Application of a class of 1-amide and 1-hydrazide substituted β-carboline derivatives as agricultural fungicides

Abstract

The present invention discloses a class of 1-amide and 1-hydrazide substituted β-carboline derivatives for use as agricultural fungicides. The present invention first provides a compound represented by formula (I): R1 is selected from carboxymethyl or carbamoyl; R2 is selected from C 1‑18 Alkyl, one or more R a C 1‑18 Alkyl, phenyl, one or more R b Any one of phenyl, 5-10 membered heteroaryl, carboxyl, #imgabs0# substituted by a group; wherein R3 is selected from phenyl or one or more R b phenyl substituted with a group; R a or R b are independently selected from halogen, C 1‑3 Alkyl, C substituted by halogen 1‑3 Alkyl, C substituted by halogen 1‑3 Alkoxy, methoxy, formyl, and nitro groups. This invention uses β-carboline as the parent nucleus and primarily introduces amide and hydrazide groups at position 1 to synthesize a series of 1-amide and 1-hydrazide substituted β-carboline derivatives. Antibacterial activity tests showed that the 1-amide and 1-hydrazide substituted β-carboline derivatives exhibited significant inhibitory activity against a variety of agricultural plant pathogens. #imgabs1#

Description

Technical Field

[0001] The present invention relates to the synthesis of 1-amide and 1-hydrazide substituted beta-carboline derivatives and their application as fungicides in plant disease prevention and control. Background Art

[0002] Using fungicides to control plant diseases is one of the important measures to ensure high and stable yields of crops. Before the 1970s, the fungicides used were almost all traditional protective fungicides with multiple action sites and were not likely to induce resistance in pathogens. Until the late 1960s and early 1970s, with the development and widespread use of modern fungicides that are highly efficient, systemic, and selective, fungicide resistance became increasingly serious and widespread, often leading to the failure of chemical control of plant diseases and huge losses in agricultural production. (Qi Zhiqiu, Wang Jianxin, Chen Changjun, Zhou Mingguo. Progress in research on modern fungicide resistance [J]. Pesticides. 2006(10)). It can be seen that the continuous development of new fungicide varieties to solve the problem of mainstream fungicide resistance is an important direction of current pesticide research.

[0003] Carboline alkaloids are a major class of indole alkaloids, sharing a common pyridoindole tricyclic structure. β-Carboline alkaloids are the most widely distributed, abundant, and extensively studied of the carboline alkaloids in nature. β-Carbolines exhibit a variety of activities, including antitumor, antiviral, antibacterial, and antioxidant properties. Currently, their anticancer activity is the most studied, while their agricultural fungicidal activity has been rarely reported.

[0004] This patented invention uses β-carboline as the parent nucleus and introduces amide and hydrazide groups, primarily at position 1, to synthesize a series of 1-amide and 1-hydrazide substituted β-carboline derivatives. The compounds were tested for their inhibitory activity against important agricultural plant pathogenic fungi and bacteria, providing a foundation for the development of new fungicides. Summary of the Invention

[0005] In view of the deficiencies of the prior art, the first object of the present invention is to provide a class of 1-amide and 1-hydrazide substituted β-carboline derivatives; the second object is to provide the use of the aforementioned β-carboline derivatives as fungicides in plant disease control.

[0006] The technical solutions of the present invention are as follows:

[0007] In a first aspect, the present invention protects a class of 1-substituted β-carboline derivatives represented by formula (I), or pharmaceutically acceptable salts, solvates, optical isomers or polymorphs thereof:

[0008]

[0009] R1 is selected from carboxymethyl or carbamoyl;

[0010] R2 is selected from C 1-18 Alkyl, one or more R a C 1-18 Alkyl, one or more R a C 1-18 Alkoxy, phenyl, one or more R b substituted phenyl, 5-10 membered heteroaryl, carboxyl Any of;

[0011] Wherein, R3 is selected from phenyl or one or more R b phenyl substituted with a group;

[0012] R a or R b are independently selected from halogen, C 1-3 Alkyl, C substituted by halogen 1-3 Alkyl, C substituted by halogen 1-3 Alkoxy, methoxy, formyl, nitro.

[0013] In a specific embodiment,

[0014] R1 is selected from carboxymethyl or carbamoyl;

[0015] R2 is selected from methyl, phenyl, benzyl, phenethyl, 2-chlorophenyl, 2-fluorophenyl, 2-iodophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 2,4,5-trichlorophenyl, 3-ethylindole, 5-1,2,3-thiadiazole, 2-thiazole, 2-benzimidazole, 1-piperidine, 2-pyridine, 3-pyrazole; carboxyl, n-propyl, isopropyl, ethyl, 2-chloroethyl, octadecyl, cyclohexyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,5-dimethoxyphenyl, 3-chlorophenyl, 3-fluorophenyl, 4-bromophenyl, 3-bromophenyl, 4-iodophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-dichlorophenyl, 1-piperidine, 3-pyrazole, 3-pyridine, 1-methyl-3-pyridine, Any of;

[0016] Wherein, R3 is selected from phenyl, 2-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 4-methoxyphenyl, 4-chlorophenyl, 2-chlorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-nitrophenyl, 4-bromophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, benzoyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 3-chlorophenyl, 3-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 2,3,4,5,6-pentafluorophenyl, 4-isobutylphenyl, 2-naphthyl, piperidine, any one of 2,3,5,6-tetrafluoro-4-phenyltrifluoromethyl.

[0017] In a specific embodiment, the present invention provides a 1-amide substituted β-carboline derivative represented by formula (I), or a pharmaceutically acceptable salt, solvate, optical isomer or polymorph thereof:

[0018]

[0019] When R1 = carboxymethyl,

[0020] R2 is selected from any one of methyl, isopropyl, phenyl, benzyl, phenethyl, 2-chlorophenyl, 2-fluorophenyl, 2-iodophenyl, 2-methylphenyl, 2-methoxyphenyl, 2-trifluoromethylphenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 2,4,5-trichlorophenyl, 3-ethylindole, 5-1,2,3-thiadiazole, 2-thiazole, 2-benzimidazole, 1-piperidine, 2-pyridine, and 3-pyrazole;

[0021] When R1 = carbamoyl,

[0022] R2 is selected from carboxyl, n-propyl, isopropyl, ethyl, 2-chloroethyl, octadecyl, cyclohexyl, phenyl, benzyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,5-dimethoxyphenyl, phenethyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-bromophenyl, 3-bromophenyl, 4-iodophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-dichlorophenyl, 1-piperidine, 3-pyrazole, 3-ethylindole, 5-1,2,3-thiadiazole.

[0023] In a specific embodiment, the present invention provides a 1-hydrazide-substituted β-carboline derivative represented by formula (II), or a pharmaceutically acceptable salt, solvate, optical isomer or polymorph thereof:

[0024]

[0025] When R1 = carboxymethyl,

[0026] R3 is selected from any one of phenyl, 4-methylphenyl, 2-chlorophenyl, 4-methoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-nitrophenyl, 4-bromophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, and benzoyl;

[0027] When R1 = carbamoyl,

[0028] R3 is selected from any one of phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-trifluoromethoxyphenyl, 4-trifluoromethylphenyl, 3-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, benzoyl, 2-methylphenyl, 3-methylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 2,3,4,5,6-pentafluorophenyl, 4-isobutylphenyl, 2-naphthyl, piperidine, 2,3,5,6-tetrafluoro-4-phenyltrifluoromethyl.

[0029] In a specific embodiment, the present invention also protects the following 1-substituted β-carboline derivatives or pharmaceutically acceptable salts, solvates, optical isomers or polymorphs thereof:

[0030]

[0031]

[0032]

[0033] In a second aspect, the present invention further protects a pharmaceutical composition comprising the aforementioned β-carboline derivative or a pharmaceutically acceptable salt, solvate, optical isomer or polymorph thereof.

[0034] In a third aspect, the present invention also protects the use of the aforementioned β-carboline derivatives or pharmaceutically acceptable salts, solvates, optical isomers or polymorphs thereof in the preparation of preparations for inhibiting plant pathogenic fungi.

[0035] The plant pathogenic fungi are preferably selected from any one or more of the following: Botrytis cinerea, Gaeumannomyces graminisis, Sclerotinia sclerotiorum, Fusarium graminearum, Phytophthora capsici, and Fusarium moniliforme.

[0036] Among them, Botrytis cinerea often causes strawberry gray mold, Gaeumannomyces graminisis often causes wheat take-all disease, Sclerotinia sclerotiorum often causes rapeseed sclerotinia, Fusarium graminearum often causes wheat fusarium head blight, Phytophthora capsici often causes pepper blight, and Fusarium moniliforme often causes rice seedling rot.

[0037] In a fourth aspect, the present invention also protects the use of the aforementioned β-carboline derivatives or acceptable salts thereof in the preparation of preparations for inhibiting plant pathogenic bacteria.

[0038] The plant pathogenic bacteria are preferably selected from any one or more of the following: Pseudomonas syringaepv.glycinea, Xanthomonas oryzaeoryzae pv.oryzae, Xanthomonas oryzae oryzae pv.oryzicola, and Gram-positive bacteria Clavibacter michiganensesubsp.sepedonicum.

[0039] Among them, Pseudomonas syringae pv.glycinea often causes soybean spot disease, Xanthomonas oryzae oryzae pv.oryzae often causes rice bacterial leaf blight, Xanthomonas oryzae oryzae pv.oryzicola often causes rice bacterial leaf streak disease, and the Gram-positive bacterium Clavibacter michiganense subsp.sepedonicum often causes potato ring rot.

[0040] This patented invention uses β-carboline as the parent nucleus and introduces amide and hydrazide groups, primarily at position 1, to synthesize a series of 1-amide and 1-hydrazide-substituted β-carboline derivatives. The compounds were tested for their inhibitory activity against important agricultural plant pathogens and bacteria. The results showed that the 1-amide and 1-hydrazide-substituted β-carboline derivatives exhibited significant inhibitory activity against a variety of agricultural plant pathogens.

[0041] The present invention provides a method for preparing the above-mentioned 1-substituted β-carboline derivatives, which comprises the following steps:

[0042] Step 1. Synthesis of 1-carboxy-3-methoxycarbonyl-2,3,4,9-tetrahydro-β-carboline: To 50 mL of water were added 0.5 mL of concentrated H₂SO₄ and 50% aqueous glyoxylic acid (3.6 mL, 24.5 mmol, 1.0 equiv), followed by L-tryptophan methyl ester hydrochloride (6.3 g, 24.5 mmol, 1.0 equiv). The mixture was stirred at room temperature overnight and adjusted to pH 6-7 with 1 mol / L sodium hydroxide, resulting in the precipitation of a white solid. The white slurry was filtered, and the filter cake was washed three times with water to yield 1-carboxy-3-methoxycarbonyl-2,3,4,9-tetrahydro-β-carboline (6.4 g, 95%) as a white solid.

[0043] Step 2. Synthesis of 1-carboxy-3-methoxycarbonyl β-carboline (A7). 1-Carboxy-3-methoxycarbonyl 2,3,4,9-tetrahydro β-carboline (5.5 g, 20 mmol, 1.0 equiv) was dissolved in 50 mL of DMSO, and DBU (6.1 g, 40 mmol, 2.0 equiv) and CuBr2 (0.9 g, 4 mmol, 0.2 equiv) were added. The reaction was stirred at room temperature for 24 hours, after which a yellow solid precipitated. The solid product was filtered and washed three times with DMSO and then with petroleum ether to afford compound A7 (5.0 g, 92%) as a yellow solid.

[0044] Step 3. Synthesis of 1-carboxy-3-carbamoyl β-carboline (C7). Compound A7 (2.5 g, 9.2 mmol) was dissolved in a mixture of methanol (100 mL) and aqueous ammonia (100 mL), heated under reflux, and stirred overnight. After the reaction, the mixture was filtered, the methanol evaporated, and the pH of the filtrate was adjusted to 7-8 with 1 mol / L HCl solution. The precipitated solid was filtered and washed three times with water to obtain Compound C7 (2.0 g, 85%) as a yellow solid.

[0045] Step 4. Synthesis of 1-Amide and 1-Hydrazide Substituted β-Carboline Derivatives. Dissolve compound A7 (271 mg, 1.0 mmol, 1.0 equiv) or C7 (256 mg, 1.0 mmol, 1.0 equiv) in 30 mL of DCM, then add an amine (0.8 mmol, 0.8 equiv) or hydrazine (0.8 mmol, 0.8 equiv). Next, add PyBOP (Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) (520 mg, 1.0 mmol, 1.0 equiv) and stir at room temperature overnight. After the reaction, if solid precipitation is observed, filter the precipitated solid and wash it three times with DCM to obtain the corresponding product. The product purity can be improved by recrystallization from a mixture of ethyl acetate and methanol. If no solid precipitation occurs, wash it three times with NH4Cl and saturated NaCl, then dry it over anhydrous Na2SO4. The mixture is then concentrated in vacuo and purified by column chromatography to obtain the corresponding product.

[0046] Beneficial effects:

[0047] This study uses β-carboline as a nucleus and introduces amide and hydrazide groups, primarily at position 1, to synthesize a series of 1-amide and 1-hydrazide-substituted β-carboline derivatives. The compounds were tested for their inhibitory activity against important agricultural plant pathogens and bacteria. The results showed that the 1-amide and 1-hydrazide-substituted β-carboline derivatives exhibited significant inhibitory activity against a variety of plant pathogens. DETAILED DESCRIPTION

[0048] The present invention is further described in detail below with reference to the examples. Reagents or instruments used without manufacturer's indication are considered to be conventional products that can be purchased on the market.

[0049] The present invention provides a method for preparing the above-mentioned 1-substituted β-carboline derivatives, which comprises the following steps:

[0050] Step 1. Synthesis of 1-carboxy-3-methoxycarbonyl-2,3,4,9-tetrahydro-β-carboline: To 50 mL of water were added 0.5 mL of concentrated H₂SO₄ and 50% aqueous glyoxylic acid (3.6 mL, 24.5 mmol, 1.0 equiv), followed by L-tryptophan methyl ester hydrochloride (6.3 g, 24.5 mmol, 1.0 equiv). The mixture was stirred at room temperature overnight and adjusted to pH 6-7 with 1 mol / L sodium hydroxide, resulting in the precipitation of a white solid. The white slurry was filtered, and the filter cake was washed three times with water to yield 1-carboxy-3-methoxycarbonyl-2,3,4,9-tetrahydro-β-carboline (6.4 g, 95%) as a white solid.

[0051] Step 2. Synthesis of 1-carboxy-3-methoxycarbonyl β-carboline (A7). 1-Carboxy-3-methoxycarbonyl 2,3,4,9-tetrahydro β-carboline (5.5 g, 20 mmol, 1.0 equiv) was dissolved in 50 mL of DMSO, and DBU (6.1 g, 40 mmol, 2.0 equiv) and CuBr2 (0.9 g, 4 mmol, 0.2 equiv) were added. The reaction was stirred at room temperature for 24 hours, after which a yellow solid precipitated. The solid product was filtered and washed three times with DMSO and then with petroleum ether to afford compound A7 (5.0 g, 92%) as a yellow solid.

[0052] Step 3. Synthesis of 1-carboxy-3-carbamoyl β-carboline (C7). Compound A7 (2.5 g, 9.2 mmol) was dissolved in a mixture of methanol (100 mL) and aqueous ammonia (100 mL), heated under reflux, and stirred overnight. After the reaction, the mixture was filtered, the methanol evaporated, and the pH of the filtrate was adjusted to 7-8 with 1 mol / L HCl solution. The precipitated solid was filtered and washed three times with water to obtain Compound C7 (2.0 g, 85%) as a yellow solid.

[0053] Step 4. Synthesis of 1-Amide and 1-Hydrazide Substituted β-Carboline Derivatives. Dissolve compound A7 (271 mg, 1.0 mmol, 1.0 equiv) or C7 (256 mg, 1.0 mmol, 1.0 equiv) in 30 mL of DCM, then add an amine (0.8 mmol, 0.8 equiv) or hydrazine (0.8 mmol, 0.8 equiv). Next, add PyBOP (Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) (520 mg, 1.0 mmol, 1.0 equiv) and stir at room temperature overnight. After the reaction, if solid precipitation is observed, filter the precipitated solid and wash it three times with DCM to obtain the corresponding product. The product purity can be improved by recrystallization from a mixture of ethyl acetate and methanol. If no solid precipitation occurs, wash it three times with NH4Cl and saturated NaCl, then dry it over anhydrous Na2SO4. The mixture is then concentrated in vacuo and purified by column chromatography to obtain the corresponding product.

[0054] The preferred compounds of the present invention and their preparation methods are illustrated in combination with the above preparation methods, but the present invention is not limited thereto.

