Amide derivative and application thereof

Abstract

The invention relates to the technical field of medicines, and particularly discloses an amide derivative and application thereof, and the amide derivative has a compound structure as shown in a formula (I) or a formula (II). The compound provided by the invention is an MC4R antagonist with a novel structure, has nanomole-level molecular level antagonistic activity, and can be used for preparing medicines for treating cachexia and anorexia.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, in particular to an amide derivative and application thereof. Background Art

[0002] Weight disorders include obesity, anorexia, and cachexia, which cause abnormal changes in weight and appetite. Anorexia patients experience a significant decrease in appetite due to psychological or physiological factors, eating far less than their body needs, leading to rapid weight loss. Cachexia often develops secondary to serious chronic illnesses, such as cancer and HIV. Patients experience not only a loss of appetite but also significant loss of muscle and fat tissue, resulting in significant weight loss. These conditions severely impact patients' quality of life and physical and mental health. Existing treatments for cachexia and anorexia primarily include nutritional support, medication, and psychotherapy, but these approaches have numerous limitations. For example, while nutritional support can improve nutritional status in some patients, it is difficult to fundamentally address the loss of appetite and metabolic disorders. Commonly used medications, such as motility regulators and appetite stimulants, have limited efficacy and are associated with side effects, such as nausea, vomiting, and arrhythmias. Psychological therapy, while helpful for some patients, is less effective for cachexia and anorexia caused by chronic illnesses. In addition, patients' compliance with existing treatments is poor, further affecting the treatment effect.

[0003] The melanocortin receptor family is a subfamily of the GPCR superfamily with therapeutic potential, and includes MC1R, MC2R, MC3R, MC4R, and MC5R. Melanocortin receptors (MC1R-MC5R) are located on multiple cell types and are distributed throughout different systems of the body. MC1R is expressed in skin melanocytes and plays an important role in determining skin and hair pigmentation; it is also expressed in leukocytes and may mediate anti-inflammatory properties. MC2R is primarily expressed in the adrenal cortex (ACTH), mediating the effects of ACTH on steroid secretion. MC3R is distributed in multiple regions of the central nervous system and peripheral tissues and is involved in the regulation of energy homeostasis. MC4R is primarily expressed in the central nervous system and plays a key regulatory role in food intake and energy metabolism. MC5R is present in peripheral tissues and is primarily involved in exocrine function.

[0004] The melanocortin 4 receptor (MC4R) is a key member of the melanocortin receptor family, primarily expressed in the hypothalamus, brainstem, and other parts of the central nervous system. It participates in regulating a variety of physiological functions, including appetite, energy metabolism, and weight balance. By blocking MC4R, MC4R antagonists can effectively increase appetite, promote weight gain, and regulate metabolic disorders. Because MC4R antagonists specifically block MC4R and directly act on key targets for appetite regulation, they can more accurately improve patients' symptoms of anorexia and increase food intake.

[0005] ML00253764 is a representative MC4R antagonist developed by Millennium Pharmaceuticals, Inc. for oncology applications. By selectively antagonizing MC4R, it significantly increases appetite, promotes weight gain, and improves metabolic disorders in cachexia patients. In preclinical studies, ML00243764 demonstrated significant appetite stimulation and weight gain effects. Currently, the drug is in the preclinical development stage.

[0006] According to incomplete statistics, the incidence of cachexia in patients with malignant tumors worldwide is as high as 60%-80%, and in patients with advanced cancer, this proportion is as high as 80%-90%. The high incidence of cachexia and anorexia and the limitations of existing treatments make the development of new and effective therapeutic drugs of great clinical need and market value. The development of MC4R antagonists is not only expected to improve patients' treatment outcomes and quality of life, but also to reduce the care burden on patients, their families, and society, which has significant social significance. In addition, with the increasing aging of the global population and the increase in chronic diseases, the incidence of cachexia and anorexia is likely to rise further, and the market potential for MC4R antagonists is huge; for this purpose, an amide derivative and its application are provided. Summary of the Invention

[0007] The purpose of the present invention is to provide an amide derivative and its application in view of the defects of the prior art, so as to solve the problems raised by the above background technology.

[0008] To achieve the above-mentioned object, the present invention provides the following technical solution: an amide derivative, a compound having a structure as shown in general formula (I) or (II), an enantiomer or a pharmaceutically acceptable salt thereof:

[0009]

[0010] When R1 is C, R2 is N, and R3 is N;

[0011] n is independently 1 or 2;

[0012] R4 is independently H or CH3;

[0013] R5 is a substituted aromatic ring.

[0014] As a preferred technical solution of the present invention, R5 is selected from p-fluorophenyl, 3,5-difluorophenyl, 2,4,5-trifluorophenyl, p-tolyl, 4-methoxyphenyl, 3-pyridyl, 2-naphthyl, 4-biphenyl, 2-phenylpropyl, 2-fluorophenylpropyl or 2-(4-methoxyphenyl)propyl.

[0015] As a preferred technical solution of the present invention, exemplary compounds of the compound represented by general formula (I) or general formula (II) are shown below:

[0016]

[0017]

[0018]

[0019]

[0020]

[0021]

[0022] As a preferred technical solution of the present invention, the pharmaceutically acceptable salt of the compound is a salt formed by the compound and an acid: oxalate, hydrochloride, bromate, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, gluconate, saccharate, benzoate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate.

[0023] A pharmaceutical composition comprising the above-mentioned amide derivative as an active ingredient, wherein the amide derivative is a compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0024] Use of the above-mentioned amide derivative or the above-mentioned pharmaceutical composition in preparing a drug for treating cachexia and anorexia.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows: the compound provided by the present invention is a novel MC4R antagonist with nanomolar molecular-level antagonistic activity, has a better effective dose than ML00253764, has good potential and application prospects, and can be used to prepare drugs for the treatment of cachexia and anorexia. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 1-[2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-(4-fluorophenyl)ethanone 1 H-NMR spectrum;

[0027] Figure 21-[2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-(4-fluorophenyl)ethanone 13 C-NMR spectrum;

[0028] Figure 3 This is the HR-MS spectrum of 1-[2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-(4-fluorophenyl)ethanone. DETAILED DESCRIPTION

[0029] The preferred embodiments of the present invention are described in detail below so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more precise definition of the protection scope of the present invention.

[0030] The structures of the compounds of the examples were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS); NMR shifts (δ) are given in ppm; NMR measurements were performed using a Bruker AVANCE III HD 500 NMR spectrometer, the solvent was deuterated chloroform (CDCl3), and the internal standard was tetramethylsilane (TMS).

[0031] MS was determined using an Agilent 1260HPLC-6520Accurate-Mass Q-Tof mass spectrometer under the following test conditions: electrospray ionization (ESI) source, positive ion mode.

[0032] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.2mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm.

[0033] Silica gel column chromatography generally uses Yantai Huanghai 300-400 mesh silica gel as the carrier;

[0034] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C-30°C;

[0035] The progress of the reactions in the examples was monitored by thin layer chromatography (TLC).

[0036] Example 1: Preparation of 1-[2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-(4-fluorophenyl)ethanone (1);

[0037]

[0038] Step 1: 7 g (51.8 mmol, 1.04 eq) of 3-fluoro-2-methylbenzonitrile and 10 g (55.8 mmol, 1.1 eq) of hexamethylphosphoric triamide (HMPA) were added to a 100 mL three-necked flask. The atmosphere was purged with nitrogen three times, followed by the addition of anhydrous tetrahydrofuran and the reaction mixture. The temperature was cooled to -78°C. After 5 minutes, 30 mL (280.0 mmol, 1.2 eq) of lithium diisopropylamide (LDA, 2 mol / L) was added dropwise. A dark red solution was formed and stirring was continued for 15 minutes. 14 g (50.0 mmol, 1.1 eq) of 4-bromo-2-bromomethyl-1-methoxybenzene was added to another two-necked flask. The atmosphere was purged with nitrogen three times, followed by the addition of 20 mL of tetrahydrofuran. This was added dropwise to the reaction mixture, resulting in a dark green color. After the addition was complete, the mixture was stirred for 1.5 hours while incubating. The reaction was monitored for completion by TLC. The solution, which turned dark green, was then heated and quenched by the addition of 150 mL of saturated aqueous NH4Cl. The mixture was diluted with ethyl acetate and water, and the organic and aqueous phases were separated. The organic phase was further washed with brine, dried over anhydrous sodium sulfate, filtered, and then spin-dried. The residue was purified by column chromatography (PE:EA = 30:1) to obtain 10.3 g of intermediate 1-1 as a white powder, with a yield of 73.6%. 1 H NMR(600MHz,Chloroform-d)δ7.39(dd,J=7.3,1.6Hz,1H),7.28(m,2H),7.24(dd,J=8.4,1.5Hz,1 H),7.11(d,J=2.5Hz,1H),3.81(s,3H),3.14(m,2H),2.90(dd,J=8.9,6.7Hz,2H).(+)-HR-ESI-MS m / z 334.0(calcd.334.0for C 16 H 14 BrFNO + [M+H] + );

[0039] Step 2: Add intermediate 1-11g (3.0mmol, 1.0eq) and 10mL of ethylenediamine to a 15mL sealed tube. Seal the vial with parafilm and equip it with a hydrogen sulfide vent. Slowly add dilute sulfuric acid dropwise to the sodium hydrosulfide and pass it through the sealed tube for approximately 5 minutes. The mixture is then heated to 100°C in a sealed tube for 18 hours. After cooling to room temperature, the reaction is monitored for completion by TLC. The residue is dissolved in water and extracted 2-3 times with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue is purified by column chromatography (DCM:MeOH = 10:1-2:1). 0.7g of ML00253764 is obtained as a white powder in a 70.0% yield. 1H NMR(600MHz,Chloroform-d)δ7.28–7.26(m,1H),7.21–7.18(m,2H),7.14(d,J=2.5Hz,1H),7.11(m,1 H),6.69(d,J=8.6Hz,1H),3.71(s,3H),3.70–3.67(m,4H),3.15–3.11(m,2H),2.85(t,J=7.6Hz,2H). 13 C NMR (151MHz, CDCl3) δ164.50,164.48,162.44,160.81,156.60,132.90,132.32,129.84,128.08,127.97,127.43, 127.37,124.13,124.11,116.72,116.57,112.47,111.90,55.51,49.91,30.37,26.38,26.36.(+)-HR-ESI-MSm / z 377.1(calcd.377.1for C 18 H 19 BrFN2O + [M+H] + );

