Nicotinamide derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a nicotinamide derivative or a pharmaceutically acceptable salt thereof. The invention also discloses a preparation method of the derivative. The nicotinamide derivative or the medicinal salt thereof can be effectively used for preparing medicines for preventing and / or treating cancers, wherein the cancers comprise at least one of glioma, breast cancer, liver cancer, lung cancer, colorectal cancer, leukemia, pancreatic cancer, osteosarcoma, cervical cancer, ovarian cancer, kidney cancer and esophageal cancer. The compound provided by the invention has broad-spectrum anticancer activity, and provides a new choice for the development of anticancer drugs.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology. More specifically, it relates to a nicotinamide derivative, its preparation method, and its applications. Background Technology

[0002] Currently, mainstream clinical anticancer therapies include chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, these therapies have significant limitations. Chemotherapy, lacking tumor targeting, results in strong systemic toxicity and poor patient tolerance; simultaneously, due to the genetic instability of tumor cells, it easily leads to multidrug resistance, directly causing treatment failure. While targeted therapy improves precision, its reliance on specific molecular targets limits its applicability to certain populations and faces the challenge of drug resistance mutations. Immunotherapy, as an emerging approach, relies on the complex tumor microenvironment, resulting in significant fluctuations in response rates among different individuals and the risk of triggering autoimmune reactions. Therefore, developing a highly effective, low-toxicity, broad-spectrum anticancer drug has become a critical technical problem urgently needing to be solved in this field. Summary of the Invention

[0003] In view of the problems existing in the prior art and in order to meet clinical needs, the present invention solves the problems existing in the prior art to a certain extent. The present invention provides a novel nicotinamide derivative, which has good anti-tumor activity. This type of compound can be used to prepare drugs for treating cancer.

[0004] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: According to a first aspect of the present invention, a nicotinamide derivative or a pharmaceutically acceptable salt thereof is provided, the compound being shown in Formula I: Formula I in, The X structure in Equation I is as follows: , Any one of them; The structure of ring A in formula I is as follows: , , , , , , , Any one of them; The R in the cyclic A structure can be independently selected from any one of hydrogen, alkyl, cycloalkyl, alkoxy, halogen, amino, nitrile, and nitro groups.

[0005] In some of these embodiments, when the R group is selected from any one of alkyl, cycloalkyl, and alkoxy groups, the R group may be further substituted by one or more halogen, nitrile, alkyl, or alkoxy groups.

[0006] In some of these embodiments, the compound structure of the nicotinamide derivative or its pharmaceutically acceptable salt includes: , , , , , , , , , At least one of them.

[0007] In some of these embodiments, the compound structure of the nicotinamide derivative or its pharmaceutically acceptable salt includes... , , , , At least one of them.

[0008] According to another aspect of the present invention, a pharmaceutical composition is provided, the pharmaceutical composition comprising the aforementioned compounds.

[0009] In some of these embodiments, the pharmaceutical composition comprises isotopically labeled derivatives of the aforementioned compounds.

[0010] In some of these embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable salt of the aforementioned compound.

[0011] In some of these embodiments, the pharmaceutical composition comprises a prodrug of the aforementioned compound or a solvation thereof.

[0012] In some embodiments, the pharmaceutical composition further includes a pharmaceutically acceptable excipient or a pharmaceutically acceptable salt thereof, and a suitable carrier or excipient.

[0013] According to another aspect of the invention, the invention provides an application in the preparation of medicaments for the prevention and / or treatment of cancer, comprising the aforementioned compounds or the aforementioned pharmaceutical compositions.

[0014] In some of these embodiments, the cancer includes at least one of glioma, breast cancer, liver cancer, stomach cancer, leukemia, lung cancer, pancreatic cancer, osteosarcoma, ovarian cancer, kidney cancer, and skin cancer.

[0015] According to another aspect of the present invention, a pharmaceutical preparation is provided comprising the aforementioned compound, its salt or crystal form thereof, and pharmaceutically acceptable excipients or auxiliary ingredients.

[0016] In some of these embodiments, the formulation may be at least one of tablets, capsules, granules, powders, pills, injections, creams, or gels.

[0017] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0018] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms. Preferably, it is an alkyl group containing 1 to 10 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, more preferably an alkyl group containing 1 to 3 carbon atoms, and most preferably methyl. Non-limiting examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc., and their various branched isomers. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable linking point, preferably by one or more of the following groups, independently selected from halogen, hydroxyl, cyano, nitro, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0019] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.

