CN108689938B - Polysubstituted indazoles and their use as IDO inhibitors - Google Patents
Polysubstituted indazoles and their use as IDO inhibitors Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a polysubstituted indazole compound shown as a formula (I), and also discloses a preparation method of the compound and application of the compound as an IDO inhibitor. The compound of the present invention can be used for preventing and/or treating various diseases, such as Alzheimer disease, cataract, infection related to cell immune activation, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism disorder, etc.
Description
Technical Field
The present invention relates to indazoles, to a process for their preparation and to their use as IDO inhibitors.
Background
Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme which catalyzes the epoxidation and cleavage of indole in Indoleamine molecules such as tryptophan and the like so as to decompose and metabolize the indole according to the canine uric acid pathway.
IDO plays an important role in the process of tumor immune exemption and tumorigenesis. Under normal conditions, IDO is expressed at a low level in vivo, most tumor cells form high-expression IDO, L-tryptophan is converted into N-formyl kynurenine, the tryptophan concentration in the microenvironment of the cells is reduced, the synthesis of tryptophan-dependent T cells is stopped at G1, and the proliferation of the T cells is inhibited, so that the killing effect of the immune system of the body on tumor tissues is inhibited. Meanwhile, the metabolite of tryptophan has cytotoxicity under the action of IDO, and can directly dissolve T cells.
Therefore, inhibiting the activity of IDO can effectively prevent the degradation of tryptophan around tumor cells and promote the proliferation of T cells, thereby enhancing the attack capability of the body on the tumor cells. Moreover, the IDO inhibitor can be used together with chemotherapeutic drugs to reduce drug resistance of tumor cells, thereby enhancing the antitumor activity of conventional cytotoxic therapy. The administration of an IDO inhibitor also enhances the therapeutic efficacy of the therapeutic vaccine in cancer patients.
Besides playing an important role in tumor cell resistance, IDO is also closely associated with the pathogenesis of a variety of diseases associated with cellular immune activation. IDO has been shown to be a target for serious diseases associated with cellular immune activation, such as infections, malignancies, autoimmune diseases, aids, and the like. Meanwhile, IDO inhibition is an important treatment strategy for patients suffering from nervous system diseases such as depression and Alzheimer's disease. Therefore, the IDO inhibitor has wide clinical application prospect.
Disclosure of Invention
In order to solve the problems, the invention provides a compound or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the structure of the compound is shown as the formula (I):
wherein the content of the first and second substances,
R1selected from hydrogen or C1～C6An alkyl group;
R2selected from hydrogen or-NH-R6；
R3Selected from hydrogen or halogen;
R4selected from hydrogen or halogen;
R5selected from hydrogen or-NH-R6；
R6Selected from the group consisting of cyclohexanone group, -CH2-R7or-CH2-CH(R8)-R9；
R7、R9Selected from-CON (OH) -R10Substituted or unsubstituted 4-to 6-membered cycloalkyl or 4-to 6-membered heterocyclyl, said substituted cycloalkyl or heterocyclyl being selected from hydroxy, -COOH or-COOR11Substituted with the substituent(s);
R8is selected from C1～C6Alkyl or hydroxy substituted C1～C6An alkyl group;
R10is selected from 4-6 membered heterocyclic group;
R11is selected from C1～C6An alkyl group;
wherein, only when R is2Is selected from-NH-R6When R is5Selected from hydrogen.
Further, R2Selected from hydrogen, R3Selected from halogen, R4Selected from hydrogen, R5Is selected from-NH-R6；
Or, R2Is selected from-NH-R6、R3Selected from hydrogen, R4Selected from halogen, R5Selected from hydrogen.
Further, the heteroatom of the heterocyclic group is nitrogen or oxygen.
Further, the cycloalkyl group is cyclohexyl.
Further, the halogen is selected from fluorine, chlorine or bromine.
Further, said R6Selected from one of the following groups:
further, the compound is selected from one of the following compounds:
the invention also provides the application of the compound, or a prodrug thereof, or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof in preparing IDO inhibitor medicines.
Further, the drug is a drug for preventing and/or treating alzheimer's disease, cataract, infection associated with cellular immune activation, autoimmune disease, aids, cancer, depression or tryptophan metabolism disorder.
The invention also provides a pharmaceutical composition, which is a preparation prepared by taking the compound, or a prodrug thereof, or an optical isomer thereof, or a racemic mixture thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
Said C is1～C6Alkyl is C1、C2、C3、C4、C5、C6Alkyl of (2), i.e. straight-chain or branched alkyl having 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butylButyl, sec-butyl, pentyl, hexyl and the like.
The prodrugs are derivatives of the aforementioned compounds which may themselves have poor activity or even no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis or otherwise) to the corresponding biologically active form.
The preparation can comprise injection or oral preparation.
Key intermediates and compounds of the present invention are isolated and purified by means of isolation and purification methods commonly used in organic chemistry.
