Androgen receptor antagonist with disubstituted-N-(substituted polyoxocyclo-2-yl) propanamide structure as well as preparation method and application of androgen receptor antagonist

Abstract

The invention relates to an androgen receptor antagonist with a disubstituted-N-(substituted polynary fused cyclo-2-yl) propanamide structure as well as a preparation method and application of the androgen receptor antagonist, the androgen receptor antagonist is shown in a general formula I, and the androgen receptor antagonist inhibits growth and proliferation of prostate cancer cells by inhibiting AR activity and blocking an androgen signal channel. Compared with the traditional AR antagonist, the novel compound provided by the invention has a novel action mechanism, and effectively overcomes the problem of drug resistance of the existing drug.

Description

Technical Field

[0001] This invention relates to a class of androgen receptor antagonists having a disubstituted -N-(substituted polycyclic cyclo-2-yl)propionamide structure, their preparation methods and applications, belonging to the pharmaceutical field. Background Technology

[0002] The androgen receptor (AR) plays a crucial role in the development and progression of prostate cancer. Prostate cancer is a malignant tumor dependent on the androgen signaling pathway. Androgens bind to the AR, activating the expression of downstream target genes, thereby promoting the proliferation and survival of prostate cancer cells. Traditional treatments for prostate cancer, such as surgery, radiotherapy, and chemotherapy, are generally effective in the early stages of the disease. However, for advanced or recurrent prostate cancer, especially castration-resistant prostate cancer (CRPC), treatment efficacy is significantly reduced.

[0003] In recent years, the application of androgen deprivation therapy (ADT) and novel anti-androgen drugs (such as abiraterone and enzalutamide) has significantly improved the prognosis of prostate cancer patients. However, as treatment progresses, cancer cells acquire drug resistance through mechanisms such as AR variants, AR ligand binding domain (LBD) point mutations, and AR overexpression. Therefore, the development of novel and highly effective AR antagonists is of great significance for overcoming drug resistance and improving the prognosis of CRPC patients. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides an AR antagonist with a disubstituted -N-(substituted multi-cyclic-2-yl)propionamide structure, its preparation method, and its application.

[0005] The AR antagonist of this invention inhibits the growth and proliferation of prostate cancer cells by suppressing the transcriptional activity of AR and blocking the androgen signaling pathway. Compared with traditional AR antagonists, the novel compound of this invention has a novel mechanism of action and effectively overcomes the drug resistance problem of existing drugs.

[0006] Unless otherwise stated, the following terms as used in this invention have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0007] Terminology Explanation:

[0008] In this invention, "C1-C8" refers to having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and so on. "4-8" refers to having 4, 5, 6, 7, or 8 ring atoms, and so on.

[0009] "C1-C8 alkyl": refers to straight-chain or branched alkyl groups having 1-8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or similar groups. The term "C2-C6 alkenyl": refers to straight-chain or branched alkenyl groups having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or similar groups.

[0010] "C2-C6 alkynyl": refers to a straight-chain or branched alkynyl group with 2-6 carbon atoms, such as ethynyl, propynyl or similar groups.

[0011] "C3-C6 cycloalkyl": refers to cycloalkyl groups with 3-6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or similar groups.

[0012] "C5-C7 cycloalkenyl": refers to a cyclic alkenyl group with 5-7 carbon atoms and one or more double bonds, such as cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl or similar groups.

[0013] "C1-C6 alkoxy": refers to straight-chain or branched alkoxy groups having 1-6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, or similar groups.

[0014] "Halogen": refers to fluorine, chlorine, bromine, or iodine. The term "halogenated" refers to a group substituted with one or more of the same or different halogen atoms, such as trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl, or similar groups.

[0015] "alkyl": refers to a group formed by removing one hydrogen atom from an alkane molecule.

[0016] "alkylene": refers to a group formed by removing two hydrogen atoms from an alkane molecule.

[0017] "Aryl": refers to a hydrocarbon group containing one or more aromatic rings. For example, the term "C6-C10 aryl" refers to an aromatic cyclic group with 6 to 10 carbon atoms that does not contain heteroatoms on the ring, such as phenyl, naphthyl, etc.

[0018] "Heteroaryl": refers to a heteroaromatic system containing 1 to 4 heteroatoms, including nitrogen, oxygen, and sulfur. For example, 4-8-membered heteroaryl refers to a heteroaromatic system containing 4-8 ring atoms, and 4-10-membered heteroaryl refers to a heteroaromatic system containing 4-10 ring atoms, including but not limited to pyrroleyl, furanyl, thiopheneyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridinyl, pyranyl, pyridazinyl, benzimidazolyl, triazolyl, indoleyl, etc.

[0019] "Heterocyclic group": refers to a cyclic group containing at least one cyclic heteroatom (e.g., N, O, or S). Typically, the heterocycle contains no more than 4 nitrogen atoms, no more than 2 oxygen atoms, and / or no more than 2 sulfur atoms. Unless otherwise specified, the heterocyclic group can be a saturated, partially unsaturated, or fully unsaturated ring. Exemplary heterocyclic groups include, but are not limited to, morpholino, hexahydroisoindolyl, tetrahydrofuranyl, and tetrahydropyrroleyl.

[0020] This invention is achieved through the following technical solution:

[0021] On one hand, the present invention relates to compounds as represented by general formula I or pharmaceutically acceptable salts, prodrugs, stereoisomers or deuterated derivatives thereof:

[0022]

[0023] In Formula I, structure A is H, a substituted or unsubstituted C4-C10 aromatic ring, or a substituted or unsubstituted 4-10 membered aromatic heterocycle; structure B is a substituted or unsubstituted C4-C10 aromatic ring or a substituted or unsubstituted 4-10 membered aromatic heterocycle.

[0024] R1 and R2 are substituted or unsubstituted groups selected from the following group:

[0025] C1-C8 alkyl, C1-C8 alkoxy, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, 4-10 membered heterocyclic, C6-C10 aryl, 4-10 membered heteroaryl, -(C1-C4 alkylene)(C3-C10 cycloalkyl), -(C1-C4 alkylene)(C3-C10 cycloalkenyl), -(C1-C4 alkylene)(C6-C10 aryl), -(C1-C4 alkylene)(4-10 membered heteroaryl), -(C1-C4 alkylene)(4-10 membered heterocyclic), -S / O(C3-C10 cycloalkyl), -S / O(C3-C10 cycloalkenyl), -S / O (C6-C10 aryl), -S / O (4-10 heteroaryl), -S / O (4-10 heterocyclic), -S / O (C3-C10 cycloalkyl), -S / O (C3-C10 cycloalkenyl), -S / O (C6-C10 aryl), -S / O (4-10 heteroaryl), -S / O (4-10 heterocyclic), -S / O (C1-C4 alkylene)(C3-C10 cycloalkyl), -S / O (C1-C4 alkylene)(C3-C10 cycloalkenyl), -S / O (C1-C4 alkylene)(C6-C10 aryl), -S / O (C1-C4 alkylene)(4-1 -0 heteroaryl), -S / O(C1-C4 alkylene)(4-10 heterocyclic), -(C1-C4 alkylene)(C3-C10 cycloalkyl), -(C1-C4 alkylene)(C3-C10 cycloalkenyl), -(C1-C4 alkylene)(C6-C10 aryl), -(C1-C4 alkylene)(4-10 heteroaryl), -(C1-C4 alkylene)(4-10 heterocyclic), -S / O(C3-C10 cycloalkyl), -S / O(C3-C10 cycloalkenyl), -S / O(C6-C10 aryl), -S / O(4-10 heteroaryl), -S / O(4 -10-membered heterocyclic group), -S / O(C3-C10 cycloalkyl), -S / O(C3-C10 cycloalkenyl), -S / O(C6-C10 aryl), -S / O(4-10-membered heteroaryl), -S / O(4-10-membered heterocyclic group), -S / O(C1-C4 subalkyl)(C3-C10 cycloalkyl), -S / O(C1-C4 subalkyl)(C3-C10 cycloalkenyl), -S / O(C1-C4 subalkyl)(C6-C10 aryl), -S / O(C1-C4 subalkyl)(4-10-membered heteroaryl), -S / O(C1-C4 subalkyl)(4-10-membered heterocyclic group);The substitution mentioned therein refers to substitution by one or more groups selected from the group consisting of: halogen, cyano, nitro, hydroxy, mercapto, carboxyl, ketone, aldehyde, ester, oxo (=O), C1-C8 alkyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, C1-C8 alkoxy / thio, C1-C6 haloalkoxy / thio, C3-C6 cycloalkoxy / thio, C3-C6 halocycloalkoxy / thio, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, 4-10 heteroaryl, or 4-8 heterocyclic.

