Benzenesulfonamide compounds, pharmaceutical compositions and applications thereof

Abstract

The present invention discloses a benzenesulfonamide compound, a pharmaceutical composition and application thereof. The compound of the present invention has the effect of promoting melanin production, has obvious effect and low toxicity, and can be used for preparing a drug for treating skin depigmentation or depigmentation-related diseases, wherein the skin depigmentation includes vitiligo, tuberous sclerosis, Ito hypopigmentation, mottled disease, oculocutaneous albinism syndrome, phenylketonuria, idiopathic punctate hypopigmentation, Comfetti spots, Vagabond's leukosis, etc.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a benzenesulfonamide compound, a pharmaceutical composition thereof and an application thereof. Background Art

[0002] Depigmentation is a disease caused by the loss or loss of skin pigment. Patients have patches on their skin or mucous membranes that are lighter than normal skin color. It can occur anywhere on the body, but is more common on the face, neck, back of the hands, and other parts. Vitiligo is the most influential and well-known skin disease among all depigmentation diseases. Its incidence rate is much higher than that of cancer. Although it is not fatal, it can destroy the appearance and often causes a heavy psychological burden on patients, seriously affecting their lives. It is more common in young people, with a similar incidence rate between men and women. The incidence rate is higher in spring and summer, and it often occurs in exposed and rubbed parts. Sun exposure, psychological factors, and trauma are common predisposing factors for vitiligo. It is easier for clinical dermatologists to diagnose vitiligo, but it is more difficult to treat. The disease has a certain degree of adverse effects on the patient's physical and mental health.

[0003] Melanin production is closely related to the pathogenesis of depigmentation disorders, including vitiligo. Melanocytes are cells responsible for producing skin pigments, and melanin stimulates the activity of these cells, which in turn affects the pigmentation of the skin. However, in depigmentation disorders, the function of these melanocytes is impaired or destroyed, resulting in the appearance of white spots on the skin. Although the specific mechanism has not yet been fully elucidated, studies have shown that abnormal melanin levels or abnormal melanocytes may be related to the occurrence of depigmentation disorders.

[0004] Therefore, promoting the connection between melanin production and depigmentation has become an important direction of current research. Developing an efficient and low-toxic drug to promote melanin production and thus treat depigmentation disorders such as vitiligo has important scientific research significance and application value. Summary of the invention

[0005] Objective of the invention: One of the objectives of the present invention is to provide a benzenesulfonamide compound of general formula I or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in,

[0008] X is selected from -NH, -O or (CH2) n ;

[0009] n = 0, 1, 2 or 3;

[0010] R1 is selected from nitro, alkoxy, haloalkyl or halogen;

[0011] R2, R3, and R4 are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, carboxyl, C1-C8 alkyl, alkoxy, haloalkyl, amino, aminomethyl, aminoethyl, aminoisopropyl, dimethylamino, -NHC(O)OC1-C6 alkyl, formamide, aminomethylformamide, or methoxycarbonyl.

[0012] In certain preferred embodiments,

[0013] X is selected from -NH, -O or (CH2) n ;

[0014] n = 0 or 1;

[0015] R1 is selected from nitro;

[0016] R2 is selected from hydrogen or C1-C3 alkoxy;

[0017] R3 is selected from hydrogen, halogen, hydroxy, alkoxy, carboxyl, carboxyl, aminomethylcarboxyl, aminomethylcarboxyl or methoxycarbonyl;

[0018] R4 is selected from hydrogen, halogen, hydroxyl, cyano, nitro, carboxyl, C1-C3 alkyl, C1-C3 alkoxy, haloalkyl, amino, aminomethyl, aminoethyl, aminoisopropyl, dimethylamino, -NHC(O)OC(CH3)3, formamide, aminomethylformamide or methoxycarbonyl.

[0019] In certain more preferred embodiments,

[0020] X is selected from -NH, -O or (CH2) n ;

[0021] n = 0 or 1;

[0022] R1 is selected from nitro;

[0023] R2 is selected from hydrogen or methoxy;

[0024] R3 is selected from hydrogen, fluorine, hydroxy, methoxy, carboxyl, formamide, aminomethylformamide or methoxycarbonyl;

[0025] R4 is selected from hydrogen, fluorine, hydroxy, cyano, nitro, carboxyl, methyl, methoxy, trifluoromethyl, amino, aminomethyl, aminoethyl, aminoisopropyl, dimethylamino, -NHC(O)OC(CH3)3, formamide, aminomethylformamide or methoxycarbonyl.

[0026] In some preferred embodiments, the pharmaceutically acceptable salts include acid addition salts formed between the compound of formula I and the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid; and also include acid salts formed between the compound of formula I and inorganic bases.

[0027] In some more preferred embodiments, the pharmaceutically acceptable salts include alkaline metal cation salts, alkaline earth metal cation salts and ammonium cation salts. Further, the ions used for salt formation include sodium, potassium, calcium, zinc, magnesium or aluminum.

[0028] The compounds of the general formula I of the present invention are preferably the following compounds:

[0029]

[0030]

[0031]

[0032]

[0033] The above-mentioned compounds of general formula I of the present invention may also exist in the form of their salts, which are converted in vivo into compounds of general formula I. For example, within the scope of the present invention, the compounds of the present invention are converted into pharmaceutically acceptable salt forms according to processes known in the art, and they are used in the form of salts.

[0034] The present invention also provides a method for preparing a compound having the general formula I, comprising the reaction steps shown in Scheme 1:

[0035]

[0036] Solution 1

[0037] The intermediate NA is reacted with the intermediate NB under the action of a base to prepare compound I (A), wherein R is selected from hydrogen, hydroxyl, cyano, nitro, methyl, methoxy, trifluoromethyl, amino, aminomethyl, aminoethyl, aminoisopropyl, dimethylamino, -NHC(O)OC(CH3)3; R1 is as defined in general formula I.

[0038] The method for preparing the compound of the general formula I of the present invention further comprises the reaction steps as shown in Scheme 2:

[0039]

[0040] Solution 2

[0041] Compound I(B) is prepared by coupling reaction of intermediate NC and intermediate ND under the action of palladium catalyst, wherein R1, R3 and R4 are as defined in general formula I.

[0042] The method for preparing the compound of the general formula I of the present invention further comprises the reaction steps as shown in Scheme 3:

[0043]

[0044] Solution 3

[0045] The intermediate NG is reacted with the intermediate NA in the presence of a base to prepare compound I (C), wherein R1, R3, R4, and X are as defined in general formula I.

[0046] The compounds of the general formula I of the present invention can be prepared by the above or similar preparation methods, and the corresponding starting materials can be selected according to the different substituents and the different positions of the substituents. It should be appreciated by those skilled in the art that the above routes are helpful for understanding the present invention, but do not limit the content of the present invention. Unless otherwise specified, the variables are defined as mentioned in the general formula I.

[0047] Another object of the present invention is to provide a pharmaceutical composition, which comprises a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0048] The pharmaceutical composition of the present invention can be administered in various known ways, such as orally, parenterally, by inhalation spray or via an implanted reservoir. The pharmaceutical composition of the present invention can be administered alone or in combination with other drugs. Oral compositions can be in any oral acceptable dosage form, including but not limited to tablets, capsules, emulsions, suspensions, dispersions and solutions.

[0049] A pharmaceutically acceptable carrier refers to an excipient or diluent that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound. Commonly used pharmaceutically acceptable carriers include stabilizers, diluents, surfactants, lubricants, antioxidants, adhesives, colorants, fillers, emulsifiers, etc. Sterile injectable compositions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Pharmaceutically acceptable carriers and solvents that can be used include water, mannitol, sodium chloride solution, etc. Topical compositions can be formulated into oils, lotions, creams, etc. Carriers for compositions include vegetable oils or mineral oils, animal fats, and high molecular weight alcohols, etc. A pharmaceutically acceptable carrier is a carrier in which the active ingredient is soluble.

[0050] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The dosage level selected depends on a variety of factors, including the activity of the specific compound of the present invention or its salt used, the route of administration, the time of administration, the excretion rate of the specific composition used, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific composition used, the age, sex, weight, general health and previous medical history of the patient being treated, and similar factors well known in the medical field.

[0051] Another object of the present invention is to provide a compound of formula I or a pharmaceutically acceptable salt thereof for use in the preparation of a drug for treating skin depigmentation or depigmentation-related diseases. The drug is a melanin-promoting drug containing a benzenesulfonamide compound. The skin depigmentation includes vitiligo, tuberous sclerosis, Ito's hypopigmentation, mottled disease, oculocutaneous albinism syndrome, phenylketonuria, idiopathic punctate hypopigmentation, Comfetti spots or Vagabond's leukosis.

[0052] Unless otherwise specified, the terms in this invention generally have the following meanings:

[0053] Me is methyl, Et is ethyl, and Boc is tert-butyloxycarbonyl.

[0054] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having the stated number of carbon atoms.

[0055] The term "C1-C8 alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 8 carbon atoms. C1-C8 alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl, etc.

[0056] The term "C1-C3 alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 3 carbon atoms.

[0057] The term "alkoxy" refers to an O-alkyl group. The term "C1-C3 alkoxy" refers to an O-C1-C3 alkyl group.

[0058] The term "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0059] Beneficial effects:

[0060] The benzenesulfonamide compounds of general formula I prepared by the present invention and their pharmaceutically acceptable salts have the effect of promoting melanin production, with obvious effect and low toxicity. Therefore, the above compounds can be used to prepare drugs for treating depigmentation or depigmentation-related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0061] Figure 1 The effects of compounds I-1 to I-15 of the present invention on the activity of B16F10 cells;

[0062] Figure 2 The effects of compounds I-16 to I-30 of the present invention on the viability of B16F10 cells;

[0063] Figure 3 The activation effect of compounds I-1 to I-15 of the present invention on tyrosinase;

[0064] Figure 4 The activation effect of compounds I-16 to I-25 and I-28 to I-30 of the present invention on tyrosinase;

[0065] Figure 5 The effects of compounds I-1 to I-15 of the present invention on the melanin content of B16F10 cells;

[0066] Figure 6 The effects of compounds I-16 to I-30 of the present invention on the melanin content of B16F10 cells;

[0067] Figure 7 The effect of the compound I-21 of the present invention on the expression of tyrosinase and MITF proteins;

[0068] Figure 8 This is the therapeutic effect of the compound I-21 of the present invention on vitiligo model mice. DETAILED DESCRIPTION

[0069] The preparation method of the compound of general formula I of the present invention is described below in conjunction with specific examples, but these specific methods do not constitute any limitation to the present invention. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily performed by a technician in the field to which the present invention belongs. The starting materials, reaction reagents, etc. used in the specific examples of the present invention are all commercially available. The present invention can be prepared in the form of a salt by a salt-forming method commonly used in the art, for example: at room temperature, the compound is dissolved in hydrochloric acid ethanol for reaction to generate a hydrochloride; or benzenesulfonic acid is added thereto for reaction to generate a benzenesulfonate.

[0070] Synthesis of intermediates:

[0071] N-(2-Chloropyrimidin-4-yl)-4-nitrobenzenesulfonamide (1c)

[0072]

[0073] 2-Chloro-4-aminopyrimidine (500mg, 3.86mmol) was dissolved in 8mL THF, and sodium tert-butoxide (297g, 3.09mmol) was added in batches under stirring in an ice bath (0℃), and stirred in an ice bath (0℃) for 0.5 hours. Then 4-nitrobenzenesulfonyl chloride (570mg, 2.57mmol) was added in batches, and the solution was stirred at room temperature for 0.5 hours. TLC was monitored until the reaction end point. The reaction solution was poured into 50mL ice water, and the reaction solution was extracted with ethyl acetate three times, 50mL each time. The organic phases were combined and washed with saturated brine three times, 50mL each time. The organic phases were dried over anhydrous sodium sulfate overnight, and the anhydrous sodium sulfate was removed by filtration. The filtrate was concentrated under reduced pressure to obtain a white crude product. 602mg of white solid was separated by rapid column chromatography (PE:EA=2:1, v:v), with a yield of 74%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.15 (s, 1H), 8.53-8.38 (m, 3H), 8.31-8.19 (m, 2H), 7.01 (d, J = 5.7Hz, 1H).

