Androgen receptor and glucocorticoid receptor dual-target inhibitors and uses thereof

Abstract

The application discloses application of the compound in a prostate cancer medicine, application of the compound as an androgen receptor and glucocorticoid receptor double-targeting antagonist, and application of the compound in preparation of a prostate cancer medicine. Based on screening of an active compound, three rings and three chains of the compound are modified, and a total of 134 derivatives are designed and synthesized. Optimization of the rings focuses on changes in electron density and hydrophobicity of the rings; optimization of the chains focuses on length and structure of the chains. Through optimization of the rings and the chains, 16 derivatives with better inhibitory activity on AR are screened, wherein RAp7, RDm19 and RDp12 exhibit better inhibitory activity on GR, and RDm19 is subjected to in-vitro protein inhibition experiment, cell proliferation inhibition experiment and experiment of inhibiting growth of a transplanted tumor in a nude mouse. RDm19 exhibits better inhibitory activity on tumors. Through optimization of the three rings and the three chains of the compound, a series of derivatives are obtained, wherein the compound RDm19 exhibits better inhibitory activity on AR and GR, and has potential application prospect in treatment of CRPC.

Description

Technical fields:

[0001] This invention relates to the use of a class of dual-target inhibitors of androgen receptors and glucocorticoid receptors in the treatment of prostate cancer. Background technology:

[0002] Prostate cancer (PCa) is the second leading cause of cancer death among men worldwide and the second leading cause of cancer-related deaths in men in Europe and the United States. In my country, PCa is a common malignant tumor among middle-aged and elderly men. With the deepening of population aging and changes in dietary structure and lifestyle, the incidence of PCa is increasing year by year, becoming a major malignant tumor threatening the health of middle-aged and elderly men in China. In 2020, there were approximately 115,000 new cases of PCa and approximately 51,000 deaths in my country. Androgen deprivation therapy (ADT) is currently the main treatment for prostate cancer (PCa). This method includes surgical castration, medical castration, and a combination of both. However, due to compensatory changes in hormone secretion, ADT loses its therapeutic effect, and PCa can transform into castration-resistant prostate cancer (CRPC). Androgen receptor (AR) antagonists are an important means of treating CRPC, but as treatment progresses, CRPC develops varying degrees of resistance to antagonists. Research into the mechanisms of CRPC resistance and clinical treatment has become a hot topic in current cancer treatment research.

[0003] Currently, there are multiple mechanisms of resistance to CRPC, including AR-V7, AR mutations, and bypass signaling regulation. Glucocorticoid receptor (GR) overexpression is an important form of bypass regulation. Since both AR and GR are nuclear receptors and share high structural similarity, GR can replace AR in activating the expression of its downstream proteins. Treatment for CRPC typically uses second-generation androgen receptor antagonists such as enzalutamide and apalutamide. Numerous data indicate that although enzalutamide and similar drugs initially show significant inhibitory effects, with continued treatment, they promote increased GR expression in patients. GR can regulate approximately 50% of the downstream genes in the AR pathway, thereby promoting PCa growth and proliferation. GR agonists, such as dexamethasone, promote the development of drug resistance in PCa cells, while GR antagonists can restore the sensitivity of PCa cells to enzalutamide. Therefore, blocking the AR and GR signaling pathways has become an effective strategy for overcoming CRPC.

[0004] In the initial screening of the compound library, we obtained an active compound that we found could inhibit the activity of AR and GR at the protein level and had good binding affinity to AR and GR. Therefore, based on this compound, we structurally modified its three rings and three chains, designing and synthesizing a total of 134 derivatives. Ring optimization focused on changes in electron density and hydrophobicity; chain optimization focused on chain length and structure. Through ring and chain optimization, we screened 16 derivatives with good inhibitory activity against AR, among which RAp7, RDm19, and RDp12 showed good inhibitory activity against GR. We conducted in vitro protein inhibition experiments, cell proliferation inhibition experiments, and experiments inhibiting the growth of transplanted tumors in nude mice with RDm19. RDm19 showed good inhibitory activity against tumors in all these experiments. In summary, we obtained active compounds through screening and further optimized them to obtain compounds with better activity. Compound RDm19, in particular, showed good inhibitory activity against AR and GR and has promising potential for development and application as an anti-prostate cancer drug. Summary of the Invention:

[0005] The purpose of this invention is to find dual-target inhibitors of androgen receptors and glucocorticoid receptors, and to provide dual-target inhibitors of androgen receptors and glucocorticoid receptors and their applications.

[0006] The structures described in this invention are shown in structural formulas (I-1), (I-2), and (I-3):

[0007]

[0008]

[0009] Ring A is independently selected from: indole ring, 5-bromoindole ring, isoquinoline, 2-naphthylamine, cycloheptaneamine, 6-amino-1,2,3,4-tetrahydro-1-naphthone, m-aminoacetanilide, p-methylaniline, m-fluoroaniline, p-trifluoromethylaniline, p-cyanoaniline, p-aminoacetophenone, benzocaine, 4-amino-N-methylbenzamide;

[0010] Ring B is independently selected from: 4-(chlorosulfonyl)benzoic acid, 5-(chlorosulfonyl)-2-fluorobenzoic acid;

[0011] C ring is independently selected from: furan, thiazole, pyridine, benzene, cyclohexane, piperidine;

[0012] The D ring is independently selected from: 2-aminothiazole, 2-thiophene methylamine, 3-aminomethylpyridine, pyridazine-3-amine, 4-aminopyrimidine, aminopyrazine, indole, indoline, 5-aminoindole, (1H-benzimidazole-2-methylene)amine, 2-aminobenzothiazole, 2-amino-6-methoxybenzothiazole, 2-amino-6-fluorobenzothiazole, adamantane, 4-aminotetrahydropyran, m-aminoacetanilide, m-aminoanisole, 4-isopropylaniline, p-aminobenzonitrile, 4-aminoacetophenone, 4-amino-N-methylbenzamide, 3,5-difluorobenzylamine, 3-fluorobenzylamine, p-bromobenzylamine, riluzole, 3-fluoroaniline;

[0013] L1 is independently selected from: amide bond, 1-Boc-4-piperidinic acid;

[0014] L2 is independently selected from: ether bond, amide bond, 1-Boc-4-piperidinic acid;

[0015] L3 is independently selected from: methoxy, 2-fluoroethoxy, 2-bromoethoxy, tetrabutyl glycine, 2-(tert-butoxycarbonylamino)-1-ethyl, S)-(-)-2-(tert-butoxycarbonylamino)-1-propanol, 1-tert-butoxycarbonylpiperazine, ethyl 4-piperidinecarboxylate; ethyl hexahydroisonicotinamide, di-n-butylamino, isopropylamino, isopropyloxy, cyano, phenoxy, p-tolueneamino, 1-adamantaneamino, pyrrolidinyl, cyclopropylamino, morpholine.

[0016] The structures of the A-ring modified meta-derivatives described in this invention are shown in formulas (II-1) and (II-2):

[0017]

[0018]

[0019] The structure of the meta-derivative modified with ring B of the compound described in this invention is shown in formula (III):

[0020]

[0021] The structures of the C-ring modified meta derivatives of the compounds described in this invention are shown in formulas (IV-1) and (IV-2):

[0022]

[0023] The structures of the D-ring modified benzamide derivatives of the compounds described in the invention are shown in formulas (V-1) and (V-2):

[0024]

[0025]

[0026] The structures of the benzamide derivatives modified with compound A chain described in the invention are shown in formulas (VI-1) and (VI-2):

[0027]

[0028] The structures of the benzamide derivatives modified with compound B chain described in this invention are shown in formulas (VII-1) and (VII-2):

[0029]

[0030] The structures of the benzamide derivatives modified with the C chain of the compounds described in this invention are shown in formulas (VIII-1) and (VIII-2):

[0031] Attached Figure Description

[0032] Figure 1 This is a preliminary screening diagram of the AR transcriptional repression activity of the compound described in Example 135 of the present invention;

[0033] Figure 2 This is a preliminary screening diagram of the GR transcriptional repression activity of the compound described in Example 136 of this invention; Figure 3 The compound RDm19 described in Example 137 of this invention exhibits IC50 activity against GR and AR transcriptional repression. 50 picture; Figure 4 This is an experimental diagram illustrating the inhibition of prostate cancer cell proliferation by compound RDm19 as described in Example 138 of this invention. Figure 5 This is an in vivo experimental diagram of the compound RDm19 described in Example 139 of the present invention, which inhibits prostate cancer growth in vivo. Detailed Implementation The following examples are only intended to help those skilled in the art better understand the present invention, and are not intended to limit the present invention in any way.

