Isoquinoline compound, preparation method and application thereof

Abstract

This invention provides an isoquinoline compound, its preparation method, and its applications, belonging to the fields of organic synthesis and medicinal chemistry. Specifically, this invention provides a method for preparing an isoquinoline compound of general formula (I), or its stereoisomers, optically pure isomers, hydrates, solvates, crystals, or pharmaceutically acceptable salts and mixtures thereof, and its pharmaceutical uses. The compound shows promise for treating colorectal cancer, ulcerative colitis, and other tumors and digestive system diseases.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and medicinal chemistry, specifically relating to an isoquinoline compound, its preparation method, and its application. Background Technology

[0002] Colorectal cancer is a common malignant tumor of the gastrointestinal tract. Early symptoms are often subtle. As the tumor grows, patients may experience rectal bleeding, diarrhea, alternating diarrhea and constipation, and localized abdominal pain. In later stages, systemic symptoms such as anemia and weight loss may occur. Colorectal cancer patients may also have comorbidities such as ulcerative colitis, colorectal adenoma, and Crohn's disease.

[0003] Currently, the clinical treatment of colorectal cancer combines surgical resection with drug therapy. For early-stage colorectal cancer without distant metastasis, radical surgical resection is the primary treatment. If the tumor invades surrounding tissues and organs, en bloc resection of the intestinal segment is necessary. However, most cancer patients are diagnosed at middle or late stages, and surgery is often not an option, making chemotherapy an essential treatment option. Given the limitations of current treatment methods, finding new and effective drugs for colorectal cancer has become particularly crucial.

[0004] In recent years, extracting substances with antitumor activity from natural plants has become a new trend. Berberine, also known as berberine hydrochloride, is a quaternary ammonium isoquinoline alkaloid extracted from the rhizomes of plants in the genera *Berberis* and *Coptis*. Berberine hydrochloride was first approved for marketing in China on January 1, 1981, as a drug for intestinal infections, and subsequently approved for indications including diarrhea and infections. In recent years, the bioactivity of berberine hydrochloride in antitumor activity has been continuously verified.

[0005] For example, Chinese patent CN107417695A discloses a berberine derivative, its synthesis method, and its application in the preparation of products for the prevention, relief, and / or treatment of tumors. The solubility of these berberine derivatives in organic solvents is significantly improved compared to the raw material, berberine chloride quaternary ammonium salt compounds. The berberine derivatives exhibit good inhibitory effects on HT29 human colon cancer cells, HCT116 human colon cancer cells, and MDAMB231 human breast cancer cells, with inhibitory strength significantly higher than that of berberine quaternary ammonium salt raw materials, or comparable to or higher than that of positive control drugs, and can be used to prepare products for the prevention, relief, and / or treatment of tumors.

[0006] For example, Chinese patent CN110066275A discloses a berberine derivative NBD-125 and its applications. The berberine derivative NBD-125 can be used in the preparation of antitumor drugs, including those for colon cancer. Through modification of berberine, the obtained berberine derivative NBD-125 exhibits superior performance compared to berberine in terms of RXRα transcriptional activation activity, solubility, and colon cancer cell inhibitory activity.

[0007] In addition, numerous mechanistic studies and clinical trials have demonstrated the effectiveness of berberine hydrochloride in the prevention and treatment of colorectal cancer.

[0008] In summary, berberine hydrochloride not only has anti-colorectal cancer effects, but its therapeutic effect on diarrhea can alleviate the symptoms of colorectal cancer patients. Its regulation of intestinal flora and mucosal barrier function, and its protective effect on the digestive system, can reduce further carcinogenesis in colorectal cancer patients, leading to a better prognosis. Therefore, berberine hydrochloride is an ideal drug for treating colorectal cancer. Using berberine hydrochloride as a lead compound, structural modification to enhance its anti-colorectal cancer efficacy holds promise for developing novel colorectal cancer drugs. Summary of the Invention

[0009] Based on the shortcomings of existing technologies, this invention uses berberine hydrochloride as a lead compound and improves its bioavailability through structural modification, providing the possibility for the development of novel colorectal cancer drugs.

[0010] To achieve the above objectives, the present invention is implemented through the following technical solution:

[0011] One object of the present invention is to provide an isoquinoline compound of formula (I), or a stereoisomer, optically pure isomer, hydrate, solvate, crystal or pharmaceutically acceptable salt thereof, or mixture thereof.

[0012]

[0013] in,

[0014] R1 and R2 are connected to form a substituted 3-10 membered heterocyclic alkyl ring; wherein the substituent is selected from at least one hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C8 heterocyclic alkyl, C3-C8 cycloalkyl, methoxycarbonyl, and the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, and S;

[0015] R3 is selected from -CH3 or -(CH2). m -, m represents 1-7;

[0016] R4 and R5 are each independently hydrogen, or connected to form a substituted 3-6 membered heterocyclic alkyl ring; wherein the substituent is selected from at least one hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C8 heterocyclic alkyl, hydroxyl, amino, carboxyl, methoxycarbonyl, and the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, and S;

[0017] R6 is selected from hydrogen, substituted C1-C18 alkyl, substituted C1-C18 haloalkyl, substituted C6-C10 aryl, substituted C5-C10 heteroaryl, substituted C3-C8 cycloalkyl, substituted C2-C8 heterocyclic alkyl, substituted C4-C12 spirocyclic or substituted C4-C12 bridged cycloalkyl, wherein the substituent is selected from at least one hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C3 fluoroalkoxy, C2-C8 heterocyclic alkyl, hydroxyl, amino, methylamino, dimethylamino, acetamino, carboxyl, methoxycarbonyl or nitro, and the heteroaryl or heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, S;

[0018] A represents O, N, S, halogen, -OH, -NHCO-, -OCO-, -NHCOCH2-, -NHSO2-, or no atomic substitution;

[0019] n represents 1-7;

[0020] Y represents any acid forming an anion.

[0021] Preferably, when R3 is selected from -CH3; R1 and R2 are connected to form a substituted 5-membered heterocyclic alkyl ring or a 7-membered heterocyclic alkyl ring; wherein the substituent is selected from at least one hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C8 heterocyclic alkyl, C3-C8 cycloalkyl, methoxycarbonyl, and the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, and S;

[0022] R3 is selected from -(CH2). m - At that time, the ring formed by connecting R1 and R2 is selected from R4 and R5 are linked to form an unsubstituted 3-6 membered heterocyclic alkyl ring, wherein the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, and S;

[0023] A is selected from O, N, -OH, -NHCO-, -OCO-, halogens, or no atomic substitution;

[0024] R6 is selected from H, substituted C1-C18 alkyl, substituted C4-C12 bridged cycloalkyl, substituted C3-C8 cycloalkyl or heterocycloalkyl, wherein the cycloalkyl is a ternary, quaternary, pentaneary or hexacyclic cycloalkyl containing 3-8 C atoms, the heterocycloalkyl is a quaternary, pentaneary or hexacyclic heterocycle containing 1-3 O, N or S atoms, and the substituent is H, halogen, unsaturated bond or carbonyl.

[0025] In a preferred embodiment, when R3 is selected from -CH3; the ring formed by the connection of R1 and R2 is selected from any of the following structures:

[0026] In a preferred embodiment, R3 is selected from -(CH2). m - At that time, the ring formed by connecting R1 and R2 is selected from

[0027] The ring formed by connecting R3 and R4 is selected from any of the following structures:

[0028] In another preferred embodiment, R3 is selected from -(CH2). m - At that time, the ring formed by connecting R1 and R2 is selected from The R5 is selected from any of the following structures: H,

[0029] -CH(CH3)2、-CH2(CH2) n CH3(n=0-9), -(CH2)4CH(CH3)2, -CH(CH3)(CH2)4CH3.

[0030] Preferably, the isoquinoline compound, or its stereoisomers, optically pure isomers, hydrates, solvates, crystals, or pharmaceutically acceptable salts and mixtures thereof, are selected from any of the following compounds:

[0031]

[0032]

[0033]

[0034] The pharmaceutically acceptable salt is a salt formed by an isoquinoline compound of formula (I) and any of the following acids:

[0035] The acid is selected from any one of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, citric acid, and ferulic acid.

[0036] Another object of the present invention is to provide a method for preparing the compound shown in formula (I), as follows:

[0037] 1. The synthetic routes for compounds I-1 to I-8 are as follows:

[0038]

[0039] The steps are as follows:

[0040] Using berberine hydrochloride as a raw material, a ring-opening reaction was carried out in the presence of an initiator to obtain intermediate 1; intermediate 1 and a halogenated compound were subjected to a substitution reaction to obtain isoquinoline compounds I-1 to I-9.

[0041] The initiator is trifluoromethanesulfonic acid.

[0042] In the substitution reaction described above, acetonitrile is used as the solvent and anhydrous potassium carbonate is used as the base.

[0043] 2. The synthetic route for compound I-9 is as follows:

[0044]

[0045] The specific steps are as follows:

[0046] Berberine hydrochloride was used as a raw material, and berberine was obtained by high-temperature pyrolysis reaction, followed by substitution reaction to prepare compound I-9.

[0047] The high-temperature pyrolysis temperature is 180-190℃, and the vacuum degree is 20-30 mmHg;

[0048] The substitution reaction is carried out using acetonitrile as a solvent at a temperature of 70-80℃.

[0049] 3. The synthetic routes for compounds I-10 to I-38 are as follows:

[0050]

[0051] The specific steps are as follows:

[0052] Berberine hydrochloride was used as a raw material, and berberine was obtained by high-temperature pyrolysis reaction. Then, compounds I-10 to I-38 were prepared by multi-step substitution reaction.

[0053] The high-temperature pyrolysis temperature is 180-190℃, and the vacuum degree is 20-30 mmHg;

[0054] The substitution reaction is carried out using DMF as solvent and anhydrous potassium carbonate as base at a temperature of 70-80℃.

[0055] 4. The synthetic routes for compounds I-39 to I-44 are as follows:

[0056]

[0057] The specific steps are as follows:

[0058] Compounds I-39 to I-44 were prepared from berberine hydrochloride as raw material through high-temperature pyrolysis, substitution, amination and condensation reactions.

[0059] The high-temperature pyrolysis temperature is 180-190℃, and the vacuum degree is 20-30 mmHg;

[0060] The substitution reaction is carried out using acetonitrile or DMF as solvent and anhydrous potassium carbonate or sodium hydride as base.

[0061] The condensation reaction uses N,N'-dicyclohexylcarbodiimide (DCC) as the condensing agent.

[0062] The substituents in the compounds prepared in the above methods are:

[0063] R1 and R2 are connected to form a substituted 3-10 membered heterocyclic alkyl ring; wherein the substituent is selected from at least one hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C8 heterocyclic alkyl, C3-C8 cycloalkyl, methoxycarbonyl, and the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, and S;

[0064] R3 is selected from -CH3 or -(CH2). m -, m represents 1-7;

[0065] R4 and R5 are each independently hydrogen, or connected to form a substituted 3-6 membered heterocyclic alkyl ring; wherein the substituent is selected from at least one hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C8 heterocyclic alkyl, hydroxyl, amino, carboxyl, methoxycarbonyl, and the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, and S;

[0066] R6 is selected from hydrogen, substituted C1-C18 alkyl, substituted C1-C18 haloalkyl, substituted C6-C10 aryl, substituted C5-C10 heteroaryl, substituted C3-C8 cycloalkyl, substituted C2-C8 heterocyclic alkyl, substituted C4-C12 spirocyclic or substituted C4-C12 bridged cycloalkyl, wherein the substituent is selected from at least one hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C3 fluoroalkoxy, C2-C8 heterocyclic alkyl, hydroxyl, amino, methylamino, dimethylamino, acetamino, carboxyl, methoxycarbonyl or nitro, and the heteroaryl or heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, S;

[0067] A represents O, N, S, halogen, -OH, -NHCO-, -OCO-, -NHCOCH2- or -NHSO2- or no atomic substitution;

[0068] m represents 1-7, n represents 1-7;

[0069] Y represents any acid forming an anion.

[0070] In a preferred embodiment, when R3 is selected from -CH3, the ring formed by the connection of R1 and R2 is selected from any of the following structures:

[0071] In a preferred embodiment, R3 is selected from -(CH2). m - At that time, the ring formed by connecting R1 and R2 is selected from The ring formed by connecting R3 and R4 is selected from any of the following structures:

[0072] In another preferred embodiment, R3 is selected from -(CH2). m - At that time, the ring formed by connecting R1 and R2 is selected from The R5 is selected from any of the following structures: H,

[0073] -CH(CH3)2、-CH2(CH2) n CH3(n=0-9), -(CH2)4CH(CH3)2, -CH(CH3)(CH2)4CH3.

[0074] A third object of the present invention is to provide the use of the isoquinoline compounds represented by formula (I) in the preparation of medicaments for treating tumors and gastrointestinal diseases. The tumors are selected from colorectal cancer, and the gastrointestinal diseases are selected from ulcerative colitis or other gastrointestinal-related diseases.

