Acetophenone oxime compounds and applications thereof

Abstract

Disclosed are acetophenone oxime compounds and a preparation method thereof, and specifically disclosed are compounds represented by formula (II) and pharmaceutically acceptable salts thereof.

Description

[0001] This invention claims the following priority:

[0002] CN202010847864.2, application date: August 20, 2020;

[0003] CN202110109311.1, application date: January 26, 2021;

[0004] CN202110123369.1, application date: January 28, 2021. Technical Field

[0005] This invention relates to novel acetophenone oxime compounds and methods for their preparation, specifically to compounds represented by formula (II) and their pharmaceutically acceptable salts. Background Technology

[0006] Sphingosine-1-phosphate receptor (S1P) is a G protein-coupled receptor expressed on the cell membrane surface of lymphocytes, glial cells, and cardiovascular endothelial cells. It regulates innate and adaptive immune responses by recognizing sphingosine-1-phosphate, a sphingolipid with important biological functions, and participates in various physiological and pathological processes such as apoptosis, autophagy, lymphocyte migration, and the release of inflammatory factors. Currently, five S1P subtypes have been identified in mammals. 1-3 Widely expressed in the central nervous system, immune system, and atrioventricular conduction system, S1P4 is mainly expressed in the immune system, while S1P5 is mainly expressed in the central nervous system. Studies have shown that S1P1 agonists can induce the internalization of S1P1 on the surface of lymphocytes, preventing lymphocytes from sensing the S1P concentration gradient, inhibiting the migration of lymphocytes from secondary lymphoid organs (such as lymph nodes) to tissues, promoting lymphocyte homing, reducing the number of lymphocytes in the peripheral circulation system, preventing lymphocytes from reaching inflammatory lesions or graft sites, reducing excessive inflammation, and thus having an immunomodulatory effect.

[0007] Currently, three S1P agonists have been approved for marketing. Novartis' first-generation non-selective S1Ps (S1P1, S1P3, S1P4, S1P5) agonist Fingolimod was approved by the FDA in 2010 for the treatment of relapsing-remitting multiple sclerosis (RRMS). The second-generation selective S1P1 agonist Siponimod was approved by the FDA in 2019 for the treatment of relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS). Bristol-Myers Squibb's second-generation selective S1P1 agonist Ozanimod was approved by the FDA in 2020 for the treatment of relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS). Furthermore, various S1P1 agonists are currently in clinical trials for the treatment of autoimmune diseases such as systemic lupus erythematosus (SLE), ulcerative colitis (UC), Crohn's disease (CD), and psoriasis, as well as inflammatory stress injuries such as acute ischemic stroke (AIS) and hemorrhagic stroke (ICH). Therefore, the development of selective small-molecule S1P1 agonists holds great promise for future applications. Summary of the Invention

[0008] This invention provides compounds of formula (II) or pharmaceutically acceptable salts thereof.

[0009]

[0010] in,

[0011] Structural unit Selected from m is selected from 1 and 2;

[0012] T1 is selected from CR5 and N;

[0013] R1 and R2 are independently selected from H, -L1-NR, respectively. a -L2-COOH, -L1-NR a -L2-cyclopropyl, -azacyclobutyl-COOH and -piperidinyl-COOH, the -L1-NR a -L2-COOH, -L1-NR a -L2-cyclopropyl, -azacyclobutyl-COOH and -piperidin-COOH are optionally separated by 1, 2 or 3 R... b replace;

[0014] L1 is selected from a single bond or CH2;

[0015] L2 is selected from C 1-3 alkyl;

[0016] R3 and R5 are independently selected from H, F, Cl, Br, CN, and C, respectively.1-3 Alkyl, the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R groups. c replace;

[0017] R4 is selected from -OC 1-6 Alkyl, -OC 1-3 alkyl-cyclopropyl, -OC 3-6 cycloalkyl and C 3-6 cycloalkyl, the C 1-3 Alkyl, C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally surrounded by 1, 2 or 3 Rs. d replace;

[0018] R6 is selected from H and NR. a -C 1-3 alkyl-COOH, the NR a -C 1-3 Alkyl-COOH may be optionally surrounded by 1, 2 or 3 Rs e replace;

[0019] R a Selected from H and CH3;

[0020] R b Selected from H, F, Cl, Br, I and COOH;

[0021] R c and R d They are each independently selected from H, F, Cl, Br, and I;

[0022] R e They are selected independently from H, F, Cl, Br and I, respectively.

[0023] In some embodiments of the present invention, R1 is selected from H, -NH-CH2-COOH and -NH-CH2CH2-COOH, and other variables are as defined in the present invention.

[0024] In some embodiments of the present invention, L2 is selected from CH2, CH2CH2, CH(CH2)2 and CH2CH2CH2, and other variables are as defined in the present invention.

[0025] In some embodiments of the present invention, R2 is selected from H, -NH-CH2-COOH, -NH-CH2CH2-COOH, -N(CH3)-CH2CH2-COOH, The -NH-CH2-COOH, -NH-CH2CH2-COOH, -N(CH3)-CH2CH2-COOH, Choose 1, 2, or 3 Rs bReplacement, other variables as defined in this invention.

[0026] In some embodiments of the present invention, R2 is selected from H, -NH-CH2-COOH, -NH-CH2CH2-COOH, -N(CH3)-CH2CH2-COOH, Other variables are as defined in this invention.

[0027] In some embodiments of the present invention, R3 is selected from H, F, Cl, Br, CN and CF3, and other variables are as defined in the present invention.

[0028] In some embodiments of the present invention, R4 is selected from -OC. 1-4 Alkyl, -OC 1-3 Alkyl-cyclopropyl, -O-cyclopropyl, -O-cyclopentyl, and cyclohexyl, wherein -OC 1-4 Alkyl, -OC 1-3 Alkyl-cyclopropyl, -O-cyclopropyl, -O-cyclopentyl, and cyclohexyl are optionally separated by 1, 2, or 3 R's. d Replacement, other variables as defined in this invention.

[0029] In some embodiments of the present invention, R4 is selected from... Other variables are as defined in this invention.

[0030] In some embodiments of the present invention, R5 is selected from H and F, and other variables are as defined in the present invention.

[0031] In some embodiments of the present invention, R6 is selected from H, -NH-CH2-COOH, -NH-CH2CH2-COOH, -N(CH3)-CH2CH2-COOH and -NH-(CH2)3-COOH, and other variables are as defined in the present invention.

[0032] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from...

[0033]

[0034] in,

[0035] m, T1, R1, R2, R3, R4 and R6 are as defined in this invention.

[0036] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from...

[0037]

[0038] Among them, T1, R3, R4, L2, m and R aAs defined in this invention.

[0039] This invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0040]

[0041] in,

[0042] m is selected from 1 and 2;

[0043] T1 is selected from CR5 and N;

[0044] R1 and R2 are independently selected from H, -L1-NR, respectively. a -L2-COOH, -L1-NR a -L2-cyclopropyl, -azacyclobutyl-COOH and -piperidinyl-COOH, the -L1-NR a -L2-COOH, -L1-NR a -L2-cyclopropyl, -azacyclobutyl-COOH and -piperidin-COOH are optionally separated by 1, 2 or 3 R... b replace;

[0045] L1 is selected from a single bond or CH2;

[0046] L2 is selected from C 1-3 alkyl;

[0047] R3 and R5 are independently selected from H, F, Cl, Br, CN, and C, respectively. 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R groups. c replace;

[0048] R4 is selected from -OC 1-6 Alkyl, -OC 1-3 alkyl-cyclopropyl, -OC 3-6 cycloalkyl and C 3-6 cycloalkyl, the C 1-3 Alkyl, C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally surrounded by 1, 2 or 3 Rs. d replace;

[0049] R a Selected from H and CH3;

[0050] R b Selected from H, F, Cl, Br, I and COOH;

[0051] R c and R d They are selected independently from H, F, Cl, Br and I, respectively.

[0052] In some embodiments of the present invention, R1 is selected from H, -NH-CH2-COOH and -NH-CH2CH2-COOH, and other variables are as defined in the present invention.

[0053] In some embodiments of the present invention, L2 is selected from CH2, CH2CH2, CH(CH2)2 and CH2CH2CH2, and other variables are as defined in the present invention.

[0054] In some embodiments of the present invention, R2 is selected from H, -NH-CH2-COOH, -NH-CH2CH2-COOH, -N(CH3)-CH2CH2-COOH, The -NH-CH2-COOH, -NH-CH2CH2-COOH, -N(CH3)-CH2CH2-COOH, Choose 1, 2, or 3 Rs b Replacement, other variables as defined in this invention.

[0055] In some embodiments of the present invention, R2 is selected from H, -NH-CH2-COOH, -NH-CH2CH2-COOH, -N(CH3)-CH2CH2-COOH, Other variables are as defined in this invention.

[0056] In some embodiments of the present invention, R3 is selected from H, F, Cl, Br, CN and CF3, and other variables are as defined in the present invention.

[0057] In some embodiments of the present invention, R4 is selected from -OC. 1-4 Alkyl, -OC 1-3 Alkyl-cyclopropyl, -O-cyclopropyl, -O-cyclopentyl, and cyclohexyl, wherein -OC 1-4 Alkyl, -OC 1-3 Alkyl-cyclopropyl, -O-cyclopropyl, -O-cyclopentyl, and cyclohexyl are optionally separated by 1, 2, or 3 R's. d Replacement, other variables as defined in this invention.

[0058] In some embodiments of the present invention, R4 is selected from... Other variables are as defined in this invention.

[0059] In some embodiments of the present invention, R5 is selected from H and F, and other variables are as defined in the present invention.

[0060] Some solutions in this invention are derived from arbitrary combinations of the above variables.

[0061] This invention provides the following compounds or pharmaceutically acceptable salts thereof.

[0062]

[0063]

[0064] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from...

[0065]

[0066]

[0067] The present invention also provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating ischemic stroke.

[0068] Technical effect

[0069] The compounds of this invention exhibit significant selective S1P1 agonist activity and good pharmacokinetic properties. They can improve the infarct area in an ischemia-reperfusion model and have good metabolic stability.

[0070] Definitions and Explanations

[0071] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0072] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0073] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0074] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0075] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0076] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0077] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0078] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on a chemically feasible basis.

[0079] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0080] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0081] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0082] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in that group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the text indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2 of the phenyl group. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0083] Unless otherwise specified, the term "C" 1-6 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 Alkyl groups include C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-4 C6 and C5 alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

[0084] Unless otherwise specified, the term "C" 1-4 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 Alkyl groups include C 1-2 C 1-3 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), etc.

[0085] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0086] Unless otherwise specified, "C 3-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic system. 3-6 Cycloalkyl groups include C 3-5 C 4-5 and C 5-6 Cycloalkyl groups, etc.; they can be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0087] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including C 1-3 C 1-6 C 1-9 C 3-6 C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12 Similarly, n-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0088] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0089] The structures of the compounds of this invention can be confirmed by conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed by conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After scanning and collecting relevant data, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0090] The solvent used in this invention is commercially available.

[0091] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names.

[0092] Instruction manual illustrations

[0093] Figure 1 Percentage of cerebral infarction. Detailed Implementation

[0094] The present invention will be described in detail below with reference to examples, but this does not imply any adverse limitation on the invention. The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.

[0095] Intermediate A

[0096]

[0097] Synthesis route:

[0098]

[0099] Step 1: Synthesis of compound A-3

[0100] Compound A-2 (0.94 g, 9.14 mmol) was dissolved in N,N-dimethylformamide (30 mL), and potassium tert-butoxide (1.03 g, 9.14 mmol) was added. The reaction mixture was stirred at 20 °C for 0.5 h. Intermediate A-1 (2.50 g, 9.14 mmol) dissolved in N,N-dimethylformamide (30 mL) was added to the reaction mixture, and the mixture was stirred at 20 °C for 12 h. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3), washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20 / 1, petroleum ether / ethyl acetate) to give compound A-3.

[0101] The MS-ESI calculated value is [M+H]. + 296, measured value 296.

[0102] Step 2: Synthesis of Intermediate A

[0103] Under nitrogen protection, zinc chloride (5.81 g, 42.61 mmol) was dissolved in N-methylpyrrolidone (50 mL) at 100 °C. The reaction solution was cooled to 25 °C, and compound A-4 (4.09 g, 28.41 mmol) was added. The reaction solution was stirred at 25 °C for 10 minutes. The mixture was concentrated under reduced pressure, and compound A-3 (2.10 g, 7.10 mmol) and bis(tri-tert-butylphosphine)palladium (0.36 g, 0.71 mmol) were added. The reaction solution was stirred at 140 °C for 1.3 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5 / 1, petroleum ether / ethyl acetate) to give intermediate A.

[0104] The MS-ESI calculated value is [M+H]. + 344, measured value 344.

