hz,1H),6.43(t,J＝6.0Hz,1H),4.62–4.53(m,4H),3.67(q,J＝6.0Hz,2H),3.59(q,J＝7.0Hz,2H),2.92(d,J＝7.4Hz,2H).
Example 9: synthesis of (Z) -N- ((1- (2- ((4- (N- (3-bromobenzyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) -5-fluoropyridine carboxamide (I-9)
Using compound X-1 (0.1 g,0.26 mmol), 5-fluoro-N- (propyl-2-yn-1-yl) pyridine carboxamide (XI-7, 55mg,0.31 mmol) and copper sulfate (8 mg,0.05 mmol)/sodium ascorbate (20 mg,0.10 mmol) as raw materials, the same procedure as for I-1 gave 49mg of white solid I-9, yield 33.9%, m.p.139.0-140.0deg.C. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):10.82(s,1H),9.19(t,J＝6.1Hz,1H),8.65(d,J＝2.8Hz,1H),8.12(dd,J＝8.7,4.7Hz,1H),7.96(s,1H),7.94–7.88(m,1H),7.43–7.36(m,2H),7.25(t,J＝7.6Hz,1H),7.18(d,J＝7.8Hz,1H),7.05(t,J＝7.2Hz,1H),6.41(t,J＝5.9Hz,1H),4.58–4.50(m,6H),3.65(q,J＝6.0Hz,2H).
Example 10: synthesis of (Z) -4-bromo-N- ((1- (2- ((4- (N- (3-bromobenzyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) ethyl) -1H-1,2, 3-triazol-4-yl) methyl) -1H-pyrrole-2-carboxamide (I-10)
Using compound X-1 (0.1 g,0.26 mmol), 4-bromo-N- (propyl-2-yn-1-yl) -1H-pyrrole-2-carboxamide (XI-8, 70mg,0.31 mmol) and copper sulfate (8 mg,0.05 mmol)/sodium ascorbate (20 mg,0.10 mmol) as starting materials, the same procedure as for I-1 gave 47mg of white solid I-10 in 29.9% yield, m.p.161.0-162.0deg.C. 1 H-NMR(400MHz,DMSO-d 6 ),δ(ppm):11.85(s,1H),10.83(s,1H),8.64(t,J＝5.8Hz,1H),7.95(s,1H),7.42–7.37(m,2H),7.25(t,J＝7.7Hz,1H),7.18(d,J＝7.8Hz,1H),7.06(t,J＝7.1Hz,1H),6.99–6.98(m,1H),6.90–6.85(m,1H),6.41(t,J＝6.0Hz,1H),4.58–4.51(m,4H),4.45(d,J＝5.6Hz,2H),3.66(q,J＝6.0Hz,2H).
Example 11: synthesis of (Z) -N- ((1- (3- ((4- (N- (3-bromobenzyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) propyl) -1H-1,2, 3-triazol-4-yl) methyl) pyrrole carboxamide (I-11)
Synthesis of 3- (3-bromobenzyl) -3- (4- ((3-bromopropyl) amino) -1,2, 5-oxadiazol-3-yl) -1,2, 4-oxadiazol-5 (4H) -one (VIII-4)
Starting with compound VI-1 (736 mg,2.0 mmol), 3-bromopropylamine hydrobromide (VII-2,875 mg,4.0 mmol) and 2mol/L sodium hydroxide solution (2.0 mL,4.0 mmol), the same procedure as VIII-1 gave 450mg of oily VIII-4 in 49.0% yield.
Synthesis of 3- (4- (4-azidopropyl) amino) -1,2, 5-oxadiazol-3-yl) -4- (3-bromobenzyl) -1,2, 4-oxadiazol-5 (4H) -one (IX-4)
Starting with compound VIII-4 (400 mg,0.87 mmol) and sodium azide (61 mg,0.96 mmol), the same procedure as IX-1 was followed, without further purification treatment, to give 330mg of oily IX-4 in 90.9% yield. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):7.62(s,1H),7.57–7.51(m,1H),7.40–7.31(m,2H),6.64(t,J＝5.8Hz,1H),5.11(s,2H),3.59(t,J＝6.6Hz,2H),3.41(q,J＝6.5Hz,2H),2.17(p,J＝6.7Hz,2H).