[0034] Example 1: Synthesis of ethyl 5-(3-(indoline-1-ylsulfonyl)benzamide)thiophene-2-carboxylate (RAm1)

[0035]

[0036] Take 1a (1.2 mmol, 1.2 eq) and 0.40 mL (5 mmol, 5 eq) of pyridine in a dry three-necked flask, add 10 mL of anhydrous THF to dissolve, and then add 0.22 g (1 mmol, 1 eq) of a THF solution of m-chlorosulfonylbenzoic acid (2) dropwise to the system while stirring at 0 °C. After the addition is complete, heat the system to reflux and react for 5 h. The reaction is detected by TLC to indicate the end of the reaction. Evaporate the solvent under reduced pressure, add ethyl acetate and 2 M hydrochloric acid to the system to remove excess pyridine, separate the liquids, add 2 M sodium hydroxide to the organic phase to adjust the pH to 10, separate the liquids, take the aqueous phase, adjust the pH to 3, extract with ethyl acetate, filter, concentrate the filtrate under reduced pressure to obtain the crude product, and then separate by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1, v / v) to obtain product 3a, with a yield of 68%.

[0037] 0.34 g (2 mmol, 1 eq) of 5-nitrothiophene-2-carboxylic acid (4) was placed in a dry reaction flask, 10 mL of anhydrous ethanol was added, and then 0.24 mL (5 mmol, 5 eq) of thionyl chloride was added to the system under stirring. The mixture was heated to reflux and reacted for 8 h. The reaction was then detected by TLC to indicate the end of the reaction. The reaction system was cooled to room temperature, the solvent was evaporated under reduced pressure, water was added to the system, and the mixture was extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate and filtered. The crude product obtained by concentration of the filtrate under reduced pressure was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 7:1, v / v) to obtain the yellow solid product ethyl 5-nitro-2-furanocarboxylate (5), with a yield of 75%.

[0038] In a dry 50 mL three-necked flask, 10 mL of ethanol, 2.5 mL of water, 1.34 g (25 mmol, 5 eq) of ammonium chloride, and 1.40 g (25 mmol, 5 eq) of iron powder were added sequentially. The mixture was then heated to reflux with stirring, and 1.01 g (5 mmol, 1 eq) of ethyl 5-nitro-2-thiophenecarboxylate (5) was added in portions. After the addition was complete, the mixture was kept at this temperature for 4 h. The reaction was stopped when TLC showed that the reaction was complete. The reaction solution was hot-filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. 40 mL of water was added to the concentrated viscous liquid, followed by 40 mL of ethyl acetate with stirring. The pH was adjusted to 7-8 with sodium bicarbonate. After filtration, the liquid was separated, and the organic phase was dried with anhydrous sodium sulfate. After filtration, the solid obtained by concentration of the filtrate under reduced pressure was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1, v / v) to obtain the brownish-red solid product ethyl 5-aminothiophene-2-carboxylate (6), with a yield of 73%.

[0039] 0.10 g (0.36 mmol, 1.2 eq) of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH) was placed in a dry reaction flask. 3 mL of acetonitrile was added, and the mixture was stirred at 25 °C to dissolve. Then, 85.00 μL (1.05 mmol, 3.5 eq) of N-methylimidazolium (NMI), 0.30 mmol (1.0 eq) of 3a, and 0.06 g (0.36 mmol, 1.2 eq) of ethyl 5-aminothiophene-2-carboxylate (6) were added to the system. After the addition was complete, the mixture was heated to reflux and reacted for 6 h. The reaction was then stopped by TLC. The reaction system was cooled to room temperature, washed with distilled water, extracted with ethyl acetate, separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4:1, v / v) to give a white solid product RDm1, with a yield of 84%.

[0040] 1 H NMR(600MHz,DMSO-d6)δ12.16(s,1H),8.36(s,1H),8.19(d,J=7.7Hz,1H),7.93( d,J=7.8Hz,1H),7.66(t,J=7.8Hz,1H),7.56(d,J=4.0Hz,1H),7.43(d,J=8.1Hz,1 H),7.12(t,J=7.8Hz,1H),7.06(d,J=7.3Hz,1H),6.89(t,J=5.9Hz,2H),4.16(q,J =7.1Hz,2H),3.89(t,J=8.4Hz,2H),2.82(t,J=8.3Hz,2H),1.19(t,J=7.1Hz,3H).

[0041] Example 2: Synthesis of ethyl 5-(3-((5-bromoindol-1-yl)sulfonyl)benzamide)thiophene-2-carboxylate (RAm2)

[0042]

[0043] Using 3b and 6 as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RAm2 with a yield of 75%.

[0044] 1H NMR (400MHz, DMSO-d6) δ12.26(s,1H),8.46(t,J=1.6Hz,1H),8.32(d,J=8.0H z,1H),8.04(d,J=8.3Hz,1H),7.79(t,J=7.9Hz,1H),7.67(d,J=4.2Hz,1H),7 .45(d,J=8.4Hz,1H),7.41–7.36(m,2H),6.99(d,J=4.2Hz,1H),4.27(q,J=7. 1Hz, 2H), 4.00 (t, J = 8.5Hz, 2H), 2.94 (t, J = 8.4Hz, 2H), 1.30 (t, J = 7.1Hz, 3H).

[0045] Example 3: Ethyl 5-(3-((3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)benzamide)thiophene-2-carboxylate (RAm3)

[0046]

[0047] Using 3c and 6 as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RAm2 with a yield of 55%.

[0048] 1 H NMR (400MHz, DMSO-d6) δ12.23(s,1H),11.18(s,1H),8.45(s,1H),8.24(d,J=8.0Hz,1H),8.02(d,J=8.5Hz,1H),7.77(t,J=7.9Hz,1H) ,7.68(d,J=8.8Hz,1H),7.63(d,J=4.2Hz,1H),7.23(d,J=8.8Hz,1H),6.95(d,J=4.2Hz,1H),4.27–4.20(m,1H),1.26(t,J=7.1Hz,2H).

[0049] Example 14: Ethyl 5-(4-(indoline-1-ylsulfonyl)benzamide)thiophene-2-carboxylate (RAp1)

[0050]

[0051] Using 9a and 6 as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RAP1 with a yield of 78%.

[0052] 1H NMR(600MHz,DMSO-d6)δ12.27(s,1H),8.15(d,J=8.3Hz,2H),8.01(d,J=8.3Hz ,2H),7.64(d,J=4.1Hz,1H),7.51(d,J=8.1Hz,1H),7.22(t,J=7.7Hz,1H),7.1 7(d,J=7.3Hz,1H),7.00(t,J=7.4Hz,1H),6.97(d,J=4.2Hz,1H),4.25(q,J=7. 1Hz, 2H), 3.98 (t, J = 8.4Hz, 2H), 2.92 (t, J = 8.4Hz, 2H), 1.29 (t, J = 7.1Hz, 3H).

[0053] Example 15: Ethyl 5-(4-((5-bromoindol-1-yl)sulfonyl)benzamide)thiophene-2-carboxylate (RAp2)

[0054]

[0055] Using 9b and 6 as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RAP2 with a yield of 48%.

[0056] 1 H NMR (400MHz, DMSO-d6) δ12.21(s,1H),8.15(d,J=8.5Hz,2H),8.02(d,J=8.5Hz,2H),7.65(d,J=4.2Hz,1H),7.48–7.44(m,1H),7.39 (d,J=7.6Hz,2H),6.96(d,J=4.2Hz,1H),4.26(q,J=7.1Hz,2H),3.99(t,J=8.5Hz,2H),2.94(t,J=8.4Hz,2H),1.30(t,J=7.1Hz,3H).

[0057] Example 16: 5-(4-((3,4,4a,8a-tetrahydroisoquinoline-2(1H)-yl)sulfonyl)benzamide)thiophene-2-carboxylic acid ethyl ester (RAp3)

[0058]

[0059] Using 9c and 6 as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RAP3 with a yield of 73%.

[0060] 1H NMR (600MHz, DMSO-d6) δ12.25(s,1H),8.22(d,J=8.5Hz,2H),8.03(d,J=8.5Hz,2H),7.66(d,J=4.2Hz,1H),7.17–7.13(m,3H),7.12(d,J=4.7 Hz,1H),6.99(d,J=4.2Hz,1H),4.28(d,J=5.0Hz,2H),4.27–4.24(m,2H),3.38(t,J=6.0Hz,2H),2.86(t,J=5.9Hz,2H),1.30(t,J=7.1Hz,3H).

