CN112979571A - AKR1C3 selective inhibitor, preparation method and application thereof - Google Patents

AKR1C3 selective inhibitor, preparation method and application thereof Download PDF

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CN112979571A
CN112979571A CN202110205333.8A CN202110205333A CN112979571A CN 112979571 A CN112979571 A CN 112979571A CN 202110205333 A CN202110205333 A CN 202110205333A CN 112979571 A CN112979571 A CN 112979571A
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akr1c3
methoxy
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CN112979571B (en
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孙昊鹏
刘阳
何思雨
褚相霖
郭青龙
赵丽
冯锋
柳文媛
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Nanjing Qinling Pharmaceutical Technology Co ltd
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China Pharmaceutical University
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    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
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Abstract

The invention discloses an AKR1C3 selective inhibitor and a preparation method and application thereof, and discloses an AKR1C3 selective inhibitor with a benzamide structure shown in formula (I) and a preparation method thereof, and a target activity test proves that the compound has the activity of obviously inhibiting AKR1C3, can be used as a medicine for further developing and treating and/or preventing diseases by inhibiting aldone reductase AKR1C3, and has an opportunity to lay a molecular foundation for the research of related mechanics of tumor drug resistance.

Description

AKR1C3 selective inhibitor, preparation method and application thereof
Technical Field
The invention relates to an AKR1C3 inhibitor, a preparation method and application thereof, in particular to an AKR1C3 selective inhibitor, a preparation method and application thereof.
Background
Aldehyde ketoreductase 1C (AKR1C) is a subfamily of the Aldehyde Ketoreductase (AKR) superfamily. The human AKR1C subfamily consists of four subtypes (AKR1C1-AKR1C4), which, as phase i metabolic enzymes, are dependent on Nicotinamide Adenine Dinucleotide Phosphate (NADPH) to play a key role in the steroid reduction process. The substrates for these enzymes are wide ranging and include endogenous steroids, prostaglandins, exogenous compounds, and the like.
AKR1C3 has very high sequence homology with AKR1C1, AKR1C2 and AKR1C 4(>86%) but they exhibit different distribution preferences and biological functions. AKR1C1 and AKR1C2 are widely expressed in different tissue types. Among them, AKR1C1 promotes progesterone inactivation and mainly functions as 20-ketosteroid reductase. AKR1C2 can mediate inactivation of potent androgen 5 alpha-dihydrotestosterone, and mainly plays a role as 3-ketosteroid reductase; AKR1C4 is expressed only in the liver and is involved in bile synthesis. AKR1C4 is most catalytically efficient for the formation of 5 α/5 β -tetrahydro steroids; AKR1C3 is expressed in endocrine organs (prostate, adrenal, breast and uterus) and is involved in de novo synthesis of adrenal and steroids; it acts primarily as a 17-ketoreductase, capable of converting delta4-androstene-3, 17-dione and 5 α -androstene-3, 17-dione to testosterone and 5 a-dihydrotestosterone, respectively. Among them, testosterone and 5 a-dihydrotestosterone act as more potent androgens, with enhanced affinity for androgen receptors. In addition, AKR1C3 can also alter the affinity of estrogen receptors and progesterone receptors for ligands in a receptor-mediated manner by reducing estrone, progesterone. Notably, in the prostate gland, AKR1C2 and AKR1C3 have diametrically opposed catalytic effects on the activation of 5 α -dihydrotestosterone. Thus whenHighly selective AKR1C3 inhibitors have many advantages for specific diseases. For example, in prostate cancer, selective AKR1C3 inhibitors are expected to have a beneficial effect in the treatment of prostate cancer, whereas inhibition of AKR1C2 activity, for example, would otherwise enhance prostate proliferation signals.
At the same time, AKR1C3 also exerts a regulatory role in cell proliferation in a hormone-independent manner. AKR1C3, acting as prostaglandin F2 synthase, catalyzes the conversion of prostaglandin D2(PGD2) to 9 α, 11 β -PGF2 α and converts prostaglandin H2(PGH2) to PGF2 α.9 alpha, 11 beta-PGF 2 alpha and PGF2 alpha can stimulate mitogen-activated protein kinase (MAPK) cascade signaling pathway to act on PGF receptor to promote cell proliferation. Thus, as PGF2 synthase, AKR1C3 plays a crucial regulatory role in cell proliferation in a hormone-independent manner. Further study of the pathological mechanisms associated with AKR1C3 may make it a useful target for the treatment of hormone-independent diseases.
In addition, due to the wide range of substrates, AKR1C3 has a dual function in the metabolism of the exogenous compound. In one aspect, AKR1C3 mediates the inactivation of anthracyclines and the development of resistance through its role of carbonyl reductase. On the other hand, AKR1C3 induces activation of nitrogen mustard anticancer drugs by acting as a nitroreductase, converting the nitro group to hydroxylamino group.
In conclusion, AKR1C3 can be a potential marker for a variety of cancer progression processes and an important therapeutic target. The high expression of AKR1C3 is closely related to tumor invasion and chemotherapy drug resistance. Currently, few studies on the biological function of AKR1C3 and inhibitors are reported, and the development of inhibitors specifically targeting AKR1C3 can provide a new treatment strategy for treating tumors. Meanwhile, the high-selectivity AKR1C3 inhibitor can also be applied as a tool molecule for pathological mechanism research. More importantly, the discovery of the effective AKR1C 3-targeted novel-structure drug can provide a new research direction for reversing drug resistance and overcome the key problem in tumor treatment.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a selective AKR1C3 inhibitor with high selectivity and strong activity; another object of the present invention is to provide a process for the preparation of said selective inhibitors of AKR1C 3. The last item of the invention is to provide the use of said selective inhibitors of AKR1C 3.