[0040] Step 3: 0.38 g (1.0 mmol, 1.0 eq) ML00253764, 0.17 g (1.1 mmol, 1.1 eq) p-fluorophenylacetic acid, 0.23 g (1.2 mmol, 1.2 eq) EDCI, 0.02 g (0.16 mmol, 0.16 eq) DMAP, and 20 mL DCM were added to a 25 mL vial and stirred at room temperature for 2 h. The reaction was monitored for completion by TLC. Water was added and stirred to separate the layers. The aqueous layer was extracted 2-3 times with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and then spin-dried. The organic phase was purified by column chromatography (PE:EA = 1:1) to afford 0.17 g of compound 1 as a light yellow oil in a 44.7% yield. 1 H NMR(600MHz,Chloroform-d)δ7.28(dd,J=8.7,2.5Hz,2H),7.25(d,J=6.2Hz,1H),7.19(d,J=2.5Hz,1H),7.15(t,J=9.1Hz,1H),7. 08(d,J=7.6Hz,1H),6.71(d,J=8.7Hz,1H),6.66(m,1H),6.52(s,2H),4.07(m,9.6Hz,4H),3.76(s,3H),3.30(s,2H),2.83(s,4H). 13CNMR(151MHz,CDCl3)δ166.73,163.68,163.60,162.28,162.03,161.95, 160.64,156.63,136.97,133.89,132.45,132.09,130.07,127.97,124.2 8,117.08,112.62,112.30,112.27,112.17,112.14,102.86,102.70,102 .53,55.57,53.44,53.27,47.46,30.26,27.29,27.28.(+)-HR-ESI-MSm / z 513.0991(calcd.513.0989forC 26 H 24 BrF2N2O2 + [M+H] + ).

[0041] Example 2: Preparation of 1-(2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl)-2-(3,5-difluorophenyl)ethanone (2);

[0042]

[0043] Compound 2 was prepared according to Step 3 of Example 1 using 0.2 g (1.2 mmol, 1.2 eq) of 3,5-difluorophenylacetic acid instead of p-fluorophenylacetic acid to obtain 0.16 g of compound 2 as a light yellow oil in a yield of 42.1%. 1 H NMR (600MHz, Chloroform-d) δ7.28(dd,J=8.7,2.5Hz,1H),7.24(dd,J=8.1,5.4Hz,1H),7.19(d,J=2.6Hz,1H),7.13(t,J=9.0Hz,1H),7.08(d,J= 7.6Hz,1H),6.99–6.94(m,1H),6.92(t,J=8.6Hz,2H),6.70(d,J=8.7Hz, 1H), 4.13–3.99 (m, 4H), 3.75 (s, 3H), 3.33 (s, 2H), 2.81 (d, J = 7.0Hz, 4H). 13C NMR (151MHz, CDCl3) δ167.84,162.74,162.21,161.11,160.57,156.63,134.19,132.48,132.25,130.69,130.64,130.02,129.12,127.84,12 4.24,116.81,115.44,115.30,112.60,112.13,55.58,53.34,47.39,30.27,27.35,27.33.(+)-HR-ESI-MSm / z513.0898(calcd.513.0895for C 26 H 23 BrF3N2O2 + [M+H] + ).

[0044] Example 3: Preparation of 1-(2-{2-[(5-bromo-2-methoxyphenyl)ethyl]-3-fluorophenyl}-4,5-dihydro-1H-imidazol-1-yl)-2-(2,4,5-trifluorophenyl)ethanone (3);

[0045]

[0046] Compound 3 was prepared according to Step 3 of Example 1 using 0.21 g (1.1 mmol, 1.1 eq) of 2,4,5-trifluorophenylacetic acid instead of p-fluorophenylacetic acid to obtain 0.18 g of compound 3 as a light yellow oil in a yield of 47.4%. 1 H NMR(604MHz,Chloroform-d)δ7.50–7.44(m,2H),7.37(t,J=7.5Hz,1H),7.35(m,1H),7.26(dd,J=7.5,2.0Hz,1H),7.01(dd,J=7.3,2.0Hz,1H),6.98(s,1H ),6.88(d,J=7.4Hz,1H),4.05–4.00(m,3H),3.93(s,1H),3.84(d,J=16.2Hz, 5H), 3.02–2.96 (m, 2H), 2.84 (d, J=12.4Hz, 1H), 2.79 (dd, J=12.4, 1.1Hz, 1H). 13C NMR (151MHz, Common NMR Solvents)δ170.57,160.38,159.65,159.17,158.23,149.28,149.12,134.06,133.47,129.72,129.09,128.74,128.31, 127.04,124.89,119.56,117.95,115.43,115.23,111.80,58.48,56.14,50.52,37.22,32.50,30.68.(+)-HR-ESI-MSm / z 549.0791(calcd.549.0795for C 26 H 22 BrF4N2O2 + [M+H] + ).

[0047] Example 4: Preparation of 1-[2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-(p-tolyl)ethanone (4);

[0048]

[0049] Compound 4 was prepared according to Step 3 of Example 1 using 0.17 g (1.1 mmol, 1.1 eq) of p-tolueneacetic acid instead of p-fluorophenylacetic acid to obtain 0.13 g of compound 4 as a light yellow oil in a yield of 34.2%. 1 H NMR(604MHz,Chloroform-d)δ7.47(dd,J=7.5,2.0Hz,1H),7.37(t,J=7.5Hz,1H),7.35(m,1H ),7.26(dd,J=7.5,2.0Hz,1H),7.22(m,2H),7.10(m,2H),7.01(dd,J=7.3,2.0Hz,1H),6.88(d ,J=7.4Hz,1H),4.00(s,1H),3.93(s,1H),3.85(s,2H),3.83(s,3H),3.80(t,J=1.0Hz,2H),3. 02–2.96(m,2H),2.84(d,J=12.4Hz,1H),2.79(dd,J=12.4,1.1Hz,1H),2.34(d,J=2.0Hz,1H). 13CNMR(151MHz,Common NMR Solvents)δ171.41,160.38,159.17,159.01,139.98,138.45,134.06,133.47,131.57,131.16,129.72,129.09,128 .74,128.31,127.04,117.95,115.43,115.23,58.48,56.14,50.52,40.56,32.50,30.68,22.18.(+)-HR-ESI-MSm / z 509.1231(calcd.509.1234for C 27 H 27 BrFN2O2 + [M+H] + ).

[0050] Example 5: Preparation of 1-[2-(2-{5-bromo-2-methoxyphenethyl}-3-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-(4-methoxyphenyl)ethanone (5);

[0051]

[0052] Compound 5 was prepared according to Step 3 of Example 1 using 0.18 g (1.1 mmol, 1.1 eq) of 4-methoxyphenylacetic acid instead of p-fluorophenylacetic acid to obtain 0.15 g of compound 5 as a light yellow oil in a yield of 39.5%. 1 H NMR(600MHz,Chloroform-d)δ7.28(dd,J=8.6,2.5Hz,1H),7.23(m,1H),7.18(d,J=2.5Hz,1H),7.14–7.09(m,1H),7.07(d,J=7.7Hz,1H),6.9 6–6.89(m,2H),6.79–6.75(m,2H),6.70(d,J=8.7Hz,1H),4.11–3.99(m,4H),3.75(s,3H),3.74(s,3H),3.33(s,2H),2.78(d,J=33.1Hz,4H). 13C NMR (151MHz, CDCl3) δ168.36,162.18,160.54,158.66,156.65,134.33,132.47,132.37,130.47,130.07,130.02,129.94,127.76,125.38,124.2 1,116.77,114.10,113.99,112.57,112.10,55.57,55.26,53.44,47.33,30.25,27.31,27.29.(+)-HR-ESI-MSm / z525.1191(calcd.525.1189for C 27 H 27 BrFN2O3 + [M+H] + ).

[0053] Example 6: Preparation of 1-[2-(2-{5-bromo-2-methoxyphenethyl}-3-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-(pyridin-3-yl)ethanone (6);

[0054]

[0055] Compound 6 was prepared according to Step 3 of Example 1 using 0.15 g (1.1 mmol, 1.1 eq) of 3-pyridineacetic acid instead of p-fluorophenylacetic acid to obtain 0.12 g of compound 6 as a light yellow oil in a yield of 31.5%. 1 H NMR(600MHz,Chloroform-d)δ8.45(dd,J=4.9,1.6Hz,1H),8.17(s,1H),7.45–7.38(m,1H),7.28(dd,J=8.7,2.5Hz,1H),7.27–7.23(m,1H),7.20(d, J=2.5Hz,1H),7.19–7.12(m,2H),7.12–7.07(m,1H),6.71(d,J=8.7Hz,1H) ,4.16–4.01(m,4H),3.76(s,3H),3.32(s,2H),2.84(p,J=7.1,6.6Hz,4H). 13C NMR (151MHz, CDCl3) δ167.04,162.27,160.63,156.62,150.12,148.46,136.90,133.98,132.48,132.10,130.06,129.34 ,128.03,124.27,123.32,117.11,112.61,112.15,55.60,53.45,47.44,40.97,30.27,27.36,27.35.(+)-HR-ESI-MSm / z 496.1025(calcd.496.1036for C 25 H 24 BrFN3O2 + [M+H] + ).

