A NAMPT inhibitor, compositions, methods of preparation and uses

Abstract

The present application belongs to the technical field of medicine, and particularly relates to a NAMPT inhibitor, a composition, a preparation method and use, a structural formula of which is: or R 1 H or Br; M is C or N, Y is C or N, Z is C or N; n=0, 1 or 2, or L is an amino group, a thiourea group, a urea group, R 2 H, CH3, CF3, OCH3, F or Cl; R is H, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group; X is F, Cl or Br; the compound of the present application is determined by an MTT method to have an effect of inhibiting proliferation of gastric cancer cells, has significant anti-gastric cancer activity, and has higher activity than that of apatinib at a cell level, and can be used for preparing an anti-gastric cancer drug.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a NAMPT inhibitor, a composition, a preparation method and use. BACKGROUND

[0002] Gastric cancer is a common digestive system malignant tumor in the world. Although with the continuous development of surgical, radiotherapy and immunotherapy and other treatment methods, the diagnosis and treatment of gastric cancer have been improved compared with the past, the five-year survival rate of patients is still about 25%-35%, and the five-year survival rate of advanced gastric cancer is only about 6%. Traditional chemotherapeutic drugs are the main treatment drugs for advanced gastric cancer, including platinum drugs (oxaliplatin, cisplatin), fluorouracil drugs (fluorouracil, capecitabine), paclitaxel and irinotecan, but these drugs are all cytotoxic drugs, lack of selectivity, and have various adverse reactions, especially in the process of combined drug use, there is still a big development bottleneck in the treatment of gastric cancer. With the development of gene sequencing technology, precise treatment has become an important idea for the treatment of gastric cancer, and according to the molecular typing of patients, corresponding targeted drugs are selected for individualized treatment of patients, which has become an inevitable trend of targeted treatment of gastric cancer. In recent decades, some targeted drugs (ramucirumab and apatinib, etc.) have also been developed for the treatment of gastric cancer, although they have achieved success in the treatment of gastric cancer, but for many patients who do not express or lowly express these target points, there is still a lack of effective targeted treatment means. It can be seen that the research and development of gastric cancer related treatment targets and drugs are of great significance to the comprehensive treatment of gastric cancer, and the development of new anti-gastric cancer targeted drugs is imminent.

[0003] Metabolic reprogramming is one of the hallmark features of cancer, and the most prominent feature in tumor metabolism is abnormal energy metabolism. Nicotinamide adenine dinucleotide (NAD + ) is a coenzyme for redox reactions, which mediates redox reactions in various metabolic pathways, including glycolysis, and is the core of energy metabolism. NAD + also affects many key cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cell aging and immune cell function. Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme in the NAD + salvage pathway, and targeting NAMPT can lead to depletion of NAD + , inhibit ATP synthesis, and further regulate tumor cell metabolism and NAD +Synthetic capacity. A large number of studies have found that NAMPT is overexpressed in colorectal cancer, prostate cancer, breast cancer, gastric cancer and acute myeloid leukemia 17 and other human malignancies, and is related to the occurrence and prognosis of tumors. NAMPT is highly expressed in tumor transformation to compensate for increased metabolic demand, and overexpression of NAMPT can increase tumor cell proliferation, colony formation and resistance to apoptosis. Recent studies have revealed other roles of NAMPT in cancer biology, including DNA repair mechanisms, cross-talk with oncogenic signaling pathways, cancer cell stemness, and immune response. In addition, studies have shown that NAMPT inhibitor FK866 can inhibit gastric cancer cell proliferation and induce apoptosis to increase the chemosensitivity of gastric cancer cells to fluorouracil. NAMPT has become a promising target for cancer treatment. Currently, five NAMPT inhibitors FK866, CHS828, CB30865, GMX177 and KPT-9274 have entered clinical studies. Three of them were terminated due to their toxic side effects, and so far no NAMPT inhibitor has been approved for marketing. Because NAD + NAMPT inhibitors exhibit effects in targeting cancer cells while also having significant toxic effects on normal cells. Therefore, how to reduce toxicity is the biggest challenge faced by NAMPT inhibitor development.

[0004] NAMPT has a synthetic lethal relationship with the key enzyme nicotinic acid phosphoribosyltransferase (NAPRT) in the Press-Handler pathway, and the strategy of combining NAMPT with nicotinic acid based on the concept of synthetic lethality reduces the toxic side effects. Other studies have shown that NAMPT inhibitors exhibit significantly higher efficacy in cancer cells that lack NAPRT expression and are completely dependent on NAMPT for NAD + synthesis. SUMMARY

[0005] The technical problem to be solved by the present application is to provide a NAMPT inhibitor, composition, preparation method and application, and to improve the inhibition effect.

[0006] The present application provides a NAMPT inhibitor, the structural formula of which is:

[0007] or

[0008] R 1 H or Br (Br is preferably 3-Br or 4-Br, 4 is the site where Z is located, and 3 is the site of C above Z);

[0009] M is C or N, Y is C or N, and Z is C or N;

[0010] n = 0, 1 or 2, or for

[0011] L is amino, thiourea, urea,

[0012] R 2 is H, CH3, CF3, OCH3, F or Cl (F or Cl is preferably substituted at position 2, i.e., position 2 is a substitution site closer to R);

[0013] R is H, methyl, ethyl, isopropyl or cyclopropyl;

[0014] X is F, Cl or Br.

[0015] Preferably, M is C, Y is N, Z is C, R1 is H, R 2 For H.

[0016] Preferably, n=1 or 2, L is a thiourea group, a urea group or

[0017] Preferably, R is H or methyl.

[0018] Preferably, n=1, L is urea or

[0019] Preferably, it is a pharmaceutically acceptable salt formed by the compound of the structural formula and an acid, wherein the acid is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, fumaric acid, citric acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0020] An embodiment of the present invention provides a composition comprising the NAMPT inhibitor and a pharmaceutically acceptable excipient, wherein the excipient is at least one of a diluent, a lubricant, a binder, a disintegrant, a surfactant, a film-forming material, a coating material, and a capsule material.

[0021] The embodiment of the present invention provides a method for preparing the NAMPT inhibitor, comprising the following steps:

[0022] Triphosgene and pyridine are reacted, and then compound 6 and compound 5 are added in sequence, reacted, and treated to obtain the NAMPT inhibitor;

[0023] The structural formula of compound 6 is The R 4 is H or Me;

[0024] The structural formula of compound 5 is The R 3 NH3, OH, NHCH3, NO2 or NH2;

[0025] The structural formula of the NAMPT inhibitor is,

[0026] R 1 is H or Br;

[0027] M is C or N, Y is C or N, and Z is C or N;

[0028] n = 0, 1 or 2, or for

[0029] L is amino, thiourea, urea,

[0030] R 2 is H, CH3, CF3, OCH3, F or Cl;

[0031] R is H, methyl, ethyl, isopropyl or cyclopropyl;

[0032] X is F, Cl or Br.

[0033] An embodiment of the present invention provides a use of the NAMPT inhibitor or the composition, wherein the NAMPT inhibitor or the composition is used to prepare a drug for inhibiting NAMPT.

[0034] Preferably, the drug that inhibits NAMPT is an anti-tumor drug, and the tumor is colorectal cancer, prostate cancer, breast cancer, gastric cancer or acute myeloid lymphocytic leukemia.

[0035] Preferably, the tumor is gastric cancer.

[0036] The present invention has the beneficial effect of providing a NAMPT inhibitor with a complex rigid skeleton and a simple synthetic route, prepared in 4-5 steps. The anthranilamide compound has been shown to inhibit the proliferation of gastric cancer cells as determined by the MTT assay, exhibiting significant anti-gastric cancer activity and exhibiting higher activity than apatinib at the cellular level, and can be used to prepare anti-gastric cancer drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 These are the experimental results of compound NHWL024068 inducing S and G2 / M phase arrest of gastric cancer cells.

[0038] Figure 2 These are the experimental results of compound NHWL024068 inducing apoptosis of gastric cancer cells.

[0039] Figure 3 These are the results of the mitochondrial damage experiment of compound NHWL024068.

[0040] Figure 4Transwell migration experiment results of compound NHWL024068.

[0041] Figure 5 Monoclonal formation experiment results of compound NHWL024068.

[0042] Figure 6 EDU anti-proliferation experiment results of compound NHWL024068. DETAILED DESCRIPTION

[0043] Example 1

[0044] A preparation method of a NAMPT inhibitor, comprising the following steps:

[0045] (1) Compound 1 and 1,4-dibromobutane are added to a mixed solvent of acetonitrile and water (acetonitrile: water = 20: 1), and then a catalyst potassium iodide and a base potassium carbonate are added, and the reaction is carried out at 100°C under oil bath for 7.5h. After the reaction is completed, the filter is extracted with water and ethyl acetate, and the organic phase is collected, dried and separated by column chromatography to obtain compound 2.

[0046] The structural formula of compound 1 is The structural formula of compound 2 is

[0047] The molar ratio of compound 1 to 1,4-dibromobutane is 1:2; the molar ratio of compound 1 to potassium iodide is 1:1; the molar ratio of compound 1 to potassium carbonate is 1:2.2, and the molar volume ratio of compound 1 to the mixed solvent of acetonitrile and water is 1mol:10mL.

[0048] (2) Compound 2 and 10% sodium hydroxide are added to methanol, and the reaction is carried out under condensation reflux at 85°C for 24h. After the reaction is completed, the solvent is evaporated by rotary evaporation, extracted with water and ethyl acetate, and the water phase is collected. The pH is adjusted to 4 with 10% hydrochloric acid, and then dichloromethane is added for extraction. The organic phase is collected, dried and obtained as compound 3.

[0049] The structural formula of compound 3 is

[0050] Every 5nMol of compound 2 needs 2ml of 10% sodium hydroxide solution and 10mL of methanol.

[0051] (3) Using compound 3 and compound 4 as raw materials, 1-ethyl-(3- dimethylaminopropyl) carbonyldiimide hydrochloride (EDCI) as a condensing agent, 1- hydroxybenzotriazole (HOBT) as a catalyst, triethylamine as a base, and dichloromethane as a solvent, the above raw materials were mixed, and reacted at room temperature for 4.5 h. After the reaction was completed, the reaction was quenched with water, extracted with water and dichloromethane, the organic phase was collected, rotary evaporated, and column chromatography was used for separation to obtain compound 5.