Synthesis of (Z) -4- ((4-azidopropyl) amino) -N- (3-bromobenzyl) -N' -hydroxy-1, 2, 5-oxadiazole-3-carboxamidine (X-4)
Starting from compound IX-4 (300 mg,0.65 mmol) and 2mol/L sodium hydroxide solution (0.7 mL,1.30 mmol), the same procedure as X-1 gave 195mg of X-4 as a yellow solid in 75.8% yield, m.p.68.0-70.0deg.C. 1 H-NMR(300MHz,CDCl 3 ),δ(ppm):10.86(s,1H),7.42(d,J＝9.1Hz,2H),7.27–7.21(m,2H),7.10(t,J＝7.1Hz,1H),6.32(t,J＝5.9Hz,1H),4.61(d,J＝7.1Hz,2H),3.40(s,2H),3.28(q,J＝6.5Hz,2H),1.83(p,J＝6.7Hz,2H).
Synthesis of (Z) -N- ((1- (3- ((4- (N- (3-bromobenzyl) -N' -hydroxyformamidine) -1,2, 5-oxadiazol-3-yl) amino) propyl) -1H-1,2, 3-triazol-4-yl) methyl) pyrrole carboxamide (I-11)
Using compound X-4 (0.10 g,0.25 mmol), XI-1 (48 mg,0.30 mmol) and copper sulfate (8 mg,0.05 mmol)/sodium ascorbate (20 mg,0.10 mmol) as starting materials, the same procedure as for I-1 gave 40mg of light brown solid I-11 in 29.6% yield, m.p.56.0-58.0deg.C. 1 H-NMR(300MHz,DMSO-d 6 ),δ(ppm):10.86(s,1H),9.23(t,J＝6.0Hz,1H),8.67(d,J＝4.7Hz,1H),8.09(d,J＝7.6Hz,1H),8.04(dd,J＝7.3,1.7Hz,1H),8.00(s,1H),7.65–7.61(m,1H),7.43(s,1H),7.39(d,J＝7.7Hz,1H),7.30–7.18(m,2H),7.09(t,J＝7.1Hz,1H),6.34(t,J＝5.8Hz,1H),4.61–4.57(m,4H),4.38(t,J＝7.0Hz,2H),3.20(q,J＝6.6Hz,2H),2.10(p,J＝6.9Hz,2H).
Example 12: activity assay of the inventive Compounds for inhibiting IDO2 at the enzyme level
(1) Experimental method
Establishing an IDO2 enzyme activity inhibition molecular screening model, and determining by the following method: IDO enzymes can catalyze the epoxidation cleavage of pyrrole on tryptophan to produce N '-formylkynurenine (N' -formylkynurenine). In a room temperature environment, 40nM IDO enzyme and 900. Mu.M L-tryptophan were mixed, and a reaction buffer (20mM ascorbate,3.5m μm methylene blue and 0.2.2 mg/mL cathepsin 50mM potassium phosphate buffer pH 6.5) was added, and the mixture was reacted at room temperature for 3 hours, followed by UV measurement on a microplate reader at a detection wavelength of 321nM. The experimental results are shown in Table 1.
(2) Experimental results
TABLE 1 inhibitory Activity of target Compounds against IDO2 at the enzyme level
The results in Table 1 show that the compounds of the present invention have a certain inhibitory activity against IDO2 at a concentration of 100nM, wherein the inhibitory activity of compound I-1 against IDO2 is optimal.
Example 13: experiment for evaluating anti-inflammatory effects of Compounds I-1 and I-2 based on xylene-induced mouse ear swelling model
(1) Experimental method
ICR mice were randomly divided into model and each study group, 8 per group. Naphtroproxen (150 mg. Kg) as positive control group -1 ) The administration dose of the target compound is 100 mg.kg -1 Each test drug was dosed with 5% cmc-Na solution: polyoxyethylated castor oil (EL 40) =95:5 was prepared at 10mg/mL and administered by gavage at 0.2mL/10 g. After 1 hour of administration, the right ear and both sides of the mouse are uniformly coated with 25 mu L of dimethylbenzene for inflammation, and after 1 hour, the mice are killed by adopting a cervical dislocation method, and after the ears are cut off, the mice are unhaired, punched and weighed, and the swelling rate and the swelling inhibition rate are calculated. The experimental results are shown in Table 2.