One or more compounds of the present invention may be used in combination with each other, or alternatively, in combination with any other active agent, for the preparation of IDO inhibitors. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
The pharmaceutically acceptable auxiliary material of the invention refers to a substance contained in a dosage form except for an active ingredient.
Experiments prove that the indazole compound provided by the invention has an excellent inhibiting effect on IDO, and can be used for preventing and/or treating various diseases, such as Alzheimer disease, cataract, infection related to cellular immune activation, autoimmune diseases, AIDS, cancer, depression or tryptophan metabolic disorder and the like.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
In the present invention, the meanings of the acronyms are as follows:
DCM: dichromethane, Dichloromethane.
DMAP: 4-dimethylaminopyrdine, 4-Dimethylaminopyridine.
DIBAL-H: diisobutylaluminum hydride, Diisobutylaluminum hydride.
MeOH: methyl alcohol, methanol.
EA: ethyl acetate, Ethyl acetate.
Et3N: triethylamine, Triethylamine.
SOCl2: thionyl chloride, Thionyl chloride.
PE: petroleum ether, Petroleum ether.
TFA: tallow Fatty Acid, trifluoroacetic Acid.
THF: tetrahydrofuran, Tetrahydrofuran.
Detailed Description
The preparation method of the key intermediates LWQ-148 and LWQ-193 is self-synthesis in a laboratory, and other reagents and initial raw materials used in the invention are cheap and easily available and are purchased from Chengdong chemical reagent company except special instructions.
(1) Synthesis of Compounds LWQ-148
1 Synthesis of Compound 4 a:
slowly adding the raw material TCCA (640mg, 2.74mmol) into a 2d (1g, 5.49mmol) concentrated sulfuric acid (25mL) solution at room temperature, and stirring for 4h when the addition is finished at 130 ℃; TLC showed the starting material reaction was complete and finally 872.6mg of white powder was obtained, yield: 73.6 percent.
2 synthesis of compound 5 a:
starting material 4a (5.9g, 23.60mmol) was dissolved in methanol (10mL)1, 4-dioxane (5mL), 10N HCl (12mL) Fe (3.96g, 70.80mmol) was added under ice-bath, and after addition, stirring was continued at 80 ℃ for 3h, TLC indicated complete reaction of starting material. Finally, 3.55g of a pale yellow powder was obtained, yield: 68.4 percent.
3 Synthesis of Compounds LWQ-147:
dissolving raw material 5a (3.55g, 16.13mmol) with AcOH (15mL), adding an aqueous solution (5mL) of sodium nitrite (2.23g, 32.26mmol) at 0 ℃, and after completion of addition, stirring at rt for 6 h; TLC showed the starting material was completely reacted and finally 2.7g of orange powder was received, yield: 72.5 percent.
1H NMR(400MHz,CDCl3,ppm):δ14.04(s,1H),8.56(s,1H),8.23(s,1H),8.13(s,1H,)；13C NMR(300MHz,CDCl3,ppm):δ140.3,133.3,133.1,130.4,118.9,118.0,114.8；HRMS(AP-ESI)Calcd.for C7H4ClN3O2:219.9890(M+Na)+.Found:219.0458.
Synthesis of Compound LWQ-148
Dissolving LWQ-147(3.4g, 14.05mmol) of raw material in ethanol (20mL) and water (10mL), adding ammonium chloride (376mg, 7.02mmol) and Fe (3.9g, 70.25mmol) at rt, and stirring at 80 deg.C for 4 h; TLC showed the starting material was completely reacted and finally 2.73g of orange powder was received, yield: 70.2 percent.
1H NMR(400MHz,DMSO,ppm)δ12.75(s,1H),8.10(s,1H),6.62(s,1H),6.13(s,1H).13C NMR(300MHz,d6-DMSO,ppm):δ145.0,143.6,131.9,127.8,112.0,107.1,100.4；HRMS(AP-ESI)Calcd.for C7H6ClN3:190.0148(M+Na)+.Found:190.0677.
(2) Synthesis of Compound LQW-193
1 Synthesis of Compound 11:
starting material 10(1.00g,4.32mmol) was dissolved in 15mL AcOH and an aqueous solution (2mL) of sodium nitrite (0.66mg,9.52mmol) was added at 0 ℃. After addition, rt stirred for 6 h. TLC monitoring the reaction of the raw materials completely, spin-drying the reaction solution, extracting, and purifying the crude product by column chromatography to obtain an orange powder compound (0.5mg, 2.07mmol), yield: 47.7 percent.
2 Synthesis of Compound LQW-193:
dissolving compound 11(0.34g,1.40mmol) in ethanol (10mL) and water (5mL), adding ammonium chloride (38mg,0.70mmol) and Fe (0.39g,7.02mmol) at room temperature under stirring, heating to 80 deg.C after the addition, and stirring for 4 h; TLC shows that the raw material is reacted completely, solid in the reaction solution is filtered, the filter cake is washed by EA for multiple times, the filtrate is dried by spinning, the residue is diluted by water, EA is extracted for 3 times, and saturated saline is washed for 3 times, dried and concentrated. Column chromatography of the crude product (PE: EA ═ 1:1) gave the compound LQW-193 as a pale yellow powder (0.15mg,0.71mmol), yield: 50.5 percent.
