CN107840826B - 1H-indazole derivatives and application thereof as IDO (intermediate bonded oxygen) inhibitor - Google Patents
1H-indazole derivatives and application thereof as IDO (intermediate bonded oxygen) inhibitor Download PDFInfo
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- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention discloses a 1H-indazole derivative shown in 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 invention relates to 1H-indazole derivatives, a preparation method thereof and application thereof 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 1H-indazole derivative or a pharmaceutically acceptable salt or 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 H, halogen, C1～C6Alkyl or C1～C6A haloalkyl group;
R2selected from substituted or unsubstituted aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is independently substituted with one or more substituents selected from halogen, -NH2、-(CH2)aOH, -COOH, nitro, C1～C6Alkyl radical, C1～C6Haloalkyl, -CONH-R3or-NH-R4Substituted with the substituent(s);
R3is selected from C1～C6An alkyl group;
R4(ii) select-CH2COOH or 5-6 membered cycloalkyl or C1～C6Alkyl-substituted cycloalkyl groups;
a is 0 or 1.
Further, said R1Selected from H, Cl, Br, -CF3、-CHX2、-CH2X or-CH3。
Further, said C1～C6The alkyl group is selected from methyl.
Further, said C1～C6Haloalkyl is trifluoromethyl.
Further, the aryl is selected from phenyl, the heteroaryl is selected from benzothiophene, the cycloalkyl is selected from cyclohexyl, and the heterocyclic group is selected from a 4-6-membered nitrogen heterocyclic group.
Further, said R2Selected from the group consisting ofOne of them is:
further, the compound is selected from one of the following compounds:
the invention also provides the application of the compound shown in the formula (I), the compound shown in the formula (II), or the pharmaceutically acceptable salt, the prodrug or the solvate thereof in preparing IDO inhibitor medicines,
R1as defined above.
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 characterized in that: the compound or the pharmaceutically acceptable salt thereof is used as an active ingredient, and pharmaceutically acceptable auxiliary materials are added to prepare the preparation.
Said C is1～C6Alkyl is C1、C2、C3、C4、C5、C6The alkyl group of (1) is a straight or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, and the like.
In the present invention, the meanings of the acronyms are as follows:
and (3) DHP: 1,4-Dihydropyridine, Dihydropyridine ester.
DMF: dimethylformamide, Dimethylformamide.
DCC: dicyclohexylcarbodiimide (Dicyclohexylcarbodiimide).
DIBAL-H: diasobutylaluminum bydride, diisobutylaluminium hydride
DIEA: n, N-Diisopropylethylamine, N, N-Diisopropylethylamine.
EA: ethyl acetate, Ethyl acetate.
EDCI: 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride.
Et3N: triethylamine, Triethylamine.
HOBT: 1-Hydroxybenzotriazole, 1-Hydroxybenzotriazole.
HATU: 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate.
PE: petroleum ether, Petroleum ether.
TFA: tallow Fatty Acid, trifluoroacetic Acid.
THF: tetrahydrofuran, Tetrahydrofuran.
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.
Detailed Description
The reagents and starting materials were obtained from commercially available commercial sources, except for starting materials specifically labeled for the source, which were purchased from Douglas chemical company.
Example 1 Synthesis of intermediate starting Material
(1) Synthesis of 5a and 5b
Synthesis of 2, 5-dimethyl-1, 3-dinitrobenzene (2a)
After dissolving xylene (1a) (2.00mL, 16.23mmol) in 20mL concentrated sulfuric acid in a dry 50mL pear-shaped flask, potassium nitrate (4.91g, 48.68mmol) was slowly added under stirring at room temperature, and the reaction was stirred at room temperature for 2 hours, the reaction mixture was slowly poured into ice water, filtered, the cake was dried under vacuum, and purified by column chromatography (PE: EA 80:1) to obtain a pale yellow solid (2a) (1.62g, yield 51%). And (3) structural identification:1H-NMR(400MHz,CDCl3,ppm):δ13.0(br,1H,NH),7.42(s,2H,Ar-H),2.45(s,6H,CH3).ESI-MS:197.05[M+H].