[0056] Example 7: Preparation of 1-(2-(2-(5-bromo-2-methoxyphenethyl)-4-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl)-2-(naphthalen-2-yl)ethanone-1(7);

[0057]

[0058] Compound 7 was prepared according to Step 3 of Example 1 using 0.2 g (1.1 mmol, 1.1 eq) of 2-naphthylacetic acid instead of p-fluorophenylacetic acid to obtain 0.16 g of compound 7 as a light yellow oil in a yield of 42.1%. 1 H NMR(604MHz,Chloroform-d)δ7.93(d,J=0.8Hz,1H),7.88(d,J=14.1Hz,2H),7.67(s ,1H),7.51(s,1H),7.45–7.41(m,1H),7.40(s,1H),7.35(m,1H),7.26(dd,J=7.5,2.0 Hz,1H),7.05–7.00(m,2H),6.88(d,J=7.4Hz,1H),4.00(s,1H),3.93(s,1H),3.87–3 .81(m,7H),2.96(m,2H),2.87(dd,J=12.4,1.1Hz,1H),2.83(dd,J=12.4,0.9Hz,1H). 13C NMR (151MHz, Common NMR Solvents)δ170.38,165.01,160.08,158.89,138.77,137.73,137.10,136.70,134.06,133.47,131.54,131.32,130.24,130.22,130.06, 129.98,128.97,127.73,126.81,126.70,117.95,115.49,115.23,113.25,58.48,56.14,50.52,40.23,37.49,32.53.(+)-HR-ESI-MSm / z 545.1230 (calcd.545.1234 for C 30 H 27 BrFN2O2 + [M+H] + ).

[0059] Example 8: Preparation of 1-[2-(2-(5-bromo-2-methoxyphenethyl)-4-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-biphenyl-4-ylethanone (8);

[0060]

[0061] Compound 8 was prepared according to Step 3 of Example 1 using 0.23 g (1.1 mmol, 1.1 eq) of 4-biphenylacetic acid instead of p-fluorophenylacetic acid to obtain 0.19 g of compound 8 as a light yellow oil in a yield of 50.0%. 1 H NMR(600MHz,Chloroform-d)δ7.52(d,J=7.7Hz,2H),7.46(d,J=7.7Hz,2H),7.41(t,J=7.6Hz,2H),7.32(t,J=7.4Hz,1H),7.28–7.25(m,1H ),7.23(s,1H),7.19(d,J=2.6Hz,1H),7.10(m,4H),6.67(d,J=8.7Hz,1H),4.19–3.97(m,4H),3.72(s,3H),3.49–3.32(m,2H),2.82(s,4H). 13C NMR (151MHz, CDCl3) δ167.97,162.20,160.56,156.63,140.63,140.08,134.22,132.47,132.33,129.96,129.46,128.80,128.74,127.78 ,127.29,127.27,127.19,127.02,124.24,116.70,112.58,112.11,55.54,53.35,47.38,42.34,30.27,27.33,27.32.(+)-HR-ESI-MSm / z 571.1393(calcd.571.1396for C 32 H 29 BrFN2O2 + [M+H] + ).

[0062] Example 9: Preparation of 1-{2-[2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl]-4,5-dihydro-1H-imidazol-1-yl}-2-phenylpropan-1-one (9);

[0063]

[0064] Compound 9 was prepared according to Step 3 of Example 1 using 0.17 g (1.1 mmol, 1.1 eq) of 2-phenylpropionic acid instead of p-fluorophenylacetic acid to obtain 0.13 g of compound 9 as a light yellow oil in a yield of 34.2%. 1 H NMR(604MHz,Chloroform-d)δ7.47(dd,J=7.5,2.0Hz,1H),7.40–7.19(m,8H),7.01(dd,J=7.3,2.0Hz,1H),6.88(d,J=7.4Hz,1H),4.01(s,1H),3.89(d ,J=2.2Hz,2H),3.87(s,1H),3.83(s,3H),3.02–2.96(m,2H),2.84(d,J=12. 4Hz, 1H), 2.79 (dd, J=12.4, 1.1Hz, 1H), 2.66 (t, J=0.9Hz, 1H), 1.33 (s, 3H). 13C NMR (151MHz, Common NMR Solvents)δ172.62,160.38,159.17,156.50,143.50,134.06,133.47,131.97,131.37,130.81,129.09,128.74,128 .58,128.31,127.04,117.95,115.43,115.23,58.52,56.14,51.33,46.05,32.50,30.68,17.62.(+)-HR-ESI-MSm / z 509.1031(calcd.509.1234for C 27 H 27 BrFN2O2 + [M+H] + ).

[0065] Example 10: Preparation of 1-[2-(2-{5-bromo-2-methoxyphenethyl}-3-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-(4-fluorophenyl)propan-1-one (10);

[0066]

[0067] Compound 10 was prepared according to Step 3 of Example 1 using 0.18 g (1.1 mmol, 1.1 eq) of 2-fluorophenylpropionic acid instead of p-fluorophenylacetic acid to obtain 0.15 g of compound 10 as a light yellow oil in a yield of 39.5%. 1 H NMR(600MHz,Chloroform-d)δ7.27(d,J=2.5Hz,1H),7.25–7.20(m,1H),7.15–7.09(m,2H),7.06–6.96(m,3H),6.91(t,J=8.5 Hz,2H),6.68(d,J=8.6Hz,1H),4.10–3.77(m,4H),3.72–3.66(m,3H),3.60(s,1H),2.80–2.46(m,4H),1.29(d,J=6.9Hz,3H). 13C NMR (151MHz, CDCl3) δ175.18,170.78,162.73,162.00,161.10,160.37,156.60,135.8 0,135.77,134.69,132.74,132.47,132.38,129.89,129.08,129.02,128.96,127.56,1 27.50,123.92,116.52,116.37,115.81,115.72,115.67,115.58,112.54,112.10,55. 55,55.50,53.71,46.96,40.29,40.20,30.24,27.29,27.27,20.46.(+)-HR-ESI-MSm / z 527.1143(calcd.527.1146forC 27 H 26 BrF2N2O2 + [M+H] + ).

[0068] Example 11: Preparation of 1-[2-(3-fluoro-2-{2-[5-bromo-2-methoxyphenyl]ethyl}phenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-(4-methoxyphenyl)propan-1-one (11);

[0069]

[0070] Compound 11 was prepared according to Step 3 of Example 1 using 0.2 g (1.1 mmol, 1.1 eq) of 2-(4-methoxyphenyl)propionic acid instead of p-fluorophenylacetic acid to obtain 0.16 g of compound 11 as a light yellow oil in a yield of 42.1%. 1 H NMR(600MHz,Chloroform-d)δ7.25–7.19(m,2H),7.14–7.08(m,2H),6.99(d,J=7.7Hz,3H),6.76(d,J=8.1Hz,2H),6.67(d,J=8 .7Hz,1H),4.08–3.80(m,4H),3.75(s,3H),3.68(d,J=6.3Hz,3H),3.61–3.53(m,1H),2.81–2.54(m,4H),1.28(d,J=6.9Hz,3H). 13C NMR (151MHz, CDCl3) δ175.92,171.12,161.97,160.34,158.74,157.89,156 .62,134.89,132.60,132.37,132.06,129.78,128.56,128.47,127.42,127. 36,123.86,116.34,116.19,114.27,112.49,112.03,77.27,77.06,76.84, 63.15,55.48,55.26,30.21,27.21,27.19,20.36,13.93.(+)-HR-ESI-MSm / z 539.1349(calcd.539.1346for C 28 H 29 BrFN2O3 + [M+H] + ).

[0071] Example 12: Preparation of 1-[2-(2-{5-bromo-2-methoxyphenethyl}-3-fluorophenyl)-5,6-dihydropyrimidin-1(4H)-yl]-2-(4-fluorophenyl)ethanone (12);

[0072]

[0073] Step 1: Add Intermediate 1-11g (3.0mmol, 1.0eq) and 10mL of 1,3-propylenediamine to a 15mL sealed tube. Seal the vial with parafilm and equip it with a hydrogen sulfide vent. Slowly add dilute sulfuric acid dropwise to the sodium hydrosulfide and pass it through the sealed tube for approximately 5 minutes. The mixture is then heated to 100°C in a sealed tube for 18 hours. After cooling to room temperature, the reaction is monitored for completion by TLC. The residue is dissolved in water and extracted 2-3 times with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, filtered, and spin-dried to dryness. The residue is purified by column chromatography (DCM:MeOH = 10:1-2:1). 0.67g of Intermediate 12-1 is obtained as a white powder in a 67.0% yield.

[0074] 1H NMR(600MHz,Chloroform-d)δ7.28–7.26(m,1H),7.18(m,1H),7.14–7.07(m,2H),7.04–7.00(m,1H),6.70(d,J=8.7Hz,1H),3.68(s,3H), 3.25(t,J=5.8Hz,4H),2.95–2.91(m,2H),2.84(dd,J=8.8,6.5Hz,2H),1.80(q,J=5.8Hz,2H).(+)-HR-ESI-MSm / z391.1(calcd.391.1for C 19 H 21 BrFN2O + [M+H] + )

[0075] Step 2: 0.39 g (1.2 mmol, 1.0 eq) of intermediate 12-1, 0.17 g (1.1 mmol, 1.1 eq) of p-fluorophenylacetic acid, 0.23 g (1.2 mmol, 1.2 eq) of EDCI, 0.02 g (0.16 mmol, 0.16 eq) of DMAP, and 20 mL of DCM were added to a 25 mL vial. After stirring at room temperature for 2 h, the reaction was monitored for completion by TLC. Water was added, stirred, and the layers separated. Extraction was performed. A small amount of 1 mol / L dilute hydrochloric acid (pH neutral) was added dropwise to the aqueous phase. The aqueous layer was extracted 2-3 times with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 0.16 g of compound 12 as a light yellow oil in a yield of 41.0%. 1 H NMR(604MHz,Chloroform-d)δ7.47(dd,J=7.5,2.0Hz,1H),7.37(t,J=7.5Hz,1H),7.35(m,1H) ,7.30(m,2H),7.26(dd,J=7.5,2.0Hz,1H),7.07–7.02(m,2H),7.01(dd,J=7.3,2.0Hz,1H),6.8 8(d,J=7.4Hz,1H),3.83(d,J=2.0Hz,4H),3.79(t,J=1.0Hz,2H),3.74(d,J=10.4Hz,2H),3.59 (s,1H),3.02–2.96(m,2H),2.84(d,J=12.4Hz,1H),2.79(dd,J=12.4,1.1Hz,1H),1.97(s,1H). 13C NMR (151MHz, Common NMR Solvents)δ170.07,163.94,160.90,160.38,159.17,134.06,133.47,133.05,132.85,129.09,129.01,128.74,128.31,127.05,11 7.95,117.00,115.43,115.23,56.14,50.74,46.41,40.48,32.50,30.68,26.94.(+)-HR-ESI-MSm / z527.1143(calcd.527.1140for C 27 H 26 BrF2N2O2 + [M+H] + ).