The technical scheme is as follows: the AKR1C3 selective inhibitor of the invention is a compound shown in a general formula (I) or a pharmaceutically acceptable salt thereof:
Figure BDA0002950249730000021
wherein R is1Represents
Figure BDA0002950249730000022
Phenyl, methoxy, methyl, hydrogen or halogen; r2Represents
Figure BDA0002950249730000023
Hydrogen or halogen; r3Represents
Figure BDA0002950249730000024
Methyl, methoxy, halogen, phenyl or hydrogen; r4Represents halogen, hydrogen, methoxy or nitro; r5Represents a sulfonamide group or hydrogen; n is an integer of 0 to 2.
Further, R1Represents
Figure BDA0002950249730000025
Phenyl, methoxy, methyl or hydrogen; r2Represents
Figure BDA0002950249730000026
Or hydrogen; r3Represents
Figure BDA0002950249730000027
Methyl, methoxy, chloro, phenyl or hydrogen; r4Represents chlorine, hydrogen, methoxy or nitro; r5Represents a sulfonamide group or hydrogen; n is 1 or 2.
The compound is selected from any one of the following compounds:
Figure BDA0002950249730000031
the preparation method of the AKR1C3 selective inhibitor comprises the following steps: substituted 2-hydroxybenzoic acid methyl ester is taken as a starting material, and after nucleophilic substitution reaction with 4- (chloromethyl) -3, 5-dimethylisoxazole, ester groups in an intermediate structure are hydrolyzed into carboxyl groups, and then are respectively subjected to condensation reaction with 4- (2-aminoethyl) benzene sulfonamide and 4- (aminomethyl) benzene sulfonamide hydrochloride to obtain the compound shown in the formula (I).
The preparation method of the AKR1C3 selective inhibitor comprises the following steps: substituted methyl benzoate is taken as a starting material, and is subjected to ester hydrolysis to obtain carboxyl, and then the carboxyl is subjected to condensation reaction with 4- (2-aminoethyl) benzenesulfonamide and 4- (aminomethyl) benzenesulfonamide hydrochloride respectively to obtain the compound shown as the formula (I).
The preparation method of the AKR1C3 selective inhibitor comprises the following steps: after nucleophilic substitution reaction of 3-hydroxybenzoic acid methyl ester and 4- (chloromethyl) -3, 5-dimethyl isoxazole, ester groups in the intermediate structure are hydrolyzed into carboxyl groups, and then the carboxyl groups are respectively condensed with 4- (2-aminoethyl) benzene sulfonamide and 4- (aminomethyl) benzene sulfonamide hydrochloride to obtain the compound shown in the formula (I).
The preparation method of the AKR1C3 selective inhibitor comprises the following steps:
substituted methyl 2-hydroxybenzoate
Figure BDA0002950249730000041
Is the initial raw material, and is obtained after nucleophilic substitution reaction with 4- (chloromethyl) -3, 5-dimethylisoxazole
Figure BDA0002950249730000042
And hydrolyzing ester groups in the intermediate structure into carboxyl under an alkaline condition, and then respectively carrying out condensation reaction with 4- (2-aminoethyl) benzenesulfonamide and 4- (aminomethyl) benzenesulfonamide hydrochloride to obtain a compound shown in the formula (I), wherein the reaction route is as follows:
Figure BDA0002950249730000043
substituted methyl benzoate is used as a starting material, and an intermediate is obtained after ester group is hydrolyzed into carboxyl under alkaline condition
Figure BDA0002950249730000044
Then carrying out condensation reaction with 4- (2-aminoethyl) benzene sulfonamide to obtain the compound shown as the formula (I), wherein the reaction route is as follows:
Figure BDA0002950249730000045
taking 3-hydroxybenzoic acid methyl ester as an initial raw material, and obtaining an intermediate after nucleophilic substitution reaction with 4- (chloromethyl) -3, 5-dimethyl isoxazole
Figure BDA0002950249730000046
Then hydrolyzing the ester group into carboxyl under the alkaline condition, and respectively carrying out condensation reaction with 4- (2-aminoethyl) benzene sulfonamide and 4- (aminomethyl) benzene sulfonamide hydrochloride to obtain the compound shown in the formula (I), wherein the reaction route is as follows:
Figure BDA0002950249730000051
using methyl 4-hydroxybenzoate as initial raw material, and carrying out nucleophilic substitution reaction with 4- (chloromethyl) -3, 5-dimethylisoxazole to obtain intermediate
Figure BDA0002950249730000052
Then hydrolyzing ester groups in the intermediate structure into carboxyl under the alkaline condition, and respectively carrying out condensation reaction with 4- (2-aminoethyl) benzenesulfonamide and 4- (aminomethyl) benzenesulfonamide hydrochloride to obtain a compound shown as a formula (I); the reaction route is as follows:
Figure BDA0002950249730000053
the compound or the pharmaceutically acceptable salt thereof can be applied to the preparation of medicines for preventing or treating cancers and reversing tumor resistance.
A pharmaceutical composition of the invention comprising a compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The dosage form of the pharmaceutical composition is capsules, pills, tablets, granules or injections.
The composition of the invention comprises a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable carrier.
The composition of the invention contains a therapeutically effective amount of the compound of the invention and pharmaceutically acceptable auxiliary materials.
The medicine is prepared by the compound of the invention and a pharmaceutically acceptable carrier; the dosage form of the medicine is capsule, pill, tablet, granule, injection, powder, syrup, liquid, suspension, injection, etc.
The compound can effectively inhibit the activity of AKR1C3, and can be used as a precursor which is further developed to play an anti-tumor role by inhibiting the activity of AKR1C 3.
The compounds of the present invention may be combined with known anti-hyperproliferative, cytostatic or cytotoxic substances for the treatment of cancer.
The pharmaceutically acceptable salt is selected from sodium salt, hydrochloride, maleate and citrate; the pharmaceutically acceptable salts of the compounds of formula (I) have the same or better pharmacodynamic activity as the compounds of formula (I).
The compound of the invention has the same or better pharmacodynamic activity on preventing or treating tumors as the compound shown in the general formula (I).
The clinical administration mode of the compound of the invention can adopt oral administration, injection and other modes.