[0026] The R3 group is selected from halogen, hydroxyl, mercapto, nitro, cyano, carboxyl, ketone, aldehyde, ester, C1-C8 alkyl, C1-C8 haloalkyl, C1-C6 alkoxy / thio, C1-C6 haloalkoxy / thio, C2-C6 alkenyl, C2-C6 alkenyl / thio, C3-C6 cycloalkyl, C3-C6 cycloalkoxy / thio, C2-C6 alkynyl, and C2-C6 alkynyl / thio.

[0027] According to a preferred embodiment of the present invention, when A is H, the R3 substituent is located on ring B.

[0028] The substitutions mentioned above refer to substitution by one or more groups selected from the group consisting of: halogen, hydroxyl, mercapto, nitro, cyano, carboxyl, ketone, aldehyde, ester, C1-C8 alkyl, C1-C8 haloalkyl, C1-C6 alkoxy / thio, C1-C6 haloalkoxy / thio, C2-C6 alkenyl, C2-C6 alkenyl / thio, C3-C6 cycloalkyl, C3-C6 cycloalkoxy / thio, C2-C6 alkynyl, and C2-C6 alkynyl / thio.

[0029] In the above description, thiazole / oxazole refers to the thiazole ring or the oxazole ring, oxygen / sulfur group refers to the oxygen group or the sulfur group, and S / O refers to oxygen or sulfur.

[0030] According to a preferred embodiment of the present invention, R1 and R2 preferably have one of the following structures:

[0031] H, CH3, CH2CH3

[0032] According to a preferred embodiment of the present invention, structure A preferably has one of the following structures:

[0033]

[0034] According to a preferred embodiment of the present invention, structure B preferably has one of the following structures:

[0035]

[0036] On the other hand, the present invention provides a method for preparing the above-mentioned compound or its pharmaceutically acceptable salt, prodrug, stereoisomer or deuterated product.

[0037] The preparation method of the above-mentioned compound or its pharmaceutically acceptable salt, prodrug, stereoisomer or deuterated derivative includes the following steps:

[0038] 1) Compound 8 and compound 9 were mixed and coupled to obtain compound 10;

[0039] 2) Compound 10 and compound 11 were dehydrated and condensed to obtain a disubstituted-N-(substituted polycyclic cyclo-2-yl)propionamide compound. The disubstituted-N-(substituted polycyclic cyclo-2-yl)propionamide compound was then subjected to salt formation to obtain a pharmaceutically acceptable salt of the disubstituted-N-(substituted polycyclic cyclo-2-yl)propionamide compound. The synthetic route is as follows:

[0040]

[0041] In another aspect, the present invention provides a method for preparing the above-mentioned compound or its pharmaceutically acceptable salt, prodrug, stereoisomer, or deuterated derivative, comprising the following steps:

[0042] 1) Compound 1, Compound 2 and Compound 3 are mixed. Compound 1 and Compound 2 undergo a condensation reaction and are then reduced and aminationd with Compound 3 to obtain Compound 4.

[0043] 2) Compound 4 and compound 5 were mixed and subjected to substitution, elimination, and cyclization reactions to obtain compound 6;

[0044] 3) Compound 6 and compound 7 were dehydrated and condensed to obtain a disubstituted-N-(substituted polycyclic cyclo-2-yl)propionamide compound. The disubstituted-N-(substituted polycyclic cyclo-2-yl)propionamide compound was then subjected to salt formation to obtain a pharmaceutically acceptable salt of the disubstituted-N-(substituted polycyclic cyclo-2-yl)propionamide compound. The synthetic route is as follows:

[0045]

[0046] In another aspect, the present invention provides the use of the above-mentioned compounds or their pharmaceutically acceptable salts, prodrugs, stereoisomers or deuterated derivatives.

[0047] A pharmaceutical composition for treating tumors includes at least one active ingredient and at least one pharmaceutically acceptable carrier, wherein the active ingredient is a compound of general formula I or a pharmaceutically acceptable salt thereof, a prodrug (ester or phosphate ester), a stereoisomer, or a deuterated product.

[0048] The use of the above-mentioned compounds or their pharmaceutically acceptable salts, prodrugs, stereoisomers or deuterated derivatives in the preparation of drugs for the treatment or prevention of prostate cancer, wherein the drugs are made from the analogues and pharmaceutically acceptable salts and pharmaceutically acceptable carriers or excipients.

[0049] The pharmaceutically acceptable salts include hydrochloride, benzenesulfonate, methylbenzenesulfonate, phosphate, maleate, sulfate, acetate, citrate, fumarate, or tartrate, etc.

[0050] It also includes pharmaceutically acceptable excipients, diluents, or carriers.

[0051] The pharmaceutical composition is formulated as a gas, liquid, or solid preparation.

[0052] The term "pharmaceutically acceptable carrier" refers to conventional drug carriers in the pharmaceutical field, including conventional diluents and excipients such as water, fillers such as starch, binders such as cellulose derivatives and gelatin, humectants such as glycerin, disintegrants such as agar and calcium carbonate, adsorbents such as kaolin and soap clay, surfactants such as hexadecyl alcohol, absorption promoters such as quaternary ammonium compounds, lubricants such as talc, and flavorings and sweeteners may be added when necessary.

[0053] The pharmaceutical formulations are suitable for administration via any suitable route, such as nasal spray, oral spray (inhaler), oral (including sublingual or sublingual administration), rectal administration, local administration (including sublingual, sublingual, or transdermal administration), vaginal administration, or parenteral administration (including subcutaneous, intramuscular, intravenous, or intradermal injection). The formulations described in this invention can be prepared by any method known in pharmaceutical science. For example, methods involving mixing the active ingredient with a carrier or excipient.

[0054] Antitumor drugs that can be used in combination with the compounds provided by this invention or their pharmaceutically acceptable salts include, but are not limited to, at least one of the following: mitotic inhibitors (such as vincristine); tubulolytic inhibitors (such as paclitaxel); alkylating agents (such as cisplatin); antimetabolites (such as 5-fluorouracil); intercalable antibiotics (such as areazon); enzymes (such as aspartase); topoisomerase inhibitors (such as etoposide and camptothecin); biological response modifiers (such as interferon); and proteasome inhibitors (such as bortezomib).

[0055] Through multiple experiments, this invention has confirmed that the compounds synthesized in this invention have an inhibitory effect on prostate cancer, with most of the compounds selectively exhibiting significant inhibitory effects on prostate cancer.

[0056] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. The various features disclosed in the specification can be replaced by any alternative features that provide the same, equivalent, or similar purpose. Attached Figure Description

[0057] Figures 1-6These are the NMR spectra of some compounds;

[0058] Figures 7-12 These are mass spectra of some of the compounds.

[0059] Figure 13 This indicates the inhibitory activity of the compound against clinically drug-resistant AR mutants.

[0060] Figure 14 This study investigated the in vivo activity of the compound against hormone-sensitive prostate cancer (LNCaP model).

[0061] Figure 15 The in vivo activity of the compound in enzalutamide-resistant prostate cancer (LNCaP-EnzR model) was investigated. Detailed Implementation

[0062] The present invention will be further described below with reference to specific embodiments.

[0063] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0064] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0065] The specific embodiments described below are for illustrative purposes only and should not be construed as limiting the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims. The compounds of this invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0066] Example 1: Preparation of N-(6-methoxybenzothiazol-2-yl)-3-(4-methoxyphenyl)-3-(1H-pyrrolo-1-yl)propionamide (X3)

[0067] 1) Preparation of 3-amino-3-(4-methoxyphenyl)propionic acid

[0068]

[0069] 5 mmol of 4-methoxybenzaldehyde, 10 mmol of malonic acid and 10 mmol of ammonium acetate were added to a 50 mL two-necked flask. 20 mL of ethanol was added to suspend and stir the mixture. The mixture was heated to 78 °C. As the reaction proceeded, the solution changed from turbid to clear. After a period of time, a large amount of solid precipitated out. The solid was refluxed for 17 h and then filtered. The filter cake was washed three times with 95% ethanol, dried under vacuum and used directly in the next step of the reaction.

[0070] 2) Preparation of 3-(4-methoxyphenyl)-3-(1H-pyrrolo-1-yl)propionic acid

[0071]

[0072] 2 mmol of 3-amino-3-(4-methoxyphenyl)propionic acid and 2.1 mmol of 2,5-dimethyltetrahydrofuran were added to a 25 mL two-necked flask, followed by the slow addition of 5 mL of glacial acetic acid. The mixture was stirred at 60 °C for 1.5 h, and the clear solution gradually turned dark brown. After the reaction was complete, most of the solvent was evaporated by rotary evaporation, diluted with 15 mL of dichloromethane, and then impurities were washed away with 1 M hydrochloric acid. The organic phases were combined, dried over anhydrous sodium sulfate, and then evaporated by rotary evaporation. The product was dried in a vacuum oven. The yield was 70%, and the product was a white solid.