[0076] Example 13: Preparation of 1-[2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-5,6-dihydropyrimidin-1(4H)-yl]-2-(3,5-difluorophenyl)ethanone (13);

[0077]

[0078] Compound 13 was prepared according to Step 2 of Example 12 using 0.2 g (1.2 mmol, 1.2 eq) of 3,5-difluorophenylacetic acid instead of p-fluorophenylacetic acid to obtain 0.15 g of compound 13 as a light yellow oil in a yield of 38.5%. 1 H NMR(604MHz,Chloroform-d)δ7.47(dd,J=7.5,2.0Hz,1H),7.37(t,J=7.5Hz,1H),7.35( m,1H),7.31(m,2H),7.26(dd,J=7.5,2.0Hz,1H),7.01(dd,J=7.3,2.0Hz,1H),6.92(t,J= 2.0Hz,1H),6.88(d,J=7.4Hz,1H),3.85–3.81(m,6H),3.74(d,J=10.4Hz,2H),3.59(s,1H ),3.02–2.96(m,2H),2.84(d,J=12.4Hz,1H),2.79(dd,J=12.4,1.1Hz,1H),1.97(s,1H). 13C NMR (151MHz, Common NMR Solvents)δ169.85,163.92,160.90,160.38,159.17,138.18,134.06,133.47,129.09,129.01,128.74,128.31,127 .05,117.95,115.43,115.23,114.38,108.39,56.14,50.74,46.41,40.16,32.50,30.68,26.94.(+)-HR-ESI-MSm / z 545.1401(calcd.545.1406for C 27 H 25 BrF3N2O2 + [M+H] + ).

[0079] Example 14: Preparation of 1-[2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl]-5,6-dihydro-1(4H)-pyrimidinyl-2-(2,4,5-trifluorophenyl)ethanone (14);

[0080]

[0081] Compound 14 was prepared according to Step 2 of Example 12 using 0.21 g (1.1 mmol, 1.1 eq) of 2,4,5-trifluorophenylacetic acid instead of p-fluorophenylacetic acid to obtain 0.16 g of compound 14 as a light yellow oil in a yield of 41.0%. 1 H NMR(604MHz,Chloroform-d)δ7.50–7.44(m,2H),7.37(t,J=7.5Hz,1H),7.35(m,1H),7 .26(dd,J=7.5,2.0Hz,1H),7.01(dd,J=7.3,2.0Hz,1H),6.98(s,1H),6.88(d,J=7.4Hz ,1H),4.02(d,J=0.9Hz,2H),3.83(d,J=2.0Hz,4H),3.74(d,J=9.1Hz,2H),3.59(s,1H) ,3.02–2.96(m,2H),2.84(d,J=12.4Hz,1H),2.79(dd,J=12.4,1.1Hz,1H),1.97(s,1H). 13C NMR (151MHz, Common NMR Solvents)δ170.57,160.90,160.38,159.17,158.23,149.28,149.12,134.06,133.47,129.09,129.01,128.74,128.31,127 .05,124.72,119.56,117.95,115.43,115.23,111.80,56.14,50.74,46.14,37.23,32.50,30.68,26.99.(+)-HR-ESI-MSm / z 563.0948(calcd.563.0952for C 27 H 24 BrF4N2O2 + [M+H] + ).

[0082] Example 15: Preparation of 1-[2-(2-(2-methoxy-5-bromophenethyl)-3-fluorophenyl)-5,6-dihydropyrimidin-1(4H)-yl]-2-(p-tolyl)ethanone (15);

[0083]

[0084] Compound 15 was prepared according to Step 2 of Example 12 using 0.17 g (1.1 mmol, 1.1 eq) of p-tolueneacetic acid instead of p-fluorophenylacetic acid to obtain 0.12 g of compound 15 as a light yellow oil in a yield of 30.1%. 1 H NMR(604MHz,Chloroform-d)δ7.47(dd,J=7.5,2.0Hz,1H),7.37(t,J=7.5Hz,1H),7.35(m,1H),7.2 6(dd,J=7.5,2.0Hz,1H),7.22(m,2H),7.10(m,2H),7.01(dd,J=7.3,2.0Hz,1H),6.88(d,J=7.4Hz, 1H),3.83(d,J=2.0Hz,4H),3.80(t,J=1.0Hz,2H),3.74(d,J=10.4Hz,2H),3.59(s,1H),3.02–2.96 (m,2H),2.84(d,J=12.4Hz,1H),2.79(dd,J=12.4,1.1Hz,1H),2.34(t,J=1.0Hz,3H),1.97(s,1H). 13C NMR (151MHz, Common NMR Solvents)δ170.94,160.90,160.38,159.17,139.98,138.43,134.06,133.47,131.57,131.16,129.09,129.01,128.74 ,128.31,127.05,117.95,115.43,115.23,56.14,50.74,46.41,40.56,32.50,30.68,26.94,22.18.(+)-HR-ESI-MSm / z 523.1396(calcd.523.1391for C 28 H 29 BrFN2O2 + [M+H] + ).

[0085] Example 16: Preparation of 1-[2-(3-fluoro-2-(5-bromo-2-methoxyphenethyl)phenyl)-5,6-dihydropyrimidin-1(4H)-yl]-2-(4-methoxyphenyl)ethanone (16);

[0086]

[0087] Compound 16 was prepared according to Step 2 of Example 12 using 0.18 g (1.1 mmol, 1.1 eq) of 4-methoxyphenylacetic acid instead of p-fluorophenylacetic acid to obtain 0.14 g of compound 16 as a light yellow oil in a yield of 35.9%. 1 H NMR(604MHz,Chloroform-d)δ7.47(dd,J=7.5,2.0Hz,1H),7.37(t,J=7.5Hz,1H),7.35(m,1H ),7.26(dd,J=7.5,2.0Hz,1H),7.18(m,2H),7.01(dd,J=7.3,2.0Hz,1H),6.88(d,J=7.4Hz,1H ),6.86–6.81(m,2H),3.83(d,J=2.0Hz,4H),3.81–3.77(m,5H),3.74(d,J=10.4Hz,2H),3.59( s,1H),3.02–2.96(m,2H),2.84(d,J=12.4Hz,1H),2.79(dd,J=12.4,1.1Hz,1H),1.97(s,1H). 13C NMR (151MHz, Common NMR Solvents)δ170.07,160.90,160.78,160.38,159.17,134.06,133.47,131.89,129.84,129.09,129.01,128.74,128.31 ,127.05,117.95,116.33,115.43,115.23,56.14,55.76,50.74,46.41,40.41,32.50,30.68,26.94.(+)-HR-ESI-MSm / z 539.1347(calcd.539.1340for C 28 H 29 BrFN2O3 + [M+H] + ).

[0088] Example 17: Preparation of 1-[2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-5,6-dihydropyrimidin-1(4H)-yl]-2-(pyridin-3-yl)ethanone (17);

[0089]

[0090] Compound 17 was prepared according to Step 2 of Example 12 using 0.15 g (1.1 mmol, 1.1 eq) of 3-pyridineacetic acid instead of p-fluorophenylacetic acid to obtain 0.10 g of compound 17 as a light yellow oil in a yield of 25.6%. 1 H NMR(604MHz,Chloroform-d)δ8.55(d,J=1.3Hz,1H),8.46(dd,J=5.1,1.3Hz,1H),7.52(m,1H ),7.47(dd,J=7.5,2.0Hz,1H),7.40–7.33(m,2H),7.31–7.24(m,2H),7.01(dd,J=7.3,2.0Hz, 1H),6.88(d,J=7.4Hz,1H),3.89(s,2H),3.83(d,J=2.0Hz,4H),3.74(d,J=10.4Hz,2H),3.59( s,1H),3.02–2.96(m,2H),2.84(d,J=12.4Hz,1H),2.79(dd,J=12.4,1.1Hz,1H),1.97(s,1H). 13C NMR (151MHz, Common NMR Solvents)δ170.91,160.90,160.38,159.17,150.02,149.36,134.06,133.47,132.33,131.42,129.09,129.01,128.74 ,128.31,127.05,125.42,117.95,115.43,115.23,56.14,50.74,46.14,40.49,32.50,30.68,26.94.(+)-HR-ESI-MSm / z 510.1180(calcd.510.1187for C 26 H 26 BrFN3O2 + [M+H] + ).

[0091] Example 18: Preparation of 1-(2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-5,6-dihydropyrimidin-1(4H)-yl)-2-(naphthalen-2-yl)ethanone (18);

[0092]

[0093] Compound 18 was prepared according to Step 2 of Example 12 using 0.2 g (1.1 mmol, 1.1 eq) of 2-naphthylacetic acid instead of p-fluorophenylacetic acid to obtain 0.16 g of compound 18 as a light yellow oil in a yield of 41.0%. 1 H NMR(604MHz,Chloroform-d)δ7.93(d,J=0.8Hz,1H),7.88(d,J=14.1Hz,2H),7.67(s,1H),7.51(s,1H ),7.47(dd,J=7.5,2.0Hz,1H),7.40(s,1H),7.37(t,J=7.5Hz,1H),7.35(m,1H),7.26(dd,J=7.5,2.0 Hz,1H),7.01(dd,J=7.3,2.0Hz,1H),6.88(d,J=7.4Hz,1H),3.86–3.81(m,6H),3.74(d,J=10.4Hz,2H ),3.59(s,1H),3.02–2.96(m,2H),2.84(d,J=12.4Hz,1H),2.79(dd,J=12.4,1.1Hz,1H),1.97(s,1H). 13C NMR (151MHz, Common NMR Solvents)δ170.11,160.90,160.38,159.17,138.73,137.73,136.70,134.06,133.47,131.32,130.24,130.22,130.06,129.98,129.09,1 29.01,128.74,128.31,127.73,127.05,126.70,117.95,115.43,115.23,56.14,50.74,46.41,40.31,32.50,30.68,26.94.(+)-HR-ESI-MS m / z 559.1395 (calcd.559.1391 for C 31 H 29 BrFN2O2 + [M+H] + ).