[0052] The structural formula of compound 4 is

[0053] The structural formula of compound 5 is

[0054] The molar ratio of compound 3 to compound 4 was 1:1.5; the molar ratio of compound 3 to EDCI was 1:1.5; the molar ratio of compound 3 to HOBT was 1:1.5; the molar ratio of compound 3 to triethylamine was 1:2, and the ratio of compound 3 to dichloromethane was 1 mol:10 mL.

[0055] (4) Triphosgene and pyridine were added to dichloromethane under ice bath conditions, and the reaction was carried out at room temperature for 0.5 h under argon protection. Then compound 6 was added and the reaction was continued at room temperature for 0.5 h. Then compound 5 was added and the reaction was continued at room temperature for 3.5 h. After the reaction was completed, water and dichloromethane were used for extraction, the organic phase was collected, rotary evaporated, and column chromatography was used for separation to obtain the target product.

[0056] The structural formula of compound 6 is

[0057] The structural formula of the target product is

[0058] n=0, 1 or 2, or is

[0059] L is amino, thiourea, urea,

[0060] R 2 =H, CH3, CF3, OCH3 (CH3, CF3, OCH3 are preferably 2 or 3), F or Cl (preferably 2), R=H, methyl, ethyl, isopropyl or cyclopropyl;

[0061] X is F, Cl or Br.

[0062] R 3 is NH2, OH, NHCH3 or NO2. R 4 =H or Me.

[0063] The molar ratio of compound 5 and compound 6 is 1:1, the molar ratio of compound 5 and triphosgene is 3.4:1, the molar ratio of compound 5 and pyridine is 1:2, and the ratio of compound 5 and dichloromethane is 1:10 mL.

[0064] Example 2

[0065] The structural formula of compound 7 is as follows:

[0066]

[0067] The preparation method of compound 7 is based on Example 1, in the target product, n is determined to be 1, R 2 =H, R=H; L is urea. The corresponding adjustment of the related raw materials can be obtained.

[0068] Example 3

[0069] The structural formula of the compound of Example 3 is as follows:

[0070]

[0071] The preparation method of the compound of Example 3 is that compound 7 is added to tetrahydrofuran, sodium hydride is slowly added under ice bath stirring, 1,3-dibromopropane is added after reaction for 1 h at room temperature under argon protection, and the reaction is carried out under condensation reflux at 75°C for 24 h. After the reaction is completed, water and dichloromethane are used for extraction, the organic phase is collected, rotary evaporation is performed, and column chromatography separation is performed to obtain the compound of Example 3.

[0072] The ratio of compound 7 and tetrahydrofuran is 1 mol:10 mL, the molar ratio of compound 7 and sodium hydride is 1:10, and the molar ratio of compound 7 and 1,3-dibromopropane is 1:10.

[0073] Example 4

[0074] A preparation method of an NAMPT inhibitor comprises the following steps:

[0075] (1) Using 4-aminobenzonitrile and benzyl bromide as raw materials, potassium iodide as a catalyst, potassium carbonate as a base, N,N-dimethylformamide as a solvent, mixing the above raw materials, and reacting for 12 h at 25°C under argon protection, after the reaction is completed, water and ethyl acetate are used for extraction, the organic phase is collected, rotary evaporation is performed, and column chromatography separation is performed to obtain 4-benzylaminobenzonitrile.

[0076] The molar ratio of 4-aminobenzonitrile and benzyl bromide is 1:4, the molar ratio of 4-aminobenzonitrile and potassium iodide is 1:0.3, the molar ratio of 4-aminobenzonitrile and potassium carbonate is 1:5, and the ratio of 4-aminobenzonitrile and N,N-dimethylformamide is 1 mol:10 mL.

[0077] (2) 4-benzylaminobenzonitrile was added to a tetrahydrofuran solution of compound 9, and the reaction was carried out at room temperature for 2.5 h. After the reaction was completed, sodium borohydride and methanol solvent were added, and the reaction was carried out at room temperature for 8.5 h. After the reaction was completed, water and dichloromethane were used for extraction, the organic phase was recovered, and rotary evaporation was performed. Compound 10 was obtained by column chromatography.

[0078] The structural formula of compound 9 is R = H, Me (±), Et, i-Pr or

[0079] The structural formula of compound 10 is R = H, Me (±), Et, i-Pr or

[0080] The reaction scheme is as follows:

[0081]

[0082] The molar ratio of 4-benzylaminobenzonitrile to compound 9 was 1:1.25, the molar ratio of 4-benzylaminobenzonitrile to sodium borohydride was 1:2.5, the molar concentration of compound 9 in the tetrahydrofuran solution was 1 mol / L, and the ratio of 4-benzylaminobenzonitrile to methanol solvent was 1 mol:10 mL.

[0083] (3) Compound 3 and compound 10 of Example 1 were used as raw materials, 1-ethyl-(3-dimethylaminopropyl) carbonyl diimide hydrochloride (EDCI) was used as a condensing agent, 1-hydroxybenzotriazole (HOBT) was used as a catalyst, triethylamine was used as a base, dichloromethane was used as a solvent, the above raw materials were mixed, and the reaction was carried out at room temperature for 4.5 h. After the reaction was completed, water was used for quenching, water and dichloromethane were used for extraction, the organic phase was collected, rotary evaporation was performed, and column chromatography was used for separation to obtain compound 11.

[0084] The structural formula of compound 11 is R = H, Me (±), Et, i-Pr or

[0085] The molar ratio of compound 3 to compound 10 was 1:1.5; the molar ratio of compound 3 to EDCI was 1:1.5; the molar ratio of compound 3 to HOBT was 1:1.5; the molar ratio of compound 3 to triethylamine was 1:2, and the ratio of compound 3 to dichloromethane was 1 mol:10 mL.

[0086] (4) Compound 11 and palladium-carbon were added to methanol, and the reaction was carried out at 45°C for 5.5 h under a hydrogen atmosphere. After the reaction was completed, diatomite was used for suction filtration, methanol was used for washing, the filtrate was collected, and rotary evaporation was performed to obtain compound 12.

[0087] The structural formula of compound 12 is R = H, Me(±), Et, i-Pr or

[0088] The molar ratio of compound 11 to palladium on carbon is 1:0.3, and the ratio of compound 11 to methanol is 1 mol:10 mL.

[0089] (5) Triphosgene and pyridine are added to dichloromethane under ice bath conditions, and the reaction is carried out at room temperature for 0.5 h under argon protection. Then, compound 6 is added, and the reaction is continued at room temperature for 0.5 h. Then, compound 12 is added, and the reaction is carried out at room temperature for 3.5 h. After the reaction is completed, water and dichloromethane are used for extraction, the organic phase is collected, and rotary evaporation is performed. Column chromatography is used for separation to obtain the target product.

[0090] The structural formula of compound 6 is

[0091] The structural formula of the target product is R = H, Me(±), Et, i-Pr or

[0092] The molar ratio of compound 12 to compound 6 is 1:1; the molar ratio of compound 6 to triphosgene is 3.4:1; the molar ratio of compound 6 to pyridine is 1:2, and the ratio of compound 6 to dichloromethane is 1 mol:10 mL.

[0093] The reaction scheme is as follows:

[0094]

[0095] Example 5

[0096] A preparation method of an NAMPT inhibitor comprises the following steps:

[0097] Compound 8 and N,N'-disuccinimidyl carbonate are used as raw materials, DIPEA is used as a base, dichloromethane is used as a solvent, and the above raw materials are mixed. After the reaction is carried out at room temperature for 0.5 h under argon protection, compound 5 of Example 1 is added, and the reaction is carried out at room temperature for 6-7 h. After the reaction is completed, citric acid is used for quenching, water and dichloromethane are used for extraction, the organic phase is collected, and rotary evaporation is performed. Column chromatography is used for separation to obtain the target product.

[0098] The structural formula of compound 8 is

[0099] The structural formula of the target product is

[0100] R 1 is H or Br, and Br is preferably at positions 3 and 4;

[0101] M is C or N, Y is C or N, and Z is C or N.

[0102] R 2 is H, CH3, CF3, OCH3, F or Cl;

[0103] R is H, methyl, ethyl, isopropyl or cyclopropyl;

[0104] X is F, Cl or Br.

[0105] The molar ratio of compound 8 to N, N'-disuccinimidyl carbonate is 1:2, the molar ratio of compound 8 to DIPEA is 1:3, the molar ratio of compound 8 to compound 5 is 1:1, and the ratio of compound 8 to dichloromethane is 1 mol:10 mL.

[0106] Example 6

[0107] A preparation method of an NAMPT inhibitor, comprising the following steps:

[0108] (1) Taking compound 8 and CDI of Example 5 as raw materials, and taking tetrahydrofuran as a solvent, the raw materials are mixed, and after reaction at room temperature for 1 h, compound 13, DBU as a catalyst and TEA as an amine are sequentially added, and reaction is carried out at room temperature for 6 h. After the reaction is completed, the solvent is spin-dried, extracted with water and dichloromethane, the organic phase is collected, spin-dried, and column chromatography is used for separation to obtain compound 14.

[0109] In the formula, the structural formula of compound 13 is

[0110] The structural formula of compound 14 is

[0111] The molar ratio of compound 13 to compound 8 is 1:1, the molar ratio of compound 13 to CDI is 1:1.5, the molar ratio of compound 13 to DBU is 1:1, the molar ratio of compound 13 to TEA is 1:1.5, and the ratio of compound 13 to dichloromethane is 1 mol:10 mL.

[0112] (2) Taking compound 3 of Example 1 and compound 14 as raw materials, taking HATU as a condensing agent, taking DIPEA as a base, and taking DMF as a solvent, the raw materials are mixed, and reaction is carried out at room temperature for 6 h. After the reaction is completed, extraction is carried out with water and ethyl acetate, the organic phase is collected, spin-dried, and column chromatography is used for separation to obtain a target product.

[0113] In the formula, the structural formula of the target product is

[0114] R 1 is H or Br;

[0115] M is C or N, Y is C or N, and Z is C or N;

[0116] R 2 is H, CH3, CF3, OCH3, F or Cl;

[0117] X is F, Cl or Br.

