Telomerase inhibitor and application thereof

Abstract

The invention discloses a telomerase inhibitor and application thereof, and belongs to the technical field of medicinal chemistry, and the telomerase inhibitor is a compound as shown in a general formula I and pharmaceutically acceptable salt, ester or deuterated substance thereof. The invention also discloses a pharmaceutical composition containing the compound as shown in the general formula I, and application of the pharmaceutical composition and the compound as shown in the general formula I in preparation of antitumor drugs. The telomerase inhibitor and the telomerase inhibitor composition are suitable for promoting permeation of immune cells to tumor tissues and inducing immune exposure of the tumor tissues, so that the anti-tumor immunocompetence of an organism is improved or the curative effect of other anti-tumor immunotherapy is enhanced.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a class of telomerase inhibitors and uses thereof. Background Art

[0002] 85-90% of tumors rely on telomerase to maintain telomere length, thereby avoiding cell growth arrest and apoptosis caused by progressive shortening of telomeres. Therefore, inhibiting telomerase is an important way to develop anti-tumor drugs. At present, there are no small molecule telomerase inhibitors on the market, but several have entered clinical or preclinical studies. The fastest-progressing THIO (6-thio-dG) has conducted multiple Phase II clinical studies and obtained at least 10 tumor-related indications. Low-dose THIO combined with PD-1 or PD-L1 immune drugs has extraordinary efficacy in treating tumor models of colorectal cancer, liver cancer and small cell lung cancer. Even advanced tumors can be completely eliminated, and targeted immune memory against cancer cells can be established. As of the end of 2023, THIO has been granted "orphan drug" status by the US FDA for liver cancer, small cell lung cancer and glioblastoma. In June 2024, the first oligonucleotide telomerase inhibitor Rytelo (imetelstat) was approved by the FDA for the treatment of myelodysplastic syndrome (MDS), a blood cancer. It can be seen that telomerase has good clinical application prospects as an anti-cancer target.

[0003] Although the research and development of existing telomerase inhibitors has made certain progress, their inhibitory activity is generally not strong. The most representative small molecule telomerase inhibitor BIBR1532 has an inhibitory activity of about 0.1μM, but many small molecule telomerase inhibitors including BIBR1532 have stopped in the preclinical stage due to insufficient in vivo activity. The recently approved Rytelo belongs to the oligonucleotide class. Compared with small molecules, it has poor stability, poor membrane permeability and is prone to cause unexpected immune responses, which limits its use. Although THIO is a small molecule, it is a nucleoside analog with poor selectivity and high toxicity. Therefore, the development of non-nucleoside highly active small molecule telomerase inhibitors is expected to break through the research and development bottleneck of existing telomerase inhibitors and have broad-spectrum anti-tumor potential. Summary of the invention

[0004] In view of the shortcomings of current telomerase inhibitors, such as insufficient activity and limited in vivo application, the present invention proposes and confirms a class of diaromatic ketone compounds as highly active small molecule telomerase inhibitors, which have clear anti-tumor activity and the effect of activating anti-tumor immunity in vivo and in vitro.

[0005] The technical solution of the present invention is as follows:

[0006] A class of diaromatic ketone compounds is used as a highly active small molecule telomerase inhibitor, wherein the telomerase inhibitor is a compound as shown in the general formula I and a pharmaceutically acceptable salt, ester or deuterated product thereof:

[0007]

[0008] Wherein, R1 is selected from any one of hydrogen, nitro, acetylamino, halogen or C1-C3 haloalkyl; R2 and R3 are each independently selected from any one of hydrogen, nitro, acetylamino, halogen, C1-C3 haloalkyl, 1-dimethylamino-2-propynyl, substituted or unsubstituted C3-C20 nitrogen-containing heterocyclic group, substituted or unsubstituted C5-C14 heteroaryl; R4 and R5 are each independently selected from any one of hydrogen, methyl, dimethylamino, substituted or unsubstituted C3-C20 nitrogen-containing heterocyclic group, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C5-C14 heteroaryl; X is selected from any one of oxygen, carbonyl, amide or aminoacyl; n is each independently selected from an integer of 0 to 6.

[0009] Furthermore, R1 is selected from any one of hydrogen, nitro or acetylamino, preferably hydrogen.

[0010] Furthermore, R2 and R3 are each independently selected from any one of hydrogen, nitro, halogen, 1-dimethylamino-2-propynyl, and a substituted or unsubstituted C3-C7 nitrogen-containing heterocyclic group.

[0011] Furthermore, the substituted or unsubstituted C3-C7 nitrogen-containing heterocyclic group is selected from any one of the following groups:

[0012] Further, R4 is selected from hydrogen or phenyl, preferably hydrogen.

[0013] Further, R5 is selected from hydrogen or methyl, preferably methyl.

[0014] Furthermore, X is a carbonyl group.

[0015] Furthermore, n is selected from an integer of 0 to 2, and is preferably 1.

[0016] According to a specific embodiment of the present invention, the telomerase inhibitor is selected from the following compounds and pharmaceutically acceptable salts, esters or deuterated derivatives thereof:

[0017]

[0018]

[0019] Furthermore, the pharmaceutically acceptable salt of the compound represented by the general formula I is selected from hydrochloride, methanesulfonate, fumarate, tartrate, citrate, maleate, sodium salt or potassium salt.

[0020] Furthermore, the pharmaceutically acceptable ester of the compound represented by the general formula I is selected from succinate, succinate, phosphate, glycine or other amino acid esters.

[0021] The present invention also provides a telomerase inhibitor composition, comprising the compound represented by the aforementioned general formula I and its pharmaceutically acceptable salt, ester or deuterated product thereof and at least one pharmaceutically acceptable carrier or excipient.

[0022] Furthermore, the telomerase inhibitor composition further comprises at least one other therapeutic agent.

[0023] The dosage form of the telomerase inhibitor composition is any dosage form that is clinically or pharmaceutically acceptable.

[0024] Another technical solution of the present invention is to provide a compound as shown in general formula I and its pharmaceutically acceptable salt, ester or deuterated product or the use of the above-mentioned telomerase inhibitor composition in the preparation of anti-tumor drugs

[0025] In addition, the present invention also provides a use of a compound as shown in general formula I and a pharmaceutically acceptable salt, ester or deuterated product thereof or the aforementioned telomerase inhibitor composition in the preparation of a PDL1 inhibitor enhancing drug.