[0094] Example 19: Preparation of 2-([1,1'-biphenyl]-4-yl)-1-(2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-5,6-dihydropyrimido[1,4]pyridin-1(4H)-yl)ethan-1-one (19);

[0095]

[0096] Compound 19 was prepared according to Step 2 of Example 12 using 0.23 g (1.1 mmol, 1.1 eq) of 4-biphenylacetic acid instead of p-fluorophenylacetic acid to obtain 0.17 g of compound 19 as a light yellow oil in a yield of 43.4%. 1 H NMR(604MHz,Chloroform-d)δ7.62–7.55(m,4H),7.47(dd,J=7.5,2.0Hz,1H),7.46–7.40(m ,2H),7.40–7.31(m,5H),7.26(dd,J=7.5,2.0Hz,1H),7.01(dd,J=7.3,2.0Hz,1H),6.88(d, J=7.4Hz,1H),3.83(d,J=2.0Hz,4H),3.80(t,J=1.0Hz,2H),3.74(d,J=10.4Hz,2H),3.59(s ,1H),3.02–2.96(m,2H),2.84(d,J=12.4Hz,1H),2.79(dd,J=12.4,1.1Hz,1H),1.97(s,1H). 13CNMR(151MHz,Common NMR Solvents)δ170.96,160.90,160.38,159.17,142.30,142.19,137.43,134.06,133.47,131.50,130.87,130.59,130.19,129.09 ,129.01,128.74,128.31,127.05,117.95,115.43,115.23,56.14,50.74,46.41,40.50,32.50,30.68,26.94.(+)-HR-ESI-MSm / z 585.1542(calcd.585.1547for C 33 H 31 BrFN2O2 + [M+H] + ).

[0097] Example 20: Preparation of 1-(2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-5,6-dihydropyrimidin-1(4H)-yl)-2-propiophenone (20);

[0098]

[0099] Compound 20 was prepared according to Step 2 of Example 12 using 0.17 g (1.1 mmol, 1.1 eq) of 2-phenylpropionic acid instead of p-fluorophenylacetic acid to obtain 0.12 g of compound 20 as a light yellow oil in a yield of 30.8%. 1 H NMR(604MHz,Chloroform-d)δ7.47(dd,J=7.5,2.0Hz,1H),7.40–7.19(m,8H),7.01(dd,J=7.3,2.0Hz,1H),6.88(d,J=7.4Hz,1H),3.86(s,1H),3.83(d,J=2 .0Hz,4H),3.75(d,J=3.5Hz,2H),3.02–2.96(m,2H),2.84(d,J=12.4Hz,1H),2 .79(dd,J=12.4,1.1Hz,1H),2.66(t,J=1.0Hz,1H),1.97(s,1H),1.33(s,3H). 13C NMR (151MHz, Common NMR Solvents)δ172.76,160.83,160.38,159.17,143.50,134.06,133.47,131.97,131.37,130.81,129.09,128.74,128.31 ,127.76,127.05,117.95,115.43,115.23,56.14,50.74,46.21,46.07,32.50,30.68,27.16,17.62.(+)-HR-ESI-MSm / z 523.1387(calcd.523.1391for C 28 H 29 BrFN2O2 + [M+H] + ).

[0100] Example 21: Preparation of 1-(2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-5,6-dihydropyrimidin-1(4H)-yl)-2-(4-fluorophenyl)propanone (21);

[0101]

[0102] Compound 21 was prepared according to Step 2 of Example 12 using 0.18 g (1.1 mmol, 1.1 eq) of 2-fluorophenylpropionic acid instead of p-fluorophenylacetic acid to obtain 0.14 g of compound 21 as a light yellow oil in a yield of 35.9%. 1 H NMR(604MHz,Chloroform-d)δ7.47(dd,J=7.5,2.0Hz,1H),7.40–7.33(m,4H),7.26(dd,J =7.5,2.0Hz,1H),7.09–7.04(m,2H),7.01(dd,J=7.3,2.0Hz,1H),6.88(d,J=7.4Hz,1H),3 .86(s,1H),3.83(d,J=2.0Hz,4H),3.75(d,J=3.5Hz,2H),3.02–2.96(m,2H),2.84(d,J=12 .4Hz,1H),2.79(dd,J=12.4,1.1Hz,1H),2.77(t,J=1.0Hz,1H),1.97(s,1H),1.33(s,3H). 13C NMR (151MHz, Common NMR Solvents)δ172.32,164.11,160.83,160.38,159.17,140.41,134.06,133.47,131.65,129.09,128.74,128.31,127.76,127.05,117.9 5,117.39,115.43,115.23,56.14,50.74,46.21,44.69,32.50,30.68,27.16,17.62.(+)-HR-ESI-MSm / z541.1293(calcd.541.1297for C 28 H 28 BrF2N2O2 + [M+H] + );

[0103] Example 22: Preparation of 1-(2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-5,6-dihydropyrimidin-1(4H)-yl)-2-(4-methoxyphenyl)propan-1-one (22);

[0104]

[0105] Compound 21 was prepared according to Step 2 of Example 12 using 0.2 g (1.1 mmol, 1.1 eq) of 2-(4-methoxyphenyl)propionic acid instead of p-fluorophenylacetic acid to obtain 0.16 g of compound 12 as a light yellow oil in a yield of 42.9%. 1 H NMR(604MHz,Chloroform-d)δ7.47(dd,J=7.5,2.0Hz,1H),7.37(t,J=7.5Hz,1H),7.35(m,1H),7.26(d d,J=7.5,2.0Hz,1H),7.22–7.17(m,2H),7.01(dd,J=7.3,2.0Hz,1H),6.88(d,J=7.4Hz,1H),6.88–6.8 3(m,2H),3.86(s,1H),3.83(d,J=2.0Hz,4H),3.78(s,3H),3.75(d,J=3.5Hz,2H),3.02–2.96(m,2H),2 .84(d,J=12.4Hz,1H),2.79(dd,J=12.4,1.1Hz,1H),2.77(t,J=1.0Hz,1H),1.97(s,1H),1.33(s,3H). 13C NMR(151MHz,Common NMR Solvents)δ172.32,160.83,160.69,160.38,159.17,137.45,134.06,133.47,131.34,129.09,128.74,128.31,127.76, 127.05,117.95,116.28,115.43,115.23,56.14,55.76,50.74,46.21,44.69,32.50,30.68,27.16,17.62.(+)-HR-ESI-MSm / z 553.1492(calcd.553.1497for C 28 H 28 BrFN2O3 + [M+H] + ).

[0106] Example 23: Preparation of 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(4-fluorophenyl)ethanone (23);

[0107]

[0108] Step 1: Add 1.89 g (1.0 mmol, 1.0 eq) of 2-bromo-6-fluorotoluene, 1.12 g (6.0 mmol, 6.0 eq) of N-BoC-piperazine, 1.12 g (5.0 mmol, 0.05 eq) of palladium acetate, 0.24 g (0.5 mmol, 0.05 eq) of X-Pho5, 1.57 g (14.0 mmol, 1.4 eq) of potassium tert-butyrate, and 50 mL of toluene to a 100 mL vial. The atmosphere was purged with nitrogen three times, the temperature was raised to 100°C, and the mixture was stirred for 1.5 h. The reaction was complete by TLC. The residue was dissolved in water and extracted with ethyl acetate 2-3 times. The organic phase was dried over anhydrous sodium sulfate, filtered, and then spin-dried. The residue was purified by column chromatography (PE:EA = 10:1). 1.1 g of intermediate 23-1 was obtained as a white powder in a 58.2% yield. 1 H NMR(604MHz,Chloroform-d)δ7.17(t,J=7.5Hz,1H),6.87(dd,J=7.5,2.0Hz,1H),6.72(dd, J=7.5,2.0Hz,1H),3.65(s,2H),3.59(s,2H),3.05(s,4H),2.19(s,3H).(+)-HR-ESI-MSm / z 295.2(calcd.295.2for C 16 H 24 FN2O2 + [M+H]+ );

[0109] Step 2: 0.65 g (2.2 mmol, 1.1 eq) of intermediate 23-1 and 0.54 g (3.0 mmol, 1.5 eq) of hexamethylphosphoramide (HMPA) were added to a 100 mL two-necked flask. The atmosphere was purged with nitrogen three times, and 20 mL of tetrahydrofuran was added. The solution turned pale red or yellow. The temperature was cooled to -78°C, and 0.32 g (3.0 mmol, 1.5 eq) of lithium diisopropylamide (LDA, 2 mol / L) was added dropwise. To another two-necked flask, 0.56 g (2.0 mmol, 1.0 eq) of 4-bromo-2-bromomethyl-1-methoxybenzene was added dropwise. The atmosphere was purged with nitrogen three times, and 20 mL of tetrahydrofuran was added dropwise until the solution turned pale red to 100 mL. Stirring was continued for 1.5 h after the addition, and the reaction was monitored for completion by TLC. The temperature was warmed to room temperature, and the reaction was quenched by the addition of saturated aqueous ammonium chloride. The mixture was diluted with ethyl acetate and water, and the organic and aqueous phases were separated. The organic phase was further washed with brine, dried over anhydrous sodium sulfate, filtered, and then spin-dried. The residue was purified by column chromatography (PE:EA = 30:1) to obtain 0.4 g of intermediate 23-2 as a white powder, with a yield of 71.4%. 1 H NMR(604MHz,Chloroform-d)δ7.35(m,1H),7.26(dd,J=7.5,2.0Hz,1H),7.22(t,J=7.5Hz ,1H),6.94(dd,J=7.5,2.0Hz,1H),6.88(d,J=7.4Hz,1H),6.69(dd,J=7.5,2.0Hz,1H),3. 83(s,3H),3.65(s,2H),3.59(s,2H),3.08(s,4H),2.95(dd,J=12.4,1.1Hz,1H),2.87(d, J=12.4Hz,1H),2.77(dd,J=12.4,0.9Hz,1H),2.66(d,J=12.4Hz,1H).(+)-HR-ESI-MSm / z 493.1(calcd.493.1for C 24 H 31 BrFN2O3 + [M+H] + );