1H NMR(400MHz,DMSO)δ12.76(s,1H),7.90(s,1H),7.11(d,J＝1.1Hz,1H),6.58(d,J＝0.9Hz,1H),5.67(s,1H).13C NMR(101MHz,DMSO)δ139.9,133.4,125.8,122.8,120.4,120.1,110.0.ESI-MS:211.9745[M+H].
EXAMPLE 1 Synthesis of Compounds LWQ-136, LWQ-138, LWQ-156, LWQ-167, LWQ-223
The synthetic route is as follows:
1 synthesis of raw materials LWQ-221:
taking a dry 50mL pear-shaped bottle, dissolving 2-methyl-1, 3-dinitrobenzene (CAS: 606-20-2, 5.00g, 27.45mmol, purchased from Douer Co., Ltd.) in 30mL concentrated sulfuric acid, slowly adding 1, 3-dibromo-5, 5-dimethylhydantoin (CAS: 77-48-5, 4.29g, 15.00mmol, purchased from Douer Co., Ltd.) under stirring in an ice bath, after dropwise addition, stirring at room temperature for reaction for 15h, and after TLC shows that the raw materials are completely reacted, slowly pouring the reaction liquid into ice water, filtering, and drying a filter cake in vacuum to obtain white solid powder 5-bromo-2 methyl-1, 3-dinitrobenzene (6.59g, 92% yield).
Taking a dry 50mL pear-shaped bottle, dissolving 5-bromo-2-methyl-1, 3-dinitrobenzene (5.00g, 19.16mmol) in 20mL methanol and 10mL dioxane, slowly adding 16.48mL concentrated hydrochloric acid and iron powder (3.22g, 57.47mmol) at room temperature under stirring, heating to 80 ℃ after the addition is finished, stirring and refluxing for 12h, wherein TLC shows that the raw materials are basically reacted completely, concentrating the reaction liquid, and purifying the crude product by column chromatography (PE: EA is 5:1) to obtain 5-bromo-2-methyl-3-nitroaniline as light yellow solid powder ((2.74g, yield 62%).
Taking a dry 25mL pear-shaped bottle, dissolving 5-bromo-2-methyl-3-nitroaniline (0.40g, 1.73mmol) in 7mL glacial acetic acid, slowly dropwise adding 2mL sodium nitrite (0.24g, 3.46mmol) solution into the reaction solution at 0 ℃ under mechanical stirring, heating to room temperature, stirring for reaction for 12H after the addition is finished, TLC shows that the raw material is completely reacted, adding water into the reaction solution to dilute the reaction solution to precipitate a solid, filtering, drying a filter cake in vacuum, and purifying by column chromatography (PE: EA is 5:1) to obtain yellow solid powder 6-bromo-4 nitro-1H-indazole LWQ-221(0.40g, yield is 96%).
And (3) structural identification: the HPLC profile was identical to that of a control CAS:885518-46-7 (available from south-reaching-Jiangsu Biotech Co., Ltd.) of the same structure. Purity 98% by HPLC;1H-NMR(400MHz,d6-DMSO,ppm):δ12.46(br,1H),8.30(s,1H),8.20(s,1H),8.12(s,1H),4.60(br,2H).
2 Synthesis of Compound 33:
raw material LWQ-221(30mg, 0.1239mmol) was dissolved in THF (5ml), sodium hydride (10mg, 0.1488mmol) was added at 0 deg.C, and after the addition was completed, stirring was performed for 3h, methyl iodide (8.5. mu.L, 0.1325mmol) was added, and after the addition was completed, the solution was transferred to rt and stirred for 3 h. TLC showed the starting material reaction was complete. Finally, 19mg of a pale yellow solid was taken, yield: 67.9 percent.
3 Synthesis of Compound 34:
the starting materials 33(19mg, 0.0745mmol), ammonium chloride (5mg, 0.0372mmol) were dissolved in ethanol and water (3ml:1.5ml), Fe (21mg, 0.357mmol) was added with stirring, and after the addition was completed, the mixture was brought to 80 ℃ and stirred under reflux for 4 h. TLC showed the starting material reaction was complete, finally 12mg of light yellow solid was taken, yield: 74 percent;
1H NMR(400MHz,CDCl3)δ7.88(d,J＝0.9Hz,1H),6.98(d,J＝1.1Hz,1H),6.49(d,J＝1.3Hz,1H),4.30–4.09(m,1H),4.00(s,1H).
synthesis of 4 Compounds LWQ-136
Dissolve starting material 34(70mg,0.2431mmol) with starting material 35(50mg,0.3159mmol) and dihydropyridine ester (109mg,0.4298mmol) in DCM; to MeOH, 2ml was added TFA (23ul,0.2431mmol) with stirring. After the addition, the mixture is stirred and refluxed for 3 hours at the temperature of 40 ℃. TLC showed the starting material to react completely, and finally 23mg of a pale yellow foamy solid was obtained. Yield: 22.1 percent.