Has the advantages that: compared with the prior art, the invention has the following remarkable advantages: according to the invention, the effect on the aldehyde ketone reductase 1C3 target is evaluated by the aldehyde ketone reductase inhibition activity and selectivity, and the discovery shows that most of related compounds have good inhibition activity and selectivity on AKR1C3, and enrich the structural types of the existing AKR1C3 inhibitor, which is particularly important for treating diseases related to AKR1C3 overexpression, and particularly has good application prospects in the anti-tumor field.
Detailed Description
The technical solution of the present invention is further illustrated by the following examples. The structure of the compound was determined by Nuclear Magnetic Resonance (NMR). The apparatus is a Bruker AVANCE-300 nuclear magnetic resonance apparatus, and the determination solvent is CDCl3Or DMSO-d6Internal standard TMS, chemical shift 10-6ppm。
Example 1
(1) Synthesis of methyl 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzoate (intermediate 2a)
Methyl 2-hydroxybenzoate 1a (130. mu.L, 1.21mmol) was dissolved in acetonitrile (6.57ml), and 4- (chloromethyl) -3, 5-dimethylisoxazole (163. mu.L, 1.21mmol), potassium carbonate solid (268mg,1.97mmol) and potassium iodide solid (114mg,0.66mmol) were added successively to the reaction solution, followed by heating at 80 ℃ and stirring overnight. After the reaction, 20mL of water was added, extraction was carried out three times with ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the mixture was subjected to silica gel column chromatography (eluent: PE/EA. RTM. 15/1, v/v). Intermediate methyl 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzoate was obtained (white solid, 100mg, yield 30%).1H NMR(300MHz,DMSO-d6)δ7.67(dd,J＝7.7,1.8Hz,1H),7.59(ddd,J＝9.1,7.4,1.8Hz,1H),7.31(d,J＝8.1Hz,1H),7.08(td,J＝7.6,0.8Hz,1H),5.02(s,2H),3.77(s,3H),2.43(s,3H),2.27(s,3H).
(2) Synthesis of 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzoic acid (intermediate 3a)
To a solution of intermediate 2a (0.1g, 0.38mmol) in ethanol (5mL) was added an aqueous solution of 2N NaOH (5 mL). Heated and stirred at 80 ℃ for 2 hours. After completion of the reaction, ethanol in the reaction mixture was distilled off under reduced pressure, and then the reaction mixture was acidified (pH 2) with 2N HCl solution (18mL), and dried by suction filtration to give intermediate 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzoic acid (white solid, 65mg, yield 67%).
1H NMR(300MHz,DMSO-d6)δ7.65(dd,J＝7.7,1.8Hz,1H),7.58(ddd,J＝9.1,7.4,1.8Hz,1H),7.32(d,J＝8.1Hz,1H),7.09(td,J＝7.6,0.8Hz,1H),5.02(s,2H),2.41(s,3H),2.23(s,3H).
(3) Synthesis of 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylphenethyl) benzamide
To a solution of intermediate 3a (0.1g, 0.4mmol) in DMF (6mL) at room temperature was added 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (230mg, 0.6mmol) and N, N-diisopropylethylamine (100. mu.L, 0.6mmol) and after activation 4- (2-aminoethyl) benzenesulfonamide (121.5mg, 0.6mmol) was added. After the reaction, 30mL of water was added to the reaction solution, which was then filtered and dried to obtain an off-white solid, which was recrystallized to obtain 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylphenethyl) benzamide (Compound 1, white solid, 150mg, yield 86%), and it was detected by TLC as a little bit with dark spots under an ultraviolet lamp at 254nm and no fluorescence at 365 nm.1H NMR(300MHz,DMSO-d6)δ8.14(t,J＝5.5Hz,1H),7.73(d,J＝8.3Hz,2H),7.56(dd,J＝7.6,1.7Hz,1H),7.50–7.42(m,1H),7.37(s,1H),7.34(s,1H),7.31(s,2H),7.22(d,J＝8.1Hz,1H),7.04(t,J＝7.4Hz,1H),5.02(s,2H),3.48(q,J＝6.9Hz,2H),2.81(t,J＝7.1Hz,2H),2.41(s,3H),2.21(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝3.082min,98.625％.
Example 2
Synthesis of 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylbenzyl) benzamide
To a solution of intermediate 3a (200mg,0.8mmol) in DMF (12mL) at room temperature was added 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (460mg, 1.2mmol) and N, N-diisopropylethylamine (400. mu.L, 2.4mmol) and after activation for half an hour 4- (aminomethyl) benzenesulfonamide hydrochloride (270mg, 1.2 mmol). After completion of the reaction, 60mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate three times. The combined organic layers are washed with brine and then added with anhydrous sulfurAnd (5) drying the sodium salt. The solvent was distilled off under pressure and the resulting solid was recrystallized to give 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylbenzyl) benzamide (Compound 2, off-white solid, 170mg, yield 53%), which was detected by TLC as a little dark spot at 254nm under an ultraviolet lamp and no fluorescence at 365 nm.1H NMR(300MHz,DMSO-d6)δ8.67(t,J＝6.0Hz,1H),7.77–7.70(m,2H),7.62(dd,J＝7.6,1.8Hz,1H),7.51(ddd,J＝9.1,7.3,1.8Hz,1H),7.42–7.33(m,4H),7.29(dd,J＝8.5,1.0Hz,1H),7.09(td,J＝7.4,0.9Hz,1H),5.07(s,2H),4.51(d,J＝6.0Hz,2H),2.41(s,3H),2.19(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝2.238min,99.225％.
Example 3
Synthesis of 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -4-methyl-N- (4-sulfamoylphenethyl) benzamide
By referring to the synthesis of example 1, methyl 2-hydroxybenzoate in example 1 was replaced with methyl 2-hydroxy-4-methylbenzoate to give 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -4-methyl-N- (4-sulfamoylphenethyl) benzamide (Compound 3), which was detected by TLC as a dot with dark spots at 254nm and no fluorescence at 365 nm.1H NMR(300MHz,DMSO-d6)δ8.03(t,J＝5.5Hz,1H),7.77–7.70(m,2H),7.55(d,J＝7.8Hz,1H),7.38–7.28(m,4H),7.11–7.05(m,1H),6.87(d,J＝7.8Hz,1H),5.03(s,2H),3.48(q,J＝6.8Hz,2H),2.79(t,J＝7.1Hz,2H),2.41(s,3H),2.34(s,3H),2.19(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝14.091min,96.153％.