[0074] (S)-1-([1,1'-biphenyl]-4-yl)ethan-1-amine (1b)

[0075]

[0076] Dissolve (S)-1-(4-bromophenyl)ethyl-1-amine (328mg, 1.64mmol), phenylboronic acid (300mg, 2.46mmol), Pd[P(Ph)3]4 (95mg, 0.082mmol) in 6mL acetonitrile, add K2CO3 aqueous solution (1.5ml, 5M), evacuate with nitrogen protection, heat to reflux and stir for 12 hours. Monitor the reaction by TLC until the end point. Cool the reaction solution to room temperature, filter to remove insoluble matter, dissolve the reactant in ethyl acetate, slowly add concentrated hydrochloric acid to the organic phase to adjust the pH to 1, and then stir in an ice bath (0℃) for about 1.5 hours. Wash the mixed solution with water 3 times, 50mL each time, and combine the aqueous phases. Use 5M NaOH to adjust the pH of the aqueous solution to 10. The mixed solution was extracted three times with ethyl acetate, each time with about 50 mL. The organic phases were combined, washed three times with saturated brine, each time with 50 mL, and dried over anhydrous sodium sulfate overnight. The anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. 372 mg of a white oil was obtained by separation by flash column chromatography (PE:EA=1:1, v:v). The yield was 93%. 1H NMR (400MHz, DMSO-d6) δ (ppm) 7.63-7.58 (m, 4H), 7.50-7.43 (m, 4H), 7.40-7.34 (m, 1H), 4.20 (q, J = 6.6Hz, 1H), 1.46 (d, J = 6.6Hz, 3H).

[0077] (S)-1-(4'-(Trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethan-1-amine (2b)

[0078]

[0079] The synthesis and treatment steps of compound 2b were the same as those of compound 1b. (S)-1-(4-bromophenyl)ethan-1-amine (300 mg, 1.5 mmol) and 4-trifluoromethylphenylboronic acid (427 mg, 2.25 mmol) were added and separated by flash column chromatography (PE:EA=1:1, v:v) to obtain 372 mg of a yellow solid 2b with a yield of 94%. 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.38-8.25(m,2H),7.99-7.92(m,2H),7.77-7.67(m, 2H),7.58-7.48(m,2H),4.05(q,J=6.6Hz,1H),1.87(s,2H),1.28(d,J=6.6Hz,3H).

[0080] (S)-1-(4'-nitro-[1,1'-biphenyl]-4-yl)ethan-1-amine (3b)

[0081]

[0082] The synthesis and treatment steps of compound 3b were the same as those of compound 1b. (S)-1-(4-bromophenyl)ethan-1-amine (300 mg, 1.5 mmol) and 4-nitrobenzeneboric acid (378 mg, 2.25 mmol) were added and separated by flash column chromatography (PE:EA=1:1, v:v) to give 341 mg of a yellow solid 3b with a yield of 92%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)8.29(d,J=8.8Hz,2H),7.73(d,J=8.8Hz,2H),7.60 (d, J=8.3Hz, 2H), 7.49 (d, J=8.2Hz, 2H), 4.21 (q, J=6.6Hz, 1H), 1.43 (d, J=6.6Hz, 3H).

[0083] (S)-4'-(1-aminoethyl)-[1,1'-biphenyl]-4-carbonitrile (4b)

[0084]

[0085] The synthesis and treatment steps of compound 4b are the same as those of compound 1b. (S)-1-(4-bromophenyl)ethan-1-amine (300 mg, 1.5 mmol) and 4-cyanophenylboronic acid (330 mg, 2.25 mmol) are added and separated by flash column chromatography (PE:EA=1:1, v:v) to obtain 289 mg of a yellow solid 4b with a yield of 84%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)8.38-8.26(m,2H),7.81-7.70(m,2H),7.67 -7.59(m,2H),7.56-7.45(m,2H),4.23(q,J=6.6Hz,1H),1.46(d,J=6.6Hz,3H).

[0086] (S)-1-(4'-Methyl-[1,1'-biphenyl]-4-yl)ethan-1-amine (5b)

[0087]

[0088] The synthesis and treatment steps of compound 5b were the same as those of compound 1b. (S)-1-(4-bromophenyl)ethan-1-amine (300 mg, 1.5 mmol) and 4-methylphenylboronic acid (306 mg, 2.25 mmol) were added and separated by flash column chromatography (PE:EA=1:1, v:v) to give 291 mg of a yellow solid 5b with a yield of 92%. 1 H NMR(400MHz,DMSO-d6)δ(ppm)7.60-7.55(m,2H),7.53-7.50(m,2H),7.46-7.41(m,2 H), 7.27 (d, J = 8.0Hz, 2H), 4.19 (q, J = 6.6Hz, 1H), 2.42 (s, 3H), 1.46 (d, J = 6.6Hz, 3H).

[0089] (S)-4'-(1-aminoethyl)-[1,1'-biphenyl]-4-amine (6b)

[0090]

[0091] The synthesis and treatment steps of compound 6b were the same as those of compound 1b. (S)-1-(4-bromophenyl)ethan-1-amine (300 mg, 1.5 mmol) and 4-aminophenylboronic acid pinacol ester (493 mg, 2.25 mmol) were added and separated by flash column chromatography (PE:EA=1:1, v:v) to obtain 289 mg of a yellow solid 6b with a yield of 91%.1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.45 (d, J = 8.2Hz, 2H), 7.39-7.28 (m, 4H), 6.67-6.58 (m, 2H), 5.17 (s, 2H), 3.99 (q, J = 6.6Hz, 1H), 1.26 (d, J = 6.6Hz, 3H).

[0092] N-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (7a)

[0093]

[0094] Dissolve 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500mg, 2.28mmol) in 10mL DMF, add K2CO3 (473mg, 3.42mmol) and iodomethane (324mg, 2.28mmol). Stir the mixture at 50°C for 14 hours and monitor the reaction end point by TLC. Return the reaction solution to room temperature, pour into 50mL water, extract with ethyl acetate three times, 50mL each time, combine the organic phases, wash with saturated brine three times, 50mL each time, dry the organic phase with anhydrous sodium sulfate overnight, filter to remove anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure to obtain a white oily crude product. Purify by rapid silica gel column (PE:EA=15:1, v:v) to obtain 387mg of white solid with a yield of 72%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.43-7.36 (m, 2H), 6.51-6.45 (m, 2H), 6.04 (q, J = 4.9Hz, 1H), 2.68 (d, J = 5.0Hz, 3H), 1.25 (s, 12H).

[0095] (S)-4'-(1-aminoethyl)-N-methyl-[1,1'-biphenyl]-4-amine (7b)

[0096]

[0097] The synthesis and treatment steps of compound 7b are the same as those of compound 1b. (S)-1-(4-bromophenyl)ethan-1-amine (300 mg, 1.5 mmol) and 7a (349 mg, 1.50 mmol) are added and separated by flash column chromatography (PE:EA=1:1, v:v) to obtain 317 mg of gray solid 7b with a yield of 93%. 1H NMR(400MHz,DMSO-d6)δ(ppm)7.52-7.44(m,2H),7.44-7.38(m,2H),7.38-7.31(m,2H),6.64-6.55 (m,2H),5.76(d,J=5.0Hz,1H),4.00(q,J=6.4Hz,1H),2.71(d,J=5.1Hz,3H),1.27(d,J=6.6Hz,3H).

[0098] N-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (8a)

[0099]

[0100] The synthesis and treatment steps of compound 8a were the same as those of compound 7a. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 2.28 mmol) and iodoethane (356 mg, 2.28 mmol) were added and separated by flash column chromatography (PE:EA=15:1, v:v) to obtain 391 mg of white solid 8a with a yield of 69%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.41-7.36 (m, 2H), 6.54-6.47 (m, 2H), 6.00-5. 89(m,1H),3.05(qd,J=7.2,5.3Hz,2H),1.25(s,12H),1.15(t,J=7.1Hz,3H).

[0101] (S)-4'-(1-aminoethyl)-N-ethyl-[1,1'-biphenyl]-4-amine (8b)

[0102]

[0103] The synthesis and treatment steps of compound 8b were the same as those of compound 1b. (S)-1-(4-bromophenyl)ethan-1-amine (300.00 mg, 1.5 mmol) and 8a (371 mg, 1.50 mmol) were added and separated by flash column chromatography (PE:EA=1:1, v:v) to obtain 302 mg of gray solid 8b with a yield of 87%. 1H NMR(300MHz,Chloroform-d)δ(ppm)7.61-7.56(m,2H),7.49-7.43(m,2H),7.34-7.28(m,2H),6.73-6.67(m, 2H), 4.32 (tq, J=5.9, 5.0Hz, 1H), 3.11 (pd, J=5.6, 1.6Hz, 2H), 1.41 (d, J=4.9Hz, 3H), 1.19 (t, J=5.6Hz, 3H).

[0104] N-Isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (9a)

[0105]

[0106] The synthesis and treatment steps of compound 9a were the same as those of compound 7a. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 2.28 mmol) and 2-iodopropane (388 mg, 2.28 mmol) were added and separated by flash column chromatography (PE:EA=15:1, v:v) to obtain 416 mg of white solid 9a with a yield of 70%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.40-7.34 (m, 2H), 6.54-6.47 (m, 2H), 5.80 (d, J = 7.9Hz, 1H), 1.25 (s, 12H), 1.13 (d, J = 6.3Hz, 6H).

[0107] (S)-4'-(1-aminoethyl)-N-isopropyl-[1,1'-biphenyl]-4-amine (9b)

[0108]

[0109] The synthesis and treatment steps of compound 9b were the same as those of compound 1b. (S)-1-(4-bromophenyl)ethan-1-amine (300.00 mg, 1.5 mmol) and 9a (392 mg, 1.50 mmol) were added and separated by flash column chromatography (PE:EA=1:1, v:v) to obtain 347 mg of gray solid 9b with a yield of 91%. 1 H NMR (300 MHz, DMSO-d6) δ (ppm) 7.52-7.41 (m, 4H), 7.37-7.31 (m, 4H), 6.62 (d, J = 8.6 Hz, 1H), 3.96 (q, J = 6.6 Hz, 1H), 1.22 (t, J = 6.4 Hz, 6H), 1.15 (d, J = 6.3 Hz, 3H).

[0110] N,N-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (10a)

[0111]

[0112] The synthesis and treatment steps of compound 10a were the same as those of compound 7a. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 2.28 mmol) and iodomethane (809 mg, 5.71 mmol) were added and separated by flash column chromatography (PE:EA=20:1, v:v) to obtain 391 mg of white solid 10a with a yield of 68%. 1 H NMR (400 MHz, Chloroform-d) δ (ppm) 7.75-7.69 (m, 2H), 6.74-6.69 (m, 2H), 3.01 (s, 6H), 1.35 (s, 12H).

[0113] (S)-4'-(1-aminoethyl)-N,N-dimethyl-[1,1'-biphenyl]-4-amine (10b)

[0114]

[0115] The synthesis and treatment steps of compound 10b were the same as those of compound 1b. (S)-1-(4-bromophenyl)ethan-1-amine (300.00 mg, 1.5 mmol) and 10a (370 mg, 1.50 mmol) were added and separated by flash column chromatography (PE:EA=1:1, v:v) to obtain 331 mg of gray solid 10b with a yield of 91%. 1 H NMR (400 MHz, Chloroform-d) δ (ppm) 7.63-7.46 (m, 4H), 7.46-7.34 (m, 2H), 6.89-6.77 (m, 2H), 4.17 (q, J = 6.6 Hz, 1H), 3.02 (s, 6H), 1.45 (d, J = 6.6 Hz,3H).

[0116] (S)-tert-Butyl (4'-(1-aminoethyl)-[1,1'-biphenyl]-4-yl)carbamate (11b)

[0117]

[0118] The synthesis and treatment steps of compound 11b were the same as those of compound 1b. (S)-1-(4-bromophenyl)ethan-1-amine (300.00 mg, 1.5 mmol) and (4-((tert-butoxycarbonyl)amino)phenyl)boric acid (353 mg, 1.50 mmol) were added and separated by flash column chromatography (PE:EA=1:1, v:v) to give 390 mg of gray solid 11b with a yield of 83%. 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 9.42 (s, 1H), 7.59-7.50 (m, 6H), 7.45-7.39 (m, 2H), 4.02 (q, J = 6.7 Hz, 1H), 1.49 (s, 9H), 1.27 (d, J = 6.6 Hz, 3H).

[0119] (S)-4'-(1-aminoethyl)-[1,1'-biphenyl]-4-ol (12b)

[0120]

[0121] The synthesis and treatment steps of compound 12b were the same as those of compound 1b. (S)-1-(4-bromophenyl)ethan-1-amine (300 mg, 1.5 mmol) and 4-hydroxyphenylboronic acid (308 mg, 2.25 mmol) were added and separated by flash column chromatography (PE:EA=1:1, v:v) to obtain 301 mg of a yellow solid 12b with a yield of 94%. 1 H NMR (400 MHz, Chloroform-d) δ (ppm) 9.52 (s, 1H), 7.54-7.43 (m, 4H), 7.42-7.35 (m, 2H), 6.88-6.79 (m, 2H), 4.01 (q, J = 6.6 Hz, 1H), 1.27 (d, J = 6.6 Hz,3H).

[0122] (S)-1-(4'-methoxy-[1,1'-biphenyl]-4-yl)ethan-1-amine (13b)

[0123]

[0124] The synthesis and treatment steps of compound 13b were the same as those of compound 1b. (S)-1-(4-bromophenyl)ethan-1-amine (300 mg, 1.5 mmol) and 4-methoxyphenylboronic acid (342 mg, 2.25 mmol) were added and separated by flash column chromatography (PE:EA=1:1, v:v) to obtain 318 mg of white solid 13b with a yield of 93%. 1H NMR (400MHz, Chloroform-d) δ (ppm) 7.61-7.50 (m, 4H), 7.45-7.39 (m, 2H), 7.04-6.96 (m, 2H), 4.18 (q, J = 6.6Hz, 1H), 3.87 (s, 3H), 1.45 (d, J = 6.6Hz, 3H).