[0020] "Alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl is defined as described above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, etc. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio groups.

[0021] "Pharmaceutical composition" means containing one or more of the compounds described in this invention or their pharmaceutically acceptable salts, or their prodrugs, in combination with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to promote the absorption of the active ingredient by an organism, thereby facilitating the exertion of the active ingredient's biological activity within the organism.

[0022] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0023] The present invention has achieved the following beneficial effects: 1: This invention provides a novel type of nicotinamide derivative and a method for its preparation. The preparation process is simple and easy to operate, and is suitable for large-scale production.

[0024] 2: This invention provides a pharmaceutical composition, and provides the use of the aforementioned compound and pharmaceutical composition in the preparation of antitumor drugs for prevention and / or treatment.

[0025] 3: Finally, the present invention also provides an application of a pharmaceutical preparation. Detailed Implementation

[0026] The present invention will be further described below with reference to embodiments. Obviously, based on the above description of the present invention, and according to ordinary technical knowledge and common practice in the art, various other modifications, substitutions, or alterations can be made without departing from the basic technical concept of the present invention. The present invention will be further described in detail below through specific embodiments. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above description of the present invention fall within the scope of the present invention.

[0027] In the following embodiments, unless otherwise specified, all raw materials used are commercially available products that can be purchased directly or can be prepared using conventional methods in the art. Room temperature refers to 25 ± 5°C.

[0028] Example 1: Preparation of 5-fluoro-N-(pyridin-3-yl)thiophene-2-carboxamide

[0029] 5-Fluorothiophene-2-carboxylic acid (1 equiv), HATU (1.2 equiv), DIPEA (3 equiv), and m-aminopyridine were dissolved in 10 mL of dichloromethane. After stirring at room temperature for 16 h, the reaction solution was concentrated and washed successively with saturated sodium bicarbonate solution and dilute hydrochloric acid (20 mL × 3), and extracted with ethyl acetate (20 mL × 3). The collected organic layer was then dried with anhydrous sodium sulfate, and the solvent was removed from the filtrate by vacuum distillation. The solution was then purified by silica gel column chromatography with petroleum / ethyl acetate (5:1; v / v) to obtain target compound 1. The chromatographic data are shown below.

[0030] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.46 (s, 1H), 8.86 (s, 1H), 8.32 (d, J =4.9 Hz, 1H), 8.10 (d, J = 8.6 Hz, 1H), 7.82 (t, J = 4.0 Hz, 1H), 7.45 – 7.33(m, 1H), 6.92 (d, J = 2.6 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 169.99,167.08, 160.24, 145.24, 142.32, 135.68, 129.11, 128.17, 124.11, 110.76. TOF-MS m / z: calcd for: C 10 H8FN2OS + [M + H] + : 223.0336; found: 223.0331. Example 2 Preparation of 5-phenyl-N-(pyridin-3-yl)thiophene-2-carboxamide The target compound 2 was synthesized according to the method in Example 1, and the spectral data are as follows.

[0031] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.47 (s, 1H), 8.91 (d, J = 2.5 Hz, 1H),8.36 – 8.27 (m, 1H), 8.15 (d,J = 8.2 Hz, 1H), 8.05 (d, J = 4.0 Hz, 1H), 7.81– 7.71 (m, 2H), 7.65 (d, J = 4.0 Hz, 1H), 7.47 (t, J = 7.5 Hz, 2H), 7.43 –7.34 (m, 2H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 165.07, 160.54, 149.34, 145.13,142.33, 138.52, 135.90, 133.33, 131.26, 129.78, 129.28, 127.82, 126.24,125.00, 124.10. TOF-MS m / z: calcd for: C 16 H 13 N2OS + [M + H] + : 281.0743; found:281.0752. Example 3 Preparation of 5-(4-fluorophenyl)-N-(pyridin-3-yl)thiophene-2-carboxamide The target compound 3 was synthesized according to the method in Example 1, and the spectral data are as follows.