synthesis of 2-methyl-5-trifluoromethyl-1, 3-dinitrobenzene (2b)
2-methyl-5-trifluoromethyl-1, 3-dinitrobenzene (2b) was prepared as a yellow solid in 75% yield according to the method for preparing 2, 5-dimethyl-1, 3-dinitrobenzene (2a) from 4-trifluoromethyl-toluene (1b) (CAS: 6140-17-6, available from Dougenok reagent). And (3) structural identification:1H-NMR(400MHz,CDCl3,ppm):δ13.0(br,1H,NH),8.29(s,2H,Ar-H),2.69(s,3H,CH3).ESI-MS:251.02[M+H].
synthesis of 2, 5-dimethyl-3-nitroaniline (3a)
2, 5-dimethyl-1, 3-dinitrobenzene (2a) (196.0mg,1.00mmol) was dissolved in MeOH (6mL) and dioxane (3mL), concentrated hydrochloric acid (0.60mL) and Fe (168.90mg,3.00mmol) were added, and the reaction was stirred to 80 ℃ for 12 h. Filtering, spin-drying the reaction solution, and saturating NaHCO3Adjusting the pH value of the solution to 7-8, extracting with EA for three times, and using saturated salt for an organic layerWashed with water, dried over anhydrous magnesium sulfate and spin-dried to obtain 142.8mg of a pale yellow solid with a yield of 86%.
Synthesis of 2-methyl-5-trifluoromethyl-3-nitroaniline (3b)
Following the procedure for the preparation of 5-bromo-2-methyl-3-nitroaniline (3a) in example 1, 2-methyl-5-trifluoromethyl-3-nitroaniline (3b) was prepared in the form of a yellow solid with a yield of 68%.
Synthesis of 6-methyl-4-nitro-1H-indazole (4a)
2, 5-dimethyl-3-nitroaniline (9a) (83.0mg,0.50mmol) was dissolved in glacial acetic acid (3mL) and NaNO was added2(69.0mg,1.00mmol) was dissolved in water (0.5mL) and NaNO was added with stirring at room temperature2Slowly dripping the aqueous solution into a glacial acetic acid solution of 2, 5-dimethyl-3-nitroaniline (3a), separating out solids, stirring at room temperature for reaction for 13h, pouring the reaction solution into ice water, filtering, and drying a filter cake in a vacuum drying oven for 12h to obtain 79.6mg of yellow solids with the yield of 90%. Purity 98% by HPLC; and (3) structural identification:1H-NMR(400MHz,d6-DMSO,ppm):δ12.46(br,1H),8.20(s,1H),8.10(s,1H),7.87(s,1H),2.35(s,3H).ESI-MS:178.18[M+H].
synthesis of 6-trifluoromethyl-4-nitro-1H-indazole (4b)
According to the method for producing 6-bromo-4 nitro-1H-indazole (4a), 6-trifluoromethyl-4 nitro-1H-indazole (4b) was produced with a yield of 79%. Purity by HPLC was 98%. And (3) structural identification:1H-NMR(400MHz,d6-DMSO,ppm):δ12.46(br,1H),8.20(s,1H),8.12(s,1H),7.80(s,1H).ESI-MS:232.13[M+H].
synthesis of 6-methyl-1H-indol-4-amine (5a)
Dissolving 6-methyl-4-nitro-1H-indazole (4a) (50mg,0.28mmol) serving as a raw material in a mixed solvent of ethanol (2mL) and water (1mL), adding ammonium chloride (1.6mg,0.03mmol), adding iron powder (79.1mg,1.41mmol), heating to 80 ℃, stirring for reaction for 0.5H, filtering the reaction solution while hot, and washing filter residues with ethanol. The ethanol was removed under reduced pressure and the aqueous layer was extracted three times with EA. The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, spun dry, and passed through a column (PE: EA ═ 10:1) to give 34.9mg of a pale yellow solid with a yield of 84%. Purity 98% by HPLC;1H-NMR(400MHz,d6-DMSO,ppm):δ12.46(br,1H),7.70(s,1H),7.16(s,1H),6.85(s,1H),4.60(br,2H),2.21(s,3H).ESI-MS:148.10[M+H].
synthesis of 6-trifluoromethyl-1H-indazol-4-amine (5b)
The compound 4-trifluoromethyl-toluene (4b) was used as the starting material. See compound 5a for compound 5 b. Yellow solid, yield 95%. Purity 98% by HPLC;1H-NMR(400MHz,CDCl3,ppm):δ13.0(br,1H,NH),8.10(s,1H,indazole-H),7.21(s,1H,indazole-H),6.58(s,1H,indazole-H),4.37(br,2H,NH2).ESI-MS:202.05[M+H].