[0073] 1 H NMR (400MHz, CDCl3) δ12.52(s,1H),7.34(d,2H),7.18(d,2H),6.80(d,2H),6.18(d,2H),5.29(t,1H),3.80(s,3H),2.90(m,1H),2.66(m,1H). 13 C NMR (101MHz, CDCl3) δ175.49,159.06,134.18,126.15,120.49,114.91,108.54,60.58,55.32,41.30.ESI-MS: m / z246.11[M+H] + C 14 H 15 NO3 (245.11).

[0074] 3) Preparation of N-(6-methoxybenzothiazol-2-yl)-3-(4-methoxyphenyl)-3-(1H-pyrrolo-1-yl)propionamide (X3)

[0075]

[0076] 1 mmol of 3-(4-methoxyphenyl)-3-(1H-pyrrolo-1-yl)propionic acid, 1 mmol of 6-methoxybenzothiazol-2-amine, 1.5 mmol of 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC), and 0.1 mmol of 4-dimethylaminopyridine (DMAP) were dissolved in 5 mL of dichloromethane and stirred overnight. The solution was diluted with dichloromethane, washed three times with 1 M hydrochloric acid, once with saturated sodium bicarbonate solution, and once with saturated sodium chloride solution. The organic phases were combined, and the dichloromethane was evaporated to dryness. The solution was resuspended in 1 mL of water, stirred for 5 min, filtered, and the filter cake was washed with water and dried under vacuum. The yield was 53%, and the solid was white.

[0077] 1 H NMR(400MHz,Chloroform-d)δ12.01(s,1H),7.62(m,1H),7.58(m,1H),7.34(d,2H),7.18(d,2H),7.0 2(m,1H),6.80(d,2H),6.18(d,2H),5.29(t,1H),3.80(s,3H),3.71(s,3H),2.90(m,1H),2.66(m,1H). 13 C NMR(101MHz,Chloroform-d)δ174.25,159.67,159.06,155.69,145.33,135.08,131.89,126. 30,120.83,118.83,114.91,113.37,108.52,106.19,60.61,55.32,54.73,42.30.ESI-MS:m / z 408.13[M+H] + C 22 H 21 N3O3S(407.13).

[0078] Example 2: Preparation of N-(6-methoxybenzothiazol-2-yl)-3-(4-methylphenyl)-3-phenylpropionamide (X40)

[0079] 1) Preparation of 3-(4-methoxyphenyl)-3-phenylpropionic acid

[0080]

[0081] 1.48 g of cinnamic acid, 2.72 g of p-methylphenylboronic acid, 112 mg of palladium acetate, and 156 mg of 2,2'-bipyridine were added to a mixed solution of 10 ml glacial acetic acid, 20 ml tetrahydrofuran, and 6 ml water. The mixture was refluxed at 80 °C for 24 h. After the reaction was complete, the solution was evaporated to dryness, diluted with dichloromethane, washed three times with water, dried over anhydrous sodium sulfate, and then evaporated to dryness again. The product did not require purification and was used directly in the next reaction.

[0082] 2) Preparation of N-(6-methoxybenzo[d]thiazolyl)-3-(4-methylphenyl)-3-phenylpropionamide

[0083]

[0084] 3) The synthesis of the target compound was similar to that in Example 1, except that 3-(4-methylphenyl)-3-phenylpropionic acid was used as the starting material in step 3), and the final product was purified by column chromatography. Yield: 65%, white solid.1 H NMR(400MHz,Chloroform-d)δ7.62(d,J=8.9Hz,1H),7.28(d,J=2.5Hz,1H),7.19(dd,J=8.5,6.5H z,2H),7.13–6.97(m,8H),4.63(t,J=7.8Hz,1H),3.88(s,3H),3.16(d,J=7.7Hz,2H),2.24(s,3H). 13 C NMR(101MHz,Chloroform-d)δ169.73,157.87,157.28,143.08,139.80,136.36,129.40,128.68,127 .45,127.35,126.70,120.50,115.85,104.61,55.92,46.45,42.93,20.96.ESI-MS:m / z403.14[M+H] + C 24 H 21 N2O2S(402.14).

[0085] Example 3: Preparation of N-(isoquinoline-3-yl)-3-(4-methoxyphenyl)-3-(1H-pyrrolo-1-yl)propionamide (X86)

[0086] Steps 1) and 2) are the same as in Example 1;

[0087] Step 3) The synthesis of the target compound is similar to that in Example 1, except that isoquinoline-3-amine is used instead of 6-methoxybenzothiazole-2-amine in step 3). Yield: 47%. 1 H NMR(600MHz,DMSO-d6)δ10.70(s,1H),9.12(d,J=0.9Hz,1H),8.40(s,1H),8.0 5–8.01(m,1H),7.85(dd,J=8.5,1.1Hz,1H),7.69(ddd,J=8.2,6.8,1.3Hz,1H), 7.51(ddd,J=8.1,6.8,1.1Hz,1H),7.24–7.17(m,2H),6.94–6.86(m,4H),5.97 (t,J=2.1Hz,2H),5.73(dd,J=9.1,6.6Hz,1H),3.71(s,3H),3.51–3.33(m,2H). 13C NMR (151MHz, DMSO-d6) δ167.87,157.99,150.67,146.35,136.48,133.12,130.30,126.98,126. 95,125.72,125.22,125.08,118.84,113.23,107.15,106.05,57.86,54.47,41.39.ESI-MS:m / z 372.16[M+H] + C 23 H 21 N3O2(371.16).

[0088] Example 4: Preparation of N-(benzothiazol-2-yl)-3-(4-methoxyphenyl)-3-(1H-pyrrolo-1-yl)propionamide (X1) - Steps 1) and 2) are the same as in Example 1;

[0089] Step 3) The synthesis of the target compound is similar to that in Example 1, except that benzothiazole-2-amine is used instead of 6-methoxybenzothiazole-2-amine in step 3). Yield: 79%. 1 H NMR (600MHz, DMSO-d6) δ7.95–7.89(m,1H),7.70(d,J=8.1Hz,1H),7.41(ddd,J=8.4,7.2,1.3Hz,1H),7.27(td,J=7.6 ,7.2,1.2Hz,1H),7.23–7.18(m,2H),6.92–6.83(m,4H),5.98(t,J=2.2Hz,2H),5.77–5.73(m,1H),3.72(s,3H),3.51

[0090] –3.37(m,2H). 13 C NMR(151MHz,DMSO-d6)δ169.94,159.11,149.06,133.93,131.95,128.06,126.42, 123.74,122.05,120.79,119.91,114.33,108.30,58.66,55.56,42.10.ESI-MS:m / z 378.12[M+H] + C 21 H 19 N3O2S(377.11).

[0091] Example 5: Preparation of 3-(4-methoxyphenyl)-3-(1H-pyrrolo-1-yl)-N-(6-trifluoromethylbenzothiazol-2-yl)propionamide (X2)

[0092] Steps 1) and 2) are the same as in Example 1;

[0093] Step 3) The synthesis of the target compound is similar to that in Example 1, except that 6-trifluoromethylbenzothiazole-2-amine is used instead of 6-methoxybenzothiazole-2-amine in step 3), with a yield of 77%. 1 H NMR(600MHz,DMSO-d6)δ8.47(dd,J=1.9,1.0Hz,1H),7.96–7.84(m,1H),7.74(dd,J=8.6,1.9Hz,1H),7.25– 7.18(m,2H),6.92–6.87(m,4H),5.98(t,J=2.1Hz,2H),5.79–5.74(m,1H),3.72(s,3H),3.61–3.43(m,2H). 13 CNMR(151MHz,DMSO-d6)δ169.99,161.25,159.17,151.68,133.70,132.40,128.07,125.93, 124.32,124.13,123.44,121.44,119.91,114.36,108.38,58.51,55.56,41.70.ESI-MS:m / z 446.11[M+H] + C 22 H 18 F3N3O2S(445.10).