1H NMR(400MHz,DMSO)δ9.32(s,1H),8.18(s,1H),7.22–7.15(m,3H),6.98(s,1H),6.74(d,J＝8.5Hz,2H),6.11(d,J＝1.1Hz,1H),4.30(s,1H),3.91(s,3H).13C NMR(101MHz,DMSO)δ143.88,141.87,131.60,122.30,112.86,100.66,99.18,71.71,46.19,44.60,35.84,31.17,29.63,25.47,24.94.HRMS(AP-ESI)Calcd.for C16H22BrN3O 374.0844(M+Na)+.Found:374.0677.
The compounds LWQ-138 and LWQ-156 were prepared from LWQ-148 and LWQ-193, respectively, and 35, respectively, by a method similar to that for the synthesis of LWQ-136.
LWQ-156：1H NMR(400MHz,CDCl3)δ7.94(s,1H),6.96(s,1H),6.33(s,1H),3.53(dt,J＝14.3,4.9Hz,1H),3.30(m,2H),2.07–1.95(m,1H),1.91–1.65(m,4H),1.44–1.19(m,3H).13C NMR(101MHz,CDCl3)δ142.78,141.80,131.87,123.05,112.67,102.78,101.12,49.34,44.08,36.09,30.95,29.66,25.22,24.56.ESI-MS:346.0525[M+Na]
LWQ-138: yield: 52.8 percent; a yellow-white solid; 1H NMR (400MHz, DMSO) δ 12.77(s,1H),8.19(s,1H),6.64(s,1H),6.59(s,1H),6.06(s,1H),4.75(d, J ═ 5.2Hz,1H),3.78-3.50(M,1H),3.18(dd, J ═ 9.8,4.9Hz,1H),2.91-2.83(M,1H),1.93(d, J ═ 12.7Hz,1H),1.69-1.46(M,1H),1.32-0.90(M,1H), HRMS (AP-ESI) calcd. for C14H18ClN3O 302.1036(M + Na. und: 302.0978).
LWQ-167 starting from compound 7 and compound 35 a. Reference was made to the synthesis of compounds LWQ-136.1H NMR(400MHz,DMSO)δ11.97(s,1H),8.12(s,1H),6.34(s,1H),6.79(s,1H),6.16(s,1H),4.72(d,J＝5.2Hz,1H),3.78–3.50(m,1H),3.18(dd,J＝9.8,4.9Hz,1H),2.91–2.83(m,1H),1.93(d,J＝12.7Hz,1H),1.69–1.46(m,1H),1.32–0.90(m,1H).HRMS(AP-ESI)Calcd.for C14H18BrN3O 346.0633(M+Na)+.Found:346.0778.
LWQ-223 starting from compound 7 and compound 35 b. Reference was made to the synthesis of compounds LWQ-136. LWQ-223 yield: 77.8 percent; a tan solid;1H NMR(400MHz,DMSO)δ13.31(s,2H),9.15(s,3H),8.10(s,3H),7.54(s,2H),7.04(s,2H),5.33(s,2H),2.52(s,7H),2.22(d,J＝5.6Hz,4H),1.96(d,J＝5.6Hz,5H),1.25(s,1H).HRMS(AP-ESI)Calcd.for C13H14BrN3O 331.0218(M+Na)+.Found:331.0129.
the structure of the aforementioned compounds is shown below:
EXAMPLE 2 Synthesis of Compounds LWQ-154, LWQ-155, LWQ-158, LWQ-159, LWQ-165, LWQ-166
The synthetic route is as follows:
1 Synthesis of intermediate 37b
Under Ar gas, triphenylphosphine methyl bromide (5.34g,15.06mmol) was dissolved in redistilled THF and cooled to-78 ℃. 2.5M n-butyllithium (6.00mL,15.06mmol) was slowly added dropwise, and after completion of addition, the mixture was stirred at the same temperature for 1 hour, a THF solution of Compound 36(2.00g,10.04mmol) was added, and the mixture was stirred for 1 hour, gradually rising to 0 ℃. Adding saturated ammonium chloride aqueous solution to stop reaction, spin-drying the reaction solution, adding water to dilute the residue, extracting with EA for 3 times, washing with saturated sodium chloride aqueous solution for 2 times, drying, and concentrating. The crude product was purified by column chromatography (PE: EA ═ 20: 1) to give compound 37b (600g,3.04mmol) as a colorless oily liquid with a yield of 30%.