[0061] Example 17: Ethyl 5-(4-(N-(naphthyl-2-yl)aminosulfonyl)benzamide)thiophene-2-carboxylate (RAp4)

[0062]

[0063] Using 9d and 6 as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RAp4 with a yield of 63%.

[0064] 1 H NMR(400MHz,DMSO-d6)δ12.64(s,1H),10.57(s,1H),8.24(d,J=8.3Hz,2H),8 .04(d,J=8.1Hz,1H),7.90(d,J=7.9Hz,1H),7.86(d,J=8.2Hz,2H),7.81(d,J =8.2Hz,1H),7.65(d,J=4.2Hz,1H),7.48(dd,J=15.3,7.5Hz,2H),7.41(t,J= 7.9Hz,1H),7.18–7.12(m,2H),4.26(q,J=7.1Hz,2H),1.30(t,J=7.1Hz,3H).

[0065] Example 18: Ethyl 5-(4-(N-cycloheptylsulfonyl)benzamide)thiophene-2-carboxylate (RAp5)

[0066]

[0067] Using 9e and 6 as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RAp5 with a yield of 50%.

[0068] 1H NMR (400MHz, DMSO-d6) δ12.22(s,1H),8.18(d,J=8.4Hz,2H),7.99(d,J=8.4Hz,2H),7.86(d,J=7.5Hz,1H),7.67(d,J=4.2Hz,1H ),6.99(d,J=4.2Hz,1H),4.27(q,J=7.1Hz,2H),1.67–1.57(m,2H),1.54–1.34(m,9H),1.30(t,J=7.1Hz,4H),1.28–1.14(m,3H).

[0069] Example 19: Ethyl 5-(4-(N-(3-acetaminophenyl)aminosulfonyl)benzamide)thiophene-2-carboxylate (RAp6)

[0070]

[0071] Using 9f and 6 as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RAP6 with a yield of 73%.

[0072] 1 H NMR(600MHz,DMSO-d6)δ12.63(s,1H),10.47(s,1H),10.10(s,1H),8.52(s,1H),8. 40(d,J=7.8Hz,1H),7.98(d,J=7.8Hz,1H),7.74(t,J=7.8Hz,1H),7.66(d,J=4.2Hz, 1H),7.50(s,1H),7.30(d,J=8.2Hz,2H),7.16(d,J=4.2Hz,1H),7.11(t,J=8.1Hz,1H ),6.77(d,J=8.0Hz,1H),4.27(q,J=7.1Hz,2H),2.00(s,3H),1.30(t,J=7.1Hz,3H).

[0073] Example 20: Ethyl 5-(4-(N-(p-toluene)aminosulfonyl)benzamide)thiophene-2-carboxylate (RAp7)

[0074]

[0075] Using 9g and 6g as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RAp7 with a yield of 65%.

[0076] 1H NMR (600MHz, DMSO-d6) δ12.17(s,1H),10.29(s,1H),8.11(d,J=8.2Hz,2H),7.89(d,J=8.2Hz,2H),7.65(d,J=4.1Hz,1H),7. 05(d,J=8.1Hz,2H),6.99(d,J=8.2Hz,2H),6.95(d,J=4.1Hz,1H),4.26(q,J=7.0Hz,2H),2.19(s,3H),1.29(t,J=7.1Hz,3H).

[0077] Example 26: Ethyl 5-(4-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)thiophene-2-carboxylate (RBm1)

[0078]

[0079] Using 11a and 6 as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RBm1 with a yield of 76%.

[0080] 1 H NMR (600MHz, DMSO-d6) δ12.32(s,1H),8.17–8.11(m,2H),7.81–7.76(m,2H),7.65(d,J=4.2Hz,1H),7.63(d,J=8.2Hz,1H),7.24–7.18(m,1H),7.1 5–7.07(m,2H),7.00(d,J=4.2Hz,1H),4.26(q,J=7.1Hz,2H),3.88–3.76 (m,2H),2.43(t,J=6.6Hz,2H),1.68–1.53(m,2H),1.29(t,J=7.1Hz,2H).

[0081] Example 27: Ethyl 5-(5-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-2-fluorobenzamide)thiophene-2-carboxylate (RBm2)

[0082]

[0083] Using 11b and 6 as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RBm2 with a yield of 66%.

[0084] 1H NMR (600MHz, DMSO-d6) δ12.30(s,1H),8.05(dd,J=6.2,2.4Hz,1H),7.78(t,J=8.5,4.3 ,2.5Hz,1H),7.66(d,J=4.2Hz,1H),7.61(d,J=4.1Hz,1H),7.60–7.57(m,1H),7.24–7.1 6(m,1H),7.11(s,1H),7.10(d,J=1.6Hz,1H),6.89(d,J=4.2Hz,1H),4.27(q,J=7.1Hz,2 H),3.87–3.76(m,2H),2.48(t,J=6.6Hz,2H),1.70–1.60(m,2H),1.30(t,J=7.1Hz,3H).

[0085] Example 28: Ethyl 5-(3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)furan-2-carboxylate (RCm1)

[0086]

[0087] Using 13a and 12 as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RCm1 with a yield of 45%.

[0088] 1 H NMR (400MHz, DMSO-d6) δ12.28(s,1H),8.38(s,1H),8.29(d,J=6.8Hz,1H),7.73 –7.66(m,2H),7.62(d,J=8.2Hz,1H),7.38(d,J=3.6Hz,1H),7.24–7.18(m,1H), 7.10(dd,J=7.9,5.4Hz,2H),6.63(d,J=3.6Hz,1H),4.28(q,J=7.1Hz,2H),3.88 –3.76(m,2H),2.43(t,J=6.6Hz,2H),1.68–1.55(m,2H),1.30(t,J=7.1Hz,3H).

[0089] Example 29: 2-(3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)thiazole-5-carboxylic acid ethyl ester (RCm2)

[0090]

[0091] Using 13b and 12 as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RCm2 with a yield of 45%.

[0092] 1 H NMR (600MHz, DMSO-d6) δ13.57(s,1H),8.46(s,1H),8.35(d,J=7.3Hz,1H),8.27(s,1H),7.73(dt,J=15.4,7.8Hz,2H),7.63(d,J=8.3Hz,1H),7.21( t,J=6.2Hz,1H),7.10(d,J=6.4Hz,2H),4.31(q,J=7.1Hz,2H),3.86–3.82 (m,2H),2.43(t,J=6.5Hz,2H),1.66–1.59(m,2H),1.32(t,J=7.1Hz,3H).

[0093] Example 30: Ethyl 6-(3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)pyridinecarboxylate (RCm3)

[0094]

[0095] Using 13c and 12 as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RCm3 with a yield of 72%.

[0096] 1 H NMR (400MHz, DMSO-d6) δ11.50(s,1H),8.37(d,J=8.3Hz,1H),8.32(s,1H),8.29(d,J=6 .6Hz,1H),8.06(t,J=7.9Hz,1H),7.87(d,J=7.5Hz,1H),7.67(d,J=6.8Hz,2H),7.63(d, J=8.4Hz,1H),7.24–7.18(m,1H),7.09(d,J=4.5Hz,2H),4.38(q,J=7.1Hz,2H),3.86–3 .79(m,2H),2.44(t,J=6.6Hz,2H),1.61(dd,J=12.2,6.2Hz,2H),1.34(t,J=7.1Hz,3H).

[0097] Example 31: Ethyl 4-(3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)benzoate (RCm4)

[0098]

[0099] Using 13d and 12 as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RCm4 with a yield of 56%.

[0100] 1H NMR(600MHz,DMSO-d6)δ10.81(s,1H),8.25(s,1H),8.24(s,1H),7.98(d,J=8.7Hz,2H ),7.93(d,J=8.8Hz,2H),7.75(d,J=7.9Hz,1H),7.72(t,J=7.5Hz,1H),7.62(d,J=8.2 Hz,1H),7.24–7.18(m,1H),7.09(d,J=1.7Hz,1H),7.09(s,1H),4.31(q,J=7.1Hz,2H) ,3.89–3.78(m,2H),2.44(t,J=6.6Hz,2H),1.66–1.57(m,2H),1.33(t,J=7.1Hz,3H).

[0101] Example 32 (1r,4r)-4-(3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)cycloheptane-1-carboxylic acid (RCm5)

[0102]

[0103] Using 13e and 12 as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RCm5 with a yield of 71%.