[0105] Intermediate B

[0106]

[0107] Synthesis route:

[0108]

[0109] Step 1: Synthesis of compound B-3

[0110] The hydrochloride salt of compound B-2 (0.40 g, 2.84 mmol) was dissolved in methanol (7.5 mL), and triethylamine (0.29 g, 2.84 mmol) was added. The reaction mixture was stirred at 25 °C for 15 minutes. After cooling to 0 °C in an ice bath, compound B-1 (0.4 g, 1.90 mmol), 2-methylpyridine-N-methylborane (0.30 g, 2.84 mmol), and acetic acid (1.5 mL) were added to the reaction mixture. The reaction mixture was stirred at 25 °C for 1 hour. Saturated sodium bicarbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (25 mL × 3), washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give compound B-3.

[0111] The MS-ESI calculated value is [M+H]. + 298, measured value 298.

[0112] Step 2: Synthesis of compound B-4

[0113] Compound B-3 (0.30 g, 1.01 mmol) was dissolved in toluene (10 mL), and tributyl(1-ethoxyethylene)tin (0.73 g, 2.01 mmol) and bis(triphenylphosphine)palladium dichloride (0.07 g, 0.1 mmol) were added. The reaction mixture was stirred at 110 °C for 6 hours under nitrogen protection. A saturated potassium fluoride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (25 mL × 3), washed with saturated brine (25 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was directly proceeded to the next step (1 / 1, petroleum ether / ethyl acetate) to obtain compound B-4.

[0114] Step 3: Synthesis of Intermediate B

[0115] Compound B-4 (0.20 g, 0.69 mmol) was dissolved in acetone (11 mL), and concentrated hydrochloric acid (0.44 g, 12 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. Saturated sodium bicarbonate solution (25 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated brine (25 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (0 / 1, petroleum ether / ethyl acetate) to give intermediate B.

[0116] The MS-ESI calculated value is [M+H]. + 262, measured value 262.

[0117] Intermediate C

[0118]

[0119] Synthesis route:

[0120]

[0121] Step 1: Synthesis of compound C-2

[0122] The hydrochloride salt of compound C-1 (0.31 g, 2.49 mmol) was dissolved in methanol (7.5 mL), and triethylamine (0.25 g, 2.49 mmol) was added. The reaction mixture was stirred at 25 °C for 15 minutes. After cooling to 0 °C in an ice bath, compound B-1 (0.35 g, 1.66 mmol), 2-methylpyridine-N-methylborane (0.27 g, 2.49 mmol), and acetic acid (1.5 mL) were added to the reaction mixture. The reaction mixture was stirred at 25 °C for 1 hour. A saturated sodium bicarbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (25 mL × 3), washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give compound C-2.

[0123] 1 H NMR (400MHz, CD3OD) δ = 7.33 (s, 1H), 7.25 (d, J = 8.0Hz, 1H), 7.09 (d, J = 8.0Hz, 1H), 3 .73(s,3H),3.66-3.58(m,1H),3.45(s,2H),3.17-3.06(m,2H),2.80-2.68(m,2H).

[0124] Step 2: Synthesis of compound C-3

[0125] Compound C-2 (0.08 g, 0.26 mmol) was dissolved in toluene (10 mL), and tributyl(1-ethoxyethylene)tin (0.19 g, 0.53 mmol) and bis(triphenylphosphine)palladium dichloride (0.02 g, 0.03 mmol) were added. The reaction mixture was stirred at 110 °C for 6 hours under nitrogen protection. A saturated potassium fluoride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (25 mL × 3), washed with saturated brine (25 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was directly used in the next step (1 / 1, petroleum ether / ethyl acetate) to obtain crude compound C-3.

[0126] Step 3: Synthesis of intermediate C

[0127] The crude product of compound C-3 (0.10 g, 0.36 mmol) was dissolved in acetone (11 mL), and concentrated hydrochloric acid (0.44 g, 12 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. Saturated sodium bicarbonate solution (25 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated brine (25 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give intermediate C.

[0128] The MS-ESI calculated value is [M+H]. + 248, measured value 248.

[0129] Intermediate D

[0130]

[0131] Synthesis route:

[0132]

[0133] Step 1: Synthesis of compound D-2

[0134] Compound D-1 (0.50 g, 3.47 mmol) was dissolved in dichloromethane (10 mL), and Dysmartin oxidant (3.24 g, 7.63 mmol) was added. The reaction mixture was stirred at 25 °C for 12 hours. At 0 °C, saturated sodium bicarbonate (20 mL) and water (10 mL) were added to the reaction mixture. The mixture was extracted with dichloromethane (30 mL × 3), washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5 / 1, petroleum ether / ethyl acetate) to give compound D-2.

[0135] Step 2: Synthesis of compound D-4

[0136] Compound D-3 (3.00 g, 14.21 mmol) was dissolved in isopropanol (200 mL), and sodium cyanoborohydride (4.47 g, 71.07 mmol) and ammonium acetate (21.91 g, 284.29 mmol) were added. The reaction mixture was stirred at 25 °C for 1 hour, and then stirred at 80 °C for 11 hours. Water (300 mL) was added to the reaction mixture at 25 °C, and the mixture was extracted with ethyl acetate (100 mL × 4), washed with water (150 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give compound D-4.

[0137] The MS-ESI calculated value is [M-NH2+H]. + 197, measured value 197.

[0138] Step 3: Synthesis of compound D-5

[0139] Compounds D-2 (0.17 g, 1.20 mmol) and D-4 (0.10 g, 0.47 mmol) were dissolved in dichloromethane (10 mL), and sodium borohydride acetate (0.17 g, 0.80 mmol) and acetic acid (0.05 g, 0.80 mmol) were added. The reaction mixture was stirred at 25 °C for 12 hours. The mixture was concentrated under reduced pressure, and saturated sodium bicarbonate was added to the reaction mixture. The mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give compound D-5.

[0140] The MS-ESI calculated value is [M+H]. + 338, measured value 338.

[0141] Step 4: Synthesis of compound D-6

[0142] Compound D-5 (0.09 g, 0.27 mmol) was dissolved in toluene (10 mL), and tributyl(1-ethoxyethylene)tin (0.19 g, 0.53 mmol) and bis(triphenylphosphine)palladium dichloride (0.02 g, 0.03 mmol) were added. The reaction mixture was stirred at 110 °C for 6 hours under nitrogen protection. A saturated potassium fluoride solution (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was directly proceeded to the next step (1 / 1, petroleum ether / ethyl acetate) to obtain crude compound D-6.

[0143] Step 5: Synthesis of intermediate D

[0144] The crude compound D-6 (0.12 g, 0.36 mmol) was dissolved in acetone (11 mL), and concentrated hydrochloric acid (0.44 g, 12 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. Saturated sodium bicarbonate solution (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (40 mL × 3), washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give intermediate D.

[0145] The MS-ESI calculated value is [M+H]. + 302, measured value 302.

[0146] Intermediate E

[0147]

[0148] Synthesis route:

[0149]

[0150] Step 1: Synthesis of compound E-2

[0151] Compound E-1 (1.33 g, 9.70 mmol) was dissolved in acetonitrile (40 mL), and NBS (1.73 g, 9.70 mmol) was added. The reaction solution was reacted at 25 °C for 1 hour. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate) to give compound E-2.

[0152] 1 H NMR (400MHz, CDCl3) δ = 7.60-7.45 (m, 2H).

[0153] Step 2: Synthesis of compound E-3

[0154] Compound E-2 (1.00 g, 4.63 mmol), potassium carbonate (1.92 g, 13.89 mmol), and isopropane iodide (1.57 g, 9.26 mmol) were added to N,N-dimethylformamide (10 mL), and the mixture was reacted at 70 °C for 2 hours. The mixture was cooled to 20 °C, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10 / 1, petroleum ether / ethyl acetate) to give compound E-3.

[0155] 1 H NMR (400MHz, CDCl3) δ = 7.58-7.41 (m, 2H), 4.82-4.61 (m, 1H), 1.42 (d, J = 8.0Hz, 6H).

[0156] Step 3: Synthesis of compound E-4

[0157] Under argon protection, compound E-3 (1.00 g, 3.87 mmol), triethylamine (10 mL), and Pd(dppf)Cl2 (0.57 g, 0.78 mmol) were added to methanol (30 mL) and N,N-dimethylformamide (10 mL). The reaction was stirred at 80 °C under carbon monoxide (50 psi) for 48 hours. After cooling to 20 °C, the mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5 / 1, petroleum ether / ethyl acetate) to give compound E-4.

[0158] Step 4: Synthesis of compound E-5

[0159] Under nitrogen protection, starting material E-4 (0.65 g, 2.74 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C, and lithium borohydride (0.48 g, 21.92 mmol) was added to the reaction solution. The reaction was carried out at 45 °C for 1 hour. Water (0.7 mL) was added, the mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate) to give compound E-5.

[0160] Step 5: Synthesis of compound E-6

[0161] Under nitrogen protection, carbon tetrabromide (0.99 g, 2.98 mmol) and triphenylphosphine (0.69 g, 2.61 mmol) were added to a tetrahydrofuran (10 mL) solution of compound E-5 (0.52 g, 2.49 mmol), and the mixture was stirred at 25 °C for 15 hours. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5 / 1, petroleum ether / ethyl acetate) to give compound E-6.

[0162] 1 H NMR (400MHz, CDCl3) δ = 7.41-7.35 (m, 2H), 4.80-4.69 (m, 1H), 4.42 (s, 2H), 1.42 (d, J = 4.0Hz, 6H).

[0163] Step 6: Synthesis of intermediate E

[0164] Under nitrogen protection, potassium tert-butoxide (0.20 g, 1.76 mmol) was added to a solution of raw material A-2 (0.18 g, 1.76 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 20 °C for 0.5 hours. A solution of intermediate E-6 in N,N-dimethylformamide (2 mL) was added dropwise to the reaction mixture, and the mixture was stirred at 20 °C for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10 / 1, petroleum ether / ethyl acetate) to give compound E.

[0165] The MS-ESI calculated value is [M+H]. + 295, measured value 295.

[0166] intermediate F

[0167]

[0168] Synthesis route:

[0169]

[0170] Step 1: Synthesis of compound F-2

[0171] The hydrochloride salt of compound C-1 (7.73 g, 61.60 mmol) and triethylamine (7.19 g, 71.07 mmol) were dissolved in tetrahydrofuran (100 mL). Tetraisopropyltitanium oxychloride (26.93 g, 94.76 mmol) and compound F-1 (10.00 g, 47.38 mmol) were added, and the reaction mixture was stirred at 65 °C for 12 hours. Methanol (100 mL) and sodium borohydride (3.59 g, 94.76 mmol) were added, and the reaction mixture was stirred at 15 °C for 3 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL × 4), washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give compound F-2.

[0172] The MS-ESI calculated value is [M+H]. + 314, measured value 314.

[0173] Step 2: Synthesis of compound F-3

[0174] Compound F-2 (7.00 g, 22.42 mmol) was dissolved in toluene (100 mL), and tributyl(1-ethoxyethylene)tin (16.19 g, 44.84 mmol) and bis(triphenylphosphine)palladium dichloride (1.57 g, 2.24 mmol) were added. The reaction mixture was stirred at 110 °C for 12 hours under nitrogen protection. A saturated potassium fluoride solution (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL × 3), washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was directly used in the next step (1 / 1, petroleum ether / ethyl acetate) to obtain compound F-3.

[0175] Step 3: Synthesis of intermediate F

[0176] Compound F-3 (5.00 g, 16.48 mmol) was dissolved in acetone (100 mL), and concentrated hydrochloric acid (20 mL, 14.56 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. Saturated sodium bicarbonate solution (150 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 4), washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give intermediate F.

[0177] The MS-ESI calculated value is [M+H]. + 276, measured value 276.

[0178] intermediate G

[0179]

[0180] Synthesis route:

[0181]

[0182] Step 1: Synthesis of compound G-2

[0183] Compound G-1 (4.00 g, 23.51 mmol), isopropane iodoformate (3.40 g, 19.98 mmol), and potassium carbonate (6.50 g, 47.02 mmol) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 25 °C for 15 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 2), washed successively with water (30 mL × 2) and saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate) to give compound G-2.

[0184] MS-ESI calculated value [M+H] + 213, measured value 213.

[0185] 1 H NMR (400MHz, DMSO-d6) δ = 7.81-7.58 (m, 2H), 7.28 (t, J = 8.4Hz, 1H), 4.84–4.72 (m, 1H), 3.82 (s, 3H), 1.31 (d, J = 8.0Hz, 6H).

[0186] Step 2: Synthesis of compound G-3

[0187] Compound G-2 (4.28 g, 20.17 mmol) was dissolved in tetrahydrofuran (50 mL), and lithium borohydride (3.51 g, 161.34 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. The reaction solution was slowly added dropwise to 100 mL of saturated ammonium chloride solution, extracted with ethyl acetate (50 mL × 2), washed successively with water (50 mL × 2) and saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate) to give compound G-3.