[0075] A fourth object of the present invention is to provide a pharmaceutical composition comprising an isoquinoline compound or a stereoisomer, an optically pure isomer, a hydrate, a solvate, a crystal or a pharmaceutically acceptable salt thereof, and a mixture thereof, as shown in formula (I) above, and a pharmaceutically acceptable carrier.

[0076] A fourth object of the present invention is to provide the use of the above-described pharmaceutical composition in the preparation of medicaments for treating tumors and gastrointestinal diseases. The tumors are selected from colorectal cancer, and the gastrointestinal diseases are selected from ulcerative colitis or other gastrointestinal-related diseases.

[0077] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0078] (1) The compound described in this invention has an inhibitory effect on the growth of HCT116 human colorectal cancer cells and LoVo human colorectal cancer cells, and a repair effect on the DSS-induced Caco-2 cell damage model.

[0079] (2) The compounds described in this invention have promising applications in the treatment of tumors and digestive system diseases such as colorectal cancer and ulcerative colitis. Attached Figure Description

[0080] Figure 1 The 1H NMR spectrum of compound I-1;

[0081] Figure 2 The carbon NMR spectrum of compound I-1;

[0082] Figure 3 The 1H NMR spectrum of compound I-4;

[0083] Figure 4 The 1H NMR spectrum of compound I-5;

[0084] Figure 5 The 1H NMR spectrum of compound I-6;

[0085] Figure 6 The 1H NMR spectrum of compound I-7;

[0086] Figure 7 The 1H NMR spectrum of compound I-8;

[0087] Figure 8 The 1H NMR spectrum of compound I-9;

[0088] Figure 9 The carbon NMR spectrum of compound I-9;

[0089] Figure 10 The 1H NMR spectrum of compound I-10;

[0090] Figure 11 The 1H NMR spectrum of compound I-11;

[0091] Figure 12 The 1H NMR spectrum of compound I-12;

[0092] Figure 13 The 1H NMR spectrum of compound I-14;

[0093] Figure 14 The carbon NMR spectrum of compound I-14;

[0094] Figure 15 The 1H NMR spectrum of compound I-15;

[0095] Figure 16 The 1H NMR spectrum of compound I-16;

[0096] Figure 17 The 1H NMR spectrum of compound I-17;

[0097] Figure 18 The 1H NMR spectrum of compound I-18;

[0098] Figure 19 The carbon NMR spectrum of compound I-18;

[0099] Figure 20 The 1H NMR spectrum of compound I-19;

[0100] Figure 21 The 1H NMR spectrum of compound I-20;

[0101] Figure 22 The 1H NMR spectrum of compound I-21;

[0102] Figure 23 The 1H NMR spectrum of compound I-22;

[0103] Figure 24 The 1H NMR spectrum of compound I-23;

[0104] Figure 25 The 1H NMR spectrum of compound I-24;

[0105] Figure 26 The 1H NMR spectrum of compound I-25;

[0106] Figure 27 The 1H NMR spectrum of compound I-26;

[0107] Figure 28 The 1H NMR spectrum of compound I-27;

[0108] Figure 29The 1H NMR spectrum of compound I-28;

[0109] Figure 30 The 1H NMR spectrum of compound I-29;

[0110] Figure 31 The 1H NMR spectrum of compound I-30;

[0111] Figure 32 The 1H NMR spectrum of compound I-31;

[0112] Figure 33 The 1H NMR spectrum of compound I-32;

[0113] Figure 34 The 1H NMR spectrum of compound I-33;

[0114] Figure 35 The 1H NMR spectrum of compound I-34;

[0115] Figure 36 The 1H NMR spectrum of compound I-35;

[0116] Figure 37 The 1H NMR spectrum of compound I-36;

[0117] Figure 38 The carbon NMR spectrum of compound I-36;

[0118] Figure 39 The 1H NMR spectrum of compound I-37;

[0119] Figure 40 Carbon NMR spectrum of compound I-37

[0120] Figure 41 The 1H NMR spectrum of compound I-38;

[0121] Figure 42 The 1H NMR spectrum of compound I-40;

[0122] Figure 43 The carbon NMR spectrum of compound I-40;

[0123] Figure 44 The 1H NMR spectrum of compound I-41;

[0124] Figure 45 The 1H NMR spectrum of compound I-42;

[0125] Figure 46 The 1H NMR spectrum of compound I-43;

[0126] Figure 47The carbon NMR spectrum of compound I-43;

[0127] Figure 48 The 1H NMR spectrum of compound I-44;

[0128] Figure 49 The carbon NMR spectrum of compound I-44;

[0129] Figure 50 The compound's repair effect on DSS-induced Caco-2 cell damage (* indicates a significant difference compared to the Control group, P < 0.05; # indicates a significant difference compared to the M group, P < 0.05). Detailed Implementation

[0130] The present application will now be described in detail with reference to specific embodiments.

[0131] Terminology Explanation:

[0132] In this document, unless otherwise specified, the term "substitution" refers to the substitution of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: C1-C18 alkyl, C3-C10 cycloalkyl, C1-C10 alkoxy, halogen, hydroxyl, carboxyl (-COOH), C2-C10 ester, amino, and phenyl; wherein the phenyl includes unsubstituted phenyl or substituted phenyl having 1 to 3 substituents selected from: halogen, C1-C18 alkyl, cyano, hydroxyl, nitro, C3-C10 cycloalkyl, C1-C10 alkoxy, and amino.

[0133] The term “C1-C6 alkyl” refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.

[0134] The term "C2-C8 heterocyclic alkyl" refers to a group formed by losing a hydrogen atom from a 3-8 membered saturated ring having 1-3 heteroatoms selected from the group consisting of N, S, and O; for example, pyrrolidinyl, piperidinyl, piperazineyl, morpholinyl, or similar groups.

[0135] The term "C5-C10 heteroaryl" refers to a group formed by losing a hydrogen atom from a 5-8 aryl group having 1-3 heteroatoms selected from the group consisting of N, S, and O, wherein the cyclic system of each heteroaryl group can be monocyclic or polycyclic; for example, pyrrole, pyridinyl, thiophene, furanyl, imidazolyl, pyrimidinyl, benzothiophene, indolyl, imidazopyridinyl, quinolinyl, or similar groups.

[0136] The term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or similar groups.

[0137] The term "halogen" refers to F, Cl, Br, and I.

[0138] Unless otherwise specified, the structural formulas described in this invention are intended to include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers), is within the scope of this invention.

[0139] In this article, the form “C1-C6” indicates that the group can have 1 to 6 carbon atoms, such as 1, 2, 3, 4 or 5.

[0140] Example 1: Synthesis of Compound I-1

[0141] Step 1):

[0142]

[0143] Berberine hydrochloride (10.02 g, 26.95 mmol) was added to a 500 mL three-necked flask and dissolved in xylene (100 mL). Trifluoromethanesulfonic acid (24.26 g, 161.68 mmol) was slowly added dropwise with stirring at room temperature over 15 min. After stirring at room temperature for 2 h, 1 mol / L HCl was slowly added dropwise under ice bath conditions, gradually precipitating a yellowish-brown solid. The precipitate was filtered, and the filter cake was washed three times with water (70 mL) and twice with petroleum ether (70 mL), then dried under vacuum. The filter cake was slurried with ethyl acetate:methanol = 8:1 (1 g / 6 mL), and filtered to obtain 8.28 g of a yellow solid (intermediate 1), with a yield of 85.6%. This solid was directly added to the next step without further purification.

[0144] HRMS(ESI):m / z[M-Cl]+.Calcd for 324.1231; Found:324.1233.

[0145] Step 2):

[0146]

[0147] Intermediate 1 (2.12 g, 5.89 mmol) was added to a 250 mL three-necked flask, followed by acetonitrile (50 mL), 1,3-dibromo-2-methylpropane (7.62 g, 35.35 mmol), and ground anhydrous potassium carbonate (2.44 g, 17.67 mmol). The mixture was heated at 75 °C for 7 h, and the reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and dichloromethane (50 mL) was added. The mixture was then washed with water (40 mL × 3) and saturated sodium chloride aqueous solution (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Column chromatography (eluent: dichloromethane: methanol = 150:1-70:1) yielded 603 mg of a yellow solid (compound I-1), with a yield of 22.3% and a purity of 98.19%.

[0148] HRMS(ESI):m / z[M-Br]+.Calcd for 378.1700; Found:378.1693.

[0149] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.89 (s, 1H), 8.99 (s, 1H), 8.21 (d, J = 9.2Hz, 1H), 8.01 (d, J = 9.1Hz, 1H), 7.84 (s, 1H), 7. 07(s,1H),4.93(d,J=6.4Hz,2H),4.35-4.31(m,2H),4.10(s,3H),4.07(s,3H),3.82(s,2H),3.19(d,J=6.4Hz,2H),2.44 -2.39(m,1H),0.99(d,J=6.8Hz,3H).

[0150] 13 C NMR(151MHz,DMSO-d6)δ(ppm):153.14,150.44,145.47,143.57,136.85,132.79,130.36,126.64,123.54, 121.68,121.46,120.76,120.43,118.58,75.65,75.48,61.81,56.96,55.23,39.96,34.78,25.51,13.22.

[0151] Example 2: Synthesis of Compound I-2

[0152]

[0153] Intermediate 1 (500 mg, 1.39 mmol) was added to a 100 mL three-necked flask, followed by acetonitrile (20 mL), 1,3-dibromoacetone (1.80 g, 8.34 mmol), and ground anhydrous potassium carbonate (576 mg, 4.17 mmol). The mixture was heated at 70 °C for 5 h, and the reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and dichloromethane (20 mL) was added. The mixture was then washed with water (20 mL × 3) and saturated sodium chloride aqueous solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Column chromatography (eluent: dichloromethane: methanol = 150:1-70:1) yielded 113 mg of a yellow solid (compound I-2), with a yield of 17.7% and a purity of 94.82%.

[0154] HRMS(ESI):m / z[M-Br]+.Calcd for 378.1336; Found:378.1329.

[0155] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.89 (s, 1H), 8.97 (s, 1H), 8.21 (d, J = 9.2Hz, 1H), 8.01 (d, J = 9.1Hz, 1H), 7.8 2(s,1H),7.06(s,1H),4.96-4.88(m,4H),4.27-4.21(m,2H),4.10(s,3H),4.07(s,3H),3.20-3.18(m,2H).

[0156] Example 3: Synthesis of Compound I-3

[0157]

[0158] Intermediate 1 (300 mg, 0.83 mmol) was added to a 100 mL three-necked flask, followed by acetonitrile (15 mL), methyl 3-bromo-2-(bromomethyl)propionate (650 mg, 2.50 mmol), and ground anhydrous potassium carbonate (345 mg, 2.50 mmol). The mixture was heated at 70 °C for 5 h, and the reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and dichloromethane (15 mL) was added. The mixture was then washed with water (20 mL × 3) and saturated sodium chloride aqueous solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Column chromatography (eluent: dichloromethane: methanol = 150:1-75:1) yielded 61 mg of a yellow solid (compound I-3), with a yield of 14.6% and a purity of 93.61%.

[0159] HRMS(ESI):m / z[M-Br]+.Calcd for 422.1599; Found:422.1591.

[0160] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.90 (s, 1H), 8.99 (s, 1H), 8.20 (d, J = 9.2Hz, 1H), 8.00 (d, J = 9.1Hz, 1H), 7.81 (s, 1H), 7.06 ( s,1H),4.90-4.73(m,2H),4.27-4.20(m,4H),3,92(s,3H),3.90(s,3H),3.72(s,3H),3.28-3.23(m,1H),3.13-3.10(m,2H).

[0161] Example 4: Synthesis of Compound I-4

[0162]

[0163] Intermediate 1 (2.08 g, 5.78 mmol) was added to a 250 mL three-necked flask, followed by acetonitrile (60 mL), 1,1-bis-bromomethylcyclopropane (7.90 g, 34.68 mmol), and ground anhydrous potassium carbonate (2.40 g, 17.34 mmol). The mixture was heated at 75 °C for 7 h, and the reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and dichloromethane (50 mL) was added. The mixture was then washed with water (40 mL × 3) and saturated sodium chloride aqueous solution (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Column chromatography (eluent: dichloromethane: methanol = 150:1-60:1) yielded 990 mg of a yellow solid (compound I-4), with a yield of 36.4% and a purity of 97.4%.

[0164] HRMS(ESI):m / z[M-Br]+.Calcd for 390.1700; Found:390.6993.

[0165] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.90 (s, 1H), 9.02 (s, 1H), 8.21 (d, J = 9.2Hz, 1H), 8.02 (d, J = 9.0Hz, 1H), 7.89 (s, 1H), 7.1 1(s,1H),4.97-4.94(m,2H),4.10(s,3H),4.07(s,3H),4.02(s,2H),3.98(s,2H),3.23-3.20(m,2H),0.72-0.67(m,4H).