[0032] 1 H NMR (400 MHz, DMSO- d 6 ) δ 13.48 (s, 1H), 8.76 (d, J = 4.4 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 7.79 (dd, J = 8.4, 5.3 Hz, 2H), 7.71 (d, J = 4.0Hz, 1H), 7.54 (d, J = 3.9 Hz, 2H), 7.38 (dd, J = 14.9, 8.5 Hz, 1H), 7.29 (t, J = 8.7 Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 164.05, 163.23, 161.60, 151.59,149.04, 140.08, 135.10, 134.85, 133.79, 129.94, 128.60, 125.20, 121.19,116.82, 116.61. TOF-MS m / z: calcd for: C 16 H 11 ONaSF + [M + H] + : 321.0475; found:321.0468. Example 4 Preparation of N-(1H-benzo[d]imidazol-2-yl)nicotinamide Nicotinic acid (1 equiv), HATU (1.2 equiv), DIPEA (3 equiv), and 1H-benzo[d]imidazole-2-amine were dissolved in 10 mL of dichloromethane. After stirring at room temperature for 16 h, the reaction solution was concentrated and washed successively with saturated sodium bicarbonate solution and dilute hydrochloric acid (20 mL × 3), and extracted with ethyl acetate (20 mL × 3). The collected organic layer was then dried with anhydrous sodium sulfate, and the solvent was removed from the filtrate by vacuum distillation. The solution was then purified by silica gel column chromatography with petroleum / ethyl acetate (5:1; v / v) to obtain the target compound 4. The chromatographic data are shown below.

[0033] 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.48 (s, 1H), 9.29 (s, 1H), 8.73 (d, J =3.2 Hz, 1H), 8.44 (d, J = 7.9 Hz, 1H), 8.16 (s, 1H), 7.60 – 7.50 (m, 1H), 7.50 – 7.40 (m, 2H), 7.26 – 7.11 (m, 2H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 169.76,152.43, 151.18, 150.09, 136.36, 132.50, 131.97, 123.88, 122.59, 113.02. TOF-MS m / z: calcd for: C 13 H 11 ON4O+ [M + H] + : 239.0927; found: 239.0937. Example 5 Preparation of N-(5-phenylthiazol-2-yl)nicotinamide The target compound 5 was synthesized according to the method in Example 4, and the spectral data are as follows.

[0034] 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.97 (s, 1H), 9.23 (s, 1H), 8.94 – 8.65(m, 1H), 8.49 – 8.31 (m, 1H), 7.99 (s, 1H), 7.73 – 7.62 (m, 2H), 7.62 – 7.55(m, 1H), 7.50 – 7.39 (m, 2H), 7.37 – 7.28 (m, 1H). 13 C NMR (101 MHz, DMSO- d 6 )δ 164.58, 158.25, 153.38, 149.68, 136.39, 134.07, 131.91, 129.71, 128.62,128.16, 126.24, 124.07. TOF-MS m / z: calcd for: C 15 H 12 ON3S + [M + H] + : 282.0696;found: 282.0702. Example 6 Preparation of N-(thiazol-2-yl)nicotinamide The target compound 6 was synthesized according to the method in Example 4, and the spectral data are as follows.

[0035] 1 H NMR (400 MHz, DMSO- d 6 ) δ 12.88 (s, 1H), 9.21 (s, 1H), 8.78 (d, J =4.8 Hz, 1H), 8.41 (d, J = 8.1 Hz, 1H), 7.57 (s, 2H), 7.31 (s, 1H). 13 C NMR (101 MHz, DMSO-) d6 ) δ 164.48, 159.20, 153.52, 149.63, 137.77, 136.33, 128.71,124.04, 114.51. TOF-MS m / z: calcd for: C9H8ON3S + [M + H] + : 206.0383; found: 206.0392. Example 7 Preparation of N-(1H-indole-5-yl)nicotinamide The target compound 7 was synthesized according to the method in Example 4, and the spectral data are as follows.

[0036] 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.10 (s, 1H), 10.33 (s, 1H), 9.18 (s,1H), 8.75 (d, J = 4.9 Hz, 1H), 8.34 (d, J = 7.9 Hz, 1H), 8.05 (s, 1H), 7.62 –7.50 (m, 1H), 7.49 – 7.39 (m, 2H), 7.36 (t, J = 2.8 Hz, 1H), 6.46 (s, 1H). 13 CNMR (101 MHz, DMSO- d 6 ) δ 164.09, 152.26, 149.13, 135.81, 133.65, 131.50,127.92, 126.51, 123.92, 116.52, 112.81, 111.65, 101.74. TOF-MS m / z: calcdfor: C 14 H 12 ON3 + [M + H] + : 238.0975; found: 238.0984. Example 8 Preparation of N-(2,3-dihydrobenzo[b][1,4]dioxanepenta[1,2-a]pyridin-6-yl)nicotinamide The target compound 8 was synthesized according to the method in Example 4, and the spectral data are as follows.