(2) synthesis of 5c and 5d
The starting material 6-bromo-4-nitro-1H-indazole (4c) or 6-chloro-4-nitro-1H-indazole (4d) (8.26mmol, available from south Jiangsu Biotech Ltd.) was dissolved in a mixed solvent of ethanol (20mL) and water (10mL), ammonium chloride (221.5mg,4.13mmol) was added, a portion of iron powder (1.3g,23.46mmol) was added first, the temperature was raised to 80 ℃ and the reaction was stirred for 45 minutes, the remaining iron powder (1.0g,17.86mmol) was added and the reaction was stirred for 20 minutes. After TLC detection of the reaction completion of the starting material, the reaction solution was filtered while hot, and the residue was washed with ethanol (10 mL). Ethanol was removed under reduced pressure and the aqueous layer was extracted three times with EA (20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous magnesium sulfate, spin-dried and column-chromatographed (PE: EA ═ 8:1) to give a pale yellow solid in 92-94% yield. The purity is 98% by HPLC; structural characterization of 5 c:1H-NMR(400MHz,d6-DMSO,ppm):δ12.46(br,1H),8.15(s,1H),7.56(s,1H),6.88(s,1H),5.80(br,2H).ESI-MS:213.05[M+H]structural characterization of 5 d:1H-NMR(400MHz,d6-DMSO,ppm):δ12.46(br,1H),8.14(s,1H),7.54(s,1H),6.89(s,1H),5.78(br,2H).ESI-MS:168.03[M+H].
example 2 Synthesis of Compounds N1, N2, N3, N4 and N5 of the invention
6-bromo-N- (3-trifluoromethylbenzyl) -1H-indazol-4-amine (N1).
Amine 5c (0.28mmol) and benzaldehyde 6(0.24mmol) were dissolved in dichloromethane (DCM, 3mL) and DHP (83.5mg,0.33mmol) and appropriate amount added
(840.2mg), trifluoroacetic acid (TFA, 17.6 μ L,0.24mmol) was added dropwise thereto, the mixture was refluxed at 40 ℃ for 12 hours, and the reaction mixture was filtered, spin-dried, and subjected to column chromatography (PE: EA ═ 10:1) to obtain compound N1. The yield is 53.9%; a red powdered solid;1H-NMR(400MHz,d6-CDCl3,ppm):δ8.00(s,1H,indazole-H3),7.69(s,1H,Ar-H),7.63-7.50(m,3H,Ar-H),7.06(s,1H,Ar-H),6.34(s,1H,Ar-H),4.56(d,2H,J＝4.4Hz,benzyl-CH2).13C-NMR(100MHz,d6-CDCl3,ppm):δ141.9,141.7,139.2,131.7,131.4,130.8,129.4,124.6,124.3,122.9,112.5,103.5,102.2,47.6.ESI-MS:370.01[M+H].
the corresponding aldehyde starting materials were selected and prepared in a similar manner to give compounds N2, N3, N4, N5, with the following results and characterization:
4- ((6-bromo-1H-indazol-4-amino) methyl) benzothiophene (N2), yield 31.8%; a yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):δ14.09(s,1H,indazole-NH),7.90(d,1H,J＝7.0Hz,Ar-H),7.80(d,1H,J＝7.0Hz,Ar-H),7.48(s,1H,NH),7.44(s,1H,Ar-H),7.22(s,1H,Ar-H),6.70(s,1H,Ar-H),6.59(s,1H,Ar-H),4.76(d,2H,J＝5.0Hz,benzyl-CH2).ESI-MS:356.99[M+H].
3- ((6-bromo-1H-indazol-4-amino) methyl) phenol (N3) yield 49.6%; a light yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):δ12.97(s,1H,indazole-NH),9.63(s,1H,OH),8.23(s,1H,indazole-H),7.12(t,2H,J＝7.7Hz,NH),6.82-6.78(m,3H,Ar-H),6.03(d,1H,J＝0.9Hz,Ar-H),5.77(s,1H,Ar-H),4.36(d,2H,J＝5.8Hz,benzyl-CH2).13C-NMR(100MHz,d6-DMSO,ppm):δ158.0,143.2,141.4,132.6,129.9,121.8,118.0,115.3,114.2,114.0,112.6,101.1,100.1,46.3.ESI-MS:318.02[M+H].