[0104] 1 H NMR (400MHz, DMSO-d6) δ8.53(d,J=7.7Hz,1H),8.12(s,1H),8.10(d,J=7.4Hz,1H),7.66(s,1H),7. 64(d,J=4.8Hz,1H),7.60(d,J=9.7Hz,2H),7.22–7.16(m,1H),7.11–7.05(m,2H),3.82–3.76(m,2H ),3.74(dd,J=7.6,3.7Hz,1H),3.60(s,3H),2.42(t,J=6.6Hz,2H),2.35–2.23(m,1H),2.01–1.92( m,2H),1.88(d,J=10.0Hz,2H),1.63–1.56(m,2H),1.50–1.40(m,2H),1.35(dt,J=9.5,6.0Hz,2H).

[0105] Example 33: Ethyl 4-(3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)piperidine-1-carboxylate (RCm6)

[0106]

[0107] Using 13f and 12 as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RCm6 with a yield of 65%.

[0108] 1 H NMR (600MHz, CDCl3) δ8.03(d,J=7.7Hz,1H),7.89(s,1H),7.75(d,J=8.2Hz,1H),7.6 2(d,J=7.8Hz,1H),7.45(t,J=7.8Hz,1H),7.19(t,J=7.6Hz,1H),7.09(t,J=7.4Hz,1H ),7.00(d,J=7.4Hz,1H),6.70(d,J=7.8Hz,1H),4.29–3.94(m,5H),3.83–3.69(m,2H) ,2.37(t,J=6.6Hz,2H),1.66–1.55(m,2H),1.26(t,J=7.1Hz,4H),0.91–0.74(m,1H).

[0109] Example 34: Ethyl 5-(4-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)furan-2-carboxylate (RCp1)

[0110]

[0111] Using 14a and 11a as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RCp1 with a yield of 51%.

[0112] 1 H NMR (400MHz, DMSO-d6) δ12.18(s,1H),8.12(d,J=8.1Hz,2H),7.74(d,J=8.1Hz,2H),7.62(d,J=8.2Hz,1H),7.37(d,J=3.5Hz,1H),7.22(t,J=7.2Hz,1H ),7.14–7.07(m,2H),6.61(d,J=3.5Hz,1H),4.28(q,J=7.1Hz,2H),3.85–3. 78(m,2H),2.44(t,J=6.6Hz,2H),1.68–1.56(m,2H),1.29(t,J=7.0Hz,3H).

[0113] Example 35: 2-(4-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)thiazole-5-carboxylic acid ethyl ester (RCp2)

[0114]

[0115] Using 14b and 11a as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RCp2 with a yield of 66%.

[0116] 1 H NMR (600MHz, DMSO-d6) δ13.32(s,1H),8.25(s,1H),8.20(d,J=8.3Hz,2H),7.77(d,J=8.3Hz,2H),7.62(d,J=8.2Hz,1H),7.22(t,J=7.5H z,1H),7.11(q,J=7.5Hz,2H),4.30(q,J=7.1Hz,2H),3.85–3.80(m,2H),2.44(t,J=6.6Hz,2H),1.65–1.59(m,2H),1.31(t,J=7.1Hz,3H).

[0117] Example 41: 3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-N-(thiazolyl-2-yl)benzamide (RDm1)

[0118]

[0119] Using 12 and 15a as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RDm1 with a yield of 60%.

[0120] 1 H NMR (600MHz, DMSO-d6) δ13.05(s,1H),8.45(s,1H),8.35(d,J=7.2Hz,1H),7.71( t,J=5.2Hz,1H),7.69(d,J=7.7Hz,1H),7.64(d,J=8.2Hz,1H),7.59(d,J=3.5Hz,1 H),7.31(d,J=2.9Hz,1H),7.20(dd,J=10.6,4.0Hz,1H),7.09(d,J=7.5Hz,1H),7. 07(d,J=6.5Hz,1H),3.89–3.79(m,2H),2.42(t,J=6.5Hz,2H),1.66–1.55(m,2H).

[0121] Example 42: 3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-N-(thiophen-2-ylmethyl)benzamide (RDm2)

[0122]

[0123] Using 12 and 15b as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RDm2 with a yield of 77%.

[0124] 1 H NMR(400MHz, DMSO-d6)δ9.45(t,J=5.8Hz,1H),8.18(s,1H),8.13(d,J=7.3Hz,1H),7 .68(d,J=7.9Hz,1H),7.65(d,J=7.4Hz,1H),7.61(d,J=8.3Hz,1H),7.42(d,J=5.0Hz, 1H),7.22–7.16(m,1H),7.12–7.06(m,2H),7.03(d,J=2.9Hz,1H),7.00–6.96(m,1H) ,4.64(d,J=5.8Hz,2H),3.84–3.75(m,2H),2.42(t,J=6.6Hz,2H),1.64–1.54(m,2H).

[0125] Example 43: 3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-N-(pyridin-3-ylmethyl)benzamide (RDm3)

[0126]

[0127] Using 12 and 15c as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RDm3 with a yield of 57%.

[0128] 1 H NMR (400MHz, DMSO-d6) δ9.37(t,J=5.8Hz,1H),8.55(d,J=1.7Hz,1H),8.48(dd,J=4.8,1.6Hz ,1H),8.17(t,J=1.4Hz,1H),8.16–8.13(m,1H),7.71(t,J=7.9,4.0,1.8Hz,1H),7.69–7.63( m,2H),7.61(d,J=8.1Hz,1H),7.38(t,J=7.8,4.8,0.7Hz,1H),7.22–7.16(m,1H),7.11–7.05 (m,2H),4.50(d,J=5.8Hz,2H),3.82–3.76(m,2H),2.42(t,J=6.6Hz,2H),1.64–1.56(m,2H).

[0129] Example 44: 3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-N-(pyridazin-3-yl)benzamide (RDm4)

[0130]

[0131] Using 12 and 15 days as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RDm4 with a yield of 77%.

[0132] 1 H NMR (400MHz, DMSO-d6) δ11.83(s,1H),9.05(dd,J=4.7,1.4Hz,1H),8.39(d,J=1.4Hz,1 H),8.37(d,J=1.0Hz,1H),8.33(dt,J=7.0,1.7Hz,1H),7.77(dd,J=9.0,4.7Hz,1H),7.7 4–7.71(m,1H),7.69(d,J=7.7Hz,1H),7.63(d,J=8.2Hz,1H),7.21(dt,J=8.4,4.4Hz,1 H),7.09(d,J=4.2Hz,2H),3.89–3.78(m,2H),2.45(t,J=6.6Hz,2H),1.68–1.59(m,2H).

[0133] Example 45: 3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-N-(pyrimidin-4-yl)benzamide (RDm5)

[0134]

[0135] Using 12 and 15e as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RDm5 with a yield of 53%.

[0136] 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),8.99(d,J=0.7Hz,1H),8.75(d,J=5.8Hz,1H ),8.31(s,1H),8.28(dd,J=5.2,3.5Hz,1H),8.20(dd,J=5.8,1.2Hz,1H),7.72(dd, J=8.0,1.7Hz,1H),7.70–7.66(m,1H),7.62(d,J=8.2Hz,1H),7.23–7.18(m,1H),7 .09(d,J=4.6Hz,2H),3.87–3.79(m,2H),2.44(t,J=6.6Hz,2H),1.67–1.58(m,2H).

[0137] Example 59: N-(3-cyanophenyl)-3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide (RDm19)

[0138]

[0139] Using 12 and 15s as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RDm19 with a yield of 53%.

[0140] 1 H NMR (600MHz, DMSO-d6) δ10.88(s,1H),8.23(dd,J=6.9,4.6Hz,2H),7.97(d,J=8.7Hz,2H),7.85(d,J=8.7Hz,2H),7.75(d,J=8.0Hz,1H),7.72 (t,J=7.6Hz,1H),7.62(d,J=8.2Hz,1H),7.22–7.18(m,1H),7.10–7.06(m,2H),3.87–3.75(m,2H),2.44(t,J=6.6Hz,2H),1.66–1.58(m,2H).

[0141] Example 65: 4-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-N-(thiazolyl-2-yl)benzamide (RDp1)

[0142]

[0143] Using 8a and 16a as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RDp1 with a yield of 66%.

[0144] 1 H NMR (600MHz, DMSO-d6) δ8.18(d,J=8.5Hz,2H),7.75(d,J=8.5Hz,2H),7.62(d,J=8.2Hz,1H),7.58(d,J=3.6Hz,1H),7.31(d,J=3.6Hz ,1H),7.23–7.20(m,1H),7.12(d,J=7.5Hz,1H),7.10(d,J=7.4Hz,1H),3.86–3.80(m,2H),2.44(t,J=6.6Hz,2H),1.66–1.58(m,2H).

[0145] Example 66: 4-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-N-(thiophen-2-ylmethyl)benzamide (RDp2)

[0146]

[0147] Using 8a and 16b as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RDp2 with a yield of 75%.