Example 4
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylphenethyl) benzamide
Referring to the synthesis of example 1, methyl 2-hydroxybenzoate in example 1 was replaced with methyl 4-hydroxybenzoate to give 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylphenethyl) benzamide (Compound 4), which was detected by TLC as a dot with dark spots at 254nm and no fluorescence at 365 nm.1H NMR(300MHz,DMSO-d6)δ8.47(t,J＝5.6Hz,1H),7.86–7.79(m,2H),7.78–7.72(m,2H),7.47–7.39(m,2H),7.31(s,2H),7.11–7.04(m,2H),4.98(s,2H),3.50(q,J＝6.8Hz,2H),2.92(t,J＝7.2Hz,2H),2.42(s,3H),2.22(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝12.253min,99.093％.
Example 5
Synthesis of 3- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylphenethyl) benzamide
Referring to the synthesis procedure of example 1, methyl 2-hydroxybenzoate in example 1 was replaced with methyl 3-hydroxybenzoate to give 3- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylphenethyl) benzamide (Compound 5), which was detected by TLC as a dot with dark spots at 254nm under an ultraviolet lamp and no fluorescence at 365 nm.1H NMR(300MHz,DMSO-d6)δ8.62(t,J＝5.6Hz,1H),7.83–7.73(m,2H),7.50–7.37(m,5H),7.33(s,2H),7.18(dt,J＝7.5,2.1Hz,1H),4.99(s,2H),3.54(q,J＝7.1Hz,3H),2.95(t,J＝7.2Hz,2H),2.44(s,3H),2.25(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝3.137min,97.313％.
Example 6
(1) Synthesis of methyl 3- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzoate (intermediate 2b)
Referring to the synthesis of example 1, methyl 2-hydroxybenzoate from example 1- (1) was replaced with methyl 3-hydroxybenzoate to give methyl 3- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzoate as intermediate.1H NMR(300MHz,DMSO-d6)δ8.00–7.92(m,2H),7.18–7.11(m,2H),5.04(s,2H),3.84(s,3H),2.44(s,3H),2.24(s,3H).
(2) Synthesis of 3- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzoic acid (intermediate 3b)
By substituting intermediate 2a in example 1- (2) for intermediate 2b with reference to the synthesis procedure in example 1, intermediate 3- ((3, 5-dimethylisoxazol-4-yl) methoxy) benzoic acid was obtained.1H NMR(300MHz,DMSO-d6)δ7.61–7.49(m,2H),7.43(t,J＝7.9Hz,1H),7.26(ddd,J＝8.2,2.7,1.1Hz,1H),5.00(s,2H),2.42(s,3H),2.22(s,3H).
(3) Synthesis of 3- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylphenethyl) benzamide
Referring to the synthesis of example 1, intermediate 3a from example 1- (3) was replaced with intermediate 3b and 4- (2-aminoethyl) benzenesulfonamide was replaced with 4- (aminomethyl) benzenesulfonamide hydrochloride to give 3- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylphenethyl) benzamide (compound 6) with dark spots at 254nm and no fluorescence at 365 nm.1H NMR(300MHz,DMSO-d6)δ9.17(t,J＝5.9Hz,1H),7.81(d,J＝8.2Hz,2H),7.53(t,J＝9.3Hz,4H),7.44(t,J＝7.8Hz,1H),7.35(s,2H),7.21(d,J＝7.8Hz,1H),5.01(s,2H),4.56(d,J＝5.8Hz,2H),2.44(s,3H),2.25(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝3.078min,98.785％.
Example 7
Synthesis of 4-chloro-2- (((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylphenethyl) benzamide
By referring to the synthesis method of example 1, methyl 2-hydroxybenzoate in example 1 was replaced with methyl 4-chloro-2-hydroxybenzoate to obtain 4-chloro-2- (((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylphenethyl) benzamide (Compound 7), which was detected by TLC as a spot with dark spot at 254nm under an ultraviolet lamp and no fluorescence at 365nm,1H NMR(300MHz,DMSO-d6)δ8.14(t,J＝5.6Hz,1H),7.72(d,J＝8.2Hz,2H),7.52(d,J＝8.2Hz,1H),7.39–7.28(m,5H),7.11(dd,J＝8.2,1.8Hz,1H),5.08(s,2H),3.46(q,J＝6.8Hz,2H),2.79(t,J＝7.2Hz,2H),2.42(s,3H),2.21(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝3.565min,98.248％.
example 8
Synthesis of 4-chloro-2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylbenzyl) benzamide
Referring to the synthesis of example 6, methyl 3-hydroxybenzoate in example 6 was replaced with methyl 4-chloro-2-hydroxybenzoate to give 4-chloro-2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylbenzyl) benzamide (Compound 8), which was detected by TLC as a dot with dark spots at 254nm and no fluorescence at 365 nm.1H NMR(300MHz,DMSO-d6)δ8.68(t,J＝6.0Hz,1H),7.73(d,J＝8.0Hz,2H),7.62(d,J＝8.2Hz,1H),7.46–7.31(m,5H),7.16(dd,J＝8.2,1.8Hz,1H),5.12(s,2H),4.50(d,J＝6.0Hz,2H),2.43(s,3H),2.19(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝3.486min,99.113％.