4- ((6-bromo-1H-indazol-4-amino) methyl) benzyl alcohol (N4), yield 49.6%; a light yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):δ12.84(s,1H,indazole-NH),8.22(s,1H,indazole-H3),7.35-7.27(m,5H,Ar-H),6.82(s,1H,NH),6.03(d,1H,J＝1.1Hz,Ar-H),5.15(s,1H,OH),4.47(s,2H,CH 2NH),4.42(s,2H,CH 2COOH).13C-NMR(100MHz,d6-DMSO,ppm):δ143.2,142.2,141.6,138.2,132.6,127.2,127.1,121.7,112.6,101.2,100.3,63.2,48.2.ESI-MS:332.03[M-H].
6-bromo-N- (4-nitrobenzyl) -1H-indazol-4-amine (N5) as a light brown solid; the yield is 63.1%;1H-NMR(400MHz,d6-DMSO,ppm):δ12.90(s,1H,indazole-NH),8.23(d,2H,J＝3.8Hz,Ar-H),8.22(s,1H,indazole-H),7.65(d,2H,J＝8.6Hz,Ar-H),7.48(s,1H,-NH),6.86(s,1H,Ar-H),6.01(s,1H,Ar-H),4.62(d,2H,J＝4.8Hz,benzyl-CH2).13C-NMR(100MHz,d6-DMSO,ppm):δ148.5,147.8,147.0,142.7,132.5,128.5,124.1,121.7,112.6,101.3,45.8.ESI-MS:347.01[M+H].
example 3 Synthesis of Compounds N6 and N7 of the invention
4- ((6-methyl-1H-indazol-4-amino) methyl) benzoic acid (N6).
Compound N6 was synthesized in a similar manner to that in example 2, except that compound 5a was used instead of compound 5c, to give compound N6. The yield is 42.0%; a pale yellow powdery solid;1H-NMR(400MHz,d6-DMSO,ppm):δ12.72(s,2H,COOH and indazole-NH),8.12(s,2H,indazole-H3and NH),7.91(d,2H,J＝8.1Hz,Ar-H),7.50(d,2H,J＝8.1Hz,Ar-H),6.47(s,1H,Ar-H),5.77(s,1H,Ar-H),4.50(s,2H,benzyl-CH2),2.21(s,3H,CH3),ESI-MS:282.12[M+H].
4- ((6-methyl-1H-indazol-4-amino) methyl) benzyl alcohol (N7).
Selecting corresponding aldehyde raw materials, and preparing the compound N7 according to a similar method, wherein the yield is 53.7%; a pale yellow powdery solid;1H-NMR(400MHz,d6-DMSO,ppm):δ9.23(s,2H,indazole-NH and OH),8.12(s,1H,indazole-H),7.19(d,2H,J＝8.4Hz,Ar-H),6.72(d,2H,J＝8.4Hz,Ar-H),6.47(s,1H,Ar-H),5.87(s,1H,Ar-H),4.29(d,2H,J＝8.4Hz,benzyl-CH2),4.29(s,3H,CH3).ESI-MS:254.12[M+H].
example 4 Synthesis of Compounds N8, N9, N10, N11 and N12 of the invention
6-trifluoromethyl-N- (3-trifluoromethylbenzyl) -1H-indazol-4-amine (N8).
Compound N1 was synthesized in a similar manner to that in example 2, except that compound 5b was used instead of compound 5c, to give compound N8. The yield is 34.5%; a yellow solid; 1H-NMR (400MHz, d 6-CDCl)3,ppm):δ10.92(s,1H,indazole-NH),8.11(s,1H,indazole-H3),7.72(s,1H,Ar-H),7.65-7.51(m,2H,Ar-H and NH),7.20(s,1H,Ar-H),6.41(s,1H,Ar-H),4.61(d,2H,J＝5.2Hz,benzyl-CH2).13C-NMR(100MHz,d6-CDCl3,ppm):δ166.0,162.2,141.8,141.0,140.4,139.1,131.7,130.9,129.4,124.7,124.6,124.5,124.4,123.1,114.9,97.1,96.0,61.5.ESI-MS:360.09[M+H].