[0188] 1H NMR (400MHz, DMSO-d6) δ = 7.14-7.02 (m, 3H), 5.17 (t, J = 5.8Hz, 1H), 4.61–4.51 (m, 1H), 4.41 (d, J = 5.8Hz, 2H), 1.26 (d, J = 8.0Hz, 6H).

[0189] Step 3: Synthesis of compound G-4

[0190] Compound G-3 (3.50 g, 19.00 mmol) was dissolved in tetrahydrofuran (50 mL) at 0 °C, and carbon tetrabromide (7.56 g, 22.80 mmol) and triphenylphosphine (5.23 g, 19.95 mmol) were added. The mixture was stirred at 25 °C for 15 hours. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate) to give compound G-4.

[0191] 1 H NMR (400MHz, DMSO-d6) δ = 7.32-7.26 (m, 1H), 7.23-7.17 (m, 1H), 7.17-7.10 (m, 1H), 4.72-4.60 (m, 3H), 1.27 (d, J = 8.0Hz, 6H).

[0192] Step 4: Synthesis of intermediate G

[0193] Compound A-2 (1.44 g, 13.99 mmol) was dissolved in N,N-dimethylformamide (5 mL) at 25 °C. Potassium tert-butoxide (1.57 g, 13.99 mmol) was added and the mixture was stirred for 40 minutes. Compound G-4 (2.88 g, 11.66 mmol) was then added, and the reaction mixture was stirred for 5 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 2). The extract was washed successively with water (20 mL × 2) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate) to give intermediate G.

[0194] MS-ESI calculated value [M+H] + 270, measured value 270.

[0195] 1 H NMR (400MHz, DMSO-d6) δ = 7.21-7.04 (m, 3H), 4.79 (s, 2H), 4.67-4.53 (m, 1H), 3. 92(q,J=8.0Hz,2H),1.87(s,3H),1.27(d,J=8.0Hz,6H),1.18(t,J=8.0Hz,3H).

[0196] intermediate H

[0197]

[0198] Synthesis route:

[0199]

[0200] Step 1: Synthesis of compound H-2

[0201] Compound H-1 (5.70 g, 21.42 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (3.13 g, 4.28 mmol) were dissolved in methanol (340 mL), triethylamine (114 mL), and N,N-dimethylformamide (114 mL). The reaction system was then replaced three times with carbon monoxide. The reaction solution was heated to 80 °C and stirred for 48 hours under a carbon monoxide atmosphere (50 Psi). The mixture was concentrated under reduced pressure, and extracted with ethyl acetate (150 mL × 2). The extract was washed successively with water (100 mL × 2) and saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate) to give compound H-2.

[0202] 1 H NMR (400MHz, CD3OD) δ = 8.26-8.15 (m, 2H), 7.31-7.20 (m, 1H), 5.11-5.03 (m, 1H), 3.93-3.86 (m, 3H), 2.07-1.69 (m, 8H).

[0203] Step 2: Synthesis of compound H-3

[0204] Compound H-2 (1.70 g, 6.93 mmol) was dissolved in tetrahydrofuran (45 mL) at 25 °C. Lithium borohydride (1.21 g, 55.45 mmol) was added at 0 °C, and the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was slowly added dropwise to a saturated ammonium chloride solution (200 mL), extracted with ethyl acetate (50 mL × 2), washed successively with water (20 mL × 2) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate) to give compound H-3.

[0205] 1H NMR (400MHz, DMSO-d6) δ = 7.63-7.50 (m, 2H), 7.19 (d, J = 8.6Hz, 1H), 5.26 (t, J =5.8Hz, 1H), 4.97 (t, J = 5.6Hz, 1H), 4.43 (d, J = 5.8Hz, 2H), 1.97-1.53 ​​(m, 8H).

[0206] Step 3: Synthesis of compound H-4

[0207] Compound H-3 (1.26 g, 5.80 mmol) was dissolved in tetrahydrofuran (20 mL) at 0 °C, and carbon tetrabromide (2.31 g, 6.96 mmol) and triphenylphosphine (1.60 g, 6.09 mmol) were added. The reaction mixture was stirred at 25 °C for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate) to give compound H-4.

[0208] 1 H NMR (400MHz, DMSO-d6) δ = 7.81 (d, J = 2.0Hz, 1H), 7.72 (dd, J = 2.4, 8.8Hz, 1H), 7.25 (d, J = 8.8Hz, 1H), 5.06-4.96 (m, 1H), 4.70 (s, 2H), 1.99-1.61 (m, 8H).

[0209] Step 4: Synthesis of compound H

[0210] Compound A-2 (477.02 mg, 4.63 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of potassium tert-butoxide (519.09 mg, 4.63 mmol). After stirring for 40 minutes, compound H-4 (1.08 g, 3.85 mmol) was added, and the mixture was stirred at 25 °C for 5 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 1), washed successively with water (20 mL × 2) and saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate) to give intermediate H.

[0211] MS-ESI calculated value [M+H] + 303, measured value 303.

[0212] 1H NMR (400MHz, DMSO-d6) δ = 7.67-7.57 (m, 2H), 7.21 (d, J = 8.8Hz, 1H), 4.98 (m, 1H), 4.82 (s, 2 H), 3.91 (m, 2H), 2.00-1.89 (m, 2H), 1.87 (s, 3H), 1.78-1.55 (m, 6H), 1.17 (t, J = 6.8Hz, 3H).

[0213] Intermediate I

[0214]

[0215] Synthesis route:

[0216]

[0217] Step 1: Synthesis of compound I-2

[0218] Compound I-1 (1.00 g, 5.36 mmol), isopropane iodoformate (774.38 mg, 4.56 mmol), and potassium carbonate (1.48 g, 10.72 mmol) were dissolved in N,N-dimethylformamide (2 mL) and stirred at 25 °C for 18 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 2), washed successively with water (30 mL × 2) and saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate) to give compound I-2.

[0219] MS-ESI calculated value [M+H] + 229, measured value 229.

[0220] 1 H NMR (400MHz, DMSO-d6) δ = 7.94-7.80 (m, 2H), 7.27 (d, J = 8.8Hz, 1H), 4.80 (s, J = 6.0Hz, 1H), 3.82 (s, 3H), 1.32 (d, J = 8.0Hz, 6H).

[0221] Step 2: Synthesis of compound I-3

[0222] Compound I-2 (0.90 g, 3.94 mmol) was dissolved in tetrahydrofuran (10 mL) at 25 °C. Lithium borohydride (0.69 g, 31.49 mmol) was added at 0 °C, and the reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was slowly added dropwise to 100 mL of saturated ammonium chloride solution, extracted with ethyl acetate (50 mL × 2), washed successively with water (50 mL × 2) and saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate) to give compound I-3.

[0223] 1 H NMR (400MHz, DMSO-d6) δ = 7.34 (d, J = 2.0Hz, 1H), 7.22-7.16 (m, 1H), 7.09 (d, J = 8.6Hz, 1H) ,5.19(t,J=5.8Hz,1H),4.66-4.55(m,1H),4.41(d,J=5.8Hz,2H),1.27(d,J=8.0Hz,6H).

[0224] Step 3: Synthesis of compound I-4

[0225] Compound I-3 (0.61 g, 3.04 mmol) was dissolved in tetrahydrofuran (10 mL) at 0 °C, and carbon tetrabromide (1.21 g, 3.65 mmol) and triphenylphosphine (837.20 mg, 3.19 mmol) were added. The reaction mixture was stirred at 25 °C for 15 hours. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate) to give compound I-4.

[0226] 1 H NMR (400MHz, DMSO-d6) δ = 7.51 (d, J = 2.4Hz, 1H), 7.35 (dd, J = 2.0, 8.6Hz, 1H), 7.12 (d, J = 8.6Hz, 1H), 4.73-4.60 (m, 3H), 1.28 (d, J = 8.0Hz, 6H).

[0227] Step 4: Synthesis of Intermediate I

[0228] Compound A-2 (0.31 g, 3.01 mmol) was dissolved in N,N-dimethylformamide (5 mL), and potassium tert-butoxide (0.34 g, 3.01 mmol) was added. After stirring for 40 minutes, compound I-4 (0.66 g, 2.50 mmol) was added, and the mixture was stirred at 25 °C for 5 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 2). The mixture was washed successively with water (10 mL × 2) and saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate) to give intermediate I.

[0229] 1 H NMR (400MHz, DMSO-d6) δ = 7.38 (d, J = 2.0Hz, 1H), 7.25 (dd, J = 2.0, 8.4Hz, 1H), 7.12 (d, J = 8.6Hz, 1H), 4.79 ( s, 2H), 4.69-4.60 (m, 1H), 3.97-3.88 (m, 2H), 1.89-1.82 (m, 3H), 1.28 (d, J = 6.0Hz, 6H), 1.22-1.14 (m, 3H).

[0230] MS-ESI calculated value [M+H] + 286, measured value 286.

[0231] Intermediate J

[0232]

[0233] Synthesis route:

[0234]

[0235] Step 1: Synthesis of compound J-2

[0236] Compound J-1 (5.00 g, 25.12 mmol), silver carbonate (20.78 g, 75.37 mmol), and isopropane iodide (8.54 g, 50.25 mmol) were added to toluene (50 mL). The reaction mixture was stirred at 50 °C for 1 hour. After cooling to 20 °C, the mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10 / 1, petroleum ether / ethyl acetate) to give compound J-2.

[0237] 1 H NMR (400MHz, CDCl3) δ = 8.28 (d, J = 2.4Hz, 1H), 7.86 (d, J = 2.4Hz, 1H), 5.35-5.22 (m, 1H), 1.32 (d, J = 6.4Hz, 6H).

[0238] Step 2: Synthesis of compound J-3

[0239] Compound J-2 (5.00 g, 20.74 mmol), triethylamine (100 mL), and Pd(dppf)Cl2 (3.04 g, 4.15 mmol) were added to methanol (300 mL) and N,N-dimethylformamide (100 mL). The reaction was stirred at 80 °C under carbon monoxide (50 psi) for 48 hours. The reaction solution was cooled to 20 °C, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5 / 1, petroleum ether / ethyl acetate) to give compound J-3.

[0240] 1 H NMR (400MHz, CDCl3) δ = 8.95 (d, J = 2.0Hz, 1H), 8.45 (d, J = 2.5Hz, 1H), 5.56-5.47 (m, 1H), 3.94 (s, 3H), 1.43 (d, J = 8.0Hz, 6H).

[0241] Step 3: Synthesis of compound J-4

[0242] Under nitrogen protection, compound J-3 (1.00 g, 4.54 mmol) was dissolved in tetrahydrofuran (15 mL), and lithium aluminum hydride (1.72 g, 45.41 mmol) was added at -40 °C. The mixture was stirred at -40 °C for 2 hours. Water (1 mL) was added, the mixture was filtered, and the solution was concentrated under reduced pressure to obtain crude compound J-4.

[0243] 1 H NMR (400MHz, CDCl3) δ = 8.32 (d, J = 2.5Hz, 1H), 7.91 (d, J = 2.5Hz, 1H), 5.57-5.37 (m, 1H), 4.43 (s, 2H), 3.94 (s, 1H), 1.41 (d, J = 6.4Hz, 6H).

[0244] Step 4: Synthesis of compound J-5

[0245] Under nitrogen protection, carbon tetrabromide (2.07 g, 6.24 mmol) and triphenylphosphine (1.43 g, 5.46 mmol) were added to a solution of crude compound J-4 (1.00 g, 5.20 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at 25 °C for 15 hours. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (10 / 1, petroleum ether / ethyl acetate) to give compound J-5.

[0246] 1H NMR (400MHz, CDCl3) δ = 8.25 (d, J = 2.4Hz, 1H), 7.83 (d, J = 2.4Hz, 1H), 5.38-5.15 (m, 1H), 4.35 (s, 2H), 1.42-1.40 (m, 6H).

[0247] Step 5: Synthesis of intermediate J

[0248] Under nitrogen protection, potassium tert-butoxide (0.24 g, 2.16 mmol) was added to a solution of compound A-2 (0.22 g, 2.16 mmol) and N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 20 °C for 0.5 hours. Then, N,N-dimethylformamide (5 mL) of compound J-5 was added dropwise to the reaction mixture, and the reaction was carried out at 20 °C for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3), washed with saturated brine (50 mL) and water (50 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10 / 1, petroleum ether / ethyl acetate) to give intermediate J. MS-ESI calculated value [M+H] + 278, measured value 278.

[0249] intermediate K

[0250]

[0251] Synthesis route:

[0252]

[0253] Step 1: Synthesis of compound K-2

[0254] Under nitrogen protection, compound K-1 (1.00 g, 4.87 mmol) was dissolved in tetrahydrofuran (10 mL), followed by the addition of boron trifluoride diethyl ether solution (0.69 g, 4.87 mmol) and borane tetrahydrofuran solution (9.75 mL, 9.75 mmol), and stirred at 20 °C for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3), washed successively with saturated brine (50 mL) and water (50 mL), filtered, and concentrated under reduced pressure to obtain crude compound K-2.