[0094] Example 6: Preparation of 3-(4-methoxyphenyl)-3-(1H-pyrrolo-1-yl)-N-(6-methylbenzothiazol-2-yl)propionamide (X4)

[0095] Steps 1) and 2) are the same as in Example 1;

[0096] Step 3) The synthesis of the target compound is similar to that in Example 1, except that 6-methylbenzothiazole-2-amine is used instead of 6-methoxybenzothiazole-2-amine in step 3), with a yield of 83%. 1 H NMR (600MHz, DMSO-d6) δ7.73(dt,J=1.7,0.8Hz,1H),7.61(d,J=8.2Hz,1H),7.24(dd,J=8.2,1.8Hz,1H),7.23–7.17(m,2 H),6.92–6.87(m,4H),5.98(t,J=2.2Hz,2H),5.74(dd,J=9.1,6.6Hz,1H),3.72(s,3H),3.51–3.38(m,2H),2.40(s,3H). 13C NMR(151MHz,DMSO-d6)δ169.28,159.15,157.21,146.86,133.77,133.51,131.97,128.05, 127.92,121.74,120.64,119.89,114.35,108.36,58.55,55.56,41.71,21.44.ESI-MS:m / z 392.14[M+H] + C 22 H 21 N3O2S(391.13)

[0097] Example 7: Preparation of N-(6-cyanobenzothiazol-2-yl)-3-(4-methoxyphenyl)-3-(1H-pyrrolo-1-yl)propionamide (X25)

[0098] Steps 1) and 2) are the same as in Example 1;

[0099] Step 3) The synthesis of the target compound is similar to that in Example 1, except that 6-cyanobenzothiazole-2-amine is used instead of 6-methoxybenzothiazole-2-amine in step 3), with a yield of 86%. 1 H NMR (600MHz, DMSO-d6) δ8.55(dd,J=1.7,0.6Hz,1H),7.87(dd,J=8.4,0.6Hz,1H),7.83(dd,J=8.4,1.7Hz,1H),7.24– 7.18(m,2H),6.92–6.86(m,4H),5.98(t,J=2.2Hz,2H),5.76(dd,J=9.1,6.6Hz,1H),3.72(s,3H),3.55–3.42(m,2H). 13 C NMR(151MHz,DMSO-d6)δ168.95,160.85,158.10,150.99,132.53,131.50,129.04,126.98,12 6.45,118.81,118.54,113.29,107.33,104.79,57.35,54.49,40.68.ESI-MS:m / z403.12[M+H] + C 22 H 18 N4O2S(402.11).

[0100] Example 8: Preparation of 3-(4-methoxyphenyl)-N-(5-methylthiazolyl-2-yl)-3-(1H-pyrrolo-1-yl)propionamide (X5) was carried out using the same steps 1) and 2) as in Example 1;

[0101] Step 3) The synthesis of the target compound is similar to that in Example 1, except that 5-methylthiazol-2-amine is used instead of 6-methoxybenzothiazol-2-amine in step 3), with a yield of 85%. 1 H NMR (600MHz, DMSO-d6) δ11.99(s,1H),7.19–7.15(m,2H),7.10(q,J=1.3Hz,1H),6.90–6.86(m,2H),6.85(t,J=2.2Hz,2H),5.97(t,J=2 .2Hz,2H),5.69(dd,J=9.1,6.6Hz,1H),3.71(s,3H),3.38(dd,J=15.3,9.1Hz,1H),3.29(dd,J=15.3,6.6Hz,1H),2.30(d,J=1.3Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ155.21,134.05,132.75,125.61,107.23,57.56,54.48,40.34,10.43.ESI-MS:m / z 342.12[M+H] + C 18 H 19 N3O2S(341.11).

[0102] Example 9: Preparation of 3-(4-methoxyphenyl)-N-(thiazol-2-yl)-3-(1H-pyrrolo-1-yl)propionamide (X6)

[0103] Steps 1) and 2) are the same as in Example 1;

[0104] Step 3) The synthesis of the target compound is similar to that in Example 1, except that thiazole-2-amine is used instead of 6-methoxybenzothiazole-2-amine in step 3), with a yield of 88%. 1 H NMR(600MHz,DMSO-d6)δ12.20(s,1H),7.44(d,J=3.5Hz,1H),7.21–7.15(m,3H),6.92–6.83 (m,4H),5.97(t,J=2.1Hz,2H),5.71(dd,J=9.1,6.6Hz,1H),3.71(s,3H),3.45–3.33(m,2H). 13 C NMR (151MHz, DMSO-d6) δ167.19,158.05,157.03,136.97,132.74,126.94,118.78,113.26,107.26,57.53,54.47,40.35.ESI-MS: m / z 328.11[M+H] +C 17 H 17 N3O2S(327.10).

[0105] Example 10: Preparation of 3-(4-methoxyphenyl)-N-(benzoxazol-2-yl)-3-(1H-pyrrolo-1-yl)propionamide (X7) - Steps 1) and 2) are the same as in Example 1;

[0106] Step 3) The synthesis of the target compound is similar to that in Example 1, except that benzoxazolazole-2-amine is used instead of 6-methoxybenzothiazole-2-amine in step 3), with a yield of 91%. 1 H NMR (600MHz, DMSO-d6) δ7.61–7.53(m,2H),7.28(dtd,J=23.4,7.5,1.3Hz,2H),7.24–7.19(m,2H),6. 91–6.87(m,4H),5.98(t,J=2.2Hz,2H),5.71(dd,J=8.9,6.6Hz,1H),3.72(s,3H),3.57–3.36(m,2H). 13 C NMR (151MHz, DMSO-d6) δ158.05,154.33,146.89,132.78,127.09,118.82,117.57,113.26,109.42,107.24,57.40,54.49,41.29.ESI-MS: m / z 362.15[M+H] + C 21 H 19 N3O3(361.14).

[0107] Example 11: Preparation of 3-(4-methoxyphenyl)-N-(oxazol-2-yl)-3-(1H-pyrrolo-1-yl)propionamide (X18)

[0108] Steps 1) and 2) are the same as in Example 1;

[0109] Step 3) The synthesis of the target compound is similar to that in Example 1, except that oxazol-2-amine is used instead of 6-methoxybenzothiazole-2-amine in step 3), with a yield of 82%. 1 H NMR(600MHz,DMSO-d6)δ11.30(s,1H),7.82(d,J=0.9Hz,1H),7.23–7.13(m,2H),7.06(s,1H),6 .95–6.81(m,4H),5.98(t,J=2.2Hz,2H),5.66(dd,J=8.8,6.7Hz,1H),3.72(s,3H),3.32(s,2H).13 C NMR(151MHz,DMSO-d6)δ158.03,125.90,118.76,113.24,57.40,54.48.ESI-MS:m / z 312.13[M+H] + C 17 H 17 N3O3(311.12).

[0110] Example 12: Preparation of N-(6-fluorobenzothiazol-2-yl)-3-(4-methoxyphenyl)-3-(1H-pyrrolo-1-yl)propionamide (X19)

[0111] Steps 1) and 2) are the same as in Example 1;

[0112] Step 3) The synthesis of the target compound is similar to that in Example 1, except that 6-fluorobenzothiazole-2-amine is used instead of 6-methoxybenzothiazole-2-amine in step 3), with a yield of 88%. 1 H NMR(600MHz,Chloroform-d)δ7.64–7.58(m,1H),7.53(dt,J=7.9,1.9Hz,1H),7.17(td,J=8.8,2.5Hz,1H),6.98(d,J=8.3Hz,2H),6.8 2–6.75(m,2H),6.59–6.48(m,2H),6.06(dt,J=3.1,1.5Hz,2H),5.72(dd,J=8.4,6.2Hz,1H),3.75(d,J=1.2Hz,3H),3.32–3.17(m,2H). 13 C NMR(151MHz,Chloroform-d)δ168.45,160.57,159.40,158.95,158.72,144.03,131.66,127.59,121.4 2,121.36,119.32,115.03,114.87,114.18,108.88,108.21,108.03,58.57,55.27,43.26.ESI-MS:m / z 418.10[M+Na] + C 21 H 18 FN3O2S(395.11).

[0113] Example 13: Preparation of 3-(4-methoxyphenyl)-N-(5-nitrobenzothiazol-2-yl)-3-(1H-pyrrolo-1-yl)propionamide (X21)

[0114] Steps 1) and 2) are the same as in Example 1;

[0115] Step 3) The synthesis of the target compound is similar to that in Example 1, except that 5-nitrobenzothiazole-2-amine is used instead of 6-methoxybenzothiazole-2-amine in step 3), with a yield of 28%. 1 H NMR(600MHz,Chloroform-d)δ8.58(d,J=2.2Hz,1H),8.18(dd,J=8.7,2.1Hz,1H),7.91(d,J=8.7Hz,1H),7.18–7.14(m,2H),6 .87–6.83(m,2H),6.73(t,J=2.1Hz,2H),6.15(t,J=2.2Hz,2H),5.76(dd,J=9.0,5.9Hz,1H),3.78(s,3H),3.49–3.34(m,2H). 13 C NMR(151MHz,Chloroform-d)δ168.61,159.50,148.24,146.98,138.96,131.57,127.63,1 21.90,119.73,119.47,118.67,116.27,114.31,109.20,58.70,55.32,43.31.ESI-MS:m / z 445.09[M+Na] + C 21 H 18 N4O4S(422.10).