[0166] Example 5: Synthesis of Compound I-5

[0167]

[0168] Intermediate 1 (2.05 g, 5.69 mmol) was added to a 250 mL three-necked flask, followed by acetonitrile (50 mL), 3,3-bis(bromomethyl)oxetane (8.31 g, 34.08 mmol), and ground anhydrous potassium carbonate (2.36 g, 17.07 mmol). The mixture was heated at 75 °C for 7 h, and the reaction was monitored by TLC until complete. The reaction solution was cooled to room temperature, and dichloromethane (50 mL) was added. The mixture was then washed with water (40 mL × 3) and saturated sodium chloride aqueous solution (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. Column chromatography (eluent: dichloromethane: methanol = 150:1-60:1) yielded 1.33 g of a yellow solid (compound I-5), with a yield of 36.4% and a purity of 97.4%.

[0169] HRMS(ESI):m / z[M-Br]+.Calcd for 406.1649; Found:406.1642.

[0170] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.90 (s, 1H), 9.00 (s, 1H), 8.21 (d, J = 9.2Hz, 1H), 8.02 (d, J = 9.1Hz, 1H), 7.88 (s, 1H), 7.1 1(s,1H),4.94(t,J=6.3Hz,2H),4.49(s,4H),4.48(s,2H),4.47(s,2H),4.10(s,3H),4.07(s,3H),3.20(t,J=6.4Hz,2H).

[0171] Example 6: Synthesis of Compound I-6

[0172]

[0173] Intermediate 1 (300 mg, 0.83 mmol) was added to a 50 mL three-necked flask, along with DMF (10 mL), 1,1-dichlorodimethyl ether (287 mg, 2.50 mmol), and ground anhydrous potassium carbonate (345 mg, 2.50 mmol). The mixture was heated at 56 °C for 3.5 h. After cooling the reaction solution to room temperature, water (25 mL) was added, resulting in the precipitation of a yellow solid, which was then filtered. The filter cake was washed three times with petroleum ether (20 mL) and dried to obtain a yellow solid. Column chromatography (eluent: dichloromethane: methanol = 150:1-80:1) yielded 52 mg of the yellow solid (compound I-6), with a yield of 15.6% and a purity of 97.75%.

[0174] HRMS(ESI):m / z[M-Br]+.Calcd for 366.1341; Found:366.1336.

[0175] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.90 (s, 1H), 8.96 (s, 1H), 8.21 (d, J = 9.1Hz, 1H), 8.00 (d, J = 9.1Hz, 1H), 7.90 (s, 1H) ),7.27(s,1H),7.19(s,1H),4.94(t,J=6.4Hz,2H),4.10(s,3H),4.07(s,3H),3.41(s,3H),3.23(t,J=6.2Hz,2H).

[0176] Example 7: Synthesis of Compound I-7

[0177]

[0178] Intermediate 1 (300 mg, 0.83 mmol) was added to a 50 mL three-necked flask, followed by acetonitrile (15 mL), ethyl dibromoacetate (615 mg, 2.50 mmol), and ground anhydrous potassium carbonate (345 mg, 2.50 mmol). The mixture was heated at 70 °C for 5 h. The reaction solution was cooled to room temperature, and dichloromethane (20 mL) was added. The mixture was then washed with water (20 mL × 3) and saturated sodium chloride aqueous solution (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure. Column chromatography (eluent: dichloromethane: methanol = 150:1-70:1) yielded 54 mg of a yellow solid (compound I-7), with a yield of 13.3% and a purity of 99.26%.

[0179] HRMS(ESI):m / z[M-Br]+.Calcd for 408.1442; Found:408.1439.

[0180] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.90 (s, 1H), 8.94 (s, 1H), 8.21 (d, J = 9.2Hz, 1H), 7.99 (d, J = 9.1Hz, 1H), 7.89 (s, 1H), 7.20 (s, 1H), 6.8 5(s,1H),4.94(dt,J=10.6,6.5Hz,2H),4.27(q,J=7.1Hz,2H),4.10(s,3H),4.08(s,3H),3.23(t,J=6.4Hz,2H),1.26(t,J=7.1Hz,3H).

[0181] Example 8: Synthesis of Compound I-8

[0182]

[0183] Intermediate 1 (500 mg, 1.39 mmol) was added to a 50 mL three-necked flask, followed by acetonitrile (25 mL), 1,1-dibromopinazone (2.15 g, 8.34 mmol), and ground anhydrous potassium carbonate (576 mg, 4.17 mmol). The mixture was heated at 70 °C for 4 h. The reaction solution was cooled to room temperature, and dichloromethane (25 mL) was added. The mixture was then washed with water (30 mL × 3) and saturated sodium chloride aqueous solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation of the filtrate. Column chromatography (eluent: dichloromethane: methanol = 150:1–60:1) yielded a yellow solid (compound I-8).

[0184] 150mg, yield 21.6%, purity: 99.62%.

[0185] HRMS(ESI):m / z[M-Br]+.Calcd for 420.1706; Found:420.1696.

[0186] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.88 (s, 1H), 8.92 (s, 1H), 8.20 (d, J = 9.1Hz, 1H), 7.98 (d, J = 9.1Hz, 1H), 7.84 (s, 1H) ),7.22(s,1H),7.14(s,1H),4.94(d,J=6.2Hz,2H),4.10(s,3H),4.07(s,3H),3.21(t,J=6.3Hz,2H),1.25(s,9H).

[0187] Example 9: Synthesis of Compound I-9

[0188] Step 1):

[0189]

[0190] Berberine hydrochloride (30.02 g, 83.90 mmol) was added to a 1000 mL round-bottom flask. The mixture was subjected to a vacuum of 20-30 mmHg and pyrolyzed at 190 °C for 6 h. The yellow solid gradually turned dark red, and TLC monitoring confirmed the reaction was complete. After cooling the flask to room temperature, 22.63 g of dark red powder (berberine hydrochloride) was collected, yielding a yield of 75.4%.

[0191] HRMS(ESI):m / z[M-Br]+.Calcd for 357.0768; Found:357.0761.

[0192] Step 2):

[0193]

[0194] Berberine hydrochloride (3.02 g, 8.44 mmol) was added to a 250 mL three-necked flask, followed by acetonitrile (50 mL) and 3-bromomethyl-3-methyl-1-oxetane (8.30 g, 50.64 mmol). The mixture was heated at 75 °C for 22 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from red turbidity to dark brown turbidity, and finally to bluish-brown turbidity. Some acetonitrile was removed by vacuum distillation, and the mixture was filtered. The filter cake was washed twice with ethyl acetate (20 mL) to obtain a brown solid. Column chromatography (eluent: dichloromethane: methanol = 100:1-40:1) was used to separate the solid into a dark yellow solid. The crude product was slurried with ethyl acetate: methanol = 10:1 (1 g / 10 mL), filtered, and the filter cake was washed three times with n-hexane (15 mL × 3) to obtain a bright yellow solid (compound I-9) of 2.19 g, yield 53.4%, purity: 98.46%.

[0195] HRMS(ESI):m / z[M-Br]+.Calcd for 406.1649; Found:406.1638.

[0196] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.68 (s, 1H), 8.97 (s, 1H), 8.22 (d, J = 9.1Hz, 1H), 8.03 (d, J = 9.1Hz, 1H), 7.80 (s, 1H), 7.09 (s, 1H), 6.17 (s,2H),4.95(t,J=6.3Hz,2H),4.73(d,J=5.9Hz,2H),4.41(d,J=5.9Hz,2H),4.35(s,2H),4.06(s,3H),3.23-3.19(m,2H),1.49(s,3H).

[0197] 13 C NMR(151MHz,DMSO-d6)δ(ppm):150.26,149.74,147.58,144.96,142.45,137.35,132.91,130.59,126.49,123 .61,121.27,120.31,120.19,108.32,105.34,102.00,78.43(2C),78.39,56.97,55.45,39.00,26.22,20.87.

[0198] Example 10: Synthesis of Compound I-10

[0199] Step 1):

[0200]

[0201] Berberine hydrochloride (5.06 g, 14.14 mmol) was added to a 250 mL three-necked flask, followed by acetonitrile (50 mL) and 3,3-bis(bromomethyl)oxetane (2.07 g, 84.84 mmol). The mixture was heated at 75 °C for 20 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from red turbidity to yellowish-brown turbidity. The reaction solution was cooled to room temperature and filtered. The filter cake was washed twice with ethyl acetate (30 mL) to obtain a yellowish-brown solid. Column chromatography (eluent: dichloromethane: methanol = 100:1-40:1) was used to separate the solid into a yellow solid. The crude product was slurried with ethyl acetate: methanol = 8:1 (1 g / 10 mL), and filtered to obtain 3.79 g of a bright yellow solid, yield 47.1%, purity: 95.86%.

[0202] HRMS(ESI):m / z[M-Br]+.Calcd for 484.0755; Found:484.0746.

[0203] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.71 (s, 1H), 8.98 (s, 1H), 8.23 ​​(d, J = 9.2Hz, 1H), 8.04 (d, J = 9.1Hz, 1H), 7.81 (s, 1H), 7.10 (s, 1H), 6.18 (s ,2H),4.95(t,J=6.4Hz,2H),4.67(d,J=6.4Hz,2H),4.59(s,2H),4.53(d,J=6.4Hz,2H),4.17(s,2H),4.08(s,3H),3.22(t,J=6.3Hz,2H).

[0204] Step 2):

[0205]

[0206] Intermediate 2 (200 mg, 0.35 mmol) was added to a 25 mL three-necked flask, followed by DMF (8 mL), cyclopropionic acid (90 mg, 1.05 mmol), sodium iodide (52 mg, 0.35 mmol), and triethylamine (106 mg, 1.05 mmol). The mixture was heated at 90 °C for 2 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a reddish-brown clarity. The reaction solution was cooled to room temperature, and ethyl acetate (10 mL) and petroleum ether (10 mL) were added. A yellow solid precipitated and was filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) to obtain the yellow solid. The crude product was slurried with ethyl acetate: methanol = 6:1 (1 g / 10 mL), filtered, and the filter cake was washed three times with n-hexane (6 mL × 3) to obtain 51 mg of a bright yellow solid (compound I-10), with a yield of 25.5% and a purity of 97.5%.

[0207] HRMS(ESI):m / z[M-Br]+.Calcd for 490.1861; Found:490.1861.

[0208] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.70 (s, 1H), 8.98 (s, 1H), 8.22 (d, J = 9.2Hz, 1H), 8.04(d,J=9.1Hz,1H),7.81(s,1H),7.10(s,1H),6.18(s,2H),4.94(t,J=6.3Hz, 2H),4.69(d,J=6.4Hz,2H),4.56(d,J=6.4Hz,2H),4.53(s,2H),4.52(s,2H),4.0 6(s,3H),3.24-3.21(m,2H),1.73(s,1H),0.95-0.91(m,2H),0.89-0.88(m,2H).

[0209] Example 11: Synthesis of Compound I-11

[0210]

[0211] Intermediate 2 (200 mg, 0.35 mmol) was added to a 25 mL three-necked flask, followed by DMF (8 mL), cyclopropionic acid (78 mg, 1.05 mmol), sodium iodide (52 mg, 0.35 mmol), and triethylamine (106 mg, 1.05 mmol). The mixture was heated at 75 °C for 3 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear brown color. After cooling to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) to obtain the yellow solid. The crude product was slurried with ethyl acetate: methanol = 6:1 (1 g / 10 mL), filtered, and the filter cake was washed three times with n-hexane (6 mL × 3) to obtain 53 mg of a bright yellow solid (compound I-11), with a yield of 27.1% and a purity of 92.37%.

[0212] HRMS(ESI):m / z[M-Br]+.Calcd for 478.1861; Found:478.1866.

[0213] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.69 (s, 1H), 8.96 (s, 1H), 8.23 ​​(d, J = 9.1Hz, 1H ),8.04(d,J=9.1Hz,1H),7.80(s,1H),7.10(s,1H),6.18(s,2H),4.94(t,J=6.3 Hz,2H),4.69(d,J=6.4Hz,2H),4.57(d,J=6.4Hz,2H),4.54(s,2H),4.51(s,2H) ,4.06(s,3H),3.24-3.21(m,2H),2.41(q,J=7.5Hz,2H),1.06(t,J=7.5Hz,3H).

[0214] Example 12: Synthesis of Compound I-12

[0215]

[0216] Intermediate 2 (200 mg, 0.35 mmol) was added to a 25 mL three-necked flask, followed by DMF (8 mL), 3-furoic acid (118 mg, 1.05 mmol), sodium iodide (52 mg, 0.35 mmol), and triethylamine (106 mg, 1.05 mmol). The mixture was heated at 75 °C for 3 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. Filter cake column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) yielded 146 mg of a yellow solid (compound I-12), with a yield of 69.9% and a purity of 94.68%.

[0217] HRMS(ESI):m / z[M-Br]+.Calcd for 516.1653; Found:516.1653.