Example 9
Synthesis of 5-chloro-2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylphenethyl) benzamide
By referring to the synthesis procedure of example 1, methyl 2-hydroxybenzoate in example 1 was replaced with methyl 5-chloro-2-hydroxybenzoate to obtain 5-chloro-2- (((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylphenethyl) benzamide (Compound 9), which was detected by TLC as a dot with dark spots at 254nm under an ultraviolet lamp and no fluorescence at 365 nm.1H NMR(300MHz,DMSO-d6)δ8.28(t,J＝5.5Hz,1H),7.75(d,J＝8.3Hz,2H),7.58–7.49(m,2H),7.38(d,J＝8.3Hz,2H),7.34(s,2H),7.28(d,J＝8.7Hz,1H),5.05(s,2H),3.49(q,J＝6.8Hz,2H),2.83(t,J＝7.1Hz,2H),2.43(s,3H),2.22(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝2.771min,98.432％.
Example 10
Synthesis of 5-chloro-2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylbenzyl) benzamide
Referring to the synthesis of example 6, methyl 3-hydroxybenzoate in example 6 was replaced with methyl 5-chloro-2-hydroxybenzoate to give 5-chloro-2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylbenzyl) benzamide (Compound 10), which was detected by TLC as a dot with dark spots at 254nm under an ultraviolet lamp.1H NMR(300MHz,DMSO-d6)δ8.78(t,J＝6.0Hz,1H),7.74(d,J＝8.3Hz,2H),7.61–7.53(m,2H),7.40(d,J＝8.4Hz,2H),7.36(s,2H),7.34–7.28(m,1H),5.08(s,2H),4.50(d,J＝6.0Hz,2H),2.41(s,3H),2.18(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝2.238min,99.225％.
Example 11
Synthesis of 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -4-methoxy-N- (4-sulfamoylphenethyl) benzamide
Synthesis of reference example 1Method, methyl 2-hydroxybenzoate from example 1 was replaced with methyl 2-hydroxy-4-methoxybenzoate to give 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -4-methoxy-N- (4-sulfamoylphenethyl) benzamide (Compound 11), which was detected by TLC as a dot with dark spots at 254nm under UV lamp and no fluorescence at 365 nm.1H NMR(300MHz,DMSO-d6)δ7.91(t,J＝5.5Hz,1H),7.74(s,1H),7.70(d,J＝8.4Hz,2H),7.35–7.29(m,4H),6.76(d,J＝2.2Hz,1H),6.64(dd,J＝8.7,2.3Hz,1H),5.08(s,2H),3.82(s,3H),3.48(q,J＝6.9Hz,2H),2.78(t,J＝7.1Hz,2H),2.42(s,3H),2.19(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝3.212min,99.607％.
Example 12
Synthesis of 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -4-methyl-N- (4-sulfamoylbenzyl) benzamide
Referring to the synthesis of example 6, methyl 3-hydroxybenzoate in example 6 was replaced with methyl 2-hydroxy-4-methylbenzoate to give 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -4-methyl-N- (4-sulfamoylbenzyl) benzamide (Compound 12) which was detected by TLC as a dot with dark spots at 254nm under an ultraviolet lamp.1H NMR(300MHz,DMSO-d6)δ8.53(t,J＝6.0Hz,1H),7.71(d,J＝8.4Hz,2H),7.56(d,J＝7.8Hz,1H),7.37(s,1H),7.34(d,J＝2.1Hz,3H),7.11(s,1H),6.89(d,J＝7.7Hz,1H),5.05(s,2H),4.48(d,J＝6.0Hz,2H),2.39(s,3H),2.36(s,3H),2.15(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝3.179min,99.555％.
Example 13
Synthesis of 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -4-methoxy-N- (4-sulfamoylbenzyl) benzamide
Referring to the synthesis of example 6, methyl 3-hydroxybenzoate in example 6 was replaced with methyl 2-hydroxy-4-methoxybenzoate to give 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -4-methyl-N- (4-sulfamoylbenzyl) benzamide (Compound 13) which was detected by TLC as a dot with dark spots under UV 254 nm.1H NMR(300MHz,DMSO-d6)δ8.40(t,J＝6.0Hz,1H),7.72(dd,J＝8.5,3.3Hz,3H),7.36(s,1H),7.33(s,3H),6.80(d,J＝2.2Hz,1H),6.66(dd,J＝8.7,2.3Hz,1H),5.10(s,2H),4.48(d,J＝5.9Hz,2H),3.83(s,3H),2.39(s,3H),2.14(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝3.290min,99.441％.
Example 14
Synthesis of 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylbenzyl) benzamide
Referring to the synthesis of example 6, methyl 3-hydroxybenzoate in example 6 was replaced with methyl 4-hydroxybenzoate to give 4- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N- (4-sulfamoylbenzyl) benzamide (Compound 14), which was detected by TLC as a dot with dark spots at 254nm under UV lamp.1H NMR(300MHz,DMSO-d6)δ9.03(t,J＝5.9Hz,1H),7.92(d,J＝8.8Hz,2H),7.80(d,J＝8.3Hz,2H),7.50(d,J＝8.3Hz,2H),7.34(s,2H),7.12(d,J＝8.8Hz,2H),5.02(s,2H),4.55(d,J＝5.8Hz,2H),2.45(s,3H),2.25(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝2.283min,98.432％.
Example 15
Synthesis of N- (4-sulfamoylphenethyl) benzamide
With reference to the synthesis method of example 1- (3), intermediate 3a in example 1- (3) was converted to benzoic acid to give N- (4-sulfamoylphenethyl) benzamide (Compound 15), which was detected by TLC as a dot with dark spots at 254nm under an ultraviolet lamp and no fluorescence at 365 nm.1H NMR(300MHz,DMSO-d6)δ8.62(t,J＝5.5Hz,1H),7.87–7.81(m,2H),7.78(d,J＝8.3Hz,2H),7.59–7.43(m,5H),7.33(s,2H),3.55(q,J＝6.9Hz,2H),2.96(t,J＝7.2Hz,2H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝2.002min,98.599％.