[0116] Example 14: Preparation of 3-(4-methoxyphenyl)-N-(4-nitrobenzothiazol-2-yl)-3-(1H-pyrrolo-1-yl)propionamide (X22)

[0117] Steps 1) and 2) are the same as in Example 1;

[0118] Step 3) The synthesis of the target compound is similar to that in Example 1, except that 4-nitrobenzothiazole-2-amine is used instead of 6-methoxybenzothiazole-2-amine in step 3), with a yield of 60%. 1 H NMR(600MHz,Chloroform-d)δ8.23(dd,J=8.0,1.1Hz,1H),8.09(dd,J=7.9,1.1Hz,1H),7.44(t,J=8.0Hz,1H),7.06–7.00(m,2H),6.8 3–6.77(m,2H),6.61(t,J=2.2Hz,2H),6.08(t,J=2.2Hz,2H),5.72(dd,J=8.4,6.4Hz,1H),3.76(s,3H),3.29(qd,J=15.2,7.4Hz,2H).13 C NMR(151MHz,Chloroform-d)δ169.07,161.88,159.40,141.24,140.40,135.64,131.70,1 27.61,127.51,123.36,123.29,119.34,114.26,108.93,58.53,55.30,43.14.ESI-MS:m / z 445.09[M+Na] + C 21 H 18 N4O4S(422.10).

[0119] Example 15: Preparation of 3-(4-methoxyphenyl)-N-(6-nitrobenzothiazol-2-yl)-3-(1H-pyrrolo-1-yl)propionamide (X23)

[0120] Steps 1) and 2) are the same as in Example 1;

[0121] Step 3) The synthesis of the target compound is similar to that in Example 1, except that 6-nitrobenzothiazole-2-amine is used instead of 6-methoxybenzothiazole-2-amine in step 3), with a yield of 87%. 1 H NMR(600MHz,Chloroform-d)δ8.71(t,J=2.4Hz,1H),8.29(dt,J=9.0,2.4Hz,1H),7.75(dd,J=8.9,2.2Hz,1H),7.22–7.13(m,2H),6. 89–6.84(m,2H),6.75(t,J=2.1Hz,2H),6.14(q,J=2.0Hz,2H),5.81(dd,J=8.5,6.4Hz,1H),3.78(d,J=1.7Hz,3H),3.46–3.31(m,2H). 13 C NMR(151MHz,Chloroform-d)δ169.28,162.77,159.44,152.88,143.99,132.43,131.99,1 27.71,122.05,120.72,119.62,118.20,114.29,108.80,58.60,55.34,42.72.ESI-MS:m / z 423.11[M+H] + C 21 H 18 N4O4S(422.10).

[0122] Example 16: Preparation of 3-(4-methoxyphenyl)-N-(7-nitrobenzothiazol-2-yl)-3-(1H-pyrrolo-1-yl)propionamide (X24)

[0123] Steps 1) and 2) are the same as in Example 1;

[0124] Step 3) The synthesis of the target compound is similar to that in Example 1, except that 7-nitrobenzothiazole-2-amine is used instead of 6-methoxybenzothiazole-2-amine in step 3), with a yield of 66%. 1 H NMR(600MHz,Chloroform-d)δ8.28(dd,J=8.1,1.0Hz,1H),8.02(dd,J=8.0,1.0Hz,1H),7.59(t,J=8.1Hz,1H),7.21–7.18(m,2H),6. 89–6.86(m,2H),6.77(q,J=3.7,2.9Hz,2H),6.14(q,J=3.7,2.9Hz,2H),5.84–5.79(m,1H),3.78(d,J=1.1Hz,3H),3.43–3.35(m,2H). 13 C NMR(151MHz,Chloroform-d)δ169.20,162.39,159.42,150.71,142.76,132.11,12 7.77,127.00,126.26,120.20,119.75,119.62,114.29,108.74,55.35.ESI-MS:m / z 423.11[M+H] + C 21 H 18 N4O4S(422.10).

[0125] Example 17: Preparation of 3-(4-(tert-butyl)phenyl)-N-(6-cyanobenzothiazol-2-yl)-3-(1H-pyrrolo-1-yl)propionamide (X28)

[0126] The preparation method was carried out according to steps 1), 2), and 3) of Example 1, except that 4-tert-butylbenzaldehyde was used instead of 4-methoxybenzaldehyde in step 1), and 6-cyanobenzothiazole-2-amine was used instead of 6-methoxybenzothiazole-2-amine in step 1), with a yield of 56%. 1H NMR(600MHz,Chloroform-d)δ8.12(t,J=1.8Hz,1H),7.76(dd,J=8.5,1.9Hz,1H),7.67(dt,J=8.4,1.7Hz,1H),7.36(dd,J=8.4,1.9H z,2H),7.17–7.11(m,2H),6.81–6.71(m,2H),6.20–6.12(m,2H),5.77(dd,J=9.3,5.6Hz,1H),3.46–3.34(m,2H),1.29–1.28(m,9H). 13 C NMR(151MHz,Chloroform-d)δ168.43,160.54,151.48,151.13,136.47,132.78,129.73,126.18,1 25.97,121.66,119.87,119.57,118.87,109.36,107.31,58.96,43.39,34.57,31.24.ESI-MS:m / z 451.16[M+Na] + C 25 H 24 N4OS(428.16).

[0127] Example 18: Preparation of N-(6-cyanobenzothiazol-2-yl)-3-cyclohexyl-3-(1H-pyrrolo-1-yl)propionamide (X33)

[0128] The preparation method was carried out according to steps 1), 2), and 3) of Example 1, except that cyclohexyl formaldehyde was used instead of 4-methoxybenzaldehyde in step 1), and 6-cyanobenzothiazole-2-amine was used instead of 6-methoxybenzothiazole-2-amine in step 1), with a yield of 87%. 1 H NMR(600MHz,Chloroform-d)δ8.11(d,J=1.8Hz,1H),7.80–7.60(m,2H),6.60(t,J=2.3Hz,2H),6.11(q ,J=2.6Hz,2H),4.16(td,J=9.6,3.7Hz,1H),3.11–2.77(m,2H),1.86–1.78(m,2H),1.33–0.83(m,9H). 13C NMR(151MHz,Chloroform-d)δ169.52,161.11,151.12,132.73,129.69,126.22,121.45, 119.26,118.91,108.84,107.16,62.16,43.03,41.32,30.41,29.25,25.98.ESI-MS:m / z 401.14[M+Na] + C 21 H 22 N4OS(378.15).

[0129] Example 19: Preparation of N-(6-cyanobenzothiazol-2-yl)-3-(1H-pyrrolo-1-yl)-3-(4-(trifluoromethyl)phenyl)propionamide (X31)

[0130] The preparation method was carried out according to steps 1), 2), and 3) of Example 1, except that 4-trifluoromethylbenzaldehyde was used instead of 4-methoxybenzaldehyde in step 1), and 6-cyanobenzothiazole-2-amine was used instead of 6-methoxybenzothiazole-2-amine in step 1), with a yield of 46%. 1 H NMR(600MHz,Chloroform-d)δ8.13(d,J=1.7Hz,1H),7.78–7.65(m,2H),7.59(d,J=8.1Hz,2H),7.28( s,2H),6.70(t,J=2.1Hz,2H),6.19(t,J=2.1Hz,2H),5.89(dd,J=8.7,5.9Hz,1H),3.48–3.33(m,2H). 13 C NMR(151MHz,Chloroform-d)δ167.94,160.84,151.02,143.69,132.74,130.57,129.83,12 6.64,126.32,126.05,121.56,119.55,118.80,109.81,107.47,58.58,42.82.ESI-MS:m / z 441.10[M+H] + C 22 H 15 F3N4OS(440.09).

[0131] Example 20: Preparation of N-(6-cyanobenzothiazo-2-yl)-3-(6-methoxypyridin-3-yl)-3-(1H-pyrrolo-1-yl)propionamide (X34)

[0132] The preparation method was carried out according to steps 1), 2), and 3) of Example 1. In step 1), 6-methoxynicotinaldehyde was used to replace 4-methoxybenzaldehyde, and in step 3), 6-cyanobenzothiazole-2-amine was used to replace 6-methoxybenzothiazole-2-amine, with a yield of 41%. 1 H NMR (400MHz, DMSO-d6) δ8.61(d,J=1.6Hz,1H),8.17(d,J=2.5Hz,1H),7.97–7.85(m,2H),7.69(dd,J=8.7,2.6Hz,1H),7.00( t,J=2.2Hz,2H),6.86(d,J=8.6Hz,1H),6.06(t,J=2.1Hz,2H),5.88(dd,J=8.7,6.9Hz,1H),3.87(s,3H),3.72–3.53(m,2H). 13 C NMR (101MHz, DMSO-d6) δ169.87,163.58,161.89,152.06,145.43,137.88,132.58,130.34,130. 14,127.55,121.76,119.85,119.63,110.93,108.74,105.89,56.31,53.68,41.21.ESI-MS:m / z 404.10[M+H] + C 21 H 17 N5O2S(403.11).