[0218] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.71 (s, 1H), 8.97 (s, 1H), 8.47 (s, 1H), 8.20 (d, J = 9.2Hz, 1H), 8.03 (d, J = 9.1Hz, 1H), 7.84 (m, 1H), 7.79 (s, 1H), 7.0 9(s,1H),6.83(s,1H),6.18(s,2H),4.93(t,J=6.3Hz,2H),4.74-4.72(m, 4H), 4.63 (d, J = 6.5Hz, 2H), 4.58 (s, 2H), 4.00 (s, 3H), 3.23-3.20 (m, 2H).

[0219] Example 13: Synthesis of Compound I-13

[0220] Step 1):

[0221]

[0222] Berberine hydrochloride (23.47 g, 65.60 mmol) was added to a 500 mL three-necked flask, along with anhydrous acetonitrile (150 mL) and 1,1-bis-bromomethylcyclopropane (89.71 g, 393.60 mmol). The mixture was heated at 72 °C for 8 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from red turbidity to yellowish-brown turbidity. The reaction solution was cooled to room temperature and filtered to obtain a yellowish-brown filter cake. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-50:1) to give 17.26 g of a bright yellow solid (intermediate 3), with a yield of 47.9%. Purity: 97.24%.

[0223] HRMS(ESI):m / z[M-Br]+.Calcd for 468.0805; Found:468.0810.

[0224] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.70 (s, 1H), 8.97 (s, 1H), 8.20 (d, J = 9.2Hz, 1H), 8.02 (d, J = 9.1Hz, 1H), 7.79 (s, 1H), 7.09 (s, 1H), 6 .17(s,2H),4.96(t,J=6.3Hz,2H),4.24(s,2H),4.06(s,3H),3.93(s,2H),3.23-3.20(m,2H),1.02-1.00(m,2H),0.85-0.82(m,2H).

[0225] Step 2):

[0226]

[0227] Intermediate 3 (200 mg, 0.42 mmol) was added to a 38 mL thick-walled pressure-resistant flask, along with ground anhydrous potassium carbonate (174 mg, 1.26 mmol), DMF (6 mL), and tetrahydropyrrole (179 mg, 2.52 mmol). The mixture was heated at 60 °C for 4.5 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling the reaction solution to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. The filter cake was slurried with ethyl acetate:methanol at a ratio of 1:1 (1 g / 8 mL), filtered, and washed three times with n-hexane (5 mL × 3) to obtain 32 mg of a bright yellow solid (compound I-13), with a yield of 14.1% and a purity of 98.36%.

[0228] HRMS(ESI):m / z[M-Br]+.Calcd for 459.2279; Found:459.2285.

[0229] 1H NMR (600MHz, DMSO-d6) δ (ppm): 9.69 (s, 1H), 8.96 (s, 1H), 8.19 (d, J = 9.1Hz, 1H), 8.00 (d, J = 9.1Hz, 1H), 7.81 (s, 1H), 7.10 (s, 1H), 6.18 (s, 2H), 4.91(t,J=6.3Hz,2H),4.17(s,2H),4.04(s,3H),3.23(t,J=6.3Hz,2H) ,2.53(s,2H),1.72-1.67(m,4H),0.69-0.66(m,4H),0.48-0.46(m,4H).

[0230] Example 14: Synthesis of Compound I-14

[0231]

[0232] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by anhydrous tetrahydrofuran (6 mL) and cyclopropane (146 mg, 2.52 mmol). 60% NaH (50 mg, 1.26 mmol) was slowly added dropwise under ice bath conditions. The reaction was allowed to proceed for 24 h at room temperature, and TLC was used to monitor the reaction until complete. The reaction was quenched by adding methanol dropwise under ice bath conditions, and the solution gradually changed from a pale yellow turbidity to a clear orange. Column chromatography (eluent: dichloromethane: methanol = 100:1-40:1) yielded 47 mg of a yellow solid (compound I-14), with a yield of 23.0% and a purity of 99.05%.

[0233] HRMS(ESI):m / z[M-Br]+.Calcd for 406.1649; Found:406.1638.

[0234] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.77 (s, 1H), 8.95 (s, 1H), 8.18 (d, J = 9.1Hz, 1H), 7.99 (d, J = 9.1Hz, 1H), 7.80 (s, 1H), 7.10 (s, 1H), 6.18 (s, 2H), 4.92 (t, J = 6.3Hz, 2H), 4.80 (t, J = 5.5Hz, 1H), 4.21 (s, 2H), 4.04 (s, 3H), 3.59 (d, J = 5.5Hz, 2H), 3.24-3.20 (m, 2H), 0.61-0.55 (m, 4H).

[0235] 13C NMR(151MHz,DMSO-d6)δ(ppm):150.37,149.72,147.59,145.22,142.96,137.30,132.95,130.54,126.64,12 3.16,121.51,120.35,120.15,108.33,105.32,101.99,78.43,64.14,56.94,55.44,26.25,23.08,8.27(2C).

[0236] Example 15: Synthesis of Compound I-15

[0237]

[0238] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), cyclopropionic acid (108 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 90 °C for 3.5 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. Filter cake column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) yielded 72 mg of a yellow solid (compound I-15), with a yield of 30.9% and a purity of 95.57%.

[0239] HRMS(ESI):m / z[M-Br]+.Calcd for 474.1912; Found:474.1912.

[0240] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.70 (s, 1H), 8.97 (s, 1H), 8.20 (d, J = 9.2Hz, 1H) ,8.01(d,J=9.1Hz,1H),7.81(s,1H),7.10(s,1H),6.18(s,2H),4.95(t,J=6.3Hz ,2H),4.25(s,2H),4.16(s,2H),4.04(s,3H),3.24-3.20(m,2H),1.70-1.66(m,1 H),0.91-0.88(m,2H),0.86-0.83(m,2H),0.82-0.79(m,2H),0.73-0.70(m,2H).

[0241] Example 16: Synthesis of Compound I-16

[0242]

[0243] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), cyclopropionic acid (126 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 60 °C for 3.5 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. Filter cake column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) yielded 92 mg of a yellow solid (compound I-16), with a yield of 38.5% and a purity of 95.24%.

[0244] HRMS(ESI):m / z[M-Br]+.Calcd for 488.2068; Found:488.2076.

[0245] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.70 (s, 1H), 8.95 (s, 1H), 8.20 (d, J = 9.1Hz, 1H), 8.00 (d,J=9.1Hz,1H),7.81(s,1H),7.10(s,1H),6.18(s,2H),4.95(t,J=6.3Hz,2H),4.29( s,2H),4.16(s,2H),4.03(s,3H),3.24-3.21(m,2H),2.26(d,J=7.1Hz,2H),0.96-0.9 1(m,1H),0.81-0.77(m,2H),0.74-0.69(m,2H),0.43-0.39(m,2H),0.10-0.07(m,2H).

[0246] Example 17: Synthesis of Compound I-17

[0247]

[0248] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), 2,2-difluorocyclopropanecarboxylic acid (154 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 70 °C for 3 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. Filter cake column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) yielded 104 mg of a yellow solid (compound I-17), with a yield of 41.9% and a purity of 95.24%.

[0249] HRMS(ESI):m / z[M-Br]+.Calcd for 510.1723; Found:510.1731.

[0250] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.68 (s, 1H), 8.95 (s, 1H), 8.20 (d, J = 9.2Hz ,1H),8.01(d,J=9.1Hz,1H),7.81(s,1H),7.10(s,1H),6.18(s,2H),4.94(t ,J=6.3Hz,2H),4.36(s,2H),4.16(s,2H),4.03(s,3H),3.24-3.20(m,2H),2 .90-2.93(m,1H),2.11-2.00(m,2H),0.85-0.81(m,2H),0.77-0.73(m,2H).

[0251] Example 18: Synthesis of Compound I-18

[0252]

[0253] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), cyclobutylcarboxylic acid (126 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 75 °C for 3 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) to obtain a yellow solid. The crude product was slurried with ethyl acetate: methanol = 3:1 (1 g / 8 mL), filtered, and the filter cake was washed three times with n-hexane (6 mL × 3) to obtain 92 mg of a bright yellow solid (compound I-18), with a yield of 38.5% and a purity of 96.69%.

[0254] HRMS(ESI):m / z[M-Br]+.Calcd for 488.2073; Found:488.2074.

[0255] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.69 (s, 1H), 8.96 (s, 1H), 8.20 (d, J = 9.2Hz, 1H), 8.01 (d,J=9.1Hz,1H),7.80(s,1H),7.10(s,1H),6.18(s,2H),5.63(s,2H),4.95(t,J=6.3H z,2H),4.31-4.26(m,2H),4.16(s,2H),4.03(s,3H),3.25-3.21(m,2H),2.61-2.56(m, 1H),2.21-2.11(m,2H),2.02-1.99(m,2H),0.81-0.78(d,J=m,2H),0.73-0.70(m,2H).

[0256] 13 C NMR(151MHz,DMSO-d6)δ(ppm):174.32,149.88,149.25,147.11,144.52,142.00,136.85,132.40,130.06,126.00,122.98,120 .92,119.82,119.67,107.85,104.83,101.52,77.05,66.27,56.41,54.90,36.67,25.73,24.14(2C),20.21,17.24,8.31(2C).

[0257] Example 19: Synthesis of Compound I-19

[0258]

[0259] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), bicyclo[1.1.1]pentane-1-carboxylic acid (141 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 70 °C for 2.5 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling the reaction solution to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. Filter cake column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) yielded 85 mg of a yellow solid (compound I-19), with a yield of 34.9% and a purity of 95.49%.

[0260] HRMS(ESI):m / z[M-Br]+.Calcd for 500.2068; Found:500.2068.

[0261] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.68 (s, 1H), 8.96 (s, 1H), 8.20 (d, J = 9.2Hz, 1H), 8.01 (d, J = 9.1Hz, 1H), 7.81 (s, 1H), 7.10 (s, 1H), 6.18 (s, 2H), 4.94 (d,J=6.4Hz,2H),4.26(s,2H),4.14(s,2H),4.03(s,3H),3.24-3.21(m,2 H),2.42(s,1H),2.00-1.97(m,6H),0.81-0.78(m,2H),0.72-0.69(m,2H).

[0262] Example 20: Synthesis of Compound I-20

[0263]

[0264] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (164 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 70 °C for 3 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling the reaction solution to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. The filter cake was separated by column chromatography (eluent: dichloromethane:methanol = 100:1-60:1) to obtain a yellow solid. The crude product was slurried with ethyl acetate:methanol = 3:1 (1 g / 8 mL), filtered, and the filter cake was washed three times with n-hexane (10 mL × 3) to obtain 166 mg of bright yellow solid (compound I-20), yield: 66.1%, purity: 96.21%.

[0265] HRMS(ESI):m / z[M-Br]+.Calcd for 518.1974; Found:518.1975.

[0266] 1 H NMR(600MHz,DMSO-d6)δ(ppm):9.67(s,1H),8.96(s,1H),8.20(d,J=9.1Hz,1H),8.01(d,J=9.1Hz,1H),7.81(s,1H),7.10(s,1H),6.18(s,2H ),4.94(t,J=6.2Hz,2H),4.32(s,2H),4.14(s,2H),4.02(s,3H),3.25- 3.21(m,2H),2.35-2.32(m,6H),0.82-0.79(m,2H),0.73-0.70(m,2H).

[0267] Example 21: Synthesis of Compound I-21

[0268]

[0269] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), 3-oxocyclobutanecarboxylic acid (144 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 70 °C for 2 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. The reaction solution was cooled to room temperature, and ethyl acetate (10 mL) and petroleum ether (10 mL) were added. A yellow solid precipitated and was filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) to obtain a yellow solid. The crude product was slurried with ethyl acetate: methanol = 3:1 (1 g / 8 mL), filtered, and the filter cake was washed three times with n-hexane (5 mL × 3) to obtain 30 mg of a bright yellow solid (compound I-21), with a yield of 12.3% and a purity of 93.58%.

[0270] HRMS(ESI):m / z[M-Br]+.Calcd for 502.1866; Found:502.1867.

[0271] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.69 (s, 1H), 8.95 (s, 1H), 8.20 (d, J = 9.1Hz ,1H),8.01(d,J=9.1Hz,1H),7.81(s,1H),7.11(s,1H),6.18(s,2H),4.95(t ,J=6.2Hz,2H),4.35(s,2H),4.15(s,2H),4.02(s,3H),3.38-3.36(m,1H),3 .34-3.33(m,2H),3.26-3.21(m,4H),0.82-0.81(m,2H),0.76-0.74(m,2H).

[0272] Example 22: Synthesis of Compound I-22

[0273]

[0274] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), 3,3-difluorocyclobutanecarboxylic acid (171 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 70 °C for 4 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling the reaction solution to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) to obtain a yellow solid. The crude product was slurried with ethyl acetate: methanol = 3:1 (1 g / 10 mL), filtered, and the filter cake was washed three times with n-hexane (8 mL × 3) to obtain 138 mg of bright yellow solid (compound I-22), yield 54.4%, purity: 95.29%.