The corresponding aldehyde starting materials were selected and prepared in a similar manner to give compounds N9, N10, N11 and N12. The results and characterization were as follows:
4- ((6-trifluoromethyl-1H-indazol-4-amino) methyl) benzothiophene (N9), yield 54.7%; a yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):δ13.21(s,1H,indazole-NH),8.37(s,1H,indazole-H3),7.88(d,1H,J＝7.8Hz,Ar-H),7.78(d,1H,J＝7.6Hz,Ar-H),7.60(s,1H,NH),7.05(s,1H,Ar-H),6.36(s,1H,Ar-H),4.82(d,2H,J＝5.9Hz,benzyl-CH2).13C-NMR(100MHz,d6-DMSO,ppm):δ145.3,142.7,140.5,140.0,139.2,132.7,128.6,126.7,124.8,124.4,123.7,122.9,121.8,115.3,95.8,94.0,42.6.ESI-MS:348.07[M+H].
n-methyl-3- (((6-trifluoromethyl-1H-indol-4-) amino) methyl) benzamide (N10), yield 60.5%; a yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):δ13.18(s,1H,indazole-NH),8.43(s,1H,CONH),8.37(s,1H,indazole-H),7.91(s,1H,Ar-H),7.72(d,1H,J＝7.7Hz,Ar-H).7.55(d,1H,J＝7.7Hz,Ar-H).7.46-7.41(m,2H,Ar-H),6.15(s,1H,Ar-H),4.55(d,2H,J＝5.8Hz,benzyl-CH2),2.78(d,3H,J＝4.5Hz,-CH3).13C-NMR(100MHz,d6-DMSO,ppm):δ167.1,143.1,140.5,140.1,135.2,132.7,130.2,128.6,125.9,124.0,115.1,95.4,93.7,46.5,31.1.ESI-MS:349.12[M+H].
(1S,2S) -2- ((6-bromo-1H-indazol-4-amino) methyl) cyclohexylAlcohol n11. yield 52.7%; a beige solid;1H-NMR(400MHz,d6-DMSO,ppm):δ13.10(s,1H,indazole-NH),8.34(s,1H,indazole-H),6.95(s,1H,Ar-H),6.27(s,1H,Ar-H)),3.69-3.65(m,1H,cyclohexanol-H),3.24-3.18(m,1H,cyclohexanol-H),2.98-2.92(m,1H,cyclohexanol-H),1.97-1.88(m,2H,CH2NH),1.59-0.98(m,8H,cyclohexanol-H).13C-NMR(100MHz,d6-DMSO,ppm):δ143.8,140.7,132.6,129.1,126.9,124.2,114.9,93.0,71.7,46.3,44.7,36.0,29.7,25.5,24.9.ESI-MS:314.15[M+H].
3- ((6-trifluoromethyl-1H-indazol-4-amino) methyl) benzoic acid (N12) yield 81.2%; a yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):δ13.11(s,2H,COOH and indazole-NH),8.36(d,1H,J＝0.6Hz,Ar-H),8.01(s,1H,Ar-H),7.84(d,1H,J＝7.7Hz,Ar-H),7.66(d,1H,J＝7.7Hz,Ar-H),7.51-7.46(m,2H,NH and Ar-H),7.00(s,1H,Ar-H),6.15(s,1H,Ar-H),4.58(d,2H,J＝6.0Hz,).ESI-MS:336.09[M+H].
EXAMPLE 5 Synthesis of Compound N13 of the present invention
6-chloro-N- (3-trifluoromethylbenzyl) -1H-indazol-4-amine (N13).
Compound N13 was synthesized in a similar manner to that in example 2, except that compound 5d was used instead of compound 5c, to give compound N13. The yield is 58 percent; a yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):δ12.42(s,2H,COOH and indazole-NH),8.14(s,2H,indazole-H3and NH),8.05(d,2H,J＝8.1Hz,Ar-H),7.76(d,2H,J＝8.1Hz,Ar-H),6.58(s,1H,Ar-H),5.79(s,1H,Ar-H),4.58(s,2H,benzyl-CH2)；ESI-MS:302.02[M+H].
EXAMPLE 6 Synthesis of Compound N14 of the present invention
Synthesis of Compound (9)
The raw material (5b) (150mg,0.746mmol) and the raw material (8) (185.4mg,0.896mmol) were dissolved in DCM (7mL), DHP (264.2mg,1.04mmol) was added thereto, trifluoroacetic acid (55.8uL,0.746mmol) was added dropwise, the reaction was refluxed at 40 ℃ for 12 hours, and the reaction mixture was filtered, dried by spinning, and passed through a column (DCM: MeOH ═ 80:1) to obtain 203.8mg of the compound (9) as a yellow solid in a yield of 72.3%.