[0055] Example 1: Preparation of 3-(methoxycarbonyl)-9H-pyrido[3,4-b]indole-1-carboxylic acid (A7)

[0056]

[0057] Step 1. Synthesis of 1-carboxy-3-methoxycarbonyl-2,3,4,9-tetrahydro-β-carboline: To 50 mL of water were added 0.5 mL of concentrated H₂SO₄ and 50% aqueous glyoxylic acid (3.6 mL, 24.5 mmol, 1.0 equiv), followed by L-tryptophan methyl ester hydrochloride (6.3 g, 24.5 mmol, 1.0 equiv). The mixture was stirred at room temperature overnight and adjusted to pH 6-7 with 1 mol / L sodium hydroxide, resulting in the precipitation of a white solid. The white slurry was filtered, and the filter cake was washed three times with water to yield 1-carboxy-3-methoxycarbonyl-2,3,4,9-tetrahydro-β-carboline (6.4 g, 95%) as a white solid.

[0058] Step 2. Synthesis of 1-carboxy-3-methoxycarbonyl β-carboline (A7). 1-Carboxy-3-methoxycarbonyl 2,3,4,9-tetrahydro β-carboline (5.5 g, 20 mmol, 1.0 equiv) was dissolved in 50 mL of DMSO, and DBU (6.1 g, 40 mmol, 2.0 equiv) and CuBr2 (0.9 g, 4 mmol, 0.2 equiv) were added. The reaction was stirred at room temperature for 24 hours, after which a yellow solid precipitated. The solid product was filtered and washed three times with DMSO and then with petroleum ether to afford compound A7 (5.0 g, 92%) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ12.02(s,1H,NH),9.10(s,1H,Ar-H),8.45(d,J=7.9Hz,1H,Ar-H),7.86(d,J= 8.2Hz,1H,Ar-H),7.63(t,J=7.5Hz,1H,Ar-H),7.34(t,J=7.5Hz,1H,Ar-H),3.97(s,3H,COOCH3); 13C NMR (151MHz, DMSO) δ166.6,165.7,141.7,137.0,135.7,130.9,129.4,122.2,120.9,120.4,120 .3,113.3,52.3; LC–MS(ESI+)m / z:calcd.for[M+H]+,C14H11N2O4,271.0713,found:271.0728.

[0059] Example 2: Preparation of 1-(benzylcarbamoyl)-3-methoxycarbonyl β-carboline (3ba)

[0060]

[0061] Compound A7 (271 mg, 1.0 mmol, 1.0 equiv) was dissolved in 30 mL of DCM, followed by the addition of aniline (0.8 mmol, 0.8 equiv). Next, PyBOP (Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) (520 mg, 1.0 mmol, 1.0 equiv) was added, and the mixture was stirred overnight at room temperature. After the reaction, if solid precipitation was observed, the precipitated solid was filtered and washed three times with DCM to obtain the corresponding product. The product purity was improved by recrystallization from a mixture of ethyl acetate and methanol to obtain 3ba as a yellow powder in a 93% yield. 1 H NMR (400 MHz, DMSO-d6) δ H12.31(s,1H),10.51(s,1H),9.16(s,1H),8.48(d,J=7.9,1H),7.99–7.91(m,2H),7.90–7.84(m,1H),7.66(ddd ,J=8.2,7.1,1.1,1H),7.45(dd,J=8.5,7.3,2H),7.41–7.34(m,1H),7.20(td,J=7.3,1.1,1H),4.01(s,3H); 13C NMR(125MHz DMSO-d6)δ C 165.85,163.65,142.59,138.40,136.16,135.37,132.45,131.73,129.95,129.39,124.64, 122.78,121.33,120.83,120.74,120.54,113.87,52.91; LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 20 H 16 N3O3,346.12,Found:346.32; Calcd.for[M+Na] + ,C 20 H 15 N3NaO3,368.10,Found:368.31.

[0062] Example 3: Preparation of 1-(carbamoyl)-3-methoxycarbonyl β-carboline (3aa)

[0063]

[0064] The preparation method was the same as that of Example 2, except that methylamine was used instead of aniline to obtain 3aa as a white solid in a yield of 65%. 1 H NMR (400 MHz, DMSO-d6) δ H 12.14(s,1H),9.09(s,1H),8.66(q,J=4.8,1H),8.44(d,J=7.9,1H),7.85(dt,J=8.4,1.0,1H),7.6 3(ddd,J=8.3,7.1,1.2,1H),7.34(ddd,J=8.0,7.1,1.0,1H),3.96(s,3H),2.98(d,J=4.9,3H); 13C NMR(125MHz DMSO-d6)δ C194.76,165.77,142.90,137.07,135.80,135.19,132.00,130.11,122.92, 121.95,121.77,120.60,113.89,52.79; LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 15 H 14 N3O3,284.10,Found:284.24.

[0065] Example 4: Preparation of 1-(isopropylcarbamoyl)-3-methoxycarbonyl β-carboline (3ab)

[0066]

[0067] The preparation method was the same as in Example 2, except that isopropylamine was used instead of aniline to obtain 3ab as a white solid in a yield of 68%. 1 H NMR(400MHz,Chloroform-d)δ10.65(s,1H),8.94(s,1H),8.18(t,J=7.3Hz,2H),7.67–7.54(m, 2H),7.36(ddd,J=8.0,6.9,1.3Hz,1H),4.45–4.29(m,1H),4.06(s,3H),1.38(d,J=6.6Hz,6H); 13 C NMR (151MHz, CDCl3) δ166.2,165.2,141.4,137.0,136.0,132.1,131.6,129.8,122. 1,121.3,121.1,120.2,112.4,52.8,41.7,22.9; LC–MS(ESI+)m / z:calcd.for[M+H] + ,C 17 H 18 N3O3,312.1343,found:312.1349.

[0068] Example 5: Preparation of 1-(benzylcarbamoyl)-3-methoxycarbonyl β-carboline (3bb)

[0069]

[0070] The preparation method was the same as in Example 2, except that benzylamine was used instead of aniline to obtain 3bb as a white powder with a yield of 93%. 1H NMR(400MHz,Chloroform-d)δ12.18(s,1H),9.19(t,J=6.4Hz,1H),9.11(d,J=0.7Hz, 1H),8.48–8.42(m,1H),7.85(dt,J=8.3,1.0Hz,1H),7.63(ddd,J=8.3,7.1,1.2Hz,1H) ,7.46–7.41(m,2H),7.35(ddt,J=8.8,7.0,1.6Hz,3H),7.29–7.23(m,1H),4.66(d,J= 6.4Hz,2H),3.96(s,3H),2.69(s,1H),1.99(s,1H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 21 H 17 N3O3,360.13,Found:360.35; Calcd.for[M+Na] + ,C 21 H 10 N2NaO2,382.12,Found:382.30.

[0071] Example 6: Preparation of 1-(phenethylcarbamoyl)-3-methoxycarbonyl β-carboline (3bc)

[0072]

[0073] The preparation method was the same as in Example 2, except that phenylethylamine was used instead of aniline to obtain 3bc as a white solid in 89% yield. 1 H NMR(400MHz,Chloroform-d)δ10.61(s,1H),8.95(s,1H),8.47(t,J=6.1Hz,1H),8.19(d,J=7.9Hz,1H),7.66–7.56(m,2H ),7.40–7.28(m,6H),4.05(s,3H),3.80(dt,J=7.9,6.4Hz,2H),3.03(t,J=7.5Hz,2H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 22 H 20 N3O3,374.15,Found:374.35; Calcd.for[M+Na] + ,C 22 H 19 N3NaO3,396.13,Found:396.33.

[0074] Example 7: Preparation of 1-((2-chlorophenyl)carbamoyl)-3-methoxycarbonyl β-carboline (3bd)

[0075]

[0076] The preparation method was the same as step 4, except that 2-chloroaniline was used instead of aniline to obtain 3bd as a white solid in a yield of 75%. 1 H NMR(400MHz,Chloroform-d)δ10.56(s,1H),10.34(s,1H),8.96(s,1H),8.20(d,J=8.0Hz,1H),8.04(t,J=2.0Hz,1H),7.70 –7.58(m,4H),7.43–7.36(m,1H),7.33(t,J=8.1Hz,1H),7.18–7.13(m,1H),4.09(s,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 20 H 15 ClN3O3,380.08Found:380.26;Calcd.for[M+Na] + ,C 20 H 14 ClN3NaO3,402.06,Found:402.28.

[0077] Example 8: Preparation of 1-((2-fluorophenyl)carbamoyl)-3-methoxycarbonyl β-carboline (3be)

[0078]

[0079] The preparation method was the same as that of Example 2, except that 2-fluoroaniline was used instead of aniline to obtain 3be as a yellow solid with a yield of 82%. 1 HNMR(400MHz,Chloroform-d)δ10.50(s,1H),10.40(s,1H),9.00(s,1H),8.49(td,J=7.9,1.6Hz,1H),8.22(d,J=7.9Hz,1H ),7.73–7.56(m,2H),7.40(ddd,J=7.9,6.7,1.3Hz,1H),7.24–7.11(m,3H),4.09(s,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 20 H 15 FN3O3,364.11,Found:363.30; Calcd.for[M+Na] + ,C20 H 14 FN3NaO3,386.09,Found:386.28.

[0080] Example 9: Preparation of 1-((2-iodophenyl)carbamoyl)-3-methoxycarbonyl β-carboline (3bf)

[0081]

[0082] The preparation method was the same as in Example 2, except that 2-iodoaniline was used instead of aniline to obtain 3bf as a yellow solid with a yield of 71%. LC–MS (ESI+) m / z: Calcd. for [M+H] + ,C 20 H 15 IN3O3,472.02,Found:472.22;Calcd.for[M+Na] + ,C 20 H 14 IN3NaO3,494.00,Found:494.16.

[0083] Example 10: Preparation of 1-(o-tolylcarbamoyl)-3-methoxycarbonyl β-carboline (3bg)

[0084]

[0085] The preparation method was the same as in Example 2, except that 2-methylaniline was used instead of aniline to obtain 3bg as a yellow solid with a yield of 91%. LC–MS (ESI+) m / z: Calcd. for [M+H] + ,C 21 H 18 N3O3,360.13,Found:360.28; Calcd.for[M+Na] + ,C 21 H 17 N3NaO3,382.12,Found:382.26.

[0086] Example 11: Preparation of 1-((2-methoxyphenyl)carbamoyl)-3-methoxycarbonyl β-carboline (3bh)

[0087]

[0088] The preparation method was the same as in Example 2, except that 2-methoxyaniline was used instead of aniline to obtain 3bh as a yellow oil in 82% yield. 1H NMR (400MHz, DMSO-d6) δ12.37(s,1H),10.79(s,1H),9.18(s,1H),8.58(dd,J= 7.9,1.4Hz,1H),8.50(d,J=7.9Hz,1H),7.89(d,J=8.2Hz,1H),7.67(ddd,J=8.3 ,7.1,1.2Hz,1H),7.41–7.35(m,1H),7.18(qd,J=8.2,1.8Hz,2H),7.07(ddd,J= 8.5,6.9,2.0Hz,1H),4.01(d,J=5.8Hz,6H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 21 H 18 N3O4,376.13,Found:376.77; Calcd.for[M+Na] + ,C 21 H 17 N3NaO4,398.11,Found:398.26.

[0089] Example 12: Preparation of 1-((2-trifluoromethylphenyl)carbamoyl)-3-methoxycarbonyl β-carboline (3bi)

[0090]

[0091] The preparation method was the same as that of Example 2, except that 2-trifluoromethylaniline was used instead of aniline to obtain 3bi as a yellow oil in 86% yield. 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),10.85(s,1H),9.20(s,1H),8.59(d,J=8.2Hz,1H),8.50(d,J=7.9Hz,1 H),7.91–7.77(m,3H),7.71–7.64(m,1H),7.49–7.35(m,2H),3.99(s,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 21 H 15 F3N3O3,414.11,Found:414.29; Calcd.for[M+Na] + ,C 21 H 14 F3N3NaO3,436.09,Found:436.27.

[0092] Example 13: Preparation of 1-((4-chlorophenyl)carbamoyl)-3-methoxycarbonyl β-carboline (3bk)

[0093]

[0094] The preparation method was the same as that of Example 2, except that 4-chloroaniline was used instead of aniline to obtain 3bk as a yellow oil in 81% yield. 1 HNMR(400MHz,Chloroform-d)δ10.58(s,1H),10.32(s,1H),9.00(s,1H),8.23(d,J=7.9Hz,1H),7.84( d,J=8.6Hz,2H),7.71–7.61(m,2H),7.45–7.35(m,3H),4.10(s,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 20 H 15 ClN3O3,380.08,Found:380.26; Calcd.for[M+Na] + ,C 20 H 14 ClN3NaO3,402.06,Found:402.25.

[0095] Example 14: Preparation of 1-((3-trifluoromethylphenyl)carbamoyl)-3-methoxycarbonyl β-carboline (3bn)

[0096]

[0097] The preparation method was the same as that of Example 2, except that 3-trifluoromethylaniline was used instead of aniline to obtain 3bn as a yellow oil in a yield of 65%. 1 H NMR (400MHz, DMSO-d6) δ12.32 (s, 1H), 10.81 (s, 1H), 9.16 (d, J = 0.6Hz, 1H), 8.60(t,J=2.0Hz,1H),8.48(d,J=7.9Hz,1H),8.17–8.06(m,1H),7.87(dt,J= 8.2,1.0Hz,1H),7.66(tdd,J=8.3,6.9,5.0Hz,2H),7.57–7.50(m,1H),7.37( ddd,J=8.0,7.1,1.0Hz,1H),4.01(s,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 20 H 15ClN3O3,380.08,Found:380.26; Calcd.for[M+Na] + ,C 20 H 14 ClN3NaO3,402.06,Found:402.25.

[0098] Example 15: Preparation of 1-((2,4,5-trichlorophenyl)carbamoyl)-3-methoxycarbonyl β-carboline (3bo)

[0099]

[0100] The preparation method was the same as in Example 2, except that 2,4,5-trichloroaniline was used instead of aniline to obtain 3bo as a yellow oil with a yield of 69%. LC–MS (ESI+) m / z: Calcd. for [M+H] + ,C 20 H 13 Cl3N3O3,448.00,Found:448.17; Calcd.for[M+Na] + ,C 20 H 12 Cl3N3NaO3,469.98, Found:470.19.

[0101] Example 16: Preparation of 1-((2-(1H-indol-3-yl)ethyl)carbamoyl)-3-methoxycarbonyl β-carboline (3ca)

[0102]

[0103] The preparation method was the same as that in Example 2, except that tryptamine was used instead of aniline to obtain 3ca as a yellow oil in 89% yield. 1H NMR (400 MHz, DMSO-d6) δH 12.20 (1H, s, NH), 10.89–10.83 (1H, m, NH), 9.10 (1H, s, Ar-H), 8.79 (1H, t, J = 6.1, CONH), 8.45 (1H, d, J = 7.9, Ar-H), 7.87 (1H, dt, J = 8.4, 1.0, Ar-H), 7.70 (1H, d, J = 7.8, Ar-H), 7.64 (1H, ddd, J = 8.3, 7.1, 1.2, Ar-H), 7.39–7.32 (2H,m,Ar-H),7.24(1H,d,J=2.3,Ar-H),7.09(1H,ddd,J=8.2,6.9,1.2,Ar-H),7.00(1H,ddd,J=7.9,6.9,1.1,A r-H),3.97(3H,s,COOCH3),3.75(2H,q,J=6.8,CH2),3.08(2H,t,J=7.5,CH2); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C24H 21 N4O3,413.16,Found:413.35;Calcd.for[M+Na]+,C 24 H 20 N4NaO3,435.14,Found:435.33.

[0104] Example 17: Preparation of 1-(5-carbamoyl-1,2,3-thiadiazole)-3-methoxycarbonyl β-carboline (3cb)

[0105]

[0106] The preparation method was the same as that of Example 2, except that 5-amino-1,2,3-thiadiazole was used instead of aniline to obtain 3cb as a white solid in a yield of 56%. 1 H NMR (400MHz, DMSO-d6) δ12.21(s,1H),9.21(s,1H),8.55–8.47(m,1H),7.91(d,J=8.2Hz,1H),7.69(ddd,J=8.2,7.1,1.2Hz,1H),7.57( dd,J=5.9,3.2Hz,2H),7.40(ddd,J=8.0,7.1,1.0Hz,1H),7.19(dd,J=6.0,3.2Hz,2H),4.02(s,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C16 H 12 N5O3S,354.07,Found:354.26;Calcd.for[M+Na] + ,C 16 H 11 N5NaO3S,376.05,Found:376.24.