[0255] Step 2: Synthesis of compound K-3

[0256] Under nitrogen protection, carbon tetrabromide (2.08 g, 6.24 mmol) and triphenylphosphine (1.44 g, 5.46 mmol) were added to a solution of crude compound K-2 (1.0 g, 5.23 mmol) in tetrahydrofuran (10 mL). The reaction mixture was reacted at 25 °C for 15 hours. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (5 / 1, petroleum ether / ethyl acetate) to obtain crude compound K-3.

[0257] 1 H NMR (400MHz, CDCl3) δ = 7.58 (d, J = 2.0Hz, 1H), 7.55-7.51 (m, 1H), 6.94 (d, J = 9.0Hz, 1H), 4.71-4.62 (m, 1H), 4.44 (s, 2H), 1.42 (d, J = 4.0Hz, 6H).

[0258] Step 3: Synthesis of intermediate K

[0259] Under nitrogen protection, potassium tert-butoxide (0.97 g, 8.66 mmol) was added to a solution of compound A-2 (0.89 g, 8.66 mmol) in N,N-dimethylformamide (20 mL), and the reaction mixture was incubated at 20 °C for 0.5 h. Then, a solution of crude intermediate K-3 (2.00 g, 7.87 mmol) in N,N-dimethylformamide (10 mL) was added dropwise to the reaction mixture, and the reaction mixture was incubated at 20 °C for 2 h. Water (50 mL) was added to the reaction mixture, followed by ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL) and water (50 mL), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10 / 1, petroleum ether / ethyl acetate) to obtain intermediate K.

[0260] 1 H NMR (400MHz, CDCl3) δ = 7.55 (d, J = 2.0Hz, 1H), 7.48 (dd, J = 2.0, 8.0Hz, 1H), 6.92 (d, J = 12.0Hz, 1H), 4.82 (s ,2H),4.67-4.61(m,1H),3.97(q,J=8.0Hz,2H),1.92(s,3H),1.40(d,J=8.0Hz,6H),1.25(t,J=8.0Hz,3H).

[0261] intermediate L

[0262]

[0263] Synthesis route:

[0264]

[0265] Step 1: Synthesis of compound L-2

[0266] Compound L-1 (4.00 g, 18.17 mmol), potassium carbonate (7.53 g, 54.51 mmol), and isopropane iodide (6.18 g, 36.34 mmol) were added to N,N-dimethylformamide (40 mL). The reaction mixture was stirred at 70 °C for 2 hours. After cooling to 20 °C, the mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10 / 1, petroleum ether / ethyl acetate) to give compound L-2.

[0267] 1 H NMR (400MHz, CDCl3) δ = 8.25 (d, J = 2.0Hz, 1H), 8.15 (dd, J = 2.0, 8.0Hz, 1H), 7.01 (d, J = 12.0Hz, 1H), 4.77-4.69 (m, 1H), 3.91 (s, 3H), 1.40 (d, J = 8.0Hz, 6H).

[0268] Step 2: Synthesis of compound L-3

[0269] Under nitrogen protection, compound L-2 (1.00 g, 3.81 mmol) was dissolved in tetrahydrofuran (20 mL), and lithium borohydride (0.66 g, 30.51 mmol) was added at 20 °C. The reaction was carried out at 50 °C for 14 hours. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate) to give compound L-3.

[0270] 1 H NMR (400MHz, CDCl3) δ = 7.56 (d, J = 1.6Hz, 1H), 7.46 (dd, J = 2.0, 8.0Hz, 1H), 6.99 (d, J = 8.0Hz, 1H), 4.69-4.61 (m, 3H), 1.34 (br s, 1H), 1.36 (d, J = 6.0Hz, 6H).

[0271] Step 3: Synthesis of compound L-4

[0272] Under nitrogen protection, carbon tetrabromide (1.53 g, 4.61 mmol) and triphenylphosphine (1.06 g, 4.03 mmol) were added to a solution of starting material L-3 (0.90 g, 3.46 mmol) in tetrahydrofuran (15 mL). The reaction mixture was reacted at 25 °C for 15 hours. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (5 / 1, petroleum ether / ethyl acetate) to give compound L-4.

[0273] Step 4: Synthesis of intermediate L

[0274] Under nitrogen protection, potassium tert-butoxide (0.23 g, 2.02 mmol) was added to a solution of compound A-2 (0.21 g, 2.02 mmol) in N,N-dimethylformamide (5 mL), and the reaction mixture was stirred at 20 °C for 0.5 h. Then, a solution of compound L-4 (0.50 g, 1.68 mmol, 1 eq) in N,N-dimethylformamide (1 mL) was added dropwise to the reaction mixture, and the reaction mixture was stirred at 20 °C for 2 h. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3), washed successively with saturated brine (50 mL) and water (50 mL), concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10 / 1, petroleum ether / ethyl acetate) to give intermediate L.

[0275] MS-ESI calculated value [M+H] + 320, measured value 320.

[0276] intermediate M

[0277]

[0278] Synthesis route:

[0279]

[0280] Step 1: Synthesis of compound M-1

[0281] Compound F-1 (5.50 g, 26.06 mmol) and the hydrochloride salt of compound B-2 (5.20 g, 33.88 mmol) were dissolved in tetrahydrofuran (60 mL). Isopropyl titanate (14.81 g, 52.12 mmol) and triethylamine (3.96 g, 39.09 mmol) were added to the reaction solution. The reaction was carried out at 65 °C for 12 hours. After the reaction was completed, the solution was cooled to 20 °C, and methanol (60 mL) and sodium borohydride (1.97 g, 52.12 mmol) were added to the reaction solution. The reaction was carried out at 15 °C for 3 hours. Water (150 mL) was added to the reaction solution, and the solution was extracted with ethyl acetate (250 mL × 3), washed with saturated brine (250 mL) and water (250 mL), and concentrated under reduced pressure to obtain compound M-1.

[0282] MS-ESI calculated value [M+H] + 328, measured value 328.

[0283] Step 2: Synthesis of compound M-2

[0284] Under nitrogen protection, formaldehyde (0.12 g, 1.53 mmol) was added to a formic acid (10 mL) solution of compound M-1 (0.1 g, 0.31 mmol). The reaction solution was reacted at 60 °C for 15 hours. The crude product of compound M-2 was obtained by concentration under reduced pressure.

[0285] MS-ESI calculated value [M+H] + 342, measured value 342.

[0286] Step 3: Synthesis of compound M-3

[0287] Under nitrogen protection, crude compound M-2 (0.86 g, 2.53 mmol) was dissolved in toluene (10 mL), and tributyl(1-ethoxyvinyl)tin (1.72 g, 45.41 mmol) and dichlorobis(triphenylphosphine)palladium (0.18 g, 0.25 mmol) were added. The mixture was reacted at 110 °C for 14 hours. The solution was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give compound M-3.

[0288] 1 H NMR(400MHz, CDCl3)δ=7.46-7.39(m,2H),7.23-7.19(m,1H),5.01-4.92(m,1H),4 .54(d,J=2.0Hz,1H),4.35(t,J=8.0Hz,1H),4.10(d,J=2.4Hz,1H),3.86(q,J=8.0H z,2H),2.97-2.82(m,1H),2.79-2.65(m,3H),2.49-2.36(m,2H),2.19-2.07(m,3H ), 2.07-1.90 (m, 2H), 1.62-1.55 (m, 1H), 1.37 (t, J = 8.0Hz, 2H), 1.21-1.15 (m, 6H).

[0289] Step 4: Synthesis of intermediate M

[0290] Concentrated hydrochloric acid (1.2 mL, 14.40 mmol) was added to a 6 mL acetone solution of compound M-3 (0.20 g, 0.60 mmol), and the reaction solution was reacted at 25 °C for 2 hours. Water (15 mL) was added to the reaction solution, and the pH was adjusted to 8 with sodium bicarbonate solution. The mixture was extracted with ethyl acetate (20 mL × 3), washed with saturated brine (20 mL) and water (20 mL), and concentrated under reduced pressure to obtain intermediate M.

[0291] MS-ESI calculated value [M+H] + 304, measured value 304.

[0292] intermediate N

[0293]

[0294] Synthesis route:

[0295]

[0296] Step 1: Synthesis of compound N-3

[0297] Compound N-1 (3.50 g, 15.9 mmol) was dissolved in N,N-dimethylformamide (35 mL). Potassium carbonate (6.59 g, 47.7 mmol) and compound N-2 (4.36 g, 31.8 mmol) were added to the reaction mixture, and the reaction mixture was reacted at 85 °C for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0, V / V) to obtain compound N-3.

[0298] MS-ESI calculated value [M+H] + 277, measured value 277.

[0299] Step 2: Synthesis of compound N-4

[0300] Lithium aluminum hydride (717 mg, 18.9 mmol) was dissolved in tetrahydrofuran (30 mL). Under nitrogen protection at 0 °C, a tetrahydrofuran solution (15 mL) of compound N-3 (3.48 g, 12.6 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at 0–10 °C for 1 hour. Water (0.72 mL), 10% sodium hydroxide aqueous solution (0.72 mL), and water (2.16 mL) were added sequentially to the reaction mixture. The reaction mixture was stirred at 15 °C for 0.5 hours. The suspension was filtered, the filter cake was washed with ethyl acetate (50 mL × 1), the organic phase was washed with saturated brine (40 mL × 1), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain compound N-4.

[0301] 1 H NMR (400MHz, CD3Cl) δ = 7.57 (s, 1H), 7.46 (br d,J=8.4Hz,1H),6.96(d,J=8.4Hz,1H),4.65(s,2H),3.81(d,J=6.4Hz,2H),2.22-2.07(m,1H),1.05(d,J=6.8Hz,6H).

[0302] Step 3: Synthesis of compound N-5

[0303] Compound N-4 (3.11 g, 12.5 mmol) was dissolved in tetrahydrofuran (30 mL), and carbon tetrabromide (5.40 g, 16.3 mmol) and triphenylphosphine (3.61 g, 13.8 mmol) were added. The mixture was stirred at 25 °C for 12 hours. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 40 / 1, V / V) to give compound N-5.

[0304] 1 H NMR (400MHz, CD3Cl) δ = 7.60 (d, J = 2.1Hz, 1H), 7.53-7.48 (m, 1H), 6.94 (d, J = 8.5Hz, 1H), 4.49 (s, 2H), 3.82 (d, J = 6.3Hz, 2H), 2.21-2.09 (m, 1H), 1.05 (d, J = 6.8Hz, 6H).

[0305] Step 4: Synthesis of intermediate N

[0306] Compound A-2 (1.54 g, 14.0 mmol) was dissolved in tetrahydrofuran (20 mL), and a tetrahydrofuran solution of potassium tert-butoxide (1 M, 30.0 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0–5 °C for 1 hour. A tetrahydrofuran solution of compound N-5 (4.65 g, 15.0 mmol) (20 mL) was then added dropwise, and the reaction mixture was stirred at 0–20 °C for 1 hour. A saturated ammonium chloride aqueous solution (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0–20 / 1, V / V) to give intermediate N.

[0307] MS-ESI calculated value [M+H] + 334, measured value 334.

[0308] Intermediate O

[0309]

[0310] Synthesis route:

[0311]

[0312] Step 1: Synthesis of compound O-3

[0313] Compound O-1 (5.00 g, 22.7 mmol) was dissolved in N,N-dimethylformamide (50 mL). Potassium carbonate (12.6 g, 90.9 mmol) and bromoethylcyclopropane O-2 (1.57 g, 9.26 mmol) were added to the reaction mixture, and the reaction mixture was reacted at 70 °C for 12 hours. Water (80 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate (10 g), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 40 / 1, V / V) to obtain the crude product of compound O-3.

[0314] MS-ESI calculated value [M+H] + 275, measured value 275.

[0315] Step 2: Synthesis of compound O-4

[0316] Under nitrogen protection, lithium aluminum hydride (1.39 g, 36.7 mmol) was dissolved in tetrahydrofuran (60 mL). A tetrahydrofuran (30 mL) solution of crude compound O-3 (6.7 g, 24.43 mmol) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at 10 °C for 1 hour. Water (1.39 mL), 10% sodium hydroxide aqueous solution (1.39 mL), and water (4.17 mL) were added sequentially to the reaction mixture. The reaction mixture was stirred at 10 °C for 0.5 hours. The suspension was filtered, the filter cake was washed with ethyl acetate (30 mL × 2), the organic phase was washed with saturated brine (60 mL × 1), and the organic phase was dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated under reduced pressure to give compound O-4.

[0317] 1 H NMR (400MHz, CD3Cl) δ = 7.55 (s, 1H), 7.44 (d, J = 8.0Hz, 1H), 6.95 (br d,J=8.4Hz,1H),4.62(s,2H),3.93(d,J=6.4Hz,2H),1.30-1.25(m,1H),0.67-0.59(m,2H),0.44-0.35(m,2H).