[0026] In particular, the telomerase inhibitor and telomerase inhibitor composition of the present invention are suitable for promoting the penetration of immune cells into tumor tissues and inducing immune exposure of tumor tissues, thereby improving the body's anti-tumor immune ability or enhancing the efficacy of other anti-tumor immunotherapies.

[0027] In particular, the telomerase inhibitor and telomerase inhibitor composition of the present invention are suitable for use as a drug for advanced or recurrent malignant tumors that are sensitive or insensitive to anti-PD1 / PDL1 therapy.

[0028] The dosage of the compound of the present invention is 1 mg-1000 mg / day, and may deviate from this range depending on the severity of the disease or the dosage form.

[0029] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

[0030] The term "inhibitor" as used herein refers to the inhibition of telomerase activity, thereby resulting in attrition and shortening of telomeric repeat sequences.

[0031] The "pharmaceutical carrier" refers to conventional drug carriers in the pharmaceutical field, including conventional diluents, excipients (such as water, etc.), fillers (such as starch, etc.), binders (such as cellulose derivatives, gelatin, etc.), wetting agents (such as glycerol, etc.), disintegrants (such as agar, calcium carbonate, etc.), absorption promoters (such as quaternary ammonium compounds, etc.), surfactants (such as hexadecanol, etc.), adsorption carriers (such as kaolin and soap clay, etc.), lubricants (such as talc, etc.), and flavoring agents, sweeteners, etc. may also be added if necessary.

[0032] The "pharmaceutically acceptable dosage form" is suitable for administration by any appropriate route, such as oral (including buccal or sublingual administration), rectal administration, nasal administration, topical administration (including buccal, sublingual or transdermal administration), vaginal administration or parenteral administration (including subcutaneous injection, intramuscular injection, intravenous injection or intradermal injection). These preparations can be prepared by any method known in the field of pharmacy. For example, by mixing the active ingredient with a carrier or excipient. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The immunohistochemical examination diagram in the experiment to verify the effect of telomerase inhibitor in inducing immune exposure of tumor tissue in Example 29 of the present invention is shown;

[0034] Figure 2 The figure shows the average optical density analysis result in the experiment to verify the effect of telomerase inhibitor on inducing immune exposure of tumor tissue in Example 29 of the present invention;

[0035] Figure 3 It is an analysis chart of the in vivo anti-tumor activity research experiment of tumor-bearing mice in each drug-administered group in Example 30 of the present invention, wherein A is a photo of the tumor tissue removed from the tumor-bearing mouse; B is the weighed mass of the tumor tissue, C is the tumor growth curve, and D is the weight change of the mouse during the treatment. DETAILED DESCRIPTION

[0036] It should be noted that, in the case of no conflict, the embodiments in the present application and the features in the embodiments can be combined with each other. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper limit and the lower limit of the scope is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or the intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope. The present invention will be described in detail below in conjunction with the embodiments.

[0037] Taking compound 3 and compound 6 (route I) as examples, the preparation methods of some compounds of the present invention are as follows:

[0038]

[0039] In route I, the reactants and reaction conditions involved are: a is polyphosphoric acid, 90°C;

[0040] b is morpholine, BINAP (1,1'-binaphthyl-2,2'-bis(diphenylphosphine), palladium acetate, cesium carbonate, 1,4-dioxane, N2, 90°C;

[0041] c is 1-dimethylamine-2-propyne, bistriphenylphosphine palladium dichloride, cuprous iodide, triphenylphosphine, triethylamine, N,N-dimethylformamide, water, N2, 70°C.

[0042] Taking compound 7 (route II) as an example, the preparation methods of some compounds of the present invention are as follows:

[0043]

[0044] The reactants and reaction conditions involved in route II are: a is N2, 125°C;

[0045] b is Eaton's reagent, N2, 50°C;

[0046] c is sodium hydroxide, methanol, 65°C;

[0047] d is morpholine, palladium acetate, cesium carbonate, 1,4-dioxane, N2, 90°C.

[0048] Taking compound 10 (route III) as an example, the preparation methods of some compounds of the present invention are as follows:

[0049]

[0050] The reactants and reaction conditions involved in route III are: a is potassium carbonate, N,N-dimethylformamide, 45°C;

[0051] b is magnesium powder, iodine, tetrahydrofuran, N2, room temperature to 65°C;

[0052] c is tetrahydrofuran, N2, room temperature;

[0053] d is IBX (2-iodoacetylbenzoic acid), dimethyl sulfoxide, room temperature.

[0054] Taking compound 18 (route IV) as an example, the preparation methods of some compounds of the present invention are as follows:

[0055]

[0056] The reactants and reaction conditions involved in route II are: a is palladium trifluoroacetate, 5,5'-dimethyl-2,2-bipyridine, methanesulfonic acid, 2-methyltetrahydrofuran, H2O, N2, 80°C;

[0057] b is acetic anhydride, triethylamine, chloroform, 60℃.

[0058] Taking compound 19 (route V) as an example, the preparation methods of some compounds of the present invention are as follows:

[0059]

[0060] The reactants and reaction conditions involved in route V are: a is cesium carbonate, copper iodide, N,N-dimethylglycine hydrochloride, 1,4-dioxane, N2, 90°C;

[0061] b is 3-hydroxyazetidine hydrochloride, BINAP (1,1'-binaphthyl-2,2'-bis(diphenylphosphine), palladium acetate, cesium carbonate, 1,4-dioxane, N2, 90°C.

[0062] Taking compound 25 (Route VI) as an example, the preparation methods of some compounds of the present invention are as follows:

[0063]

[0064] The reactants and reaction conditions involved in route VI are: a is HOBt (1-hydroxybenzotriazole), HATu (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), DIPEA (N,N-diisopropylethylamine), dimethyl sulfoxide, room temperature;

[0065] b is 4-hydroxypiperidine, BINAP (1,1'-binaphthyl-2,2'-bis(diphenylphosphine), palladium acetate, cesium carbonate, 1,4-dioxane, N2, 90°C.