[0148] 1H NMR (400MHz, DMSO-d6) δ9.38(t,J=5.7Hz,1H),7.97(d,J=8.1Hz,2H),7.70(d ,J=8.1Hz,2H),7.61(d,J=8.2Hz,1H),7.40(d,J=5.0Hz,1H),7.20(t,J=7.4Hz ,1H),7.13–7.06(m,2H),7.03(d,J=3.0Hz,1H),6.96(t,J=4.1Hz,1H),4.62( d,J=5.7Hz,2H),3.84–3.75(m,2H),2.42(t,J=6.6Hz,2H),1.62–1.53(m,2H).

[0149] Example 67: 4-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-N-(pyridin-3-ylmethyl)benzamide (RDp3)

[0150]

[0151] Using 8a and 16c as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RDp3 with a yield of 53%.

[0152] 1 H NMR(600MHz, DMSO-d6)δ9.32(t,J=5.8Hz,1H),8.55(d,J=1.7Hz,1H),8.47(dd,J= 4.7,1.4Hz,1H),8.01–7.96(m,2H),7.74–7.71(m,1H),7.71–7.68(m,2H),7.61(d, J=8.1Hz,1H),7.36(dd,J=7.8,4.8Hz,1H),7.22–7.18(m,1H),7.12–7.07(m,2H),4 .49(d,J=5.8Hz,2H),3.82–3.77(m,2H),2.42(t,J=6.6Hz,2H),1.62–1.56(m,2H).

[0153] Example 68: 4-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-N-(pyridazin-3-yl)benzamide (RDp4)

[0154]

[0155] Using 8a and 16d as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RDp4 with a yield of 49%.

[0156] 1H NMR (400MHz, DMSO-d6) δ11.69(s,1H),9.05(dd,J=4.7,1.4Hz,1H),8.36(dd,J=9. 0,1.4Hz,1H),8.20–8.09(m,2H),7.78–7.73(m,3H),7.63(d,J=8.2Hz,1H),7.25–

[0157] 7.20(m,1H),7.16–7.08(m,2H),3.88–3.75(m,2H),2.46(t,J=6.7Hz,2H),1.69–1.51(m,2H).

[0158] Example 69: 4-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-N-(pyrimidin-4-yl)benzamide (RDp5)

[0159]

[0160] Using 8a and 16e as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RDp5 with a yield of 57%.

[0161] 1 H NMR (400MHz, DMSO-d6) δ11.50(s,1H),8.97(s,1H),8.75(d,J=5.8Hz,1H),8.18(dd,J=5.8,1.1Hz,1H),8.10(d,J=8.5Hz,2H),7.73(d,J =8.4Hz,2H),7.62(d,J=8.2Hz,1H),7.24–7.18(m,1H),7.16–7.05(m,2H),3.85–3.78(m,2H),2.45(t,J=6.7Hz,2H),1.66–1.57(m,2H).

[0162] Example 74: N-((1H-benzo[d]imidazol-2-yl)methyl)-4-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide (RDp10)

[0163]

[0164] Using 8a and 16j as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RDp10 with a yield of 78%.

[0165] 1H NMR (600MHz, DMSO-d6) δ12.28(s,1H),9.41(t,J=5.7Hz,1H),8.05(d,J=8.6Hz,2H ),7.73(d,J=8.6Hz,2H),7.63(d,J=8.3Hz,1H),7.55(d,J=7.6Hz,1H),7.44(d,J= 7.6Hz,1H),7.23–7.19(m,1H),7.15(dd,J=16.4,7.5Hz,2H),7.12–7.07(m,2H),4 .69(d,J=5.7Hz,2H),3.84–3.80(m,2H),2.43(t,J=6.6Hz,2H),1.65–1.54(m,2H).

[0166] Example 75: N-(benzo[d]thiazolyl)-4-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide (RDp11)

[0167]

[0168] Using 8a and 16k as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RDp11 with a yield of 61%.

[0169] 1 H NMR(600MHz,DMSO-d6)δ13.20(s,1H),8.23(d,J=8.5Hz,2H),8.04(d,J=7.9Hz,1 H),7.79(s,1H),7.77(d,J=8.5Hz,2H),7.62(d,J=8.4Hz,1H),7.51–7.47(m,1H) ,7.38–7.34(m,1H),7.24–7.20(m,1H),7.13(dd,J=7.5,1.0Hz,1H),7.10(d,J=7 .4Hz,1H),3.83(dd,J=6.7,5.3Hz,2H),2.45(t,J=6.6Hz,2H),1.66–1.58(m,2H).

[0170] Example 76: 4-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)-N-(6-(trifluoromethoxy)benzo[d]thiazolyl-2-yl)benzamide (RDp12)

[0171]

[0172] Using 8a and 16l as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid RDp12 with a yield of 63%.

[0173] 1 H NMR (600MHz, DMSO-d6) δ13.24(s,1H),8.23(d,J=8.3Hz,2H),8.18(s,1H),7.88(d,J=7.5Hz,1H),7.78(d,J=8.3Hz,2H),7.63(d,J=8.2Hz,1H),7.47 (d,J=8.6Hz,1H),7.22(t,J=7.5Hz,1H),7.12(d,J=7.5Hz,1H),7.10(d,J =7.9Hz,1H),3.86–3.80(m,2H),2.45(t,J=6.6Hz,2H),1.65–1.59(m,2H).

[0174] Example 88: Ethyl 5-(3-(1,2,3,4-tetrahydroquinoline-1-formyl)benzamide)thiophene-2-carboxylate (LAm1)

[0175]

[0176] Weigh 0.33 g (2 mmol, 1 eq) of isophthalic acid (17a) into a clean reaction flask, add 10 mL of N,N-dimethylformamide (DMF), and then add 0.91 g (2.4 mmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 0.70 mL (4 mmol, 2 eq) of N,N-diisopropylethylamine (DIPEA) and 0.30 mL (2.4 mmol, 1.2 eq) of tetrahydroquinoline (10) to the system while stirring. Heat to 80 °C and react for 6 h. The reaction is then stopped by TLC. The solvent was evaporated under reduced pressure. Ethyl acetate and 2M hydrochloric acid were added to the system to remove excess pyridine. The mixture was separated, and 2M sodium hydroxide was added to the organic phase to adjust the pH to 10. The mixture was separated again, and the aqueous phase was collected. The pH of the aqueous phase was then adjusted to 3, and the aqueous phase was extracted with ethyl acetate. The mixture was filtered, and the crude product obtained by concentration under reduced pressure was then separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1, v / v) to give a white solid product 18a, with a yield of 55%.

[0177] Take 0.10 g (0.36 mmol, 1.2 eq) of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH) in a dry reaction flask, add 3 mL of acetonitrile, stir to dissolve at 25 °C, and then add 85.00 μL of [amount missing] to the system.

[0178] (1.05 mmol, 3.5 eq) N-methylimidazole (NMI), 0.08 g (0.30 mmol, 1.0 eq) of compound 18a, and 0.06 g (0.36 mmol, 1.2 eq) of ethyl 5-aminothiophene-2-carboxylate (6) were added. The mixture was heated to reflux and reacted for 6 h. The reaction was stopped by TLC. The reaction mixture was cooled to room temperature, washed with distilled water, extracted with ethyl acetate, separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1, v / v) to give a white solid product LAm1, with a yield of 69%.

[0179] 1 H NMR (600MHz, DMSO-d6) δ12.10(s,1H),8.10(s,1H),8.04(d,J=7.4Hz,1H),7.66(d,J= 4.2Hz,1H),7.51(dd,J=13.7,6.2Hz,2H),7.22(d,J=7.4Hz,1H),7.02(t,J=7.9Hz,1H ),6.97(d,J=4.2Hz,1H),6.91(t,J=7.3Hz,1H),6.83(s,1H),4.27(q,J=7.1Hz,2H),3 .79(t,J=6.3Hz,2H),2.85(t,J=6.6Hz,2H),2.01–1.95(m,2H),1.30(t,J=7.1Hz,3H).

[0180] Example 89: 5-(3-((4-(1,2,3,4-tetrahydroquinoline-1-formyl)piperidin-1-yl)sulfonyl)benzamide)thiophene-2-carboxylic acid ethyl ester (LAm2)

[0181]

[0182] 0.46 g (2 mmol, 1 eq) of 1-Boc-4-piperidinic acid (19) and 10 mL of N,N-dimethylformamide (DMF) were added to a reaction flask. Then, under stirring, 0.91 g (2.4 mmol, 1.5 eq) of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), 0.70 mL (4 mmol, 2 eq) of N,N-diisopropylethylamine (DIPEA) and 0.30 mL (2.4 mmol, 1.2 eq) of tetrahydroquinoline (10) were added to the system. The temperature was raised to 80 °C and the reaction was allowed to proceed for 8 h. The reaction was then detected by TLC. The reaction system was cooled to room temperature, and a saturated NaCl solution was added to the system. The mixture was then extracted with ethyl acetate, separated, and the organic phase was dried with anhydrous sodium sulfate. After filtration, the crude product obtained by concentration of the filtrate under reduced pressure was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 6:1, v / v) to give a white solid product 20, with a yield of 77%.