[0318] Step 3: Synthesis of compound O-5

[0319] Compound O-4 (5.37 g, 21.8 mmol) was dissolved in tetrahydrofuran (50 mL). Carbon tetrabromide (8.68 g, 26.2 mmol) and triphenylphosphine (6.01 g, 22.9 mmol) were added to the system, and the mixture was stirred at 25 °C for 12 hours. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 40 / 1, V / V) to obtain compound O-5.

[0320] 1 H NMR (400MHz, CD3Cl) δ = 7.62-7.58 (m, 1H), 7.53-7.47 (m, 1H), 6.94 (d, J = 8.6Hz, 1H), 4.49 (s,2H),3.95(d,J=6.6Hz,2H),1.31-1.26(m,1H),0.67-0.61(m,2H),0.43-0.37(m,2H).

[0321] Step 4: Synthesis of intermediate O

[0322] Compound A-2 (1.40 g, 13.6 mmol) was dissolved in tetrahydrofuran (30 mL), and a tetrahydrofuran solution of potassium tert-butoxide (1 M, 27.17 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, and then a tetrahydrofuran solution of compound O-5 (4.20 g, 13.6 mmol) (30 mL) was added dropwise. The mixture was stirred at 15 °C for 12 hours. A saturated ammonium chloride aqueous solution (50 mL) was added to the system, and the mixture was extracted with ethyl acetate (50 mL × 2). The extract was dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 40 / 1, V / V) to give intermediate O.

[0323] MS-ESI calculated value [M+H] + 332, measured value 332.

[0324] intermediate P

[0325]

[0326] Synthesis route:

[0327]

[0328] Step 1: Synthesis of compound P-3

[0329] Compound P-1 (1 g, 4.54 mmol), compound P-2 (787.69 mg, 5.45 mmol), and potassium carbonate (941.69 mg, 6.81 mmol) were added to N,N-dimethylformamide (10 mL), and the mixture was heated to 65 °C for 14 hours. After cooling the reaction solution to room temperature, water (10 mL) was added, and the reaction solution was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound P-3.

[0330] MS-ESI calculated value [M+H] + 271, measured value 271.

[0331] Step 2: Synthesis of compound P-4

[0332] Under nitrogen protection, lithium aluminum hydride (168.59 mg, 4.44 mmol) was dissolved in 10 mL of tetrahydrofuran at 0 °C. Compound P-3 (800 mg, 2.96 mmol) in tetrahydrofuran (10 mL) was added dropwise to the reaction system, and the reaction was carried out at 0-25 °C for 1 hour. The reaction was quenched by adding water (0.1 mL), a 10% sodium hydroxide aqueous solution (0.1 mL), and water (0.3 mL) sequentially. The mixture was stirred at 25 °C for 0.5 hours, then anhydrous sodium sulfate was added. The mixture was then filtered and concentrated to obtain compound P-4.

[0333] 1 H NMR (400MHz, CD3Cl) δ=7.70-7.53(m,1H),7.47(d,J=8.6Hz,1H),7.27-7.17(m,1H),6.66-6.23(m,1H),4.65(s,2H),2.04(s,1H).

[0334] Step 3: Synthesis of compound P-5

[0335] Compound P-4 (415 mg, 1.71 mmol) was dissolved in tetrahydrofuran (4 mL), and carbon tetrabromide (682.04 mg, 2.06 mmol) and triphenylphosphine (472 mg, 1.8 mmol) were added. The mixture was then stirred at 25 °C for 12 hours. Compound P-5 was obtained by directly concentrating the reaction solution under reduced pressure. 1 H NMR (400MHz, CD3Cl) δ = 7.62 (d, J = 2.1Hz, 1H), 7.55-7.48 (m, 1H), 7.28-7.16 (m, 1H), 6.67-6.23 (m, 1H), 4.48-4.29 (m, 2H).

[0336] Step 4: Synthesis of intermediate P

[0337] Compound A-2 (150.77 mg, 1.46 mmol) was dissolved in tetrahydrofuran (2 mL), and potassium tert-butoxide (328.13 mg, 2.92 mmol) was added at 0 °C. The mixture was then dissolved in tetrahydrofuran (2 mL) at 0-5 °C and reacted for 1 hour. A solution of compound P-5 (446 mg, 1.46 mmol) in tetrahydrofuran (2 mL) was then slowly added dropwise to the reaction mixture, and the reaction was carried out at 0-20 °C for 12 hours. After the reaction was completed, 10 mL of ammonium chloride aqueous solution was added for quenching, followed by extraction with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate P.

[0338] MS-ESI calculated value [M+H] + 328, measured value 328.

[0339] intermediate Q

[0340]

[0341] Synthesis route:

[0342]

[0343] Step 1: Synthesis of compound Q-3

[0344] Compound Q-1 (5.50 g, 25.0 mmol) was dissolved in N,N-dimethylformamide (55 mL). Potassium carbonate (13.0 g, 93.9 mmol) and bromocyclopentane Q-2 (10.5 g, 70.4 mmol) were added to the reaction mixture, and the reaction mixture was reacted at 70 °C for 2 hours. The solvent was removed under reduced pressure, and water (100 mL) was added to the residue. The mixture was extracted with ethyl acetate (100 mL × 3), and the organic phase was washed with saturated sodium chloride (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound Q-3.

[0345] 1 H NMR (400MHz, CD3Cl) δ = 8.25 (d, J = 2.1Hz, 1H), 8.19-8.12 (m, 1H), 7.01 (d, J = 8.7 Hz,1H),4.98-4.91(m,1H),3.91(s,3H),1.99-1.77(m,6H),1.74-1.60(m,2H).

[0346] Step 2: Synthesis of compound Q-4

[0347] Lithium aluminum hydride (1.52 g, 40.0 mmol) was dissolved in tetrahydrofuran (75 mL). Under nitrogen protection at 0 °C, a tetrahydrofuran solution (25 mL) of compound Q-3 (7.70 g, 26.7 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at 0–25 °C for 1 hour. Batches of intermediate Q-3 (700 mg) were combined, and water (1.5 mL), 15% sodium hydroxide aqueous solution (1.5 mL), and water (4.6 mL) were added dropwise to the reaction mixture sequentially. The reaction mixture was stirred at 15 °C for 0.5 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (50 mL). The organic phase was washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure after filtration to obtain compound Q-4.

[0348] 1H NMR (400MHz, CD3Cl) δ = 7.56 (d, J = 1.8Hz, 1H), 7.49-7.42 (m, 1H), 6.98 (d, J = 8.6Hz, 1H), 4 .92-4.84(m,1H),4.64(s,2H),1.94-1.86(m,4H),1.85-1.82(m,2H),1.70-1.59(m,2H).

[0349] Step 3: Synthesis of compound Q-5

[0350] Compound Q-4 (7.00 g, 26.9 mmol) was dissolved in tetrahydrofuran (80 mL), and carbon tetrabromide (10.7 g, 32.3 mmol) and triphenylphosphine (7.41 g, 28.2 mmol) were added. The mixture was stirred at 25 °C for 12 hours. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 1 to 10 / 1, V / V) to give compound Q-5.

[0351] 1 H NMR (400MHz, CD3Cl) δ = 7.58 (d, J = 2.0Hz, 1H), 7.52-7.45 (m, 1H), 6.95 (d, J = 8.6 Hz,1H),4.93-4.83(m,1H),4.49(s,2H),1.96-1.77(m,6H),1.71-1.59(m,2H).

[0352] Step 4: Synthesis of intermediate Q

[0353] Compound A-2 (2.13 g, 20.6 mmol) was dissolved in tetrahydrofuran (70 mL), and potassium tert-butoxide (4.63 g, 41.3 mL) was added in portions at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, and then a tetrahydrofuran solution of compound 5 (6.67 g, 20.6 mmol) (70 mL) was added dropwise. The reaction mixture was stirred at 0–20 °C for 12 hours. A saturated ammonium chloride aqueous solution (105 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 1–10 / 1, V / V) to give intermediate Q.

[0354] MS-ESI calculated value [M+H] + 346, measured value 346.

[0355] intermediate R

[0356]

[0357] Synthesis route:

[0358]

[0359] Step 1: Synthesis of compound R-2

[0360] Compound R-1 (8.00 g, 35.5 mmol) was dissolved in isopropanol (50 mL). Sodium cyanoborocyanate (11.2 g, 178 mmol) and ammonium acetate (54.8 g, 711 mmol) were added to the reaction solution, and the mixture was stirred at 15 °C for 4 hours, followed by stirring at 90 °C for 12 hours. The reaction solution was cooled to room temperature and poured into cold water (500 mL). The pH was adjusted to 9 with an aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane (200 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound R-2.

[0361] Step 2: Synthesis of R-4 formate

[0362] Compound R-2 (8.4 g, 29.8 mmol), compound R-3 (4.85 g, 41.8 mmol), and glacial acetic acid (1.71 mL, 29.8 mmol) were dissolved in dichloromethane (100 mL), and the reaction mixture was stirred at 25 °C for 1 hour. Sodium borohydride acetate (19.0 g, 89.5 mmol) was then added to the reaction mixture, and the mixture was stirred at 30 °C for 12 hours. Water (150 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate (30 g), filtered, and concentrated under reduced pressure. The crude product was then separated by high performance liquid chromatography (HPLC) (column: Phenomenex lμna C18 250 × 50 mm × 10 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 15%-45%, 15 min) to obtain the formate salt of compound R-4.

[0363] MS-ESI calculated value [M+H] + 326 and 328, actual measured values ​​are 326 and 328.

[0364] Step 3: Synthesis of compound R-5

[0365] The formate of compound R-4 (1.67 g, 3.77 mmol) was dissolved in dichloromethane (25 mL). Triethylamine (2.10 mL, 15.1 mmol) and di-tert-butyl dicarbonate (1.23 g, 5.66 mmol) were added to the reaction mixture, and the reaction mixture was stirred at 25 °C for 12 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate (10 g), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 50 / 1 to 20 / 1, V / V) to give compound R-5.

[0366] MS-ESI calculated value [M+H] + 426 and 428, actual measured values ​​are 426 and 428.

[0367] Step 4: Synthesis of compound R-7

[0368] Compound R-5 (940 mg, 2.20 mmol), bis(triphenylphosphine)palladium dichloride (155 mg, 220 μmol), and compound R-6 (5.43 mmol, 1.83 mL) were dissolved in toluene (15 mL). The gas was purged three times with nitrogen, and the reaction mixture was stirred at 110 °C under nitrogen protection for 6 hours. At 20 °C, saturated potassium fluoride aqueous solution (50 mL) was added to the reaction mixture, and the reaction mixture was stirred for 1 hour. The reaction mixture was filtered and extracted with ethyl acetate (40 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound R-7.

[0369] MS-ESI calculated value [M+H] + 418, measured value 418.

[0370] Step 5: Synthesis of intermediate R

[0371] The crude compound R-7 (1.80 g, 4.31 mmol) was dissolved in acetone (30 mL), and hydrochloric acid (1 M, 6.47 mL) was added to the reaction mixture. The reaction mixture was stirred at 15 °C for 10 minutes. Saturated sodium bicarbonate aqueous solution (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (40 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1–5 / 1, V / V) to give intermediate R.

[0372] MS-ESI calculated value [M+Na] + 412, measured value 412.

[0373] intermediate S

[0374]

[0375] Synthesis route:

[0376]

[0377] Step 1: Synthesis of compound S-3

[0378] Compound S-2 (2.47 g, 14.9 mol) was dissolved in dichloromethane (20 mL). Triethylamine (2.08 mL, 14.9 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 25 °C for 0.5 h. Compound D-3 (3.00 g, 14.2 mmol) and acetic acid (3.25 mL, 56.9 mmol) were added, and the reaction mixture was stirred at 25 °C for 0.5 h. Sodium borohydride acetate (7.53 g, 35.5 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 25 °C for 12 h. Saturated sodium bicarbonate aqueous solution (100 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1 to 2 / 1, V / V) to obtain compound S-3.

[0379] MS-ESI calculated value [M+H] + 324 and 326, actual measured values ​​are 324 and 326.

[0380] 1 H NMR (400MHz, CD3Cl) δ = 7.38 (s, 1H), 7.30-7.25 (m, 1H), 7.13 (d, J = 8.0Hz, 1H), 4.19-4.13(m,2H),3.88-3.80(m,1H),3.64-3.57(m,1H),3.56-3.49(m,1H),3 .46(t,J=7.2Hz,1H),3.41-3.35(m,1H),3.35-3.27(m,1H),3.10-2.98(m,1H) ,2.84-2.73(m,1H),2.16-2.07(m,1H),1.98-1.88(m,1H),1.29-1.26(m,3H).