[0118] The molar ratio of compound 3 to compound 14 is 1:1, the molar ratio of compound 3 to HATU is 1:1.2, the molar ratio of compound 3 to DIPEA is 1:2, and the ratio of compound 3 to DMF is 1 mol:10 mL.

[0119] Example 7

[0120] The structural formula of the compound of Example 7 is as follows:

[0121]

[0122] R 2 is H, CH3, CF3, OCH3, F or Cl,

[0123] R is H, methyl, ethyl, isopropyl or cyclopropyl,

[0124] X is F, Cl, Br.

[0125] The preparation method of the compound of Example 7 is as follows: 3-bromomethylpyridine and compound 5 of Example 1 are used as raw materials, copper powder and potassium iodide are used as catalysts, potassium carbonate is used as a base, DMF is used as a solvent, the reaction is carried out under argon protection at 80°C under condensation reflux for 2h, after the reaction is completed, filtration is performed, the filtrate is extracted with water and ethyl acetate, the organic phase is collected, and column chromatography is performed to separate to obtain the compound of Example 7.

[0126] The molar ratio of compound 5 to 3-bromomethylpyridine is 1:1, the molar ratio of compound 5 to copper powder is 1:0.5, the molar ratio of compound 5 to potassium iodide is 1:1, the molar ratio of compound 5 to potassium carbonate is 1:2.5, and the ratio of compound 5 to DMF is 1 mol:10 mL.

[0127] Example 8

[0128] A preparation method of an NAMPT inhibitor, comprising the following steps:

[0129] (1) The preparation method of the compound of Example 8 is as follows: compound 15 and compound 5 of Example 1 are used as raw materials, dichloromethane is used as a solvent, the raw materials are mixed, and after reaction at room temperature for 0.5h, sodium hydroxide is added, and reaction is performed at room temperature for 6h, after the reaction is completed, extraction is performed with water and dichloromethane, the organic phase is collected, dried, and column chromatography is performed to separate to obtain compound 16.

[0130] The structural formula of compound 15 is as follows:

[0131] The structural formula of compound 16 is

[0132] The molar ratio of compound 5 to compound 15 is 1:1, the molar ratio of compound 5 to sodium hydroxide is 1:0.2, and the ratio of compound 5 to dichloromethane is 1 mol:10 mL.

[0133] (2) Using 3-aminomethylpyridine and compound 16 as raw materials, sodium hydroxide as a base, and DMF as a solvent, the raw materials are mixed and reacted at 60°C for 6h. After the reaction is completed, water and ethyl acetate are used for extraction, the organic phase is collected, dried, and column chromatography is used for separation to obtain the target product.

[0134] The structural formula of the target product is

[0135] R 2 is H, CH3, CF3, OCH3, F or Cl,

[0136] R is H, methyl, ethyl, isopropyl or cyclopropyl,

[0137] X is F, Cl, Br.

[0138] The molar ratio of compound 16 to 3-aminomethylpyridine is 1:1, the molar ratio of compound 16 to sodium hydroxide is 1:0.2, and the ratio of compound 16 to dichloromethane is 1 mol:10 mL.

[0139] Example 9

[0140] The reaction scheme is as follows.

[0141]

[0142] When the structural formula of the NAMPT inhibitor is:

[0143]

[0144] wherein R 1 is H, Z is C, Y is N, and M is C; n is 1, and L is R is H, and X is F. R 2 Different, the compound number is shown in the following table.

[0145]

[0146]

[0147] When the structural formula of the NAMPT inhibitor is:

[0148]

[0149] wherein X is F.

[0150] R 1 , R 2 , M, Y, Z are different, and the compound numbers are shown in the following table.

[0151] Compound No. [R 1 ]]> [R 2 ]]> M Y Z N1 H H N C C N2 H H C C N N3 H 3-CF3 C N C N4 H F C N C N17 H 3-Cl C N C N6 H 3-Br C N C N7 H 3-CH3 C N C N8 H 2-OCH3 C N C N9 H 2-F C N C N10 H 2-Cl C N C N11 H 2-CH3 C N C N12 H 2-Br C C N N13 H 2-Br N C C N14 H 2-Br C C C N15 3，-Br H C N C N16 4，-Br H C N C

[0152] When the structural formula of the NAMPT inhibitor is:

[0153]

[0154] wherein R 1 is H, Z is C, Y is N, and M is C; X is F.

[0155] n, L, R 2 , R are different, and the compound numbers are shown in the following table.

[0156]

[0157]

[0158] The nuclear magnetic resonance data of each of the above compounds are as follows.

[0159] pyridin-2-ylmethyl(4-(5-fluoro-2-(pyrrolidin-1-yl)benzamido)benzyl)carbamate (N1): white solid, yield 80%, purity 98.7%. 1 H NMR (500 MHz, Chloroform-d) δ 12.08 (s, 1H), 8.60 (d, J = 5.0 Hz, 1H), 7.90 (dd, J = 9.5, 3.2 Hz, 1H), 7.70 (t, J = 7.3 Hz, 1H), 7.65 - 7.59 (m, 2H), 7.33 (dd, J = 29.7, 8.0 Hz, 3H), 7.26 - 7.20 (m, 2H), 7.18 - 7.12 (m, 1H), 5.26 (s, 2H), 5.23 (s, 1H), 4.39 (d, J = 6.0 Hz, 2H), 3.25 - 3.12 (m, 4H), 2.12 - 2.01 (m, 4H). 13C NMR (125 MHz, Chloroform-d) δ 163.4, 163.3, 159.5 (d, J = 244.2 Hz), 155.9, 155.4, 155.4, 147.8, 144.4, 138.7, 138.1, 133.9, 130.0, 128.5, 123.4, 122.4, 122.1 (d, J = 7.6 Hz), 119.9, 119.0 (d, J = 22.5 Hz), 117.7 (d, J = 24.2 Hz), 65.9, 53.8, 44.8, 24.6.

[0160] pyridin-4-ylmethyl(4-(5-fluoro-2-(pyrrolidin-1-yl)benzamido)benzyl)carbamate (N2): pale yellow solid, yield 82%, purity 98.3%. 1 H NMR (500 MHz, Chloroform-d) δ 12.12 (s, 1H), 8.58 (d, J = 5.2 Hz, 2H), 7.90 (dd, J = 9.6, 3.2 Hz, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.26 - 7.21 (m, 2H), 7.19 - 7.11 (m, 1H), 5.23 (q, J = 8.3, 7.2 Hz, 1H), 5.15 (s, 2H), 4.38 (d, J = 6.0 Hz, 2H), 3.21 - 3.12 (m, 4H), 2.10 - 2.01 (m, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 163.4, 163.4, 159.4 (d, J = 244.0 Hz), 156.0, 149.9, 145.8, 144.5, 144.5, 138.2, 133.8, 129.8 (d, J = 7.0 Hz), 128.5, 122.1 (d, J = 7.7 Hz), 121.8, 112.0, 119.1 (d, J = 22.5 Hz), 117.7 (d, J = 24.2 Hz), 64.8, 53.8, 44.8, 24.6.

[0161] pyridin-3-ylmethyl(4-(5-fluoro-2-(pyrrolidin-1-yl)benzamido)-2-(trifluoromethyl)benzyl)carbamate (N3): white solid, yield 42%, purity 95.4%. 1H NMR (500 MHz, Chloroform-d) δ 12.55 (s, 1H), 8.51 (d, J = 23.8 Hz, 2H), 7.93 (s, 1H), 7.82 (dd, J = 9.5, 3.2 Hz, 1H), 7.73 - 7.59 (m, 2H), 7.48 (d, J = 8.4 Hz, 1H), 7.24 - 7.18 (m, 2H), 7.13 - 7.07 (m, 1H), 5.30 (t, J = 6.4 Hz, 1H), 5.07 (s, 2H), 4.45 (d, J = 6.3 Hz, 2H), 3.12 - 3.06 (m, 4H), 2.03 - 1.98 (m, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 163.5, 163.5, 159.6 (d, J = 244.6 Hz), 156.1, 149.4, 144.6 (d, J = 2.7 Hz), 138.4, 136.1, 131.7, 131.6, 129.6 (d, J = 6.8 Hz), 129.2 - 128.5 (q, J = 30.0 Hz), 127.38 - 120.84 (q, J = 272.5), 123.5, 122.9, 122.6 (d, J = 7.8 Hz), 119.5 (d, J = 22.6 Hz), 117.7 (d, J = 24.3 Hz), 117.4 - 117.2 (q, J = 6.3 Hz), 64.3, 54.0, 41.5, 41.5, 24.6.

[0162] pyridin-3-ylmethyl(2-fluoro-4-(5-fluoro-2-(pyrrolidin-1-yl)benzamido)benzyl)carbamate (N4): white solid, yield 67%, purity 98.7%. 1 H NMR (500 MHz, Chloroform-d) δ 12.40 (s, 1H), 8.61 (s, 1H), 8.56 (dd, J = 4.9, 1.7 Hz, 1H), 7.90 (dd, J = 9.5, 3.2 Hz, 1H), 7.78 - 7.63 (m, 2H), 7.34 - 7.27 (m, 3H), 7.20 - 7.14 (m, 1H), 7.11 (dd, J = 8.2, 2.0 Hz, 1H), 5.23 (t, J = 6.0 Hz, 1H), 5.13 (s, 2H), 4.39 (d, J = 6.2 Hz, 2H), 3.20 - 3.12 (m, 4H), 2.11 - 2.05 (m, 4H). 13C NMR (125 MHz, Chloroform-d) δ 163.4, δ 163.4, δ 162.1 (d, J = 241.2 Hz), δ 159.6 (d, J = 244.5 Hz), 156.1, 149.3, 144.6, 139.8 (d, J = 11.2 Hz), 136.1, 132.2, 130.4 (d, J = 5.5 Hz), 129.7 (d, J = 7.0 Hz), 123.5, 122.5 (d, J = 7.8 Hz), 120.5 (d, J = 15.4 Hz), 119.4 (d, J = 22.5 Hz), 117.7 (d, J = 24.4 Hz), 114.9 (d, J = 3.1 Hz), 107.4 (d, J = 26.6 Hz), 64.2, 53.9, 39.1, 24.6.