[0125] (S)-1-(3'-methoxy-[1,1'-biphenyl]-4-yl)ethan-1-amine (14b)

[0126]

[0127] The synthesis and treatment steps of compound 14b were the same as those of compound 1b. (S)-1-(4-bromophenyl)ethan-1-amine (300 mg, 1.5 mmol) and 3-methoxyphenylboronic acid (342 mg, 2.25 mmol) were added and separated by flash column chromatography (PE:EA=1:1, v:v) to obtain 309 mg of white solid 14b with a yield of 90%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)7.56-7.51(m,2H),7.44-7.39(m,2H),7.34(ddt,J=6.3,4 .6,2.1Hz,2H),7.08-6.99(m,2H),4.18(q,J=6.8Hz,1H),3.84(s,3H),1.46(d,J=6.6Hz,3H).

[0128] (S)-1-(2'-methoxy-[1,1'-biphenyl]-4-yl)ethan-1-amine (15b)

[0129]

[0130] The synthesis and treatment steps of compound 15b were the same as those of compound 1b. (S)-1-(4-bromophenyl)ethan-1-amine (300 mg, 1.5 mmol) and 2-methoxyphenylboronic acid (342 mg, 2.25 mmol) were added and separated by flash column chromatography (PE:EA=1:1, v:v) to obtain 297 mg of white solid 15b with a yield of 86%. 1H NMR (400MHz, Chloroform-d) δ (ppm) 7.66-7.53 (m, 2H), 7.51-7.41 (m, 2H), 7.38 (t, J = 7.9Hz, 1H), 7.27-7 .07(m,2H),6.91(ddd,J=8.3,2.6,1.0Hz,1H),4.20(q,J=6.6Hz,1H),3.89(s,3H),1.45(d,J=6.7Hz,3H).

[0131] 2-Hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (16a)

[0132]

[0133] 5-Bromo-2-hydroxybenzamide (500 mg, 2.31 mmol), potassium acetate (454 mg, 4.63 mmol), Pd(dppf)Cl2 (85 mg, 0.115 mmol) and biboronic acid pinacol ester (882 mg, 3.47 mmol) were dissolved in 20 mL of 1,4-dioxane. Under nitrogen protection, the mixture was heated and stirred at 90 °C for 12 hours, and the reaction was monitored by TLC until the end point. The reaction solution was cooled to room temperature, the solvent was dried under reduced pressure, 100 mL of water was poured into the reaction solution, and the mixture was extracted with ethyl acetate three times, about 50 mL each time. The organic phases were combined and washed with saturated brine three times, 50 mL each time, and dried over anhydrous sodium sulfate overnight. The anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The white solid 16a 1.18 g was separated by rapid column chromatography (PE:EA=10:1, v:v) with a yield of 98%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 12.54 (s, 1H), 7.90-7.85 (m, 2H), 7.00 (d, J = 8.4Hz, 1H), 1.36 (s, 12H).

[0134] 2-Hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (17a)

[0135]

[0136] The synthesis and treatment steps of compound 17a were the same as those of 16a. 4-bromo-2-hydroxybenzamide (600 mg, 2.78 mmol) and biboric acid pinacol ester (1.06 g, 4.17 mmol) were added and separated by flash column chromatography (PE:EA=10:1, v:v) to obtain 550 mg of white solid 17a with a yield of 74%. 1H NMR (400MHz, DMSO-d6) δ (ppm) 12.77 (s, 1H), 8.41 (s, 1H), 7.93 (s, 1H), 7.85 (d, J = 8.1Hz, 1H), 7.15-7.10 (m, 2H), 1.30 (s, 12H).

[0137] Methyl 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (18a)

[0138]

[0139] The synthesis and treatment steps of compound 18a were the same as those of 16a. Methyl 5-bromo-2-hydroxybenzenecarboxylate (1.00 g, 4.33 mmol) and biboric acid pinacol ester (1.65 g, 6.49 mmol) were added and separated by flash column chromatography (PE:EA=10:1, v:v) to obtain 1.18 g of white solid 18a with a yield of 98%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.77 (s, 1H), 8.12 (d, J = 1.6Hz, 1H), 7.76 (dd, J = 8.3, 1.7Hz, 1H), 6.99 (d, J = 8.3Hz, 1H), 3.91 (s, 3H), 1.29 (s, 12H).

[0140] Methyl 2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (19a)

[0141]

[0142] The synthesis and treatment steps of compound 19a were the same as those of 16a. Methyl 4-bromo-2-hydroxybenzenecarboxylate (2.00 g, 8.66 mmol) and biboric acid pinacol ester (3.30 g, 12.98 mmol) were added and separated by flash column chromatography (PE:EA=10:1, v:v) to obtain 2.17 g of white solid 19a with a yield of 90%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.38 (s, 1H), 7.76 (d, J = 7.8Hz, 1H), 7.25-7.17 (m, 2H), 3.89 (s, 3H), 1.30 (s, 12H).

[0143] (S)-N-(2-((1-(4-bromophenyl)ethyl)amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (16c)

[0144]

[0145] 1c (1.0 g, 3.18 mmol), (S)-1-(4-bromophenyl)ethan-1-amine (1.27 g, 6.36 mmol), DIPEA (954 mg, 4.77 mmol) were dissolved in 15 mL of n-butanol, strictly evacuated with nitrogen protection, heated to reflux at 110°C, reacted for 36 h, and monitored by TLC until the reaction end point. The reaction solution was cooled to room temperature, the solvent was dried in vacuo, and 513 mg of a yellow solid was obtained by rapid silica gel column chromatography (DCM: MeOH = 100: 1, v: v), with a yield of 33%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.89 (s, 1H), 8.23 ​​(d, J=7.7Hz, 2H), 8.14-7.86 (m, 2H), 7.65 (d, J= 19.8Hz, 2H), 7.46 (d, J = 8.0Hz, 2H), 7.22 (d, J = 8.1Hz, 2H), 6.01 (s, 1H), 4.83 (s, 1H), 1.33 (s, 3H).

[0146] 2,2,6-Trimethyl-4H-benzo[d][1,3]dioxin-4-one (20a)

[0147]

[0148] Dissolve 5-methylsalicylic acid (1.0 g, 6.57 mmol) in 5 mL of anhydrous acetone, cool at -8 °C for 30 minutes, slowly add 1.5 mL of acetic anhydride and two drops of concentrated sulfuric acid under low temperature stirring, and continue stirring at -8 °C for 12 hours. Monitor the reaction by TLC until the end point. Slowly add the reaction solution dropwise to 100 mL of saturated sodium bicarbonate solution, extract with ethyl acetate three times, 50 mL each time, combine the organic phases, wash with saturated brine three times, 50 mL each time, dry over anhydrous sodium sulfate overnight, filter to remove anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure to obtain 1.14 g of white solid, which is directly used in the next step. 1 H NMR (300MHz, Chloroform-d) δ (ppm) 7.77 (d, J = 2.6 Hz, 1H), 7.37 (dd, J = 8.3, 2.3 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 2.35 (s, 3H), 1.74 (s, 6H).

[0149] 2,2,7-Trimethyl-4H-benzo[d][1,3]dioxin-4-one (21a)

[0150]

[0151] The synthesis and treatment steps of compound 21a were the same as those of 20a. 4-Methylsalicylic acid (2.0 g, 10.00 mmol) was added to obtain 2.32 g of white solid 21a with a yield of 92%, which was directly used in the next step. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.75 (d, J = 8.0 Hz, 1H), 7.03 (ddd, J = 7.9, 1.6, 0.7 Hz, 1H), 6.96-6.93 (m, 1H), 2.37 (s, 3H), 1.68 (s, 6H).

[0152] 6-(Bromomethyl)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (20b)

[0153]

[0154] 20a (1.0 g, 5.20 mmol), N-bromosuccinimide (1.11 g, 6.24 mmol), benzoyl peroxide (75% hydrate, 353 g, 1.09 mmol) were dissolved in 10 mL of carbon tetrachloride and heated to 75 °C under nitrogen protection and stirred for 2 hours. TLC was monitored until the reaction end point. The reaction was cooled to room temperature, the reaction solution was poured into 80 mL of water, extracted with dichloromethane three times, 100 mL each time, the organic phases were combined, washed with saturated brine three times, 100 mL each time, dried over anhydrous sodium sulfate overnight, filtered to remove anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. 839 mg of white solid was obtained by rapid silica gel column chromatography (PE:EA=20:1, v:v), with a yield of 65%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 8.00 (d, J = 2.2Hz, 1H), 7.62 (dd, J = 8.5, 2.3Hz, 1H), 6.98 (d, J = 8.4Hz, 1H), 4.50 (s, 2H), 1.76 (s, 6H).

[0155] 7-(Bromomethyl)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (21b)

[0156]

[0157] The synthesis and treatment steps of compound 21b were the same as those of 20b. 21a (1.0 g, 5.20 mmol) was added and purified by flash silica gel column chromatography (PE:EA=20:1, v:v) to obtain 789 mg of white solid 21a in a yield of 57%. 1H NMR (400MHz, DMSO-d6) δ (ppm) 7.86 (d, J = 8.0 Hz, 1H), 7.28 (dd, J = 8.0, 1.6 Hz, 1H), 7.21 (d, J = 1.6 Hz, 1H), 4.72 (s, 2H), 1.69 (s, 6H).

[0158] (S)-tert-Butyl (1-(4-bromophenyl)ethyl)carbamate (20c)

[0159]

[0160] (S)-1-(4-bromophenyl)eth-1-amine (2.00 g, 10.00 mmol) and triethylamine (1.21 g, 12.00 mmol) were dissolved in 50 mL of anhydrous CH2Cl2, and slowly added dropwise to a solution of Boc2O (2.62 mg, 12.00 mmol) in anhydrous CH2Cl2 (10 mL) under an ice bath (0°C), and stirred at room temperature for 24 hours. TLC was monitored until the reaction end point. The reaction mixture was poured into 200 mL of water, extracted three times with dichloromethane, the organic phases were combined, washed three times with saturated brine, 50 mL each time, dried over anhydrous sodium sulfate overnight, filtered to remove anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. 2.96 g of white solid was obtained by rapid column chromatography (PE:EA=20:1, v:v), with a yield of 98%. 1 HNMR (400MHz, Chloroform-d) δ (ppm) 7.50-7.43 (m, 2H), 7.24-7.16 (m, 2H), 4.77 (s, 1H), 1.43 (s, 12H).

[0161] (S)-tert-Butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (20d)

[0162]

[0163] The synthesis and treatment steps of compound 20d were the same as those of 16a. 20c (500 mg, 1.67 mmol) and bipyraclostrobin (634 g, 2.50 mmol) were added and separated by flash column chromatography (PE:EA=20:1, v:v) to give 346 g of colorless oil 20d in a yield of 59%. 1 H NMR (300MHz, Chloroform-d) δ (ppm) 7.86-7.73 (m, 2H), 7.32 (d, J = 7.7Hz, 2H), 4.82 (s, 1H), 1.44 (s, 9H), 1.36 (s, 12H), 1.28 (d, J = 2.4Hz, 3H).

[0164] (S)-tert-Butyl (1-(4-((2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-6-yl)methyl)phenyl)ethyl)carbamate (20e)

[0165]

[0166] The synthesis and treatment steps of compound 20e were the same as those of 1b. 20b (600 mg, 2.22 mmol) and 20d (803 mg, 2.32 mmol) were added and separated by flash column chromatography (PE:EA=20:1, v:v) to obtain 620 mg of white solid 20e with a yield of 68%. 1 H NMR(400MHz,DMSO-d6)δ(ppm)7.70(d,J=2.3Hz,1H),7.56(dd,J=8.4,2.3Hz,1H),7.24-7.18(m,4H),7 .05(d,J=8.4Hz,1H),4.63-4.52(m,1H),3.94(s,2H),1.67(s,6H),1.36(s,9H),1.27(d,J=7.0Hz,3H).

[0167] (S)-tert-Butyl (1-(4-((2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-7-yl)methyl)phenyl)ethyl)carbamate (21e)

[0168]

[0169] The synthesis and treatment steps of compound 21e were the same as those of 1b. 21b (750 mg, 2.76 mmol) and 20d (1.00 g, 2.90 mmol) were added and separated by flash column chromatography (PE:EA=20:1, v:v) to obtain 778 mg of white solid 21e with a yield of 69%. 1 H NMR(400MHz,DMSO-d6)δ(ppm)7.77(d,J=8.0Hz,1H),7.26-7.18(m,4H),7.08(dd,J=8.0,1.6Hz,1 H), 6.96 (s, 1H), 4.67-4.51 (m, 1H), 3.97 (s, 2H), 1.67 (s, 6H), 1.36 (s, 9H), 1.27 (d, J = 7.0Hz, 3H).