[0381] Step 2: Synthesis of compound S-5

[0382] Compound S-3 (1.50 g, 4.63 mmol), bis(triphenylphosphine)palladium dichloride (325 mg, 463 μmol), and compound R-6 (9.25 mmol, 3.12 mL) were dissolved in toluene (20 mL). The mixture was purged three times with nitrogen, and the reaction mixture was stirred at 110 °C under nitrogen protection for 6 hours. A saturated aqueous solution of potassium fluoride (50 mL) was added to the reaction mixture at 20 °C. The reaction mixture was filtered and extracted with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate (10 g), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1 to 3 / 1, V / V) to obtain compound S-5.

[0383] MS-ESI calculated value [M+H] + 316, measured value 316.

[0384] Step 3: Synthesis of intermediate S

[0385] Compound S-5 (250 mg, 793 μmol) was dissolved in acetone (40 mL). Hydrochloric acid (12 M, 2.64 mL) was added to the reaction mixture, and the reaction mixture was stirred at 20 °C for 1 hour. Saturated sodium bicarbonate aqueous solution (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin-layer chromatography (petroleum ether / ethyl acetate, 1 / 1, V / V) to obtain intermediate S.

[0386] MS-ESI calculated value [M+H] + 288, measured value 288.

[0387] 1 H NMR (400MHz, CD3Cl) δ = 7.85 (br d, J = 4.6Hz, 2H), 7.38 (br d, J = 7.7Hz, 1H), 4.00 (br s, 1H), 3.74-3.61 (m, 2H), 3.57 (br d, J = 6.7Hz, 1H), 3.46 (br d,J=7.2Hz,1H),3.41-3.33(m,1H),3.19-3.04(m,2H),2.93-2.81(m,2H ),2.59(s,3H),2.23-2.14(m,1H),2.02-1.98(m,1H),1.30-1.27(m,3H).

[0388] intermediate T

[0389]

[0390] Step 1: Synthesis of compound T-2

[0391] Compound D-3 (5.00 g, 23.69 mmol) was dissolved in methanol (75 mL), and ammonium formate (15 g, 237.88 mmol) was added. After stirring at 25 °C for 1 hour, sodium cyanoborohydride (4.5 g, 71.61 mmol) was added to the system, and the temperature was raised to 60 °C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure to remove some of the solvent, and water (20 mL) was added to the system. The mixture was extracted with dichloromethane (50 mL × 3), and the combined organic phases were washed with water (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the residue obtained from the reduced pressure concentration was added with ethyl acetate solution (3 mL, 4 M) and stirred at 30 °C for 0.5 hours. The filtered solid was dissolved in water, and the pH was adjusted to 9 with 5% sodium carbonate aqueous solution. The aqueous phase was extracted with ethyl acetate (150 mL × 3), and the combined organic phases were washed with water (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and directly concentrated under reduced pressure to obtain compound T-2.

[0392] Step 2: Synthesis of compound T-4

[0393] Compounds T-2 (1.37 g, 6.34 mmol) and T-3 (2.16 g, 12.68 mmol) were dissolved in dichloromethane (35 mL). Acetic acid (380.87 mg, 6.34 mmol) was added, and the mixture was stirred at 25 °C for 10 hours. Sodium borohydride acetate (4.03 g, 19.03 mmol) was then added, and the mixture was stirred at 25 °C for 3 hours. A 10% sodium bicarbonate aqueous solution (10 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product of compound T-4.

[0394] The MS-ESI calculated value is [M+H]. + 366 and 368, actual measured values ​​are 366 and 368.

[0395] Step 3: Synthesis of compound T-5

[0396] The crude product of compound T-4 (3.8 g, 10.37 mmol) was dissolved in dichloromethane (120 mL), and triethylamine (3.15 g, 31.12 mmol) and di-tert-butyl dicarbonate (3.40 g, 15.56 mmol) were added. The mixture was stirred at 25 °C for 12 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then separated by silica gel column chromatography (petroleum ether / ethyl acetate, 40 / 1 to 10 / 1, V / V) to obtain compound T-5.

[0397] Step 4: Synthesis of compound T-7

[0398] Compound T-5 (2.3 g, 4.93 mmol) was dissolved in toluene (25 mL) under nitrogen protection. Tributyl(1-ethoxyethylene)tin (5.24 g, 14.51 mmol) and bis(triphenylphosphine)palladium dichloride (0.35 g, 0.49 mmol) were added, and the reaction mixture was stirred at 110 °C for 6 hours. A saturated potassium fluoride aqueous solution (100 mL) was added to the reaction mixture, and the mixture was stirred at 20 °C for 1 hour. The reaction system was filtered, and the filtrate was extracted with ethyl acetate (100 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was the crude product of compound T-7.

[0399] The MS-ESI calculated value is [M+H]. + 458, measured value 458.

[0400] Step 5: Synthesis of intermediate T

[0401] The crude product of compound T-7 (2.52 g, 5.51 mmol) was dissolved in dichloromethane (25 mL), and acetic acid (25 mL, 437.12 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove some of the solvent. A 10% sodium bicarbonate aqueous solution (50 mL) was added, and the mixture was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed successively with water (50 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue obtained was intermediate T.

[0402] The MS-ESI calculated value is [M+H]. + 288, measured value 288.

[0403] intermediate U

[0404]

[0405] Synthesis route:

[0406]

[0407] Step 1: Synthesis of compound U-3

[0408] Compound U-2 (13.2 g, 94.8 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (6.59 mL, 47.4 mmol) was added dropwise. The mixture was stirred at 20 °C for 30 min. Then, compound D-3 (10.0 g, 47.4 mmol) and acetic acid (8.13 mL, 142 mmol) were added to the system, and the mixture was stirred at 20 °C for 30 min. Sodium borohydride acetate (30.1 g, 142 mmol) was added, and the reaction mixture was stirred at 20 °C for 12 h. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate, V / V) to give compound U-3.

[0409] MS-ESI calculated value [M+H] + 298 and 300, actual measured values ​​are 298 and 300.

[0410] Step 2: Synthesis of compound U-4

[0411] Compound U-3 (10.5 g, 35.1 mmol) was dissolved in dichloromethane (100 mL). Di-tert-butyl dicarbonate (9.18 g, 42.1 mmol) and triethylamine (14.6 mL, 105 mmol) were added dropwise to the system, and the mixture was stirred at 25 °C for 8 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 2). The combined organic phases were washed with saturated sodium chloride aqueous solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5 / 1, petroleum ether / ethyl acetate, V / V) to give compound U-4.

[0412] MS-ESI calculated value [M+Na] + 420 and 422, actual measured values ​​are 420 and 422.

[0413] Step 3: Synthesis of intermediate U

[0414] Compound U-4 (2.00 g, 5.02 mmol), vinyl n-butyl ether (1.94 mL, 15.1 mmol), palladium acetate (56.4 mg, 251 μmol), 1,3-bis(diphenylphosphine propane) (207 mg, 502 μmol), and triethylamine (839 μL, 6.03 mmol) were dissolved in 1-butyl-3-methylimidazolium tetrafluoroborate (8 mL). The mixture was purged with nitrogen three times and stirred at 110 °C for 12 hours under nitrogen protection. Water (50 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3 / 1, petroleum ether / ethyl acetate, V / V) to give intermediate U.

[0415] MS-ESI calculated value [M-100+H] + 262, measured value 262.

[0416] intermediate V

[0417]

[0418] Synthesis route:

[0419]

[0420] Step 1: Synthesis of compound V-3

[0421] Compound B-2 (3.97 g, 28.43 mmol), compound D-3 (5 g, 23.69 mmol), and triethylamine (9.89 mL, 71.07 mmol) were dissolved in tetrahydrofuran (50 mL). Tetraisopropyl titanate (13.47 g, 47.38 mmol) was added dropwise, and the mixture was stirred at 65 °C for 12 hours. Then, methanol (10 mL), acetic acid (10 mL), and sodium cyanoborohydride (2.98 g, 47.38 mmol) were added to the system, and the mixture was stirred at 25 °C for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was stirred for 0.5 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride aqueous solution (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then separated and purified by silica gel column chromatography (2 / 1, petroleum ether / ethyl acetate, V / V) to give compound V-3.

[0422] Step 2: Synthesis of compound V-5

[0423] Compound V-3 (2.00 g, 6.13 mmol), bis(triphenylphosphine)palladium dichloride (430 mg, 613 μmol), and compound R-6 (14.5 mmol, 4.91 mL) were dissolved in toluene (20 mL). The mixture was purged three times with nitrogen, and the reaction mixture was stirred at 110 °C under nitrogen protection for 6 hours. A saturated aqueous solution of potassium fluoride (200 mL) was added to the reaction mixture at 20 °C. The reaction mixture was filtered and extracted with ethyl acetate (200 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound V-5.

[0424] MS-ESI calculated value [M+H] + 318, measured value 318.

[0425] Step 3: Synthesis of intermediate V

[0426] Compound V-5 (2.00 g, 6.30 μmol) was dissolved in acetone (40 mL). Hydrochloric acid (1 M, 12.6 mL) was added to the reaction mixture, and the reaction mixture was stirred at 25 °C for 2 hours. Saturated sodium bicarbonate aqueous solution (300 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1 to 2 / 1, V / V) to obtain intermediate V.

[0427] MS-ESI calculated value [M+H] + 290, measured value 290.

[0428] Example 1

[0429]

[0430] Synthesis route:

[0431]

[0432] Step 1: Synthesis of Compound 1-1

[0433] Intermediate A (0.26 g, 0.75 mmol) was dissolved in methanol (10 mL), and hydrogen chloride / ethyl acetate (3.11 mL, 12.44 mmol) was added. The reaction mixture was stirred at 25 °C for 0.5 h. Triethylamine (1.01 g, 9.95 mmol) and intermediate B (0.13 g, 0.50 mmol) were added to the reaction mixture, and the mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10 / 1, dichloromethane / methanol) to give compound 1-1.

[0434] The MS-ESI calculated value is [M+H].+ 517, measured value 517.

[0435] Step 2: Synthesis of trifluoroacetate of compound 1

[0436] Compound 1-1 (0.16 g, 0.31 mmol) was dissolved in tetrahydrofuran (5 mL) and water (1 mL), and lithium hydroxide monohydrate (0.26 g, 6.19 mmol) was added. The reaction solution was stirred at 25 °C for 12 hours. 1 M hydrochloric acid was added to the reaction solution to bring the pH to 4. The reaction solution was concentrated under reduced pressure, and the crude product was separated by preparative high performance liquid chromatography (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: 0.075% trifluoroacetic acid aqueous solution-acetonitrile; gradient: acetonitrile 49%-79%, 8 min) to obtain the trifluoroacetate of compound 1.

[0437] The MS-ESI calculated value is [M+H]. + 503, measured value 503.

[0438] 1 H NMR(400MHz, CD3OD)δ=7.64(s,1H),7.60–7.57(m,2H),7.55-7.51(m,2H),7.31–7.27(m,2H),5.21(s,2H),4.16-4.07(m,1H),3. 48–3.39(m,2H),3.20–3.10(m,2H),2.96–2.88(m,1H),2.65(t,J=8.0Hz,2H),2.25(s,3H),1.90-1.75(m,6H),1.58-1.34(m,6H).

[0439] Example 2

[0440]

[0441] Synthesis route:

[0442]

[0443] Step 1: Synthesis of Compound 2-1

[0444] Intermediate A (0.04 g, 0.12 mmol) was dissolved in methanol (10 mL), and hydrogen chloride / ethyl acetate (0.51 mL, 2.02 mmol) was added. The reaction mixture was stirred at 25 °C for 0.5 h. Triethylamine (0.16 g, 1.62 mmol) and intermediate C (0.02 g, 0.08 mmol) were added to the reaction mixture, and the mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give compound 2-1.

[0445] 1 H NMR (400MHz, CD3OD) δ = 7.64 (s, 1H), 7.61-7.56 (m, 1H), 7.55-7.51 (m, 1H), 7.47 (s, 1H), 7.4 1(d,J=8.0Hz,1H),7.18(d,J=8.0Hz,1H),5.19(s,2H),3.73(s,3H),3.66–3.59(m,1H),3.4 6(s,2H),3.18–3.11(m,2H),2.96–2.88(m,1H),2.81–2.73(m,2H),2.25-2.21(m,3H),1.89 –1.83(m,2H),1.80-1.76(m,1H),1.81–1.74(m,2H),1.58–1.48(m,2H),1.41-1.28(m,3H).

[0446] Step 2: Synthesis of trifluoroacetate of compound 2

[0447] Compound 2-1 (0.03 g, 0.05 mmol) was dissolved in tetrahydrofuran (4 mL) and water (1 mL), and lithium hydroxide monohydrate (0.04 g, 1.00 mmol) was added. The reaction mixture was stirred at 25 °C for 12 hours. 1 M hydrochloric acid was added to the reaction mixture until the pH reached 4. The reaction mixture was concentrated under reduced pressure. The crude product was separated by preparative high performance liquid chromatography (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: 0.075% trifluoroacetic acid aqueous solution-acetonitrile; gradient: acetonitrile 50%-80%, 8 min) to obtain the trifluoroacetate of compound 2.