[0275] HRMS(ESI):m / z[M-Br]+.Calcd for 524.1880; Found:524.1879.

[0276] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.68 (s, 1H), 8.96 (s, 1H), 8.20 (d, J = 9.1Hz, 1H) ,8.01(d,J=9.1Hz,1H),7.80(s,1H),7.11(s,1H),6.18(s,2H),4.95(t,J=6.3Hz ,2H),4.33(s,2H),4.15(s,2H),4.02(s,3H),3.25-3.21(m,2H),3.17-3.11(m,1 H),2.93-2.85(m,2H),2.80-2.71(m,2H),0.80-0.82(m,2H),0.75-0.73(m,2H).

[0277] Example 23: Synthesis of Compound I-23

[0278]

[0279] Intermediate 3 (300 mg, 0.64 mmol) was added to a 25 mL three-necked flask, followed by DMF (8 mL), cyclopentanoic acid (219 mg, 1.92 mmol), sodium iodide (96 mg, 0.64 mmol), and triethylamine (194 mg, 1.92 mmol). The mixture was heated at 75 °C for 2.5 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling to room temperature, ethyl acetate (12 mL) and petroleum ether (12 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) to obtain a yellow solid. The crude product was slurried with ethyl acetate: methanol = 2:1 (1 g / 6 mL), filtered, and the filter cake was washed three times with n-hexane (8 mL × 3) to obtain 146 mg of a bright yellow solid (compound I-23), with a yield of 39.2% and a purity of 95.16%.

[0280] HRMS(ESI):m / z[M-Br]+.Calcd for 502.2230; Found:502.2234.

[0281] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.69 (s, 1H), 8.96 (s, 1H), 8.20 (d, J = 9.2Hz, 1H), 8.0 1(d,J=9.1Hz,1H),7.81(s,1H),7.10(s,1H),6.18(s,2H),4.97-4.93(m,2H),4.27( s,2H),4.15(s,2H),4.03(s,3H),3.25-3.21(m,2H),2.80-2.75(m,1H),1.84-1.78( m,2H),1.69-1.64(m,2H),1.58-1.50(m,4H),0.80-0.78(m,2H),0.72-0.70(m,2H).

[0282] Example 24: Synthesis of Compound I-24

[0283]

[0284] Intermediate 3 (300 mg, 0.64 mmol) was added to a 25 mL three-necked flask, followed by DMF (8 mL), 3-furoic acid (215 mg, 1.92 mmol), sodium iodide (96 mg, 0.64 mmol), and triethylamine (194 mg, 1.92 mmol). The mixture was heated at 75 °C for 3.5 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling the reaction solution to room temperature, ethyl acetate (12 mL) and petroleum ether (12 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. The filter cake was separated by column chromatography (eluent: dichloromethane:methanol = 100:1-60:1) to obtain a yellow solid. The crude product was slurried with dichloromethane:methanol = 6:1 (1 g / 6 mL), filtered, and the filter cake was washed three times with n-hexane (8 mL × 3) to obtain 146 mg of bright yellow solid (compound I-24), yield 39.3%, purity: 95.16%.

[0285] HRMS(ESI):m / z[M-Br]+.Calcd for 500.1709; Found:500.1711.

[0286] 1 H NMR(600MHz,DMSO-d6)δ(ppm):9.70(s,1H),8.94(s,1H),8.42(s,1H),8.18(d, J=9.2Hz,1H),8.00(d,J=9.1Hz,1H),7.82(t,J=1.7Hz,1H),7.80(s,1H),7.10( s,1H),6.81-6.80(m,1H),6.18(s,2H),4.92(t,J=6.3Hz,2H),4.44(s,2H),4.2 2(s,2H),3.97(s,3H),3.24-3.20(m,2H),0.85-0.82(m,2H),0.81-0.78(m,2H).

[0287] Example 25: Synthesis of Compound I-25

[0288]

[0289] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), 3-cyclopentenic acid (141 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 70 °C for 4 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling the reaction solution to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) to obtain a yellow solid. The crude product was slurried with ethyl acetate: methanol: dichloromethane = 2:1:1 (1 g / 8 mL), filtered, and the filter cake was washed three times with n-hexane (6 mL × 3) to obtain 54 mg of bright yellow solid (compound I-25), yield 22.1%, purity: 95.74%.

[0290] HRMS(ESI):m / z[M-Br]+.Calcd for 500.2068; Found:500.2073.

[0291] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.68 (s, 1H), 8.95 (s, 1H), 8.20 (d, J = 9.2Hz, 1H), 8 .01(d,J=9.1Hz,1H),7.80(s,1H),7.10(s,1H),6.18(s,2H),5.64(s,2H),4.96-4. 92(m,2H),4.29(s,2H),4.15(s,2H),4.02(s,3H),3.23-3.21(m,2H),3.19-3.16(m ,1H),2.63-2.57(m,2H),2.55-2.51(m,2H),0.81-0.79(m,2H),0.73-0.71(m,2H).

[0292] Example 26: Synthesis of Compound I-26

[0293]

[0294] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), 3-oxo-1-cyclopentanecarboxylic acid (161 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 75 °C for 3 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. Filter cake column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) yielded 35 mg of a yellow solid (compound I-26), with a yield of 14.0% and a purity of 95.34%.

[0295] HRMS(ESI):m / z[M-Br]+.Calcd for 516.2017; Found:516.2014.

[0296] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.68 (s, 1H), 8.96 (s, 1H), 8.20 (d, J = 9.1Hz, 1H), 8.01 ( d,J=9.1Hz,1H),7.80(s,1H),7.11(s,1H),6.18(s,2H),4.95(t,J=6.3Hz,2H),4.32(s ,2H),4.17-4.12(m,2H),4.03(s,3H),3.25-3.21(m,3H),2.43-2.30(m,2H),2.26-2.2 0(m,1H),2.19-2.16(m,2H),2.02-1.97(m,1H),0.82-0.80(m,2H),0.74-0.72(m,2H).

[0297] Example 27: Synthesis of Compound I-27

[0298]

[0299] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), naphthenic acid (159 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 75 °C for 3 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. Filter cake column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) yielded 45 mg of a yellow solid (compound I-27), with a yield of 18.0% and a purity of 95.93%.

[0300] HRMS(ESI):m / z[M-Br]+.Calcd for 514.2225; Found:514.226.

[0301] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.69 (s, 1H), 8.96 (s, 1H), 8.20 (d, J = 9.2Hz, 1H), 8.01 (d, J = 9. 1Hz,1H),7.80(s,1H),7.10(s,1H),6.18(s,2H),5.63(s,2H),4.95(t,J=6.2Hz,2H),4.31-4.2 7(m,2H),4.16(s,2H),4.03(s,3H),3.24-3.22(m,2H),2.61-2.56(m,1H),2.21-2.11(m,2H), 2.03-1.98(m,2H),1.92-1.88(m,1H),1.58-1.54(m,1H),0.81-0.79(m,2H),0.73-0.71m,2H).

[0302] Example 28: Synthesis of Compound I-28

[0303]

[0304] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), tetrahydropyran-4-carboxylic acid (164 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 75 °C for 2 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling the reaction solution to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. Filter cake column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) yielded a yellow solid. The crude product was slurried with ethyl acetate: methanol: dichloromethane = 2:1:1 (1 g / 8 mL), filtered, and the filter cake was washed three times with n-hexane (6 mL × 3) to give 35 mg of a bright yellow solid (compound I-28), yield 13.9%, purity: 97.63%.

[0305] HRMS(ESI):m / z[M-Br]+.Calcd for 518.2174; Found:518.2179.

[0306] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.69 (s, 1H), 8.97 (s, 1H), 8.20 (d, J = 9.2Hz, 1H), 8.01 (d, J = 9. 1Hz,1H),7.81(s,1H),7.10(s,1H),6.18(s,2H),4.95(t,J=6.3Hz,2H),4.29(s,2H),4.14(s, 2H),4.03(s,3H),3.80-3.77(m,2H),3.35-3.33(m,2H),3.24-3.20(m,2H),2.63(ddd,J=11.2 ,7.2,4.0Hz,1H),1.77-1.72(m,2H),1.58-1.51(m,2H),0.81-0.78(m,2H),0.73-0.70(m,2H).

[0307] Example 29: Synthesis of Compound I-29

[0308]

[0309] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), isobutyric acid (111 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 75 °C for 3 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. The reaction solution was cooled to room temperature, and ethyl acetate (10 mL) and petroleum ether (10 mL) were added. A yellow solid precipitated and was filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) to obtain a yellow solid. The crude product was slurried with ethyl acetate: methanol = 6:1 (1 g / 10 mL), filtered, and the filter cake was washed three times with n-hexane (6 mL × 3) to obtain 74 mg of a bright yellow solid (compound I-29), with a yield of 31.7% and a purity of 94.1%.

[0310] HRMS(ESI):m / z[M-Br]+.Calcd for 476.2068; Found:476.2074.

[0311] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.69 (s, 1H), 8.96 (s, 1H), 8.20 (d, J = 9.2Hz, 1H),8.01(d,J=9.1Hz,1H),7.80(s,1H),7.10(s,1H),6.18(s,2H),4.97-4.9 4(m,2H),4.27(s,2H),4.16(s,2H),4.03(s,3H),3.25-3.22(m,2H),2.61-2 .54(m,1H),1.09(s,3H),1.08(s,3H),0.81-0.79(m,2H),0.72-0.70(m,2H).

[0312] Example 30: Synthesis of Compound I-30

[0313]

[0314] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), butyric acid (111 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 75 °C for 2 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) to obtain a yellow solid. The crude product was slurried with ethyl acetate: methanol = 5:1 (1 g / 10 mL), filtered, and the filter cake was washed three times with n-hexane (5 mL × 3) to obtain 32 mg of a bright yellow solid (compound I-30), with a yield of 13.7% and a purity of 94.48%.

[0315] HRMS(ESI):m / z[M-Br]+.Calcd for 476.2068; Found:476.2069.

[0316] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.69 (s, 1H), 8.95 (s, 1H), 8.20 (d, J = 9.1Hz, 1H), 8 .01(d,J=9.1Hz,1H),7.80(s,1H),7.10(s,1H),6.18(s,2H),4.95(t,J=6.2Hz,2H ),4.27(s,2H),4.15(s,2H),4.03(s,3H),3.25-3.21(m,2H),2.33(t,J=7.3Hz,2H ),1.55-1.52(m,2H),0.87(t,J=7.4Hz,3H),0.80-0.78(m,2H),0.72-0.70(m,2H).

[0317] Example 31: Synthesis of Compound I-31

[0318]

[0319] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), n-valeric acid (129 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 75 °C for 2 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. The reaction solution was cooled to room temperature, and ethyl acetate (10 mL) and petroleum ether (10 mL) were added. A yellow solid precipitated and was filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) to obtain a yellow solid. The crude product was slurried with ethyl acetate: methanol = 5:1 (1 g / 10 mL), filtered, and the filter cake was washed three times with n-hexane (6 mL × 3) to obtain a bright yellow solid (compound I-31) of 71 mg, with a yield of 29.6% and a purity of 94.08%.

[0320] HRMS(ESI): m / z[M-Br] + .Calcd for 490.2225;Found:490.2223.

[0321] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.69 (s, 1H), 8.96 (s, 1H), 8.20 (d, J = 9.2Hz, 1H), 8.01 (d,J=9.1Hz,1H),7.80(s,1H),7.11(s,1H),6.18(s,2H),4.97-4.93(m,2H),4.26(s,2 H),4.15(s,2H),4.03(s,3H),3.25-3.21(m,2H),2.33(t,J=7.4Hz,2H),1.52-1.47(m ,2H),1.28-1.22(m,2H),0.83(t,J=7.4Hz,3H),0.80-0.78(m,2H),0.72-0.70(m,2H).

[0322] Example 32: Synthesis of Compound I-32

[0323]

[0324] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), hexanoic acid (146 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 75 °C for 2 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. The reaction solution was cooled to room temperature, and ethyl acetate (10 mL) and petroleum ether (10 mL) were added. A yellow solid precipitated and was filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) to obtain a yellow solid. The crude product was slurried with ethyl acetate: methanol = 6:1 (1 g / 10 mL), filtered, and the filter cake was washed three times with n-hexane (5 mL × 3) to obtain 46 mg of a bright yellow solid (compound I-32), with a yield of 18.7% and a purity of 95.03%.

[0325] HRMS(ESI): m / z[M-Br] + .Calcd for 504.2381;Found:504.2381.

[0326] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.70 (s, 1H), 8.96 (s, 1H), 8.20 (d, J = 9.1Hz, 1H) ,8.01(d,J=9.1Hz,1H),7.81(s,1H),7.11(s,1H),6.18(s,2H),4.97-4.93(m,2H ),4.26(s,2H),4.15(s,2H),4.03(s,3H),3.24-3.21(m,2H),2.32(t,J=7.4Hz,2 H),1.53-1.48(m,2H),1.25-1.20(m,4H),0.83-0.78(m,5H),0.73-0.69(m,2H).