[0107] Example 18: Preparation of 1-(2-carbamoylthiazole)-3-methoxycarbonyl β-carboline (3cc)

[0108]

[0109] The preparation method was the same as that of Example 2, except that 2-aminothiazole was used instead of aniline to obtain 3 cc of a white solid with a yield of 44%. 1 HNMR(400MHz,Chloroform-d)δ10.44(s,1H),8.99(s,1H),8.20(d,J=7.9Hz,1H),7.70–7.58(m ,3H),7.43–7.37(m,1H),7.09(d,J=3.6Hz,1H),4.08(s,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 17 H 13 N4O3S,353.07,Found:353.24;Calcd.for[M+Na] + ,C 17 H 12 N4NaO3S,375.05,Found:375.22.

[0110] Example 19: Preparation of 1-(2-carbamoyl(1H-benzo[d]imidazole))-3-methoxycarbonyl β-carboline (3cd)

[0111]

[0112] The preparation method was the same as in Example 2, except that 2-aminobenzimidazole was used instead of aniline to obtain 1-(2-carbamoyl(1H-benzo[d]imidazole))-3-methoxycarbonylβ-carboline as a white solid in 45% yield. LC–MS (ESI+) m / z: Calcd. for [M+H] + ,C 21 H 16 N5O3,386.13,Found:386.28;Calcd.for[M+Na] + ,C 21 H 15N5NaO3,408.11,Found:408.27.

[0113] Example 20: Preparation of 1-(1-formylaminopiperidine)-3-methoxycarbonyl β-carboline (3ce)

[0114]

[0115] The preparation method was the same as that of Example 2, except that 1-aminopiperidine was used instead of aniline to obtain 3ce as a white solid in a yield of 29%. 1 HNMR (400MHz, DMSO-d6) δ12.13(s,1H),9.40(s,1H),9.10(s,1H),8.45(d,J=7.8Hz,1H),7.84(d,J=8.2Hz,1H),7.64(ddd,J=8.3,7.1,1.2Hz,1H),7. 35(ddd,J=8.0,7.1,1.0Hz,1H),3.97(s,3H),2.95(t,J=5.4Hz,4H),1.66(p,J=5.5Hz,4H),1.43(d,J=7.4Hz,2H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 19 H 21 N4O3,353.16,Found:353.31;Calcd.for[M+Na] + ,C 19 H 20 N4NaO3,375.14,Found:375.29.

[0116] Example 21: Preparation of 1-(2-carbamoylpyridine)-3-methoxycarbonyl β-carboline (3cf)

[0117]

[0118] The preparation method was the same as that of Example 2, except that 2-aminopyridine was used instead of aniline to obtain 3cf as a white solid in a yield of 45%. 1HNMR(400MHz,DMSO-d6)δ12.37(s,1H),10.48(s,1H),9.18(d,J=2.0Hz,1H), 8.54–8.43(m,2H),8.39(dd,J=8.3,1.0Hz,1H),7.97(td,J=7.8,1.9Hz,1H),7 .91–7.84(m,1H),7.67(ddd,J=8.2,7.2,1.2Hz,1H),7.42–7.33(m,1H),7.26 (ddd,J=7.2,4.9,1.0Hz,1H),4.01(s,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 19 H 15 N4O3,347.11,Found:347.29; Calcd.for[M+Na] + ,C 19 H 14 N4NaO3,369.10,Found:369.27.

[0119] Example 22: Preparation of 1-(3-carbamoyl-4H-pyrazine)-3-methoxycarbonyl-β-carboline (3cg)

[0120]

[0121] The preparation method was the same as in Example 2, except that 3-aminopyrazole was used instead of aniline to obtain 3cg of a white solid with a yield of 48%. LC–MS (ESI+) m / z: Calcd. for [M+H] + ,C 17 H 14 N5O3,336.11,Found:336.30; Calcd.for[M+Na] + ,C 17 H 13 N5NaO3,358.09,Found:358.28.

[0122] Example 23: Preparation of 1-carboxylic acid-3-carbamoyl β-carboline (C7)

[0123]

[0124] Compound A7 (2.5 g, 9.2 mmol) was dissolved in a mixture of methanol (100 mL) and aqueous ammonia (100 mL), heated under reflux and stirred overnight. After the reaction, the mixture was filtered, the methanol evaporated to dryness, and the pH of the filtrate was adjusted to 7-8 with 1 mol / L HCl solution. The precipitated solid was filtered and washed three times with water to obtain Compound C7 (2.1 g, 85%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H,NH),9.10(s,1H,Ar-H),8.87(d,J=2.8Hz,1H,CONH2),8.44(d,J=7.9Hz,1H,Ar-H),7.84(d ,J=8.2Hz,1H,Ar-H),7.64(ddd,J=8.3,7.1,1.2Hz,1H,Ar-H),7.59–7.52(m,1H,CONH2),7.34(td,J=7.5,7.1,0.9Hz,1H,Ar-H); 13 C NMR(151MHz, DMSO)δ166.4,166.1,142.3,138.9,136.5,132.2,129.7,127.6,122.5,121.0,120.6,118.1,113.4; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 13 H 10 N3O3,256.0717,found:256.0713.

[0125] Example 24: Preparation of 1-N-propylformamide-3-carbamoyl β-carboline (4aa)

[0126]

[0127] The preparation method was the same as that of Example 2, except that n-propylamine was used instead of aniline and C7 was used instead of A7 to obtain 4aa as a white solid in a yield of 68%. 1H NMR(400MHz, DMSO-d6)δ12.00(s,1H),9.52(t,J=6.1Hz,1H),9.00(s,1H),8.87( d,J=2.7Hz,1H),8.40(d,J=7.9Hz,1H),7.83(d,J=8.2Hz,1H),7.60(ddd,J=8.3, 5.2,1.2Hz,2H),7.31(ddd,J=8.0,7.1,1.0Hz,1H),3.41(dt,J=7.7,6.4Hz,2H), 1.67(h,J=7.3Hz,2H),0.97(t,J=7.4Hz,3H).;LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 16 H 17 N4O2,297.14,Found:297.30; Calcd.for[M+Na] + ,C 16 H 16 N4NaO2,319.12,Found:319.29.

[0128] Example 25: Preparation of 1-N-isopropylformamide-3-carbamoyl β-carboline (4ab)

[0129]

[0130] The preparation method was the same as that of Example 2, except that isopropylamine was used instead of aniline and C7 was used instead of A7 to obtain 4ab as a white solid in 87% yield. 1 H NMR (400MHz, DMSO-d6) δ12.02(s,1H),9.17(d,J=8.5Hz,1H),9.01(s,1H),8.95(d,J=2.8Hz,1H),8.40(d,J=7.9Hz,1H),7.83(d,J=8.2Hz ,1H),7.72–7.55(m,2H),7.31(ddd,J=8.0,7.1,1.0Hz,1H),4.42–4.22(m,1H),1.32(d,J=6.6Hz,6H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 16 H 17 N4O2,297.14,Found:297.34; Calcd.for[M+Na] + ,C 16 H 16 N4NaO2,319.12,Found:319.32.

[0131] Example 26: Preparation of 1-N-ethylformamide-3-carbamoyl β-carboline (4ac)

[0132]

[0133] The preparation method was the same as that of Example 2, except that aniline was replaced by ethylamine and A7 was replaced by C7 to obtain 4ac as a white solid in 76% yield. 1 H NMR (400MHz, DMSO-d6) δ12.02(s,1H),9.56(t,J=6.0Hz,1H),9.02(s,1H),8.88(d,J=2.7Hz,1H),8.41(d,J=7.9Hz,1H),7.84(d,J=8.2Hz,1H),7 .61(ddd,J=8.3,5.5,1.2Hz,2H),7.32(td,J=7.5,7.1,1.0Hz,1H),3.55–3.43(m,2H),1.26(t,J=7.2Hz,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 15 H 15 N4O2,283.12,Found:283.37;Calcd.for[M+Na] + ,C 15 H 14 N4NaO2,305.10,Found:305.32.

[0134] Example 27: Preparation of 1-N-(2-chloroethyl)formamide-3-carbamoyl β-carboline (4ad)

[0135]

[0136] The preparation method was the same as that of Example 2, except that 2-chloroethylamine was used instead of aniline and C7 was used instead of A7 to obtain 4ad as a white solid in a yield of 69%. 1 H NMR (400MHz, DMSO-d6) δ12.06(s,1H),9.75(t,J=5.9Hz,1H),9.04(s,1H),8.87(d,J=2.7Hz,1H),8.43(d,J=7.8Hz,1H),7.84(d,J=8.2Hz,1H),7.67(d ,J=2.7Hz,1H),7.62(ddd,J=8.3,7.0,1.2Hz,1H),7.36–7.29(m,1H),3.88(t,J=6.2Hz,2H),3.78(q,J=6.2Hz,2H); LC–MS(ESI+)m / z:Calcd.for[M+H]+ ,C 15 H 14 ClN4O2,317.08,Found:317.29; Calcd.for[M+Na] + ,C 15 H 13 ClN4NaO2,339.06,Found:339.27.

[0137] Example 28: Preparation of 1-N-octadecylcarboxamide-3-carbamoyl β-carboline (4ae)

[0138]

[0139] The preparation method was the same as that of Example 2, except that octadecylamine was used instead of aniline and C7 was used instead of A7 to obtain 4ae as a white solid in a yield of 45%. 1 H NMR (400MHz, DMSO-d6) δ12.01(s,1H),9.51(t,J=6.1Hz,1H),8.99(d,J=5.7Hz,1H),8.87(s,1H),8.40(d,J=8.0Hz,1H),7.82 (d,J=8.1Hz,1H),7.65–7.55(m,2H),7.31(t,J=7.5Hz,1H),1.22(dd,J=14.6,6.0Hz,37H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 31 H 47 N4O2,507.37,Found:507.56; Calcd.for[M+Na] + ,C 31 H 46 N4NaO2,529.35,Found:529.59.

[0140] Example 29: Preparation of 1-N-cyclopropylcarboxamide-3-carbamoyl β-carboline (4ag)

[0141]

[0142] The preparation method was the same as that of Example 2, except that cyclohexylamine was used instead of aniline and C7 was used instead of A7 to obtain 4ag as a white solid in a yield of 35%. 1H NMR (400MHz, DMSO-d6) δ12.00(s,1H),9.15(d,J=8.6Hz,1H),9.01(s,1H),8.95(d,J=2.7Hz,1H),8.40(d, J=7.8Hz,1H),7.83(d,J=8.3Hz,1H),7.61(ddd,J=15.4,8.2,1.9Hz,2H),7.31(td,J=7.5,7.1,1.0Hz,1H) ,4.20–3.73(m,1H),1.92(d,J=11.8Hz,2H),1.83(d,J=12.8Hz,2H),1.69(d,J=12.7Hz,1H),1.53(qd,J=1 2.4,3.2Hz,2H),1.44–1.29(m,2H),1.18(tdd,J=12.5,9.0,3.7Hz,1H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 19 H 21 N4O2,337.17,Found:337.39; Calcd.for[M+Na] + ,C 19 H 20 N4NaO2,359.15,Found:359.35.

[0143] Example 30: Preparation of 1-N-phenylformamide-3-carbamoyl β-carboline (4ba)

[0144]

[0145] The preparation method was the same as in Example 2, except that C7 was used instead of A7 to obtain 4ba as a white solid in 88% yield. 1 H NMR (400MHz, DMSO-d6) δ12.16(s,1H),10.96(s,1H),9.10(s,1H),9.09(d,J=2.4Hz,1H),8.45(d,J=7.9Hz,1H),7.97–7.92(m,2H),7.86(dt,J= 8.4,1.0Hz,1H),7.69–7.60(m,2H),7.50–7.43(m,2H),7.34(ddd,J=8.1,7.1,1.0Hz,1H),7.24–7.17(m,1H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 19 H 15 N4O2,331.12,Found:331.53.

[0146] Example 31: Preparation of 1-N-benzylformamide-3-carbamoyl β-carboline (4bb)

[0147]

[0148] The preparation method was the same as in Example 2, except that benzylamine was used instead of aniline and C7 was used instead of A7 to obtain 4bb as a white solid in 85% yield. LC–MS (ESI+) m / z: Calcd. for [M+H] + ,C 20 H 17 N4O2,345.14,Found:345.36; Calcd.for[M+Na] + ,C 20 H 16 N4NaO2,367.12,Found:367.35.

[0149] Example 32: Preparation of 1-N-o-methylphenylcarboxamide-3-carbamoyl β-carboline (4bc)

[0150]

[0151] The preparation method was the same as that of Example 2, except that 2-methylaniline was used instead of aniline and C7 was used instead of A7 to obtain 4bc as a white solid in a yield of 75%. 1 H NMR (400MHz, DMSO-d6) δ12.08(s,1H),10.91(s,1H),9.09(s,1H),9.00(d,J=2.4Hz,1H),8.45(d,J=7.9Hz,1H),7.89–7.81(m,1H), 7.63(ddd,J=8.3,5.5,1.2Hz,2H),7.51(dd,J=7.8,1.4Hz,1H),7.40–7.22(m,4H),2.36(s,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 20 H 17 N4O2,345.14,Found:345.32; Calcd.for[M+Na] + ,C 20 H 16 N4NaO2,367.12,Found:367.30.

[0152] Example 33: Preparation of 1-N-m-methylphenylcarboxamide-3-carbamoyl β-carboline (4bd)

[0153]

[0154] The preparation method was the same as that of Example 2, except that 3-methylaniline was used instead of aniline and C7 was used instead of A7 to obtain 4bd as a white solid in a yield of 73%. 1 HNMR(400MHz, DMSO-d6)δ12.20(s,1H),10.92(s,1H),9.12(d,J=5.9Hz,2H),8.45(d,J=7.9Hz,1H),7.90–7.82(m,2H),7.77–7.68(m, 2H),7.64(ddd,J=8.3,7.0,1.2Hz,1H),7.35(t,J=7.8Hz,2H),7.03(d,J=7.7Hz,1H),2.39(s,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 20 H 17 N4O2,345.14,Found:345.30; Calcd.for[M+Na] + ,C 20 H 16 N4NaO2,367.12,Found:367.28.

[0155] Example 34: Preparation of 1-N-p-methylphenylcarboxamide-3-carbamoyl β-carboline (4be)

[0156]

[0157] The preparation method was the same as in Example 2, except that aniline was replaced by 4-methylaniline and A7 was replaced by C7 to obtain 4be as a white solid in a yield of 79%. LC–MS (ESI+) m / z: Calcd. for [M+H] + ,C 20 H 17 N4O2,345.14,Found:345.36; Calcd.for[M+Na] + ,C 20 H 16 N4NaO2,367.12,Found:367.35.

[0158] Example 35: Preparation of 1-N-m-methoxyphenylcarboxamide-3-carbamoyl β-carboline (4bg)

[0159]

[0160] The preparation method was the same as that of Example 2, except that aniline was replaced by 3-methoxyaniline and A7 was replaced by C7 to obtain 4bg as a white solid in a yield of 52%. 1H NMR (400MHz, DMSO-d6) δ12.20(s,1H),10.94(s,1H),9.13(d,J=2.8Hz,2H),8.46(d,J=7.8Hz,1H),7.88(d,J=8.2Hz,1H),7.72(d,J=2.5Hz ,1H),7.69–7.61(m,2H),7.57–7.51(m,1H),7.36(q,J=7.7,7.1Hz,2H),6.84–6.76(m,1H),3.83(s,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 20 H 17 N4O3,361.13,Found:361.36; Calcd.for[M+Na] + ,C 20 H 16 N4NaO3,383.11,Found:383.31.

[0161] Example 36: Preparation of 1-N-p-methoxyphenylcarboxamide-3-carbamoyl β-carboline (4bh)

[0162]

[0163] The preparation method was the same as that of Example 2, except that 4-methoxyaniline was used instead of aniline and C7 was used instead of A7 to obtain 4bh as a white solid in a yield of 57%. 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),10.90(s,1H),9.10(d,J=3.3Hz,2H),8.44(d,J=7.9Hz,1H),7.94–7.77(m,3H),7 .74–7.59(m,2H),7.34(ddd,J=8.0,7.1,1.0Hz,1H),7.10–6.99(m,2H),3.80(s,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 20 H 17 N4O3,361.13,Found:361.35; Calcd.for[M+Na] + ,C 20 H 16 N4NaO3,383.11,Found:383.30.