[0133] Example 21: Preparation of N-(6-cyanobenzothiazol-2-yl)-3-(2-methoxypyrimidin-5-yl)-3-(1H-pyrrolo-1-yl)propionamide (X35)

[0134] The preparation method was carried out according to steps 1), 2), and 3) of Example 1. In step 1), 2-methoxypyrimidine-5-carboxaldehyde was used to replace 4-methoxybenzaldehyde, and in step 3), 6-cyanobenzothiazole-2-amine was used to replace 6-methoxybenzothiazole-2-amine, with a yield of 44%. 1 H NMR(400MHz,DMSO-d6)δ12.89(s,1H),8.56(d,J=3.3Hz,3H),7.99–7.78(m,2H),7.00(t,J=2.2Hz,2H) ,6.03(t,J=2.2Hz,2H),5.89(t,J=7.7Hz,1H),5.76(s,1H),3.89(s,3H),3.61(dd,J=7.9,1.9Hz,2H). 13C NMR (101MHz, DMSO-d6) δ169.74,165.10,161.87,158.37,152.06,132.59,130.14,128. 77,127.54,121.78,119.88,119.61,109.09,105.91,55.38,55.18,54.40.ESI-MS:m / z 405.10[M+H] + C 20 H 16 N6O2S(404.11).

[0135] Example 22: Preparation of 3-(4-isopropoxyphenyl)-3-phenyl-N-(thiazol-2-yl)propionamide (X66)

[0136] The preparation method was carried out according to steps 1), 2), and 3) of Example 2, except that in step 1), 4-isopropoxyphenylboronic acid was used instead of p-methylphenylboronic acid, and in step 2), thiazole-2-amine was used instead of 6-methoxybenzothiazole-2-amine, with a yield of 60%. 1 H NMR(600MHz,Chloroform-d)δ7.44(d,J=4.4Hz,1H),7.32–7.23(m,4H),7.26–7.19(m,1H),7.19–7.13(m,2H),7.09(d,J=4.6Hz, 1H),6.88–6.82(m,2H),4.65(hept,J=5.7Hz,1H),4.62–4.55(m,1H),3.01(d,J=7.8Hz,2H),1.34(s,1H),1.30(d,J=5.7Hz,3H). 13 C NMR(151MHz,Chloroform-d)δ172.92,161.95,157.74,143.35,138.72,135.50,128. 66,128.65,127.57,127.22,117.06,112.15,68.55,47.22,43.73,22.00.ESI-MS:m / z 367.14[M+H] + C 21 H 22 F3N2O2S(366.14).

[0137] Example 23: Preparation of 3-(4-isopropoxyphenyl)-3-phenyl-N-(6-cyanobenzothiazol-2-yl)propionamide (X45)

[0138] The preparation method was carried out according to steps 1), 2), and 3) of Example 2, except that in step 1), 4-isopropoxyphenylboronic acid was used instead of p-methylphenylboronic acid, and in step 2), 6-cyanobenzothiazole-2-amine was used instead of 6-methoxybenzothiazole-2-amine, with a yield of 55%. 1 H NMR(600MHz,Chloroform-d)δ8.04(d,J=1.6Hz,1H),7.69(d,J=8.4Hz,1H),7.61(dd,J=8.4,1.6Hz,1H),7.22(t,J=7.6Hz,2H),7.17–7.11(m ,3H),7.07–7.03(m,2H),6.77–6.69(m,2H),4.55(t,J=7.8Hz,1H),4.40(h,J=6.1Hz,1H),3.16(d,J=7.8Hz,2H),1.22(dd,J=6.1,4.7Hz,6H). 13 C NMR(151MHz,Chloroform-d)δ169.86,161.08,156.87,142.91,134.28,132.31,129.94,128.87,128.53, 127.45,126.98,126.26,121.19,118.74,116.12,107.51,69.87,46.22,43.50,22.04,22.02.ESI-MS:m / z 442.14[M+H] + C 26 H 23 N3O2S(441.15).

[0139] Example 24: Preparation of 3-(4-methoxyphenyl)-3-phenyl-N-(6-methoxybenzothiazol-2-yl)propionamide (X41)

[0140] The preparation method was carried out according to steps 1), 2), and 3) of Example 2, except that 4-methoxyphenylboronic acid was used instead of p-methylphenylboronic acid in step 1), with a yield of 71%. 1 H NMR(400MHz,Chloroform-d)δ7.62(d,J=8.9Hz,1H),7.28(d,J=2.5Hz,1H),7.24–7.18(m,2H),7.15–7 .00(m,6H),6.77–6.72(m,2H),4.62(t,J=7.8Hz,1H),3.88(s,3H),3.71(s,3H),3.15(d,J=7.8Hz,2H). 13C NMR(101MHz,Chloroform-d)δ169.77,158.30,157.29,143.19,134.88,128.68,128.50,1 27.42,126.70,120.44,115.88,114.07,104.61,55.91,55.18,46.07,43.08.ESI-MS:m / z 419.13[M+H] + C 24 H 22 N2O3S(418.14)

[0141] Example 25: Preparation of 3-(4-isopropoxyphenyl)-3-phenyl-N-(6-methoxybenzothiazol-2-yl)propionamide (X42)

[0142] The preparation method was carried out according to steps 1), 2), and 3) of Example 2, except that 4-isopropoxyphenylboronic acid was used instead of p-methylphenylboronic acid in step 2), with a yield of 74%. 1 H NMR(400MHz,Chloroform-d)δ7.55(d,J=8.9Hz,1H),7.22(d,J=2.6Hz,1H),7.14–7.07(m,2H),7.05–6.94(m,4H),6.92–6.86(m,2H), 6.67–6.61(m,2H),4.51(t,J=7.7Hz,1H),4.36(hept,J=6.1Hz,1H),3.81(s,3H),3.02(d,J=7.7Hz,2H),1.19(dd,J=6.1,1.8Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ169.73,157.45,157.09,156.62,143.28,134.75,128.63,128.48,127 .42,126.64,120.93,115.87,115.57,104.53,69.76,55.89,46.09,43.11,22.07,22.03.ESI-MS:m / z 447.17[M+H] + C 26 H 26 N2O3S(446.17).

[0143] Example 26: Preparation of 3-(4-methoxyphenyl)-3-phenyl-N-(thiazolyl-2-yl)propionamide (X67)

[0144] The preparation method was carried out according to steps 1), 2), and 3) of Example 2, except that 4-methoxyphenylboronic acid was used instead of p-methylphenylboronic acid in step 1), with a yield of 67%. 1 H NMR(600MHz,Chloroform-d)δ7.31(dd,J=5.5,3.6Hz,1H),7.20–7.17(m,2H),7.14(tt,J=4.6,1.9Hz,2H),7.12–7.04(m,3H ),6.89(t,J=2.8Hz,1H),6.72(dq,J=9.2,2.8Hz,2H),4.66–4.56(m,1H),3.67(d,J=2.7Hz,3H),3.13(dd,J=7.6,2.6Hz,2H). 13 C NMR(151MHz,Chloroform-d)δ169.20,159.58,158.29,143.56,136.21,135.28,1 28.70,128.58,127.51,126.65,114.09,113.74,55.21,46.06,42.83.ESI-MS:m / z 339.11[M+H] + C 19 H 18 N2O2S(338.11)

[0145] Example 27: Preparation of 3,3-diphenyl-N-(thiazolyl-2-yl)propionamide (X76)

[0146] The preparation method was carried out according to steps 1), 2), and 3) of Example 2, except that phenylboronic acid was used instead of p-methylphenylboronic acid in step 1), with a yield of 86%. 1 H NMR(600MHz,Chloroform-d)δ7.31(d,J=3.6Hz,1H),7.20–7.12(m,8H),7.12–7 .05(m,2H),6.89(d,J=3.6Hz,1H),4.66(t,J=7.7Hz,1H),3.16(d,J=7.7Hz,2H). 13 C NMR(151MHz,Chloroform-d)δ169.19,159.77,159.75,143.22,136.15,128.71,127.61,126.73,113.77,46.81,42.57.ESI-MS:m / z 307.10[M+H] + C 18 H 16 N2OS(308.10)

[0147] Example 28: Preparation of N-(5-cyanobenzothiazol-2-yl)-3-(4-methoxyphenyl)-3-(1H-pyrrolo-1-yl)propionamide (X92)

[0148] The preparation method was carried out according to steps 1), 2), and 3) of Example 1, except that 5-cyanobenzothiazole-2-amine was used instead of 2-aminothiazole in step 3), with a yield of 67%. 1 H NMR(400MHz,Chloroform-d)δ7.98(d,J=2.6Hz,1H),7.80(d,J=8.8Hz,1H),7.60(dd,J=8.8,2.6Hz,1H),7.48–7.39(m,2H) ,7.19–7.11(m,2H),7.08–6.97(m,3H),6.49(t,J=2.1Hz,2H),5.87(dd,J=9.3,5.6Hz,1H),4.06(s,3H),3.52–3.34(m,2H). 13 C NMR(101MHz,Chloroform-d)δ168.44,159.64,137.39,133.61,131.71,127.76,125.33,125 .20,119.72,116.95,116.14,114.44,109.62,59.48,55.48,44.91.ESI-MS:m / z403.12[M+H] + C 22 H 19 N4O2S(403.12).