[0066] In addition, compounds 1-6, 12-14 are prepared with reference to route I, compounds 7-9, 15-17 are prepared with reference to route II, compounds 10, 11 are prepared with reference to route III, compound 18 is prepared with reference to route IV, compounds 19-24 are prepared with reference to route V, and compounds 25-27 are prepared with reference to route VI. It should be noted that the specific examples included below are for illustration and should not be construed as limiting the scope of the present invention. In addition, it should be understood that after reading the content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and such equivalent forms also fall within the scope defined by the claims attached to this application.

[0067] Example 1

[0068] The synthesis of (3,4-dimethoxyphenyl)(3-(piperazin-1-yl)phenyl)methanone (i.e., TCB-1 in Table 1) comprises the following steps:

[0069] (1) Synthesis of (3-bromophenyl)(3,4-dimethoxyphenyl)methanone (30)

[0070]

[0071] 3-Bromobenzoic acid (5 g, 54.02 mmol, 1.0 eq), o-phenylenedimethyl ether (5 g, 54.02 mmol, 1.0 eq) and polyphosphoric acid (20 g) were added to a round-bottom flask in sequence, and stirred at 90°C for 2 hours. After TLC (thin layer chromatography) showed that the reaction was complete, dichloromethane was extracted, and the mixture was washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution in sequence. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain 5.5 g of a white solid with a yield of 69%.

[0072] (2) Synthesis of tert-butyl 4-(3-(3,4-dimethoxybenzoyl)phenyl)piperazine-1-carboxylate (31)

[0073]

[0074] Compound 30 (500 mg, 1.56 mmol, 1 eq), N-BOC-piperazine (189.7 mg, 1.88 mmol, 1.2 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (194.6 mg, 0.31 mmol, 0.2 eq), palladium acetate (35.1 mg, 0.16 mmol, 0.1 eq), cesium carbonate (1527.3 mg, 4.69 mmol, 3 eq) and 1,4-dioxane (8 ml) were added to a round-bottom flask in sequence, and stirred at 90°C for 4 hours under nitrogen protection. After TLC showed that the reaction was complete, dichloromethane was added to the reaction system, and the system was washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution in sequence. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain 196.5 mg of a yellow solid with a yield of 37%.

[0075] (3) Synthesis of (3,4-dimethoxyphenyl)(3-(piperazin-1-yl)phenyl)methanone (1)

[0076]

[0077] Compound 31 (500 mg, 1.56 mmol, 1 eq) was added to a round-bottom flask in sequence, and dichloromethane (4 ml, DCM) and trifluoroacetic acid (1 ml, TFA) were added, and the mixture was stirred at room temperature (rt) for 2 hours. After TLC showed that the reaction was complete, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution were added to the reaction system, and the mixture was washed twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain 96.5 mg of a yellow solid with a yield of 87%.

[0078] The yellow solid was subjected to nuclear magnetic resonance and electrospray ionization mass spectrometry (ESI-MS) detection, and the nuclear magnetic resonance and mass spectrometry results were: 1 H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H); 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03; ESI-HRMS:calcd for C 19 H 23 N2O3[M+H] + :327.1709;found:327.1713.

[0079] Example 2

[0080] The synthesis of (3,4-dimethoxyphenyl)(3-(3-hydroxypyrrolidin-1-yl)phenyl)methanone (i.e., TCB-2 in Table 1) is as follows:

[0081]

[0082] Compound 2 was prepared with reference to Example 1, except that N-BOC-piperazine was replaced by 3-hydroxypyrrolidine in step (2).

[0083] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H); 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03; ESI-HRMS:calcd for C 19 H 22 NO4[M+H] + :328.1549;found:328.1553.

[0084] Example 3

[0085] The synthesis of (3,4-dimethoxyphenyl)(3-morpholinylphenyl)methanone (TCB-3 in Table 1) is as follows:

[0086]

[0087] Compound 3 was prepared with reference to Example 1, except that N-BOC-piperazine was replaced by morpholine in step (2).

[0088] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H); 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03; ESI-HRMS:calcd for C 19 H 22 NO4[M+H] + :328.1549;found:328.1553.

[0089] Example 4

[0090] The synthesis of (3,4-dimethoxyphenyl)(3-(4-hydroxypiperidin-1-yl)phenyl)methanone (i.e., TCB-4 in Table 1) is as follows:

[0091]

[0092] Compound 4 was prepared with reference to Example 1, except that N-BOC-piperazine was replaced by 4-hydroxypiperidine in step (2).

[0093] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 20 H 24 NO4[M+H] + :342.1705;found:342.1710.

[0094] Example 5

[0095] The synthesis of (3,4-dimethoxyphenyl)(3-(3-hydroxyazetidin-1-yl)phenyl)methanone (i.e., TCB-5 in Table 1) is as follows:

[0096]

[0097] Compound 5 was prepared with reference to Example 1, except that N-BOC-piperazine was replaced by 3-methylazetidine hydrochloride in step (2).

[0098] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 18 H 20 NO4[M+H] + :314.1392;found:314.1398.

[0099] Example 6

[0100] The synthesis of (3,4-dimethoxyphenyl)(3-(3-(dimethylamino)prop-1-ynyl-1-phenyl)methanone (i.e., TCB-6 in Table 1) is as follows:

[0101]

[0102] In a round-bottom flask, compound 30 (1000 mg, 3.12 mmol, 1 eq), 1-dimethylamine-2-propyne (353.3 mg, 4.25 mmol, 1.36 eq), bistriphenylphosphine palladium dichloride (219.3 mg, 0.31 mmol, 0.1 eq), cuprous iodide (119.0 mg, 0.62 mmol, 0.2 eq), triphenylphosphine (163.9 mg, 0.62 mmol, 0.2 eq), triethylamine (474.3 mg, 4.69 mmol, 1.5 eq) and a mixed solvent (N,N-dimethylformamide: water = 9:1, 10 ml) were added in sequence, and the reaction was stirred at 70 ° C for 6 hours under nitrogen protection. After TLC showed that the reaction was complete, dichloromethane was added to the reaction system, and the mixture was washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution in sequence. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 565.3 mg of a yellow solid with a yield of 56%.