[0037] 1H NMR (400 MHz, DMSO- d 6 ) δ 10.28 (s, 1H), 9.09 (d, J = 2.2 Hz, 1H),8.79 – 8.70 (m, 1H), 8.32 – 8.21 (m, 1H), 7.62 – 7.48 (m, 1H), 7.40 (d, J =2.5 Hz, 1H), 7.24 – 7.15 (m, 1H), 6.84 (d, J = 8.7 Hz, 1H), 4.26 – 4.23 (m,2H), 4.23 – 4.18 (m, 2H). 13 C NMR (101 MHz, DMSO- d 6 ) δ 164.08, 152.44, 149.07,143.35, 140.35, 135.81, 132.91, 131.08, 123.92, 117.20, 114.10, 109.97,64.65, 64.44. TOF-MS m / z: calcd for: C 14 H 13 N2O3 + [M + H] + : 257.0921; found:257.0928. Example 9 Preparation of 2-(4-fluorophenyl)-4-methyl-N-(pyridin-3-yl)thiazole-5-carboxamide

[0038] 4-Fluorophenylthiamine (1 equiv) and ethyl 2-chloroacetate (1 equiv) were added to 10 mL of anhydrous ethanol and heated under reflux for 12 h to initiate a cyclization reaction. After the reaction was complete, the product was precipitated by cooling and crystallization, and then separated by filtration to obtain the cyclized product ethyl 2-(4-fluorophenyl)-4-methylthiazol-5-carboxylic acid ester. Subsequently, this intermediate was added to a mixed solvent (total volume 7 mL) prepared by THF, methanol and water in a volume ratio of 3:3:1, and LiOH·H2O (2.5 equiv) was added. The reaction was stirred at room temperature for 4 h. After the reaction was completed, the hydrolysate was carefully acidified to acidic with hydrochloric acid and thoroughly washed with cold water to precipitate 2-(4-fluorophenyl)-4-methylthiazol-5-carboxylic acid. Finally, this carboxylic acid product (1 equiv), HATU (1.2 equiv), DIPEA (3 equiv), and m-aminopyridine (1.2 equiv) were dissolved in 10 mL of dichloromethane and stirred at room temperature for 16 h. After h, the mixture was washed sequentially with saturated sodium bicarbonate solution and dilute hydrochloric acid (20 mL × 3), extracted with ethyl acetate (20 mL × 3), and then dried with anhydrous sodium sulfate. The solvent in the filtrate was removed by vacuum distillation, and then purified by silica gel column chromatography with petroleum / ethyl acetate (5:1; v / v) to obtain the target compound 9. The chromatographic data are as follows.

[0039] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.45 (s, 1H), 8.86 (d, J = 2.6 Hz, 1H),8.44 – 8.24 (m, 1H), 8.18 – 8.06 (m, 1H), 8.07 – 7.86 (m, 2H), 7.41 (d, J =9.0 Hz, 1H), 7.38 (d, J = 5.1 Hz, 1H), 7.35 (s, 1H), 2.66 (s, 3H). 13 C NMR (101 MHz, DMSO-) d 6 ) δ 165.95, 165.40, 162.92, 160.64, 157.07, 145.42, 142.50,135.77, 129.43, 129.18, 128.07, 125.98, 124.08, 117.09, 116.87, 17.66. TOF-MSm / z: calcd for: C 16 H13 N2O3 + [M + H] + : 314.0758; found: 314.0768. Example 10 Preparation of 4-methyl-N-(pyridin-3-yl)-2-(4-(trifluoromethyl)phenyl)thiazole-5-carboxamide The target compound 10 was synthesized according to the method of Example 9, and the spectral data are as follows.