[0149] Example 29: Preparation of N-(7-cyanobenzothiazol-2-yl)-3-(4-methoxyphenyl)-3-(1H-pyrrolo-1-yl)propionamide (X93)

[0150] The preparation method was carried out according to steps 1), 2), and 3) of Example 1, except that 7-cyanobenzothiazole-2-amine was used instead of 2-aminothiazole in step 3), with a yield of 42%. 1 H NMR(400MHz,Chloroform-d)δ7.67(d,J=2.4Hz,1H),7.43(d,J=8.8Hz,1H),7.23(dd,J=8.8,2.4Hz,1H),6.96–6.91(m,2H),6 .66–6.61(m,2H),6.51(t,J=2.1Hz,2H),5.98(t,J=2.1Hz,2H),5.33(dd,J=9.4,5.4Hz,1H),3.54(s,3H),3.01–2.87(m,2H).13 C NMR(101MHz,Chloroform-d)δ168.57,159.55,139.91,133.39,131.33,127.62,1 24.92,119.61,115.88,114.34,109.66,108.54,59.35,55.37,44.85.ESI-MS:m / z 403.12[M+H] + C 22 H 19 N4O2S(403.12).

[0151] Example 30: Preparation of N-(4-cyanobenzothiazol-2-yl)-3-(4-methoxyphenyl)-3-(1H-pyrrolo-1-yl)propionamide (X94)

[0152] The preparation method was carried out according to steps 1), 2), and 3) of Example 1, except that 4-cyanobenzothiazole-2-amine was used instead of 2-aminothiazole in step 3), with a yield of 22%. 1 H NMR(400MHz,Chloroform-d)δ8.48(d,J=8.8Hz,1H),7.76–7.65(m,2H),7.19(d,J=8.6Hz,2H),6.88(d,J=8 .7Hz,2H),6.75(t,J=2.1Hz,2H),6.17(t,J=2.1Hz,2H),5.81–5.59(m,1H),3.80(s,3H),3.36–3.16(m,2H). 13 C NMR(101MHz,Chloroform-d)δ168.51,159.50,141.42,136.19,134.02,131.67,127.66,122.7 8,119.78,119.47,114.58,114.35,109.28,109.19,103.80,59.01,55.34,44.55.ESI-MS:m / z 403.12[M+H] + C 22 H 19 N4O2S(403.12).

[0153] Experimental Example 1: Biological Activity Test of Compounds

[0154] 1. Evaluation experiment on the ability of androgen receptor transcriptional repression

[0155] Prostate cancer cells introduced with the ARR2PB promoter can express the androgen receptor-regulated green fluorescent protein EGFP. Inhibiting androgen receptor transcription with compounds reduces the protein fluorescence intensity. LNCaP-ARR2PB-EGFP cells were first cultured in androgen-free complete medium for several days until the background fluorescence value decreased to a low level, and then injected with 3.5 × 10⁻⁶ cells... 4 Cells were seeded at a density of 10 cells / well in 96-well plates. After stable cell adhesion, dihydrotestosterone (DHT) and compounds of different concentration gradients were administered. After incubation for 72 hours, the fluorescence intensity near 530 nm was detected using a multi-mode microplate reader under excitation light at 485 nm, and the half-inhibitory concentration (IC50) of the compounds antagonizing androgen receptors was quantitatively calculated. 50 Enzalutamide (Enz) was used as a positive control, and the test results of some compounds are shown in Table 1.

[0156] 2. Detection of the inhibitory activity of the compound against prostate cancer cell proliferation using the MTT assay with 3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide.

[0157] Detection method: Succinate dehydrogenase in the mitochondria of live cells can reduce exogenous MTT to water-insoluble blue-purple formazan crystals. Measuring the absorbance of formazan can quantitatively reflect the number of live cells. Using androgen-free complete culture medium at 5 × 10⁻⁶... 3 LNCaP cells were seeded at a density of cells / well in 96-well plates. After the cells were stably adhered, different concentration gradients of compounds were introduced, with enzalutamide as a positive control. After 72 hours of incubation, 10 μL of 5 mg / mL MTT was added to each well, and incubation continued for another 4 hours. Then, 100 μL of LDS-HCl-PBS triple buffer was added. The plates were incubated overnight at 37°C. The absorbance of each well was measured at 570 nm using a microplate reader and converted to the viability. The results of some compounds are shown in Table 1.

[0158] 3. To detect the inhibitory activity of the compound on the proliferation of enzalutamide-resistant cells.

[0159] Detection principle: The LNCaP-enzR enzalutamide resistance model induced by the LNCaP cell line can simulate clinical drug resistance progression and is an important tool for screening novel anti-resistance AR antagonists. Therefore, the MTT assay was used to test whether the compound could inhibit the proliferation-inhibiting activity of LNCaP-enzR cells.

[0160] Detection method: Select cells near the logarithmic growth phase. After trypsin digestion, centrifuge, remove the supernatant, resuspend the cell pellet in complete culture medium, count the cells, adjust the cell concentration with culture medium, and then perform detection at 5 × 10⁻⁶ cells / mL. 3The sample was seeded at a density of 90 μL per well in a 96-well plate, with a zeroing well and a control well. The plate was placed in a humidified, 37°C, 5% CO2 incubator. After 24 hours of incubation, 10 μL of culture medium containing the test compound was added. The final concentrations of the test compounds were 50, 16.667, 5.556, 1.852, 0.617, 0.206, 0.069, and 0.023 μM, respectively, in triplicate. The plates were then incubated for another 72 hours. 10 μL of LTT solution (5 mg / mL) was added to each well, and the plates were incubated for 3–5 hours until crystals formed. 100 μL of triplet solution was added, and the plates were incubated overnight to completely dissolve the formazan crystals. The OD values ​​were measured at 570 nm using a microplate reader. The results for some compounds are shown in Table 1.

[0161] Table 1 shows the AR transcriptional repressive activity of compounds of formula (I).

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172] Experimental Example 2: Detection of the inhibitory activity of the compound against clinically drug-resistant AR mutants.

[0173] Detection Principle: Amino acid mutations in the AR ligand binding pocket can lead to abnormal activation of the AR signaling pathway by AR antagonists or nonspecific ligands, thereby promoting tumor progression. The T877A mutation is associated with resistance to the first-generation anti-androgen hydroxyfluoroamide and can promote prostate cancer cell growth. The W742C mutation mediates the agonist effect of bicalutamide, while the T878G mutation can convert enzalutamide into a partial agonist. Furthermore, the F877L mutation is found in the plasma DNA of patients with CRPC treated with enzalutamide / apalutamide. Based on this, this invention uses a dual-luciferase reporter gene system to detect the effects of compounds on drug-resistant AR mutants (containing AR... F877L ARF877L / T878A AR W742C and AR T878G The inhibitory effect of mutants.

[0174] Detection method: PC3 cells were starved for 3 days with a culture medium containing 5% carbon-adsorbed serum, and then detected with 1×10⁻⁶ cells. 4 Cells were seeded per well in 96-well white plates. After 24 hours of cell adhesion, 50 ng of AR mutant plasmid, 20 ng of pGL4-ARR2PB-Luc plasmid, and 5 ng of Renilla plasmid, 0.25 μL of transfection reagent, and 25 μL of serum-free medium were added to each well. After 24 hours of transfection, medium containing gradient concentrations of compounds was added, and the cells were cultured for another 24 hours before luciferase activity was measured.

[0175] Test results: such as Figure 13 As shown, the first-generation AR antagonist bicalutamide (Bic) exhibits agonistic activity against the W742C mutant, while the second-generation antagonist enzalutamide (Enz) completely antagonizes the W742C mutant, but shows dose-dependent transcriptional agonistic activity against F877L and F877L / T878A, and partial agonistic activity against the T878G mutant. In contrast, compounds X3, X24, and X66 of this invention all exhibit dose-dependent antagonistic effects against F877L, F877L / T878A, W742C, and T878G mutants, indicating that the compounds of this invention can antagonize the activity of representative mutant AR induced by long-term clinical use of first- and second-generation AR antagonists.

[0176] Experimental Example 3: Detection of the in vivo activity of the compound against hormone-sensitive prostate cancer (LNCaP model).

[0177] Detection principle: A tumor model was constructed by subcutaneously transplanting human prostate cancer cells (LNCaP) into nude mice. The effects of the compound on tumor volume, weight, and plasma PSA levels in mice were observed to evaluate its in vivo antitumor activity and safety.