[0110] Step 3: Dissolve 0.4 g (0.8 mmol, 1.0 eq) of intermediate 23-2 in ethyl acetate, add hydrogen chloride in ethyl acetate, and stir at room temperature for 2 hours. Monitor the reaction for completion by TLC. Filter and wash twice with ethyl acetate to obtain 0.3 g of intermediate 23-3 as a white powder, in a 75% yield. 1H NMR (604MHz, Chloroform-d) δ7.35 (m, 1H), 7.26 (dd, J = 7.5, 2.0Hz, 1H), 7.22 (t, J = 7. 5Hz,1H),6.94(dd,J=7.5,2.0Hz,1H),6.88(d,J=7.4Hz,1H),6.69(dd,J=7.4,2.1Hz, 1H),3.83(s,3H),3.13(s,4H),2.98–2.92(m,5H),2.87(d,J=12.4Hz,1H),2.77(dd,J =12.4,0.9Hz,1H),2.66(d,J=12.4Hz,1H).(+)-HR-ESI-MSm / z393.1(calcd.393.1for C 19 H 23 BrFN2O + [M+H] + );

[0111] Step 4: 0.38 g (1.0 mmol, 1.0 eq) of intermediate 23-3, 0.17 g (1.1 mmol, 1.1 eq) of p-fluorophenylacetic acid, 0.23 g (1.2 mmol, 1.2 eq) of EDCI, 0.02 g (0.16 mmol, 0.16 eq) of DMAP, and 20 mL of DCM were added to a 25 mL vial and stirred at room temperature for 2 h. The reaction was monitored by TLC for completion. Water was added and stirred to separate the layers. The aqueous layer was extracted 2-3 times with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and then spin-dried. The organic phase was purified by column chromatography (PE:EA = 1:1) to afford 0.17 g of compound 23 as a light yellow oil in a yield of 44.7%. 1 H NMR(604MHz,Chloroform-d)δ7.35(m,1H),7.31(m,2H),7.26(dd,J=7.5,2.0Hz,1H),7.21(d, J=7.5Hz,1H),7.07–7.02(m,2H),6.94(dd,J=7.5,2.0Hz,1H),6.88(d,J=7.4Hz,1H),6.69(dd, J=7.5,2.0Hz,1H),3.83(s,3H),3.66(d,J=1.5Hz,4H),3.60(s,2H),3.08(s,4H),2.95(dd,J=1 2.4,1.1Hz,1H),2.87(d,J=12.4Hz,1H),2.77(dd,J=12.4,0.9Hz,1H),2.66(d,J=12.4Hz,1H). 13C NMR (151MHz, Common NMR Solvents)δ171.99,163.95,162.20,159.16,148.47,134.06,133.69,133.47,133.25,132.56,129.54,117 .95,117.65,117.00,116.50,115.23,112.92,56.14,55.00,47.68,41.29,31.72,29.46.(+)-HR-ESI-MSm / z 529.1291(calcd.529.1297forC 27 H 28 BrF2N2O2 + [M+H] + ).

[0112] Example 24: Preparation of 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(3,5-difluorophenyl)ethanone (24);

[0113]

[0114] Compound 24 was prepared according to Step 4 of Example 23 using 0.2 g (1.2 mmol, 1.2 eq) of 3,5-difluorophenylacetic acid instead of p-fluorophenylacetic acid to obtain 0.13 g of compound 24 as a light yellow oil in a yield of 34.2%. 1 H NMR(604MHz,Chloroform-d)δ7.35(m,1H),7.31(m,2H),7.26(dd,J=7.5,2.0Hz,1H),7.22 (t,J=7.5Hz,1H),6.96–6.90(m,2H),6.88(d,J=7.4Hz,1H),6.69(dd,J=7.5,2.0Hz,1H),3. 83(s,3H),3.74(t,J=1.0Hz,2H),3.66(s,2H),3.60(s,2H),3.08(s,4H),2.95(dd,J=12.4 ,1.1Hz,1H),2.87(d,J=12.4Hz,1H),2.77(dd,J=12.4,0.9Hz,1H),2.66(d,J=12.4Hz,1H). 13CNMR(151MHz,Common NMR Solvents)δ172.26,163.92,162.20,159.16,148.47,138.29,134.06,133.69,133.47,129.54,117.95,117 .65,116.50,115.23,114.09,112.92,108.32,56.14,55.00,47.68,40.65,31.72,29.46.(+)-HR-ESI-MSm / z 547.1209(calcd.547.1203for C 27 H 27 BrF3N2O2 + [M+H] + ).

[0115] Example 25: Preparation of 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(2,4,5-trifluorophenyl)ethanone (25);

[0116]

[0117] Compound 25 was prepared according to Step 4 of Example 23 using 0.21 g (1.1 mmol, 1.1 eq) of 2,4,5-trifluorophenylacetic acid instead of p-fluorophenylacetic acid to obtain 0.15 g of compound 25 as a light yellow oil in a yield of 39.5%. 1 H NMR(604MHz,Chloroform-d)δ7.48(t,J=1.0Hz,1H),7.35(m,1H),7.26(dd,J=7.5,2.0Hz,1H),7.2 2(t,J=7.5Hz,1H),6.98(s,1H),6.94(dd,J=7.5,2.0Hz,1H),6.88(d,J=7.4Hz,1H),6.69(dd,J=7. 5,2.0Hz,1H),3.94(d,J=1.1Hz,2H),3.83(s,3H),3.66(s,2H),3.59(s,2H),3.09(s,4H),2.95(dd ,J=12.4,1.1Hz,1H),2.87(d,J=12.4Hz,1H),2.77(dd,J=12.4,0.9Hz,1H),2.66(d,J=12.4Hz,1H). 13C NMR (151MHz, Common NMR Solvents)δ172.28,162.20,159.16,157.03,149.28,149.12,148.47,134.06,133.69,133.47,129.54,124.17,119 .88,117.95,117.65,116.50,115.23,112.92,111.80,56.14,55.00,47.62,39.61,31.72,29.46.(+)-HR-ESI-MSm / z 565.1101(calcd.565.1108for C 27 H 26 BrF4N2O2 + [M+H] + ).

[0118] Example 26: Preparation of 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(p-tolyl)ethanone (26);

[0119]

[0120] Compound 26 was prepared according to Step 4 of Example 23 using 0.17 g (1.1 mmol, 1.1 eq) of p-tolueneacetic acid instead of p-fluorophenylacetic acid to obtain 0.1 g of compound 26 as a light yellow oil in a yield of 26.3%. 1 H NMR(604MHz,Chloroform-d)δ7.35(m,1H),7.26(dd,J=7.5,2.0Hz,1H),7.24–7.19(m,3H),7.10( m,2H),6.94(dd,J=7.5,2.0Hz,1H),6.88(d,J=7.4Hz,1H),6.69(dd,J=7.5,2.0Hz,1H),3.83(s,3H ),3.71(t,J=1.0Hz,2H),3.66(s,2H),3.60(s,2H),3.08(s,4H),2.95(dd,J=12.4,1.1Hz,1H),2. 87(d,J=12.4Hz,1H),2.77(dd,J=12.4,0.9Hz,1H),2.66(d,J=12.4Hz,1H),2.34(d,J=2.0Hz,1H). 13C NMR (151MHz, Common NMR Solvents)δ171.74,162.20,159.16,148.47,139.98,137.01,134.06,133.69,133.47,131.98,131.16,129.54 ,117.95,117.65,116.50,115.23,112.92,56.14,55.00,47.68,42.18,31.72,29.46,22.18.(+)-HR-ESI-MSm / z 525.1551(calcd.525.1547for C 28 H 31 BrFN2O2 + [M+H] + ).

[0121] Example 27: Preparation of 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(4-methoxyphenyl)ethanone (27);

[0122]

[0123] Compound 27 was prepared according to Step 4 of Example 23 using 0.18 g (1.1 mmol, 1.1 eq) of 4-methoxyphenylacetic acid instead of p-fluorophenylacetic acid to obtain 0.13 g of compound 27 as a light yellow oil in a yield of 34.2%. 1 H NMR (604MHz, Chloroform-d) δ7.35 (dd, J=2.0, 1.1Hz, 1H), 7.26 (dd, J=7.5, 2.0Hz, 1H), 7.22 (t, J=7.5 Hz,1H),7.19–7.13(m,2H),6.94(dd,J=7.5,2.0Hz,1H),6.88(d,J=7.4Hz,1H),6.86–6.81(m,2H),6.6 9(dd,J=7.5,2.0Hz,1H),3.83(s,3H),3.78(s,3H),3.67–3.64(m,4H),3.60(s,2H),3.08(s,4H),2.95 (dd,J=12.4,1.1Hz,1H),2.87(d,J=12.4Hz,1H),2.77(dd,J=12.4,0.9Hz,1H),2.66(d,J=12.4Hz,1H). 13C NMR (151MHz, Common NMR Solvents)δ171.99,162.20,160.78,159.16,148.47,134.06,133.69,133.47,132.03,129.93,129.54,117.95 ,117.65,116.50,116.33,115.23,112.92,56.14,55.76,55.00,47.68,41.70,31.72,29.46.(+)-HR-ESI-MSm / z 541.1490(calcd.541.1497for C 28 H 31 BrFN2O3 + [M+H] + ).