2 Synthesis of intermediate 38a
Compound 37a (1.00g,9.04mmol) was dissolved in dichloromethane, m-chloroperoxybenzoic acid (2.82g,16.35mmol) was added, and after the addition, the mixture was heated to reflux and stirred for 4 hours. The reaction mixture was cooled to room temperature, dried and the crude product was purified by column chromatography (PE: EA ═ 20: 1) to give 38a (0.93g,7.33mmol) as a colorless oily liquid in 81% yield.
The synthesis of compound 38a was carried out in accordance with the synthesis method for compound 38a using compound 37b as a starting material, whereby compound 38b was obtained as a colorless oily liquid with a yield of 80%.
3 Synthesis of Compounds LWQ-159
Compound 7(0.1g,0.47mmol) and compound 38a (59mg,0.47mmol) were dissolved in a mixed solvent of ethanol and water (2:1), and the pH was adjusted to 10 to 11 with an aqueous sodium hydroxide solution. The temperature is increased to 110 ℃, and the mixture is refluxed and stirred for 3 hours. During the reaction, the pH of the reaction solution is maintained to 10-11. The reaction solution was spin dried and the crude product was purified by column chromatography (PE: EA ═ 1:1) to give LWQ-159 as a yellow oil-like semisolid compound (73mg,0.22mmol) with a yield of 47%.
1H NMR(400MHz,CDCl3)δ7.89(s,1H),6.98(s,1H),6.48(s,1H),4.25(s,1H),4.22-4.12(m,2H),3.88-3.84(m,1H),1.82–1.70(m,4H),1.51-1.43(m,1H),1.30-1.11(m,6H).ESI-MS:338.0790[M+H].
The compounds LWQ-158 and LWQ-166 were synthesized from compound 7 and compound 38b by the method described for the synthesis of LWQ-159, to give a pale yellow foamy solid compound LWQ-158 and a tan solid compound LWQ-166. The yields were 45% and 40%, respectively.
Compounds LWQ-158:1H NMR(400MHz,CDCl3)δ7.91(s,1H),6.96(s,1H),6.48(s,1H),4.33(s,2H),4.21-4.11(m,2H),4.03-3.98(m,1H),3.63-3.48(m,2H),3.31–3.09(m,2H),2.29-2.20(m,8.3Hz,1H),1.98-1.87(m,2H),1.47(s,9H).13C NMR(101MHz,CDCl3)δ154.5,142.1,141.1,130.9,122.4,113.1,107.2,101.7,79.4,73.3,72.3,60.4,52.9,50.6,48.6,47.7,45.8,45.4,42.6,41.6,41.2.ESI-MS:425.1110[M+H].
compounds LWQ-166:1H NMR(400MHz,DMSO)δ8.33(s,1H),6.88(s,1H),6.11(d,J＝1.5Hz,1H),6.02(s,1H),5.29(d,J＝5.7Hz,1H),4.40–4.18(m,2H),3.84(s,1H),3.19–2.93(m,2H),2.16-2.10(m,2H),1.92–1.88(m,1H),1.80–1.55(m,2H),1.40(s,9H).ESI-MS:425.1110[M+H].
compounds LWQ-154 and LWQ-155 were synthesized from LWQ-193 and compound 38a by the method described for the synthesis of LWQ-159, to give pale yellow foamy solid compounds LWQ-154 and tan solid compounds LWQ-155. The yields were 45% and 40%, respectively.
LWQ-154:1H NMR(400MHz,DMSO)δ8.10(s,1H),7.01(d,J＝1.6Hz,1H),6.28(t,J＝30.2Hz,1H),5.65(s,2H),4.90(d,J＝5.9Hz,1H),3.73(s,1H),2.10(s,1H),1.89–0.97(m,11H).ESI-MS:338.0790[M+H].
LWQ-155:1H NMR(400MHz,DMSO)δ7.87(s,1H),7.18(d,J＝1.7Hz,1H),6.70(d,J＝1.7Hz,1H),5.66(s,2H),5.54(d,J＝5.2Hz,1H),3.65–3.51(m,1H),3.18(d,J＝5.3Hz,1H),1.96–0.93(m,11H).ESI-MS:338.0790[M+H].
Synthesis of Compound LWQ-165
Compound LWQ-158(50mg,0.12mmol) was dissolved in 3mL DCM and 150. mu. LTFA was added with stirring. After the addition, the mixture was stirred at room temperature for 1 hour. Spin-drying the reaction solution, dissolving the residue with EA, adjusting pH to alkaline with saturated aqueous sodium bicarbonate solution, washing with saturated aqueous sodium chloride solution for 3 times, drying, and concentrating. The crude product was purified by column chromatography (DCM: MeOH ═ 20: 1) to give LWQ-165(21mg,0.06mmol) as a pale yellow oil, semi-solid, 50% yield.
1H NMR(400MHz,DMSO)δ8.11(s,1H),6.97(d,J＝5.2Hz,1H),6.28(s,1H),6.18(s,2H),4.25-4.23(m,2H),3.93-3.88(m,1H),3.19-2.98(m,3H),2.22-2.16(m,1H),2.00-1.82(m,2H).ESI-MS:325.0586[M+H].