[0103] 1 H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 20 H 22 NO3[M+H] + :324.1600; found:324.1606.

[0104] Example 7

[0105] The synthesis of (3-hydroxy-4-methoxyphenyl)(4-morpholinylphenyl)methanone (i.e., TCB-7 in Table 1) comprises the following steps:

[0106] (1) Synthesis of 2-methoxyphenyl-2-chloroacetate (33)

[0107]

[0108] Guaiacol (12.7 g, 102.38 mmol, 1 eq) and chloroacetyl chloride (16.5 g, 133.09 mmol, 1.3 eq) were added to a round-bottom flask in sequence, and the mixture was stirred at 125°C for 8 hours under nitrogen protection. After TLC showed that the reaction was complete, the mixture was extracted with dichloromethane, washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution in sequence, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain 19.8 g of a colorless oil with a yield of 97%.

[0109] (2) Synthesis of 5-(4-bromobenzoyl)-2-methoxyphenyl-2-chloroacetate (35)

[0110]

[0111] 4-Bromobenzoic acid (5 g, 24.98 mmol, 1.5 eq), compound 33 (3.3 g, 16.58 mmol, 1 eq) and Eaton's reagent (25 ml) were added to a round-bottom flask in sequence, and the mixture was stirred at 50°C for 4 hours under nitrogen protection. After TLC showed that the reaction was complete, dichloromethane was added, and the solution was transferred to a round-bottom flask. Saturated sodium bicarbonate solution was added under ice bath to adjust the pH of the system to 7-8, and the mixture was washed with water and saturated sodium chloride solution in sequence, extracted with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain 4.5 g of a white solid with a yield of 47%.

[0112] (3) Synthesis of (4-bromophenyl)(3-hydroxy-4-methoxyphenyl)methanone (36)

[0113]

[0114] Compound 35 (856.3 mg, 2.24 mmol, 1 eq), sodium hydroxide (358.7 mg, 8.97 mmol, 4 eq) and methanol (10 ml) were added to a round-bottom flask in sequence and stirred at 65°C for 1 hour. After TLC showed that the reaction was complete, the mixture was washed with water and saturated sodium chloride solution in sequence, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain 850.6 mg of a white solid with a yield of 47%.

[0115] (4) Synthesis of (3-hydroxy-4-methoxyphenyl) (4-morpholinylphenyl) ketone (7)

[0116]

[0117] Compound 36 (200.0 mg, 0.65 mmol, 1.0 eq), morpholine (79.4 mg, 0.78 mmol, 1.2 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (81.4 mg, 0.13 mmol, 0.2 eq), palladium acetate (14.7 mg, 0.065 mmol, 0.1 eq), cesium carbonate (638.9 mg, 1.96 mmol, 3 eq) and 1,4-dioxane (4 ml) were added to a round-bottom flask in sequence, and stirred at 90°C for 5 hours under nitrogen protection. After TLC showed that the reaction was complete, the mixture was washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution in sequence, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain 98.3 mg of a yellow solid with a yield of 46%.

[0118] 1 H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 18 H 20 NO4[M+H] + :314.1392;found:314.1398.

[0119] Example 8

[0120] The synthesis of (3-hydroxy-4-methoxyphenyl)(4-(4-hydroxypiperidin-1-yl)phenyl)methanone (i.e., TCB-8 in Table 1) is as follows:

[0121]

[0122] Compound 8 was prepared with reference to Example 7, except that morpholine was replaced by 4-hydroxypiperidine in step (4).

[0123] 1 H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 19 H 22 NO4[M+H] + :328.1549;found:328.1553.

[0124] Example 9

[0125] The synthesis of (3-hydroxy-4-methoxyphenyl)(4-(3-hydroxyazetidin-1-yl)phenyl)methanone (i.e., TCB-9 in Table 1) is as follows:

[0126]

[0127] Compound 9 was prepared with reference to Example 7, except that morpholine was replaced by 3-methylazetidine hydrochloride in step (4).

[0128] 1 H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 17 H 18 NO4[M+H] + :300.1236;found:300.1242.

[0129] Example 10

[0130] The synthesis of (4-bromophenyl)(3-methoxy-4-phenethoxyphenyl)methanone (i.e., TCB-10 in Table 1) comprises the following steps:

[0131] (1) Synthesis of 3-methoxy-4-phenylethoxybenzaldehyde (38)

[0132]

[0133] Compound 37 (1216.3 mg, 6.57 mmol, 2.0 eq), vanillin (500.0 mg, 3.29 mmol, 1.0 eq), potassium carbonate (1816.6 mg, 13.14 mmol, 4.0 eq) and N,N-dimethylformamide (10 ml) were added to a round-bottom flask in sequence, and stirred at 45°C for 6 hours. After TLC showed that the reaction was complete, it was extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution for many times, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain 841.6 mg of a colorless oil with a yield of 95%.

[0134] (2) Synthesis of (4-bromophenyl)(3-methoxy-4-phenethoxyphenyl)methanol (41)

[0135]

[0136] In a two-necked round-bottom flask, magnesium chips (120.6 mg, 4.96 mmol, 1.65 eq), a catalytic amount of iodine, and N2 protection were added. 1,4-dibromobenzene (1064.4 mg, 4.51 mmol, 1.5 eq) and tetrahydrofuran (10 ml) were slowly added at a constant pressure titration funnel at a uniform rate, and the mixture was stirred at 65°C for 3 hours. Compound 38 (770.3 mg, 3.00 mmol, 1.0 eq) was then dissolved in tetrahydrofuran (10 ml), and added to the reaction bottle containing compound 40 through a constant pressure titration funnel under an ice bath. After the addition was completed, the mixture was stirred at room temperature for 4 hours. After TLC showed that the reaction was complete, ammonium chloride solution (20 ml) was added to neutralize the mixture, and the mixture was washed with water and saturated sodium chloride solution in turn, extracted with dichloromethane twice, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain 880.3 mg of a yellow solid with a yield of 71%.

[0137] (3) Synthesis of (4-bromophenyl)(3-methoxy-4-phenethoxyphenyl)methanone (10)

[0138]

[0139] Compound 41 (831.1 mg, 2.01 mmol, 1.0 eq), IBX (844.6 mg, 3.02 mmol, 1.5 eq) and dimethyl sulfoxide (6 ml) were added to a round-bottom flask in sequence and stirred at room temperature for 5 hours. After TLC showed that the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain 294.0 mg of a yellow solid with a yield of 36%.