[0327] Example 33: Synthesis of Compound I-33

[0328]

[0329] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), heptanoic acid (164 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 75 °C for 2 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) to obtain a yellow solid. The crude product was slurried with ethyl acetate: methanol = 6:1 (1 g / 10 mL), filtered, and the filter cake was washed three times with n-hexane (6 mL × 3) to obtain 80 mg of a bright yellow solid (compound I-33), with a yield of 13.4% and a purity of 92.73%.

[0330] HRMS(ESI): m / z[M-Br] + .Calcd for 518.2538; Found:518.2540.

[0331] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.70 (s, 1H), 8.96 (s, 1H), 8.20 (d, J = 9.1Hz, 1H), 8.01(d,J=9.1Hz,1H),7.81(s,1H),7.11(s,1H),6.18(s,2H),4.95(t,J=6.2Hz,2 H),4.27(s,2H),4.15(s,2H),4.03(s,3H),3.24-3.21(m,2H),2.32(t,J=7.3Hz, 2H),1.51-1.47(m,2H),1.24-1.15(m,6H),0.83-0.78(m,5H),0.72-0.70(m,2H).

[0332] Example 34: Synthesis of Compound I-34

[0333]

[0334] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), 2-methylheptanoic acid (182 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 75 °C for 2 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. The reaction solution was cooled to room temperature, and ethyl acetate (10 mL) and petroleum ether (10 mL) were added. A yellow solid precipitated, which was then filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1 - 50:1) to obtain a yellow solid. The crude product was slurried with methanol, filtered, and the filter cake was washed three times with n-hexane (5 mL × 3) to obtain 20 mg of a bright yellow solid (compound I-34), with a yield of 7.8% and a purity of 96.36%.

[0335] HRMS(ESI): m / z[M-Br] + .Calcd for 532.2694; Found:532.2686.

[0336] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.71 (s, 1H), 8.96 (s, 1H), 8.20 (d, J = 9.1Hz, 1H), 8.01 (d, J = 9.1 Hz,1H),7.81(s,1H),7.11(s,1H),6.18(s,2H),4.96(t,J=6.2Hz,2H),4.29(q,J=11.6Hz,2H),4 .20-4.13(m,2H),4.03(s,3H),3.25-3.21(m,2H),2.44(q,J=7.0Hz,1H),1.51-1.48(m,1H),1.3 6-1.30(m,1H),1.21-1.13(m,6H),1.05(d,J=6.9Hz,3H),0.81-0.77(m,5H),0.73-0.70(m,2H).

[0337] Example 35: Synthesis of Compound I-35

[0338]

[0339] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), isooctanoic acid (182 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 75 °C for 4 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) to obtain a yellow solid. The crude product was slurried with methanol, filtered, and the filter cake was washed three times with n-hexane (8 mL × 3) to obtain 103 mg of a bright yellow solid (compound I-35), with a yield of 40.0% and a purity of 95.67%.

[0340] HRMS(ESI): m / z[M-Br] + .Calcd for 532.2694; Found:532.2684.

[0341] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.70 (s, 1H), 8.96 (s, 1H), 8.20 (d, J = 9.2Hz, 1H),8.01(d,J=9.1Hz,1H),7.80(s,1H),7.11(s,1H),6.18(s,2H),4.95(t, J=6.3Hz,2H),4.27(s,2H),4.16(s,2H),4.03(s,3H),3.23(t,J=6.2Hz,2H) ,2.33(t,J=7.3Hz,2H),1.51-1.47(m,2H),1.44-1.41(m,1H),1.24-1.21(m 2H),1.11-1.06(m,2H),0.81-0.78(m,8H),0.72-0.70(m,2H).

[0342] Example 36: Synthesis of Compound I-36

[0343]

[0344] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), nonanoic acid (199 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 75 °C for 2 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) to obtain a yellow solid. The crude product was slurried with methanol: dichloromethane = 1:7 (1 g / 8 mL), and the filter cake was washed three times with n-hexane (8 mL × 3) to obtain 110 mg of a bright yellow solid (compound I-36), with a yield of 41.8% and a purity of 98.65%.

[0345] HRMS(ESI): m / z[M-Br] + .Calcd for 546.2851;Found:546.2843.

[0346] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.70 (s, 1H), 8.96 (s, 1H), 8.20 (d, J = 9.2Hz, 1H), 8.01(d,J=9.1Hz,1H),7.80(s,1H),7.10(s,1H),6.18(s,2H),4.95(t,J=6.3Hz,2 H),4.27(s,2H),4.15(s,2H),4.03(s,3H),3.25-3.21(m,2H),2.32(t,J=7.3Hz,2 H),1.51-1.47(m,2H),1.22-1.15(m,10H),0.85-0.78(m,5H),0.72-0.70(m,2H).

[0347] 13 C NMR(151MHz,DMSO-d6)δ(ppm):173.19,150.34,149.77,147.62,145.04,142.52,137.34,132.91,130.54,126.54,123.44,121.38,120.31,1 20.17,108.35,105.32,102.02,77.57,66.73,56.90,55.40,33.44,31 .09,28.54,28.42,28.32,26.24,24.38,21.94,20.65,13.82(2C),8.86

[0348] Example 37: Synthesis of Compound I-37

[0349]

[0350] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), n-decanoic acid (217 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 75 °C for 2 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. After cooling to room temperature, ethyl acetate (10 mL) and petroleum ether (10 mL) were added, resulting in the precipitation of a yellow solid, which was then filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1 - 60:1) to obtain the yellow solid. The crude product was slurried with methanol, filtered, and the filter cake was washed three times with n-hexane (5 mL × 3) to obtain 24 mg of a bright yellow solid (compound I-37), with a yield of 13.9% and a purity of 94.93%.

[0351] HRMS(ESI): m / z[M-Br] + .Calcd for 560.3007;Found:560.2998.

[0352] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 9.70 (s, 1H), 8.96 (s, 1H), 8.20 (d, J = 9.2Hz, 1H), 8.01(d,J=9.1Hz,1H),7.80(s,1H),7.10(s,1H),6.18(s,2H),4.95(t,J=6.3Hz,2 H),4.27(s,2H),4.15(s,2H),4.03(s,3H),3.25-3.21(m,2H),2.32(t,J=7.3Hz,2 H),1.51-1.47(m,2H),1.22-1.15(m,10H),0.85-0.78(m,5H),0.72-0.70(m,2H).

[0353] 13C NMR (151MHz, DMSO-d6) δ (ppm): 173.19, 150.34, 149.77, 147.62, 145.04, 142.52, 137.34, 132.91, 130.54, 126.54, 123.44, 121.38, 120.31, 120. 17,108.35,105.32,102.02,77.57,66.73,56.90,55.40,33.44,31.14,2 8.72,28.58,28.53,28.31,26.24,24.38,21.97,20.65,13.82(2C),8.86

[0354] Example 38: Synthesis of Compound I-38

[0355]

[0356] Intermediate 3 (200 mg, 0.42 mmol) was added to a 25 mL three-necked flask, followed by DMF (6 mL), undecanoic acid (235 mg, 1.26 mmol), sodium iodide (63 mg, 0.42 mmol), and triethylamine (127 mg, 1.26 mmol). The mixture was heated at 75 °C for 2 h, and the reaction was monitored by TLC until complete. The reaction solution gradually changed from a yellow turbidity to a clear yellowish-brown. The reaction solution was cooled to room temperature, and ethyl acetate (10 mL) and petroleum ether (10 mL) were added. A yellow solid precipitated and was filtered. The filter cake was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-60:1) to obtain a yellow solid. The crude product was slurried with ethyl acetate: methanol = 5:1 (1 g / 8 mL), filtered, and the filter cake was washed three times with n-hexane (8 mL × 3) to obtain 86 mg of a bright yellow solid (compound I-38), with a yield of 31.3% and a purity of 96.79%.

[0357] HRMS(ESI): m / z[M-Br] + .Calcd for 574.3164; Found:574.3154.

[0358] 1H NMR (600MHz, DMSO-d6) δ (ppm): 9.70 (s, 1H), 8.96 (s, 1H), 8.20 (d, J = 9.2Hz, 1H), 8.01 ( d,J=9.1Hz,1H),7.81(s,1H),7.10(s,1H),6.18(s,2H),4.97-4.93(m,2H),4.27(s,2H) ,4.15(s,2H),4.03(s,3H),3.24-3.21(m,2H),2.31(t,J=7.3Hz,2H),1.49(t,J=7.2Hz ,2H),1.25-1.15(m,14H),0.83(t,J=7.1Hz,3H),0.80-0.78(m,2H),0.72-0.70(m,2H).

[0359] Example 39: Synthesis of Compound I-39

[0360] Step 1):

[0361]

[0362] Intermediate 3 (5.03 g, 10.72 mmol) was added to a 1000 mL round-bottom flask and dissolved in methanol (350 mL). Then, 25-28% ammonia solution (100 mL) and ammonium chloride (688 mg, 12.86 mmol) were added. The mixture was heated at 55 °C for 2 h. The reaction solution gradually changed from yellow turbidity to orange turbidity. TLC monitoring showed a small amount of raw material remaining. The solvent was removed by vacuum distillation to obtain an orange-yellow solid. The solid was slurried with dichloromethane:methanol = 3:1 (1 g / 8 mL) and filtered. The filter cake was slurried again with dichloromethane:methanol = 3:1 (1 g / 8 mL) and filtered to obtain 3.63 g of yellow solid (intermediate 4), yield 76.8%, purity: 91.92%.

[0363] HRMS(ESI): m / z[M-Cl] + .Calcd for 405.1809;Found:405.1814.

[0364] Step 2):

[0365]

[0366] Intermediate 4 (200 mg, 0.45 mmol) was added to a 25 mL three-necked flask, followed by DMF (8 mL) and bicyclo[2.2.1]heptane-2-carboxylic acid (76 mg, 0.54 mmol). Under ice bath conditions, N,N'-dicyclohexylcarbodiimide (186 mg, 0.90 mmol) and 4-dimethylaminopyridine (28 mg, 0.23 mmol) were slowly added. The reaction was allowed to proceed at room temperature for 11 h, and TLC was used to monitor the reaction until complete. The mixture was filtered, and the filtrate was separated by column chromatography (eluent: dichloromethane:methanol = 100:1-40:1) to obtain 42 mg of a yellow solid. This solid was dissolved in 1 mL of methanol, and the addition of 3 drops of n-hexane resulted in the precipitation of a yellow solid. The mixture was slurryed, filtered, and the filter cake was washed three times with n-hexane (6 mL × 3) to obtain 29 mg of a bright yellow solid (compound I-39), yield 11.4%, purity: 96.47%.

[0367] HRMS(ESI): m / z[M-Cl] + .Calcd for 527.2546;Found:527.2548.

[0368] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.13 (s, 1H), 8.95 (s, 1H), 8.18 (d, J = 9.1Hz, 1H), 8.05-7.96 (m, 2H), 7.80(s,1H),7.11(s,1H),6.18(s,2H),5.09-5.04(m,2H),4.08-3.95(m,5H),3.50-3.47(m,1H),3.4 0-3.36(m,1H),3.27-3.22(m,1H),2.66-2.62(m,1H),2.41(s,1H),2.24-2.13(m,2H),1.55-1.42(m, 2H),1.38-1.30(m,2H),1.24-1.21(m,1H),1.15-1.09(m,2H),1.04-0.95(m,1H),0.64-0.59(m,4H).

[0369] Example 40: Synthesis of Compound I-40

[0370]

[0371] Intermediate 4 (200 mg, 0.45 mmol) was added to a 25 mL three-necked flask, followed by DMF (8 mL) and heptanoic acid (70 mg, 0.54 mmol). Under ice bath conditions, N,N'-dicyclohexylcarbodiimide (186 mg, 0.90 mmol) and 4-dimethylaminopyridine (28 mg, 0.23 mmol) were slowly added. The reaction was allowed to proceed overnight at room temperature for 16 h, and TLC was used to monitor the reaction until complete. The mixture was filtered, and ethyl acetate (12 mL) and petroleum ether (12 mL) were added to the filtrate. A yellow solid precipitated, which was then filtered again. The precipitate was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-40:1) to obtain 42 mg of the yellow solid (compound I-40), yield 16.9%, purity: 96.03%.

[0372] HRMS(ESI): m / z[M-Cl] + .Calcd for 517.2697;Found:517.2682.

[0373] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.04 (s, 1H), 8.95 (s, 1H), 8.18 (d, J = 9.1Hz, 1H), 8.07 ( t,J=6.1Hz,1H),8.00(d,J=9.1Hz,1H),7.81(s,1H),7.11(s,1H),6.18(s,2H),5.04(t, J=6.2Hz,2H),4.04-3.99(m,5H),3.41(d,J=6.1Hz,2H),3.26-3.21(m,2H),2.12(t,J=7 .3Hz,2H),1.46-1.41(m,2H),1.14-1.10(m,6H),0.76-1.74(m,3H),0.63-0.59(m,4H).