[0183] 0.34 g (1 mmol, 1 eq) of compound 20 was placed in a clean 25 mL round-bottom flask, and 10 mL of anhydrous ethanol was added and stirred to dissolve. Then, 0.05 g (2 mmol, 2 eq) of lithium hydroxide was added to the system while stirring, and the reaction was carried out at room temperature for 4 h. The reaction was stopped by TLC. Water was added to the system, and the mixture was extracted with ethyl acetate. The liquid phase was separated, dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration under reduced pressure was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 6:1, v / v) to give brown liquid product 21, with a yield of 69%.

[0184] Take 0.15 mL (0.6 mmol, 1.2 eq) (21) into a dry three-necked flask, add 10 mL of anhydrous THF and 0.24 mL (3 mmol, 5 eq) of pyridine, and then add 0.91 g (0.5 mmol, 1 eq) of a THF solution of m-chlorosulfonylbenzoic acid (22a) dropwise to the system while stirring at 0 °C. After the addition is complete, heat the system to reflux and react for 5 h. The reaction is then detected by TLC to indicate the end of the reaction. Evaporate the solvent under reduced pressure, add ethyl acetate and 2 M hydrochloric acid to the system to remove excess pyridine, separate the liquid from the solvent, add 2 M sodium hydroxide to the organic phase to adjust the pH to 10, separate the liquid from the solvent, take the aqueous phase, adjust its pH to 3, extract with ethyl acetate, filter, concentrate the filtrate under reduced pressure to obtain the crude product, and then separate by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1, v / v) to obtain the white solid product 23a, with a yield of 42%.

[0185] 0.10 g (0.36 mmol, 1.2 eq) of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH) was placed in a dry reaction flask. 3 mL of acetonitrile was added, and the mixture was stirred at 25 °C to dissolve. Then, 85.00 μL (1.05 mmol, 3.5 eq) of N-methylimidazolium (NMI), 0.13 g (0.30 mmol, 1.0 eq) of 23a, and 0.06 g (0.36 mmol, 1.2 eq) of ethyl 5-aminothiophene-2-carboxylate (6) were added to the system. After the addition was complete, the system was heated to reflux and reacted for 6 h. The reaction was stopped by TLC. The reaction system was cooled to room temperature, washed with distilled water, extracted with ethyl acetate, separated, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 4:1, v / v) to give a white solid product LAm2, with a yield of 41%.

[0186] 1 H NMR (400MHz, DMSO-d6) δ12.27(s,1H),8.34(d,J=8.3Hz,2H),7.99(d,J=7.8Hz,1H),7.86(t,J=7.8Hz,1H),7.67(d,J= 4.2Hz,1H),7.31(s,1H),7.16(d,J=7.1Hz,1H),7.11(d,J=6.1Hz,1H),7.06(dd,J=13.6,6.2Hz,1H),7.01(d,J=4.2Hz, 1H), 4.27 (q, J = 7.1Hz, 2H), 3.68 (d, J = 11.5Hz, 2H), 3.62 (t, J = 6.4Hz, 2H), 2.84 (dd, J = 12.7, 9.2Hz, 1H), 2.66 (t, J = 6. 5Hz,2H),2.30(s,2H),1.86–1.78(m,2H),1.75(d,J=11.6Hz,2H),1.63(td,J=15.2,3.8Hz,2H),1.30(t,J=7.1Hz,3H).

[0187] Example 90: Ethyl 5-(4-(1,2,3,4-tetrahydroquinoline-1-formyl)benzamide)thiophene-2-carboxylate (LAp1)

[0188]

[0189] Using 18b and 6 as raw materials, the same preparation method as LAm1 was used to obtain white powdery solid LAp1 with a yield of 79%.

[0190] 1H NMR (400MHz, DMSO-d6) δ12.06(s,1H),7.95(d,J=8.1Hz,2H),7.65(d,J=4.2Hz,1 H),7.52(d,J=8.1Hz,2H),7.22(d,J=7.5Hz,1H),7.02(t,J=7.3Hz,1H),6.96(d,J =4.2Hz,1H),6.90(t,J=7.8Hz,1H),6.78(s,1H),4.26(q,J=7.0Hz,2H),3.78(t,J =6.4Hz,2H),2.85(t,J=6.6Hz,2H),1.98(p,J=6.4Hz,2H),1.30(t,J=7.1Hz,3H).

[0191] Example 91: 5-(4-((4-(1,2,3,4-tetrahydroquinoline-1-formyl)piperidin-1-yl)sulfonyl)benzamide)thiophene-2-carboxylic acid ethyl ester (LAp2)

[0192]

[0193] Using 13b and 6 as raw materials, the same preparation method as LAm1 was used to obtain white powdery solid LAp2 with a yield of 53%.

[0194] 1 H NMR (600MHz, DMSO-d6) δ12.27(s,1H),8.23(d,J=8.0Hz,2H),7.93(d,J=7.9Hz,2H),7.67(d,J=4.1H z,1H),7.30(s,1H),7.16(s,1H),7.10(d,J=7.5Hz,1H),7.07(s,1H),7.00(d,J=4.1Hz,1H),4.27(q ,J=7.1Hz,2H),3.67(d,J=10.9Hz,2H),3.63(t,J=6.1Hz,2H),2.84(d,J=10.8Hz,1H),2.67(s,2H), 2.30(s,2H),1.86–1.79(m,2H),1.73(s,2H),1.62(dd,J=21.3,11.3Hz,2H),1.30(t,J=7.1Hz,3H).

[0195] Example 92: Ethyl 5-((3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzyl)oxy)methyl)thiophene-2-carboxylate (LBm1)

[0196]

[0197] 0.28 g (2 mmol, 1 eq) of 5-methyl-2-thiophenecarboxylic acid (24) was placed in a dry reaction flask, 15 mL of anhydrous ethanol was added, and then 0.60 g (3 mmol, 1.5 eq) of dicyclohexylcarbodiimide (DCC) was added to the system with stirring. The mixture was heated to reflux and reacted for 8 h. The reaction was stopped by TLC. The reaction system was cooled to room temperature, the solvent was evaporated under reduced pressure, water was added to the system, and the mixture was extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate and filtered. The crude product obtained by concentration under reduced pressure was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 7:1, v / v) to obtain 0.28 g of yellow solid product ethyl 5-methyl-2-thiophenecarboxylic acid (25), with a yield of 75%.

[0198] 0.17 g (1 mmol, 1 eq) of ethyl 5-methyl-2-thiophenecarboxylate (25) and 0.02 g (0.1 mmol, 0.1 eq) of p-toluenesulfonic acid (TsOH) were dissolved in dichloroethane and stirred at room temperature. 0.18 g (1 mmol, 1 eq) of N-bromosuccinimide (NBS) was added in portions, and the mixture was heated to reflux. After 12 h, the reaction was confirmed to be complete by TLC. After cooling to room temperature, the mixture was washed with an appropriate amount of saturated brine, extracted with dichloromethane, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 8:1, v / v) to give 0.15 g of pale yellow liquid 26, with a yield of 60%.

[0199] 0.317 g (1 mmol, 1 eq) of 3-(1,2,3,4-tetrahydroquinoline-1-sulfonyl)benzoic acid (12) was weighed into a Schlenk flask. Under a nitrogen atmosphere, 10 mL of anhydrous THF was added and stirred to dissolve the product. Then, 2 mmol (2 eq) of BH3 in THF solution was added dropwise to the system at 0 °C. The reaction was allowed to proceed at room temperature, and TLC was used to determine the end of the reaction. Excess BH3 was quenched with anhydrous ethanol, and the crude product obtained by concentration under reduced pressure was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1, v / v) to give 0.27 g of white solid product 27, with a yield of 89%.

[0200] 0.12 g (0.4 mmol, 1 eq) of 27 was dissolved in 5 mL of anhydrous THF at room temperature in a Schlenk flask. Then, 0.02 g (0.8 mmol, 2 eq) of sodium hydride was added under a nitrogen atmosphere and stirred for 1 h. Next, 0.02 g (0.048 mmol, 0.12 eq) of tetrabutylammonium iodide (TBAI) and 0.10 g (0.4 mmol, 1 eq) of 26 were added. The reaction was complete by TLC after 8 h. The remaining sodium hydride was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 10:1, v / v) to give 0.13 g of a white solid (LB ml), yield 69%.