EXAMPLE 3 Synthesis of Compounds LWQ-162, LWQ-163
The synthetic route is as follows:
1 preparation of intermediate 40
3-azetidinecarboxylic acid 39(2.47g,24.46mmol) was dissolved in 30mL of methanol and SOCl was slowly added dropwise at 0 deg.C2(8.87mL,122.3 mmol). After the addition, the temperature is raised to room temperature and the mixture is stirred for 10 hours. The reaction solution was dried by spinning, and the residue was taken up with dichloromethane to spin off SOCl2The crude product is taken for 3 times to obtain colorless viscous liquid, and because the water solubility of the compound 40 is very good, the compound is directly put into the next step without further post-treatment, and the yield is quantitative.
2 preparation of intermediate 41
Compound 40(3.68g,24.46mmol) was dissolved in acetonitrile and Et was added sequentially3N(3.39mL,24.46mmol),(Boc)2Of O (5.87g,26.91mmol)Acetonitrile solution and DMAP (0.30g,2.45 mmol). After the addition, the mixture was stirred at room temperature for 5 hours. TLC detection reaction is complete, solid in reaction liquid is filtered out, and filtrate is dried by spinning to obtain crude product. The crude product was purified by column chromatography (PE: EA ═ 40:1) to give compound 41(3.00g,14.02mmol) as a colorless oily liquid with a yield of 57%.
3 preparation of intermediate 42
Dissolving compound 41(1.00g,5.30mmol) in dichloromethane, adding into a three-necked flask under Ar protection, cooling to-78 deg.C, slowly adding DIBAL-H (11.7mL,11.7mmol), stirring at the same temperature for 30min, and slowly increasing to 0 deg.C. The reaction was stopped by adding 2mL of anhydrous methanol, and 200mL of 10% aqueous citric acid solution was added. At this time, a white solid precipitated and was stirred at the temperature until the white solid disappeared. Extraction with dichloromethane was performed 3 times, dried, and the crude product was concentrated by column chromatography (PE: EA ═ 5:1) to give compound 42(0.57g,3.24mmol) as a colorless slightly viscous liquid with a yield of 61%.
Synthesis of 4 Compounds LWQ-163
Compound 7(0.1g,0.47mmol), compound 42(0.18g,0.94mmol) and dihydropyridine ester (0.17g,0.66mmol) were dissolved in a mixed solvent of DCM/MeOH, and TFA (5. mu.L, 0.05mmol) was added with stirring. After the addition, the temperature is raised to 45 ℃ for reaction for 4 h. And (3) spin-drying the reaction solution, diluting with EA, and adjusting the pH value to 8-9 by using saturated sodium bicarbonate. Drying, concentrating, and purifying the crude product by column chromatography to obtain a tan solid compound LWQ-163(0.1g,0.26mmol), with a yield of 54%.1H NMR(400MHz,CDCl3)δ10.41(s,1H),7.96(d,J＝0.9Hz,1H),7.05(d,J＝1.0Hz,1H),6.34(d,J＝1.1Hz,1H),4.43-4.40(m,1H),4.15-4.11(m,2H),3.76-3.72(m,2H),3.53-3.50(m,2H),2.96-2.87(m,1H),1.48(s,9H).ESI-MS:381.0848[M+H].
5 Synthesis of Compounds LWQ-162
Compound LWQ-163(50mg,0.13mmol) was dissolved in 1M dioxane hydrochloride and stirred at room temperature for 1 h. The reaction solution was spin-dried, diluted with aqueous sodium bicarbonate solution, EA extracted 3 times, washed 1 time with saturated aqueous sodium chloride solution, dried, concentrated, and the crude product was subjected to column chromatography to give LWQ-162(20mg,0.07mmol) as a yellow solid with a yield of 53%.
1H NMR(400MHz,CDCl3)δ8.00(s,1H),6.98(s,1H),6.45(s,1H),6.30(s,1H),6.14(s,1H),4.24-4.20(m,1H),4.08-4.04(m,2H),3.69-3.66(m,2H),3.44–3.41(m,2H).13C NMR(101MHz,DMSO)δ145.8,137.6,127.8,121.7,110.1,107.2,101.7,55.2,48.9.ESI-MS:281.0392[M+H]
EXAMPLE 4 Synthesis of Compounds LWQ-192
The synthetic route is as follows:
1 Synthesis of intermediate 44
Intermediate 7(300mg,1.41mmol), 43(422mg, 2.12mmol) dihydropyridine ester (358mg, 1.41mmol) were added to a reaction flask, dissolved in 10mL of a mixture of dichloromethane and methanol (1: 1), trifluoroacetic acid (10 μ L, 0.14mmol) was slowly added dropwise, refluxed at 45 ℃ for 3h, TLC checked for completion of the reaction, dichloromethane and methanol were dried by spin drying, and the crude product was purified by column chromatography (DCM: MeOH ═ 80:1 → 40:1) to give 432mg of intermediate 44 as a yellow solid in 77% yield.