[0448] The MS-ESI calculated value is [M+H]. + 489, measured value 489.

[0449] 1H NMR (400MHz, CD3OD) δ = 7.64 (s, 1H), 7.57 (s, 2H), 7.54-7.50 (m, 2H), 7.27 (d, J = 7.8Hz, 1H), 5.20 (s, 2H), 4.16-4.06 (m, 1H), 3.79 (s, 2H),3.45–3.37(m,2H),3.18–3.09(m,2H),2.96–2.87(m,1H),2.24(s,3H),1.90–1.82(m,2H),1.81–1.74(m,3H),1.55-1.34(m,5H).

[0450] Example 3

[0451]

[0452] Synthesis route:

[0453]

[0454] Step 1: Synthesis of Compound 3-1

[0455] Intermediate A (0.09 g, 0.25 mmol) was dissolved in methanol (10 mL), and hydrogen chloride / ethyl acetate (1.04 mL, 4.15 mmol) was added. The reaction mixture was stirred at 25 °C for 0.5 h. Triethylamine (0.34 g, 3.32 mmol) and intermediate D (0.05 g, 0.17 mmol) were added to the reaction mixture, and the mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10 / 1, dichloromethane / methanol) to give compound 3-1.

[0456] The MS-ESI calculated value is [M+H]. + 558, measured value 558.

[0457] Step 2: Synthesis of the trifluoroacetate of compound 3

[0458] Compound 3-1 (0.04 g, 0.06 mmol) was dissolved in tetrahydrofuran (4 mL), methanol (2 mL), and water (1 mL). Sodium hydroxide (0.56 g, 14 mmol) was added, and the reaction mixture was stirred at 60 °C for 2 hours. 12 M hydrochloric acid was added to the reaction mixture until the pH reached 4. The mixture was concentrated under reduced pressure, and the crude product was separated by preparative high-performance liquid chromatography (HPLC) (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: 0.075% trifluoroacetic acid aqueous solution-acetonitrile; gradient: acetonitrile 53%-83%, 8 min) to obtain the trifluoroacetate of compound 3.

[0459] The MS-ESI calculated value is [M+H]. + 529, measured value 529.

[0460] 1 H NMR(400MHz, CD3OD)δ=7.67-7.52(m,6H),5.23(s,2H),3.17–3.20(m,2H),3.08-2.86(m,2H),2.67-2 .55(m,1H),2.31–2.40(m,1H),2.27(s,3H),1.91-1.73(m,5H),1.60-1.28(m,9H),0.97–1.11(m,2H).

[0461] Example 4

[0462]

[0463] Synthesis route:

[0464]

[0465] Step 1: Synthesis of Compound 4-1

[0466] Under nitrogen protection, a methanol (8 mL) solution of intermediate E (0.15 g, 0.51 mmol) was added to hydrochloric acid / ethyl acetate (3.25 mL, 13.02 mmol), and the reaction mixture was stirred at 25 °C for 0.5 h. Triethylamine (0.93 g, 9.17 mmol) was added dropwise to the reaction mixture, followed by intermediate F (0.11 g, 0.41 mmol), and the reaction mixture was stirred at 60 °C for 14 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give compound 4-1.

[0467] Step 2: Synthesis of the hydrochloride salt of compound 4

[0468] Under nitrogen protection, compound 4-1 (0.15 g, 0.31 mmol) was dissolved in tetrahydrofuran (10 mL) and water (2 mL), and sodium hydroxide (0.97 g, 24.12 mmol) was added. The mixture was stirred at 60 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex Luna C18 150 × 30 mm × 5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 29%-49%, 7 min) to obtain the hydrochloride salt of compound 4.

[0469] MS-ESI calculated value [M+H] + 440, measured value 440.

[0470] 1H NMR(400MHz, CD3OD)δ=7.68-7.48(m,6H),5.19(s,2H),4.72–4.65(m,1H),3.83(s,2H),3.26- 3.16(m,1H),3.06-2.96(m,1H),2.64-2.54(m,1H),2.30-2.24(m,4H),1.37(d,J=4.0Hz,6H).

[0471] Example 5

[0472]

[0473] Synthesis route:

[0474]

[0475] Step 1: Synthesis of Compound 5-1

[0476] Intermediate G (1.00 g, 3.71 mmol) was dissolved in methanol (60 mL), and hydrochloric acid / ethyl acetate (15.47 mL, 61.89 mmol) was added. The mixture was stirred at 25 °C for 0.5 h. Intermediate F (0.68 g, 2.48 mmol) and triethylamine (5.01 g, 49.51 mmol) were added, and the reaction mixture was heated to 60 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give compound 5-1.

[0477] 1 H NMR (400MHz, DMSO-d6) δ = 7.52-7.44 (m, 2H), 7.33 (d, J = 7.8Hz, 1H), 7.17-7.12 ( m,3H),5.10(s,2H),4.94(s,J=6.2Hz,1H),4.65-4.55(m,2H),4.48(s,2H),4.16 (t,J=6.4Hz,1H),2.98-2.87(m,1H),2.73(t,J=7.6,15.6Hz,1H),2.30-2.22(m ,1H),2.20(s,3H),1.81-1.72(m,1H),1.28-1.27(m,6H),1.19(d,J=8.0Hz,6H).

[0478] Step 2: Synthesis of the hydrochloride salt of compound 5

[0479] Compound 5-1 (0.24 g, 0.53 mmol) was dissolved in tetrahydrofuran (8.5 mL) and water (2 mL), and sodium hydroxide (1.00 g, 24.91 mmol) was added. The reaction mixture was heated to 60 °C and stirred for 2 hours. 1 M dilute hydrochloric acid (5 mL) was added dropwise to adjust the pH of the reaction mixture to 4. The mixture was extracted with ethyl acetate (10 mL × 2), washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated into the hydrochloride salt of compound 5 by preparative high-performance liquid chromatography (column: Venusil ASB Phenyl 150 × 30 mm × 5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 35%-65%, 9 min).

[0480] MS-ESI calculated value [M+Na] + 437, measured value 437.

[0481] 1 H NMR (400MHz, DMSO-d6) δ = 7.70 (d, J = 7.8Hz, 1H), 7.63-7.51 (m, 2H), 7.23 (d, J = 12Hz, 1H), 7.18-7.12 (m, 2H), 5.11 (s, 2H), 4.82-4.74 (m, 1H), 4.68 -4.55(m,1H),3.83-3.69(m,2H),3.20-3.08(m,1H),2.91-2.81(m,1H),2 .47-2.36(m,1H),2.28-2.22(m,1H),2.21(s,3H),1.27(d,J=8.0Hz,6H).

[0482] Example 6

[0483]

[0484] Synthesis route:

[0485]

[0486] Step 1: Synthesis of Compound 6-1

[0487] Intermediate H (870.00 mg, 2.88 mmol) was dissolved in methanol (50 mL), and then hydrochloric acid / ethyl acetate (11.99 mL, 47.95 mmol) was added. The mixture was stirred at 25 °C for 0.5 h. Intermediate F (0.53 g, 1.92 mmol) and triethylamine (3.88 g, 38.36 mmol) were added, and the reaction mixture was stirred at 60 °C for 12 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give compound 6-1.

[0488] MS-ESI calculated value [M+H] + 490, measured value 490.

[0489] 1 H NMR (400MHz, DMSO-d6) δ=7.76-7.63(m,2H),7.51-7.40(m,2H),7.33(d,J=7.8Hz,1H ),7.25(d,J=8.8Hz,1H),5.12(s,2H),5.03-4.92(m,2H),4.16(t,J=6.4Hz,1H),4.03 (q,J=8.0Hz,1H),2.98-2.87(m,1H),2.77-2.68(m,1H),2.29-2.21(m,1H),2.19(s, 3H), 2.01-1.88 (m, 4H), 1.78-1.69 (m, 5H), 1.64-1.57 (m, 2H), 1.20 (d, J = 4.0Hz, 6H).

[0490] Step 2: Synthesis of the hydrochloride salt of compound 6

[0491] Compound 6-1 was dissolved in tetrahydrofuran (2 mL) and water (0.4 mL), and sodium hydroxide (193.53 mg, 4.84 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours. 1 M dilute hydrochloric acid (1 mL) was added dropwise until the pH of the reaction mixture reached 4. The mixture was filtered, and the filter cake was washed with methanol (5 mL × 3). The filter cake was then dried under vacuum to obtain the hydrochloride salt of compound 6.

[0492] MS-ESI calculated value [M+H] + 448, measured value 448.

[0493] 1 H NMR (400MHz, CD3OD) δ = 7.67-7.60 (m, 4H), 7.58-7.53 (m, 1H), 7.16 (d, J = 8.8Hz, 1H), 5.15 (s, 2H), 5 .01-4.94(m,2H),4.58(s,3H),3.50(d,J=2.8Hz,2H),3.24-3.15(m,1H),3.05-2.96(m,1H),2.63–

[0494] 2.52(m,1H),2.26(s,3H),2.06–1.93(m,3H),1.91-1.80(m,5H).

[0495] Example 7

[0496]

[0497] Synthesis route:

[0498]

[0499] Step 1: Synthesis of Compound 7-1

[0500] Intermediate I (0.15 g, 0.53 mmol) was dissolved in methanol (8.5 mL), and hydrochloric acid / ethyl acetate (2.19 mL, 8.75 mmol) was added. The mixture was stirred at 25 °C for 0.5 h. Intermediate F (0.096 g, 0.35 mmol) and triethylamine (0.71 g, 7.00 mmol) were then added. The reaction mixture was heated to 60 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give compound 7-1.

[0501] 1 H NMR (400MHz, DMSO-d6)δ=7.50-7.43(m,2H),7.37-7.27(m,2H),7.24-7.19(m,1H ),7.16-7.09(m,1H),5.09(s,1H),5.00-4.87(m,1H),4.67-4.60(m,1H),4.47(s, 1H),4.19-4.08(m,1H),4.03(q,J=8.0Hz,1H),3.17(d,J=4.0Hz,1H),3.06(s,1H) ,2.98-2.85(m,1H),2.80-2.65(m,1H),2.04-1.94(m,2H),1.28(d,J=8.0Hz,6H).

[0502] Step 2: Synthesis of the hydrochloride salt of compound 7

[0503] Compound 7-1 (0.08 mg, 0.17 mmol) was dissolved in tetrahydrofuran (3 mL) and water (0.6 mL), and sodium hydroxide (0.32 g, 8.00 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours. 1 M dilute hydrochloric acid (1.5 mL) was added dropwise to adjust the pH of the reaction mixture to 4. The mixture was filtered, and the filter cake was washed with methanol (5 mL × 3). The filter cake was collected and dried under vacuum to obtain the hydrochloride salt of compound 7.

[0504] 1H NMR(400MHz, CD3OD)δ=7.69-7.52(m,3H),7.45-7.35(m,1H),7.32-7.24(m,1H),7.10-7.00(m,1H),5.16-5.06(m, 2H),4.66-4.55(m,4H),3.55-3.46(m,2H),3.05-2.92(m,1H),2.60-2.50(m,1H),2.25(s,3H),1.35-1.32(m,6H).

[0505] Example 8

[0506]

[0507] Synthesis route:

[0508]

[0509] Step 1: Synthesis of Compound 8-1

[0510] Under nitrogen protection, hydrochloric acid / ethyl acetate (2.70 mL, 10.82 mmol) was added to a methanol (10 mL) solution of intermediate J (0.15 g, 0.54 mmol), and the reaction mixture was stirred at 20 °C for 0.5 h. Triethylamine (0.99 g, 9.74 mmol) was added dropwise to the reaction mixture, followed by intermediate F (0.12 g, 0.43 mmol), and the reaction mixture was stirred at 60 °C for 14 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give compound 8-1.

[0511] MS-ESI calculated value [M+H] + 465, measured value 465.

[0512] Step 2: Synthesis of the hydrochloride salt of compound 8

[0513] Under nitrogen protection, compound 8-1 (0.15 g, 0.32 mmol) was dissolved in tetrahydrofuran (10 mL) and water (2 mL), and sodium hydroxide (1.00 g, 25.00 mmol) was added. The reaction mixture was stirred at 60 °C for 2 hours. The solution was concentrated under reduced pressure, and the crude product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex Luna C18 150 × 30 mm × 5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 40%-70%, 9 min) to obtain the hydrochloride salt of compound 8.

[0514] 1H NMR (400MHz, CD3OD) δ = 8.43 (d, J = 4.0Hz, 1H), 8.10 (d, J = 2.0Hz, 1H), 7.68-7.63 (m, 2H), 7.59 (s, 1H), 5.50-5.40 (m, 1H), 5. 18(s,2H),3.95(s,2H),3.28-3.18(m,1H),3.07-2.97(m,1H),2.68-2.55(m,1H),2.31-2.23(m,5H),1.39(d,J=8.0Hz,6H).