[0178] Detection method: Male Balb / c nude mice aged 4-6 weeks were selected, and 100 μL of LNCaP cells (1×10⁻⁶) were added. 7 (One sample) was mixed with an equal volume of matrix gel and subcutaneously injected into the right groin of mice. Tumor volume was measured every 3 days (calculated using the formula: length × width). 2 / 2), when the tumor volume reaches 100mm 3Mice were then randomly divided into three groups: a solvent control group, an enzalutamide group (50 mg / kg, administered by gavage), an X3 group (50 mg / kg, administered by gavage), and an X3 group (20 mg / kg, administered by intraperitoneal injection). Administered once daily, and body weight was monitored during the trial to assess toxicity. After treatment, blood was collected from the orbital venous plexus, centrifuged at 5000 rpm, and the supernatant was used to determine tPSA levels. Mice were then euthanized, and tumors were completely removed and weighed.

[0179] Test results: such as Figure 14 As shown, both administration methods of X3 significantly inhibited tumor volume growth. Intraperitoneal injection of X3 (20 mg / kg) resulted in a tumor inhibition rate of 93.80%, significantly superior to the enzalutamide group (85.89%). Body weight monitoring, tumor weight, and plasma tPSA levels all confirmed that compound X3 was well-tolerated and had significant inhibitory activity against the proliferation of androgen-sensitive prostate cancer cells.

[0180] Example 4: Detection of the in vivo activity of the compound in enzalutamide-resistant prostate cancer (LNCaP-EnzR model).

[0181] Detection principle: A tumor model was constructed by subcutaneously transplanting LNCaP-EnzR into nude mice. The effects of the compound on tumor volume and mouse body weight were observed to assess its in vivo antitumor activity and safety.

[0182] Detection method: Male Balb / c nude mice aged 4-6 weeks were selected, and 100 μL of LNCaP-EnzR (1×10⁻⁶) was added. 7 (One sample) was mixed with an equal volume of matrix gel and subcutaneously injected into the right groin of mice. Tumor volume was measured every 3 days (calculated using the formula: length × width). 2 / 2), when the tumor volume reaches 100mm 3 They were then randomly divided into three groups: a solvent control group, an enzalutamide group (15 mg / kg, administered by gavage), and a compound X24 group (40 mg / kg, administered by gavage). The drugs were administered once daily, and body weight changes were monitored during the trial to assess toxicity.

[0183] Test results: such as Figure 15 As shown, in the oral administration of compound X24 at 50 mg / kg, the body weight of the treated mice did not decrease significantly throughout the dosing period, indicating that X24 has high safety. The tumor volume and endpoint tumor weight in the X24-treated group were significantly lower than those in the solvent control group, and the plasma tPSA decreased to 6.50 ng / mL, significantly lower than that in the solvent control group, indicating that X24 significantly inhibited the in vivo proliferation of enzalutamide-resistant LNCaP-enzR cell xenograft tumors.

Claims

1. A compound as shown in general formula I, or a pharmaceutically acceptable salt, prodrug, stereoisomer, or deuterated derivative thereof:

2. The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, or deuterated derivative thereof, characterized in that, In Formula I, structure A is H, a substituted or unsubstituted C4-C10 aromatic ring, or a substituted or unsubstituted 4-10 membered aromatic heterocycle; structure B is a substituted or unsubstituted C4-C10 aromatic ring or a substituted or unsubstituted 4-10 membered aromatic heterocycle. R1 and R2 are substituted or unsubstituted groups selected from the group consisting of: C1-C8 alkyl, C1-C8 alkoxy, C3-C10 cycloalkyl, C5-C10 cycloalkenyl, 4-10 membered heterocyclic, C6-C10 aryl, 4-10 membered heteroaryl, -(C1-C4 alkylene)(C3-C10 cycloalkyl), -(C1-C4 alkylene)(C3-C10 cycloalkenyl), -(C1-C4 alkylene)(C6-C10 aryl), -(C1-C4 alkylene)(4-10 membered heteroaryl), -(C1-C4 alkylene)(4-10 membered heterocyclic), -S / O(C3-C10 cycloalkyl), -S / O (C3-C10 cycloalkenyl), -S / O(C6-C10 aryl), -S / O(4-10 heteroaryl), -S / O(4-10 heterocyclic), -S / O(C3-C10 cycloalkyl), -S / O(C3-C10 cycloalkenyl), -S / O(C6-C10 aryl), -S / O(4-10 heteroaryl), -S / O(4-10 heterocyclic), -S / O(C1-C4 alkylene)(C3-C10 cycloalkyl), -S / O(C1-C4 alkylene)(C3-C10 cycloalkenyl), -S / O(C1-C4 alkylene)(C6-C10 aryl), -S / O(C1-C4 alkylene)(C6-C10 aryl), -S / O(C1-C10 cycloalkenyl) -C4 alkylene)(4-10 heteroaryl), -S / O(C1-C4 alkylene)(4-10 heterocyclic), -(C1-C4 alkylene)(C3-C10 cycloalkyl), -(C1-C4 alkylene)(C3-C10 cycloalkenyl), -(C1-C4 alkylene)(C6-C10 aryl), -(C1-C4 alkylene)(4-10 heteroaryl), -(C1-C4 alkylene)(4-10 heterocyclic), -S / O(C3-C10 cycloalkyl), -S / O(C3-C10 cycloalkenyl), -S / O(C6-C10 aryl), -S / O(4-10 heteroaryl), - S / O (4-10 membered heterocyclic group), -S / O (C3-C10 cycloalkyl), -S / O (C3-C10 cycloalkenyl), -S / O (C6-C10 aryl), -S / O (4-10 membered heteroaryl), -S / O (4-10 membered heterocyclic group), -S / O (C1-C4 subalkyl)(C3-C10 cycloalkyl), -S / O (C1-C4 subalkyl)(C3-C10 cycloalkenyl), -S / O (C1-C4 subalkyl)(C6-C10 aryl), -S / O (C1-C4 subalkyl)(4-10 membered heteroaryl), -S / O (C1-C4 subalkyl)(4-10 membered heterocyclic group);The substitution mentioned therein refers to substitution by one or more groups selected from the group consisting of: halogen, cyano, nitro, hydroxy, mercapto, carboxyl, ketone, aldehyde, ester, oxo (=O), C1-C8 alkyl, C1-C8 haloalkyl, C3-C6 cycloalkyl, C1-C8 alkoxy / thio, C1-C6 haloalkoxy / thio, C3-C6 cycloalkoxy / thio, C3-C6 halocycloalkoxy / thio, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, 4-10 heteroaryl, or 4-8 heterocyclic. The R3 group is selected from halogen, hydroxyl, mercapto, nitro, cyano, carboxyl, ketone, aldehyde, ester, C1-C8 alkyl, C1-C8 haloalkyl, C1-C6 alkoxy / thio, C1-C6 haloalkoxy / thio, C2-C6 alkenyl, C2-C6 alkenyl / thio, C3-C6 cycloalkyl, C3-C6 cycloalkoxy / thio, C2-C6 alkynyl, and C2-C6 alkynyl / thio.

3. The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, or deuterated derivative thereof, characterized in that, When A is H, the R3 substituent is located on ring B.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, or deuterated derivative thereof, characterized in that, R1 and R2 preferably have one of the following structures: H、CH3、CH2CH3。 5. The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, or deuterated derivative thereof, characterized in that, Structure A is preferably one of the following structures: H。 6. The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, or deuterated derivative thereof, characterized in that, Structure B preferably has one of the following structures:

7. The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, or deuterated derivative thereof, characterized in that, Selected from one of the following compounds:

8. A method for preparing the compound of claim 1 or a pharmaceutically acceptable salt, prodrug, stereoisomer, or deuterated derivative thereof, comprising the following steps: 1) Compound 8 and compound 9 were mixed and coupled to obtain compound 10; 2) Compound 10 and compound 11 were dehydrated and condensed to obtain a disubstituted-N-(substituted polycyclic cyclo-2-yl)propionamide compound. The disubstituted-N-(substituted polycyclic cyclo-2-yl)propionamide compound was then subjected to salt formation to obtain a pharmaceutically acceptable salt of the disubstituted-N-(substituted polycyclic cyclo-2-yl)propionamide compound. The synthetic route is as follows:

9. A pharmaceutical composition for treating tumors, comprising at least one active ingredient and at least one pharmaceutically acceptable carrier, said active ingredient being a compound of general formula I as claimed in claim 1, or a pharmaceutically acceptable salt, prodrug (ester or phosphate ester), stereoisomer, or deuterated product thereof.

10. The use of the compound of claim 1 or a pharmaceutically acceptable salt, prodrug, stereoisomer, or deuterated derivative thereof in the preparation of a medicament for the treatment or prevention of prostate cancer, wherein the medicament is made from the analogue and a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient, wherein the pharmaceutically acceptable salt is a hydrochloride, benzenesulfonate, toluenesulfonate, phosphate, maleate, sulfate, acetate, citrate, fumarate, or tartrate, and further comprises a pharmaceutically acceptable excipient, diluent, or carrier, and the pharmaceutical composition is formulated in the form of a gas, liquid, or solid dosage form.

Images