Swelling ratio (%) = (right ear weight-left ear weight)/left ear weight×100%;
swelling inhibition (%) = (model group swelling rate-test group swelling rate)/model group swelling rate.
(2) Experimental results
TABLE 2 effect of target compounds I-1 and I-2 on xylene-induced ear swelling in mice
The results in Table 2 show that the target compounds I-1 and I-2 show a certain inhibition activity on mouse ear swelling induced by the dimethylbenzene, and the effect is stronger than that of the naproxen serving as a control drug. These results suggest that compounds I-1 and I-2 have better anti-inflammatory activity.
Example 14: experiment for evaluating anti-inflammatory Effect of Compound I-1 based on carrageenan model
(1) Experimental method
ICR mice were randomly divided into model and each study group, 8 per group. Naphtroproxen (100 mg. Kg) as positive control group -1 ) The administration dose of the target compound I-1 is 100 mg.kg -1 、200mg·kg -1 And 400 mg.kg -1 With 5% cmc-Na solution: polyoxyethylated castor oil (EL 40) =95:5 formulation. The administration was continuous by gastric lavage for three days, once daily at 0.2mL/10 g. After 1 hour of intragastric administration on the third day, the thickness of the right rear toe of the mice was measured, and then 25 μl of 1% carrageenan was injected into the bottom of the right toe of each mouse to cause inflammation, and the thickness of the right rear toe was measured every 1 hour, 5 times in succession. The extent of foot swelling in mice was finally assessed. The experimental results are shown in Table 3, FIG. 1, table 4 and FIG. 2.
Swelling degree (mm) =thickness of right hind foot before inflammatory-thickness of right hind foot before inflammatory;
swelling ratio (%) = (thickness of right hind foot before inflammatory-thickness of right hind foot before inflammatory)/thickness of right hind foot before inflammatory x 100%;
swelling inhibition (%) = (model group swelling rate-test group swelling rate)/model group swelling rate.
(2) Experimental results
TABLE 3 Compound I-1 induces swelling degree of mouse feet on carrageenan
a The results are expressed as mean±SD(n＝8).
TABLE 4 inhibition of carrageenan-induced murine foot swelling by Compound I-1
The results in tables 3 and 4 show that compound I-1 shows better anti-inflammatory effect in carrageenan-induced murine paw swelling model.
Claims (12)
1. An IDO inhibitor having the structure of formula (I), said IDO inhibitor comprising an isomer, a pharmaceutically acceptable salt or a mixture thereof:
wherein:
m is selected from 1,2 or 3; n is selected from 1 or 2; x is selected from O or NH;
R 1 selected from the group consisting of
R 2 Selected from H, F, cl, br, I, CF 3 、CHF 2 、CN、OCH 3 OH or CH 3 ，R 2 Is monosubstituted or disubstituted;
R 3 selected from H, F, cl or Br, R 3 Is monosubstituted; y is selected from NH or O.
2. The IDO inhibitor of claim 1, wherein in the structure:
m is selected from 1; n is selected from 1 or 2; x is selected from NH.
3. The IDO inhibitor of claim 1, wherein in the structure:
R 2 selected from H, F, cl, br, CF 3 Or CN, R 2 Is monosubstituted or disubstituted.
4. The IDO inhibitor of claim 1, wherein in the structure:
R 1 selected from:
wherein R is 3 Selected from H, F, cl, or Br, R 3 Is monosubstituted.
5. IDO inhibitor according to claim 1, characterized in that it is selected from any one of the following compounds:
6. the IDO inhibitor of any one of claims 1-5, wherein the pharmaceutically acceptable salt is a salt of the IDO inhibitor with an acid, and the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, malic acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, or ferulic acid.