Example 16
Synthesis of 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N-phenethylbenzamide
By referring to the synthesis of example 1, substituting 4- (2-aminoethyl) benzenesulfonamide in example 1- (3) with 3-phenylpropionic acid, 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -N-phenethylbenzamide (compound 16) was obtained, which was detected by TLC as a dot with dark spots at 254nm under an ultraviolet lamp and no fluorescence at 365 nm.1H NMR(300MHz,DMSO-d6)δ8.12(t,J＝5.4Hz,1H),7.64(dd,J＝7.6,1.7Hz,1H),7.53–7.45(m,1H),7.34–7.16(m,6H),7.08(t,J＝7.4Hz,1H),5.05(s,2H),3.48(q,J＝7.1Hz,2H),2.75(t,J＝7.3Hz,2H),2.43(s,3H),2.22(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝5.350min,94.147％.
Example 17
Synthesis of 2-methyl-N- (4-sulfamoylphenethyl) benzamide
Referring to the synthesis of example 1- (3), intermediate 3a in example 1- (3) was converted into 2-methylbenzoic acid to give 2-methyl-N- (4-sulfamoylphenethyl) benzamide (compound 17), which was detected by TLC as a little bit with dark spots at 254nm under an ultraviolet lamp and no fluorescence at 365 nm.1H NMR(300MHz,DMSO-d6)δ8.33(t,J＝5.6Hz,1H),7.76(d,J＝8.3Hz,2H),7.45(d,J＝8.3Hz,2H),7.30(d,J＝10.2Hz,3H),7.21(d,J＝7.0Hz,3H),3.50(q,J＝6.9Hz,2H),2.92(t,J＝7.0Hz,2H),2.24(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝2.240min,95.536％.
Example 18
Synthesis of 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -5-methoxy-N- (4-sulfamoylphenethyl) benzamide
By referring to the synthesis of example 1, methyl 2-hydroxybenzoate in example 1 was replaced with methyl 2-hydroxy-5-methoxybenzoate to give 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -5-methoxy-N- (4-sulfamoylphenethyl) benzamide (compound 18) which was detected by TLC as a dot with dark spots at 254nm and no fluorescence at 365 nm.1H NMR(300MHz,DMSO-d6)δ8.20(t,J＝5.5Hz,1H),7.76(d,J＝8.3Hz,2H),7.39(d,J＝8.3Hz,2H),7.33(s,2H),7.20–7.12(m,2H),7.05(dd,J＝8.9,3.2Hz,1H),4.97(s,2H),3.76(s,3H),3.51(q,J＝6.9Hz,2H),2.84(t,J＝7.1Hz,2H),2.40(s,3H),2.21(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝2.625min,98.049％.
Example 19
Synthesis of 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -5-methoxy-N- (4-sulfamoylbenzyl) benzamide
Referring to the synthesis of example 6, methyl 3-hydroxybenzoate in example 6 was replaced with methyl 2-hydroxy-5-methoxybenzoate to give 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -5-methoxy-N- (4-sulfamoylbenzyl) benzamide (Compound 19) which was detected by TLC as a dot with dark spots under UV 254 nm.1H NMR(300MHz,DMSO-d6)δ8.70(t,J＝6.0Hz,1H),7.74(d,J＝8.3Hz,2H),7.41(d,J＝8.3Hz,2H),7.35(s,2H),7.25–7.16(m,2H),7.08(dd,J＝9.0,3.2Hz,1H),5.00(s,2H),4.51(d,J＝5.9Hz,2H),3.77(s,3H),2.37(s,3H),2.16(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝2.574min,96.855％.
Example 20
Synthesis of 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -5-nitro-N- (4-sulfamoylphenethyl) benzamide
With reference to the synthesis procedure of example 1, methyl 2-hydroxybenzoate in example 1 was replaced with methyl 2-hydroxy-5-nitrobenzoate to give 2- ((3, 5-dimethylisoxazol-4-yl) methoxy) -5-methoxy-N- (4-sulfamoylphenethyl) benzamide (Compound 20) which was detected by TLC as a dot with dark spots at 254nm and no fluorescence at 365 nm.1H NMR(300MHz,DMSO-d6)δ8.40(dd,J＝9.0,2.9Hz,2H),8.32(d,J＝2.9Hz,1H),7.76(d,J＝8.2Hz,2H),7.46(d,J＝9.3Hz,1H),7.40(d,J＝8.2Hz,2H),7.34(s,2H),5.23(s,2H),3.52(q,J＝6.8Hz,2H),2.85(t,J＝7.2Hz,2H),2.47(s,3H),2.25(s,3H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝2.590min,95.293％.
Example 21
Synthesis of 2-methoxy-N- (4-sulfamoylphenethyl) benzamide
Referring to the synthesis of example 1- (3), intermediate 3a in example 1- (3) was converted to 2-methoxybenzoic acid to give 2-methoxy-N- (4-sulfamoylphenethyl) benzamide (Compound 21), which was detected by TLC as a little bit with dark spots at 254nm and no fluorescence at 365 nm.1H NMR(300MHz,DMSO-d6)δ8.23(t,J＝5.5Hz,1H),7.81(d,J＝8.3Hz,2H),7.75(dd,J＝7.7,1.8Hz,1H),7.53–7.44(m,3H),7.35(s,2H),7.14(d,J＝8.1Hz,1H),7.09–7.00(m,1H),3.84(s,3H),3.58(q,J＝6.9Hz,2H),2.95(t,J＝7.0Hz,2H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝2.431min,99.435％.
Example 22
Synthesis of N- (4-sulfamoylphenethyl) - [1,1' -biphenyl ] -4-carboxamide
Referring to the synthesis method of example 1- (3), intermediate 3a in example 1- (3) was converted into [1,1' -biphenyl]-4-carboxylic acid to give N- (4-sulfamoylphenethyl) - [1,1' -biphenyl]-4-carboxamide (Compound 22), detected as a spot by TLC with dark spots at 254nm and no fluorescence at 365 nm. 1H NMR (300MHz, DMSO-d6) δ 8.69(t, J ═ 5.4Hz,1H),7.95(d, J ═ 8.3Hz,2H), 7.86-7.70 (m,6H), 7.59-7.39 (m,5H),7.34(s,2H),3.58(q, J ═ 6.6Hz,2H),2.99(t, J ═ 7.0Hz,2H), HPLC (80% methanol in water with 0.1% HCOOH): t, J ═ 5.4Hz,1H),7.95(d, J ═ 8.3Hz,2H)R＝3.407min,98.921％.