[0124] Example 28: Preparation of 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)ethanone (28);

[0125]

[0126] Compound 28 was prepared according to Step 4 of Example 23 using 0.15 g (1.1 mmol, 1.1 eq) of 3-pyridineacetic acid instead of p-fluorophenylacetic acid to obtain 0.11 g of compound 28 as a light yellow oil in a yield of 28.9%. 1 H NMR(604MHz,Chloroform-d)δ8.53(d,J=1.3Hz,1H),8.46(dd,J=5.1,1.3Hz,1H),7.52(m,1H),7.35(dd ,J=2.0,1.1Hz,1H),7.31–7.24(m,2H),7.22(t,J=7.5Hz,1H),6.94(dd,J=7.5,2.0Hz,1H),6.88(d,J=7. 4Hz,1H),6.69(dd,J=7.5,2.0Hz,1H),3.83(s,3H),3.67(d,J=9.5Hz,4H),3.59(s,2H),3.09(s,4H),2.9 5(dd,J=12.4,1.1Hz,1H),2.87(d,J=12.4Hz,1H),2.77(dd,J=12.4,0.9Hz,1H),2.66(d,J=12.4Hz,1H). 13C NMR(151MHz,Common NMR Solvents)δ172.28,162.20,159.16,150.02,148.78,148.47,134.06,133.69,133.47,131.73,131.21,129.5 4,125.42,117.95,117.65,116.50,115.23,112.92,56.14,55.00,47.66,40.26,31.72,29.46.(+)-HR-ESI-MSm / z 512.1338(calcd.512.1343forC 26 H 28 BrFN3O2 + [M+H] + ).

[0127] Example 29: Preparation of 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(naphthalen-2-yl)ethanone (29);

[0128]

[0129] Compound 29 was prepared according to Step 4 of Example 23 using 0.2 g (1.1 mmol, 1.1 eq) of 2-naphthylacetic acid instead of p-fluorophenylacetic acid to obtain 0.18 g of compound 29 as a light yellow oil in a yield of 47.4%. 1 H NMR(604MHz,Chloroform-d)δ7.93(d,J=0.9Hz,1H),7.88(d,J=14.1Hz,2H),7.67(s,1H),7.51(s,1H),7.40 (s,1H),7.35(m,1H),7.26(dd,J=7.5,2.0Hz,1H),7.22(t,J=7.5Hz,1H),6.94(dd,J=7.5,2.0Hz,1H),6.88(d ,J=7.4Hz,1H),6.69(dd,J=7.5,2.0Hz,1H),3.83(s,3H),3.73(s,2H),3.66(s,2H),3.60(s,2H),3.08(s,4H) ,2.95(dd,J=12.4,1.1Hz,1H),2.87(d,J=12.4Hz,1H),2.77(dd,J=12.4,0.9Hz,1H),2.66(d,J=12.4Hz,1H). 13C NMR (151MHz, Common NMR Solvents)δ172.26,162.20,159.16,148.47,137.73,137.24,136.70,134.06,133.69,133.47,132.03,130.24,130.22,130.06,129 .98,129.54,127.73,127.02,117.95,117.65,116.50,115.23,112.92,56.14,55.00,47.68,41.51,31.72,29.46.(+)-HR-ESI-MSm / z 561.1540(calcd.561.1547for C 31 H 31 BrFN2O2 + [M+H] + ).

[0130] Example 30: Preparation of 2-([1,1′-biphenyl]-4-yl)-1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)ethanone (30);

[0131]

[0132] Compound 30 was prepared according to Step 4 of Example 23 using 0.23 g (1.1 mmol, 1.1 eq) of 4-biphenylacetic acid instead of p-fluorophenylacetic acid to obtain 0.16 g of compound 30 as a light yellow oil in a yield of 42.1%. 1 H NMR(604MHz,Chloroform-d)δ7.62–7.55(m,4H),7.46–7.40(m,2H),7.40–7.31(m,4H),7.26(dd,J=7 .5,2.0Hz,1H),7.22(t,J=7.5Hz,1H),6.94(dd,J=7.5,2.0Hz,1H),6.88(d,J=7.4Hz,1H),6.69(dd,J =7.5,2.0Hz,1H),3.83(s,3H),3.69(t,J=1.0Hz,2H),3.66(s,2H),3.60(s,2H),3.08(s,4H),2.95(d d,J=12.4,1.1Hz,1H),2.87(d,J=12.4Hz,1H),2.77(dd,J=12.4,0.9Hz,1H),2.66(d,J=12.4Hz,1H). 13C NMR (151MHz, Common NMR Solvents)δ171.77,162.20,159.16,148.47,142.30,142.19,137.35,134.06,133.69,133.47,131.38,130.87,130.59, 130.19,129.54,117.95,117.65,116.50,115.23,112.92,56.14,55.00,47.68,40.98,31.72,29.46.(+)-HR-ESI-MSm / z 587.1710(calcd.587.1704forC 33 H 33 BrFN2O2 + [M+H] + ).

[0133] Example 31: Preparation of 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-phenylpropanone (31).

[0134]

[0135] Compound 31 was prepared according to Step 4 of Example 23 using 0.17 g (1.1 mmol, 1.1 eq) of 2-phenylpropionic acid instead of p-fluorophenylacetic acid to obtain 0.13 g of compound 31 as a light yellow oil in a yield of 34.2%. 1 H NMR(604MHz,Chloroform-d)δ7.37–7.19(m,9H),6.94(dd,J=7.5,2.0Hz,1H),6.88( d,J=7.4Hz,1H),6.69(dd,J=7.5,2.0Hz,1H),3.83(s,3H),3.67(s,2H),3.58(s,2H) ,3.11(d,J=10.8Hz,4H),3.00(t,J=1.0Hz,1H),2.95(dd,J=12.4,1.1Hz,1H),2.87( d,J=12.4Hz,1H),2.77(dd,J=12.4,0.9Hz,1H),2.66(d,J=12.4Hz,1H),1.29(s,3H). 13C NMR(151MHz,CommonNMR Solvents)δ173.83,162.20,159.16,148.47,143.77,134.06,133.69,133.47,131.85,131.37,130.81,129.54 ,117.95,117.65,116.50,115.23,112.92,56.14,54.88,47.32,41.45,31.72,29.46,17.62.(+)-HR-ESI-MSm / z 525.1553(calcd.525.1547forC 28 H 31 BrFN2O2 + [M+H] + ).

[0136] Example 32: Preparation of 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(4-fluorophenyl)propanone (32);

[0137]

[0138] Compound 32 was prepared according to Step 4 of Example 23 using 0.18 g (1.1 mmol, 1.1 eq) of 2-fluorophenylpropionic acid instead of p-fluorophenylacetic acid to obtain 0.12 g of compound 32 as a light yellow oil in a yield of 31.6%. 1 H NMR(604MHz,Chloroform-d)δ7.35(m,1H),7.29–7.19(m,4H),7.06–7.01(m,2H),6.94(dd,J=7.5,2.0Hz,1H),6.88(d,J=7.4Hz,1H),6.69(dd,J=7.4 ,2.1Hz,1H),3.83(s,3H),3.09(d,J=1.6Hz,4H),2.98–2.92(m,2H),2.87( dd,J=12.4,3.1Hz,2H),2.82–2.74(m,2H),2.71–2.62(m,5H),1.16(s,3H). 13C NMR (151MHz, Common NMR Solvents)δ163.53,162.20,159.16,149.11,142.35,134.06,133.72,133.47,130.70,129.54,117.95,117.91 ,117.38,116.80,115.23,112.92,63.50,56.14,55.01,53.88,41.54,31.72,29.46,20.25.(+)-HR-ESI-MSm / z 543.1458(calcd.543.1453for C 28 H 30 BrF2N2O2 + [M+H] + ).

[0139] Example 33: Preparation of 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(4-methoxyphenyl)ethanone (33);

[0140]

[0141] Compound 33 was prepared according to Step 4 of Example 23 using 0.2 g (1.1 mmol, 1.1 eq) of 2-(4-methoxyphenyl)propionic acid instead of p-fluorophenylacetic acid to obtain 0.14 g of compound 33 as a light yellow oil in a yield of 36.8%. 1 H NMR (604MHz, Chloroform-d) δ7.35 (dd, J=2.0, 1.1Hz, 1H), 7.26 (dd, J=7.5, 2.0Hz, 1H), 7.22 (t, J=7.5 Hz,1H),7.19–7.13(m,2H),6.94(dd,J=7.5,2.0Hz,1H),6.88(d,J=7.4Hz,1H),6.86–6.81(m,2H),6.6 9(dd,J=7.5,2.0Hz,1H),3.83(s,3H),3.78(s,3H),3.67–3.64(m,4H),3.60(s,2H),3.08(s,4H),2.95 (dd,J=12.4,1.1Hz,1H),2.87(d,J=12.4Hz,1H),2.77(dd,J=12.4,0.9Hz,1H),2.66(d,J=12.4Hz,1H). 13C NMR (151MHz, Common NMR Solvents)δ171.99,162.20,160.78,159.16,148.47,134.06,133.69,133.47,132.03,129.93,129.54,117.95 ,117.65,116.50,116.33,115.23,112.92,56.14,55.76,55.00,47.68,41.70,31.72,29.46.(+)-HR-ESI-MSm / z 541.1492(calcd.541.1497for C 28 H 31 BrFN2O3 + [M+H] + ).

[0142] Example 34: In vitro cell activity test of MC4R antagonists

[0143] (1) Experimental preparation:

[0144] Cell line: flipin-293-MC4; cell culture medium: DMEM, 10% fetal bovine serum 1*pS, 200 μg / ml hygromycin; experimental buffer: HBSS, 20 mM HEPES, 0.1% BSA, 500M IBMX; positive compound: ML00253764.