Synthesis of (3- ((6- (trifluoromethyl) -1H-indol-4-) amino) phenyl) aminoacetic acid (N14)
Compound (9) (100mg,0.255mmol) was dissolved in ethanol and water (3:3mL), and sodium hydroxide (30.6mg,0.765mmol) was added thereto, the mixture was stirred at room temperature for 12 hours, the reaction mixture was stirred with ethanol under reduced pressure, the pH was adjusted to about 4 with 1N hydrochloric acid, EA was extracted, dried over anhydrous magnesium sulfate, and the mixture was applied to a column (DCM: MeOH ═ 30:1) to obtain compound N14 as a yellow solid. The yield is 42.3%; a yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):δ13.12(s,1H,indazole-NH),8.36(s,1H,indazole-H3),7.33-6.61(m,5H,Ar-H),6.41(s,1H,Ar-H),6.27(s,1H,NH),4.36(d,2H,J＝5.8Hz,benzyl-CH2),3.75(s,2H,NHCH2).13C-NMR(100MHz,d6-DMSO,ppm):δ173.0,148.8,143.4,140.6,140.4,129.4,128.9,124.5,120.0,115.6,115.1,111.6,111.0,95.2,93.6.ESI-MS:365.12[M+H].
example 7 Synthesis of Compounds N15 and N16 of the invention
Synthesis of Compound (11)
The starting material (5b) (200.0mg,1.0mmol) and the starting material (10) (181.2mg,1.2mmol) were dissolved in DCM (10mL), DHP (354.2mg,1.4mmol) was added dropwise, trifluoroacetic acid (74.5uL,1.0mmol) was added dropwise, and the reaction was refluxed at 40 ℃ for 12 hours. The reaction was filtered, spun-dried, and passed through a column (DCM 60mL, DCM: MeOH ═ 50: 1) to give compound (11)278.8mg of a yellow solid in 83.0% yield.
Synthesis of Compound (N15)
Compound (11) (200mg,0.595mmol) was dissolved in ethanol and water (1:1), ammonium chloride (16.5mg,0.3mmol) was added thereto, iron powder (166.7mg,2.98mmol) was added in portions, reaction was carried out at 80 ℃ for 30 minutes, the reaction solution was filtered while hot, the solvent was dried under reduced pressure, and column-packed (DCM: MeOH ═ 30:1) was passed through to obtain 155.9mg of compound (N15) as a pale yellow solid with a yield of 85.6%.
Synthesis of Compound (13)
The raw material (N15) (68.3mg,0.223mmol) and the raw material (12) (30.0mg,0.268mmol) were dissolved in DCM (2mL), DHP (79.1mg,0.312mmol) was added dropwise, trifluoroacetic acid (16.6uL,0.223mmol) was added dropwise, and the reaction was refluxed at 40 ℃ for 12 hours. The reaction was filtered, spun-dried, and passed through a column (DCM: MeOH: 100:1) to give compound (13)57.3mg of a pale yellow solid in 66.2% yield.
Synthesis of 3- ((3- ((6- (trifluoromethyl) -1H-indol-4-) amino) phenyl) amino) -1-cyclohexanol (N16)
Compound (13) (55mg,0.137mmol) was dissolved in ethanol (1mL), placed at 0 ℃, sodium borohydride (76.6mg,0.684mmol) was added, the mixture was warmed to room temperature and stirred for reaction for 12 hours, the reaction solution was cooled to 0 ℃, acetone (2mL) was added to quench the excess sodium borohydride, and the reaction solution was spin-dried over a column (DCM: MeOH ═ 20:1) to give a pale yellow solid compound (N16). The yield is 68.7%; a light yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):δ13.13(s,1H,indazole-NH),8.37(s,1H,indazole-H),7.32(t,1H,J＝5.2Hz,NH),7.01-6.42(m,5H,Ar-H),6.18(s,1H,Ar-H),4.59(s,1H,NH),4.42(s,1H,OH),4.35(d,2H,J＝5.6Hz,benzyl-CH2),3.57(t,1H,J＝4.1Hz,CH),2.51(d,1H,J＝1.8Hz,CH),1.66-0.89(m,8H,CH2).13C-NMR(100MHz,d6-DMSO,ppm):δ148.5,143.4,140.5,140.4,132.8,128.7,126.8,124.1,115.1,114.7,111.5,111.4,95.0,93.7,68.3,65.3,50.0,42.8,35.6,32.2,19.6.ESI-MS:405.19[M+H].
example 8 Synthesis of Compounds N17, N18, N19 and N20 of the invention
Synthesis of Compound 15
Compound 14(2.47g,24.46mmol) was dissolved in anhydrous methanol (30mL) and SOCl was added dropwise under ice bath2(8.78mL,122.30mmol), heating to room temperature after the addition, stirring for 12h, spin-drying the reaction solution to obtain a crude product, namely a white solid compound 15, and directly carrying out the next step of reaction with the yield of 99%.