7. A process for the preparation of an IDO inhibitor as defined in any one of claims 1 to 6, wherein the process comprises:
the compound (II) and the compound (III) are subjected to substitution, cyclization, oxidation, reduction-coupling, azide, ring opening and cyclization reaction to obtain a compound (I);
wherein R is 1 、R 2 The definition of m, n and X is as defined in any one of claims 1 to 5;
preparing a compound IV by substitution reaction of the compound II and substituted benzylamine III, wherein the used base is selected from triethylamine, pyridine, N-diisopropylethylamine, 4-dimethylaminopyridine, potassium carbonate, sodium carbonate, cesium carbonate or sodium acetate, and the used solvent is selected from methanol, ethanol, tetrahydrofuran or a mixed solvent of the solvents and water;
the compound IV and N, N' -carbonyl diimidazole are subjected to cyclization reaction to prepare a compound V, and the used solvent is selected from dichloromethane, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide or a mixed solvent formed by any two of the dichloromethane, the ethyl acetate, the tetrahydrofuran, the 1, 4-dioxane and the N, N-dimethylformamide;
preparing a compound VI from the compound V and hydrogen peroxide through an oxidation reaction, wherein the acid is selected from hydrochloric acid, acetic acid or trifluoroacetic acid;
preparing a compound VIII from a compound VI and a compound VII through a reduction-coupling reaction, wherein the used alkali is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide, and the used solvent is selected from dichloromethane, ethyl acetate, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide or a mixed solvent of the solvents and water;
preparing a compound IX from a compound VIII through an azide reaction, wherein an azide reagent is selected from sodium azide or azido-trimethylsilane, and a solvent is selected from tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, N-dimethylacetamide or a mixed solvent composed of any two of the above solvents;
preparing a compound X from the compound IX through a hydrolytic ring-opening reaction, wherein the used alkali is selected from lithium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate, and the used solvent is selected from methanol, tetrahydrofuran, 1, 4-dioxane, acetonitrile or a mixed solvent of N, N-dimethylformamide and water;
the compound X and the corresponding alkyne compound XI are subjected to cyclization reaction to prepare a compound I, wherein the catalyst is selected from copper sulfate/sodium ascorbate, copper chloride, copper bromide, cuprous chloride, cuprous bromide, cuprous iodide or copper powder, the inert gas is selected from nitrogen or argon, and the solvent is selected from tetrahydrofuran, 1, 4-dioxane, acetonitrile, ethanol, methanol, ethylene glycol dimethyl ether, dichloromethane, N-dimethylformamide, N-dimethylacetamide or a mixed solvent of the solvent and water;
and (3) salifying the corresponding acid with the compound (I) prepared by the method to obtain the pharmaceutically acceptable salt of the IDO inhibitor.
8. The preparation method according to claim 7, wherein the compound II and the substituted benzylamine III are subjected to substitution reaction to prepare a compound IV, wherein the base is selected from sodium carbonate, and the solvent is selected from a mixed solvent of ethanol and water;
the compound IV and N, N' -carbonyl diimidazole are subjected to cyclization reaction to prepare a compound V, and the solvent is selected from ethyl acetate;
preparing a compound VI from the compound V and hydrogen peroxide through an oxidation reaction, wherein the acid is selected from trifluoroacetic acid;
preparing a compound VIII from a compound VI and a compound VII through a reduction-coupling reaction, wherein the used alkali is selected from sodium hydroxide, and the used solvent is selected from a mixed solvent of tetrahydrofuran and water;
preparing a compound IX from a compound VIII through an azide reaction, wherein the azide reagent is selected from sodium azide, and the solvent is selected from N, N-dimethylformamide;
preparing a compound X from the compound IX through a hydrolytic ring-opening reaction, wherein the used alkali is selected from sodium hydroxide, and the used solvent is selected from a mixed solvent of methanol and water or tetrahydrofuran and water;
the compound I is prepared by cyclization reaction of the compound X and the corresponding alkyne compound XI, the catalyst is selected from copper sulfate/sodium ascorbate, and the solvent is selected from mixed solvents of tetrahydrofuran and water.
9. A pharmaceutical composition comprising an IDO inhibitor according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.
10. Use of an IDO inhibitor according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 9 for the manufacture of an IDO inhibitor medicament.
11. The use according to claim 10, wherein the IDO inhibitor drug is an IDO2 inhibitor drug.
12. The use according to claim 10, wherein the medicament is for the treatment of rheumatoid arthritis or inflammatory diseases.
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