[0170] (S)-tert-Butyl (1-(4-(4-fluoro-3-methylbenzyl)phenyl)ethyl)carbamate (22e)

[0171]

[0172] The synthesis and treatment steps of compound 22e were the same as those of 1b. 4-Fluoro-3-methylbenzyl bromide (200 mg, 0.98 mmol) and 20d (359 mg, 1.03 mmol) were added and separated by flash column chromatography (PE:EA=15:1, v:v) to give 329 mg of white solid 22e with a yield of 97%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 7.34 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.3 Hz, 3H), 7. 03(d,J=9.4Hz,1H),4.60-4.51(m,1H),3.84(s,2H),2.18(d,J=2.1Hz,3H),1.36(s,9H),1.25(s,3H).

[0173] (S)-6-(4-(1-aminoethyl)benzyl)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (20f)

[0174]

[0175] 20e (560 mg, 1.84 mmol) was dissolved in 6 mL of anhydrous CH2Cl2, stirred in an ice bath (0°C) for 15 minutes, and 2 mL of trifluoroacetic acid was slowly added dropwise, and stirred in an ice bath (0°C) for 4 hours. TLC was monitored until the reaction end point. The reaction was restored to room temperature, the reaction solution was poured into 30 mL of water, the pH was adjusted to 10 with 5 M NaOH solution, and extracted with dichloromethane three times, 50 mL each time, the organic phases were combined, washed with saturated brine three times, 50 mL each time, dried over anhydrous sodium sulfate overnight, filtered to remove anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. 400 mg of yellow solid was obtained by rapid silica gel column chromatography (DCM: MeOH = 120: 1, v: v), and the yield was 98%. 1 H NMR(300MHz,Chloroform-d)δ(ppm)7.81(d,J=2.3Hz,1H),7.39(dd,J=8.4,2.3Hz,1H),7.31(d,J=1.9Hz,1H),7.1 7(d,J=8.0Hz,2H),6.90(d,J=8.4Hz,1H),4.13(q,J=6.6Hz,1H),3.96(s,2H),1.74(s,6H),1.41(d,J=6.6Hz,3H).

[0176] (S)-7-(4-(1-aminoethyl)benzyl)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (21f)

[0177]

[0178] The synthesis and treatment steps of compound 21f were the same as those of 20f. 21e (760 mg, 1.84 mmol) was added and separated by flash column chromatography (DCM:MeOH=120:1, v:v) to obtain 520 mg of a yellow solid 21f in a yield of 90%. 1 H NMR(400MHz, DMSO-d6)δ(ppm)7.77(d,J=8.0Hz,1H),7.30(d,J=8.0Hz,2H),7.19(d,J=8.0Hz,2H),7.07(dd,J= 8.0,1.5Hz,1H),6.96(d,J=1.5Hz,1H),3.97(s,2H),3.93(d,J=6.5Hz,1H),1.66(s,6H),1.22(d,J=6.6Hz,3H).

[0179] (S)-1-(4-(4-Fluoro-3-methylbenzyl)phenyl)ethan-1-amine (22f)

[0180]

[0181] The synthesis and treatment steps of compound 22f were the same as those of 20f. 22e (760 mg, 1.84 mmol) was added and separated by flash column chromatography (DCM:MeOH=120:1, v:v) to obtain 520 mg of a yellow solid 21f with a yield of 66%. 1 H NMR(300MHz,Chloroform-d)δ(ppm)7.30(d,J=1.9Hz,1H),7.27(s,1H),7.20-7.12(m,2H),7.04 -6.88(m,3H),4.11(q,J=6.6Hz,1H),3.91(s,2H),2.25(d,J=2.0Hz,3H),1.40(d,J=6.6Hz,3H).

[0182] 4-(4-Fluoro-3-methylphenoxy)benzaldehyde (24a)

[0183]

[0184] Dissolve 4-fluoro-3-methylphenol (3.00 g, 15.86 mmol), 4-fluorobenzaldehyde (1.97 g, 15.86 mmol), K2CO3 (4.38 g, 31.71 mmol) in 15 mL DMF, heat to 120 ° C and stir for 12 hours under nitrogen protection. Monitor the reaction to the end point by TLC. Cool the reaction to room temperature, pour the reaction solution into 50 mL of water, extract with ethyl acetate three times, 50 mL each time, combine the organic phases, wash with saturated brine three times, 50 mL each time, dry over anhydrous sodium sulfate overnight, filter to remove anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure. After rapid silica gel column chromatography (PE: EA = 20: 1, v: v), 3.08 g of yellow liquid is obtained, with a yield of 84%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 9.94 (d, J = 2.5Hz, 1H), 7.98-7.81 (m, 2H), 7.17-7.00 (m, 3H), 7.00-6.85 (m, 2H), 2.31 (d, J = 2.3Hz, 3H).

[0185] (S,E)-N-(4-(4-fluoro-3-methylphenoxy)benzylidene)-2-methylpropane-2-sulfenamide (24b)

[0186]

[0187] 24a (2.00 mg, 8.96 mmol), (S)-tert-butylsulfenamide (1.58 g, 13.06 mmol), Cs2CO3 (8.49 g, 26.06 mmol) were dissolved in 30 mL of 1,2-dichloroethane, nitrogen protection, refluxed at 80 ° C for 5 h, cooled to 0 ° C after the reaction, added saturated ammonium chloride solution, and extracted with dichloromethane. The organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. White solid 24b was obtained by flash column chromatography (PE: EA = 10: 1, v: v) with a yield of 91%. 1 H NMR(400MHz,Chloroform-d)δ(ppm)8.54(s,1H),7.87-7.78(m,2H),7.08-6.97 (m, 3H), 6.90 (ddt, J = 16.0, 8.6, 3.1Hz, 2H), 2.29 (d, J = 2.1Hz, 3H), 1.27 (s, 9H).

[0188] (S)-N-((S)-1-(4-(4-fluoro-3-methylphenoxy)phenyl)ethyl)-2-methylpropane-2-sulfenamide (24c)

[0189]

[0190] 24b (2.00 g, 6.00 mmol) was dissolved in 30 mL of anhydrous DCM, the reaction solution was placed at -78°C, 7.5 mL of anhydrous THF solution (1 mol / L) of methylmagnesium bromide (894.09 mg, 7.50 mmol) was slowly added dropwise, and the reaction was continued for 2 h. The temperature was raised to -20°C and the reaction was continued for 2 h. Saturated NH4Cl aqueous solution was slowly added dropwise to quench the reaction, and the DCM extraction was performed. The organic phases were combined and dried over anhydrous Na2SO4, and separated by flash column chromatography (PE:EA=10:1, v:v) to obtain 2.05 g of a colorless oily substance with a yield of 98%. 1 H NMR (400MHz, Chloroform-d) δ (ppm) 7.30 (s, 1H), 7.27 (s, 1H), 6.98 (t, J=8.9Hz, 1H), 6.95-6.90 (m, 2H), 6.88 (dd, J= 6.3, 2.9Hz, 1H), 6.85-6.79 (m, 1H), 4.14 (q, J = 7.1Hz, 1H), 2.27 (d, J = 2.0Hz, 3H), 1.55 (d, J = 6.7Hz, 3H), 1.22 (s, 9H).

[0191] (S)-1-(4-(4-Fluoro-3-methylphenoxy)phenyl)ethan-1-amine (24d)

[0192]

[0193] 24c (1.90 g, 5.44 mmol) was added to a concentrated hydrochloric acid / methanol (v:v=1:2) system and stirred at room temperature for 2 h. After monitoring by TLC until the reaction was complete, the product was concentrated under reduced pressure to remove methanol. The residue was diluted with water and the pH was adjusted to 10. The product was extracted with dichloromethane. The organic phases were combined and concentrated under reduced pressure. The product was purified by flash column chromatography (PE:EA=3:1, v:v) to obtain 1.02 g of a colorless oily liquid with a yield of 76%. 1 HNMR(300MHz,Chloroform-d)δ(ppm)7.30(d,J=1.9Hz,1H),7.27(s,1H),7.20-7.12(m,2H ),7.04-6.88(m,3H),4.11(q,J=6.6Hz,1H),2.25(d,J=2.0Hz,3H),1.40(d,J=6.6Hz,3H).

[0194] (S)-N-(2-((1-(4-((2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-6-yl)methyl)phenyl)ethyl))amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (20 g)

[0195]

[0196] 20f (360 mg, 1.15 mmol), 1c (400 mg, 1.25 mmol), DIPEA (436 mg, 0.11 mmol) were dissolved in 8 mL of n-butanol, strictly evacuated with nitrogen protection, heated to reflux at 110 ° C, and reacted for 48 hours. TLC was monitored until the end of the reaction. The reaction solution was cooled to room temperature, the solvent was dried in vacuo, dissolved in ethyl acetate, washed three times with water, washed three times with saturated brine, dried over anhydrous sodium sulfate, and the solvent was dried, and 291 mg of a light yellow solid was obtained by rapid silica gel column chromatography (DCM: MeOH = 80: 1, v: v), with a yield of 41%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.78 (s, 1H), 8.23 ​​(s, 2H), 8.02 (s, 3H), 7.69 (d, J = 2.3Hz, 2H), 7.54 (dd, J = 8.4, 2.3Hz ,1H),7.19(s,4H),7.05(d,J=8.4Hz,1H),6.00(s,1H),4.76(s,1H),3.95(s,2H),1.67(s,6H),1.32(d,J=5.7Hz,3H).

[0197] (S)-N-(2-((1-(4-((2,2-dimethyl-4-oxo-4H-benzo[d][1,3]dioxin-7-yl)methyl)phenyl)ethyl))amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (21 g)

[0198]

[0199] The synthesis and treatment steps of compound 21g were the same as those of compound 20g. 21f (460 mg, 1.48 mmol) and 1c (310 mg, 1.61 mmol) were added and separated by flash column chromatography (DCM:MeOH=70:1, v:v) to obtain 20g310 mg of a light yellow solid with a yield of 35%. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 10.86 (s, 1H), 8.22 (s, 2H), 7.99 (s, 2H), 7.77 (d, J = 8.0Hz, 2H), 7.58 (s, 1H), 7.19 (s, 4H) ,7.06(dd,J=8.0,1.6Hz,1H),6.96(d,J=1.6Hz,1H),5.98(s,1H),4.73(s,1H),3.97(s,2H),1.67(s,6H),1.24(s,3H).

[0200] Example 1: (S)-N-(2-((1-([1,1'-biphenyl]-4-yl)ethyl)amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (I-1)

[0201]

[0202] 1b (200 mg, 1.01 mmol), 1c (213 mg, 0.675 mmol), DIPEA (436 mg, 0.11 mmol) were dissolved in 8 mL of n-butanol, strictly evacuated with nitrogen protection, heated to reflux at 110 ° C, and reacted for 48 hours. TLC was monitored until the reaction end point. The reaction solution was cooled to room temperature, the solvent was dried in vacuum, dissolved in ethyl acetate, washed three times with water, washed three times with saturated brine, dried over anhydrous sodium sulfate, and the solvent was dried, and 80 mg of light yellow solid was obtained by rapid silica gel column chromatography (DCM: MeOH = 80: 1, v: v), with a yield of 25%, and HPLC purity: 99.08%. Mp: 184-185 ° C. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.24 (s, 3H), 8.03 (s, 2H), 7.88 (s, 1H), 7.64 (dd, J = 7.1, 1.5Hz, 2H), 7.61-7.5 5(m,2H),7.47(t,J=7.7Hz,2H),7.36(ddt,J=10.0,6.7,2.5Hz,3H),6.03(s,1H),4.88(s,1H),1.38(s,3H). 13 CNMR (126 MHz, DMSO-d6) δ (ppm) 166.90, 164.61, 162.16, 153.79, 149.13, 142.89, 140.52, 140.37, 139.41, 139.03, 133.44, 129.35, 128.36, 127.82, 127.73, 127.14, 127.10, 127.07, 127.05, 126.80, 124.36, 110.59, 49.66, 22.26. HRMS (ESI): calculated value C 24 H 21 N5O4S,[M+H] + m / z, 476.1387; found 476.1384.

[0203] Example 2: (S)-4-nitro-N-(2-((1-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ethyl)amino)pyrimidin-4-yl)benzenesulfonamide (I-2)

[0204]

[0205] Referring to the synthesis method of Example 1, the yield was 43%, HPLC purity: 97.27%, Mp: 214-216°C. 1 H NMR(400MHz,DMSO-d6)δ(ppm)11.95(br,1H),8.20(s,2H),7.99(s,2H),7.92-7.78(m,5H),7.78-7.57(m,3H),

[0206] 7.45-7.31(m,2H),6.02(s,1H),4.89(s,1H),1.36(d,J=16.4Hz,3H). 13 C NMR (101MHz,

[0207] DMSO-d6)δ(ppm)173.10,162.84,161.32,160.14,153.39,151.36,148.31,144.86,143.76,138.30,137.81,13 4.49,134.01,128.92,128.60,128.40,128.04,127.77,126.80,126.77,124.95,124.07,110.88,49.57,22.10.