Synthesis of Compound 16
Compound 15(3.68g,24.46mmol) was dissolved in acetonitrile (25mL) and Et was added dropwise under ice bath3N (3.39mL,24.46 mmol). Will (Boc)2O (5.87g,26.91mmol) was dissolved in acetonitrile (5mL) and added dropwise to the reaction mixture. After the addition, the temperature is raised to room temperature and the mixture is stirred for 4 hours, then the solid in the reaction solution is filtered, the filtrate is dried by spinning, and the residue is dissolved by adding water. Extracting with EA for 3 times, mixing organic layers, washing with saturated sodium chloride aqueous solution once, drying the organic layer with anhydrous magnesium sulfate, filtering, and spin-drying to obtain crude product. The crude product was purified by column chromatography (PE: EA ═ 20:1) to give compound 16(3.00g,9.73mmol) as a pale yellow oil in 65% yield.
Synthesis of Compound 17
Compound 16(2.00g,10.64mmol) was placed in a three-necked flask, DCM was added under argon to dissolve it, and the flask was stirred at-78 ℃. After 10min DIBAL-H (2.3mL,1M) was slowly added dropwise. After the addition was completed, the mixture was stirred at-78 ℃ for 30min, and then quenched with 2mL of anhydrous methanol. After 5min, move to ice bath. 200mL of a 10% citric acid aqueous solution was added to the reaction mixture, and a solid was precipitated. Stirring in ice bath for 30min until the solid disappeared, extracting the aqueous layer with EA 3 times, combining the organic layers, washing once with saturated aqueous sodium chloride solution, and drying over anhydrous magnesium sulfate. Filtering, and spin-drying the filtrate to obtain a crude product, namely a light yellow transparent oily liquid compound 17. The next reaction step is directly carried out, and the yield is 99 percent.
Synthesis of Compound 18
Compound 5b (200mg,1.00mmol), compound 17(471mg,2.99mmol) and DHP (352mg,1.39mmol) were dissolved in DCM and TFA (74. mu.l, 1.00mmol) was added dropwise with stirring. After the addition, the temperature is raised to reflux and stirring for 12 hours, and the reaction solution is dried by spinning to obtain a crude product. The crude product was purified by column chromatography (DCM: MeOH ═ 60:1) to give compound 18(100mg,0.27mg) as an orange solid. The yield thereof was found to be 27%.
Synthesis of N- (3-methyl-azacyclobutane) -6-trifluoromethyl-1H-indol-4-amine (N17)
Compound 18(50mg,0.14mmol) was dissolved in DCM (2mL) and TFA (0.30mL,2.63mmol) was added dropwise with stirring. After the addition, the reaction solution was stirred at room temperature for 3 hours, and the crude product was obtained by spin-drying the reaction solution, which was purified by column chromatography (DCM: MeOH ═ 20:1) to obtain a yellow solid compound N17. The yield is 63.0%; a solid of earthy yellow color;1H-NMR(400MHz,d6-DMSO,ppm):δ8.31(s,1H,indazole-H),6.99(s,1H,Ar-H),6.74(t,1H,J＝5.3Hz,NH),6.19(s,1H,Ar-H),3.59(m,2H,CH2),3.45-3.42(m,2H,CH2),3.28(d,2H,J＝6.5Hz,benzyl-CH2),2.97-2.90(m,2H,CH and NH).13C-NMR(100MHz,d6-DMSO,ppm):δ143.5,140.6,132.6,128.8,126.8,124.1,114.9,95.0,92.9,50.7,47.0,33.9.ESI-MS:271.11[M+H].