[0201] 1 H NMR (400MHz, CDCl3) δ7.81(d,J=8.2Hz,1H),7.70(d,J=3.7Hz,1H),7.58(d,J=5.7Hz,1H),7. 55(d,J=6.7Hz,2H),7.43(t,J=7.7Hz,1H),7.21(t,J=7.8Hz,1H),7.08(t,J=7.4Hz,1H),7.0 0(d,J=7.4Hz,1H),6.96(d,J=3.7Hz,1H),4.64(s,2H),4.54(s,2H),4.38(q,J=7.1Hz,2H),3 .87–3.80(m,2H),2.45(t,J=6.7Hz,2H),1.67(dd,J=12.5,6.4Hz,2H),1.40(t,J=7.1Hz,3H).

[0202] MS-ESI calcd for C 24 H 26 NO5S2[M+H] + 472.1252, found 472.1223.

[0203] Example 95: Ethyl 5-((4-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzyloxy)methyl)thiophene-2-carboxylate (LBp1)

[0204]

[0205] Using 31 and 26 as raw materials, the same preparation method as LBm1 was used to obtain white powdery solid LBp1 with a yield of 52%.

[0206] 1H NMR (400MHz, DMSO-d6) δ7.70(d,J=3.8Hz,1H),7.62(d,J=5.4Hz,1H),7.60(d ,J=6.2Hz,2H),7.50(d,J=8.3Hz,2H),7.22–7.17(m,1H),7.16(d,J=3.8Hz,1H ),7.11–7.05(m,2H),4.77(s,2H),4.64(s,2H),4.28(q,J=7.1Hz,2H),3.81– 3.73(m,2H),2.42(t,J=6.6Hz,2H),1.63–1.53(m,2H),1.29(t,J=7.1Hz,3H).

[0207] Example 98: Methyl 2-(3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)thiophene-3-carboxylate (LCm1)

[0208]

[0209] Using 12 and 34a as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid LCm1 with a yield of 67%.

[0210] 1 H NMR (400MHz, DMSO-d6) δ11.79 (s, 1H), 8.19 (d, J = 7.3Hz, 2H), 7.85 (d, J = 8.0Hz, 1H),7.80(d,J=7.6Hz,1H),7.64(d,J=8.3Hz,1H),7.28(d,J=5.8Hz,1H),7.26–

[0211] 7.20(m,1H),7.17(d,J=5.7Hz,1H),7.14–7.07(m,2H),3.91(s,3H),3.89–3.79(m,2H),2.44(t,J=6.6Hz,2H),1.68–1.59(m,2H).

[0212] Example 99: Methyl 5-(3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)thiophene-2-carboxylate (LCm2)

[0213]

[0214] Using 12 and 34b as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid LCm2 with a yield of 67%.

[0215] 1H NMR(400MHz,DMSO-d6)δ12.27(s,1H),8.33(s,1H),8.31–8.26(m,1H),7.7 5(d,J=0.8Hz,1H),7.75–7.73(m,1H),7.68(d,J=4.2Hz,1H),7.62(d,J=8. 2Hz,1H),7.25–7.18(m,1H),7.11–7.07(m,2H),7.00(d,J=4.2Hz,1H),3.8 3(d,J=5.9Hz,2H),3.81(s,3H),2.43(t,J=6.6Hz,2H),1.67–1.58(m,2H).

[0216] Example 100: 2-Fluoroethyl 5-(3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)thiophene-2-carboxylate (LCm3)

[0217]

[0218] Using 12 and 35a as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid LCm3 with a yield of 78%.

[0219] 1 H NMR(600MHz,DMSO-d6)δ12.31(s,1H),8.33(s,1H),8.30–8.27(m,1H),7.77–7.7 4(m,2H),7.72(d,J=4.2Hz,1H),7.62(d,J=8.3Hz,1H),7.23–7.19(m,1H),7.12–

[0220] 7.07(m,2H),7.01(d,J=4.2Hz,1H),4.78–4.75(m,1H),4.71–4.66(m,1H),4.53–4.48( m,1H),4.47–4.44(m,1H),3.85–3.80(m,2H),2.43(t,J=6.6Hz,2H),1.65–1.60(m,2H).

[0221] Example 101: 5-(3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)thiophene-2-carboxylic acid 2-bromoethyl ester (LCm4)

[0222]

[0223] Using 12 and 35b as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid LCm4 with a yield of 66%.

[0224] 1 H NMR(400MHz, DMSO-d6)δ8.19(dt,J=7.8,1.3Hz,1H),8.04(t,J=1.6Hz,1H),7.87–7.84(m,1H),7 .72(t,J=7.8Hz,1H),7.61(d,J=8.1Hz,1H),7.35(d,J=4.1Hz,1H),7.21–7.16(m,1H),7.08(td, J=7.4,1.1Hz,1H),7.06–7.02(m,1H),6.77(s,2H),5.90(d,J=4.2Hz,1H),4.53(dd,J=6.1,2.9H z,2H),4.43(dd,J=5.7,3.2Hz,2H),3.80–3.74(m,2H),2.37(t,J=6.7Hz,2H),1.60–1.52(m,2H).

[0225] Example 102 (5-(3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)thiophene-2-formyl)glycine tert-butyl ester (LCm5)

[0226]

[0227] Using 12 and 36a as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid LCm5 with a yield of 43%.

[0228] 1 H NMR (400MHz, DMSO-d6) δ12.06 (s, 1H), 8.71 (t, J = 6.0Hz, 1H), 8.32 (s, 1H), 8. 31–8.26(m,1H),7.73(dd,J=3.6,1.4Hz,2H),7.64–7.59(m,2H),7.24–7.17(m ,1H),7.12–7.06(m,2H),6.95(d,J=4.1Hz,1H),3.87(d,J=5.9Hz,2H),3.82( dd,J=6.7,5.2Hz,2H),2.44(t,J=6.6Hz,2H),1.66–1.59(m,2H),1.43(s,9H).

[0229] Example 103: 2-((tert-Butoxycarbonyl)amino)5-(3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)thiophene-2-carboxylic acid ethyl ester (LCm6)

[0230]

[0231] Using 12 and 35c as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid LCM6 with a yield of 43%.

[0232] 1 H NMR(400MHz,DMSO-d6)δ12.24(s,1H),8.32(s,1H),8.31–8.26(m,1H),7.78–7.7 1(m,2H),7.69(d,J=4.2Hz,1H),7.62(d,J=8.1Hz,1H),7.24–7.18(m,1H),7.12–

[0233] 7.06(m,2H),7.04(t,J=5.6Hz,1H),6.99(d,J=4.2Hz,1H),4.19(t,J=5.5Hz,2H),3.86–3 .78(m,2H),3.27(q,J=5.6Hz,2H),2.43(t,J=6.6Hz,2H),1.67–1.59(m,2H),1.38(s,8H).

[0234] Example 104 (S)-2-((tert-Butoxycarbonyl)amino)propyl5-(3-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)thiophene-2-carboxylate (LCm7)

[0235]

[0236] Using 12 and 35 days as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid LCM7 with a yield of 56%.

[0237] 1 H NMR(400MHz,DMSO-d6)δ12.24(s,1H),8.33(s,1H),8.30–8.26(m,1H),7.77–7.7 1(m,2H),7.69(d,J=4.2Hz,1H),7.62(d,J=8.1Hz,1H),7.24–7.18(m,1H),7.12–

[0238] 7.06(m,2H),6.99(d,J=4.2Hz,1H),6.91(d,J=8.3Hz,1H),4.15–4.01(m,2H),3.90–

[0239] 3.84(m,1H),3.84–3.80(m,2H),2.43(d,J=6.6Hz,2H),1.67–1.59(m,2H),1.37(s,8H),1.10(d,J=6.8Hz,3H).

[0240] Example 117: Methyl 2-(4-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)thiophene-3-carboxylate (LCp1)

[0241]

[0242] Using 11a and 34a as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid LCP1 with a yield of 67%.

[0243] 1 H NMR (400MHz, DMSO-d6) δ11.80(s,1H),8.08(d,J=8.3Hz,2H),7.87(d,J=8.3Hz,2H),7.62(d,J=8.2Hz,1H),7.27(d,J=5.7Hz,1H),7. 25–7.19(m,1H),7.16(d,J=5.7Hz,1H),7.12–7.10(m,2H),3.89(s,3H),3.86–3.81(m,2H),2.46(t,J=6.6Hz,2H),1.69–1.60(m,2H).