[0208] HRMS (ESI): Calculated value C 25 H 20 F3N5O4S,[M+H] + m / z, 544.1261; found 544.1257.

[0209] Example 3: (S)-4-nitro-N-(2-((1-(4'-nitro-[1,1'-biphenyl]-4-yl)ethyl)amino)pyrimidin-4-yl)benzenesulfonamide (I-3)

[0210]

[0211] Referring to the synthesis method of Example 1, the yield was 27%, HPLC purity: 98.41%, Mp: 194-195°C. 1 H NMR(400MHz,DMSO-d6)δ(ppm)11.23(s,1H),8.35-8.29(m,2H),8.21(s,2H),8.10-7.90(m,4H) ,7.82(s,1H),7.75-7.62(m,3H),7.42(d,J=7.4Hz,2H),6.04(s,1H),4.93(s,1H),1.40(s,3H). 13C NMR (101 MHz, DMSO-d6) δ (ppm) 167.47, 160.17, 156.87, 152.20, 149.15, 147.61, 147.32, 140.99, 138.95, 137.46, 129.35, 128.93, 128.72, 128.65, 128.26, 127.98, 127.86, 125.19, 125.11, 124.93, 124.30, 111.01, 60.80, 21.80. HRMS (ESI): calculated value C 24 H 20 N6O6S,[M+H] + m / z, 521.1238; found 521.1227.

[0212] Example 4: (S)-N-(2-((1-(4'-cyano-[1,1'-biphenyl]-4-yl)ethyl)amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (I-4)

[0213]

[0214] Referring to the synthesis method of Example 1, the yield was 30%, HPLC purity: 96.85%, Mp: 134-135°C. 1 H NMR(400MHz,DMSO-d6)δ(ppm)11.22(s,1H),8.21(s,2H),8.01(s,2H),7.95-7.90(m,2H),7.90-7.84(m,2H),7.71-7 .66(m,2H),7.53-7.45(m,1H),7.39(d,J=7.7Hz,2H),7.22(d,J=8.3Hz,1H),6.03(s,1H),4.91(s,1H),1.39(s,3H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 160.84, 159.29, 157.50, 151.32, 149.41, 145.41, 140.91, 139.59, 137.79, 133.85, 132.71, 132.06, 130.10, 129.29, 128.46, 128.01, 127.92, 127.80, 124.82, 124.31, 122.76, 119.97, 110.90, 50.38, 21.52. HRMS (ESI): calculated value C 25 H 20 N6O4S,[M+H] + m / z, 501.1340; found 501.1341.

[0215] Example 5: (S)-N-(2-((1-(4'-methyl-[1,1'-biphenyl]-4-yl)ethyl)amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (I-5)

[0216]

[0217] Referring to the synthesis method of Example 1, the yield was 36%, HPLC purity: 98.73%, Mp: 157-158°C. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.22 (s, 2H), 8.00 (s, 2H), 7.82 (s, 1H), 7.63 (s, 1H), 7.54 (dd, J= 10.5, 7.9Hz, 4H), 7.28 (t, J = 10.9Hz, 4H), 6.00 (s, 1H), 4.83 (s, 1H), 2.34 (s, 3H), 1.36 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ (ppm) 166.03, 160.39, 157.88, 157.12, 152.89, 149.47, 147.57, 144.96, 142.77, 139.83, 137.94, 137.61, 135.15, 132.44, 130.43, 128.99, 127.49, 127.37, 127.31, 127.16, 124.87, 109.29, 58.20, 30.79, 21.61. HRMS (ESI): calculated value C 25 H 23 N5O4S,[M+H] + m / z, 490.1544; found 490.1539.

[0218] Example 6: (S)-N-(2-((1-(4'-amino-[1,1'-biphenyl]-4-yl)ethyl)amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (I-6)

[0219]

[0220] Referring to the synthesis method of Example 1, the yield was 30%, HPLC purity: 99.60%, Mp: 169-171°C.

[0221] 1H NMR(400MHz,DMSO-d6)δ(ppm)8.25(s,2H),8.04(s,2H),7.68(s,2H),7.57-7.39(m ,4H),7.34-7.17(m,2H),6.87-6.72(m,2H),6.02(s,1H),4.83(s,1H),1.35(s,3H). 13 CNMR (101 MHz, DMSO-d6) δ (ppm) 161.03, 159.54, 158.53, 150.84, 149.62, 141.56, 140.11, 137.40, 135.72, 129.51, 128.83, 128.40, 128.35, 128.03, 127.48, 127.21, 126.44, 126.15, 124.91, 124.69, 113.67, 110.96, 60.40, 23.13. HRMS (ESI): calculated value C 24 H 22 N6O4S,[M+H] + m / z, 491.1496; found 491.1485.

[0222] Example 7: (S)-N-(2-((1-(4'-(methylamino)-[1,1'-biphenyl]-4-yl)ethyl)amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (I-7)

[0223]

[0224] Referring to the synthesis method of Example 1, the yield was 32%, HPLC purity: 98.49%, Mp: 146-148°C.

[0225] 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.24(s,3H),8.01(s,2H),7.82(s,1H),7.50-7.43(m,2H),7.43-7.37(m,2H), 7.23(s,2H),6.66-6.56(m,2H),5.98(s,1H),5.80(s,1H),4.76(s,1H),2.71(s,3H),1.27(d,J=25.7Hz,3H). 13C NMR (101 MHz, DMSO-d6) δ (ppm) 163.20, 160.07, 158.40, 150.37, 149.16, 144.70, 139.65, 131.31, 130.58, 130.12, 128.40, 127.93, 127.62, 127.54, 126.99, 126.86, 125.97, 125.78, 124.43, 124.30, 113.19, 110.93, 55.09, 40.61, 19.89. HRMS (ESI): calculated value C 25 H 24 N6O4S,[M+H] + m / z, 505.1580; found 505.1587.

[0226] Example 8: (S)-N-(2-((1-(4'-(ethylamino)-[1,1'-biphenyl]-4-yl)ethyl)amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (I-8)

[0227]

[0228] Referring to the synthesis method of Example 1, the yield was 25%, HPLC purity: 97.86%, Mp: 129-130°C.

[0229] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.36-8.15 (m, 3H), 7.68 (d, J = 29.6Hz, 1H), 7.50-7.42 (m, 2H), 7.42-7.34 (m, 2H), 7.24 (s, 4H), 6 .69-6.56(m,2H),6.01(s,1H),5.70(s,1H),4.80(s,1H),3.07(q,J=7.1Hz,2H),1.32(d,J=15.2Hz,3H),1.18(t,J=7.1Hz,3H). 13 CNMR (126 MHz, DMSO-d6) δ (ppm) 165.86, 162.62, 159.34, 150.30, 149.50, 145.24, 140.45, 133.66, 132.43, 130.53, 128.04, 128.00, 127.84, 127.36, 126.20, 126.07, 124.93, 124.84, 124.77, 124.60, 113.21, 110.11, 54.46, 38.25, 23.04, 15.38. HRMS (ESI): calculated value C 26 H26 N6O4S,[M+H] + m / z, 519.1736; found 519.1738.

[0230] Example 9: (S)-N-(2-((1-(4'-(isopropylamino)-[1,1'-biphenyl]-4-yl)ethyl)amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (I-9)

[0231]

[0232] Referring to the synthesis method of Example 1, the yield was 21%, HPLC purity: 98.10%, Mp: 136-138°C.

[0233] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.26 (s, 2H), 7.46 (d, J = 8.2Hz, 2H), 7.41-7.34 (m, 2H), 7.24 (s, 6H), 6.66-6.5 9(m,2H),6.02(s,1H),5.56(s,1H),4.79(s,1H),3.58(s,1H),1.30(d,J=45.0Hz,3H),1.15(d,J=6.3Hz,6H). 13 C NMR (126 MHz, DMSO-d6) δ (ppm) 161.06, 160.20, 153.50, 151.27, 148.24, 142.81, 136.47, 135.83, 130.16, 128.93, 127.65, 127.17, 126.95, 126.91, 125.74, 124.40, 123.62, 123.47, 123.12, 117.62, 113.21, 111.94, 68.14, 43.19, 25.21, 22.47. HRMS (ESI): calculated value C 27 H 28 N6O4S,[M+H] + m / z, 533.1893; found value 533.1896.

[0234] Example 10: (S)-N-(2-((1-(4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)ethyl)amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (I-10)

[0235]

[0236] Referring to the synthesis method of Example 1, the yield was 26%, HPLC purity: 99.47%, Mp: 169-170°C.

[0237] 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.25(s,2H),8.02(s,2H),7.80(s,1H),7.62(s,1H),7.55-7.42 (m,4H),7.26(s,2H),6.84-6.76(m,2H),6.01(s,1H),4.79(s,1H),2.94(s,6H),1.34(s,3H). 13 C NMR (126 MHz, DMSO-d6) δ (ppm) 164.55, 159.65, 156.39, 150.79, 145.38, 140.07, 135.56, 131.76, 130.53, 128.37, 128.08, 127.95, 127.48, 127.41, 126.39, 126.22, 124.88, 124.84, 124.71, 124.71, 113.61, 109.19, 61.13, 41.03, 21.57. HRMS (ESI): calcd. 26 H 26 N6O4S,[M+H] + m / z, 519.1736; found value 519.1735.

[0238] Example 11: tert-Butyl-(S)-(4'-(1-((4-((4-nitrophenyl)sulfonylamino)pyrimidin-2-yl)amino)ethyl)-[1,1'-biphenyl]-4-yl)carbamate (I-11)

[0239]

[0240] Referring to the synthesis method of Example 1, the yield was 22%, HPLC purity: 97.84%, Mp: 164-165°C.

[0241] 1 H NMR (300MHz, DMSO-d6) δ (ppm) 9.45 (s, 1H), 8.24 (d, J = 9.0Hz, 2H), 8.02 (s, 2H), 7.76 (s, 1H), 7.67 (s, 1H), 7 .53(d,J=5.0Hz,6H),7.30(d,J=7.9Hz,2H),6.02(s,1H),4.85(s,1H),1.50(s,9H),1.25(d,J=4.3Hz,3H). 13C NMR (126 MHz, DMSO-d6) δ (ppm) 166.19, 161.97, 159.53, 154.61, 153.72, 149.50, 140.01, 139.95, 139.62, 139.57, 134.39, 132.23, 128.75, 127.70, 127.53, 127.46, 127.09, 127.03, 124.90, 124.86, 119.51, 119.37, 110.40, 80.07, 49.65, 29.09, 23.04. HRMS (ESI): calculated value C 29 H 30 N6O6S,[M+H] + m / z, 591.1948; found 591.2021.

[0242] Example 12: (S)-N-(2-((1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)ethyl)amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (I-12)

[0243]

[0244] Referring to the synthesis method of Example 1, the yield was 21%, HPLC purity: 98.57%, Mp: 138-139°C.

[0245] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 9.53 (s, 1H), 8.22 (d, J = 8.6Hz, 3H), 8.00 (s, 2H), 7.47 (dd, J = 1 5.2, 8.0Hz, 5H), 7.26 (s, 2H), 6.84 (d, J = 8.1Hz, 2H), 5.97 (s, 1H), 4.78 (s, 1H), 1.34 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 162.42, 160.32, 158.11, 153.45, 147.92, 139.38, 137.49, 137.20, 136.05, 134.74, 133.95, 133.11, 132.23, 130.63, 130.03, 128.59, 128.20, 127.07, 126.96, 126.89, 126.76, 124.45, 58.54, 21.21. HRMS (ESI): calculated value C 24 H 21 N5O5S,[M+H] + m / z, 492.1263; found 492.1268.

[0246] Example 13: (S)-N-(2-((1-(4'-methoxy-[1,1'-biphenyl]-4-yl)ethyl)amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (I-13)

[0247]

[0248] Referring to the synthesis method of Example 1, the yield was 24%, HPLC purity: 98.01%, Mp: 150-152°C.

[0249] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.22 (s, 1H), 8.24 (s, 2H), 8.02 (s, 2H), 7.73 (d, J = 28.5Hz, 2H), 7.61-7.55 (m, 1H), 7.55-7.50 (m, 1H), 7 .50-7.44(m,2H),7.30(d,J=8.2Hz,1H),7.22(d,J=8.1Hz,2H),7.08-6.96(m,1H),6.04(s,1H),4.84(s,1H),3.80(s,3H),1.34(s,3H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 163.24, 161.26, 159.40, 156.69, 143.24, 141.45, 139.12, 132.82, 132.26, 131.62, 131.47, 129.65, 128.98, 128.84, 128.45, 128.24, 127.09, 126.65, 124.39, 120.37, 114.88, 102.31, 55.72, 49.92, 21.06. HRMS (ESI): calculated value C 25 H 23 N5O5S,[M+H] + m / z, 506.1420; found 506.1489.