1H NMR(400MHz,CDCl3)δ10.41(s,1H),7.96(d,J＝0.9Hz,1H),7.05(d,J＝1.0Hz,1H),6.34(d,J＝1.1Hz,1H),4.43-4.40(m,1H),4.15-4.11(m,2H),3.76-3.72(m,2H),3.43-3.51(m,2H),2.96-2.87(m,2H),1.38(s,9H).HRMS(AP-ESI)Calcd.For C13H15BrN4O2339.0378(M+H)+.Found:339.0354.
2 Synthesis of Compounds LWQ-192
Adding the intermediate 44(35mg,0.09mmol) and palladium carbon (5%) (10mg) into a three-necked flask, dissolving with 5mL of methanol, introducing hydrogen through a tee joint, ventilating for three times, reacting at room temperature for 1h, detecting complete reaction by TLC, filtering off the palladium carbon, and removing methanol to obtain LWQ-19228 mg with 93% yield.
1H NMR(400MHz,DMSO)δ12.67(s,1H),11.23(s,1H)8.01(s,1H),6.94(s,1H),6.74(s,1H),4.72(m,1H),3.78-3.50(m,4H),3.18(dd,J＝9.8,4.9Hz,2H),1.83(m,1H),1.39(m,2H).13C NMR(300MHz,d6-DMSO)δ160.42,148.43,128.0,124.8,110.25,108.75,59.44,35.16,46.46,37.64,30.53.
EXAMPLE 5 Synthesis of Compounds LWQ-186
The synthetic route is as follows:
1 Synthesis of intermediate 46
Pyridinium chlorochromate (445 mg) was added to a reaction flask, dissolved in 5mL of dichloromethane, 45(200 mg) was slowly added dropwise to a solution of pyridinium chlorochromate in dichloromethane, reacted at room temperature for 1.5h, the reaction was complete by TLC, filtered through celite, and subjected to column chromatography (PE: EA ═ 5:1) to give 124mg of a colorless transparent liquid in 63% yield.
2 Synthesis of intermediate 47
Adding the compound 46(100mg,0.90mmol) and hydroxylamine hydrochloride into a reaction bottle, dissolving by using 10mL (90% ethanol), slowly adding sodium hydroxide (327mg,8.17mmol) in batches, stirring at room temperature for 30min, then heating to 80 ℃, refluxing for 1h, detecting complete reaction by TLC, cooling the reaction liquid to room temperature, adding 10mL of dilute hydrochloric acid, extracting by using dichloromethane, drying and concentrating to obtain an intermediate 47 which is a colorless transparent liquid 123mg, wherein the yield is 100%.
3 Synthesis of intermediate 48
Compound 47(210mg,1.63mmol) was dissolved in 5mL of methanol, and sodium cyanoborohydride (174mg,2.77mmol) was added with stirring at 0 ℃ followed by slow dropwise addition of 12N concentrated hydrochloric acid and reaction at room temperature for 4 h. When the raw materials are completely reacted, adjusting the pH to 9 by using 6N sodium hydroxide aqueous solution, and then adding dichloromethane: extraction with 3:1 isopropanol, drying and concentration gave 100mg of crude product as a pale yellow liquid in 47% yield.
Synthesis of 4 Compounds LWQ-186
Intermediate 29(50mg,0.18mmol) was dissolved in 3mL of N, N-dimethylformamide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (45mg,0.23mmol), 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate (85mg,0.22mmol), N-diisopropylethylamine (60 μ L,0.36mmol) were added to a reaction flask, and intermediate 48(50mg,0.36mmol) was added to the mixture to react at room temperature for 3 hours, TLC detection was complete, a large amount of water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying and concentration were carried out to obtain a crude product, which was purified by column chromatography (DCM: MeOH 80:1 → 40:1) to obtain LWQ-37 mg of yellow solid with a yield of 53%.
1H NMR(400MHz,DMSO)δ10.02(s,1H),8.07(s,1H),6.77(s,1H),6.29(s,1H),6.16(s,2H),5.25(s,2H),3.85(d,J＝13.2Hz,2H),3.42(d,J＝7.2Hz,2H),3.29(t,J＝11.2Hz,2H),2.06–1.80(m,1H),1.57(d,J＝12.9Hz,2H),1.24–1.05(m,2H).HRMS(AP-ESI)Calcd.For C16H20BrN3O3 404.0688(M+H)+.Found:404.1054.