Example 23
Synthesis of N- (4-sulfamoylphenethyl) - [1,1' -biphenyl ] -2-carboxamide
Referring to the synthesis method of example 1- (3), intermediate 3a in example 1- (3) was converted into [1,1' -biphenyl]-2-carboxylic acid to give N- (4-sulfamoylphenethyl) - [1,1' -biphenyl]-2-carboxamide (Compound 23), detected as a spot by TLC with dark spots at 254nm and no fluorescence at 365 nm. 1H NMR (300MHz, DMSO-d6) δ 8.32(t, J ═ 5.7Hz,1H), 7.80-7.70 (m,2H),7.52(td, J ═ 7.3,1.7Hz,1H), 7.47-7.37 (m,8H),7.32(d, J ═ 8.4Hz,5H),3.35(d, J ═ 12.7Hz,2H),2.72(t, J ═ 7.1Hz,2H), HPLC (80% methanol in water with 0.1% HCOOH): t, J ═ 5.7Hz,1H), andR＝2.755min,99.227％.
example 24
Synthesis of 2- (benzyloxy) -N- (4-sulfamoylphenethyl) benzamide
Referring to the synthesis of example 1- (3), intermediate 3a in example 1- (3) was converted to 2-methoxy-1, 1' -biphenyl to give 2- (benzyloxy) -N- (4-sulfamoylphenethyl) benzamide (compound 24) which was detected by TLC as a little dark spot at 254nm under an ultraviolet lamp and no fluorescence at 365 nm.1H NMR(300MHz,DMSO-d6)δ8.27(t,J＝5.6Hz,1H),7.73(t,J＝8.0Hz,3H),7.55–7.42(m,5H),7.41–7.28(m,5H),7.22(d,J＝8.4Hz,1H),7.05(t,J＝7.5Hz,1H),5.26(s,2H),3.54(q,J＝6.7Hz,2H),2.83(t,J＝7.1Hz,2H).HPLC(80％methanol in water with 0.1％HCOOH):tR＝3.977min,97.28％.
The compounds synthesized in examples 1-24 have the structural formula:
Figure BDA0002950249730000151
Figure BDA0002950249730000161
Figure BDA0002950249730000171
Figure BDA0002950249730000181
Figure BDA0002950249730000191
the following are the results and assays for the aldehyde ketone reductase inhibitory activity of some of the compounds of the invention:
drugs and reagents: the compound prepared in the examples, AKR1C protein (self-extracted from e.coli BL21(DE3), plasmid provided by detita bio ltd), substrate (S) - (+) -1,2,3, 4-tetrahydro-1-naphthol (xylonite drug chiral technology ltd), oxidized coenzyme II free acid (shanghai-derived leaf biotechnology ltd), and control compound indomethacin were purchased from antagi.
The instrument comprises the following steps: THERMO Varioskan Flash full-wavelength multifunctional microplate reader.
The experimental method comprises the following steps:
(1)0.1M phosphate buffer (pH 7.0): 2.19g of disodium hydrogen phosphate dodecahydrate and 6.84g of sodium dihydrogen phosphate dihydrate are accurately weighed, deionized water is added to the mixture to fully dissolve the disodium hydrogen phosphate dihydrate and the mixture to a constant volume of 500mL, and the mixture is stored at 4 ℃.
(2) Substrate mother liquor: accurately weighing 14.82mg of (S) - (+) -1,2,3, 4-tetrahydro-1-naphthol, dissolving the (S) - (+) -1,2,3, 4-tetrahydro-1-naphthol in DMSO, diluting the solution to a constant volume of mL, preparing a 100mM mother solution, and storing the mother solution at 4 ℃.
(3)NADP+Mother liquor: accurately weighing 18.58mg of oxidized coenzyme II free acid, adding 0.1M phosphate buffer solution to make the volume of the solution constant to 5mL, preparing a mother solution with the concentration of 5mM, and storing the mother solution at 4 ℃.
(4) Preparing an AKR1C1 solution: the concentration of the target protein is 44.5 mu M, and the target protein is subpackaged in a small PCR tube of 200 mu L and frozen at the temperature of minus 80 ℃.
(5) Preparing an AKR1C2 solution: the concentration of the target protein is 42.5 mu M, and the target protein is subpackaged in a small PCR tube of 200 mu L and frozen at the temperature of minus 80 ℃.
(6) Preparing an AKR1C3 solution: the concentration of the target protein is 68.5 mu M, and the target protein is subpackaged in a small PCR tube of 200 mu L and frozen at the temperature of minus 80 ℃.
(7) Preparing an AKR1C4 solution: the concentration of the target protein is 69.9 mu M, and the target protein is subpackaged in a small PCR tube of 200 mu L and frozen at-80 ℃.
(8) Preparing a test solution: dissolving the compound in DMSO solution to prepare 10-1And (3) carrying out gradient dilution on the mother liquor of M to prepare 6 concentrations, wherein each concentration is provided with three multiple holes.
NADP dependent enzyme catalysis by AKR1C by Using microplate reader+Oxidation of (S) - (+) -1,2,3, 4-tetrahydro-1-naphthol of (a), determining the inhibitory capacity of the individual compounds on AKR1C subtype. The reaction system (200. mu.L) contained 100mM potassium phosphate buffer (pH 7.0), 2% DMSO (v/v), 200. mu.M NADP+Serial dilutions of the compounds, (S) - (+) -1,2,3, 4-tetrahydro-1-naphthol and AKR1C enzyme. Direct comparison of ICs for convenience50The concentrations of (S) - (+) -1,2,3, 4-tetrahydro-1-naphthol used in the inhibition tests using AKR1C1, AKR1C2, AKR1C3 and AKR1C4 were 4.9, 18.48, 238.3 and 23.45. mu.M, respectively, in terms of Km value. The concentrations of AKR1C1, AKR1C2, AKR1C3, and AKR1C4 were 34, 42, 71, and 72nM, respectively. The AKR1C enzyme was then added to initiate the reaction, the reagents were mixed and incubated at 37 ℃ for 10 minutes for fluorimetry (Ex, 340 nm; Em, 460 mM). Results of the experiment the inhibition rate of the test compound at each concentration was calculated using the fluorescence value of the control group as 100%, and the obtained results were measured using GraphPad prism (GraphPad)Software San Diego, Calif., USA) calculates corresponding IC with non-linear regression analysis model50The value is obtained.