[0140] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 22 H 20 BrO3[M+H] + :411.0596;found:411.0602.

[0141] Embodiment 11

[0142] The synthesis of (4-benzyloxy)-3-methoxyphenyl (4-bromophenyl) ketone (i.e., TCB-11 in Table 1) is as follows:

[0143]

[0144] Compound 11 was prepared by referring to Example 10, except that 3-methoxy-4-phenethoxybenzaldehyde (38) was replaced by 4-benzyloxy-3-methoxybenzaldehyde in step (2) to obtain (4-bromophenyl)(4-benzyloxy-3-methoxyphenyl)methanol, and (4-bromophenyl)(4-benzyloxy-3-methoxyphenyl)methanol was prepared by referring to step (3) of Example 10 to obtain Compound 11.

[0145] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 21 H 18 BrO3[M+H] + :397.0439;found:397.0446.

[0146] Example 12

[0147] The synthesis of (3-(2-oxa-6-azaspiro[3,3]heptane-6-yl)phenyl)(3,4-dimethoxyphenyl)methanone (i.e., TCB-12 in Table 1) is as follows:

[0148]

[0149] Compound 12 was prepared with reference to Example 1, except that N-BOC-piperazine in step (2) was replaced by 2-oxa-6-aza-spiro[3,3]heptane.

[0150] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 20 H 22 NO4[M+H] + :340.1549;found:340.1556.

[0151] Embodiment 13

[0152] The synthesis of (3-(2,6-diazaspiro[3,4]octan-6-yl)phenyl)(3,4-dimethoxyphenyl)methanone (i.e., TCB-13 in Table 1) is as follows:

[0153]

[0154] Compound 13 was prepared with reference to Example 1, except that N-BOC-piperazine in step (2) was replaced by tert-butyl 2,6-diaza-spiro[3,4]octane-2-carbonate.

[0155] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 21 H 25 N2O3[M+H] + :353.1865;found:353.1870.

[0156] Embodiment 14

[0157] The synthesis of (3-(2,7-diazaspiro[4,4]nonan-2-yl)phenyl)(3,4-dimethoxyphenyl)methanone (i.e., TCB-14 in Table 1) is as follows:

[0158]

[0159] Compound 14 was prepared with reference to Example 1, except that N-BOC-piperazine in step (2) was replaced by 2-BOC-2,7-diaza-spiro[4,4]nonane.

[0160] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 22 H 27 N2O3[M+H] + :367.2022;found:367.2028.

[0161] Embodiment 15

[0162] The synthesis of (3,4-dimethoxyphenyl)(4-nitrophenyl)methanone (i.e., TCB-15 in Table 1) is as follows:

[0163]

[0164] Compound 15 was prepared with reference to Example 7, except that 4-bromobenzoic acid in step (2) was replaced by 4-nitrobenzoic acid and 2-methoxyphenyl-2-chloroacetate was replaced by o-phenylenedimethyl ether.

[0165] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 15 H 14 NO5[M+H] + :288.0872;found:288.0879.

[0166] Example 16

[0167] The synthesis of (3,4-dimethoxyphenyl)(3-nitrophenyl)methanone (i.e., TCB-16 in Table 1) is as follows:

[0168]

[0169] Compound 16 was prepared with reference to Example 7, except that 4-bromobenzoic acid in step (2) was replaced by 3-nitrobenzoic acid and 2-methoxyphenyl-2-chloroacetate was replaced by o-phenylenedimethyl ether.

[0170] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 15 H 14 NO5[M+H] + :288.0872;found:288.0877.

[0171] Embodiment 17

[0172] The synthesis of (3,4-dimethoxyphenyl)(2-nitrophenyl)methanone (i.e., TCB-17 in Table 1) is as follows:

[0173]

[0174] Compound 17 was prepared with reference to Example 7, except that 4-bromobenzoic acid in step (2) was replaced by 2-nitrobenzoic acid and 2-methoxyphenyl-2-chloroacetate was replaced by o-phenylenedimethyl ether.

[0175] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 15 H 14 NO5[M+H] + :288.0872;found:288.0876.

[0176] Embodiment 18

[0177] The synthesis of N-(2-(3,4-dimethoxybenzoyl)phenyl)acetamide (i.e., TCB-18 in Table 1) comprises the following steps:

[0178] (1) Synthesis of (2-aminophenyl)(3,4-dimethoxyphenyl)methanone (44)

[0179]

[0180] Compound 42 (2254.8 mg, 19.09 mmol, 2.0 eq), compound 43 (1736.6 mg, 9.54 mmol, 1.0 eq), palladium trifluoroacetate (396.6 mg, 1.19 mmol, 0.125 eq), 5,5'-dimethyl-2,2-bipyridine (329.6 mg, 1.79 mmol, 0.19 eq), methanesulfonic acid (9171.6 mg, 95.43 mmol, 3 eq), 2-methyltetrahydrofuran (10 ml) and H2O (5 ml) were added to the sealed tube in sequence, and stirred at 80°C for 36 hours under nitrogen protection. After TLC showed that the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain 984.3 mg of a yellow solid with a yield of 40%.

[0181] (2) Synthesis of N-(2-(3,4-dimethoxybenzoyl)phenyl)acetamide (18)

[0182]

[0183] Compound 44 (309.0 mg, 1.20 mmol, 1.0 eq), acetic anhydride (159.5 mg, 1.56 mmol, 1.3 eq), triethylamine (182.4 mg, 1.80 mmol, 1.5 eq) and chloroform (10 ml) were added to a round-bottom flask in sequence, and stirred at 60°C for 24 hours. After TLC showed that the reaction was complete, the mixture was washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution in sequence, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain 299.0 mg of a yellow solid with a yield of 83%.

[0184] 1 H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 17 H 18 NO4[M+H] + :300.1236;found:300.1242.