EXAMPLE 6 inhibitory Activity of Compounds of the present invention on IDO protein
The recombinant human IDO protein is obtained by expressing through escherichia coli and purifying through nickel affinity chromatography. The compound has IDO inhibitory activity, and L-tryptophan is used as a substrate. The test compound was dissolved in 10% DMSO to prepare a dilution. 5uL of the dilution was added to 100. mu.L of the reaction. The 100. mu.L reaction contained 0.5% DMSO, 40nmol/L IDO, 900. mu. mol/L L-tryptophan, and other reaction co-products (potassium phosphate buffer, ascorbic acid, catalase, methylene blue). The reaction mixture was incubated at 37 ℃ for 180 minutes and stopped by the addition of trichloroacetic acid. The inhibitory activity of the compounds on IDO was evaluated by measuring the concentration of N-formyl kynurenine produced at 321nm using a Tecan Infinite M1000 microplate reader. The negative control was 5. mu.L of buffer instead of IDO. Clinical stage III IDO inhibitor INCB024360 was used as positive control to verify whether the IDO activity detection system established in this experiment was effective.
Three replicates of wells were set for each concentration. Data analysis was performed using software Graphpad Prism. Absorbance (A) in the reaction solution containing no test compoundt) Defined as 100% activity. Absorbance (A) in the reaction solution containing no IDOb) Defined as 0% activity. For the test compounds, the activity is calculated as: % activity ═ A-Ab)/(At-Ab)]X 100, wherein A is the absorbance of the reaction solution containing the test compound. The formula for calculating the inhibition rate is as follows: % inhibition is 100-% activity.
By the above experimental method, the inhibitory activity against IDO of some of the compounds of the present invention was tested. The inhibitory activity of specific compounds at a concentration of 10. mu.M is shown in Table 1.
Wherein A represents an inhibition rate of more than 80%, B represents an inhibition rate of 60-79%, and C represents an inhibition rate of 30-59%; d represents that the inhibition rate is 10-39%, E represents that the inhibition rate is less than 10%; the inhibition of the positive control at a concentration of 0.05. mu.M was 46%.
Table 1 classification of the inhibitory activity of the compounds of the invention on IDO
Experiments prove that the indazole compound provided by the invention has an excellent inhibiting effect on IDO, and can be used for preventing and/or treating various diseases, such as Alzheimer disease, cataract, infection related to cellular immune activation, autoimmune diseases, AIDS, cancer, depression or tryptophan metabolic disorder and the like.
Claims (6)
1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (I):
wherein the content of the first and second substances,
R1selected from hydrogen or C1An alkyl group;
R2selected from hydrogen, R3Selected from halogen, R4Selected from hydrogen, R5Is selected from-NH-R6；
Or, R2Is selected from-NH-R6、R3Selected from hydrogen, R4Selected from halogen, R5Selected from hydrogen;
the halogen is selected from fluorine, chlorine or bromine;
the R is6Selected from one of the following groups:
2. the compound of claim 1, wherein: the compound is selected from one of the following compounds:
3. a compound, or a pharmaceutically acceptable salt thereof, which is one of the following:
4. use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament of the IDO inhibitor class.
5. Use according to claim 4, characterized in that: the drug is a drug for preventing and/or treating Alzheimer's disease, cataract, infection related to cellular immune activation, autoimmune disease, AIDS, cancer, depression or tryptophan metabolism disorder.
6. A pharmaceutical composition characterized by: the compound or the pharmaceutically acceptable salt thereof as an active ingredient, and pharmaceutically acceptable auxiliary materials.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2004029050A1 (en) * | 2002-09-25 | 2004-04-08 | Memory Pharmaceuticals Corporation | Indazoles, benzothiazoles, and benzoisothiazoles, and preparation and uses thereof |
| WO2015150097A1 (en) * | 2014-04-04 | 2015-10-08 | Iomet Pharma Ltd | Indole derivatives for use in medicine |
| WO2016071293A2 (en) * | 2014-11-03 | 2016-05-12 | Iomet Pharma Ltd | Pharmaceutical compound |
| CN107033087A (en) * | 2016-02-04 | 2017-08-11 | 西华大学 | 1H- indazole -4- aminated compounds and its purposes as IDO inhibitor |
| CN107840826A (en) * | 2016-09-19 | 2018-03-27 | 西华大学 | 1H indazoles analog derivative and its purposes as IDO inhibitor |
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| WO2004029050A1 (en) * | 2002-09-25 | 2004-04-08 | Memory Pharmaceuticals Corporation | Indazoles, benzothiazoles, and benzoisothiazoles, and preparation and uses thereof |
| CN100484937C (en) * | 2002-09-25 | 2009-05-06 | 记忆药物公司 | Indazoles, benzothiazoles, and benzoisothiazoles, and preparation and uses thereof |
| WO2015150097A1 (en) * | 2014-04-04 | 2015-10-08 | Iomet Pharma Ltd | Indole derivatives for use in medicine |
| WO2016071293A2 (en) * | 2014-11-03 | 2016-05-12 | Iomet Pharma Ltd | Pharmaceutical compound |
| CN107033087A (en) * | 2016-02-04 | 2017-08-11 | 西华大学 | 1H- indazole -4- aminated compounds and its purposes as IDO inhibitor |
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