[0163] pyridin-3-ylmethyl(4-((5-fluoro-2-(pyrrolidin-1-yl)benzamido)methyl)phenyl)carbamate (N5): white solid, yield 56%, purity 99.5%. 1 H NMR \ (500 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.91 (t, J = 6.0 Hz, 1H), 8.65 (d, J = 2.3 Hz, 1H), 8.55 (dd, J = 4.8, 1.7 Hz, 1H), 7.88 - 7.82 (m, 1H), 7.45 - 7.37 (m, 3H), 7.25 (d, J = 8.1 Hz, 2H), 7.12 - 7.01 (m, 2H), 6.75 (dd, J = 9.1, 4.6 Hz, 1H), 5.18 (s, 2H), 4.33 (d, J = 6.0 Hz, 2H), 3.08 - 2.99 (m, 4H), 1.79 - 1.71 (m, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 165.9, 165.9, 158.7 (d, J = 242.5 Hz), 153.2, 149.5, 149.5, 144.6 (d, J = 2.7 Hz), 137.3, 136.3, 133.5, 131.9, 129.0 (d, J = 6.8 Hz), 128.8, 123.6, 120.9 (d, J = 7.6 Hz), 119.0, 118.3 (d, J = 22.4 Hz), 117.4 (d, J = 24.1 Hz), 64.3, 53.1, 43.4, 24.3.

[0164] pyridin-3-ylmethyl(2-chloro-4-(5-fluoro-2-(pyrrolidin-1-yl)benzamido)benzyl)carbamat e(N17): White solid, yield 90%, purity 99.3%. 1 H NMR (500 MHz, Chloroform-d) δ 12.36 (s, 1H), 8.61 (s, 1H), 8.56 (dd, J = 4.9, 1.5 Hz, 1H), 7.93 (s, 1H), 7.89 (dd, J = 9.5, 3.2 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.38 - 7.27 (m, 4H), 7.19 - 7.14 (m, 1H), 5.33 (t, J = 6.3 Hz, 1H), 5.13 (s, 2H), 4.43 (d, J = 6.2 Hz, 2H), 3.20 - 3.11 (m, 4H), 2.11 - 2.04 (m, 4H). 13 CNMR (125 MHz, Chloroform-d) δ 163.4, 163.4, 159.5 (d, J = 244.5 Hz), 156.1, 149.4, 149.4, 144.6 (d, J = 3.0 Hz), 139.3, 136.1, 134.1, 132.2, 131.0, 130.46, 129.6 (d, J = 6.8 Hz), 123.5, 122.5 (d, J = 7.7 Hz), 120.7, 119.4 (d, J = 22.5 Hz), 118.0, 117.7 (d, J = 24.3 Hz), 64.3, 53.9, 42.8, 24.6.

[0165] pyridin-3-ylmethyl(2-chloro-4-(5-fluoro-2-(pyrrolidin-1-yl)benzamido)benzyl)carbamat e(N17): White solid, yield 90%, purity 99.3%. 1H NMR (500 MHz, Chloroform-d) δ 12.10 (s, 1H), 8.62 (s, 1H), 8.57 (dd, J = 4.9, 1.7 Hz, 1H), 7.90 (dd, J = 9.6, 3.2 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.31 - 7.27 (m, 2H), 7.24 (d, J = 4.7 Hz, 1H), 7.18 - 7.12 (m, 1H), 5.15 (s, 2H), 4.36 (d, J = 6.0 Hz, 2H), 3.20 - 3.12 (m, 4H), 2.05 (td, J = 5.6, 4.7, 2.3 Hz, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 163.4, 163.3, 159.4 (d, J = 244.0 Hz) 156.1, 149.3, 149.3, 144.5, 144.5, 138.1, 136.2, 133.8, 132.3, 129.9 (d, J = 6.9 Hz), 128.5, 123.5, 122.1 (d, J = 7.8 Hz), 112.0, 119.1 (d, J = 22.5 Hz), 117.7 (d, J = 24.3 Hz), 64.2, 53.8, 44.8, 24.6.

[0166] pyridin-3-ylmethyl(4-(5-fluoro-2-(pyrrolidin-1-yl)benzamido)-2-methylbenzyl)carbamat e (N7): white solid, yield 52%, purity 99%. 1 H NMR (500 MHz, Chloroform-d) δ 11.97 (s, 1H), 8.62 (s, 1H), 8.57 (d, J = 3.2 Hz, 1H), 7.89 (dd, J = 9.5, 3.2 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.37 (dd, J = 8.4, 2.2 Hz, 1H), 7.29 (dd, J = 7.9, 4.8 Hz, 2H), 7.27 - 7.19 (m, 3H), 7.18 - 7.11 (m, 1H), 5.15 (s, 2H), 4.98 (s, 1H), 4.37 (d, J = 5.7 Hz, 2H), 3.20 - 3.13 (m, 4H), 2.35 (s, 3H), 2.10 - 2.01 (m, 4H). 13C NMR (125 MHz, Chloroform-d) δ 163.4, 163.4, 159.4 (d, J = 244.0 Hz), 155.9, 149.3, 149.3, 144.5 (d, J = 2.8 Hz), 138.2, 137.4, 136.1, 132.3, 131.5, 129.9 (d, J = 6.9 Hz), 129.2, 123.5, 122.0 (d, J = 7.7 Hz), 121.8, 119.0 (d, J = 22.5 Hz), 117.7 (d, J = 24.1 Hz), 117.3, 64.2, 53.7, 43.0, 24.6, 19.3.

[0167] pyridin-3-ylmethyl(4-(5-fluoro-2-(pyrrolidin-1-yl)benzamido)-3-methoxybenzyl)carbamate (N8): yellow oil solid, 30% yield, 98.3% purity. 1 H NMR (500 MHz, Chloroform-d) δ 11.67 (s, 1H), 8.54 (s, 1H), 8.51-8.43 (m, 2H), 7.75 (dd, J = 9.6, 3.2 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.25-7.17 (m, 1H), 7.14-7.08 (m, 1H), 7.07-7.00 (m, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.77 (s, 1H), 5.39 (t, J = 6.1 Hz, 1H), 5.07 (s, 2H), 4.27 (d, J = 6.0 Hz, 2H), 3.77 (s, 3H), 3.17-3.03 (m, 4H), 1.97-1.86 (m, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 164.6, 164.6, 159.4 (d, J = 241.9 Hz) 148.9, 145.2, 145.2, 135.5, 133.2, 129.8, 127.8, 124.0, 121.5, 121.5, 120.6 (d, J = 39.3 Hz), 119.8, 119.0, 118.9 (d, J = 22.4 Hz), 117.6 (d, J = 24.3 Hz), 109.9, 62.6, 55.7, 53.7, 42.2, 24.9.

[0168] pyridin-3-ylmethyl(3-fluoro-4-(2-(5-fluoro-2-(pyrrolidin-1-yl)phenyl)-2-oxoethyl)benzyl)carbamate (N9): white solid, yield 34%, purity 95.4%. 1 H NMR (500 MHz, Chloroform-d) δ 12.97 (s, 1H), 8.63 (s, 1H), 8.61-8.54 (m, 2H), 7.96 (dd, J = 9.7, 3.2 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.36-7.27 (m, 2H), 7.22-7.14 (m, 1H), 7.11-7.03 (m, 2H), 5.20 (s, 1H), 5.16 (s, 2H), 4.36 (d, J = 6.1 Hz, 2H), 3.19-3.12 (m, 4H), 2.09-2.03 (m, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 163.3, 161.0, 159.8 (d, J = 244.5 Hz), 156.0, 152.7 (d, J = 245.0 Hz), 148.7, 145.4, 145.4, 136.8, 134.3 (d, J = 6.5 Hz), 130.3 (d, J = 7.1 Hz), 126.7 (d, J = 10.9 Hz), 123.8, 123.6, 124.4 (d, J = 8.8 Hz), 122.1, 119.5 (d, J = 22.5 Hz), 117.6 (d, J = 24.3 Hz), 114.0 (d, J = 20.0 Hz), 64.2, 54.5, 44.5, 24.6.

[0169] pyridin-3-ylmethyl(3-chloro-4-(5-fluoro-2-(pyrrolidin-1-yl)benzamido)benzyl)carbamate (N10): white solid, yield 30%, purity 99.7%. 1H NMR (500 MHz, Chloroform-d) δ 12.17 (s, 1H), 8.66-8.53 (m, 3H), 7.87 (dd, J = 9.5, 3.2 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.38-7.32 (m, 1H), 7.30 (dd, J = 7.8, 4.8 Hz, 1H), 7.26-7.13 (m, 3H), 5.30 (t, J = 8.1, 4.3 Hz, 1H), 5.16 (s, 2H), 4.34 (d, J = 6.2 Hz, 2H), 3.25-3.14 (m, 4H), 2.05-1.99 (m, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 164.0, 164.0, 159.1 (d, J = 243.4 Hz), 156.2, 149.1, 145.8, 136.3, 135.0, 134.9, 132.4, 130.9, 129.6 (d, J = 6.8 Hz), 128.2, 126.8, 123.6, 123.0, 122.5, 122.2 (d, J = 7.5 Hz), 119.4 (d, J = 22.5 Hz), 117.7 (d, J = 24.3 Hz), 64.2, 54.3, 44.3, 24.9.

[0170] pyridin-3-ylmethyl(4-(5-fluoro-2-(pyrrolidin-1-yl)benzamido)-3-methylbenzyl)carbamat e (N11): white solid, yield 44%, purity 96.2%. 1 H NMR (500 MHz, Chloroform-d) δ 11.97 (s, 1H), 8.62 (d, J = 2.3 Hz, 1H), 8.57 (dd, J = 4.8, 1.7 Hz, 1H), 7.89 (dd, J = 9.5, 3.2 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.37 (dd, J = 8.3, 2.3 Hz, 1H), 7.29 (dd, J = 7.8, 4.8 Hz, 1H), 7.27-7.19 (m, 2H), 7.15 (ddd, J = 8.9, 7.3, 3.2 Hz, 1H), 5.15 (s, 2H), 4.97 (s, 1H), 4.37 (d, J = 5.6 Hz, 2H), 3.21-3.12 (m, 4H), 2.34 (s, 3H), 2.11-2.01 (m, 4H). 13C NMR (125 MHz, Chloroform-d) δ 163.4, 163.4, 159.4 (d, J = 243.8 Hz), 155.9, 149.3, 149.3, 144.4 (d, J = 3.7 Hz), 138.2, 137.4, 136.2, 132.3, 131.5, 129.9 (d, J = 6.9 Hz), 129.2, 123.5, 122.0 (d, J = 7.7 Hz), 121.8, 119.0 (d, J = 22.6 Hz), 117.7 (d, J = 24.1 Hz), 117.3, 64.2, 53.7, 43.0, 24.6, 19.3.