[0374] 13 C NMR(151MHz,DMSO-d6)δ(ppm):172.81,150.51,149.74,147.62,145.71,142.54,137.27,132.80,130.52,126.44,123.38,121.51,120 .35,120.01,108.38,105.29,102.00,77.77,56.89,55.12,41.64,35.18,30.85,28.14,26.29,25.08,21.81,21.38,13.72(2C),8.92.

[0375] Example 41: Synthesis of Compound I-41

[0376]

[0377] Intermediate 4 (200 mg, 0.45 mmol) was added to a 25 mL three-necked flask, followed by DMF (8 mL) and isooctanoic acid (78 mg, 0.54 mmol). Under ice bath conditions, N,N'-dicyclohexylcarbodiimide (186 mg, 0.90 mmol) and 4-dimethylaminopyridine (28 mg, 0.23 mmol) were slowly added. The reaction was allowed to proceed overnight at room temperature for 15 h, and TLC was used to monitor the reaction until complete. The mixture was filtered, and ethyl acetate (12 mL) and petroleum ether (12 mL) were added to the filtrate. A yellow solid precipitated, which was then filtered again. The precipitate was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-40:1) to obtain 30 mg of a yellow solid (compound I-41), yield 11.8%, purity: 93.97%.

[0378] HRMS(ESI): m / z[M-Cl] + .Calcd for 531.2854; Found:531.2854.

[0379] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.07 (s, 1H), 8.96 (s, 1H), 8.19-8.16 (m, 2H), 8.00 (d, J = 9 .1Hz,1H),7.81(s,1H),7.11(s,1H),6.18(s,2H),5.05(t,J=6.2Hz,2H),4.04-4.00(m,5H ),3.40(d,J=6.1Hz,2H),3.25-3.22(m,2H),2.14(t,J=7.3Hz,2H),1.45-1.40(m,2H),1.3 6-1.31(m,1H),1.16-1.11(m,2H),1.05-1.02(m,2H),0.73(d,J=6.6Hz,6H),0.62(s,4H).

[0380] Example 42: Synthesis of Compound I-42

[0381]

[0382] Intermediate 4 (200 mg, 0.45 mmol) was added to a 25 mL three-necked flask, followed by DMF (8 mL) and octanoic acid (78 mg, 0.54 mmol). Under ice bath conditions, N,N'-dicyclohexylcarbodiimide (186 mg, 0.90 mmol) and 4-dimethylaminopyridine (28 mg, 0.23 mmol) were slowly added. The reaction was allowed to proceed overnight at room temperature for 15 h, and TLC was used to monitor the reaction until complete. The mixture was filtered, and ethyl acetate (12 mL) and petroleum ether (12 mL) were added to the filtrate. A yellow solid precipitated, which was then filtered again. The precipitate was separated by column chromatography (eluent: dichloromethane: methanol = 100:1-40:1) to obtain 83 mg of the yellow solid (compound I-42). The crude product was dissolved in 1.5 mL of methanol, and 5 drops of n-hexane were added, resulting in the precipitation of a yellow solid. The mixture was slurryed, filtered, and the filter cake was washed three times with n-hexane (6 mL × 3) to obtain 65 mg of a bright yellow solid (compound I-43), with a yield of 25.5% and a purity of 94.59%.

[0383] HRMS(ESI): m / z[M-Cl] + .Calcd for 531.2854; Found:531.2864.

[0384] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.04 (s, 1H), 8.95 (s, 1H), 8.18 (d, J = 9.1Hz, 1H), 8.06 (t, J = 6 .1Hz,1H),8.00(d,J=9.1Hz,1H),7.81(s,1H),7.10(s,1H),6.18(s,2H),5.06-5.02(m,2H),4. 03(s,3H),4.01(s,2H),3.41(d,J=6.1Hz,2H),3.26-3.22(m,2H),2.12(t,J=7.3Hz,2H),1.46 -1.41(m,2H),1.16-1.09(m,6H),1.07-1.01(m,2H),0.76(t,J=7.3Hz,3H),0.64-0.59(m,4H).

[0385] Example 43: Synthesis of Compound I-43

[0386]

[0387] Intermediate 4 (200 mg, 0.45 mmol) was added to a 25 mL three-necked flask, followed by DMF (8 mL) and n-nonanoic acid (85 mg, 0.54 mmol). Under ice bath conditions, N,N'-dicyclohexylcarbodiimide (186 mg, 0.90 mmol) and 4-dimethylaminopyridine (28 mg, 0.23 mmol) were slowly added. The reaction was allowed to proceed overnight at room temperature for 18 h, and TLC was used to monitor the reaction until complete. The mixture was filtered, and the filtrate was added to ethyl acetate (12 mL) and petroleum ether (12 mL). A yellow solid precipitated, which was then filtered and separated by column chromatography (eluent: dichloromethane: methanol = 100:1 - 40:1) to obtain the yellow solid. The crude product was slurried with ethyl acetate: methanol = 5:1 (1 g / 8 mL), filtered, and the filter cake was washed three times with n-hexane (6 mL × 3) to give 57 mg of a bright yellow solid (compound I-43), yield 21.8%, purity: 95.75%.

[0388] HRMS(ESI): m / z[M-Cl] + .Calcd for 545.3010;Found:545.3019.

[0389] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 10.05 (s, 1H), 8.96 (s, 1H), 8.18 (d, J = 9.1Hz, 1H), 8.09 (t, J=6.1Hz,1H),8.00(d,J=9.1Hz,1H),7.81(s,1H),7.10(s,1H),6.18(s,2H),5.05(t,J=6.3 Hz,2H),4.03(s,3H),4.01(s,2H),3.41(d,J=6.1Hz,2H),3.26-3.22(m,2H),2.12(t,J=7. 3Hz, 2H), 1.46-1.40 (m, 2H), 1.17-1.02 (m, 10H), 0.78 (t, J = 7.2Hz, 3H), 0.64-0.60 (m, 4H).

[0390] 13C NMR(151MHz,DMSO-d6)δ(ppm):173.39,151.11,150.32,148.20,146.27,143.10,137.84,133.39,131.08,127.03,123.99,122.08,120.93,12 0.61,108.94,105.87,102.59,78.33,57.48,55.71,42.23,35.74,31. 65,29.21,29.06,29.04,26.89,25.71,22.50,21.95,14.38(2C),9.54.

[0391] Example 44: Synthesis of Compound I-44

[0392]

[0393] Intermediate 4 (200 mg, 0.45 mmol) was added to a 25 mL three-necked flask, followed by DMF (8 mL) and undecanoic acid (101 mg, 0.54 mmol). Under ice bath conditions, N,N'-dicyclohexylcarbodiimide (186 mg, 0.90 mmol) and 4-dimethylaminopyridine (28 mg, 0.23 mmol) were slowly added. The reaction was allowed to proceed overnight at room temperature for 17 h, and TLC was used to monitor the reaction until complete. The mixture was filtered, and the filtrate was added to ethyl acetate (12 mL) and petroleum ether (12 mL). A yellow solid precipitated, which was then filtered and separated by column chromatography (eluent: dichloromethane: methanol = 100:1-40:1) to obtain the yellow solid. The crude product was slurried with ethyl acetate: methanol = 4:1 (1 g / 8 mL), filtered, and the filter cake was washed three times with n-hexane (6 mL × 3) to give 29 mg of a bright yellow solid (compound I-44), yield 10.6%, purity: 99.75%.

[0394] HRMS(ESI): m / z[M-Cl] + .Calcd for 573.3323;Found:573.3320.

[0395] 1H NMR (600MHz, DMSO-d6) δ (ppm): 10.07 (s, 1H), 8.97 (s, 1H), 8.18 (d, J = 9.2Hz, 2H), 8.00 ( d,J=9.1Hz,1H),7.81(s,1H),7.10(s,1H),6.18(s,2H),5.06(t,J=6.2Hz,2H),4.03(s,3 H),4.01(s,2H),3.41(d,J=6.1Hz,2H),3.26-3.23(m,2H),2.13(t,J=7.3Hz,2H),1.46- 1.41(m,2H),1.21-1.19(m,2H),1.14-1.05(m,12H),0.82(t,J=7.2Hz,3H),0.62(s,4H).

[0396] 13 C NMR(151MHz,DMSO-d6)δ(ppm):172.83,150.55,149.74,147.63,145.72,1 42.53,137.25,132.81,130.49,126.43,123.43,121.51,120.35,120.04, 108.35,105.30,102.01,77.78,56.89,55.09,41.64,35.15,31.15,28.81 ,28.67,28.55(2C),28.47,26.32,25.13,21.96,21.42,13.83(2C),8.99.

[0397] Effect Experiments: Pharmacological experiments and results of the compounds prepared in the embodiments of this invention

[0398] Experimental Example 1: Inhibitory effect of the compound of the present invention on the growth of HCT116 human colorectal cancer cells.

[0399] 1.1 Experimental Materials and Instruments

[0400] HCT116 (From Bioduro), Irinotecan Hydrochloride (Adamas-beta, P2740897), McCOY's5A (ATCC, 30-2007), FBS (Gibco, 10091148), trypan blue (Gibco, 15250061), PBS, PH 7.4 (Gibco, 10010031), Penicillin / Streptomycin (100x) (Invitrogen, 15140122), 0.25% Trypsin-EDTA (ATCC, 30-2101), 96Well TC-Treated Microplates (Corning, 3599), Ultra-Low Attachment Multiple 96Well Plate (Costar, CLS7007), CellTiter-Glo 3D CellViability Assay (Promega, G9683)

[0401] 1.2 Test Methods

[0402] Pre-warm PBS, 0.25% trypsin, and cell culture medium in a 37°C water bath. Observe HCT116 cells under a microscope to assess cell status and confirm the absence of bacterial and fungal contaminants. Remove the culture medium, wash cells with 5 mL of PBS and aspirate. Add 1 mL of 0.25% trypsin / EDTA reagent to a 10 cm culture dish. Place the dish in an incubator until cell separation (1-2 minutes). Add 5 mL of fresh cell culture medium, rinse cells, and transfer to a conical tube. Collect cells into a 15 mL centrifuge tube and centrifuge at 1000 rpm for 5 minutes. After centrifugation, discard the supernatant. Resuspend cell particles in 5 mL of cell culture medium. Aspirate 20 μL of the resuspended cells for cell counting. Use Cell Counterstar to add 20 μL of dye to 20 μL of the cell suspension for cell counting. Prepare cell suspensions for each cell type according to the table below, and add 90 μL of cells to each well of a 96-well plate.

[0403] Dissolve the test compound powder in McCoy's 5A medium to prepare the top dose for each compound, and dilute the compounds to the required concentration in 96-well plates. Incubate at 37°C and 5% CO2 for 5 days. Thaw CellTiter at room temperature. 3D cell viability assay reagent, equilibrate to room temperature. Equilibrate the cell plate at room temperature for approximately 20 minutes, then add CTG reagent (50 μL / well). Incubate with shaking at room temperature for 30 minutes, avoiding light exposure. Transfer the test solution from the cell plate to an analytical plate (PE-96-well Opti plate) at 100 μL / well. After transfer, read the data using Envision, IC50. 50 The values ​​were plotted and calculated based on the logarithm of the inhibition rate and dose for each concentration of the compound.

[0404] 1.3 Test Results

[0405] The experimental results of the inhibitory effect of the compound on the growth of HCT116 human colorectal cancer cells are shown in Table 1.

[0406] Experimental Example 2: Inhibitory effect of the compound of the present invention on the growth of LoVo human colorectal cancer cells.

[0407] 2.1 Experimental Materials and Instruments

[0408] LoVo (From Bioduro), Irinotecan Hydrochloride (Adamas-beta, P2740897), McCOY's5A (ATCC, 30-2007), F-12K (ATCC, 30-2004), FBS (Gibco, 10091148), trypan blue (Gibco, 15250061), PBS, PH 7.4 (Gibco, 10010031), Penicillin / Streptomycin (100x) (Invitrogen, 15140122), 0.25% Trypsin-EDTA (ATCC, 30-2101), 96Well TC-Treated Microplates (Corning, 3599), Ultra-Low Attachment Multiple 96Well Plate (Costar, CLS7007), CellTiter-Glo 3D Cell Viability Assay(Promega, G9683)

[0409] 2.2 Test Methods

[0410] Pre-warm PBS, 0.25% trypsin, and cell culture medium in a 37°C water bath. Observe LoVo cells under a microscope to assess cell status and confirm the absence of bacterial and fungal contaminants. Remove the culture medium, wash cells with 5 mL of PBS, and aspirate. Add 1 mL of 0.25% trypsin / EDTA reagent to a 10 cm culture dish. Place the dish in an incubator until cell separation (1-2 minutes). Add 5 mL of fresh cell culture medium, rinse cells, and transfer to a conical tube. Collect cells into a 15 mL centrifuge tube and centrifuge at 1000 rpm for 5 minutes. After centrifugation, discard the supernatant. Resuspend cell particles in 5 mL of cell culture medium. Aspirate 20 μL of the resuspended cells for cell counting. Use Cell Counterstar to add 20 μL of dye to 20 μL of the cell suspension for cell counting. Prepare cell suspensions for each cell type according to the table below, and add 90 μL of cells to each well of a 96-well plate.