[0244] Example 118: Methyl 5-(4-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)thiophene-2-carboxylate (LCp2)

[0245]

[0246] Using 11a and 34b as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid LCP2 with a yield of 56%.

[0247] 1 H NMR (400MHz, DMSO-d6) δ12.25(s,1H),8.12(d,J=8.4Hz,2H),7.79(d,J=8.4Hz,2H),7.67(d,J=4.2Hz,1H),7.63(d,J=8.2Hz,1H),7. 25–7.18(m,1H),7.15–7.07(m,2H),6.98(d,J=4.2Hz,1H),3.85–3.81(m,2H),3.80(s,3H),2.44(t,J=6.6Hz,2H),1.66–1.56(m,2H).

[0248] Example 119: 2-Fluoroethyl 5-(4-((3,4-dihydroquinoline-1(2H)-yl)sulfonyl)benzamide)thiophene-2-carboxylate (LCp3)

[0249]

[0250] Using 11a and 35a as raw materials, the same preparation method as RAm1 was used to obtain white powdery solid LCP3 with a yield of 62%.

[0251] 1 H NMR (400MHz, DMSO-d6) δ12.26(s,1H),8.12(d,J=8.5Hz,2H),7.80(d,J=8.5Hz,2H),7.71( d,J=4.2Hz,1H),7.63(d,J=8.2Hz,1H),7.24–7.19(m,1H),7.11(d,J=6.5Hz,2H),6.99(d, J = 4.2 Hz, 1H), 4.80–4.76 (m, 1H), 4.68–4.65 (m, 1H), 4.54–4.50 (m, 1H), 4.46–4.42 (m, 1H), 3.85–3.81 (m, 2H), 2.44 (t, J = 6.7 Hz, 2H), 1.66–1.58 (m, 2H). Example 135 describes the initial screening of the compound for AR transcriptional repression activity. Figure 1PC-3 cells were cultured in F-12K medium containing 10% FBS in a 37°C CO2 incubator. Once the cells reached a confluence of 10cm in petri dishes, they were digested with trypsin and passaged or plated as needed. When using 6-well plates, approximately 4 × 10⁵ cells were seeded per well. After 24 hours of culture, cells were transfected in phenol red-free and serum-free RPMI 1640 medium using Lipofectamine 2000, following the manufacturer's instructions. When using 24-well plates, approximately 6 × 10⁴ cells were seeded per well. After 24 hours of culture, cells were transfected in phenol red-free and serum-free RPMI 1640 medium using Lipofectamine 2000, following the manufacturer's instructions. Six hours after transfection, the medium was replaced with phenol red-free RPMI 1640 medium containing 10% charcoal-stripped FBS. Exogenous AR transcriptional activity assay: PC-3 cells in good growth condition were digested with trypsin and diluted to a cell suspension of approximately 1.2 × 10⁵ cells / mL. The suspension was seeded into 24-well plates at a volume of 500 μL per well. After culturing for 24 h, each well was transfected with 20 ng wt-AR, 100 ng PSA-luc, and 2 ng pCMV-Renilla plasmid. 24 h after transfection, the drug solutions prepared according to the corresponding concentrations were diluted with phenol red-free RPMI 1640 medium containing 10% charcoal-stripped FBS and added to 24-well plates after the old medium was aspirated. A blank control group, an activation group, and a positive drug control group were also set up. After culturing for another 24 hours, the culture medium was discarded, and 100 μL of 1×PLB lysis buffer was added to each well. The mixture was shaken on a high-speed shaker for 20 min. The cell lysis buffer was then transferred to 1.5 mL EP tubes and centrifuged at 12000 rpm for 1 min. 20 μL of the lysis supernatant was transferred to a white, opaque 96-well plate, and the fluorescence value was measured using a 960 microplate reader according to the instructions of the Dual Luciferase Reporter System (DLC-S) kit. The inhibition rate of the compound was calculated using the DMSO activation group as a control (100%).

[0252] Example 136 describes the initial screening of the compound's GR transcriptional repression activity. Figure 2PC-3 cells in good growth condition were digested with trypsin and diluted to a cell suspension of approximately 1.2 × 10⁵ cells / mL. 500 μL of this suspension was seeded into each well of a 24-well plate. After 24 h of culture, each well was transfected with 100 ng MMTV-luc and 2 ng pCMV-Renilla plasmid. 24 h post-transfection, the prepared drug solutions were diluted with phenol red-free RPMI 1640 medium containing 10% charcoal-stripped FBS and added to the 24-well plates after the old medium was aspirated. A blank control group, an activation group, and a positive control group were also included. After culturing for another 24 hours, the culture medium was discarded, and 100 μL of 1×PLB lysis buffer was added to each well. The mixture was shaken on a high-speed shaker for 20 min. The cell lysis buffer was then transferred to a 1.5 mL EP tube and centrifuged at 12000 rpm for 1 min. 20 μL of the lysis supernatant was transferred to a white, opaque 96-well plate, and the fluorescence value was measured using a 960 microplate reader according to the instructions of the Dual Luciferase Reporter System (DLC-S) assay kit.

[0253] The compound RDm19 described in Example 137 exhibits IC50 activity against GR and AR transcriptional repression. 50 ( Figure 3 PC-3 cells in good growth condition were digested with trypsin and diluted to a cell suspension of approximately 1.2 × 10⁵ cells / mL. 500 μL of each cell was seeded into 24-well plates and cultured for 24 h. The dose-dependent inhibitory activity of RDm19 against AR and GR was measured using a dual-fluorescence reporter system. In LNCaP cells (expressing AR but not GR), RDm19 showed stronger inhibition of AR (IC50 = 0.13 μM) than ENZa (IC50 = 0.87 μM). In PC-3 cells (expressing GR but not AR), RDm19 showed weaker inhibition of GR (IC50 = 0.45 μM) than MIF (IC50 = 0.15 μM), but better than the compound (IC50 = 2.2 μM). Figure 3 ).

[0254] Example 138 describes the experiment on the inhibition of prostate cancer cell proliferation by compound RDm19. Figure 4PCa cell lines in good growth condition were digested with trypsin and diluted to approximately 2 × 10⁴ cells / mL. 200 μL of each cell suspension was seeded into 96-well plates and cultured for 24 h. Then, 1 μL of a drug solution prepared at the appropriate concentration was added to each well. Triple replicates were performed for each concentration, with a blank control and a positive control group also included. After 72 h of further culture, 20 μL of 5 g / L MTT reagent solution prepared with PBS was added to each well, and the plates were cultured for another 4 h. The 96-well plates were then removed from the incubator, the culture medium was carefully aspirated, and 100 μL of isopropanol was added to each well to dissolve the precipitate. The plates were then shaken on a high-speed shaker for 20 min, and the absorbance of each well was measured at 570 nm using a multi-mode microplate reader. Normalization was performed with the DMSO group as 100%. Cytotoxicity assays showed that RDm19 was more potent in inhibiting androgen-dependent LNCaP cells (IC50 = 3.07 μM) than ENZa (IC50 = 11.52 μM), but its inhibitory activity against non-androgen-dependent DU 145 cells was comparable to that of ENZa. Figure 4 ).

[0255] Example 139 describes an in vivo experiment on the anti-prostate cancer growth inhibition of compound RDm19. Eighteen male BALB / C-nu nude mice with 22RV1 cell tumors were subcutaneously injected. When the tumors grew to 50-100 mm³, the mice were castrated and divided into four groups of three mice each: control group (same volume of 0.5% CMC solution as the treatment group); low-concentration RDm19 group (RDm19 solution prepared with 0.5% CMC solution at a concentration of 10 mg / kg, stored at -4°C); and high-concentration RDm19 group (RDm19 solution prepared with 0.5% CMC solution at a concentration of 30 mg / kg, stored at -4°C). Preliminary results indicate that RDm19 inhibits the growth of transplanted tumors (22RV1 cells) in nude mice in a dose-dependent manner, exhibiting good in vivo activity without affecting body weight. Figure 5 ).

Claims

1. A dual-target inhibitor of androgen receptors and glucocorticoid receptors, characterized in that, As shown in the I-2 structure: ； （I-2） The I-2 structure is RDm1, RDm2, RDm3, RDm4, RDm5, RDm19, RDp2, RDp5 or RDp12; ； RDm1; ； RDm2; ； RDm3; ； RDm4; ； RDm5; ； RDm19; ； RDp2; ； RDp5 ； RDp12.

2. The use of the androgen receptor and glucocorticoid receptor dual-target inhibitor according to claim 1 in the preparation of a drug for treating prostate cancer.

Images