[0171] pyridin-4-ylmethyl(2-bromo-4-(2-(butylamino)-5-fluorobenzamido)benzyl)carbamate (N12): White solid, yield 77%, purity 97.5%. 1 H NMR (500 MHz, Chloroform-d) δ 12.12 (s, 1H), 8.59 (d, J = 5.2 Hz, 2H), 7.91 (dd, J = 9.6, 3.2 Hz, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.32 - 7.27 (m, 2H), 7.26 - 7.22 (m, 2H), 7.15 (ddd, J = 8.9, 7.2, 3.2 Hz, 1H), 5.21 (s, 1H), 5.16 (s, 2H), 4.38 (d, J = 6.0 Hz, 2H), 3.21 - 3.12 (m, 4H), 2.11 - 2.02 (m, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 163.4, 163.3, 159.4 (d, J = 244.1 Hz), 156.3, 156.1, 149.2, 144.5 (d, J = 2.8 Hz), 138.1, 137.0, 133.9, 129.9 (d, J = 6.9 Hz), 128.5, 122.9, 122.1 (d, J = 7.6 Hz), 121.8, 119.9, 119.0 (d, J = 22.4 Hz), 117.7 (d, J = 24.1 Hz), 67.1, 53.8, 44.8, 24.6.

[0172] pyridin-2-ylmethyl(2-bromo-4-(5-fluoro-2-(pyrrolidin-1-yl)benzamido)benzyl)carbamate (N13): White solid, yield 73%, purity 97.8%.1 H NMR (500 MHz, Chloroform-d) δ 12.08 (s, 1H), 8.59 (d, J = 5.0 Hz, 1H), 7.90 (dd, J = 9.6, 3.2 Hz, 1H), 7.74 - 7.66 (m, 1H), 7.64 - 7.58 (m, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 7.26 - 7.21 (m, 2H), 7.15 (ddd, J = 8.9, 7.3, 3.2 Hz, 1H), 5.26 (s, 2H), 4.39 (d, J = 5.9 Hz, 2H), 3.22 - 3.11 (m, 4H), 2.12 - 2.01 (m, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 163.4, 163.4, 159.4 (d, J = 244.0 Hz), 156.3, 149.3, 144.5, 144.4, 138.1, 137.0, 133.9, 129.9 (d, J = 6.9 Hz), 128.5, 122.9, 122.1 (d, J = 7.5 Hz), 121.8, 119.9, 119.0 (d, J = 22.5 Hz), 119.0 (d, J = 22.5 Hz), 67.1, 53.8, 44.8, 24.6.

[0173] benzyl (2-bromo-4-(5-fluoro-2-(pyrrolidin-1-yl)benzamido)benzyl)carbamate (N14): yellow solid, yield 68%, purity 98.7%. 1 H NMR (500 MHz, Chloroform-d) δ 12.07 (s, 1H), 7.90 (dd, J = 9.6, 3.1 Hz, 1H), 7.61 (d, J = 8.3 Hz, 2H), 7.40 - 7.27 (m, 7H), 7.26 - 7.22 (m, 1H), 7.15 (ddd, J = 8.9, 7.3, 3.2 Hz, 1H), 5.14 (s, 2H), 5.07 (s, 1H), 4.37 (d, J = 6.0 Hz, 2H), 3.23 - 3.12 (m, 4H), 2.12 - 2.01 (m, 4H). 13C NMR (125 MHz, Chloroform-d) δ 163.4, 163.4, 160.0 (d, J = 248.7 Hz), 156.4, 138.0, 136.5, 134.1, 130.4, 128.6, 128.5, 128.2, 128.2, 122.2, 119.9, 119.9, 119.1, δ 119.0 (d, J = 22.5 Hz), 117.7 (d, J = 24.2 Hz), 66.9, 53.9, 44.8, 24.6.

[0174] (5-bromopyridin-3-yl)methyl(4-(5-fluoro-2-(pyrrolidin-1-yl)benzamido)benzyl)carbama te (N15): yellow solid, yield 80%, purity 96.2%. 1 H NMR (500 MHz, Chloroform-d) δ 12.11 (s, 1H), 8.63 (s, 1H), 8.53 (s, 1H), 7.90 (dd, J = 9.6, 3.2 Hz, 1H), 7.86 (s, 1H), 7.66 - 7.59 (m, 2H), 7.28 (d, J = 7.9 Hz, 2H), 7.25 - 7.21 (m, 1H), 7.18 - 7.12 (m, 1H), 5.13 (s, 2H), 4.37 (d, J = 5.9 Hz, 2H), 3.20 - 3.12 (m, 4H), 2.10 - 2.02 (m, 4H). 13 C NMR (125 MHz, DMSO-d6) δ 167.2, 167.2, 156.5, δ 154.4 (d, J = 234.3 Hz), 150.1, 148.0, 143.4, 138.4, 135.6, 135.1, 128.0, 124.9 (d, J = 5.7 Hz), 120.5, 119.9, 117.4 (d, J = 21.6 Hz), 116.1 (d, J = 7.1 Hz), 115.9 (d, J = 23.0 Hz), 62.8, 50.5, 44.0, 25.6.

[0175] (6-(6-bromopyridin-3-yl)methyl(4-(5-fluoro-2-(pyrrolidin-1-yl)benzamido)benzyl)carba mate (N16): yellow solid, yield 90.3%, purity 98.7%. 1H NMR (500 MHz, Chloroform-d) δ 12.11 (s, 1H), 8.40-8.32 (m, 1H), 7.90 (dd, J = 9.5, 3.2 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 7.1 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.30-7.26 (m, 2H), 7.26-7.22 (m, 1H), 7.18-7.09 (m, 1H), 5.15 (t, J = 8.0 Hz, 1H), 5.10 (s, 2H), 4.35 (d, J = 6.0 Hz, 2H), 3.20-3.11 (m, 4H), 2.10-2.01 (m, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 162.4, 162.4, 158.4 (d, J = 244.0 Hz), 154.9, 148.8, 147.7, 143.4, 140.8, 137.5, 137.1, 131.7 (d, J = 266.4 Hz), 128.8 (d, J = 7.2 Hz), 127.4, 127.0, 121.2, 119.0, 118.1 (d, J = 22.7 Hz), 116.6 (d, J = 24.2 Hz), 62.3, 52.8, 43.8.25.6.

[0176] pyridin-3-ylmethyl(4-((5-fluoro-2-(pyrrolidin-1-yl)benzamido)methyl)-3-methylphenyl)c arbamate (N18): white solid, yield 41%, purity 96.6%. 1 H NMR (500 MHz, Chloroform-d) δ 9.63 (t, J = 5.0 Hz, 1H), 8.67 (s, 1H), 8.59 (d, J = 4.9 Hz, 1H), 7.82-7.72 (m, 2H), 7.33 (dd, J = 7.9, 4.9 Hz, 1H), 7.25-7.16 (m, 2H), 7.14-7.03 (m, 2H), 6.86 (s, 1H), 5.22 (s, 2H), 4.56 (d, J = 5.2 Hz, 2H), 3.00-2.91 (m, 4H), 2.35 (s, 3H), 1.72-1.63 (m, 4H). 13C NMR (125 MHz, Chloroform-d) δ 165.6, 165.6, 158.9 (d, J = 242.9 Hz), 153.1, 149.5, 144.6, 144.6, 137.5, 137.2, 136.3, 131.9, 131.5, 129.71, 129.2 (d, J = 6.8 Hz), 123.6, 121.3 (d, J = 7.5 Hz), 120.6, 118.4 (d, J = 22.4 Hz), 117.4 (d, J = 24.1 Hz), 116.4, 64.3, 53.2, 41.4, 24.2, 19.3.

[0177] pyridin-3-ylmethyl(4-((5-fluoro-2-(pyrrolidin-1-yl)benzamido)methyl)-2-methoxyphenyl)carbamate (N19): White solid, yield 30%, purity 99.5%. 1 H NMR (500 MHz, Chloroform-d) δ 9.56 (t, 1H), 8.71-8.55 (m, 2H), 8.04 (s, 1H), 7.79-7.71 (m, 2H), 7.35-7.29 (m, 2H), 7.09-7.02 (m, 2H), 6.94-6.87 (m, 2H), 5.21 (s, 2H), 4.54 (d, J = 5.5 Hz, 2H), 3.84 (s, 3H), 2.99-2.93 (m, 4H), 1.75-1.68 (m, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 165.9, 165.9, 158.7 (d, J = 242.7 Hz), 152.9, 149.6, 149.5, 147.8, 144.5 (d, J = 2.7 Hz), 136.3, 133.4, 131.9, 129.0 (d, J = 6.5 Hz), 126.6, 123.6, 120.9 (d, J = 7.5 Hz), 120.5, 118.3 (d, J = 22.4 Hz), 117.4 (d, J = 24.1 Hz), 110.2, 64.3, 55.8, 53.1, 43.8, 24.3.

[0178] pyridin-3-ylmethyl(4-((5-fluoro-2-(pyrrolidin-1-yl)benzamido)methyl)-3-methoxyphenyl)carbamate (N20): White solid, yield 33%, purity 95.0%. 1H NMR (500 MHz, Chloroform-d) δ 9.16 (t, J = 5.8 Hz, 1H), 8.68 (s, 1H), 8.60 (d, J = 4.9 Hz, 1H), 7.79-7.72 (m, 1H), 7.71-7.62 (m, 1H), 7.33 (dd, J = 7.9, 4.8 Hz, 2H), 7.24 (s, 1H), 7.10-6.94 (m, 3H), 6.70 (dd, J = 8.1, 2.1 Hz, 1H), 5.22 (s, 2H), 4.55 (d, J = 5.7 Hz, 2H), 3.85 (s, 3H), 3.02-2.92 (m, 4H), 1.78-1.72 (m, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 166.1, 166.1, 158.3 (d, J = 241.9 Hz), 158.2, 153.0, 149.5, 149.5, 144.5, 144.4, 138.6, 136.3, 131.9, 130.5, 128.8 (d, J = 6.7 Hz), 123.6, 121.5, 120.1 (d, J = 7.5 Hz), 118.0 (d, J = 22.3 Hz), 117.3 (d, J = 24.0 Hz), 64.3, 55.4, 52.7, 38.9, 24.5.