[0040] 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.53 (s, 1H), 8.86 (d, J = 2.6 Hz, 1H),8.37 – 8.32 (m, 1H), 8.20 (d, J = 8.1 Hz, 2H), 8.13 – 8.09 (m, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.43 – 7.38 (m, 1H), 2.69 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6 )δ 165.12, 160.46, 157.25, 145.52, 142.50, 136.24, 135.72, 131.26, 128.04,127.55, 126.94, 125.73, 124.10, 123.02, 17.65. TOF-MS m / z: calcd for:C 17 H 13 N3OF3S + [M + H] + : 364.0726; found: 364.0733. Example 11: Determination of the in vitro antitumor activity of the compounds of the present invention The mouse glioblastoma cell line GL261, human glioblastoma cell line U87, human liver cancer cell line HepG2, human lung adenocarcinoma cell line A549, human breast cancer cell line MDA-MB-231, human acute lymphoblastic leukemia cell lines MOLT-4 and CCRF-CEM, human multiple myeloma cell line MM1S, human pancreatic adenocarcinoma cell lines AsPC-1 and BxPC-3, human acute T-lymphoblastic leukemia cell line Jurkat, human acute monocytic leukemia cell line MV4-11, human embryonic kidney cells HEK, and human bone marrow stromal cell line HS-5 described in the following examples were all derived from the Cell Bank of the Chinese Academy of Sciences. The experimental methods used in the test examples of this invention were generally performed under conventional conditions or according to the conditions recommended by the commercial manufacturer. Reagents not specifically attributed are commonly used commercially available reagents.

[0041] The antitumor activity of the compounds of this invention was determined using the following method. CCRF, Jurkat, MV4-11 and MOLT-4 cells were cultured at a density of 1 × 10⁶ cells per well. 4 The density of seeding was 7 × 10⁶ cells per well in a 96-well plate, with A549, HepG2 and MDA-MB-231 seeded at 7 × 10⁶ cells per well. 3 Each of the AsPC-1 and BxPC-3 is 3 × 10⁻⁶ per hole. 3 Each MM-1S has 4×10 holes. 3 Each well was inoculated with 50 μL of culture medium. After overnight incubation, 50 μL of serially diluted compound working solution (using the appropriate culture medium) was added to each well, and incubation continued for 24 hours. Subsequently, 10 μL of CCK-8 solution was added to each well, gently mixed, and incubated for another hour. Finally, the absorbance (OD value) of each well was measured at 450 nm using a microplate reader. Nonlinear regression analysis was then performed using GraphPad Prism 9.0 software to calculate the dose-response curve and the half-maximal inhibitory concentration (IC50). 50 )value.

[0042] Table 1: Antiproliferative activity of the compounds of the present invention against mouse glioblastoma cell line GL261 and human glioblastoma cell line U87 Compd. <![CDATA[IC 50 for GL261 (nM)]]> <![CDATA[IC 50 for U87 (nM)]]> Gliocidin 292 281 1 672 628 2 535 417 3 972 698 4 1072 475 5 107 139 6 721 241 7 716 249 8 724 498 9 1058 272 10 394 250 In existing technologies, the inhibitory activity of small molecule drugs is typically defined using a general grading framework based on activity intensity. This framework is used when a small molecule drug exhibits an IC50 response to a specific cell line. 50 ≤1000nM indicates high activity; when a small molecule drug has an IC50 value for a certain cell line... 50 The range is 1000nM≤IC 50≤10000 nM indicates moderate activity. Based on the experimental data above, all compounds of this invention exhibit good anti-proliferative activity against mouse glioblastoma cell line GL261 and human glioblastoma cell line U87. Compound 5, in particular, demonstrates the strongest anti-glioma activity, exceeding that of the positive control drug Gliocidin.

[0043] Table 2: Antiproliferative activity of compound 5 and gliocidin against other tumor cells and normal cells Cell lines <![CDATA[GliocidinIC 50 (nM) a ]]> <![CDATA[Compound 5IC 50 (nM)]]> Cell lines <![CDATA[GliocidinIC 50 (nM)]]> <![CDATA[Compound 5IC 50 (nM) a ]]> HepG2 337 142 AsPC-1 630 426 A549 408 157 BxPC-3 672 408 MDA-MB-231 764 639 CCRF 593 235 MOLT-4 692 415 Jurkat 847 359 MM1S 893 672 MV4-11 891 604 HEK >10 μM >10 μM HS-5 >10 μM >10 μM The experimental data above show that compound 5 exhibits superior antiproliferative activity compared to gliocidin in all tested cancer cells. Among them, the human hepatocellular carcinoma cell line HepG2 and the human lung cancer cell line A549 showed the most significant sensitivity to both gliocidin and compound 5. Furthermore, compound 5 exhibited weak cytotoxicity against human embryonic kidney cells (HEK) and normal bone marrow stromal cells (HS-5), with an IC50 value of [missing value]. 50 All values ​​were greater than 10 μM, indicating good safety. In summary, compound 5 exhibited significantly better anti-proliferative effects than gliocidin in different tumor cell types, and also had a wider safety window relative to its antitumor efficacy.