[0250] Example 14: (S)-N-(2-((1-(3'-methoxy-[1,1'-biphenyl]-4-yl)ethyl)amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (I-14)

[0251]

[0252] Referring to the synthesis method of Example 1, the yield was 35%, HPLC purity: 98.74%, Mp: 123-125°C.

[0253] 1 H NMR(400MHz,DMSO-d6)δ(ppm)11.94(s,1H),8.23(s,2H),8.01(s,2H),7.85(s,1H),7.72-7.49(m,3H),7.36(q,J=12.0,1 0.0Hz,3H),7.22-7.14(m,2H),6.94(dd,J=8.4,2.6Hz,1H),6.01(s,1H),4.86(s,1H),3.83(s,3H),1.35(d,J=7.3Hz,3H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 164.70, 162.40, 160.72, 155.31, 151.98, 149.66, 147.73, 142.45, 139.84, 135.35, 130.97, 128.63, 127.76, 127.54, 127.34, 124.92, 124.72, 123.05, 121.84, 119.97, 113.97, 113.14, 56.10, 49.58, 31.44. HRMS (ESI): calculated value C 25 H 23 N5O5S,[M+H] + m / z, 506.1420; found 506.1499.

[0254] Example 15: (S)-N-(2-((1-(2'-methoxy-[1,1'-biphenyl]-4-yl)ethyl)amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (I-15)

[0255]

[0256] Referring to the synthesis method of Example 1, the yield was 32%, HPLC purity: 98.99%, Mp: 135-136°C.

[0257] 1 H NMR(400MHz,DMSO-d6)δ(ppm)8.41-8.13(m,4H),8.02(s,1H),7.48-7.16(m,7H),7.10(d, J=8.2Hz,1H),7.03(t,J=7.4Hz,1H),6.02(s,1H),4.83(s,1H),3.75(s,3H),1.37(s,3H). 13C NMR (101 MHz, DMSO-d6) δ (ppm) 163.07, 157.11, 153.65, 149.54, 148.13, 146.31, 143.37, 142.18, 141.34, 140.64, 137.97, 131.31, 130.41, 130.25, 129.88, 129.70, 128.80, 126.72, 125.32, 124.98, 121.75, 112.63, 56.40, 39.87, 22.1. HRMS (ESI): calculated value C 25 H 23 N5O5S,[M+H] + m / z, 506.1420; found 506.1497.

[0258] Example 16: (S)-4-Hydroxy-4'-(1-((4-((4-nitrophenyl)sulfonylamino)pyrimidin-2-yl)amino)ethyl)-[1,1'-biphenyl]-3-carboxamide (I-16)

[0259]

[0260] 16a (100 mg, 0.38 mmol), 16c (165 mg, 0.35 mmol) and Pd(dppf)Cl2 (13 mg, 17 μmol) were dissolved in 4 mL of 1,4-dioxane, and a solution of cesium carbonate (450 mg, 1.38 mmol) in water (1 mL) was added. The mixture was heated and stirred at 100°C for 6 hours under strict nitrogen protection, and the reaction was monitored by TLC until the end point. The reaction solution was cooled to room temperature, the pH was adjusted to 1 with 0.1M dilute hydrochloric acid, the insoluble matter was removed by diatomaceous earth filtration, the liquid was collected, 1,4-dioxane was removed by vortexing under reduced pressure, 30mL of water was added, and the mixture was extracted three times with 50mL of ethyl acetate each time. The organic phases were combined and washed three times with saturated brine each time with 50mL of ethyl acetate, dried over anhydrous sodium sulfate overnight, anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. 85mg of white solid was obtained by rapid silica gel column chromatography (DCM:MeOH=60:1, v:v), with a yield of 46% and a HPLC purity of 97.88%. Mp: 183-184℃. 1H NMR (400MHz, DMSO-d6) δ (ppm) 13.11 (s, 1H), 8.57 (s, 1H), 8.23 ​​(s, 2H), 8.15 (d, J = 2.3Hz, 1H), 7.98 (s, 1H), 7.72 (dd, J = 8.5, 2 .2Hz,1H),7.61(d,J=8.0Hz,2H),7.40-7.29(m,4H),6.96(d,J=8.6Hz,1H),6.00(s,1H),4.82(s,1H),1.28(d,J=16.0Hz,3H). 13 C NMR (126 MHz, DMSO-d6) δ (ppm) 173.13, 163.05, 161.62, 158.25, 149.59, 148.08, 141.25, 139.00, 133.07, 131.23, 128.86, 127.45, 127.20, 127.13, 127.01, 124.92, 124.86, 122.47, 118.88, 118.84, 115.60, 115.51, 109.50, 55.37, 23.04. HRMS (ESI): calculated value C 25 H 22 N6O6S,[M+H] + m / z, 535.1322; found 535.1328.

[0261] Example 17: (S)-3-Hydroxy-4'-(1-((4-((4-nitrophenyl)sulfonylamino)pyrimidin-2-yl)amino)ethyl)-[1,1'-biphenyl]-4-carboxamide (I-17)

[0262]

[0263] Referring to the synthesis method of Example 16, the yield was 66%, HPLC purity: 98.58%, Mp: 174-175°C.

[0264] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.18 (s, 1H), 10.75 (s, 1H), 8.44 (s, 1H), 8.12-7.76 (m, 3H), 7.63 (d, J = 8.0Hz, 3H), 7.45 (d,J=7.9Hz,2H),7.21-7.09(m,2H),6.58(d,J=8.4Hz,2H),6.07(d,J=5.4Hz,3H),5.11(q,J=7.6Hz,1H),1.43(s,3H). 13C NMR (101 MHz, DMSO-d6) δ (ppm) 172.71, 161.21, 158.05, 155.63, 153.76, 151.77, 149.06, 145.09, 144.29, 138.54, 132.67, 130.77, 129.78, 128.33, 127.03, 126.79, 126.70, 126.57, 124.44, 118.46, 117.98, 115.02, 110.40, 59.84, 22.63. HRMS (ESI): calculated value C 25 H 22 N6O6S,[M+H] + m / z, 535.1322; found 535.1328.

[0265] Example 18: (S)-4-Hydroxy-N-methyl-4'-(1-((4-((4-nitrophenyl)sulfonylamino)pyrimidin-2-yl)amino)ethyl)-[1,1'-biphenyl]-3-carboxamide (I-18)

[0266]

[0267] 18a (300 mg, 1.08 mmol), 16c (469 mg, 0.98 mmol) and Pd(dppf)Cl2 (39 mg, 51 μmol) were dissolved in 8 mL of 1,4-dioxane, and a solution of cesium carbonate (1.35 g, 4.14 mmol) in water (2 mL) was added. The mixture was heated and stirred at 100 °C for 6 hours under strict nitrogen protection, and the reaction was monitored by TLC until the end point. The reaction solution was cooled to room temperature, the pH was adjusted to 1 with 0.1 M dilute hydrochloric acid, the insoluble matter was removed by diatomaceous earth filtration, the liquid was collected, 1,4-dioxane was removed by vortexing under reduced pressure, 30 mL of water was added, and the mixture was extracted three times with ethyl acetate, each time with about 50 mL. The organic phases were combined, washed three times with saturated brine, each time with 50 mL, and dried over anhydrous sodium sulfate overnight. The anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. 131 mg of a light yellow solid was obtained by separation by flash column chromatography (DCM:MeOH=40:1, v:v) with a yield of 25% and a HPLC purity of 98.04%.

[0268] The above light yellow solid (120 mg, 0.24 mmol), methylamine hydrochloride (40 mg, 0.60 mmol) and DIPEA (154 mg, 1.20 mmol) were dissolved in 3 mL of anhydrous DMF, and HATU (170 mg, 0.44 mmol) was added under stirring in an ice bath (0°C). After stirring for 15 minutes, the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC until the end point. The reaction solution was poured into 30 mL of water, extracted with ethyl acetate three times, about 30 mL each time, and the organic phases were combined and washed with saturated brine three times, 50 mL each time, dried over anhydrous sodium sulfate overnight, filtered to remove anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The white solid was separated by rapid silica gel column chromatography (DCM: MeOH = 70: 1, v: v) to obtain 91 mg of white solid, with a yield of 80%, and HPLC purity: 99.21%. Mp: 143-144°C. 1H NMR(400MHz,DMSO-d6)δ(ppm)12.83(s,1H),8.97(s,1H),8.21(s,3H),8.12(s,1H),7.99(s,1H),7.70(d,J=8.1Hz,1H),7.66-7 .52(m,3H),7.43-7.26(m,3H),6.98(d,J=8.6Hz,1H),5.97(s,1H),4.79(s,1H),2.85(d,J=4.4Hz,3H),1.27(d,J=16.3Hz,3H). 13C NMR(126MHz,DMSO-d6)δ(ppm)170.08,162.39,160.25,159.70,157.44,148.06,142.05,138.55,132.43,132.13,130.83, 128.20,126.98,126.75,126.63,126.58,125.86,125.76,124.39,124.35,118.40,115.63,110.56,59.13,29.47,26.44. HRMS (ESI): calculated for C26H24N6O6S, [M+H]+m / z, 549.1478; found 549.1475.

[0269] Example 19: (S)-3-Hydroxy-N-methyl-4'-(1-((4-((4-nitrophenyl)sulfonylamino)pyrimidin-2-yl)amino)ethyl)-[1,1'-biphenyl]-4-carboxamide (I-19)

[0270]

[0271] Referring to the synthesis method of Example 18, the yield was 78%, HPLC purity: 98.78%, Mp: 156-158°C.

[0272] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 12.88 (s, 1H), 8.85 (q, J = 4.6Hz, 1H), 8.21 (s, 2H), 8.00 (d, J = 8.2Hz, 2H), 7.88 (d, J = 8.4Hz, 1H), 7.63(d,J=8.1Hz,2H),7.35(d,J=9.4Hz,4H),7.22-7.09(m,2H),6.01(s,1H),4.86(s,1H),2.84(d,J=4.5Hz,3H),1.37(s,3H). 13 C NMR (126 MHz, DMSO-d6) δ (ppm) 170.44, 161.62, 159.12, 156.34, 154.30, 149.54, 145.87, 144.63, 140.85, 138.51, 130.56, 128.91, 128.77, 127.74, 127.64, 127.57, 127.51, 124.86, 124.83, 117.91, 115.94, 114.82, 112.45, 60.09, 29.99, 26.96. HRMS (ESI): calcd. 26 H 24 N6O6S,[M+H] + m / z, 549.1478; found value 549.1479.

[0273] Example 20: (S)-4-Hydroxy-4'-(1-((4-((4-nitrophenyl)sulfonylamino)pyrimidin-2-yl)amino)ethyl)-[1,1'-biphenyl]-3-carboxylic acid (I-20)

[0274]

[0275] 18a (300 mg, 1.08 mmol), 16c (469 mg, 0.98 mmol) and Pd(dppf)Cl2 (39 mg, 51 μmol) were dissolved in 8 mL of 1,4-dioxane, and a solution of cesium carbonate (1.35 g, 4.14 mmol) in water (2 mL) was added. The mixture was heated and stirred at 100 °C for 6 hours under strict nitrogen protection, and the reaction was monitored by TLC until the end point. The reaction solution was cooled to room temperature, the pH was adjusted to 1 with 0.1M dilute hydrochloric acid, the insoluble matter was removed by diatomaceous earth filtration, the liquid was collected, 1,4-dioxane was removed by vortexing under reduced pressure, 30mL of water was added, and the mixture was extracted three times with ethyl acetate, each time about 50mL, the organic phases were combined, washed three times with saturated brine, each time 50mL, dried over anhydrous sodium sulfate overnight, anhydrous sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure, and 131mg of a light yellow solid was obtained by rapid column chromatography (DCM:MeOH=40:1, v:v), with a yield of 25% and a HPLC purity of 98.04%. Mp: 199-200℃. 1 H NMR (300MHz, DMSO-d6) δ (ppm) 8.20 (s, 2H), 8.01 (s, 4H), 7.85-7.70 (m, 1H), 7.54 (d, J= 7.9Hz, 2H), 7.30 (s, 3H), 7.04 (d, J = 8.6Hz, 1H), 6.01 (s, 1H), 4.84 (s, 1H), 1.36 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ (ppm) 172.93, 172.81, 162.44, 161.56, 160.51, 151.27, 149.55, 143.07, 138.82, 135.71, 134.58, 131.82, 128.83, 128.69, 127.57, 127.40, 127.06, 126.97, 125.75, 124.86, 118.66, 114.63, 110.29, 60.70, 21.99. HRMS (ESI): calculated value C 25 H 21 N5O7S,[M+H] + m / z, 536.1162; found 536.1233.

[0276] Example 21: (S)-3-Hydroxy-4'-(1-((4-((4-nitrophenyl)sulfonylamino)pyrimidin-2-yl)amino)ethyl)-[1,1'-biphenyl]-4-carboxylic acid (I-21)

[0277]

[0278] Referring to the synthesis method of Example 20, the yield was 34%, HPLC purity: 97.01%, Mp: 203-204°C.