Figure BDA0002950249730000201
TABLE 1 inhibitory Activity of the target compounds on AKR1C1, AKR1C2, AKR1C3 and AKR1C 4.
Figure BDA0002950249730000202
Figure BDA0002950249730000203
Figure BDA0002950249730000211
Figure BDA0002950249730000221
aThe concentration at which half of the compounds inhibited the activity of the aldehyde ketone reductase was expressed as the mean. + -. SEM of three independent experiments.
TABLE 2 inhibitory Selectivity of the target compounds for AKR1C1, AKR1C2, AKR1C3 and AKR1C 4.
Figure BDA0002950249730000222
Figure BDA0002950249730000223
Figure BDA0002950249730000231
Figure BDA0002950249730000241
b Selectivity indexn(SIn)＝IC50AKR1Cn/IC50AKR1C3(n＝1,2,4)
And (4) analyzing results: from the overall results of the activity test, 14 compounds have excellent inhibition selectivity on AKR1C3, and 4 compounds IC50A value of less than 100nM, wherein the IC of Compound 1950The value is 57.77nM, the activity is optimal; IC of Compound 1050The value was 63.54nM, the selectivity was optimal. Most of the compounds related by the invention have good inhibitory activity and selectivity on AKR1C3, which is particularly important for treating diseases related to AKR1C3 overexpression, and particularly has good application prospect in the anti-tumor field.

Claims (10)

1. A class of AKR1C3 selective inhibitors, characterized by: a compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure FDA0002950249720000011
wherein R is1Represents
Figure FDA0002950249720000012
Phenyl, methoxy, methyl, hydrogen or halogen; r2Represents
Figure FDA0002950249720000013
Hydrogen or halogen; r3Represents
Figure FDA0002950249720000014
Methyl, methoxy, halogen, phenyl or hydrogen; r4Represents halogen, hydrogen, methoxy or nitro; r5Represents a sulfonamide group or hydrogen; n is an integer of 0 to 2。
2. The AKR1C3 selective inhibitor according to claim 1, wherein: r1Represents
Figure FDA0002950249720000015
Figure FDA0002950249720000016
Phenyl, methoxy, methyl or hydrogen; r2Represents
Figure FDA0002950249720000017
Or hydrogen; r3Represents
Figure FDA0002950249720000018
Methyl, methoxy, chloro, phenyl or hydrogen; r4Represents chlorine, hydrogen, methoxy or nitro; r5Represents a sulfonamide group or hydrogen; n is 1 or 2.
3. The AKR1C3 selective inhibitor according to claim 1, wherein: the compound is selected from any one of the following compounds:
Figure FDA0002950249720000021
4. a process for the preparation of a selective inhibitor of AKR1C3 according to claim 1, comprising the steps of: substituted methyl 2-hydroxybenzoate
Figure FDA0002950249720000022
Is the initial raw material, and is obtained after nucleophilic substitution reaction with 4- (chloromethyl) -3, 5-dimethylisoxazole
Figure FDA0002950249720000023
Intermediate of then general formulaHydrolyzing ester groups in the intermediate structure into carboxyl under the alkaline condition, and then respectively carrying out condensation reaction with 4- (2-aminoethyl) benzenesulfonamide and 4- (aminomethyl) benzenesulfonamide hydrochloride to obtain a compound shown in a formula (I), wherein the reaction route is as follows:
Figure FDA0002950249720000031
5. a process for the preparation of a selective inhibitor of AKR1C3 according to claim 1, comprising the steps of: substituted methyl benzoate is used as a starting material, and an intermediate is obtained after ester group is hydrolyzed into carboxyl under alkaline condition
Figure FDA0002950249720000032
Then carrying out condensation reaction with 4- (2-aminoethyl) benzene sulfonamide to obtain the compound shown as the formula (I), wherein the reaction route is as follows:
Figure FDA0002950249720000033
6. a process for the preparation of a selective inhibitor of AKR1C3 according to claim 1, comprising the steps of: taking 3-hydroxybenzoic acid methyl ester as an initial raw material, and obtaining an intermediate after nucleophilic substitution reaction with 4- (chloromethyl) -3, 5-dimethyl isoxazole
Figure FDA0002950249720000034
Then hydrolyzing the ester group into carboxyl under the alkaline condition, and respectively carrying out condensation reaction with 4- (2-aminoethyl) benzene sulfonamide and 4- (aminomethyl) benzene sulfonamide hydrochloride to obtain the compound shown in the formula (I), wherein the reaction route is as follows:
Figure FDA0002950249720000035
7. a process for the preparation of a selective inhibitor of AKR1C3 according to claim 1, comprising the steps of: using methyl 4-hydroxybenzoate as initial raw material, and carrying out nucleophilic substitution reaction with 4- (chloromethyl) -3, 5-dimethylisoxazole to obtain intermediate
Figure FDA0002950249720000041
Then hydrolyzing ester groups in the intermediate structure into carboxyl under the alkaline condition, and respectively carrying out condensation reaction with 4- (2-aminoethyl) benzenesulfonamide and 4- (aminomethyl) benzenesulfonamide hydrochloride to obtain a compound shown in a formula (I), wherein the reaction route is as follows:
Figure FDA0002950249720000042
8. use of a compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of cancer and for reversing tumor resistance.
9. A pharmaceutical composition characterized by: comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
10. The pharmaceutical composition of claim 9, wherein: the dosage form of the pharmaceutical composition is capsules, pills, tablets, granules or injections.
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