[0044] Example 12 In vitro liver microsomal stability determination The test compound was dissolved in methanol at a concentration of 500 ng / mL as a stock solution, and a corresponding internal standard solution (2.5 ng / mL methanol solution) was prepared simultaneously for subsequent analysis. Metabolic stability was assessed using the Phase I metabolic stability kit, strictly following the manufacturer's operating procedures. The specific experimental procedure is as follows: Solution A (10 μL), Solution B (2 μL), 0.1 M PBS buffer (182 μL), and 1 μL of the test compound stock solution (500 ng / mL) were added sequentially to a 1.5 mL microcentrifuge tube. After incubation at 37°C for 5 min, the enzymatic reaction was initiated by adding 5 μL of mixed liver microsomes (final protein concentration 0.5 mg / mL). The reaction was terminated at predetermined time points (0 and 15 min) by adding 200 μL of ice-cold methanol containing the internal standard. After vortexing to precipitate the protein for 3 min, the mixture was centrifuged (12,000 g, 10 min), and the supernatant was analyzed by LC-MS / MS.

[0045] Table 3: Results of stability assays of compound 5 and gliocidin on liver microsomes in different species. Note: All values ​​represent the average residual compounds after 30 min of incubation in liver microsomes (n = 3).

[0046] The experimental results above show that the residual amount of compound 5 after incubation in different liver microsomes for 30 min exceeded 80% of that of Gliocidin, indicating that the metabolic stability of compound 5 is significantly better than that of Gliocidin.

[0047] In summary, this invention provides a class of nicotinamide derivatives. Cell experiments have shown that these compounds have good antitumor activity and metabolic stability, and have promising application prospects.

Claims

1. A nicotinamide derivative or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in Formula I: Equation I in, The X structure in Equation I is as follows: , Any one of them; The structure of ring A in formula I is as follows: , , , , , , , Any one of them; The R in the cyclic A structure can be independently selected from any one of hydrogen, alkyl, cycloalkyl, alkoxy, halogen, amino, nitrile, and nitro groups.

2. The nicotinamide derivative or its pharmaceutically acceptable salt according to claim 1, characterized in that, When the R group is selected from any one of alkyl, cycloalkyl, and alkoxy groups, the R group may be further replaced by one or more halogen, nitrile, alkyl, or alkoxy groups.

3. The nicotinamide derivative or its pharmaceutically acceptable salt according to claim 1, characterized in that, The structure of the compound includes: , , , , , , , , , At least one of them.

4. The nicotinamide derivative or its pharmaceutically acceptable salt according to claim 1, characterized in that, The compound structure includes , , , , At least one of them.

5. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the compound according to any one of claims 1 to 4; And / or, isotopically labeled derivatives of the compound according to any one of claims 1 to 4; And / or, a pharmaceutically acceptable salt of the compound of any one of claims 1 to 4; And / or, a prodrug or a solvation thereof of the compound described in any one of claims 1 to 4.

6. The pharmaceutical composition according to claim 5, characterized in that, The pharmaceutical composition further includes pharmaceutically acceptable excipients or their pharmaceutically acceptable salts, as well as suitable carriers or excipients.

7. An application in the preparation of drugs for the prevention and / or treatment of cancer, characterized in that, Includes the compound according to any one of claims 1 to 4 or the pharmaceutical composition according to any one of claims 5 to 6.

8. The application according to claim 7, characterized in that, The cancers mentioned include at least one of glioma, breast cancer, liver cancer, stomach cancer, leukemia, lung cancer, pancreatic cancer, osteosarcoma, ovarian cancer, kidney cancer, and skin cancer.

9. A pharmaceutical preparation, characterized in that, It includes the compounds described in any one of claims 1-4, their salts or crystal forms thereof, and pharmaceutically acceptable excipients or auxiliary ingredients.

10. The pharmaceutical preparation according to claim 9, characterized in that, The formulation may be at least one of tablets, capsules, granules, powders, pills, injections, creams, or gels.

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