[0145] (2) Antagonist detection:

[0146] After digestion, cells were suspended in assay buffer and seeded into 384-well cell culture plates. Test compounds were added to the plates and incubated at 37°C for 10 minutes. Melanotan I was then added to the plates and incubated at 37°C for 30 minutes. Dissolve the EU cAMP tracer and light anti-cAMP detection reagents and dilute them in the lysis buffer provided in the kit. Add the diluted detection reagents to the plates. Incubate at room temperature for 1 hour. Read the plates using Envision (excitation: 340 nm, emission: 618 nm and 665 nm).

[0147] (3) Main reagents and consumables for the experiment:

[0148] Fetal bovine serum, DMEM, penicillin-streptomycin, bovine serum albumin, IBMX, phosphodiesterase inhibitors, HEPES buffer, 384-well cell culture plates, cAMP assay kit, 96-well V-bottom, naturally RNase / DNase-free plates.

[0149] (4) Data processing and statistical analysis:

[0150] 1. %Inhibition calculation:

[0151] %Inhibiiton=(Signalcmpd-SignalAve_VC) / (SignalAve PC-SignalAve VC)X100.

[0152] Wherein: Signalcmpd: compound signal value; SignalAve_VC: negative control signal value; SignalAve_PC: positive control signal value; %inhibition: percentage of inhibition rate.

[0153] 2. Calculate compound IC50 using GraphPad nonlinear fitting formula:

[0154] Y=Bottom+(Top-Bottom) / (1+10((LogIC50-×)Hi1ISlope))

[0155] Where: X: logarithmic value of compound concentration; Y: percentage of inhibition rate

[0156] Table 1. Biological activities of compounds of Examples 1-33

[0157]

[0158]

[0159] Example 35: Aged rat model of the compound of the present invention

[0160] Rats aged 24-25 months were randomly divided into several groups (at least 6-8 rats per group). Each group received different doses of the antagonist (5 mg / kg). A model control group (normal saline) and a positive control group (ML00253764, 5 mg / kg) were also included, receiving an equal volume of solvent. Dosing was performed twice daily for 20 days. Food intake and body weight were recorded daily to the nearest 0.1 g. Baseline data were also recorded three days before dosing for comparison with data during the dosing period.

[0161] Example 36: Rat model induced by 5-fluorouracil chemotherapy

[0162] Rats were anorexic after a single intraperitoneal injection of 5-fluorouracil (0.003-0.006 mg / g). Body weight and food intake were monitored for 7 consecutive days, and baseline data were recorded. Rats were then given different doses of an MC4R antagonist (5 mg / kg) by gavage, and dose-dependent weight recovery and food intake were recorded.

[0163] Example 37: LPS-induced inflammatory model

[0164] Mice were intraperitoneally injected with LPS (0.01-1 mg / kg) to simulate acute inflammation-induced food suppression. A control group received saline. The two groups were then given different doses of an MC4R antagonist and their food intake was observed within 24 hours.

[0165] Table 2. Animal model experimental results

[0166]

[0167] Experimental conclusion:

[0168] Compared with ML00253764, compound 7 can significantly improve the food intake and weight gain of experimental animals (rats or mice) at its effective dose, showing the potential for treating cachexia and anorexia, and the effect of compound 7 is significantly better than that of the positive control drug.

[0169] Example 38: Preparation of tablets containing compounds 1-33

[0170]

[0171] Experimental steps:

[0172] The raw and auxiliary materials were passed through an 80-mesh sieve for later use. The prescribed amount of active ingredients, micro-cellulose, lactose, and povidone K30 were weighed and added to a high-speed mixer. The mixture was stirred at a low speed to mix evenly. An appropriate amount of purified water was added, the mixture was stirred at a low speed, and the mixture was granulated by high-speed cutting. The wet granules were dried at 60°C for 3 h, sieved through a 24-mesh sieve, and the prescribed amount of sodium carboxymethyl starch, silicon dioxide, and magnesium stearate were added. The mixture was mixed and tableted using a rotary tablet press.

[0173] Example 39: Preparation of capsules containing compound 1-33

[0174]

[0175]

[0176] Experimental steps:

[0177] The raw and auxiliary materials were sieved through an 80-mesh sieve for later use. The prescribed amount of active ingredients, lactose, starch, and povidone K30 were weighed and added to a high-speed mixer. The mixture was stirred at a low speed to mix evenly. An appropriate amount of purified water was added, the mixture was stirred at a low speed, and the mixture was granulated by high-speed cutting. The wet granules were dried at 60°C for 3h, sieved through a 24-mesh sieve, and the prescribed amount of silicon dioxide and magnesium stearate were added. The mixture was mixed and filled into capsules using a capsule filling machine.

[0178] The main reagents used in the experiment were: microcrystalline cellulose, lactose, povidone K30 (Sigma-aldrich), sodium starch glycolate, silicon dioxide, magnesium stearate, and starch.

[0179] The above embodiments merely illustrate the implementation methods of the present invention. Although the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention. It should be noted that a person skilled in the art may make various modifications and improvements without departing from the scope of the present invention, and these modifications and improvements fall within the scope of protection of the present invention.

Claims

1. An amide derivative, characterized in that The amide derivative is a compound, enantiomer or pharmaceutically acceptable salt thereof having a structure as shown in general formula (I) or (II): When R1 is C, R2 is N, and R3 is N; n is independently 1 or 2; R4 is independently H or CH3; R5 is a substituted aromatic ring.

2. The amide derivative according to claim 1, characterized in that The R5 is selected from p-fluorophenyl, 3,5-difluorophenyl, 2,4,5-trifluorophenyl, p-tolyl, 4-methoxyphenyl, 3-pyridyl, 2-naphthyl, 4-biphenyl, 2-phenylpropyl, 2-fluorophenylpropyl or 2-(4-methoxyphenyl)propyl.

3. The amide derivative according to claim 1 or 2, characterized in that The compound is any one of the following: 1-[2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-(4-fluorophenyl)ethanone; 1-(2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl)-2-(3,5-difluorophenyl)ethanone; 1-(2-{2-[(5-bromo-2-methoxyphenyl)ethyl]-3-fluorophenyl}-4,5-dihydro-1H-imidazol-1-yl)-2-(2,4,5-trifluorophenyl)ethanone; 1-[2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-(p-tolyl)ethanone; 1-[2-(2-{5-bromo-2-methoxyphenethyl}-3-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-(4-methoxyphenyl)ethanone; 1-[2-(2-{5-bromo-2-methoxyphenethyl}-3-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-(pyridin-3-yl)ethanone; 1-(2-(2-(5-bromo-2-methoxyphenethyl)-4-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl)-2-(naphthalen-2-yl)ethanone-1; 1-[2-(2-(5-bromo-2-methoxyphenethyl)-4-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-biphenyl-4-ylethanone; 1-{2-[2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl]-4,5-dihydro-1H-imidazol-1-yl}-2-phenylpropan-1-one; 1-[2-(2-{5-bromo-2-methoxyphenethyl}-3-fluorophenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-(4-fluorophenyl)propan-1-one; 1-[2-(3-Fluoro-2-{2-[5-bromo-2-methoxyphenyl]ethyl}phenyl)-4,5-dihydro-1H-imidazol-1-yl]-2-(4-methoxyphenyl)propan-1-one; 1-[2-(2-{5-bromo-2-methoxyphenethyl}-3-fluorophenyl)-5,6-dihydropyrimidin-1(4H)-yl]-2-(4-fluorophenyl)ethanone; 1-[2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-5,6-dihydropyrimidin-1(4H)-yl]-2-(3,5-difluorophenyl)ethanone; 1-[2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl]-5,6-dihydro-1(4H)-pyrimidinyl-2-(2,4,5-trifluorophenyl)ethanone; 1-[2-(2-(2-methoxy-5-bromophenethyl)-3-fluorophenyl)-5,6-dihydropyrimidin-1(4H)-yl]-2-(p-tolyl)ethanone; 1-[2-(3-fluoro-2-(5-bromo-2-methoxyphenethyl)phenyl)-5,6-dihydropyrimidin-1(4H)-yl]-2-(4-methoxyphenyl)ethanone; 1-[2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-5,6-dihydropyrimidin-1(4H)-yl]-2-(pyridin-3-yl)ethanone; 1-(2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-5,6-dihydropyrimidin-1(4H)-yl)-2-(naphthalen-2-yl)ethanone; 2-([1,1'-biphenyl]-4-yl)-1-(2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-5,6-dihydropyrimido[1,4]pyridin-1(4H)-yl)ethan-1-one; 1-(2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-5,6-dihydropyrimidin-1(4H)-yl)-2-propiophenone; 1-(2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-5,6-dihydropyrimidin-1(4H)-yl)-2-(4-fluorophenyl)propanone; 1-(2-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)-5,6-dihydropyrimidin-1(4H)-yl)-2-(4-methoxyphenyl)propan-1-one; 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(4-fluorophenyl)ethanone; 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(3,5-difluorophenyl)ethanone; 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(2,4,5-trifluorophenyl)ethanone; 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(p-tolyl)ethanone; 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(4-methoxyphenyl)ethanone; 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(pyridin-3-yl)ethanone; 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(naphthalen-2-yl)ethanone; 2-([1,1'-biphenyl]-4-yl)-1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)ethanone; 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-phenylpropanone; 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(4-fluorophenyl)propanone; 1-(4-(2-(5-bromo-2-methoxyphenethyl)-3-fluorophenyl)piperazin-1-yl)-2-(4-methoxyphenyl)ethanone.

4. The amide derivative according to any one of claims 1 to 3, characterized in that The pharmaceutically acceptable salt of the compound is a salt formed by the compound and an acid: oxalate, hydrochloride, bromate, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, tartrate, maleate, fumarate, methanesulfonate, gluconate, saccharate, benzoate, ethanesulfonate, benzenesulfonate or p-toluenesulfonate.

5. A pharmaceutical composition comprising the amide derivative according to any one of claims 1 to 4 as an active ingredient, characterized in that: The amide derivative is a compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

6. Use of the amide derivative according to any one of claims 1 to 4 or the pharmaceutical composition according to claim 5 in the preparation of a medicament for treating cachexia and anorexia.

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