[0164] Example 37: Preparation of 1-N-(2,5-dimethoxyphenyl)formamide-3-carbamoyl β-carboline (4bi)

[0165]

[0166] The preparation method was the same as that of Example 2, except that aniline was replaced by 2,5-dimethoxyaniline and A7 was replaced by C7 to obtain 4bi as a white solid in a yield of 59%. 1 H NMR(400MHz,DMSO-d6)δ12.15(s,1H),10.74(s,1H),9.08(s,1H),8.65(d,J =2.4Hz,1H),8.46(dd,J=8.0,5.0Hz,1H),7.86(t,J=8.9Hz,1H),7.70–7.56 (m,3H),7.34(td,J=7.5,7.1,1.0Hz,1H),7.08(dd,J=11.9,9.0Hz,1H),6.8 6–6.78(m,1H),3.85(s,3H),3.77(s,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 21 H 19 N4O4,391.14,Found:391.36; Calcd.for[M+Na] + ,C 21 H 18 N4NaO4,413.12,Found:413.34.

[0167] Example 38: Preparation of 1-N-phenylethylcarboxamide-3-carbamoyl β-carboline (4bj)

[0168]

[0169] The preparation method was the same as that of Example 2, except that phenylethylamine was used instead of aniline and C7 was used instead of A7 to obtain 4bj as a white solid in 70% yield. 1 H NMR(400MHz,DMSO-d6)δ12.08(s,1H),9.69(t,J=6.1Hz,1H),9.03(s,1H),8 .88(d,J=2.8Hz,1H),8.42(d,J=7.8Hz,1H),7.84(d,J=8.2Hz,1H),7.62(ddd ,J=15.3,7.7,1.9Hz,2H),7.35–7.29(m,5H),7.23(ddd,J=5.6,4.4,2.5Hz,1 H),3.72–3.58(m,2H),3.06–2.87(m,2H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 21H 19 N4O2,359.15,Found:359.37; Calcd.for[M+Na] + ,C 21 H 18 N4NaO2,381.13,Found:381.13.

[0170] Example 39: Preparation of 1-N-m-chlorophenylcarboxamide-3-carbamoyl β-carboline (4cb)

[0171]

[0172] The preparation method was the same as that of Example 2, except that aniline was replaced by 3-chloroaniline and A7 was replaced by C7 to obtain 4cb as a white solid in a yield of 62%. 1 H NMR (400MHz, DMSO-d6) δ12.21(s,1H),10.80(d,J=132.7Hz,2H),9.07(d,J=11.7Hz,1H),8.47(d,J=7.9Hz,1H),7.94(d,J=12.3Hz,3H),7. 65(t,J=7.7Hz,1H),7.48(td,J=17.5,16.3,8.0Hz,2H),7.37(t,J=7.5Hz,1H),3.92(d,J=50.1Hz,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 19 H 14 ClN4O2,365.08,Found:365.24.

[0173] Example 40: Preparation of 1-N-(4-chlorophenyl)carboxamide-3-carbamoyl β-carboline (4 cc)

[0174]

[0175] The preparation method was the same as that of Example 2, except that 4-chloroaniline was used instead of aniline and C7 was used instead of A7. 4 cc of a white solid was obtained with a yield of 68%. 1H NMR (400MHz, DMSO-d6) δ12.31(s,1H),11.29(s,1H),11.12(s,1H),9.26(s,1H),8.52(d,J=7.9Hz,1H),8.16–8.05(m,3H),7.8 9(d,J=8.2Hz,1H),7.67(ddd,J=8.2,7.1,1.1Hz,1H),7.57–7.53(m,2H),7.42–7.33(m,1H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 19 H 14 ClN4O2,365.08,Found:365.25.

[0176] Example 41: Preparation of 1-N-o-chlorophenylcarboxamide-3-carbamoyl β-carboline (4cd)

[0177]

[0178] The preparation method was the same as in Example 2, except that 2-fluoroaniline was used instead of aniline to obtain 4cd as a white solid with a yield of 42%. LC–MS (ESI+) m / z: Calcd. for [M+H] + ,C 19 H 14 FN4O2,349.11,Found:349.28; Calcd.for[M+Na] + ,C 19 H 13 FN4NaO2,371.09,Found:371.29.

[0179] Example 42: Preparation of 1-N-m-chlorophenylcarboxamide-3-carbamoyl β-carboline (4ce)

[0180]

[0181] The preparation method was the same as that of Example 2, except that aniline was replaced by 3-fluoroaniline and A7 was replaced by C7 to obtain 4ce as a white solid in a yield of 41%. 1H NMR(400MHz,DMSO-d6)δ12.21(s,1H),11.07(s,1H),9.12(d,J=15.9Hz,2H),8 .46(d,J=7.9Hz,1H),7.95(dt,J=11.8,2.3Hz,1H),7.87(d,J=8.2Hz,1H),7.80 –7.73(m,2H),7.65(ddd,J=8.2,7.0,1.2Hz,1H),7.51(q,J=7.9Hz,1H),7.35(t ,J=7.5Hz,1H),7.05(td,J=8.5,2.6Hz,1H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 19 H 14 FN4O2,349.11,Found:349.32; Calcd.for[M+Na] + ,C 19 H 13 FN4NaO2,371.09,Found:371.31.

[0182] Example 43: Preparation of 1-N-(4-Bromophenyl)carboxamide-3-carbamoylβ-carboline (4cg)

[0183]

[0184] The preparation method was the same as that of Example 2, except that 4-bromoaniline was used instead of aniline and C7 was used instead of A7 to obtain 4cg as a white solid with a yield of 58%. 1 H NMR (400MHz, DMSO-d6) δ12.18(s,1H),11.03(s,1H),9.12(s,1H),9.08(d,J=2.6Hz,1H),8.45(d,J=7.9Hz,1H),7.96–7.92(m,2H), 7.88–7.84(m,1H),7.72(d,J=2.5Hz,1H),7.69–7.61(m,3H),7.35(ddd,J=8.1,7.1,1.0Hz,1H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 19 H 14 BrN4O2,409.03,Found:409.21.

[0185] Example 44: Preparation of 1-N-m-bromophenylcarboxamide-3-carbamoyl β-carboline (4ch)

[0186]

[0187] The preparation method was the same as that of Example 2, except that aniline was replaced by 3-bromoaniline and A7 was replaced by C7 to obtain 4ch as a white solid in a yield of 40%. 1 H NMR (400MHz, DMSO-d6) δ12.22(s,1H),11.04(s,1H),9.11(d,J=15.6Hz,2H),8.46(d,J=7.9Hz,1H),8.34(t,J=1.9Hz,1H),7.94(dt,J=7.9,1.7 Hz,1H),7.86(d,J=8.1Hz,1H),7.74(d,J=2.6Hz,1H),7.65(ddd,J=8.2,7.0,1.2Hz,1H),7.48–7.32(m,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 19 H 14 BrN4O2,409.03,Found:409.25; Calcd.for[M+Na] + ,C 19 H 13 BrN4NaO2,431.01,Found:431.23.

[0188] Example 45: Preparation of 1-N-(4-iodophenyl)carboxamide-3-carbamoyl β-carboline (4ci)

[0189]

[0190] The preparation method was the same as that of Example 2, except that 4-iodoaniline was used instead of aniline and C7 was used instead of A7 to obtain 4ci as a white solid in a yield of 47%. 1 H NMR (400MHz, DMSO-d6) δ12.19(s,1H),11.00(s,1H),9.11(d,J=8.9Hz,2H),8.45(d,J=7.9Hz,1H),7.88–7.84(m,1H),7.81(s,4H ),7.72(d,J=2.5Hz,1H),7.64(ddd,J=8.2,7.1,1.2Hz,1H),7.34(ddd,J=8.0,7.1,1.0Hz,1H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 19 H 14 IN4O2,457.02,Found:457.23;Calcd.for[M+Na] + ,C 19 H13 IN4NaO2,479.00,Found:479.18.

[0191] Example 46: Preparation of 1-N-trifluoromethylphenylformamide-3-carbamoyl β-carboline (4ck)

[0192]

[0193] The preparation method was the same as that of Example 2, except that aniline was replaced by 3-trifluoromethylaniline and A7 was replaced by C7 to obtain 4ck as a white solid in a yield of 25%. 1 H NMR (400MHz, DMSO-d6) δ12.24(s,1H),11.20(s,1H),9.14(s,1H),9.10(d,J=2.6 Hz,1H),8.53(t,J=2.0Hz,1H),8.47(d,J=7.9Hz,1H),8.18(dt,J=8.2,1.4Hz,1H) ,7.89–7.84(m,1H),7.77–7.69(m,2H),7.65(ddd,J=8.3,7.1,1.2Hz,1H),7.59–7 .55(m,1H),7.35(ddd,J=8.0,7.1,1.0Hz,1H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 20 H 14 F3N4O2,399.11,Found:399.31; Calcd.for[M+Na] + ,C 20 H 13 F3N4NaO2,421.09,Found:421.32.

[0194] Example 47: Preparation of 1-N-(4-trifluoromethyl)phenylcarboxamide-3-carbamoyl β-carboline (4cl)

[0195]

[0196] The preparation method was the same as that of Example 2, except that 4-trifluoromethylaniline was used instead of aniline and C7 was used instead of A7 to obtain 4cl as a white solid in a yield of 50%. 1H NMR (400MHz, DMSO-d6) δ12.23(s,1H),11.19(s,1H),9.13(d,J=8.3Hz,2H),8.46(d,J=7.9Hz,1H),8.22(d,J=8.5Hz,2H),7.86(dd,J=8. 4,5.9Hz,3H),7.76(d,J=2.5Hz,1H),7.64(ddd,J=8.2,7.0,1.2Hz,1H),7.35(td,J=7.5,0.9Hz,1H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 20 H 14 F3N4O2,399.11,Found:399.26.

[0197] Example 48: Preparation of 1-N-(3,5-dichlorophenylformamide)-3-carbamoyl β-carboline (4co)

[0198]

[0199] The preparation method was the same as that of Example 2, except that aniline was replaced by 3,5-dichloroaniline and A7 was replaced by C7 to obtain 4co as a white solid in a yield of 36%. 1 H NMR(400MHz,DMSO-d6)δ12.23(s,1H),11.08(s,1H),9.14(s,1H),9.03(d,J =2.6Hz,1H),8.46(d,J=7.9Hz,1H),8.13(d,J=1.9Hz,2H),7.90–7.82(m,1H ),7.76(d,J=2.5Hz,1H),7.65(ddd,J=8.3,7.1,1.2Hz,1H),7.44(t,J=1.9Hz,1H),7.35(ddd,J=8.0,7.1,1.0Hz,1H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 19 H 13 Cl2N4O2,399.04,Found:399.19; Calcd.for[M+Na] + ,C 19 H 12 Cl2N4NaO2,421.02,Found:421.27.

[0200] Example 49: Preparation of 1-N-(1-formylpiperidine)-3-carbamoyl β-carboline (4eb)

[0201]

[0202] The preparation method was the same as that of Example 2, except that piperidine was used instead of aniline and C7 was used instead of A7 to obtain 4eb as a white solid in 51% yield. 1 H NMR (400MHz, DMSO-d6) δ12.03(s,1H),10.73(s,1H),10.33(s,1H),8.98(s,1H),8.42(d,J=7.9Hz,1H),7.87–7.79(m,1H),7.61(ddd,J=8.2,7. 1,1.2Hz,1H),7.31(ddd,J=8.0,7.1,1.0Hz,1H),3.24(t,J=5.4Hz,4H),3.08(t,J=5.4Hz,4H),2.69(s,3H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 18 H 19 N4O2,322.15,Found:322.40.

[0203] Example 50: Preparation of 1-N-(1H-5-formamidopyrazole)-3-carbamoyl β-carboline (4ed)

[0204]

[0205] The preparation method was the same as that of Example 2, except that aniline was replaced by 3-aminopyrazole and A7 was replaced by C7 to obtain 4ed as a white solid in a yield of 40%. 1 HNMR (400MHz, DMSO-d6) δ12.63(s,1H),12.16(s,1H),11.71(s,1H),9.36(s,1H),9.08(s,1H),8.46(dd,J=15.7,7.9Hz,1H),7.88(t,J=7.9Hz, 1H),7.78(s,1H),7.63(ddd,J=8.3,7.2,1.2Hz,1H),7.57(s,1H),7.40–7.29(m,1H),6.86(d,J=10.1Hz,1H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 16 H 13 N6O2,321.11,Found:321.27; Calcd.for[M+Na] + ,C 16 H 12 N6NaO2,343.09,Found:343.26.

[0206] Example 51: Preparation of 1-N-(2-(3-1H-indole)ethyl)formamide-3-carbamoyl β-carboline (4ee)

[0207]

[0208] The preparation method was the same as that of Example 2, except that tryptamine was used instead of aniline and C7 was used instead of A7 to obtain 4ee as a white solid in a yield of 77%. 1 H NMR (400MHz, DMSO-d6) δ12.09(s,1H),10.87(d,J=2.3Hz,1H),9.74(t,J=6.1Hz,1H),9.03(s ,1H),8.90(d,J=2.6Hz,1H),8.42(d,J=7.9Hz,1H),7.85(d,J=8.2Hz,1H),7.73–7.57(m,3H) ,7.41–7.29(m,2H),7.25(d,J=2.3Hz,1H),7.09(ddd,J=8.1,7.0,1.2Hz,1H),7.05–6.97(m, 1H),3.73(dd,J=10.3,5.1Hz,2H),3.10(t,J=7.8Hz,2H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 23 H 20 N5O2,398.16,Found:398.36; Calcd.for[M+Na] + ,C 23 H 19 N5NaO2,420.14,Found:420.34.

[0209] Example 52: Preparation of 1-N-5-(1,2,3-thiadiazole)carboxamide-3-carbamoyl β-carboline (4ef)

[0210]

[0211] The preparation method was the same as that of Example 2, except that aniline was replaced by 5-amino-1,2,3-thiadiazole and A7 was replaced by C7 to obtain 4ef as a white solid in a yield of 35%. 1H NMR (400MHz, DMSO-d6) δ11.95(s,1H),9.04(d,J=16.4Hz,2H),8.87(d,J=2.6Hz,1H),8.41(d,J=7.8Hz,1H), 7.91–7.71(m,2H),7.65–7.48(m,2H),7.31(ddd,J=8.0,7.1,1.0Hz,1H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 15 H 11 N6O2S,339.07,Found:339.28.

[0212] Example 53: Preparation of 1-(2-phenylhydrazine-1-formyl)-3-methoxycarbonyl β-carboline (3da)

[0213]

[0214] The preparation method was the same as that of Example 2, except that phenylhydrazine was used instead of aniline to obtain 3da as a white solid in a yield of 92%. 1 H NMR (400MHz, DMSO-d6) δ12.14 (s, 1H, NH), 10.32 (d, J = 2.5Hz, 1H, CO NH NH-),9.15(s,1H,Ar-H),8.47(d,J=7.9Hz,1H,CONH NH -),7.99(d,J=2.6Hz,1H,Ar-H),7.84–7.78(m,1H,Ar-H),7.63(ddd,J=8.3,7.1,1.2Hz,1H,Ar-H),7.35(ddd,J=8.1,7.1 ,1.1Hz,1H,Ar-H),7.21–7.14(m,2H),6.89–6.84(m,2H,Ar-H),6.74(tt,J=7.2,1.2Hz,1H,Ar-H),3.98(s,3H,COOCH3); 13 C NMR (151MHz, DMSO) δ165.5,164.7,149.3,142.1,135.6,135.3,131.8,131.0,129.4,128.8 ,122.3,120.8,120.4,120.3,118.8,113.4,112.7,52.4; LC–MS(ESI+)m / z:calcd.for[M+H] + ,C 20 H 17 N4O3,361.1295,found:361.1298.

[0215] Example 54: Preparation of 1-(2-p-methylphenylhydrazine-1-formyl)-3-methoxycarbonyl β-carboline (3db)

[0216]

[0217] The preparation method was the same as that in Example 2, except that 4-methylphenylhydrazine was used instead of aniline to obtain methyl1-(2-(p-tolyl)hydrazine-1-carbonyl)-9H-pyrido[3,4-b]indole-3-carboxylate as a white solid in a yield of 88%. 1 H NMR (400MHz, DMSO-d6) δ12.13 (s, 1H, NH), 10.27 (d, J = 2.9Hz, 1H, CO NH NH-),9.14(s,1H,Ar-H),8.46(d,J=7.9Hz,1H,CONH NH -),7.86–7.78(m,2H,Ar-H),7.62(ddd,J=8.2,7.0,1.2Hz,1H,Ar-H),7.40–7.32(m,1H,Ar-H) ,6.98(d,J=8.1Hz,2H,Ar-H),6.83–6.73(m,2H,Ar-H),3.97(s,3H,COOCH3),2.19(s,3H,CH3); 13 CNMR(126MHz,DMSO-D6)δ165.4,164.5,146.9,142.0,135.5,135.2,131.7,130.9,129.3,129.1, 127.5,122.2,120.7,120.3,120.1,113.3,112.9,52.2,20.1; LC–MS(ESI+)m / z:calcd.for[M+H] + ,C 21 H 19 N4O3,375.1452,found:375.1454.