[0179] pyridin-3-ylmethyl(2-fluoro-4-((5-fluoro-2-(pyrrolidin-1-yl)benzamido)methyl)phenyl)c arbamate (N21): white solid, yield 65%, purity 98.2%. 1 H NMR (500 MHz, Chloroform-d) δ 9.75 (t, J = 5.6 Hz, 1H), 8.68 (s, 1H), 8.61 (d, J = 4.9 Hz, 1H), 8.06 (s, 1H), 7.81-7.73 (m, 2H), 7.33 (dd, J = 7.9, 4.8 Hz, 1H), 7.15-7.05 (m, 4H), 6.95 (s, 1H), 5.24 (s, 2H), 4.56 (d, J = 5.6 Hz, 2H), 3.06-2.94 (m, 4H), 1.83-1.73 (m, 4H). 13C NMR (125 MHz, Chloroform-d) δ 165.9, 165.9, 158.9 (d, J = 242.7 Hz), 152.1 (d, J = 238.2 Hz), 152.8, 149.8, 149.7, 144.6 (d, J = 2.7 Hz), 136.2, 134.6, 129.0 (d, J = 6.6 Hz), 125.3, 124.0 (d, J = 3.3 Hz), 123.7, 121.2 (d, J = 7.7 Hz), 120.3, 118.5 (d, J = 22.3 Hz), 117.4 (d, J = 24.1 Hz), 114.6 (d, J = 19.5 Hz), 64.7, 53.2, 43.0, 24.3.

[0180] pyridin-3-ylmethyl(4-((5-fluoro-2-(pyrrolidin-1-yl)benzamido)methyl)-2-methylphenyl)c arbamate (N22): white solid, yield 43%, purity 95.2%. 1 H NMR (500 MHz, Chloroform-d) δ 9.55 (t, J = 5.4 Hz, 1H), 8.68 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 7.76 (dd, J = 9.4, 3.1 Hz, 3H), 7.33 (dd, J = 7.8, 4.8 Hz, 1H), 7.22 - 7.15 (m, 2H), 7.12 - 7.03 (m, 2H), 6.52 (s, 1H), 5.23 (s, 2H), 4.54 (d, J = 5.4 Hz, 2H), 3.04 - 2.93 (m, 4H), 2.24 (s, 3H), 1.75 - 1.72 (m, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 165.8, 158.8 (d, J = 242.7 Hz) 149.7, 149.7, 144.5, 144.5, 136.3, 134.9, 131.8, 130.3, 129.0 (d, J = 6.6 Hz), 126.5, 123.6, 120.9 (d, J = 7.6 Hz), 118.3 (d, J = 22.3 Hz), 117.4 (d, J = 23.9 Hz), 64.6, 60.4, 53.1, 43.4, 24.3.

[0181] pyridin-3-ylmethyl(2-chloro-4-((5-fluoro-2-(pyrrolidin-1-yl)benzamido)methyl)phenyl)c arbamate(N23): white solid, yield 30%, purity 98.4%. 1 H NMR (500 MHz, Chloroform-d) δ 9.74 (t, J = 5.7 Hz, 1H), 8.65 (d, J = 38.7 Hz, 2H), 8.13 (d, J = 8.5 Hz, 1H), 7.80 - 7.73 (m, 2H), 7.38 - 7.32 (m, 2H), 7.26 - 7.20 (m, 2H), 7.14 - 7.05 (m, 2H), 5.24 (s, 2H), 4.54 (d, J = 5.6 Hz, 2H), 3.02 - 2.96 (m, 4H), 1.80 - 1.74 (m, 4H). 13 C NMR (125 MHz, Chloroform-d) δ 165.9, 165.9, 158.9 (d, J = 243.1 Hz), 152.7, 149.7, 149.7, 144.6, 146.6, 136.4, 134.6, 133.7, 129.0 (d, J = 6.8 Hz), 128.6, 127.4, 123.7, 121.2 (d, J = 7.7 Hz), 120.1, 118.5 (d, J = 22.3 Hz), 117.4 (d, J = 24.2 Hz), 64.8, 53.3, 42.9, 24.3.

[0182] NHWL024063: white solid, yield 80%, purity 98.9%. 1 H NMR (500 MHz, Chloroform-d) δ 9.67 (t, J = 5.7 Hz, 1H), 8.45 - 8.40 (m, 3H), 7.68 (s, 1H), 7.60 (dd, J = 17.2, 8.7 Hz, 3H), 7.21 - 7.15 (m, 4H), 7.11 (d, J = 8.3 Hz, 2H), 7.05 (dd, J = 6.5, 1.7 Hz, 3H), 6.11 (t, J = 6.0 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 4.35 (d, J = 5.7 Hz, 2H), 2.96 (t, J = 6.0 Hz, 6H), 1.78 - 1.71 (m, 4H). 13C NMR (126 MHz, Chloroform-d) δ 166.92, 156.10, 148.76, 148.48, 144.77, 138.60, 135.66, 135.32, 132.50, 128.43, 123.74, 120.85, 120.05, 118.74, 118.56, 117.16, 116.97, 53.06, 43.54, 41.53, 24.61. 19 F NMR (471 MHz, Chloroform-d) δ -119.99.

[0183] NHWL024068: White solid, yield 83%, purity 99%. 1 H NMR (500 MHz, Chloroform-d) δ 9.91 - 9.87 (m, 1H), 8.41 (s, 1H), 8.40 (d, J = 4.9 Hz, 1H), 7.70 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.55 (dd, J = 9.3, 2.9 Hz, 1H), 7.17 (dd, J = 7.8, 4.9 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 8.7 Hz, 2H), 7.08 - 7.04 (m, 1H), 7.05 - 7.00 (m, 1H), 6.21 (t, J = 5.9 Hz, 1H), 5.08 (p, J = 6.8 Hz, 1H), 4.31 (qd, J = 15.4, 5.9 Hz, 2H), 3.02 - 2.95 (m, 3H), 1.85 - 1.77 (m, 4H), 1.46 (d, J = 6.9 Hz, 2H).

[0184] NHWL024072: White solid, yield 80%, purity 97.9%. 1 H NMR (500 MHz, Chloroform-d) δ 9.79 (d, J = 7.4 Hz, 1H), 8.61 (s, 1H), 8.53 (s, OH), 7.78 - 7.67 (m, 3H), 7.37 (d, J = 6.6 Hz, 2H), 7.28 - 7.22 (m, 1H), 7.09 - 7.05 (m, 1H), 7.04 - 7.00 (m, 1H), 5.22 (p, J = 7.1 Hz, 1H), 5.17 (s, 1H), 3.00 - 2.90 (m, 2H), 1.82 - 1.69 (m, 4H), 1.50 (d, J = 6.8 Hz, 2H). 13C NMR (126 MHz, Chloroform-d) δ 164.75, 153.13, 144.40, 136.97, 136.03, 131.83, 126.72, 123.38, 121.04, 118.21, 118.03, 117.30, 117.11, 64.05, 52.98, 48.38, 24.16, 21.67. 19 F NMR (471 MHz, Chloroform-d) δ -119.17.

[0185] NHWL024075: White solid, yield 80%, purity 99%. 1 H NMR (500 MHz, Chloroform-d) δ 9.78 (d, 1H), 8.61 (s, 0H), 8.53 (s, 0H), 7.75 - 7.67 (m, 0H), 7.51 - 7.19 (m, 3H), 7.11 - 6.97 (m, 1H), 2.95 (t, 2H), 1.83 - 1.65 (m, 1H), 1.50 (d, 2H). 13 C NMR (126 MHz, Chloroform-d) δ 164.99, 144.65, 138.79, 136.31, 123.66, 119.20, 118.50, 118.32, 117.62, 117.41, 64.39, 53.28, 48.65, 24.44, 21.95. 19 F NMR (471 MHz, Chloroform-d) δ -119.12.

[0186] NHWL024077: White solid, yield 80%, purity 99.8%. 1 H NMR (500 MHz, DMSO-d6) δ 8.88 (d, J = 8.0 Hz, 0H), 8.56 (s, 0H), 8.51 (s, 0H), 8.44 (d, J = 4.5 Hz, 0H), 7.69 (d, J = 7.5 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.22 (d, J = 8.1 Hz, 1H), 7.11 - 7.05 (m, 1H), 7.03 - 6.97 (m, 1H), 6.77 - 6.71 (m, 1H), 6.65 (t, J = 5.7 Hz, 1H), 4.98 (p, J = 6.9 Hz, 1H), 4.30 (d, J = 5.3 Hz, 1H), 3.00 (t, 2H), 1.76 - 1.69 (m, 2H), 1.38 (d, J = 6.8 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 166.97, 155.30, 148.72, 148.02, 143.07, 138.98, 137.04, 135.93, 134.98, 126.52, 123.46, 117.70, 116.51, 115.91, 115.48, 115.29, 50.01, 47.90, 40.48, 24.90, 22.01. 19 F NMR (471 MHz, DMSO-d6) δ -128.42.

[0187] NHWL037007: White solid, yield 80%, purity 99.3%. 1 H NMR (500 MHz, Chloroform-d) δ 9.35 (t, 1 H), 8.62 (s, 1 H), 8.53 (d, J = 4.4 Hz, 1 H), 8.02 (s, OH), 7.76 - 7.68 (m, 2 H), 7.31 - 7.25 (m, 2 H), 7.16 (d, J = 8.0 Hz, 2 H), 7.09 - 7.03 (m, 2 H), 6.61 (d, J = 8.0 Hz, 2 H), 4.49 (d, J = 5.1 Hz, 2 H), 4.39 (s, 2 H), 2.97 (t, 4 H), 1.69 (p, 5 H). 13 C NMR (126 MHz, Chloroform-d) δ 171.26, 165.80, 162.65, 149.05, 148.68, 147.12, 144.50, 135.18, 134.93, 129.46, 127.62, 123.64, 120.68, 118.26, 118.08, 117.48, 117.29, 113.21, 52.97, 45.81, 43.65, 24.33. 19 F NMR (471 MHz, Chloroform-d) δ -120.06.