[0279] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.33 (s, 1H), 8.19 (s, 2H), 7.98 (s, 2H), 7.85 (d, J = 8.4Hz, 1H), 7.64 (d, J = 8 .0Hz,2H),7.34(s,2H),7.30-7.26(m,1H),7.22(d,J=5.5Hz,3H),6.00(s,1H),4.86(s,1H),1.36(s,3H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 175.54, 173.02, 164.33, 162.58, 161.10, 149.58, 147.41, 138.57, 133.55, 131.82, 128.72, 127.91, 127.83, 127.62, 127.45, 125.27, 124.93, 124.18, 121.06, 118.36, 116.58, 115.54, 113.70, 58.15, 22.08. HRMS (ESI): calculated value C 25 H 21 N5O7S,[M+H] + m / z, 536.1162; found 536.1163.

[0280] Example 22: (S)-4-Hydroxy-4'-(1-((4-((4-nitrophenyl)sulfonylamino)pyrimidin-2-yl)amino)ethyl)-[1,1'-biphenyl]-3-carboxylic acid methyl ester (I-22)

[0281]

[0282] Compound I-20 (120 mg, 0.24 mmol) was dissolved in 3 mL of anhydrous methanol, and thionyl chloride (52 mg, 0.44 mmol) was slowly added dropwise, and heated and stirred at 65°C for 4 hours. The reaction was monitored by TLC until the end point. The reaction solution was cooled to room temperature, the solvent was dried under reduced pressure, and separated by flash column chromatography (DCM: MeOH = 100: 1, v: v) to obtain 91 mg of a white solid with a yield of 88% and a HPLC purity of 100.00%. Mp: 151-153°C. 1H NMR (400MHz, DMSO-d6) δ (ppm) 10.53 (s, 1H), 8.18 (d, J = 8.4Hz, 2H), 8.03-7.91 (m, 3H), 7.81 (dd, J = 8.6, 2.5Hz, 1H), 7.54 (d, J = 8.0H) z,2H),7.42-7.35(m,1H),7.35-7.22(m,3H),7.09(d,J=8.7Hz,1H),5.97(s,1H),4.81(s,1H),3.92(s,3H),1.35(d,J=13.1Hz,3H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 175.04, 169.53, 159.87, 158.81, 153.89, 147.64, 140.78, 140.21, 138.16, 134.66, 134.24, 131.68, 128.37, 128.18, 127.17, 126.66, 124.78, 124.45, 123.70, 123.25, 118.63, 116.12, 114.14, 53.07, 49.14, 22.62. HRMS (ESI): calculated value C 26 H 23 N5O7S,[M+H] + m / z, 550.1318; found 550.1317.

[0283] Example 23: (S)-3-Hydroxy-4'-(1-((4-((4-nitrophenyl)sulfonylamino)pyrimidin-2-yl)amino)ethyl)-[1,1'-biphenyl]-4-carboxylic acid methyl ester (I-23)

[0284]

[0285] Referring to the synthesis method of Example 22, the yield was 64%, HPLC purity: 98.79%, Mp: 167-168°C.

[0286] 1 H NMR(400MHz,DMSO-d6)δ(ppm)10.59(s,1H),8.21(s,2H),8.00(s,2H),7.89-7.82(m,1H),7.69-7.60(m,2H ),7.38(d,J=11.1Hz,3H),7.25(dd,J=6.2,1.6Hz,3H),6.02(s,1H),4.89(s,1H),3.92(s,3H),1.37(s,3H). 13C NMR (101 MHz, DMSO-d6) δ (ppm) 170.17, 166.10, 161.47, 153.30, 151.88, 149.46, 147.85, 145.60, 138.19, 136.95, 131.58, 128.73, 127.94, 127.94, 127.68, 127.49, 125.30, 124.94, 124.79, 118.87, 118.72, 115.94, 112.71, 53.52, 49.59, 30.82. HRMS (ESI): calculated value C 26 H 23 N5O7S,[M+H] + m / z, 550.1318; found 550.1316.

[0287] Example 24: (S)-2-Hydroxy-5-(4-(1-((4-((4-nitrophenyl)sulfonamido)pyrimidin-2-yl)amino)ethyl)benzyl)benzoic acid (I-24)

[0288]

[0289] Compound 20g (280mg, 0.46mmol) was dissolved in 6mL trifluoroacetic acid / water (9 / 1, v / v) and stirred at room temperature for 12 hours. TLC was used to monitor the reaction until the end point. The reaction solution was poured into 20mL water, extracted with dichloromethane three times, 20mL each time, the organic phase was combined, washed with saturated brine three times, 20mL each time, dried over anhydrous sodium sulfate overnight, filtered to remove anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. 216mg of brown solid was obtained by rapid silica gel column chromatography (DCM: MeOH = 50: 1, v: v), with a yield of 82%, and HPLC purity: 97.63%. Mp: 205-206℃. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 11.13 (s, 1H), 8.33-8.12 (m, 4H), 7.99 (s, 2H), 7.85 (s, 1H), 7.63 (d, J = 2.3Hz, 1H), 7. 36(dd,J=8.5,2.3Hz,1H),7.14(s,3H),6.88(d,J=8.4Hz,1H),6.01(s,1H),4.73(s,1H),3.86(s,2H),1.28(s,3H). 13C NMR (101 MHz, DMSO-d6) δ (ppm) 172.40, 161.79, 158.97, 158.65, 150.16, 148.92, 139.50, 136.56, 130.90, 129.27, 129.07, 127.97, 127.87, 127.20, 126.69, 125.84, 124.42, 124.22, 120.35, 119.07, 117.44, 116.10, 111.43, 49.13, 41.16, 18.54. HRMS (ESI): calculated value C 26 H 23 N5O7S,[M+H] + m / z, 550.1318; found 550.1314.

[0290] Example 25: (S)-2-Hydroxy-5-(4-(1-((4-((4-nitrophenyl)sulfonamido)pyrimidin-2-yl)amino)ethyl)benzyl)benzamide (I-25)

[0291]

[0292] Compound I-24 (100 mg, 0.18 mmol), PyBOP (142 mg, 0.26 mmol), HOBt (38 mg, 0.26 mmol) were dissolved in 3 mL of anhydrous DMF, stirred under an ice bath (0 ° C), and then DIPEA (48 mg, 0.36 mmol) and ammonium chloride (20 mg, 0.36 mmol) were added in sequence, and stirred at room temperature for 3 hours. TLC monitored the reaction until the end point. The reaction solution was poured into 30 mL of water, extracted with ethyl acetate three times, about 30 mL each time, and the organic phases were combined and washed with saturated brine three times, 50 mL each time, dried over anhydrous sodium sulfate overnight, filtered to remove anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. 78 mg of white solid was obtained by rapid silica gel column chromatography (DCM: MeOH = 50: 1, v: v), with a yield of 78%, and HPLC purity: 99.13%. Mp: 172-173 ° C. 1H NMR (400MHz, DMSO-d6) δ (ppm) 12.77 (s, 1H), 11.22 (s, 1H), 8.35 (s, 1H), 8.22 (s, 2H), 8.07-7.92 (m, 2H), 7.84 (s, 1H), 7.78 (d, J = 2.2Hz, 1H), 7.76 -7.69(m,1H),7.62(s,1H),7.22(dd,J=8.5,2.1Hz,1H),7.15(s,4H),6. 80(d,J=8.4Hz,1H),6.00(s,1H),4.72(s,1H),3.82(s,2H),1.29(s,3H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 172.88, 160.28, 157.38, 154.54, 145.43, 144.03, 141.39, 139.74, 135.46, 132.10, 129.43, 129.15, 128.67, 127.15, 126.91, 125.11, 124.93, 124.12, 118.44, 115.25, 109.73, 55.95, 41.13, 40.92, 30.04, 23.12. HRMS (ESI): calculated value C 26 H 24 N6O6S,[M+H] + m / z, 549.1478; found 549.1475.

[0293] Example 26: (S)-2-Hydroxy-4-(4-(1-((4-((4-nitrophenyl)sulfonamido)pyrimidin-2-yl)amino)ethyl)benzyl)benzoic acid (I-26)

[0294]

[0295] Referring to the synthesis method of Example 24, the yield was 77%, HPLC purity: 99.49%, Mp: 192-193°C.

[0296] 1 H NMR(400MHz,DMSO-d6)δ(ppm)11.22(s,1H),8.22(s,2H),8.00(s,2H),7.82(s,1H),7.73-7.6 0(m,2H),7.17(s,4H),6.83-6.74(m,2H),6.02(s,1H),4.75(s,1H),3.89(s,2H),1.31(s,3H). 13C NMR (101 MHz, DMSO-d6) δ (ppm) 172.85, 162.25, 159.42, 159.11, 151.36, 150.61, 146.26, 139.96, 134.78, 131.36, 129.73, 129.54, 128.43, 128.33, 127.67, 127.16, 124.88, 124.68, 120.81, 119.55, 117.90, 116.58, 111.92, 54.51, 41.63, 21.27. HRMS (ESI): calculated value C 26 H 23 N5O7S,[M+H] + m / z, 550.1318; found 550.1379.

[0297] Example 27: (S)-2-Hydroxy-4-(4-(1-((4-((4-nitrophenyl)sulfonamido)pyrimidin-2-yl)amino)ethyl)benzyl)benzamide (I-27)

[0298]

[0299] Refer to the synthesis method of Example 25, yield 81%, HPLC purity: 97.40%. Mp: 178-179°C. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 13.01 (s, 1H), 11.81 (s, 1H), 8.30 (s, 1H), 8.22 (d, J = 7.4Hz, 2H), 8.02 (s, 2H), 7.80 (s, 1H) ),7.74(d,J=8.1Hz,1H),7.63(s,2H),7.16(s,4H),6.76-6.67(m,2H),4.77(s,1H),3.86(s,2H),1.28(d,J=10.7Hz,3H. 13 C NMR (75 MHz, DMSO-d6) δ (ppm) 172.55, 162.79, 161.74, 160.68, 159.88, 148.43, 143.67, 140.45, 138.94, 135.07, 130.46, 129.17, 128.61, 127.80, 126.64, 124.43, 124.39, 119.65, 119.48, 117.88, 117.71, 112.63, 110.16, 59.26, 40.98, 21.54. HRMS (ESI): calculated value C 26 H 24 N6O6S,[M+H] +m / z, 549.1478; found 549.1475.

[0300] Example 28: (S)-N-(2-((1-(4-(4-fluoro-3-methylbenzyl)phenyl)ethyl)amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (I-28)

[0301]

[0302] Referring to the synthesis method of Example 1, the yield was 30%, HPLC purity: 99.59%, Mp: 119-121°C.

[0303] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.20 (s, 2H), 7.97 (s, 2H), 7.74 (s, 1H), 7.60 (dd, J = 19.9, 7.8Hz, 1H), 7.41 (dt, J = 42.6, 8 .6Hz,1H),7.13(d,J=2.8Hz,4H),7.07-6.97(m,2H),5.96(s,1H),4.69(s,1H),3.84(s,2H),2.18(s,3H),1.23(s,3H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 161.44, 159.05, 157.46, 150.80, 149.38, 141.16, 138.06, 138.03, 132.74, 132.69, 129.91, 129.51, 128.73, 128.65, 127.63, 127.60, 127.14, 125.07, 124.90, 115.85, 115.63, 110.68, 59.22, 49.73, 23.12, 15.15. HRMS (ESI): calculated value C 26 H 24 FN5O4S,[M+H] + m / z, 522.1533; found 522.1535.

[0304] Example 29: (S)-N-(2-((1-(4-((4-fluoro-3-methylphenyl)amino)phenyl)ethyl)amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (I-29)

[0305]

[0306] 4-Fluoro-3-methylaniline (700 mg, 0.56 mmol), 16c (400 mg, 1.33 mmol), Pd2dba3 (5 mg, 5 μmol), XPhos (9 mg, 19 μmol), sodium tert-butoxide (67 mg, 0.70 mmol) were dissolved in 8 mL of toluene and heated to 95 °C under nitrogen protection and stirred for 15 hours. TLC was monitored until the reaction end point. The reaction was cooled to room temperature, and the reaction solution was poured into 50 mL of saturated ammonium chloride solution, extracted with ethyl acetate three times, 50 mL each time, and the organic phases were combined, washed with saturated brine three times, 50 mL each time, dried over anhydrous sodium sulfate overnight, filtered to remove anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. 86 mg of brown solid was obtained by rapid silica gel column chromatography (PE:EA=1:3, v:v), with a yield of 31%, and HPLC purity: 99.49%. Mp: 151-152 °C. 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.28 (d, J = 8.3 Hz, 2H), 8.03 (s, 3H), 7.86 (s, 1H), 7.69 (s, 1H), 7.08 (s, 2H), 7.00 (t, J = 9. 1Hz,1H),6.96-6.90(m,3H),6.86(dt,J=8.1,3.6Hz,1H),6.03(s,1H),4.64(s,1H),2.18(s,3H),1.25(d,J=9.6Hz,3H). 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 160.10, 156.74, 154.40, 149.08, 143.64, 139.88, 138.83, 131.65, 130.35, 128.79, 128.37, 128.11, 127.50, 125.18, 125.00, 124.45, 120.71, 116.91, 116.32, 115.92, 115.69, 109.83, 61.14, 31.68, 14.94. HRMS (ESI): calculated value C 25 H 23 FN6O4S,[M+H] + m / z, 523, 1486; found value 523.1485.