[0218] Example 55: Preparation of 1-(2-o-chlorophenylhydrazine-1-formyl)-3-methoxycarbonyl β-carboline (3dc)

[0219]

[0220] The preparation method was the same as that in Example 2, except that 2-chlorophenylhydrazine was used instead of aniline to obtain 3dc as a yellow solid with a yield of 83%. 1HNMR(500MHz,DMSO-d6)δ12.18(s,1H,NH),10.54(s,1H,CO NH NH-),9.16(s,1H,Ar-H),8.47(d,J=7.9Hz,1H,CONH NH -),7.80(d,J=8.2Hz,1H,Ar-H),7.72(s,1H,Ar-H),7.63(ddd,J=8.3,7.1,1.2Hz,1H,Ar-H),7.35(td,J=7.6,1.1Hz,2H,A r-H),7.18–7.07(m,1H,Ar-H),6.93(dd,J=8.2,1.5Hz,1H,Ar-H),6.78(td,J=7.6,1.5Hz,1H,Ar-H),3.98(s,3H,COOCH3); 13 C NMR (126MHz, DMSO-D6) δ165.51,164.7,144.9,142.1,135.3,135.3,131.6,131.0,129.5,129.2,127. 9,122.4,120.9,120.4,120.4,119.9,117.6,113.8,113.4,52.4; LC–MS(ESI+)m / z:calcd.for[M+Na] + ,C 20 H 15 ClN4NaO3,417.0725,found:417.0720.

[0221] Example 56: Preparation of 1-(2-p-methoxyphenylhydrazine-1-formyl)-3-methoxycarbonyl β-carboline (3dd)

[0222]

[0223] The preparation method was the same as that in Example 2, except that 4-methoxyphenylhydrazine was used instead of aniline to obtain 3dd as a white solid with a yield of 89%. 1 H NMR (400MHz, DMSO-d6) δ12.13 (s, 1H, NH), 10.28 (d, J = 3.2Hz, 1H, CO NH NH-),9.13(s,1H,Ar-H),8.46(d,J=7.9Hz,1H,CONH NH-),7.81(dd,J=8.3,1.0Hz,1H,Ar-H),7.71–7.58(m,2H,Ar-H),7.34(ddd,J=8.0,7.1 ,1.0Hz,1H,Ar-H),6.89–6.74(m,4H,Ar-H),3.97(s,3H,COOCH3),3.66(s,3H,OCH3); 13 C NMR (151MHz, DMSO) δ165.4,164.6,152.9,143.1,142.0,135.5,135.2,131.8,130.9,129.3 ,122.2,120.7,120.3,120.2,114.2,113.3,55.3,52.3; LC–MS(ESI+)m / z:calcd.for[M+H] + ,C 21 H 19 N4O4,391.1401,found:391.1411.

[0224] Example 57: Preparation of 1-(2-(4-chlorophenylhydrazine-1-formyl)-3-methoxycarbonyl β-carboline (3de)

[0225]

[0226] The preparation method was the same as that in Example 2, except that 4-chlorophenylhydrazine was used instead of aniline to obtain 3de as a white solid with a yield of 85%. 1 HNMR(600MHz,DMSO-d6)δ12.14(s,1H,NH),10.44(d,J=2.4Hz,1H,CO NH NH-),9.13(s,1H,Ar-H),8.44(d,J=7.9Hz,1H,CONH NH -),8.20(d,J=2.4Hz,1H,Ar-H),7.82(d,J=8.2Hz,1H,Ar-H),7.64–7.59(m,1H,Ar-H),7.33(t ,J=7.5Hz,1H,Ar-H),7.22–7.16(m,2H,Ar-H),6.90–6.83(m,2H,Ar-H),3.97(s,3H,COOCH3); 13C NMR (151MHz, DMSO) δ165.5,164.8,148.4,142.1,135.7,135.3,131.7,131.0,129.4,128.6 ,122.3,122.1,120.8,120.4,120.4,114.2,113.4,52.4; LC–MS(ESI+)m / z:calcd.for[M+H] + ,C 20 H 16 ClN4O3,395.0905,found:395.0919.

[0227] Example 58: Preparation of 1-(2-m-chlorophenylhydrazine-1-formyl)-3-methoxycarbonyl β-carboline (3df)

[0228]

[0229] The preparation method was the same as that in Example 2, except that 3-chlorophenylhydrazine was used instead of aniline to obtain 3df as a white solid with a yield of 85%. 1 HNMR(400MHz,DMSO-d6)δ12.15(s,1H,NH),10.50(d,J=2.3Hz,1H,CO NH NH-),9.15(s,1H,Ar-H),8.47(d,J=7.9Hz,1H,CONH NH -),8.30(d,J=2.3Hz,1H,Ar-H),7.81(d,J=8.2Hz,1H,Ar-H),7.63(ddd,J=8.3,7.0,1.2Hz,1H,Ar-H) ,7.41–7.31(m,1H,Ar-H),7.18(t,J=8.0Hz,1H,Ar-H),6.88–6.71(m,3H,Ar-H),3.97(s,3H,COOCH3); 13 C NMR (126MHz, DMSO-D6) δ165.4,164.7,150.9,142.0,135.6,135.3,133.4,131.5,130.9,130.3,129. 3,122.2,120.7,120.3,120.2,118.1,113.3,111.9,111.2,52.2; LC–MS(ESI+)m / z:calcd.for[M+H] + ,C 20 H 16 ClN4O3,395.0905,found:395.0896.

[0230] Example 59: Preparation of 1-(2-m-fluorophenylhydrazine-1-formyl)-3-methoxycarbonyl β-carboline (3dg)

[0231]

[0232] The preparation method was the same as that of Example 2, except that 3-fluorophenylhydrazine was used instead of aniline to obtain 3dg as a yellow solid with a yield of 81%. 1 HNMR(600MHz,DMSO-d6)δ12.14(s,1H,NH),10.46(d,J=2.3Hz,1H,CO NH NH-),9.15(d,J=0.6Hz,1H,Ar-H),8.47(d,J=7.9Hz,1H,Ar-H),8.29(d,J=2.3Hz,1H,CONH NH -),7.81(dt,J=8.2,0.9Hz,1H,Ar-H),7.63(ddd,J=8.3,7.0,1.2Hz,1H,Ar-H),7.35(ddd,J=8.0,7.1,1.0Hz,1H,Ar-H),7.18(td,J=8.2,6. 7Hz,1H,Ar-H),6.68(ddd,J=8.3,2.2,0.9Hz,1H,Ar-H),6.59(dt,J=11.7,2.3Hz,1H,Ar-H),6.53–6.48(m,1H,Ar-H),3.98(s,3H,COOCH3); 13 CNMR (151MHz, DMSO) δ165.4, 164.7, 164.0, 162.4, 151.6 (d, J = 10.2Hz), 142.0, 135.6, 135.2, 131.6, 130.9, 130.3 (d, J = 9.7Hz), 129.4, 122. 3,120.8,120.3(d,J=5.4Hz),,113.3,108.5(d,J=1.9Hz),104.8(d,J=21.1Hz),99.1(d,J=25.6Hz),52.3; LC–MS(ESI+)m / z:calcd.for[M+H] + ,C 20 H 16 FN4O3,379.1201,found:379.1208.

[0233] Example 60: Preparation of 1-(2-o-fluorophenylhydrazine-1-formyl)-3-methoxycarbonyl β-carboline (3dh)

[0234]

[0235] The preparation method was the same as that of Example 2, except that 2-fluorophenylhydrazine was used instead of aniline to obtain 3dh as a yellow solid with a yield of 80%. 1 HNMR(400MHz,DMSO-d6)δ12.18(s,1H,NH),10.45(d,J=2.1Hz,1H,CO NH NH-),9.17(s,1H,Ar-H),8.48(d,J=7.9Hz,1H,CONH NH -),7.97(s,1H,Ar-H),7.81(d,J=8.2Hz,1H,Ar-H),7.63(ddd,J=8.2,7.0,1.1Hz,1H,Ar-H),7.35(q,J=7.6Hz,1H,Ar-H),7.14(ddd,J=12.1,8. 2,1.3Hz,1H,Ar-H),7.04–6.95(m,1H,Ar-H),6.92(td,J=8.4,1.8Hz,1H,Ar-H),6.76(tdd,J=7.2,4.8,1.8Hz,1H,Ar-H),3.98(s,3H,COOCH3); 13 C NMR (151MHz, DMSO) δ165.5,164.7,151.3,149.7,142.1,137.0(d,J=10.8Hz),135.7,135.3,131.6,131.0,129.5,124.6(d,J=3.1Hz),122. 4,120.8,120.4(d,J=9.3Hz),119.1(d,J=6.7Hz),114.9(d,J=17.7Hz),114.4(d,J=3.3Hz),113.4,52.4; LC–MS(ESI+)m / z:calcd.for[M+H] + ,C 20 H 16 FN4O3,379.1201,found:379.1200.

[0236] Example 61: Preparation of 1-(2-(4-fluorophenylhydrazine-1-formyl)-3-methoxycarbonyl β-carboline (3di)

[0237]

[0238] The preparation method was the same as that of Example 2, except that 4-fluorophenylhydrazine was used instead of aniline to obtain 3di as a yellow solid with a yield of 86%. 1 HNMR(600MHz,DMSO-d6)δ12.14(s,1H,NH),10.41(d,J=2.9Hz,1H,CONH NH-),9.14(d,J=0.7Hz,1H,Ar-H),8.45(dd,J=7.7,1.0Hz,1H,Ar-H),7.97(d,J=2.9Hz,1H,Ar-H),7.81(dd,J=8.3,0.9Hz,1H,Ar-H),7.62(ddd, J=8.3,7.1,1.2Hz,1H,Ar-H),7.34(ddd,J=8.0,7.0,1.0Hz,1H,Ar-H),7.03–6.97(m,2H,Ar-H),6.90–6.84(m,2H,Ar-H),3.97(s,3H,COOCH3); 13 C NMR (151MHz, DMSO) δ165.5,164.8,156.9,155.3,145.9(d,J=2.0Hz),142.1,135.6,135.3,131.8,131.0,129.5, 122.3,120.8,120.4,115.2(d,J=22.4Hz),,114.0(d,J=7.6Hz),113.4,52.4; LC–MS(ESI+)m / z:calcd.for[M+H] + ,C 20 H 16 FN4O3,379.1201,found:379.1197.

[0239] Example 62: Preparation of 1-(2-trifluoromethylphenylhydrazine-1-formyl)-3-methoxycarbonyl β-carboline (3dj)

[0240]

[0241] The preparation method was the same as that of Example 2, except that 4-trifluoromethylphenylhydrazine was used instead of aniline to obtain 3dj as a yellow solid in a yield of 73%. 1 H NMR(400MHz,DMSO-d6)δ12.14(s,1H,NH),10.58(s,1H,CO NH NH-),9.16(s,1H,Ar-H),8.63(s,1H,CONH NH -),8.47(d,J=7.8Hz,1H,Ar-H),7.81(d,J=8.2Hz,1H,Ar-H),7.63(ddd,J=8.3,7.1,1.2Hz,1H,Ar-H),7.49(d, J=8.5Hz,2H,Ar-H),7.36(ddd,J=8.0,7.2,1.0Hz,1H,Ar-H),6.96(d,J=8.5Hz,2H,Ar-H),3.98(s,3H,COOCH3);13 C NMR (151MHz, DMSO) δ165.6,164.8,152.6,142.1,135.7,135.3,131.6,131.1,118.45(q,J=31.7Hz),129.5,125.17(q, J=270.3Hz),126.28(q,J=3.9Hz),122.4,120.9,120.5,120.4,113.4,112.0,52.5; LC–MS(ESI+)m / z:calcd.for[M+H] + ,C 21 H 16 F3N4O3,429.1169,found:429.1179.

[0242] Example 63: Preparation of 1-(2-p-nitrophenylhydrazine-1-formyl)-3-methoxycarbonyl β-carboline (3dk)

[0243]

[0244] The preparation method was the same as that of Example 2, except that 4-nitrophenylhydrazine was used instead of aniline to obtain 3dk as a yellow solid with a yield of 57%. 1 HNMR(400MHz,DMSO-d6)δ12.15(s,1H,NH),10.82(s,1H,CO NH NH-),9.31(s,1H,CONH NH -),9.17(s,1H,Ar-H),8.48(d,J=7.9Hz,1H,Ar-H),8.15–8.04(m,2H,Ar-H),7.82(d,J=8.3Hz,1H,Ar-H),7.64(ddd,J=8.3,7.1,1.2Hz, 1H, Ar-H), 7.36 (ddd, J=8.0, 7.1, 1.0Hz, 1H, Ar-H), 6.91 (d, J=8.9Hz, 2H, Ar-H), 3.99 (s, 3H, COOCH3); LC–MS (ESI+) m / z: calcd.for[M+H] + ,C 21 H 16 F3N4O3,406.1146,found:406.1156.

[0245] Example 64: Preparation of 1-(2-(4-bromophenylhydrazine-1-formyl)-3-methoxycarbonyl β-carboline (3dl)

[0246]

[0247] The preparation method was the same as that of Example 2, except that 4-bromophenylhydrazine was used instead of aniline to obtain 3dl as a white solid with a yield of 77%. 1 HNMR(400MHz,DMSO-d6)δ12.14(s,1H,NH),10.44(d,J=2.3Hz,1H,CO NH NH-),9.15(s,1H,Ar-H),8.46(d,J=8.0Hz,1H,CONH NH -),8.21(d,J=2.2Hz,1H,Ar-H),7.81(d,J=8.3Hz,1H,Ar-H),7.62(ddd,J=8.3,7.0,1. 2Hz,1H,Ar-H),7.40–7.27(m,3H,Ar-H),6.86–6.76(m,2H,Ar-H),3.97(s,3H,COOCH3); 13 C NMR(126MHz,DMSO-D6)δ165.4,164.6,148.6,142.0,135.6,135.3,131.6,131.3and 131.2,130.9,129.3,122.1,120.7,120.3,120.2,114.58and114.61,113.3,109.5,52.19and 52.18; LC–MS(ESI+)m / z:calcd.for[M+H] + ,C 20 H 16 BrN4O3,439.0400,found:439.0400.

[0248] Example 65: Preparation of 1-(2,4-difluorophenylhydrazine-1-formyl)-3-methoxycarbonyl β-carboline (3dm)

[0249]

[0250] The preparation method was the same as that in Example 2, except that 2,4-difluorophenylhydrazine was used instead of aniline to obtain 3dm as a white solid with a yield of 80%. 1 H NMR(400MHz,DMSO-d6)δ12.16(s,1H,NH),10.44(s,1H,CO NH NH-),9.15(s,1H,Ar-H),8.47(d,J=7.9Hz,1H,CONH NH-),7.89(s,1H,Ar-H),7.81(d,J=8.2Hz,1H,Ar-H),7.63(ddd,J=8.3,7.0,1.2Hz,1H,Ar-H),7.41–7.31 (m,1H,Ar-H),7.20(ddd,J=11.7,8.9,2.7Hz,1H,Ar-H),7.01–6.83(m,2H,Ar-H),3.98(s,3H,COOCH3); 13 C NMR (151MHz, DMSO) δ165.5, 164.8, 155.0 (dd, J=236.6, 10.9Hz), 149.9 (dd, J=24 2.6,12.1Hz),142.1,135.6,135.3,133.8(dd,J=10.7,2.8Hz),131.6,131.0,129 .5,122.4,120.8,120.4,120.3,115.1(dd,J=8.8,4.7Hz),113.4,110.9(dd,J=21 .4,3.2Hz),103.7(dd,J=27.0,22.6Hz),52.4; LC–MS(ESI+)m / z:calcd.for[M+H] + ,C 20 H 15 F2N4O3,397.1107,found:397.1107.