[0188] NHWL037021: White solid, yield 80%, purity 99.2%. 1H NMR (500 MHz, Chloroform-d) δ 9.62 (t, 0H), 8.59 (s, 0H), 8.55 (d, J = 3.9 Hz, 0H), 7.74 (dd, J = 9.5, 2.8 Hz, 0H), 7.71 (d, J = 7.8 Hz, 0H), 7.34 (d, J = 8.4 Hz, 0H), 7.30 (dd, J = 7.6, 4.9 Hz, 0H), 7.13 - 7.05 (m, 1H), 5.64 (t, J = 5.4 Hz, 0H), 4.59 (d, J = 5.5 Hz, 0H), 4.46 (d, J = 6.1 Hz, 0H), 2.97 (t, J = 6.0 Hz, 1H), 1.74 (p, J = 3.2 Hz, 1H). 13 C NMR (126 MHz, Chloroform-d) δ 166.03, 154.82, 150.39, 149.19, 149.17, 135.77, 133.84, 129.13, 123.82, 121.96, 121.09, 121.03, 118.58, 118.40, 117.60, 117.41, 53.25, 43.45, 42.94, 24.45. 19 F NMR (471 MHz, Chloroform-d) δ -119.53.

[0189] NHWL037026: White solid, 80% yield, 98.2% purity. 1 H NMR (500 MHz, Chloroform-d) δ 9.55 (t, 1H), 8.58 - 8.54 (m, 1H), 7.76 (dd, J = 9.4, 2.6 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H), 7.29 (t, J = 7.1 Hz, 2H), 7.07 (td, J = 8.3, 4.7 Hz, 2H), 4.63 (s, 1H), 4.56 (d, J = 5.2 Hz, 1H), 3.02 (s, 1H), 2.98 (t, 3H), 1.74 (p, 2H). 13 C NMR (126 MHz, Chloroform-d) δ 155.58, 149.29, 138.32, 135.76, 133.41, 128.84, 123.91, 121.04, 120.98, 120.29, 118.33, 117.63, 117.44, 93.27, 53.24, 49.93, 43.59, 34.64, 24.47. 19 F NMR (471 MHz, Chloroform-d) δ -119.60.

[0190] NHWL037032: white solid, 80% yield, 99.1% purity. 1 H NMR (500 MHz, Chloroform-d) δ 9.74 (t, 1H), 8.46-8.41 (m, 1H), 7.71 (dd, J = 9.4, 2.9 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.24-7.18 (m, 1H), 7.12-7.03 (m, 1H), 4.58 (d, J = 5.7 Hz, 1H), 4.35 (d, J = 6.0 Hz, 1H), 3.25 (s, 1H), 2.98 (t, J = 5.8 Hz, 1H), 1.72 (p, J = 3.4 Hz, 1H). 13 C NMR (126 MHz, Chloroform-d) δ 166.17 (d, J = 1.7 Hz), 159.82, 157.88, 157.11, 148.92, 148.63, 144.59 (d, J = 2.6 Hz), 142.35, 138.25, 135.41, 135.20, 129.65, 127.75, 123.56, 121.20 (d, J = 7.6 Hz), 118.71, 118.54, 117.56, 117.37. 19 F NMR (471 MHz, Chloroform-d) δ -119.25.

[0191] NHWL037036: white solid, 80% yield, 99% purity. 1 H NMR (500 MHz, Chloroform-d) δ 9.49 (t, 1H), 8.57 (s, 1H), 8.53 (d, J = 3.8 Hz, 1H), 7.75-7.71 (m, 1H), 7.33 (s, 1H), 7.31 (s, 1H), 7.28 (t, J = 2.1 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.09-7.05 (m, 2H), 4.61 (s, 1H), 4.59 (d, J = 5.4 Hz, 1H), 3.70 (t, 1H), 3.34 (t, J = 6.0 Hz, 1H), 3.00 (t, J = 6.3 Hz, 3H), 2.10 (p, J = 5.9 Hz, 1H), 1.78 (p, 4H).

[0192] NHWL037038: white solid, 80% yield, 99.5% purity. 1H NMR (500 MHz, Chloroform-d) δ 9.61 (t, 0H), 8.49 (d, J = 3.7 Hz, 0H), 8.43 (s, 0H), 7.74 (dd, J = 9.4, 2.8 Hz, 0H), 7.62 (d, J = 7.8 Hz, 0H), 7.30 (d, J = 8.4 Hz, 0H), 7.25-7.23 (m, 0H), 7.11-7.02 (m, 1H), 4.55 (d, J = 5.6 Hz, 0H), 4.39 (s, 0H), 3.21 (s, 1H), 2.97 (t, J = 6.5 Hz, 1H), 2.47 (s, 1H), 1.70 (p, 1H). 13 CNMR (126 MHz, Chloroform-d) δ 129.38, 129.03 (d, J = 6.7 Hz), 124.40, 123.70, 121.06 (d, J = 7.6 Hz), 118.60, 118.42, 117.59, 117.40, 133.45-133.25 (m), 166.01 (d, J = 1.7 Hz), 161.98, 159.81, 157.88, 149.48, 148.87, 146.02, 144.56, 136.09, 135.21-135.07 (m). 19 FNMR (471 MHz, Chloroform-d) δ -119.43.

[0193] NHWL037041: white solid, yield 80%, purity 99.5%. 1 H NMR (500 MHz, Chloroform-d) δ 8.93 (t, J = 5.9 Hz, 0H), 8.60 (d, J = 2.3 Hz, 0H), 8.19 (d, J = 3.8 Hz, 1H), 7.95 (d, J = 9.2 Hz, 0H), 7.43 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 8.3, 4.7 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.13-7.04 (m, 1H), 6.76 (dd, J = 9.0, 4.6 Hz, 1H), 4.35 (d, J = 5.2 Hz, 1H), 3.06 (t, J = 6.3 Hz, 2H), 1.77 (p, J = 6.4 Hz, 2H). 13C NMR (126 MHz, DMSO-d6) δ 168.12 - 167.96 (m), 154.98, 153.12, 152.55 (d, J = 9.7 Hz), 143.12, 142.76, 152.66 - 152.52 (m), 139.91 (d, J = 11.7 Hz), 138.16 (d, J = 12.4 Hz), 136.46 (d, J = 13.0 Hz), 132.89, 128.22, 125.20, 123.67, 118.23 (d, J = 13.1 Hz), 116.61, 116.44, 115.69 (d, J = 6.9 Hz), 115.47, 115.29. 19 F NMR (471 MHz, DMSO-d6) δ -128.65.

[0194] NHWL037042: White solid, yield 80%, purity 99.8%. 1 H NMR (500 MHz, Chloroform-d) δ 9.67 (t, J = 5.7 Hz, OH), 8.36 (s, 1H), 7.65 - 7.61 (m, 1H), 7.58 (s, OH), 7.53 (d, J = 7.8 Hz, 1H), 7.22 - 7.17 (m, 1H), 7.14 (d, J = 8.5 Hz, 1H), 7.08 - 7.05 (m, 1H), 4.47 (d, J = 5.6 Hz, 1H), 3.44 (q, J = 6.7 Hz, 1H), 2.97 (t, J = 6.3 Hz, 2H), 2.79 (t, J = 6.9

[0195] Hz, 1H), 1.76 - 1.73 (m, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 166.58 (d, J = 1.8

[0196] Hz), 159.53, 157.60, 156.02, 149.87, 147.52, 144.77 (d, J = 2.8 Hz), 138.79, 136.91, 135.16, 132.42, 128.55, 123.82, 120.93 (d, J = 7.5 Hz), 119.88, 118.68, 118.50, 117.29, 117.10. 19 F NMR (471 MHz, Chloroform-d) δ -119.86.

[0197] NHWL037042: White solid, yield 80%, purity 98.5%. 1H NMR(500MHz,DMSO-d6)δ9.67(s,0H),8.95(t,J=6.0Hz,0H),8.54(d,J=2.3Hz,0H),8.45(dd,J=4.7,1.7Hz,0H),8.20(s,0H),7.74(dt,J=7.8,2.0Hz,0H),7.38-7.33(m,1H),7.29(d,J=8.4Hz,1H),7.12-7.03(m,1H),6.75(dd,J=9.1,4.6Hz,0H),4.75(d,J=5.6Hz,1H),4.37(d,J=6.0Hz,1H),3.06(t,J=6.4Hz,2H),1.79-1.75(m,3H). 13 C NMR(126MHz,Chloroform-d)δ181.71,166.31,162.69,159.94,158.01,148.99,144.75(d,J=2.8Hz),138.17,136.03,135.34,133.52,129.57,125.80,123.82,121.42(d,J=7.6Hz),118.89,118.71,117.61,117.42,53.40,46.69,43.27,36.64,31.58,24.52. 19 F NMR(471MHz,D MSO-d6)δ-128.80。

[0198] NHWL037069:白色固体,产率80%,纯度99.2%. 1 H NMR(500MHz,Chloroform-d)δ10.21(d,J=7.5Hz,1H),8.44(s,1H),8.40(d,J=4.1Hz,1H),7.91(s,1H),7.63(d,J=7.8Hz,1H),7.55(dd,J=9.3,3.1Hz,1H),7.18(dd,J=7.9,4.8Hz,1H),7.15-7.10(m,1H),7.08-7.00(m,5H),6.48(t,J=6.0Hz,1H),4.78(q,J=7.3Hz,1H),4.40-4.28(m,2H),3.01(t,J=6.0Hz,7H),1.86(d,J=12.6Hz,5H),1.76(dh,J=28.2,7.1Hz,1H),0.84(t,J=7.3Hz,3H). 13C NMR (126 MHz, Chloroform-d) δ 166.00 (d, J = 1.8 Hz), 159.80, 157.87, 156.30, 148.62, 148.20, 144.99 (d, J = 2.7 Hz), 138.59, 136.04, 135.68, 128.91 (d, J = 6.6 Hz), 126.86, 123.72, 121.91 (d, J = 7.7 Hz), 119.62, 118.88, 118.70, 117.08, 116.89, 55.54, 53.55, 41.35, 29.70, 24.72, 10.92. 19 F NMR (471 MHz, Chloroform-d) δ -118.72.