[0185] Embodiment 19

[0186] The synthesis of 1-(3-(3,4-dimethoxyphenoxy)phenyl)azetidine-3-ol (i.e., TCB-19 in Table 1) comprises the following steps:

[0187] (1) Synthesis of (2-aminophenyl)(3,4-dimethoxyphenyl)methanone (47)

[0188]

[0189] In a round-bottom flask, m-bromoiodobenzene (1500.0 mg, 5.30 mmol, 1.0 eq), 3,4-dimethoxyphenol (2452.2 mg, 15.91 mmol, 3.0 eq), cesium carbonate (5182.7 mg, 15.91 mmol, 3.0 eq), copper iodide (101.0 mg, 0.53 mmol, 0.1 eq), N,N-dimethylglycine hydrochloride (148.0 mg, 1.06 mmol, 0.2 eq) and 1,4-dioxane (20 ml) were added in sequence, and the mixture was stirred at 90°C for 5 hours under nitrogen protection. After TLC showed that the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain 1353.0 mg of a white solid with a yield of 83%.

[0190] (2) Synthesis of 1-(3-(3,4-dimethoxyphenoxy)phenyl)azetidine-3-ol (19)

[0191]

[0192] Compound 47 (359.5 mg, 1.16 mmol, 1 eq), 3-hydroxyazetidine hydrochloride (191.8 mg, 1.75 mmol, 1.2 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (145.4 mg, 0.23 mmol, 0.2 eq), palladium acetate (26.2 mg, 0.12 mmol, 0.1 eq), cesium carbonate (1140.9 mg, 3.50 mmol, 3 eq) and 1,4-dioxane (8 ml) were added to a round-bottom flask in sequence, and stirred at 90°C for 4 hours under nitrogen protection. After TLC showed that the reaction was complete, dichloromethane was added to the reaction system, and the system was washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution in sequence. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain 107.3 mg of a yellow solid with a yield of 31%.

[0193] 1 H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 17 H 20 NO4[M+H] + :302.1392;found:302.1397.

[0194] Embodiment 20

[0195] The synthesis of 1-(3-(3,4-dimethoxyphenoxy)phenyl)pyrrolidin-3-ol (i.e., TCB-20 in Table 1) is as follows:

[0196]

[0197] Compound 20 was prepared with reference to Example 19, except that 3-hydroxyazetidine hydrochloride in step (2) was replaced by 3-hydroxypyrrolidine.

[0198] 1 H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 18 H 22 NO4[M+H] + :316.1549;found:316.1555.

[0199] Embodiment 21

[0200] The synthesis of 1-(4-(3,4-dimethoxyphenoxy)phenyl)azetidine-3-ol (i.e., TCB-21 in Table 1) is as follows:

[0201]

[0202] Compound 21 was prepared with reference to Example 19, except that the intermediate bromoiodobenzene in step (1) was replaced by p-bromoiodobenzene.

[0203] 1 H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 17 H 20 NO4[M+H] + :302.1392;found:302.1399.

[0204] Embodiment 22

[0205] The synthesis of 1-(4-(3,4-dimethoxyphenoxy)phenyl)pyrrolidin-3-ol (i.e., TCB-22 in Table 1) is as follows:

[0206]

[0207] Compound 22 was prepared with reference to Example 19, except that bromoiodobenzene in step (1) was replaced by p-bromoiodobenzene, and 3-hydroxyazetidine hydrochloride in step (2) was replaced by 3-hydroxypyrrolidine.

[0208] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 18 H 22 NO4[M+H] + :316.1549;found:316.1554.

[0209] Embodiment 23

[0210] The synthesis of 1-(4-(3,4-dimethoxyphenoxy)phenyl)piperidin-4-ol (i.e., TCB-23 in Table 1) is as follows:

[0211]

[0212] Compound 23 was prepared with reference to Example 19, except that the bromoiodobenzene in step (1) was replaced by p-bromoiodobenzene, and the 3-hydroxyazetidine hydrochloride in step (2) was replaced by 4-hydroxypiperidine.

[0213] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 19 H 24 NO4[M+H] + :330.1705;found:330.1711.

[0214] Embodiment 24

[0215] The synthesis of 4-(4-(3,4-dimethoxyphenoxy)phenyl)morpholine (i.e., TCB-24 in Table 1) is as follows:

[0216]

[0217] Compound 24 was prepared with reference to Example 19, except that bromoiodobenzene in step (1) was replaced by p-bromoiodobenzene, and 3-hydroxyazetidine hydrochloride in step (2) was replaced by morpholine.

[0218] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 18 H 22 NO4[M+H] + :316.1549;found:316.1553.

[0219] Embodiment 25

[0220] Synthesis of N-(3-(4-hydroxypiperidin-1-yl)phenyl)-3,4-dimethoxybenzamide (TCB-25 in Table 1)

[0221] (1) Synthesis of N-(3-bromophenyl)-3,4-dimethoxybenzamide (50)

[0222]

[0223] m-Bromoaniline (1000.0 mg, 5.81 mmol, 1.0 eq), 3,4-dimethoxybenzoic acid (1058.9 mg, 5.81 mmol, 1.0 eq), HOBt (785.4 mg, 5.81 mmol, 1.0 eq), HATu (2210.3 mg, 5.81 mmol, 1.0 eq), DIPEA (1878.2 mg, 14.53 mmol, 2.5 eq) and N,N-dimethylformamide (10 ml) were added to a round-bottom flask in sequence, and the mixture was stirred at room temperature for 6 hours. After TLC showed that the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution in sequence, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain 1583.0 mg of a white solid with a yield of 81%.

[0224] (2) Synthesis of N-(3-(4-hydroxypiperidin-1-yl)phenyl)-3,4-dimethoxybenzamide (25)

[0225]

[0226] Compound 49 (400 mg, 1.19 mmol, 1.0 eq), 4-hydroxypiperidine (144.9 mg, 1.43 mmol, 1.2 eq), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (148.7 mg, 0.24 mmol, 0.2 eq), palladium acetate (26.8 mg, 0.12 mmol, 0.1 eq), cesium carbonate (1167.1 mg, 3.58 mmol, 3 eq) and 1,4-dioxane (8 ml) were added to a round-bottom flask in sequence, and stirred at 90°C for 10 hours under nitrogen protection. After TLC showed that the reaction was complete, dichloromethane was added to the reaction system, and the system was washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution in sequence. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column to obtain 101.5 mg of a yellow solid with a yield of 24%.