[0251] Example 66: Preparation of 1-(2,4-dichlorophenylhydrazine-1-formyl)-3-methoxycarbonyl β-carboline (3dn)

[0252]

[0253] The preparation method was the same as that of Example 2, except that 2,4-dichlorophenylhydrazine was used instead of aniline to obtain 3dn as a white solid with a yield of 72%. 1 H NMR (500MHz, DMSO-d6) δ12.16 (s, 1H, NH), 10.44 (d, J = 2.3Hz, 1H, CO NH NH-),9.15(s,1H,Ar-H),8.46(d,J=8.0Hz,1H,CONH NH-),7.89(s,1H,Ar-H),7.80(d,J=8.3Hz,1H,Ar-H),7.63(t,J=7.6Hz,1H,Ar-H),7.35(t,J=7.6Hz,1H,Ar-H),7 .19(ddd,J=11.6,8.8,2.7Hz,1H,Ar-H),6.92(dtd,J=25.0,10.1,9.7,6.6Hz,2H,Ar-H),3.97(s,3H,COOCH3); 13 C NMR (151MHz, DMSO) δ167.2,165.5,165.5,164.7,144.2,142.1,142.1,135.8,135.3,135.0,132.3,131.5,131.1,131.0,129.5,129.4,128.4 ,127.8,122.4,122.3,122.3,120.9,120.8,120.5,120.4,120.2,118.0,114.9,113.5,113.4,52.4,52.4; LC–MS(ESI+)m / z:calcd.for[M+H] + ,C 21 H 16 Cl2N4O3,429.0516,found:429.0520.

[0254] Example 67: Preparation of 1-(2,5-dichlorophenylhydrazine-1-formyl)-3-methoxycarbonyl β-carboline (3do)

[0255]

[0256] The preparation method was the same as that in Example 2, except that 2,5-dichlorophenylhydrazine was used instead of aniline to obtain 3do as a white solid with a yield of 76%. 1 H NMR(400MHz,DMSO-d6)δ12.18(s,1H,NH),10.64(s,1H,CO NH NH-),9.16(s,1H,Ar-H),8.47(d,J=7.9Hz,1H,CONH NH -),8.06(s,1H,Ar-H),7.81(dt,J=8.4,0.9Hz,1H,Ar-H),7.63(ddd,J=8.3,7.1,1.2Hz,1H,Ar-H),7.41– 7.31(m,2H,Ar-H),6.89(d,J=2.4Hz,1H,Ar-H),6.81(dd,J=8.4,2.4Hz,1H,Ar-H),3.98(s,3H,COOCH3); 13C NMR (126MHz, DMSO-D6) δ165.4,164.6,146.1,142.0,135.7,135.4,132.4,131.3,131.0,130.5,129. 4,122.2,120.8,120.3,120.3,119.0,115.9,113.3,112.9,52.2; LC–MS(ESI+)m / z:calcd.for[M+H] + ,C 20 H 15 Cl2N4O3,429.0516,found:429.0537;calcd.for[M+Na] + ,C 20 H 14 Cl2N4NaO3,451.0335,found:451.0319.

[0257] Example 68: Preparation of 1-(3,5-dichlorophenylhydrazine-1-formyl)-3-methoxycarbonyl β-carboline (3dp)

[0258]

[0259] The preparation method is the same as that of Example 2, except that 3,4-dichlorophenylhydrazine is used instead of aniline to obtain 3dp as a white solid. 1 H NMR (400MHz, DMSO-d6) δ12.13 (s, 1H, NH), 10.57 (d, J = 2.1Hz, 1H, CO NH NH-),9.15(s,1H,Ar-H),8.53–8.37(m,2H,Ar-H and CONH NH -),7.81(d,J=8.2Hz,1H,Ar-H),7.63(ddd,J=8.3,7.1,1.2Hz,1H,Ar-H),7.44–7.31(m,2H, Ar-H),7.01(d,J=2.6Hz,1H,Ar-H),6.84(dd,J=8.8,2.7Hz,1H,Ar-H),3.98(s,3H,COOCH3); 13 C NMR (151MHz, DMSO) δ165.4,164.7,149.6,142.0,135.6,135.3,131.5,131.1,130.9,130.6,129.4 ,122.3,120.8,120.4,120.3,119.4,113.5,113.3,112.9,52.3; LC–MS(ESI+)m / z:calcd.for[M+H] + ,C20 H 15 Cl2N4O3,397.1107,found:397.1111.

[0260] Example 69: Preparation of 1-(2-benzoylhydrazide-1-formyl)-3-methoxycarbonyl β-carboline (3dq)

[0261]

[0262] The preparation method was the same as that in Example 2, except that phenylhydrazide was used instead of aniline to obtain 3dq as a white solid with a yield of 88%. 1 H NMR(400MHz,DMSO-d6)δ12.18(s,1H,NH),10.64(s,1H,CO NH NH-),9.17(s,1H,Ar-H),8.48(d,J=7.9Hz,1H),8.06(s,1H),7.81(dt,J=8.4,0.9Hz,1H),7.64(ddd,J=8.3,7.1,1.2Hz,1H ),7.41–7.32(m,2H),6.90(d,J=2.4Hz,1H),6.80(d,J=2.5Hz,1H),3.99(s,3H,COOCH3); LC–MS(ESI+)m / z:calcd.for[M+H] + ,C 21 H 17 N4O4,389.1244,found:389.1246.

[0263] Example 70: Preparation of 1-(2-phenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4da)

[0264]

[0265] The preparation method was the same as that of Example 2, except that phenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4da as a white solid in a yield of 92%. 1 H NMR (600MHz, DMSO-d6) δ12.00 (s, 1H, NH), 11.25 (d, J = 2.8Hz, 1H, CO NH NH-),9.04(d,J=30.7Hz,2H,Ar-H and CONH2),8.42(d,J=7.9Hz,1H,Ar-H),8.03(d,J=2.7Hz,1H,CONH NH-),7.79(d,J=8.2Hz,1H,Ar-H),7.60(t,J=7.7Hz,1H,Ar-H),7.58–7.49(m,1H,CONH2),7.31(t,J=7. 5Hz,1H,Ar-H),7.17(t,J=7.7Hz,2H,Ar-H),6.88(d,J=8.0Hz,2H,Ar-H),6.74(t,J=7.3Hz,1H,Ar-H); 13 C NMR (151MHz, DMSO) δ166.4,164.8,149.6,142.1,138.6,135.5,131.6,130.0,129. 2,128.9,122.3,120.5,120.5,118.8,117.0,113.3,112.7; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 19 H 16 N5O2,346.13,found:346.33;calcd for[M+Na] + ,C 19 H 15 N5NaO2,368.11,found:368.31.

[0266] Example 71: Preparation of 1-(2-p-methylphenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4db)

[0267]

[0268] The preparation method was the same as that of Example 2, except that 4-methylphenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4db as a white solid in 88% yield. 1 HNMR(400MHz,DMSO-d6)δ11.99(s,1H,NH),11.24(d,J=3.0Hz,1H,CO NH NH-),9.05(s,1H,Ar-H),9.01(d,J=2.6Hz,1H,CONH2),8.42(d,J=7.8Hz,1H,Ar-H),7.87(d,J=3.0Hz,1H,CONH NH -),7.82–7.75(m,1H,Ar-H),7.65–7.50(m,2H,Ar-H and CONH2),7.31(ddd,J=8.0,7.1,1.0Hz,1H,Ar-H),6.98(d,J=8.1Hz,2H,Ar-H),6.87–6.74(m,2H,Ar-H),2.18(s,3H,CH3);13 C NMR (126MHz, DMSO-D6) δ167.2,165.2,147.4,142.4,138.8,135.9,132.0,130.4,129.8 ,129.7,128.3,122.4,121.1,120.7,117.3,113.6,113.4,20.5; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 20 H 18 N5O2,360.1455,found:360.1455.

[0269] Example 72: Preparation of 1-(2-p-methoxyphenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4dc)

[0270]

[0271] The preparation method was the same as that of Example 2, except that 4-methoxyphenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4dc as a white solid in 85% yield. 1 H NMR(500MHz,DMSO-d6)δ12.00(s,1H,NH),11.26(d,J=3.4Hz,1H,CO NH NH-),9.06(d,J=17.2Hz,2H,Ar-H and CONH2),8.42(d,J=7.7Hz,1H,Ar-H),7.80(d,J=8.2Hz,1H,Ar-H),7.73(d,J=3.4Hz,1H,CONH NH -),7.59(ddd,J=15.1,6.9,1.9Hz,2H,Ar-H),7.31(t,J=7.5Hz,1H,Ar-H),6.90–6.85(m,2H,Ar-H),6.83–6.77(m,2H,Ar-H),3.66(s,3H,OCH3); 13 C NMR (126MHz, DMSO-D6) δ166.5,164.9,153.0,143.5,142.2,138.7,135.5,131.6,130.1,129.3 ,122.3,122.2,120.6,120.5,117.0,114.4,114.4,114.3,113.3,55.4; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 20 H 18N5O3,376.1404,found:376.1403.

[0272] Example 73: Preparation of 1-(2-(4-chlorophenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4dd)

[0273]

[0274] The preparation method was the same as that of Example 2, except that 4-chlorophenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4dd as a white solid in a yield of 82%. 1 H NMR (400MHz, DMSO-d6) δ12.01 (s, 1H, NH), 11.29 (d, J = 2.5Hz, 1H, CO NH NH-),9.15–8.94(m,2H,Ar-H and CONH2),8.43(d,J=7.9Hz,1H,Ar-H),8.25(d,J=2.5Hz,1H,CONH NH -),7.79(d,J=8.2Hz,1H,Ar-H),7.66–7.53(m,2H,Ar-H and CONH2),7.32(ddd,J=8.0,7.1,1.0Hz,1H,Ar-H),7.26–7.17(m,2H,Ar-H),6.95–6.84(m,2H,Ar-H); 13 C NMR (126MHz, DMSO-D6) δ166.4,164.8,148.6,142.2,138.7,135.5,131.7,129.8,129 .3,128.7,122.3,122.1,120.5,120.5,117.1,114.1,113.3; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 19 H 15 ClN5O2,380.0909,found:380.0881.

[0275] Example 74: Preparation of 1-(2-(4-fluorophenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4de)

[0276]

[0277] The preparation method was the same as that of Example 2, except that 4-fluorophenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4de as a white solid in 88% yield. 1H NMR (400MHz, DMSO-d6) δ12.02 (s, 1H, NH), 11.29 (d, J = 2.9Hz, 1H, CO NH NH-),9.07(s,1H,Ar-H),9.02(d,J=2.6Hz,1H,CONH2),8.43(d,J=7.9Hz,1H,Ar-H),8.05(d,J=2.8Hz,1H,CONH NH -),7.80(d,J=8.2Hz,1H,Ar-H),7.65–7.54(m,2H,Ar-H and CONH2),7.36–7.28(m,1H,Ar-H),7.08–6.98(m,2H,Ar-H),6.95–6.86(m,2H,Ar-H); 13 C NMR (151MHz, DMSO) δ166.8, 165.2, 156.4 (d, J = 233.3Hz), 146.6, 142.5, 139.0, 135.8, 132.0, 130.3, 129 .6,122.6,120.9,120.8,117.4,115.7(d,J=22.3Hz),114.3(d,J=7.7Hz),113.6; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 19 H 15 FN5O2,364.1204,found:364.1216.

[0278] Example 75: Preparation of 1-(2-(4-bromophenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4df)

[0279]

[0280] The preparation method was the same as that of Example 2, except that 4-bromophenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4df as a white solid in a yield of 78%. 1 H NMR (600MHz, DMSO-d6) δ11.99 (s, 1H, NH), 11.27 (d, J = 2.6Hz, 1H, CO NH NH-),9.06(s,1H,Ar-H),9.01–8.95(m,1H,CONH2),8.42(d,J=7.9Hz,1H,Ar-H),8.25(d,J=2.5Hz,1H,CONH NH-),7.79(d,J=8.3Hz,1H,Ar-H),7.60(t,J=7.7Hz,1H,CONH2),7.57–7.51(m,1H,Ar-H),7.32(d,J=8.2Hz,3H,Ar-H),6.84(d,J=8.5Hz,2H,Ar-H); 13 C NMR (151MHz, DMSO) δ166.4,164.8,149.0,142.1,138.6,135.5,131.6,131.5,129. 8,129.3,122.3,120.5,120.5,117.1,114.6,113.3,109.5; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 19 H 15 BrN5O2,424.0404,found:424.0404;calcd for[M+Na] + ,C 19 H 14 BrN5NaO2,446.0223,found:446.0223.

[0281] Example 76: Preparation of 1-(2-p-nitrophenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4dg)

[0282]

[0283] The preparation method was the same as that of Example 2, except that 4-nitrophenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4dg as a white solid with a yield of 43%. 1 HNMR(400MHz,DMSO-d6)δ11.95(s,1H),9.41(d,J=14.2Hz,1H),9.06(s,1H ),9.02(s,1H),8.91–8.84(m,1H),8.41(d,J=7.9Hz,1H),8.18–8.13(m,1H) ,7.89–7.81(m,2H),7.61(ddd,J=8.3,7.1,1.2Hz,1H),7.53(d,J=2.5Hz,1H ),7.35–7.27(m,1H),7.02–6.89(m,2H); LC–MS(ESI+)m / z:Calcd.for[M+H] + ,C 19 H 15 N6O4,391.12,Found:391.50; Calcd.for[M+Na] + ,C 19H 14 N6NaO4,413.48,Found:413.48.

[0284] Example 77: Preparation of 1-(2-trifluoromethoxyphenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4dh)

[0285]

[0286] The preparation method was the same as that of Example 2, except that 4-trifluoromethoxyphenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4dh as a white solid in a yield of 75%. 1 H NMR (400MHz, DMSO-d6) δ12.03 (s, 1H, NH), 11.31 (d, J = 2.4Hz, 1H, CO NH NH-),9.14–8.94(m,2H,Ar-H and CONH2),8.43(d,J=7.9Hz,1H,Ar-H),8.32(d,J=2.4Hz,1H,CONH NH -),7.78(d,J=8.2Hz,1H,Ar-H),7.68–7.53(m,2H,Ar-H and CONH2),7.32(ddd,J=8.0,7.1,1.0Hz,1H,Ar-H),7.24–7.12(m,2H,Ar-H),6.98–6.89(m,2H,Ar-H); 13 C NMR (126MHz, DMSO-D6) δ166.3,164.8,148.7,142.1,140.6,138.6,135.4,131.5, 129.7,129.1,123.4–117.2(m),122.1,121.8,120.4,120.4,116.9,113.3,113.1; 19 F NMR(471MHz,DMSO-D6)δ-57.2;calcd for[M+Na] + ,C 20 H 14 F3N5NaO3,452.0941,found:452.0937.

[0287] Example 78: Preparation of 1-(2-trifluoromethylphenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4di)

[0288]

[0289] The preparation method was the same as that of Example 2, except that 4-trifluoromethylphenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4di as a white solid in a yield of 73%. 1 H NMR(400MHz,DMSO-d6)δ12.02(s,1H,NH),11.36(d,J=1.9Hz,1H,CO NH NH-),9.08(s,1H,Ar-H),8.99(d,J=2.6Hz,1H,CONH2),8.70(d,J=2.0Hz,1H,CONH NH -),8.43(d,J=7.9Hz,1H,Ar-H),7.79(d,J=8.3Hz,1H,Ar-H),7.65–7.56(m,2H,Ar-H and CONH2),7.51(d,J=8.5Hz,2H,Ar-H),7.32(ddd,J=8.0,7.1,1.0Hz,1H,Ar-H),6.99(d,J=8.5Hz,2H,Ar-H); 13 C NMR (126MHz, DMSO-D6) δ166.8,165.3,153.2,142.6,139.2,136.0,132.2,130.1,129.7,126.8(q, J=4.1,3.7Hz),126.6,124.5,122.7,121.0,120.9,119.26–112.44(m),117.6,113.7,112.5;calcd for[M+Na] + ,C 20 H 14 F3N5NaO2,436.0992,found:436.0970.

[0290] Example 79: Preparation of 1-(2-o-chlorophenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4dj)

[0291]

[0292] The preparation method was the same as that of Example 2, except that 2-chlorophenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4dj as a white solid in a yield of 64%. 1 H NMR (600MHz, DMSO-d6) δ12.04 (s, 1H, NH), 11.39 (d, J = 2.3Hz, 1H, CO NHNH-),9.10–9.05(m,1H,Ar-H),9.00(d,J=2.5Hz,1H,CONH2),8.45–8.40(m,1H,Ar-H),7.83–7.75(m,2H,Ar-H and CONH NH -),7.65–7.53(m,2H,Ar-H and CONH2),7.39–7.28(m,2H,Ar-H),7.16(td,J=7.9,1.5Hz,1H,Ar-H),6.95(dd,J=8.2,1.5Hz,1H,Ar-H),6.79(ddd,J=8.5,7.4,1.5Hz,1H,Ar-H); 13 C NMR (151MHz, DMSO) δ166.4,164.8,145.1,142.2,138.7,135.5,131.7,129.7,129.3,129. 2,127.9,122.3,120.6,120.5,119.8,117.5,117.2,113.7,113.3; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 19 H 15 ClN5O2,380.0909,found:380.0893.