[0199] NHWL037070: White solid, yield 80%, purity 99.2%. 1 H NMR (500 MHz, Chloroform-d) δ 10.59 (d, J = 8.0 Hz, 1H), 8.47 (s, 1H), 8.43 (d, J = 4.2 Hz, 1H), 7.75 (s, 1H), 7.74 (s, 1H), 7.66 (dd, J = 9.5, 3.2 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.13 - 7.06 (m, 3H), 7.00 (d, J = 8.3 Hz, 2H), 6.42 (t, J = 5.9 Hz, 1H), 4.69 (t, J = 7.6 Hz, 1H), 4.48 - 4.36 (m, 2H), 3.14 - 3.02 (m, 4H), 2.00 - 1.94 (m, 4H), 1.30 - 1.22 (m, 2H), 0.94 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 165.88, 160.33, 158.38, 156.18, 148.11, 147.56, 145.47 (d, J = 2.8 Hz), 138.34, 136.56, 135.62, 127.34, 123.98, 123.01 (d, J = 7.8 Hz), 119.72, 119.16, 118.99, 117.28, 117.09, 60.03, 54.34, 41.43, 33.78, 24.86, 19.86, 19.08. 19 F NMR (471 MHz, Chloroform-d) δ -117.60.

[0200] NHWL037071 : white solid, 80% yield, 99.6% purity. 1 H NMR (500 MHz, Chloroform-d) δ 10.47 (d, J = 7.1 Hz, 1H), 8.44 (d, J = 2.2 Hz, 1H), 8.41 (dd, J = 5.0, 1.6 Hz, 1H), 7.73 (dt, J = 7.9, 2.0 Hz, 1H), 7.68 (s, 1H), 7.64 (dd, J = 9.4, 3.1 Hz, 1H), 7.27 (t, 1H), 7.19 (dd, J = 8.9, 4.8 Hz, 1H), 7.12 - 7.09 (m, 1H), 6.31 (t, J = 5.9 Hz, 1H), 4.39 (d, J = 6.2 Hz, 1H), 3.15 - 3.01 (m, 2H), 1.97 - 1.90 (m, 3H), 1.29 - 1.24 (m, 1H), 1.14 (qt, J = 8.2, 4.9 Hz, 1H), 0.59 - 0.29 (m, 1H). 19 F NMR (471 MHz, Chloroform-d) δ -118.30.

[0201] NHWL0370783: white solid, 80% yield, 99.2% purity. 1 H NMR (500 MHz, Chloroform-d) δ 9.67 (t, J = 5.7 Hz, 1H), 8.46 (s, 1H), 8.35 (d, J = 3.9 Hz, 1H), 7.91 (s, 1H), 7.59 - 7.56 (m, 1H), 7.20 - 7.14 (m, 1H), 7.09 (d, J = 8.2 Hz, 1H), 7.05 - 7.01 (m, 1H), 6.26 (d, J = 7.4 Hz, 1H), 2.96 (t, J = 5.9 Hz, 1H), 1.74 - 1.70 (m, 1H), 1.36 (d, J = 7.0 Hz, 1H). 13 C NMR (126 MHz, Chloroform-d) δ 167.02 (d, J = 1.8 Hz), 159.26, 157.33, 155.41, 148.05, 147.51, 144.74 (d, J = 2.5 Hz), 140.37, 138.88, 134.28, 132.03, 128.45, 123.67, 120.67 (d, J = 7.4 Hz), 119.57, 118.66, 118.48, 117.12, 116.93, 52.94, 47.57, 43.63, 24.64, 22.57. 19 F NMR (471 MHz, Chloroform-d) δ -120.38.

[0202] Example 10

[0203] Determination of cell growth inhibition rate by MTT method

[0204] Test method: Seven strains of gastric cancer cells (HGC-27, MKN-28, MKN-45, AGS, SGC-7901, NCI-N86, HS746T) and two strains of normal cells (GES-1, WI-38) were respectively placed in a cell culture box at 37℃, 5% CO2, using RPMI-1640 medium containing 10% fetal bovine serum or DMEM medium. When the cells were in the logarithmic phase, 5000-8000 cells per well were inoculated in a 96-well plate, and after 24h of culture, the old culture medium was removed and the culture medium containing the sample to be tested (100mmol / L target compound DMSO stock solution was prepared into experimental concentrations of 100, 50, 25, 12.5, 6.25μmol / L) was added, and three replicate wells were set for each experimental concentration, and a blank control group was also set.

[0205] After 72h of experimental cell culture, 10μL of MTT solution was added, and after 4h of incubation, the supernatant in the 96-well plate was aspirated, 150μL of DMSO was added to each well, and shaken for 20min. The absorbance value (OD value) of each well of the 96-well plate in the experiment was measured at 570nm using an enzyme-labeled instrument, the cell proliferation inhibition rate (IR) was calculated, the cell proliferation inhibition rate % = (control well average OD value - experimental well average OD value) / (control well average OD value - blank OD value), and the half-inhibitory concentration IC50 value (means ± SD, n = 3) was calculated using SPSS 20.0, and the specific data are shown in Table 1 (the above parallel experiments were independently repeated three times).

[0206] Test results: The above test results show that the compound of the present application or its pharmaceutically acceptable salt has inhibitory activity on seven strains of gastric cancer cells (HGC-27, MKN-28, MKN-45, AGS, SGC-7901, NCI-N86, HS746T), and has no proliferation inhibitory activity on two strains of normal cells (GES-1, WI-38).

[0207] Table 1 Inhibitory activity of compounds N1-N9 on seven strains of gastric cancer cells and two strains of normal cells

[0208]

[0209] Table 2 Inhibitory activity of compounds N10-N23 on seven strains of gastric cancer cells and two strains of normal cells

[0210]

[0211] The activity data of NHWL series compounds on cancer cells and NAMPT enzyme are shown in Table 3 below.

[0212] Table 3 Inhibitory activity of NHWL series compounds on cancer cells and NAMPT enzyme

[0213]

[0214] All data were obtained by three sets of repeated independent experiments; IC50values were calculated by IBM SPSS Statistics software.

[0215] Example 11

[0216] For example, compound NHWL024068 was used to perform flow cytometry-cycle experiment to measure the ability of compound NHWL024068 to induce S and G2 / M phase arrest of gastric cancer cells (the experimental results are shown in Figure 1 ), the ability to induce apoptosis of gastric cancer cells (the experimental results are shown in Figure 2 ), and it can be seen that its induction ability is outstanding.

[0217] For example, compound NHWL024068 was used to perform mitochondrial damage experiment, and the experimental results are shown in Figure 3 , and it can be seen that its ability to induce loss of mitochondrial membrane potential of gastric cancer cells is significantly stronger than Apatinib.

[0218] For example, compound NHWL024068 was used to perform Transwell migration experiment, and the experimental results are shown in Figure 4 , and it can be seen that its ability to inhibit gastric cancer cell migration is significantly stronger than Apatinib.

[0219] For example, compound NHWL024068 was used to perform monoclonal formation experiment, and the experimental results are shown in Figure 5 , and it can be seen that its ability to resist monoclonal formation is significantly stronger than Apatinib.

[0220] For example, compound NHWL024068 was used to perform EDU anti-proliferation experiment, and the experimental results are shown in Figure 6 (50μm, 20x), and it can be seen that its anti-proliferation ability is comparable to Apatinib.

[0221] It should be understood by those skilled in the art that the above discussion of any of the embodiments is merely exemplary and is not intended to suggest that the protection scope of the present application is limited to these examples; under the idea of the present application, the above embodiments or technical features in different embodiments can also be combined, the steps can be implemented in any order, and there are many other changes of different aspects of one or more embodiments of the present application as described above. In order to be brief, they are not provided in detail.

[0222] It is intended that the embodiments of the application herein described be interpreted to cover all such modifications, alterations, and equivalents as fall within the true spirit and scope of the application. Accordingly, what is desired to be secured by Letters Patent is the subject matter as follows:

Claims

1. A NAMPT inhibitor, characterized in that it has the structural formula: ； R 1 is H or Br; M is C, Y is N, and Z is C; n=1； L is thiourea, urea or ; R 2 is H, CF3, OCH3, F or Cl; R is H, methyl, ethyl, isopropyl or cyclopropyl; X is F, Cl or Br.

2. The NAMPT inhibitor according to claim 1, characterized in that R 1 H, R 2 For H.

3. The NAMPT inhibitor according to claim 1, characterized in that R is H or methyl.

4. The NAMPT inhibitor according to claim 3, characterized in that n=1, L is urea or .

5. A salt of the NAMPT inhibitor according to any one of claims 1 to 4, characterized in that: It is a pharmaceutically acceptable salt formed by the compound of the structural formula and an acid, wherein the acid is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, fumaric acid, citric acid, benzenesulfonic acid, and p-toluenesulfonic acid.

6. A composition characterized in that: The invention comprises the NAMPT inhibitor according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient, wherein the excipient is at least one of a diluent, a lubricant, a binder, a disintegrant, a surfactant, a film-forming material, a coating material and a capsule material.

7. A method for preparing the NAMPT inhibitor according to claim 1, characterized in that: Triphosgene and pyridine are reacted, and then compound 6 and compound 5 are added in sequence, reacted, and treated to obtain the NAMPT inhibitor; The structural formula of compound 6 is , the R 4 is H; The structural formula of compound 5 is , the R 3 is NH2; The structural formula of the NAMPT inhibitor is, R 1 is H or Br; M is C, Y is N, and Z is C; n=1； L is a urea group; R 2 is H, CF3, OCH3, F or Cl; R is H, methyl, ethyl, isopropyl or cyclopropyl; X is F, Cl or Br.

8. A use of the NAMPT inhibitor according to any one of claims 1 to 4 or the composition according to claim 6, characterized in that: The NAMPT inhibitor or the composition is used to prepare a drug for treating gastric cancer, wherein the gastric cancer is HGC-27 or MKN-45.

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