[0307] Example 30: (S)-N-(2-((1-(4-(4-fluoro-3-methylphenoxy)phenyl)ethyl)amino)pyrimidin-4-yl)-4-nitrobenzenesulfonamide (I-30)

[0308]

[0309] The yield was 22% and the HPLC purity was 99.49%. Mp: 174-175°C.

[0310] 1 H NMR (400MHz, DMSO-d6) δ (ppm) 8.24 (s, 2H), 7.93 (d, J = 5.9Hz, 1H), 7.37 (s, 3H), 7.23 (s, 2H), 7.15 (t, J = 9.1Hz, 1H), 6.96 (dd, J=6.5,3.1Hz,1H),6.91-6.84(m,2H),6.37(d,J=5.9Hz,1H),5.97(s,1H),4.73(s,1H),2.21(s,3H),1.26(d,J=25.7Hz,3H).

[0311] 13 C NMR (101 MHz, DMSO-d6) δ (ppm) 165.72, 160.32, 158.61, 157.23, 156.81, 156.23, 152.54, 150.89, 148.93, 138.57, 128.18, 126.62, 126.43, 124.46, 122.53, 122.48, 118.57, 118.49, 118.15, 116.67, 116.43, 104.53, 60.29, 21.58, 14.75. HRMS (ESI): calculated value C 25 H 22 FN5O5S,[M+H] + m / z, 524, 1326; found value 524.1326.

[0312] Example 31 Biological Evaluation Experiment

[0313] (1) Analytical methods for the effects of compounds on cell viability

[0314] The effect of the example compounds on the viability of B16F10 cells was investigated by MTT assay. Cells in logarithmic growth phase were selected for MTT assay and plated on a 96-well plate at 1×10 4 / well inoculated with mouse B16F10 melanoma cells, incubated at 5% CO2 and 37°C for 24h, and removed the supernatant. In the experimental group, 200μL of DMEM medium with a drug concentration of 0.25 or 1μM was added to each well, and the concentration of 8-MOP (positive control drug) was set to 50μM, and 6 replicates were set. Directly add 200μl DMEM medium as the control group, incubate for 48h, add 20μl of MTT solution (5g / L) to each well, continue incubation at 37°C and 5% CO2 for 4h, remove the supernatant, add 150μL DMSO to each well, shake for 10min, and measure the absorbance value of each well under a 490nm microplate reader.

[0315] Cell proliferation rate = (average absorbance value of each concentration of the material to be screened / average absorbance value of the control group) × 100%.

[0316] The results of the effects of the compounds in the examples on cell viability are shown in Figure 1 , Figure 2 As shown in the figure, it can be seen from the experimental results that, except for compound I-10, the compounds of the examples of the present invention have weak cytotoxicity to B16F10 cells and can be further evaluated for in vitro activity.

[0317] (2) Analytical detection methods for the effects of compounds on tyrosinase activity

[0318] The effect of the example compounds on tyrosinase activity was investigated, and in vitro enzyme activity detection was performed. Tyrosinase was prepared into 250U / mL potassium phosphate buffer (pH=6.5, 50mM), 0.06mL potassium phosphate buffer (pH=6.5, 50mM), 0.04mL tyrosinase solution (250U / mL) and 2μL drug-containing DMSO solution were added to a 96-well plate, incubated at 30°C for 5 minutes, and then 0.1mL L-tyrosine (2mM) was added and incubated at 30°C for another 30 minutes. The absorbance value of each well was measured at 490nm microplate reader, and the activation rate (RA) was calculated according to the formula:

[0319] RA=[(CD)-(AB)] / (AB)×100%.

[0320] A is the absorbance of the system containing only tyrosinase at 490 nm;

[0321] B is the absorbance of the system without compound and tyrosinase at 490 nm;

[0322] C is the absorbance of the system containing the compound and tyrosinase at 490 nm;

[0323] D is the absorbance of the system containing only the compound at 490 nm.

[0324] The activation rate of the example compounds on tyrosinase was measured as follows: Figure 3 , Figure 4 As can be seen from the figure, it can be seen from the experimental results that compounds I-2, I-4, I-11, I-13, I-14, I-15, I-17, I-21, I-24, and I-30 in the examples of the present invention have a certain activation effect on tyrosinase, and further in vitro activity evaluation will be carried out.

[0325] (3) Analytical detection method for the effect of compounds on cellular melanin content

[0326] The effect of the example compounds on the melanin production of B16F10 cells was investigated, and the intracellular melanin content was detected. Mouse B16F10 melanoma cells were incubated on a 60mm diameter culture dish at 37°C and 5% CO2 for 24 hours, and the supernatant was removed. Only DMEM culture medium was added to the control group, and culture medium containing a certain drug concentration was added to the experimental group. 50μM 8-MOP was used as the positive control group, and each group was repeated twice. Two concentrations (0.25 and 1μM) were selected and cultured for 48 hours. After that, the cells were digested with 0.25% trypsin, washed twice with PBS, and 1ml of 1M NaOH was added to the precipitate. Incubated at 80°C for 1 hour, 4ml of distilled water was added, and NaOH was diluted to 0.2M. The absorbance at 400nm was measured under a spectrophotometer.

[0327] Melanin content = [(average value of absorbance of the screening group / number of cells) / (average value of absorbance of the control group / number of cells)] × 100%.

[0328] The results of the effects of the compounds in the examples on the melanin content of B16F10 cells are shown in Figure 5 , Figure 6 As can be seen from the figure, the compounds I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-20, I-21, I-23, I-24, I-25, I-26, I-27, I-29, and I-30 of the present invention have very good melanin-promoting effects on B16F10 cells. The example compound I-21 has the strongest melanin-promoting effect, and it was further evaluated for in vitro activity.

[0329] (4) Detection method of compound on tyrosinase and MITF protein expression

[0330] The effect of Example compound I-21 on the content of tyrosinase and MITF proteins was investigated and analyzed by Western blot.

[0331] (a) Cell culture: B16F10 cell suspension (DMEM medium) was cultured at 2×10 5 The cells were seeded at a density of / well in a six-well plate, the medium was changed after 24 hours, and drugs (compound I-21 concentration was 0.25uM or 1uM, and the positive control 8-MOP concentration was 50uM) were added. After 2 days of action, the cells were harvested for protein extraction.

[0332] (b) Protein extraction: Collect cells, wash the adherent cells in the culture dish with PBS, scrape off all the cells with a cell scraper, collect the cells from each well into a 1.5 ml EP tube, wash three times with 1 ml pre-cooled PBS, centrifuge at 2000 rpm for 5 min, carefully discard the supernatant, and keep the cell pellet for later use; add 200 ul RIPA lysis buffer (RIPA: PMSF = 100:1) to each tube and lyse on ice for 30 min, vortexing 3 times during the process; centrifuge at 4°C, 15000 rpm for 30 min, carefully aspirate the supernatant, which contains the total cell protein, and quantify the protein by BCA method.

[0333] (c) Protein denaturation: Take a solution containing 10 ug of protein in a 0.5 mL EP tube, add 5×SOD loading buffer to a final concentration of 1×SOD, dilute to 1 μg / μL with double distilled water, and heat in a 100°C water bath for 10 min to denature the protein.

[0334] (d) Sample loading: From left to right, protein marker, sample, protein marker, 20ul sample is loaded into each well, and electrophoresis buffer is added at the same time.

[0335] (e) Electrophoresis: EPS-300 electrophoresis instrument (Shanghai Tianneng Technology Co., Ltd.) was used, with the voltage of the concentrated gel at 80 V. After 30 min, it was switched to 120 V and run to the bottom of the separation gel.

[0336] (f) Transfer: Take out the electrophoresis gel and transfer the gel in the order of sponge, three-layer filter paper, gel, PVC membrane, three-layer filter paper, and sponge. During the transfer, ensure that there are no bubbles between the layers. Transfer conditions: 200mA, 90min, ice water bath.

[0337] (g) Incubation: The membrane was washed three times with TBST on a shaker at room temperature for 10 min each time, transferred to blocking solution (purchased from Sangon Biotechnology Co., Ltd.), and shaken for 2 h at room temperature; incubated with primary antibody (abcam, 170905, 303530) at 4°C overnight, washed three times with TBST on a shaker at room temperature for 10 min each time; incubated with secondary antibody (abcam, 6721) at room temperature for 2 h, washed three times with TBST at room temperature for 10 min each time, and performed chemiluminescence reaction.

[0338] (h) Color development and detection: Develop and fix the samples according to the ECL kit, and analyze the bands using a gel imaging system.

[0339] Effects of compound I-21 on tyrosinase and MITF protein expression Figure 7 Among them, the left picture shows the expression of tyrosinase and MITF proteins detected by Western blot, and the right picture shows the result after the data is standardized.

[0340] As can be seen from the figure, compared with the blank control group (Ctrl), the positive control 8-methoxypsoralen (8-MOP) has a promoting effect on the expression of tyrosinase and MITF proteins. Different concentrations of compound I-21 have a concentration-dependent effect on promoting the expression of tyrosinase protein. At the same time, the expression of MITF protein also increases with the increase of the concentration of compound I-21, and the promoting effect of compound I-21 on the expression of the two proteins is significantly better than the positive control. As can be seen from the results, the compound I-21 of the present invention has a promoting effect on protein expression, and it is further evaluated for in vivo activity.

[0341] (5) Determination of the anti-leukoplakia effect of compounds

[0342] Test samples: Example compound I-21 and positive drug Tacrolimus

[0343] Experimental method: After purchasing C57BL / 6 mice, they were kept in an SPF animal laboratory and the animals were adapted to the environment for 7 days. On the 4th day, the back hair of the 2cm×2cm area was removed with an electric shaver, and the small hairs were removed with a depilatory cream. The modeling was started after 24 hours, and the modeling cycle was 20 days. 25 C57BL / 6 mice were numbered and randomly divided into (Group I) blank control group, (Group II) hydroquinone model group, (Group III) tacrolimus (0.1%) ointment group, (Group IV) compound I-21 (0.1%) ointment low-dose group, (Group V) compound I-21 (0.3%) ointment high-dose group. (Group I) was coated with 0.5 ml / day of sterile distilled water; other groups applied 2.5% hydroquinone ointment on the test area at a dose of 100 mg / kg·d; starting from the 21st day, (Group II) hydroquinone model group, (Group III) tacrolimus (0.1%) ointment group, (Group IV) compound I-21 (0.1%) ointment low-dose group, (Group V) compound I-21 (0.3%) ointment high-dose group were administered for 21 days, and a thin layer of cream was applied to the mouse skin, gently rubbed evenly, and completely covered. The skin condition was photographed once a day, and the changes in the color of the mouse skin were closely observed during the experiment. The experimental results showed that no depigmentation was observed in the blank control group, while the back depigmentation of the mice in the hydroquinone model group was severe. In terms of the degree of depigmentation of vitiligo mice, the high-dose (0.3%) compound I-21 treatment effect was better than the positive drug tacrolimus (0.1%) treatment group, and the depigmentation of mice was improved to a certain extent.

[0344] Figure 8 The experimental results show that the compound I-21 has a significant effect of promoting melanin production and has the potential to treat vitiligo.

[0345] As described above, although the present invention has been shown and described with reference to specific preferred embodiments, it should not be construed as limiting the present invention itself. Various changes in form and details may be made without departing from the spirit and scope of the present invention as defined in the appended claims.

Claims

1. A benzenesulfonamide compound, characterized in that Selected from:

2. A pharmaceutical composition, characterized in that: It comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

3. The pharmaceutical composition according to claim 2, characterized in that: The pharmaceutically acceptable salts include acid addition salts formed between the compound of claim 1 and the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid; and also include acid salts formed between the compound of claim 1 and inorganic bases.

4. The pharmaceutical composition according to claim 2, characterized in that: The pharmaceutically acceptable salts include basic metal cation salts, alkaline earth metal cation salts and ammonium cation salts.

5. Use of the compound according to claim 1 in the preparation of a medicament for treating skin depigmentation or depigmentation-related diseases.

6. The use according to claim 5, characterized in that The drug is a melanin-promoting drug containing benzenesulfonamide compounds.

7. The use according to claim 5, characterized in that The skin depigmentation disorders include vitiligo, tuberous sclerosis, hypopigmentation of Ito, mottled disease, oculocutaneous albinism syndrome, phenylketonuria, idiopathic punctate hypopigmentation, Comfetti spots or Vagabond's albinism.

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