[0293] Example 80: Preparation of 1-(2-m-chlorophenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4dk)

[0294]

[0295] The preparation method was the same as that of Example 2, except that 3-chlorophenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4dk as a white solid in 82% yield. 1 H NMR (400MHz, DMSO-d6) δ12.02 (s, 1H, NH), 11.30 (d, J = 2.3Hz, 1H, CO NH NH-),9.07(s,1H,Ar-H),8.99(d,J=2.6Hz,1H,CONH2),8.43(d,J=7.9Hz,1H,Ar-H),8.38(d,J=2.3Hz,1H,CONH NH-),7.79(d,J=8.3Hz,1H,Ar-H),7.66–7.53(m,2H,Ar-H and CONH2),7.32(td,J=7.5,7.1,1.0Hz,1H,Ar-H),7.19(t,J=8.0Hz,1H,Ar-H),6.88–6.80(m,2H,Ar-H),6.76(ddd,J=7.9,2.0,0.9Hz,1H,Ar-H); 13 C NMR (126MHz, DMSO-D6) δ166.4,164.8,151.3,142.2,138.7,135.5,133.6,131.7,130.7,129 .7,129.3,122.2,120.6,120.5,118.2,117.2,113.3,111.8,111.2; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 19 H 15 ClN5O2,380.0909,found:380.0909;calcd for[M+Na] + ,C 19 H 14 ClN5NaO2,402.0728,found:402.0728.

[0296] Example 81: Preparation of 1-(2-o-fluorophenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4dl)

[0297]

[0298] The preparation method was the same as that of Example 2, except that 2-fluorophenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4dl as a white solid in a yield of 74%. 1 H NMR (400MHz, DMSO-d6) δ12.03 (s, 1H, NH), 11.30 (d, J = 2.3Hz, 1H, CO NH NH-),9.07(s,1H,Ar-H),9.01(d,J=2.5Hz,1H,CONH2),8.43(d,J=7.9Hz,1H,Ar-H),8.00(t,J=2.0Hz,1H,CONH NH-),7.78(d,J=8.2Hz,1H,Ar-H),7.59(ddd,J=15.7,7.3,1.9Hz,2H,Ar-Hand CONH2),7.38–7.26(m,1H,Ar-H),7.14(ddd,J=12.1,8.1,1.3Hz,1H,Ar-H),7.05–6.88(m,2H,Ar-H),6.76(tdd,J=8.1,5.9,1.8Hz,1H,Ar-H); 13 C NMR (126MHz, DMSO-D6) δ166.3,164.8,150.5(d,J=239.1Hz),142.1,138.6,137.1(d,J=10.5Hz),135.4,131.6,129.7,129 .2,124.6(d,J=3.4Hz),122.1,120.4,120.4,119.0(d,J=6.4Hz),116.9,114.9(d,J=17.8Hz),114.3(d,J=3.1Hz),113.2; 19 F NMR(471MHz,DMSO-D6)δ-133.1; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 19 H 15 FN5O2,364.1204,found:364.1204;calcd for[M+Na] + ,C 19 H 14 FN5NaO2,386.1204,found:386.1204.

[0299] Example 82: Preparation of 1-(2-m-fluorophenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4dm)

[0300]

[0301] The preparation method was the same as that of Example 2, except that 3-fluorophenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4dm as a white solid with a yield of 81%. 1 H NMR (600MHz, DMSO-d6) δ12.00 (s, 1H, NH), 11.28 (d, J = 2.4Hz, 1H, CO NH NH-),9.07(d,J=0.7Hz,1H,Ar-H),8.98(d,J=2.5Hz,1H,CONH2),8.43(dd,J=7.9,1.0Hz,1H,Ar-H),8.35(d,J=2.3Hz,1H,CONH NH -),7.80(dt,J=8.3,0.9Hz,1H,Ar-H),7.61(ddd,J=8.2,7.0,1.2Hz,1H,Ar-H),7.56(d,J=2.5Hz,1H,CONH2),7.33(ddd,J=8.0,7.1,1.0Hz,1H, Ar-H),7.20(td,J=8.2,6.7Hz,1H,Ar-H),6.71(ddd,J=8.2,2.1,0.9Hz,1H,Ar-H),6.61(dt,J=11.6,2.3Hz,1H,Ar-H),6.56–6.49(m,1H,Ar-H); 13 C NMR (151MHz, DMSO) δ166.4,164.8,163.3(d,J=240.4Hz),151.9(d,J=10.4Hz),142.1,138.6,135.5,131.6,130.5(d,J= 9.9Hz), 129.8, 129.3, 122.3, 120.5, 120.5, 117.1, 113.3, 108.5 (d, J = 2.1Hz), 104.9 (d, J = 21.2Hz), 99.1 (d, J = 25.5Hz); 19 F NMR(376MHz,DMSO-D6)δ-113.1; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 19 H 15 FN5O2,364.1204,found:364.1204;calcd for[M+Na] + ,C 19 H 14 FN5NaO2,386.1204,found:386.1204.

[0302] Example 83: Preparation of 1-(2-(2,4-dichlorophenylhydrazine)-1-formyl)-3-carbamoyl β-carboline (4dn)

[0303]

[0304] The preparation method was the same as that of Example 2, except that 2,4-dichlorophenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4dn as a white solid in a yield of 75%. 1 H NMR(500MHz,DMSO-d6)δ12.04(s,1H,NH),11.40(d,J=2.1Hz,1H,CO NHNH-),9.07(s,1H,Ar-H),8.98(d,J=2.5Hz,1H,CONH2),8.43(d,J=7.9Hz,1H,Ar-H),8.01(d,J=2.0Hz,1H,CONH NH -),7.79(d,J=8.3Hz,1H,Ar-H),7.64–7.53(m,2H,Ar-H andCONH2),7.49(d,J=2.6Hz,1H,Ar-H),7.32(t,J=7.5Hz,1H,Ar-H),7.22(dd,J=8.8,2.4Hz,1H,Ar-H),6.93(d,J=8.7Hz,1H,Ar-H); 13 C NMR (126MHz, DMSO-D6) δ166.8,165.2,144.8,142.6,139.1,136.0,132.1,130.0,129.8,129 .0,128.4,122.7,122.6,121.1,120.9,118.4,117.7,115.2,113.7; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 19 H 14 Cl2N5O2,414.0519,found:414.0524.

[0305] Example 84: Preparation of 1-(2-(3,4-dichlorophenylhydrazine)-1-formyl)-3-carbamoyl β-carboline (4dp)

[0306]

[0307] The preparation method was the same as that of Example 2, except that 3,4-dichlorophenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4dp as a white solid with a yield of 78%. 1 H NMR (400MHz, DMSO-d6) δ12.01 (s, 1H, NH), 11.32 (d, J = 2.2Hz, 1H, CO NH NH-),9.07(s,1H,Ar-H),8.97(d,J=2.6Hz,1H,CONH2),8.50(d,J=2.2Hz,1H,CONH NH-),8.43(d,J=7.9Hz,1H,Ar-H),7.84–7.75(m,1H,Ar-H),7.66–7.54(m,2H,Ar-Hand CONH2),7.40(d,J=8.8Hz,1H,Ar-H),7.32(ddd,J=8.0,7.1,1.0Hz,1H,Ar-H),7.03(d,J=2.6Hz,1H,Ar-H),6.86(dd,J=8.8,2.7Hz,1H,Ar-H); 13 C NMR (126MHz, DMSO-D6) δ166.2,164.7,149.7,142.1,138.6,135.4,131.6,131.2,130.7,129 .5,129.2,122.1,120.4,120.4,119.5,117.0,113.5,113.2,112.8; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 19 H 14 Cl2N5O2,414.0519,found:414.0519.

[0308] Example 85: Preparation of 1-(2-(2,4-difluorophenylhydrazine)-1-formyl)-3-carbamoyl β-carboline (4dq)

[0309]

[0310] The preparation method was the same as that of Example 2, except that 2,4-difluorophenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4dq as a white solid in a yield of 74%. 1 H NMR (400MHz, DMSO-d6) δ12.04 (s, 1H, NH), 11.32 (d, J = 2.4Hz, 1H, CO NH NH-),9.07(s,1H,Ar-H),9.01(d,J=2.5Hz,1H,CONH2),8.43(d,J=7.9Hz,1H,Ar-H),7.98(t,J=2.0Hz,1H,CONH NH -),7.82–7.75(m,1H,Ar-H),7.60(ddd,J=9.0,7.4,1.5Hz,2H,Ar-H and CONH2),7.32(ddd,J=8.0,7.1,1.0Hz,1H,Ar-H),7.21(ddd,J=11.6,8.9,2.7Hz,1H,Ar-H),6.93(dtd,J=17.0,8.9,6.0Hz,2H,Ar-H); 13C NMR(126MHz, DMSO-D6)δ166.3,164.8,154.9(dd,J=236.8,10.7Hz),151.0–148.6(m),142.1,138.6,135.4,133.8(dd,J=10.9,3.0Hz),131.5,129.6, 129.1,122.1,120.4,120.4,116.9,114.9(dd,J=9.1,4.8Hz),113.1,110.9(dd,J=21.8,3.5Hz),103.6(dd,J=26.9,22.5Hz); LC–MS(ESI+)m / z:calcd for[M+H] + ,C 19 H 14 F2N5O2,382.1110,found:382.1110.

[0311] Example 86: Preparation of 1-(2-(2,5-difluorophenylhydrazine)-1-formyl)-3-carbamoyl β-carboline (4dr)

[0312]

[0313] The preparation method was the same as that of Example 2, except that 2,5-difluorophenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4dr as a white solid in a yield of 72%. 1 H NMR (400MHz, DMSO-d6) δ12.05 (s, 1H, NH), 11.31 (d, J = 1.7Hz, 1H, CO NH NH-),9.08(s,1H,Ar-H),9.00(d,J=2.5Hz,1H,Ar-H),8.44(d,J=7.9Hz,1H,CONH2),8.36(d,J=1.8Hz,1H,CONH NH -),7.84–7.77(m,1H,Ar-H),7.61(ddd,J=8.3,5.4,1.2Hz,2H,Ar-H and CONH2),7.33(ddd,J=8.0,7.1,1.0Hz,1H,Ar-H),7.19(ddd,J=11.2,8.9,5.0Hz,1H, Ar-H), 6.67 (ddd, J=10.2, 6.9, 3.1Hz, 1H, Ar-H), 6.54 (tt, J=8.5, 3.2Hz, 1H, Ar-H); 13C NMR (126MHz, DMSO-D6) δ166.3, 164.8, 159.0 (d, J = 237.8Hz), 146.5 (d, J = 234.6Hz), 142.1, 138.7 (dd, J = 12.7, 10.4Hz), 138.6, 135.4, 131 .6,129.5,129.1,122.1,120.4,120.4,117.0,115.8(dd,J=20.4,10.2Hz),113.1,104.0(dd,J=24.6,7.2Hz),100.6(dd,J=28.8,3.9Hz); 19 F NMR(471MHz, DMSO-D6)δ-117.9,-138.4; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 19 H 14 F2N5O2,382.1110,found:382.1104;calcd for[M+Na] + ,C 19 H 13 F2N5NaO2,404.0930,found:404.0923.

[0314] Example 87: Preparation of 1-(2-benzoylhydrazide-1-formyl)-3-carbamoyl β-carboline (4ds)

[0315]

[0316] The preparation method was the same as that of Example 2, except that phenylhydrazide was used instead of aniline and C7 was used instead of A7 to obtain 4ds as a white solid in 89% yield. 1 H NMR(400MHz,DMSO-d6)δ12.10(s,1H,NH),11.31(s,1H,CO NH NH-),10.66(s,1H),9.10(s,1H),8.98(d,J=2.6Hz,1H),8.46(d,J=7.9Hz,1H),7.98(dt,J=6.9,1.5Hz,2H),7.82(d,J =8.3Hz,1H),7.63(qd,J=5.0,4.0,2.3Hz,3H),7.58(dd,J=8.1,6.5Hz,2H),7.40–7.28(m,1H); LC–MS(ESI+)m / z:calcd for[M+H] + ,C 20 H 16N5O3,374.1248,found:374.1255.

[0317] Example 88: Preparation of 1-(2-o-methylphenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4dt)

[0318]

[0319] The preparation method was the same as that of Example 2, except that 2-methylphenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4dt as a white solid in a yield of 76%. 1 HNMR(400MHz,DMSO-d6)δ12.03(s,1H,NH),11.31(d,J=2.8Hz,1H,CO NH NH-),9.05(d,J=14.3Hz,2H,Ar-H and CONH2),8.43(d,J=7.9Hz,1H,Ar-H),7.81–7.75(m,1H,Ar-H),7.64–7.54(m,2H,Ar-H and CONH2),7.45(d,J=2.8Hz,1H,CONH NH -),7.32(t,J=7.6Hz,1H,Ar-H),7.10–6.98(m,2H,Ar-H),6.81(dd,J=8.1,1.2Hz,1H,Ar-H),6.69(td,J=7.3,1.3Hz,1H,Ar-H),2.30(s,3H,CH3); 13 C NMR (126MHz, DMSO-D6) δ166.3,164.6,147.0,142.0,138.6,135.4,131.5,130.0,129.9,129.1 ,126.5,122.1,122.0,120.4,120.4,118.8,116.8,113.2,111.7,17.3; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 20 H 18 N5O2,360.1455,found:360.1458.

[0320] Example 89: Preparation of 1-(2-m-methylphenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4du)

[0321]

[0322] The preparation method was the same as that of Example 2, except that 3-methylphenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4du as a white solid in 85% yield.1 HNMR(500MHz,DMSO-d6)δ11.99(s,1H,NH),11.22(d,J=2.7Hz,1H,CO NH NH-),9.05(s,1H,Ar-H),9.00(d,J=2.6Hz,1H,CONH2),8.42(d,J=7.9Hz,1H,Ar-H),7.94(d,J=2.8Hz,1H,CONH NH -),7.79(d,J=8.1Hz,1H,Ar-H),7.60(ddd,J=8.3,6.9,1.2Hz,1H,Ar-H),7.54(d,J=2.6Hz,1H;CONH2),7.32(t,J=7. 5Hz,1H,Ar-H),7.05(t,J=7.6Hz,1H,Ar-H),6.71–6.65(m,2H,Ar-H),6.56(d,J=7.4Hz,1H,Ar-H),2.21(s,3H,CH3); 13 C NMR (126MHz, DMSO-D6) δ166.3,164.7,149.5,142.0,138.6,137.8,135.4,131.5,129.9,12 9.1,128.6,122.1,120.4,119.6,116.8,113.1,113.1,110.0,21.2; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 20 H 18 N5O2,360.1445,found:360.1452.

[0323] Example 90: Preparation of 1-(2-p-ethylphenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4dv)

[0324]

[0325] The preparation method was the same as that of Example 2, except that 4-ethylphenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4dv as a white solid in a yield of 78%. 1 HNMR(600MHz,DMSO-d6)δ11.98(s,1H,NH),11.23(d,J=3.0Hz,1H,CO NH NH-),9.05(d,J=0.7Hz,1H,Ar-H),9.00(d,J=2.5Hz,1H,CONH2),8.42(dt,J=7.9,0.9Hz,1H,Ar-H),7.86(d,J=3.0Hz,1H,CO NH NH-),7.78(dt,J=8.2,0.9Hz,1H,Ar-H),7.60(ddd,J=8.3,7.0,1.2Hz,1H,Ar-H),7.53(d,J=2.5Hz,1H,CONH2) ,7.31(ddd,J=8.0,7.0,1.0Hz,1H,Ar-H),7.03–6.99(m,2H,Ar-H),6.84–6.79(m,2H,Ar-H),2.50–2.46(m,2H, CH2 CH3), 1.12(t, J=7.6Hz, 3H, CH2 CH3 ); 13 C NMR (151MHz, DMSO) δ166.4,164.8,147.6,142.1,138.6,135.4,134.2,131.5,130.1,129 .2,128.1,122.2,120.5,120.5,117.0,113.3,112.9,27.5,16.2; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 21 H 20 N5O2,374.1612,found:374.1608.