[0411] Dissolve the test compound powder in F-12k medium to prepare the top dose for each compound, and dilute the compounds to the required concentration in a 96-well plate. Incubate at 37°C and 5% CO2 for 5 days. Thaw at room temperature using CellTiter- 3D cell viability assay reagent, equilibrate to room temperature. Equilibrate the cell plate at room temperature for approximately 20 minutes, then add CTG reagent (50 μL / well). Incubate with shaking at room temperature for 30 minutes, avoiding light exposure. Transfer the test solution from the cell plate to an analytical plate (PE-96-well Opti plate) at 100 μL / well. After transfer, read the data using Envision, IC50. 50 The values ​​were plotted and calculated based on the logarithm of the inhibition rate and dose for each concentration of the compound.

[0412] 3.3 Test Results

[0413] The experimental results of the inhibitory effect of the compound on the growth of LoVo human colorectal cancer cells are shown in Table 1.

[0414] Table 1. IC50 of the compounds of the present invention against the growth inhibition of human colorectal cancer cells. 50 Value (μM)

[0415]

[0416] ND = Not determined

[0417] Table 1 shows that the compounds of this invention have good inhibitory activity against human colorectal cancer cells HCT116 and LoVo. Among them, compounds I-37, I-36, and I-43 showed significantly better inhibitory activity against human colorectal cancer cells HCT116 than the first-line clinical drug irinotecan hydrochloride, while compound I-33 showed better inhibitory activity against human colorectal cancer cells LoVo than irinotecan hydrochloride.

[0418] Experimental Example 3: The repair effect of the compound of the present invention on a DSS-induced Caco-2 cell damage model.

[0419] 3.1 Experimental Materials and Instruments

[0420] DMEM medium (Gibco, C11995500BT), FBS (Pricella, 164210), trypsin (Solarbio, T1302), penicillin-streptomycin mixture (100×) (P1400, Solarbio), CCK8 (RM02823, Abclonal), DMSO (Solarbio, D8371), DSS (MP, 0216011080), biosafety cabinet (HFsafe1200LC, Shanghai Lishen Scientific Instruments Co., Ltd.), CO2 incubator (D180, Shenzhen Ruiwode Life Science Technology Co., Ltd.), inverted biological microscope (ECLIPSETs2, Nikon), hemocytometer (MF3543, Shanghai Qiujing), multi-functional microplate reader (VICTOR, NIVO), etc.

[0421] 3.2 Test Methods

[0422] Caco-2 cells were cultured (culture conditions: 89% DMEM + 10% FBS + 1% PS) to the logarithmic growth phase, digested, counted, and divided into groups of 5 × 10⁶ cells per well. 3 Cells were seeded into 96-well plates with 100 μL of complete culture medium per well and placed in a cell culture incubator. After two days, once the cells had adhered and fully expanded, the cell model was established. DSS modeling: 1.1 g of DSS powder was dissolved in 22 mL of DMEM basal medium to obtain a 5% DSS solution. This solution was added to the drug treatment group in the 96-well plates, while the control group received DMEM basal medium. After 6 hours, the DSS was removed, and drug intervention was initiated. The test compound was prepared to the required concentration using DMEM medium containing 5% FBS. The mixture was vortexed until homogeneous and added to 96-well plates. After culturing for 48 hours, CCK8 assay was performed. CCK8 working solution (CCK8:basal medium = 1:10) was prepared. The cell culture supernatant was discarded, and the CCK8 working solution was added. After incubation at 37°C for 3 hours, the absorbance was measured at 450 nm using a microplate reader, and cell viability was calculated. Cell viability (%) = (OD value of experimental group - OD value of blank culture medium) / (OD value of control group - OD value of blank culture medium) × 100%.

[0423] 3.3 Test Results

[0424] According to the appendix Figure 50 The test results showed that in the DSS-induced Caco-2 cell damage model, after adding the test compounds (at concentrations of 25 μM and 50 μM), and measuring cell viability after 48 hours, the cell viability of the compound I-9 and I-14 groups was significantly higher than that of the model group (5% DSS) (P < 0.05) and the positive control group (berberine hydrochloride group) (P < 0.05). This indicates that compounds I-9 and I-14 can repair DSS-induced cell damage, and their repair effect is superior to that of the positive control group (berberine hydrochloride). In conclusion, compounds I-9 and I-14 have significant repair effects on cell damage and exhibit significant anti-ulcerative colitis effects.

[0425] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. An isoquinoline compound of formula (I), or a stereoisomer, optically pure isomer, hydrate, solvate, crystal or pharmaceutically acceptable salt thereof, or a mixture thereof; in, R1 and R2 are connected to form a substituted 3-10 membered heterocyclic alkyl ring; wherein the substituent is selected from at least one hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C8 heterocyclic alkyl, C3-C8 cycloalkyl, methoxycarbonyl, and the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, and S; R3 is selected from -CH3 or -(CH2). m -, m represents 1-7; R4 and R5 are each independently hydrogen, or connected to form a substituted 3-6 membered heterocyclic alkyl ring; wherein the substituent is selected from at least one hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C2-C8 heterocyclic alkyl, hydroxyl, amino, carboxyl, methoxycarbonyl, and the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, and S; R6 is selected from hydrogen, substituted C1-C18 alkyl, substituted C1-C18 haloalkyl, substituted C6-C10 aryl, substituted C5-C10 heteroaryl, substituted C3-C8 cycloalkyl, substituted C2-C8 heterocyclic alkyl, substituted C4-C12 spirocyclic or substituted C4-C12 bridged cycloalkyl, wherein the substituent is selected from at least one hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C3 fluoroalkoxy, C2-C8 heterocyclic alkyl, hydroxyl, amino, methylamino, dimethylamino, acetamino, carboxyl, methoxycarbonyl or nitro, and the heteroaryl or heterocyclic alkyl contains 1-3 heteroatoms selected from N, O, S; A represents O, N, S, halogen, -OH, -NHCO-, -OCO-, -NHCOCH2-, -NHSO2-, or no atomic substitution; n represents 1-7; Y represents any acid forming an anion.

2. The isoquinoline compound, or its stereoisomers, optically pure isomers, hydrates, solvates, crystals, or pharmaceutically acceptable salts and mixtures thereof, as described in claim 1, is characterized in that: When R3 is selected from -CH3, R1 and R2 are linked to form a substituted 5-membered or 7-membered heterocyclic alkyl ring; wherein the substituent is selected from at least one hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C8 heterocyclic alkyl, C3-C8 cycloalkyl, or methoxycarbonyl, and the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, and S; when R3 is selected from -(CH2)... m - At that time, the ring formed by connecting R1 and R2 is selected from R4 and R5 are linked to form an unsubstituted 3-6 membered heterocyclic alkyl ring, wherein the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, and S; A is selected from O, N, -OH, -NHCO-, -OCO-, halogens, or no atomic substitution; R6 is selected from H, substituted C1-C18 alkyl, substituted C4-C12 bridged cycloalkyl, substituted C3-C8 cycloalkyl or heterocycloalkyl, wherein the cycloalkyl is a ternary, quaternary, pentaneary or hexacyclic cycloalkyl containing 3-8 C atoms, the heterocycloalkyl is a quaternary, pentaneary or hexacyclic heterocycle containing 1-3 O, N or S atoms, and the substituent is H, halogen, unsaturated bond or carbonyl.

3. The isoquinoline compound, or its stereoisomers, optically pure isomers, hydrates, solvates, crystals, or pharmaceutically acceptable salts and mixtures thereof, as described in claim 2, is characterized in that: When R3 is selected from -CH3, the ring formed by connecting R1 and R2 is selected from any of the following structures:

4. The isoquinoline compound, or its stereoisomers, optically pure isomers, hydrates, solvates, crystals, or pharmaceutically acceptable salts and mixtures thereof, as described in claim 2, is characterized in that: When R3 is selected from -(CH2) m - At that time, the ring formed by connecting R1 and R2 is selected from The ring formed by connecting R4 and R5 is selected from any of the following structures:

5. The isoquinoline compound, or its stereoisomers, optically pure isomers, hydrates, solvates, crystals, or pharmaceutically acceptable salts and mixtures thereof, as described in claim 2, is characterized in that: When R3 is selected from -(CH2) m - At that time, the ring formed by connecting R1 and R2 is selected from R6 is selected from any of the following structures: -CH(CH3)2、-CH2(CH2) n CH3(n=0-9), -(CH2)4CH(CH3)2, -CH(CH3)(CH2)4CH3.

6. The isoquinoline compound, or its stereoisomers, optically pure isomers, hydrates, solvates, crystals, or pharmaceutically acceptable salts and mixtures thereof, as described in claim 1, is characterized in that: The isoquinoline compounds represented by formula (Ⅰ) are any of the following compounds:

7. A method for preparing the isoquinoline compound of claim 1, characterized in that, The method is selected from the following group: (1) Using berberine hydrochloride as a raw material, a ring-opening reaction was carried out in the presence of an initiator to obtain intermediate 1; intermediate 1 and a halogenated compound underwent a substitution reaction to obtain isoquinoline compounds I-1 to I-8, as shown in reaction formula 1: Reaction 1: In formulas I-1 to I-8, R3 is selected from -CH3, and R1 and R2 are connected to form a substituted 5-membered heterocyclic alkyl ring or a 7-membered heterocyclic alkyl ring; wherein the substituent is selected from at least one hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C2-C8 heterocyclic alkyl, C3-C8 cycloalkyl, methoxycarbonyl, and the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, and S; (2) Berberine hydrochloride was used as a raw material and berberine was obtained by high-temperature pyrolysis reaction. Then, compound I-9 was prepared by substitution reaction. The specific reaction is shown in reaction formula 2: Reaction 2: (3) Using berberine hydrochloride as a raw material, berberine was obtained through a high-temperature pyrolysis reaction, and then compounds I-10 to I-38 were prepared through a multi-step substitution reaction. The specific reactions are shown in reaction formula 3: Reaction 3: In formulas I-10 to I-38, R3 is selected from -(CH2). m -, The ring formed by connecting R1 and R2 is selected from R4 and R5 are linked to form an unsubstituted 3-6 membered heterocyclic alkyl ring, wherein the heterocyclic alkyl group contains 1-3 heteroatoms selected from N, O, and S; A is selected from O, -OH, -OCO-, halogens, or without atomic substitution; R6 is selected from H, substituted C1-C18 alkyl, substituted C4-C12 bridged cycloalkyl, substituted C3-C8 cycloalkyl or heterocycloalkyl, wherein the cycloalkyl is a ternary, quaternary, quinary, or hexacyclic cycloalkyl containing 3-8 C atoms, the heterocycloalkyl is a quaternary, quinary, or hexacyclic heterocycle containing 1-3 O, N, or S atoms, and the substituent is H, halogen, unsaturated bond, or carbonyl. m represents 1-7, n represents 1-7; (4) Using berberine hydrochloride as raw material, compounds I-39 to I-44 were prepared through high-temperature pyrolysis reaction, substitution reaction, amination reaction, and condensation reaction. The specific reactions are shown in reaction formula 4. Reaction 4: In formulas I-39 to I-44, R3 is selected from -(CH2). m -, The ring formed by connecting R1 and R2 is selected from The ring formed by connecting R4 and R5 is selected from... R6 is selected from H, substituted C1-C18 alkyl, substituted C4-C12 bridged cycloalkyl, substituted C3-C8 cycloalkyl or heterocycloalkyl, wherein the cycloalkyl is a ternary, quaternary, pentaneary or hexacyclic cycloalkyl containing 3-8 C atoms, the heterocycloalkyl is a quaternary, pentaneary or hexacyclic heterocycle containing 1-3 O, N or S atoms, and the substituent is H, halogen, unsaturated bond or carbonyl.

8. The use of the isoquinoline compound of any one of claims 1-6, or its stereoisomers, optically pure isomers, hydrates, solvates, crystals, or pharmaceutically acceptable salts and mixtures thereof, or the isoquinoline compound prepared according to claim 7, in the preparation of medicaments for treating tumors and gastrointestinal diseases.

9. A pharmaceutical composition, characterized in that: The pharmaceutical composition comprises the isoquinoline compound of any one of claims 1-6, or its stereoisomers, optically pure isomers, hydrates, solvates, crystals, or pharmaceutically acceptable salts and mixtures thereof, or the isoquinoline compound prepared according to claim 7, as well as a pharmaceutically acceptable carrier and pharmaceutical excipients.

10. Use of the pharmaceutical composition of claim 9 in the preparation of a medicament for treating tumors and gastrointestinal diseases.

11. The application according to claim 8 or 10, characterized in that: The tumor is colorectal cancer, and the gastrointestinal disease is ulcerative colitis.

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