[0227] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 20 H 25 N2O4[M+H] + :357.1814;found:357.1820.

[0228] Embodiment 26

[0229] The synthesis of N-(3-(3-hydroxypyrrolidin-1-yl)phenyl)-3,4-dimethoxybenzamide (i.e., TCB-26 in Table 1) is as follows:

[0230]

[0231] Compound 26 was prepared with reference to Example 25, except that 4-hydroxypiperidine was replaced by 3-hydroxypyrrolidine in step (2).

[0232] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 19 H 23 N2O4[M+H] + :343.1658;found:343.1662.

[0233] Embodiment 27

[0234] The synthesis of N-(3,4-dimethoxyphenyl)-3-(4-hydroxypiperidin-1-yl)benzamide (i.e., TCB-27 in Table 1) is as follows:

[0235]

[0236] Compound 27 was prepared with reference to Example 25, except that 3,4-dimethoxybenzoic acid in step (1) was replaced by 3-(4-hydroxypiperidin-1-yl)benzoic acid, and 3-bromoaniline was replaced by 3,4-dimethoxyaniline.

[0237] 1H NMR(600MHz,DMSO-d6)δ8.95(s,1H),8.50(s,1H),7.97(s,1H),7.43(d,J=8.5Hz, 2H),7.25(d,J=8.2Hz,2H),6.73(d,J=8.5Hz,2H),6.66–6.60(m,2H),4.22(t,J=6. 5Hz, 1H), 3.89 (p, J=5.4Hz, 1H), 3.68 (ddd, J=52.2, 11.1, 5.0Hz, 2H), 3.15 (ddt, J= 78.7,12.5,6.0Hz,2H),3.02(t,J=4.9Hz,4H),2.45(t,J=4.9Hz,4H),2.22(s,3H). 13 C NMR (151MHz, DMSO) δ167.44,158.39,156.84,154.31,146.39,146.23,133.36,132.17,131.99,129.13,127.81,126. 05,120.54,116.13,112.24,69.38,65.50,55.17,49.38,48.50,47.34,46.21,30.48,19.13,14.03.ESI-HRMS:calcd for C 20 H 25 N2O4[M+H] + :357.1814; found:357.1819.

[0238] Embodiment 28

[0239] Telomerase inhibitory activity and antiproliferative activity test of the telomerase inhibitor of the present invention:

[0240] This example mainly uses telomerase inhibitors BIBR1532 and THIO as positive controls to evaluate the telomerase inhibitory activity and anti-proliferative activity of compounds 1-27 against HL-60 cell lines. Other compounds of the present invention have similar beneficial effects to the compounds listed below, but this should not be interpreted as the compounds of the present invention having only the following beneficial effects.

[0241] (1) Telomerase inhibition activity test

[0242] After treating HL-60 cells with target compounds at different concentration gradients for 96 hours, collect about 1 million cells in a 1.5 mL EP tube, add 200 μL of CHAPS cell lysis buffer to each tube, and lyse for 30 minutes in an ice bath. Then centrifuge at 4°C, 14000 r / min for 30 minutes, and take the supernatant for 100-fold dilution for later use.

[0243] Preparation of negative control: Take 5 μL of the above extract and heat it at 95°C for 5 min to inactivate telomerase.

[0244] TRAP-PCR: PCR uses a 25μL reaction system. The ingredients include: 1× Blend Taq buffer, 5mM MgCl2, 0.2mM dNTPs, 0.4μM forward primer, 0.4μM reverse primer, 80nM fluorescent probe, 2U Blend Taq polymerase and 1μL telomerase extract. The amplification conditions are: keep warm at 37℃ for 30min to allow the forward primer to extend under the action of telomerase, then heat to 95℃ for 3min to inactivate telomerase, followed by 2 sets of PCR cycles. The first set includes 3 cycles: 94℃-30s, 55℃-60s, 72℃-30s; the second set includes 40 cycles: 94℃-30s, 55℃-30s, 72℃-30s. The fluorescence signal of the system is detected at each annealing temperature of the second set of cycles.

[0245] By calculating the number of cycles (Ct value) of different samples reaching the exponential growth phase in the system, the relative telomerase activity of the cells in the sample group can be calculated. The relative activity of telomerase in the sample is obtained by deducting the value of the corresponding negative control group that was inactivated in advance. The telomerase activity inhibition rate and IC 50 value.

[0246] (2) Tumor cell proliferation inhibition activity test

[0247] Human leukemia cells HL-60 were selected to test the anti-tumor activity of the new molecule. The main steps are: ① Inoculate logarithmic phase cells into 96-well plates, 5000 cells per well; ② The next day, add compounds with different concentration gradients and incubate for 96 hours; ③ Add CCK-8 solution and incubate for about 1.5 hours; ④ Use an enzyme reader to detect OD 450 , calculate the inhibition rate and IC 50 value.

[0248] The results in Table 1 show that the aromatic ketone small molecules and their derivatives found in the present invention have significant telomerase inhibitory activity, and some molecules show excellent anti-tumor effects.

[0249] Table 1. Telomerase inhibitory activity and antitumor activity of target compounds TCB-1 to TCB-27

[0250]

[0251]

[0252]

[0253]

[0254] Note: “+” represents telomerase inhibition IC 50 1~10μM; “++” represents telomerase inhibition IC 50 0.1~1μM; “+++” represents telomerase inhibition IC 50 0.01~0.1μM; “++++” represents telomerase inhibition IC 50 <0.01μM. "NT" means not tested. "####" means HL-60 inhibition IC 50 Below 1μM; “###” represents HL-60 inhibition IC 50 1~10μM; “##” represents HL-60 inhibition IC 50 10~100μM; “#” represents HL-60 inhibition IC 50 Between 100 and 1000 μM.