[0326] Example 91: Preparation of 1-(2-p-isopropylphenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4dw)

[0327]

[0328] The preparation method was the same as that in Example 2, except that 4-isopropylphenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 1-(2-(4-isopropylphenyl)hydrazine-1-carbonyl)-9H-pyrido[3,4-b]indole-3-carboxamide as a white solid in a yield of 82%. 1 H NMR (600MHz, DMSO-d6) δ12.00 (s, 1H, NH), 11.24 (d, J = 2.9Hz, 1H, CO NH NH-),9.06(s,1H,Ar-H),9.02(d,J=2.5Hz,1H,CONH2),8.42(d,J=7.9Hz,1H,Ar-H),7.86(d,J=2.9Hz,1H,CO NHNH-),7.79(d,J=8.2Hz,1H,Ar-H),7.59(ddd,J=8.3,7.0,1.2Hz,1H,Ar-H),7.55(d,J=2.5Hz,1H,CON H2),7.35–7.28(m,1H,Ar-H),7.09–7.00(m,2H,Ar-H),6.87–6.79(m,2H,Ar-H),2.76(p,J=6.9Hz,1H, CH (CH3)2),1.14(d,J=7.0Hz,6H,CH (CH3)2 ); 13 C NMR (151MHz, DMSO) δ166.5,164.8,147.7,142.1,138.9,138.6,135.4,131.6,130.1,129 .2,126.6,122.3,120.5,120.5,117.0,113.3,112.9,32.7,24.3; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 22 H 22 N5O2,388.1768,found:388.1759.

[0329] Example 92: Preparation of 1-(2-perfluorophenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4dy)

[0330]

[0331] The preparation method was the same as that of Example 2, except that 2,3,4,5,6-pentafluorophenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4dy as a white solid with a yield of 80%. 1 H NMR (600MHz, DMSO-d6) δ12.04 (s, 1H, NH), 11.54 (d, J = 2.0Hz, 1H, CO NH NH-),9.05(s,1H,Ar-H),9.01(d,J=2.5Hz,1H,CONH2),8.44–8.34(m,2H,CONH NH -andAr-H),7.78(d,J=8.2Hz,1H,Ar-H),7.62–7.54(m,2H,Ar-H and CONH2),7.34–7.28(m,1H,Ar-H); 13C NMR (151MHz, DMSO) δ166.4,165.1,142.2,139.0–138.8(m),138.7,138.5-138.1(m),137.4–137.1(m),136.8–136.5(m) ,135.5,135.0-134.9(m),133.5-133.1(m),131.7,129.3,129.2,125.1–125.0(m),122.3,120.6,120.4,117.3,113.3; 19 F NMR(376MHz, DMSO-d6)δ-156.44(d,J=22.6Hz),-164.81(t,J=22.7Hz),-169.43(t,J=23.1Hz); LC–MS(ESI+)m / z:calcd for[M+H] + ,C 19 H 11 F5N5O2,436.0827,found:436.0837.

[0332] Example 93: Preparation of 1-(2-p-tert-butylphenylhydrazine-1-formyl)-3-carbamoyl β-carboline (4fa)

[0333]

[0334] The preparation method was the same as that of Example 2, except that 4-isobutylphenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4fa as a white solid in a yield of 76%. 1 H NMR (600MHz, DMSO-d6) δ11.99 (s, 1H, NH), 11.23 (d, J = 2.9Hz, 1H, CO NH NH-),9.05(s,1H,Ar-H),9.01(d,J=2.5Hz,1H,Ar-H and CONH2),8.42(dd,J=7.9,1.1Hz,1H,Ar-H),7.86(d,J=2.8Hz,1H,CONH NH -),7.78(d,J=8.2Hz,1H,Ar-H),7.59(ddd,J=8.3,7.0,1.2Hz,1H,Ar-H),7.54(d,J=2.5Hz,1H,CONH2 ),7.34–7.29(m,1H,Ar-H),7.23–7.16(m,2H,Ar-H),6.84–6.79(m,2H,Ar-H),1.22(s,9H,C(CH3)3); 13C NMR (151MHz, DMSO) δ166.4,164.8,147.3,142.1,141.2,138.6,135.4,131.5,130.1,129 .2,125.4,122.3,120.5,120.5,117.0,113.2,112.6,33.7,31.5; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 23 H 24 N5O2,402.1925,found:402.1929.

[0335] Example 94: Preparation of 1-(2-(1-naphthylhydrazine)-1-formyl)-3-carbamoyl β-carboline (4fb)

[0336]

[0337] The preparation method was the same as that of Example 2, except that 2-naphthylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4fb as a white solid in 86% yield. 1 H NMR (600MHz, DMSO-d6) δ12.00 (s, 1H, NH), 11.43 (d, J = 2.4Hz, 1H, CO NH NH-),9.09(s,1H,Ar-H),9.05(d,J=2.5Hz,1H,CONH2),8.60(d,J=2.5Hz,1H,CONH NH -),8.44(d,J=7.9Hz,1H,Ar-H),8.40–8.36(m,1H,Ar-H),7.90–7.83(m,1H,Ar-H),7.79(d,J=8.3Hz,1H,Ar-H),7.63–7.48(m,4H,Ar-H and CONH2),7.36–7.28(m,3H,Ar-H),6.87(dd,J=6.6,2.1Hz,1H,Ar-H); 13 C NMR (151MHz, DMSO) δ166.5,164.8,144.3,142.2,138.7,135.5,133.9,131.7,130.0,129.3,128.2,126. 4,125.9,124.7,122.4,122.3,121.8,120.5,120.5,118.7,117.1,113.3,105.7; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 23 H 18N5O2,396.1455,found:396.1456

[0338] Example 95: Preparation of 1-(N-(1-piperidine)formamido)-3-carbamoyl β-carboline (4fe)

[0339]

[0340] The preparation method was the same as that of Example 2, except that N-aminopiperidine was used instead of aniline and C7 was used instead of A7 to obtain 4fe as a white solid in a yield of 58%. 1 HNMR(600MHz,DMSO-d6)δ11.96(s,1H,NH),10.39(s,1H,CO NH NH-),9.00(s,1H,Ar-H),8.92(d,J=2.6Hz,1H,CONH2),8.39(d,J=7.8Hz,1H,Ar-H),7.82(d,J=8.2Hz,1H,Ar-H),7.63–7.55(m,2H,Ar-H and CONH2),7.31(t,J=7.3Hz,1H,Ar-H),3.07(t,J=5.3Hz,4H,(CH2)4),1.67(p,J=5.7Hz,4H,(CH2)4),1.44(p,J=6.0Hz,2H,(CH2)4); 13 C NMR(151MHz,DMSO)δ166.5,162.8,142.0,138.4,135.5,131.4,130.7,129.1, 122.2,120.4,120.4,116.8,113.3,54.8,25.8,23.4; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 18 H 20 N5O2,338.1612,found:338.1621.

[0341] Example 96: Preparation of 1-(2-(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenylhydrazine)-1-formyl)-3-carbamoyl β-carboline (4fg)

[0342]

[0343] The preparation method was the same as that of Example 2, except that aniline was replaced by 2,3,5,6-tetrafluoro-4-hydrazinobenzotrifluoride, and A7 was replaced by C7 to obtain 4fg as a white solid in a yield of 75%. 1H NMR(600MHz,DMSO-d6)δ12.07(s,1H,NH),11.67(s,1H,CO NH NH-),9.22(s,1H,CONH2),9.09(s,1H,Ar-H),8.97(d,J=2.6Hz,1H,CONH NH -),8.44(d,J=7.9Hz,1H,Ar-H),7.79(d,J=8.2Hz,1H,Ar-H),7.62(ddd,J=8.3,5.3,1.2Hz,2H,Ar-Hand CONH2),7.38–7.29(m,1H,Ar-H); 13 C NMR(151MHz,DMSO)δ166.5,162.8,142.0,138.4,135.5,131.4,130.7,129.1, 122.2,120.4,120.4,116.8,113.3,54.8,25.8,23.4; LC–MS(ESI+)m / z:calcd for[M+H] + ,C 20 H 11 F7N5O2,486.0795,found:486.0803.

[0344] Example 97: Preparation of 1-(2-(3,4-difluorophenylhydrazine)-1-formyl)-3-carbamoyl β-carboline (4fh)

[0345]

[0346] The preparation method was the same as that of Example 2, except that 3,4-difluorophenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4fh as a white solid in 85% yield. 1 H NMR (600MHz, DMSO-d6) δ12.00 (s, 1H, NH), 11.28 (d, J = 2.6Hz, 1H, CO NH NH-),9.06(d,J=0.7Hz,1H,Ar-H),8.97(d,J=2.4Hz,1H,CONH2),8.42(dd,J=7.8,1.0Hz,1H,Ar-H),8.27(d,J=2.5Hz,1H,CO NHNH-),7.79(dt,J=8.2,0.9Hz,1H,Ar-H),7.60(ddd,J=8.2,7.0,1.2Hz,1H,Ar-H),7.56(d,J=2.5Hz,1H,CONH2),7.32(ddd,J=8. 0,7.0,1.0Hz,1H,Ar-H),7.23(dt,J=10.6,9.0Hz,1H,Ar-H),6.83(ddd,J=12.8,6.9,2.7Hz,1H,Ar-H),6.71–6.64(m,1H,Ar-H); 13 C NMR (151MHz, DMSO) δ166.4, 164.9, 149.9 (dd, J = 242.7, 13.3Hz), 147.2 (dd, J =8.1,1.8Hz),142.8(dd,J=234.7,12.8Hz),142.2,138.6,135.5,131.6,129 .7,129.3,122.3,120.5,120.5,117.6(d,J=17.9Hz),117.1,113.3,108.3(d d,J=5.9,2.8Hz),108.2,108.2,101.2(d,J=20.7Hz); LC–MS(ESI+)m / z:calcd for[M+H] + ,C 19 H 14 F2N5O2,382.1110,found:382.1113.

[0347] Example 98: Preparation of 1-(2-(3,5-difluorophenylhydrazine)-1-formyl)-3-carbamoyl β-carboline (4fj)

[0348]

[0349] The preparation method was the same as that of Example 2, except that 3,5-difluorophenylhydrazine was used instead of aniline and C7 was used instead of A7 to obtain 4fj as a white solid in 85% yield. 1 H NMR(600MHz,DMSO-d6)δ12.01(s,1H,NH),11.30(d,J=2.1Hz,1H,CO NH NH-),9.07(s,1H,Ar-H),8.96(d,J=2.5Hz,1H,CONH2),8.64(d,J=2.0Hz,1H,CO NHNH-),8.43(d,J=7.9Hz,1H,Ar-H),7.80(d,J=8.2Hz,1H,Ar-H),7.64–7.54(m,2H,Ar-H and CONH2),7.32(t,J=7.6Hz,1H,Ar-H),6.48(dd,J=9.3,6.9Hz,3H,Ar-H); 13 C NMR (151MHz, DMSO) δ166.4, 164.8, 164.2 (d, J = 16.0Hz), 162.6 (d, J = 15.9Hz), 152.8 (t, J = 12.9Hz), 142.2, 138.6, 135.5, 131.7,129.6,129.3,122.3,120.6,120.5,117.2,113.3,95.5–94.8(m,2C),93.3(t,J=26.5Hz); LC–MS(ESI+)m / z:calcd for[M+H] + ,C 19 H 14 F2N5O2,382.1110,found:382.1114.

[0350] Example 99: Determination of Antifungal Activity of 1-Substituted β-Carboline Derivatives

[0351] The test strains were selected for activation on PDA plates, including Botrytis cinerea, Gaeumannomyces graminisis, Sclerotinia sclerotiorum, Fusarium graminearum, Phytophthora capsici, and Fusarium moniliforme. The compounds of the present invention were prepared into a series of gradient concentrations of PDA drug-containing plates, and the test strains were made into 5mm diameter cakes and placed in the center of the drug-containing culture dish. The test strains were cultured at a constant temperature of 25°C until the test strains in the blank control dish grew to the edge of the culture dish. The colony diameters of each drug-containing plate were measured by the cross-cross method, and the inhibition rate of the compound on mycelial growth was calculated. We selected 50μg·mL -1 The initial screening concentration is the concentration at which the compound has an inhibition rate of more than 50% against the corresponding pathogen. Further tests are performed at different concentrations. A standard curve is drawn with the compound concentration as the horizontal axis and the inhibition rate as the vertical axis. The concentration of the compound at which the inhibition rate is 50% is calculated (Table 1), i.e., EC 50 The results were repeated 3 times and the average value was obtained. Boscalid was used as the positive control. The EC values ​​of each compound against plant pathogens were 50The values ​​(μg / mL) are shown in Table 2.

[0352] Table 1 Compounds at 50 μg·mL -1 Mycelial growth inhibition rate at the concentration

[0353]

[0354]

[0355]

[0356] Table 2 Effective median concentration (EC) of compounds for inhibiting hyphae growth of various plant pathogenic fungi 50 )

[0357]

[0358]

[0359]

[0360] Note: “>50” means the inhibition rate is less than 50% at a concentration of 50 μg / mL.

[0361] As can be seen from Table 1, 1-amide and 1-hydrazide substituted β-carboline derivatives have good inhibitory effects on the six plant pathogenic fungi tested, and show particularly excellent inhibitory activity against the wheat take-all pathogen Gaeumannomyces graminisis. 50 From the data, it is not difficult to find that: the inhibitory activity of 1-hydrazide β-carboline derivatives (3da-4fj) against gramineous cysts is better than that of 1-amide β-carboline derivatives (3aa-4ef); when the 3-position on the pyridine ring is carbamoyl (4aa-4ef, 4da-4fj), the compounds show higher activity than carboxymethyl (A7-3cg, C7-3dp); there are 18 ECs of 1-hydrazide-3-carbamoyl β-carboline derivatives with inhibitory activity against gramineous cysts pathogens. 50 Below 1 μg / mL, compound 4dq (EC 50 =0.11 μg / mL) and 4fh (EC 50 =0.09 μg / mL) had a significantly stronger inhibitory activity against the pathogenic fungus graminearum than the positive control boscalid (EC 50 >50μg / mL and the effective drug for controlling wheat take-all, silthiopyrad (EC 50 =2.39 μg / mL). In addition, compound 4db (EC 50 =0.54 μg / mL), 4de(EC 50 =0.21 μg / mL), 4dv(EC50 =0.25 μg / mL) and 4dw (EC 50 =0.56μg / mL) had strong inhibitory activity against wheat fusarium, and they also had good inhibitory activity against other tested plant pathogenic fungi, showing good broad-spectrum antifungal activity.

[0362] Example 100: Determination of the Antibacterial Activity of 1-Substituted β-Carboline Derivatives

[0363] Test strains were selected for activation on LB plates, including Pseudomonas syringae pv. glycinea, Xanthomonas oryzae oryzae pv. oryzae, Xanthomonas oryzae oryzae pv. oryzicola, and the Gram-positive bacterium Clavibacter michiganense subsp. sepedonicum. Sterilized circular filter paper was first soaked in a solution of 1×10 4 To a solution of the test compound at a concentration of 1 μg / mL, add 5 mL of bacterial solution to 100 mL of culture medium, mix thoroughly, and pour onto a plate. A filter paper strip containing the drug was then placed on the plate and incubated at 28°C. For compounds that observed inhibition zones, we further determined their minimum inhibitory concentration (MIC) against plant pathogens using the MTT assay (Table 4), using streptomycin sulfate as a positive control.

[0364] Table 3 MIC values ​​of the inhibitory activity of the compounds against four plant pathogenic bacteria

[0365]

[0366]

[0367] As shown in the MIC values ​​in Table 3, some 1-amide and 1-hydrazide-substituted β-carboline derivatives exhibited inhibitory activity against the four plant pathogens tested, with particularly strong inhibitory activity against Pseudomonas syringae pv. glycinea and the Gram-positive bacterium Clavibacter michiganense subsp. sepedonicum. 1-Amide-3-carbamoyl β-carboline derivatives (4aa, 4ac, 4ad, and 4cj) exhibited superior inhibitory activity against Pseudomonas syringae pv. glycinea. 1-Hydrazide-3-carbamoyl β-carboline derivatives exhibited particularly potent inhibitory activity against Clavibacter michiganense subsp. sepedonicum, with compounds 4dc and 4dd exhibiting significantly stronger inhibitory activity than the positive control. Compounds 4ad, 4df, and 4dn showed inhibitory activity against Xanthomonas oryzae pv. oryzicola and their MIC values ​​were lower than that of streptomycin sulfate.

[0368] The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention and are protected by the appended claims.

Claims

1. The following compound or a pharmaceutically acceptable salt thereof:

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 2 in the preparation of a preparation for inhibiting plant pathogenic fungi.

4. The use according to claim 3, characterized in that The plant pathogenic fungi are selected from any one or more of the following: Botrytis cinerea, Gaeumannomyces graminisis, Sclerotinia sclerotiorum, Fusarium graminearum, Phytophthora capsici, and Fusarium moniliforme.

5. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 2 in the preparation of a preparation for inhibiting plant pathogenic bacteria.

6. The use according to claim 5, characterized in that The plant pathogenic bacteria are preferably selected from any one or more of the following: Pseudomonas syringae pv. glycinea, Xanthomonas oryzae oryzae pv. oryzae, Xanthomonas oryzae oryzae pv. oryzicola, and the Gram-positive bacterium Clavibacter michiganense subsp. sepedonicum.

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