n18, N19 and N20 were synthesized in a similar manner, except that the starting materials were changed to 19, 20 and 21. The results and characterization were as follows:
(R) -N- (pyrrole-2-methyl) -6- (trifluoromethyl) -1H-indol-4-amine (N18) yield 50.0%; a yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):δ8.33(s,1H,indazole-H),6.98(s,1H,NH),6.95(s,1H,Ar-H),6.65(t,1H,NH),6.22(s,1H,Ar-H),3.37-3.31(m,2H,benzyl-CH2)),3.21-3.09(m,3H,CH2and CH),2.89-2.76(m,1H,NH)1.89-1.38(m,6H,CH2).13C-NMR(100MHz,d6-DMSO,ppm):δ143.5,410.7,132.5,129.1,128.8,114.9,95.0,93.0,57.1,48.7,46.3,29.9,25.4.ESI-MS:285.13[M+H].
(R) -N- (piperidine-2-methyl) -6- (R-methyl-L-piperidine-6-methyl-piperidine-2-carboxylic acid methyl esterTrifluoromethyl) -1H-indol-4-amine (N19) yield 57.0%; a light yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):δ13.23(s,1H,indazole-NH),8.43(s,1H,indazole-H3),7.05(s,2H,NH and Ar-H),6.30(s,1H,Ar-H),3.51-3.18(m,6H,CH2and NH)1.92-1.43(m,6H,CH2).ESI-MS:399.14[M+H].
(S) -N- (piperidine-2-methyl) -6- (trifluoromethyl) -1H-indol-4-amine (N20) yield 57.0%; a light yellow solid;1H-NMR(400MHz,d6-DMSO,ppm):δ13.26(s,1H,indazole-NH),8.48(s,1H,indazole-H),7.14(t,1H,J＝5.5Hz,NH),7.06(s,1H,Ar-H),6.30(s,1H,Ar-H),3.56-3.40(m,2H,CH),2.90-2.85(m,2H,benzyl-CH2),1.92(m,1H,NH)1.70-1.44(m,5H,CH2),1.12(m,2H,CH2)13C-NMR(100MHz,d6-DMSO,ppm):δ142.9,140.6,132.9,129.0,115.3,100.0,96.0,93.2,55.2,45.9,44.5,27.1,22.7,22.2.ESI-MS:299.15[M+H].
EXAMPLE 9 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/LIDO, 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. Make itData analysis was performed with the 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 concentrations of 1. mu.M, 10. mu.M and 100. mu.M is shown in Table 1.
Wherein A represents that the inhibition rate is more than 90%, B represents that the inhibition rate is 70-89%, and C represents that the inhibition rate is 40-69%; 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 inhibitory Activity of the Compounds of the present invention on IDO
The structure-activity relationship shows that: when R is1The effect on activity was in turn: halogen element>Alkane(s)>A halogenated alkane; r2When the structure is longer, the activity is obviously reduced; r2Preferably a substituted benzene ring or a substituted aliphatic ring, and containing polar groups, e.g. OH, COOH, NH2，NO2When the compound is used, the activity of the compound is obviously increased.
Experiments prove that the 1H-indazole derivative 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 (9)
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 halogen, C1～C6Alkyl or C1～C6A haloalkyl group;
R2selected from substituted phenyl, substituted cyclohexyl or non-substituted 5-6 membered nitrogen heterocyclic group, the substituted phenyl and the substituted cyclohexyl are respectively and independently substituted by one or more groups selected from-NH2、-(CH2)aOH, nitro, -CONH-R3or-NH-R4Substituted with the substituent(s); the unsubstituted 5-to 6-membered azaheterocyclyl group is:
R3is selected from C1～C6An alkyl group;
R4selected from 5-6 membered cycloalkyl or C1～C6Alkyl-substituted 5-6 membered cycloalkyl;
a is 0 or 1.
2. The compound of claim 1, wherein: the R is1Selected from Cl, -Br, CF3-or-CH3。
3. The compound of claim 1, wherein: said C is1～C6The alkyl group is selected from methyl.
4. The compound of claim 1, wherein: said C is1～C6Haloalkyl is trifluoromethyl.
5. The compound according to any one of claims 1-4, wherein:the R is2Selected from one of the following groups:
6. a compound or a pharmaceutically acceptable salt thereof, characterized by: the compound is selected from one of the following compounds:
7. the use of a compound according to any one of claims 1 to 6, a compound of formula (II), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of IDO inhibitors,
R1as defined in any one of claims 1 to 4.
8. Use according to claim 7, 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.
9. 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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