[0255] Embodiment 29

[0256] Verification of the effect of the telomerase inhibitor of the present invention on inducing immune exposure of tumor tissue:

[0257] In this example, TCB-2 was used as a representative molecule and BIBR1532 was used as a control. The effect of polysubstituted diaryl ketone telomerase inhibitors on promoting immune cells, especially CD4 + and CD8 + The role of T cells in the infiltration of tumor tissues and inducing anti-tumor immune exposure. Briefly, 1 million CT-26 cells were subcutaneously injected unilaterally into the axilla of male Balb / c mice to bear tumors; after successful tumor bearing, they were divided into a control group, a BIBR1532 group, and a high, medium and low TCB-2 group, and were given intraperitoneal injections of drug-free solvent, 50 mg / kg BIBR1532, 10 mg / kg TCB-2, 30 mg / kg TCB-2 and 50 mg / kg TCB-2, respectively, once a day. The treatment lasted for a total of 15 days, after which the mice were killed and the tumor tissues were taken for paraffin embedding and sectioning, and immunohistochemistry (IHC) examinations of CD4, CD8 and PDL1 were performed. Figure 1 Immunohistochemical examination and Figure 2 The average optical density analysis results show that TCB-2 can dose-dependently increase the distribution of CD4 and CD8 positive T cells in tumor tissues, reduce the expression of escape antigen PDL1 in tumor tissues, induce immune exposure of tumor tissues, and enhance the body's anti-tumor immunity.

[0258] Embodiment 30

[0259] In vivo anti-tumor activity test of the telomerase inhibitor combined with the PDL1 inhibitor of the present invention:

[0260] The combination of TCB-2 and low-dose INCB086550 (a small molecule PDL1 inhibitor) can rapidly activate anti-tumor immune responses and induce tumor tissue regression in a short period of time. Briefly, 1 million CT-26 cells were injected subcutaneously in the axilla of male Balb / c mice to bear tumors; after successful tumor bearing, they were divided into a control group, an INCB086550 group, and an INCB086550+TCB-2 combination group; INCB086550 was administered by oral gavage at 20 mg / kg, and TCB-2 was injected intraperitoneally at 50 mg / kg. The control group was given a solvent control in the same manner, and the frequency of administration was once a day. The treatment lasted for a total of 13 days, after which the mice were killed, the tumors were removed, weighed, and the tumor inhibition rate was calculated. Figure 3 As shown, the results indicate that the two small molecules (INCB086550, TCB-2) work synergistically to achieve potent anti-tumor activity and avoid the low response to PD1 / PDL1 therapy or the tumor hyperprogression induced by it.

[0261] In summary, the compounds prepared by the present invention have good application prospects and can be used as highly active small molecule telomerase inhibitors to promote the penetration of immune cells into tumor tissues and induce immune exposure of tumor tissues, thereby improving the body's anti-tumor immune ability or enhancing the efficacy of other anti-tumor immunotherapies.

[0262] The above-described embodiments only represent the embodiments of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. The present invention can also be implemented in other specific ways or other specific forms without departing from the gist or essential features of the present invention. Therefore, the described embodiments should be regarded as illustrative rather than restrictive in any respect. The scope of the present invention should be described by the attached claims, and any changes equivalent to the intention and scope of the claims should also be included in the scope of the present invention.

Claims

1. A compound as shown in general formula I and a pharmaceutically acceptable salt, ester or deuterated product thereof: in, R1 is selected from any one of hydrogen, nitro, acetylamino, halogen or C1-C3 haloalkyl; R2 and R3 are each independently selected from any one of hydrogen, nitro, acetylamino, halogen, C1-C3 haloalkyl, 1-dimethylamino-2-propynyl, substituted or unsubstituted C3-C20 nitrogen-containing heterocyclic group, substituted or unsubstituted C5-C14 heteroaryl; R4 and R5 are each independently selected from any one of hydrogen, methyl, dimethylamino, substituted or unsubstituted C3-C20 nitrogen-containing heterocyclic group, substituted or unsubstituted C6-C14 aryl, substituted or unsubstituted C5-C14 heteroaryl; X is selected from any one of oxygen, carbonyl, amide or aminoacyl; n is selected from an integer of 0 to 6.

2. The compound according to claim 1 and its pharmaceutically acceptable salt, ester or deuterated substance thereof, characterized in that: R1 is selected from any one of hydrogen, nitro or acetylamino.

3. The compound according to claim 1 and its pharmaceutically acceptable salt, ester or deuterated substance thereof, characterized in that: R2 and R3 are each independently selected from any one of hydrogen, nitro, halogen, 1-dimethylamino-2-propynyl, and a substituted or unsubstituted C3-C7 nitrogen-containing heterocyclic group.

4. The compound according to claim 3 and its pharmaceutically acceptable salt, ester or deuterated product thereof, characterized in that: The substituted or unsubstituted C3-C7 nitrogen-containing heterocyclic group is selected from any one of the following groups:

5. The compound according to claim 1 and its pharmaceutically acceptable salt, ester or deuterated substance thereof, characterized in that: R4 is selected from hydrogen or phenyl; and / or, R5 is selected from hydrogen or methyl; And / or, n is an integer selected from 0-2.

6. The compound according to any one of claims 1 to 5 and its pharmaceutically acceptable salt, ester or deuterated product thereof, characterized in that: The compound represented by the general formula I is selected from the following compounds:

7. The compound according to claim 1 and its pharmaceutically acceptable salt, ester or deuterated substance thereof, characterized in that: The pharmaceutically acceptable salt of the compound represented by the general formula I is selected from hydrochloride, methanesulfonate, fumarate, tartrate, citrate, maleate, sodium salt or potassium salt; And / or, the pharmaceutically acceptable ester of the compound represented by the general formula I is selected from succinate, succinate, phosphate, glycine or other amino acid esters.

8. A pharmaceutical composition, characterized in that The invention comprises a compound represented by the general formula I as described in any one of claims 1 to 7 and a pharmaceutically acceptable salt, ester or deuterated product thereof and at least one pharmaceutically acceptable carrier or excipient.

9. Use of the compound of general formula I as claimed in any one of claims 1 to 7 and its pharmaceutically acceptable salt, ester or deuterated product thereof or the pharmaceutical composition as claimed in claim 8 in the preparation of anti-tumor drugs.

10. Use of the compound of general formula I as claimed in any one of claims 1 to 7 and its pharmaceutically acceptable salt, ester or deuterated product thereof or the pharmaceutical composition as claimed in claim 8 in the preparation of a PDL1 inhibitor enhancing drug.

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