[0515] Example 9

[0516]

[0517] Synthesis route:

[0518]

[0519] Step 1: Synthesis of Compound 9-1

[0520] Under nitrogen protection, hydrochloric acid / ethyl acetate (3.62 mL, 3.62 mL) was added to a methanol (10 mL) solution of intermediate K (0.20 g, 0.72 mmol), and the reaction was carried out at 20 °C for 0.5 h. Triethylamine (1.32 g, 13.03 mmol) was added dropwise to the reaction solution, followed by intermediate F (0.16 g, 0.58 mmol), and the reaction was carried out at 60 °C for 14 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give compound 9-1.

[0521] MS-ESI calculated value [M+H] + 464, measured value 464.

[0522] Step 2: Synthesis of the hydrochloride salt of compound 9

[0523] Under nitrogen protection, compound 9-1 (0.05 g, 0.11 mmol) was dissolved in tetrahydrofuran (5 mL) and water (1 mL), and sodium hydroxide (0.25 g, 6.26 mmol) was added. The reaction was carried out at 60 °C for 2 hours. The crude product after concentration was separated by high performance liquid chromatography (HPLC) (column: Phenomenex Luna C18 150 × 30 mm × 5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 35%-65%, 9 min) to obtain the hydrochloride salt of compound 9.

[0524] MS-ESI calculated value [M+H] + 422, measured value 422.

[0525] 1 H NMR (400MHz, CD3OD) δ=7.68-7.65(m,2H),7.64-7.63(m,2H),7.57(d,J=8.0Hz,1H),7.17(d,J=8.0Hz,1H),5.15(s,2H),4.80- 4.73(m,1H),3.92(s,2H),3.25-3.18(m,2H),3.06-2.99(m,1H),2.65-2.55(m,1H),2.33-2.23(m,4H),1.38(d,J=6.0Hz,6H).

[0526] Example 10

[0527]

[0528] Synthesis route:

[0529]

[0530] Step 1: Synthesis of Compound 10-1

[0531] Under nitrogen protection, hydrochloric acid / ethyl acetate (2 mL, 8 mmol) was added to an 8 mL methanol (8 mL) solution of intermediate L (0.10 g, 0.31 mmol), and the reaction was carried out at 25 °C for 0.5 h. Triethylamine (0.57 g, 5.64 mmol) was added dropwise to the reaction solution, followed by intermediate F (0.07 g, 0.25 mmol), and the reaction was carried out at 60 °C for 14 h. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give compound 10-1.

[0532] Step 2: Synthesis of the hydrochloride salt of compound 10

[0533] Under nitrogen protection, intermediate 10-1 (0.10 g, 0.20 mmol) was dissolved in tetrahydrofuran (10 mL) and water (2 mL), and sodium hydroxide (0.61 g, 15.28 mmol) was added. The reaction mixture was reacted at 60 °C for 2 hours. The crude product after concentration was separated by high performance liquid chromatography (HPLC) (column: Phenomenex Luna C18 150 × 30 mm × 5 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 29%-49%, 7 min) to obtain the hydrochloride salt of compound 10.

[0534] MS-ESI calculated value [M+Na] + 487, measured value 487.

[0535] 1H NMR (400MHz, CD3OD) δ = 7.69-7.54 (m, 5H), 7.16 (br d,J=8.0Hz,1H),5.17(s,2H),4.77-4.70(m,1H),3.91(s,2H),3.26-3.19(m,2 H), 3.03 (s, 1H), 2.62-2.55 (m, 1H), 2.32-2.22 (m, 4H), 1.34 (d, J = 8.0Hz, 6H).

[0536] Example 11

[0537]

[0538] Synthesis route:

[0539]

[0540] Step 1: Synthesis of Compound 11-1

[0541] Under nitrogen protection, hydrochloric acid / ethyl acetate (3.01 mL, 12.03 mmol) was added to a methanol (10 mL) solution of intermediate A (0.15 g, 0.44 mmol), and the reaction was carried out at 20 °C for 0.5 h. Triethylamine (0.80 g, 7.86 mmol) was added dropwise to the reaction solution, followed by intermediate M (0.11 g, 0.35 mmol), and the reaction was carried out at 60 °C for 14 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1 / 1, petroleum ether / ethyl acetate) to give compound 11-1.

[0542] MS-ESI calculated value [M+H] + 559, measured value 559.

[0543] Step 2: Synthesis of trifluoroacetate of compound 11

[0544] Under nitrogen protection, compound 11-1 (0.10 g, 0.18 mmol) was dissolved in tetrahydrofuran (10 mL) and water (2 mL), and sodium hydroxide (0.50 g, 12.50 mmol) was added. The mixture was reacted at 60 °C for 2 hours. After the reaction was complete, the crude product obtained by concentration was separated by high performance liquid chromatography (HPLC) (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: 0.075% trifluoroacetic acid aqueous solution-acetonitrile; gradient: acetonitrile 40%-70%, 9 min) to obtain the trifluoroacetate of compound 11.

[0545] MS-ESI calculated value [M+H] + 517, measured value 517.

[0546] 1 H NMR(400MHz, CD3OD)δ=7.70(s,1H),7.66(s,2H),7.64–7.59(m,2H),7.57-7.53(m,1H),5.25(s,2H),5.16-5.06(m,1H),3.26-3.15(m ,3H),3.13-2.98(m,1H),2.95–2.84(m,2H),2.77-2.74(m,2H),2.63-2.41(m,2H),2.29(s,3H),1.94-1.73(m,5H),1.60-1.35(m,6H).

[0547] Example 12

[0548]

[0549] Synthesis route:

[0550]

[0551] Step 1: Synthesis of Compound 12-1

[0552] Intermediate L (149 mg, 466 μmol) was dissolved in methanol (15 mL), and then hydrochloric acid / ethyl acetate (1.46 mL, 4 M) was added dropwise to the reaction solution. The reaction was carried out at 20 °C for 0.5 h. Triethylamine (471 mg, 4.66 mmol) was added dropwise to the reaction solution, followed by intermediate T (100 mg, 233 μmol). The reaction was carried out at 60 °C for 5 h. The solution was concentrated under reduced pressure to obtain crude compound 12-1.

[0553] MS-ESI calculated value [M-Boc+H] + 561, measured value 561.

[0554] Step 2: Synthesis of the hydrochloride salt of compound 12

[0555] The crude product of compound 12-1 (175 mg, 265 μmol) was dissolved in ethyl acetate (4 mL), and then hydrochloric acid / ethyl acetate (1.66 mL, 4 M) was added dropwise to the reaction solution. The reaction was carried out at 25 °C for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 6 with 1 M hydrochloric acid aqueous solution, and the solution was concentrated under reduced pressure. The concentrated crude product was separated by high performance liquid chromatography (HPLC) (column: 3-Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 38%-58%, 6.5 min) to obtain the hydrochloride salt of compound 12.

[0556] MS-ESI calculated value [M+H]+ 505, measured value 505.

[0557] 1 H NMR(400MHz, CD3OD)δ=7.68-7.55(m,5H),7.21-7.11(m,1H),5.17(s,2H),4.78-4.71(m, 1H),3.23-3.14(m,3H),3.08-2.97(m,1H),2.69-2.55(m,2H),2.44-2.21(m,4H),1.41(br d,J=3.2Hz,2H),1.34(d,J=6.0Hz,6H),1.13-1.02(m,2H).

[0558] Example 13:

[0559]

[0560] Synthesis route:

[0561]

[0562] Step 1: Synthesis of Compound 13-1

[0563] Intermediate N (155 mg, 466 μmol) was dissolved in methanol (15 mL), and then hydrochloric acid / ethyl acetate (1.46 mL, 4 M) was added dropwise to the reaction solution. The reaction was carried out at 20 °C for 0.5 hours. Triethylamine (471 mg, 4.66 mmol) was added dropwise to the reaction solution, followed by intermediate T (100 mg, 233 μmol). The reaction was carried out at 60 °C for 5 hours. The solution was concentrated under reduced pressure to obtain crude compound 13-1.

[0564] MS-ESI calculated value [M-Boc+H] + 575, measured value 575.

[0565] Step 2: Synthesis of the hydrochloride salt of compound 13

[0566] The crude product of compound 13-1 (183 mg, 271 μmol) was dissolved in ethyl acetate (4 mL), and then hydrochloric acid / ethyl acetate (1.69 mL, 4 M) was added dropwise to the reaction solution. The reaction was carried out at 25 °C for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 6 with 1 M hydrochloric acid aqueous solution, and the solution was concentrated under reduced pressure. The concentrated crude product was separated by high performance liquid chromatography (HPLC) (column: 3-Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 41%-61%, 6.5 min) to obtain the hydrochloride salt of compound 13.

[0567] MS-ESI calculated value [M+H] + 519, measured value 519.

[0568] 1 H NMR (400MHz, CD3OD) δ = 7.68-7.56 (m, 5H), 7.12 (d, J = 8.4Hz, 1H), 5.17 (s, 2H), 4.91 (br d,J=4.0Hz,2H),3.86(d,J=6.0Hz,2H),3.25-3.17(m,3H),3.08-2.97(m,1H),2.64-2.56(m,1H ),2.44-2.31(m,1H),2.25(s,3H),2.16-2.05(m,1H),1.41(d,J=3.4Hz,2H),1.13-1.02(m,8H).

[0569] Example 14

[0570]

[0571] Synthesis route:

[0572]

[0573] Step 1: Synthesis of Compound 14-1

[0574] Intermediate Q (154 mg, 466 μmol) was dissolved in methanol (15 mL), and then hydrochloric acid / ethyl acetate (1.46 mL, 4 M) was added dropwise to the reaction solution. The reaction was carried out at 20 °C for 0.5 hours. Triethylamine (471 mg, 4.66 mmol) was added dropwise to the reaction solution, followed by intermediate T (100 mg, 233 μmol). The reaction was carried out at 60 °C for 5 hours. The solution was concentrated under reduced pressure to obtain crude compound 14-1.

[0575] MS-ESI calculated value [M-Boc+H] + 573, measured value 573.

[0576] Step 2: Synthesis of the hydrochloride salt of compound 14

[0577] The crude product of compound 14-1 (169 mg, 251 μmol) was dissolved in ethyl acetate (4 mL), and then hydrochloric acid / ethyl acetate (1.57 mL, 4 M) was added dropwise to the reaction solution. The reaction was carried out at 25 °C for 12 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 6 with 1 M hydrochloric acid aqueous solution, and the solution was concentrated under reduced pressure. The concentrated crude product was separated by high performance liquid chromatography (HPLC) (column: 3-Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 38%-58%, 6.5 min) to obtain the hydrochloride salt of compound 14.

[0578] MS-ESI calculated value [M+H] + 517, measured value 517.

[0579] 1 H NMR (400MHz, CD3OD) δ = 7.69-7.54 (m, 5H), 7.12 (d, J = 8.4Hz, 1H), 5.17 (s, 2 H),4.93-4.89(m,2H),3.97(d,J=6.5Hz,2H),3.19(s,2H),3.08-2.97(m,1H ),2.65-2.55(m,1H),2.45-2.32(m,1H),2.25(s,3H),1.46-1.37(m,2H),1 .34-1.21(m,1H),1.18-1.00(m,2H),0.65-0.56(m,2H),0.43-0.34(m,2H).

[0580] Example 15

[0581]

[0582] Synthesis route:

[0583]

[0584] Step 1: Synthesis of Compound 15-1

[0585] Intermediate Q (86.8 mg, 251 μmol) was dissolved in methanol (10 mL), and then hydrochloric acid / ethyl acetate (785 μL, 4 M) was added dropwise to the reaction solution. The reaction was carried out at 20 °C for 0.5 h. Triethylamine (254 mg, 2.51 mmol) was added dropwise to the reaction solution, followed by intermediate T (54.0 mg, 126 μmol). The reaction was carried out at 60 °C for 5 h. The solution was concentrated under reduced pressure to obtain crude compound 15-1.

[0586] MS-ESI calculated value [M-Boc+H] +587, measured value 587.

[0587] Step 2: Synthesis of the hydrochloride salt of compound 15

[0588] The crude product of compound 15-1 (112 mg, 163 μmol) was dissolved in ethyl acetate (2 mL), and hydrochloric acid / ethyl acetate (1.02 mL, 4 M) was added. The mixture was reacted at 25 °C for 12 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 6 with 1 M hydrochloric acid aqueous solution, and the solution was concentrated under reduced pressure. The concentrated crude product was separated by high performance liquid chromatography (HPLC) (column: 3-Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 42%-62%, 6.5 min) to obtain the hydrochloride salt of compound 15.

[0589] MS-ESI calculated value [M+H] + 531, measured value 531.

[0590] 1 H NMR (400MHz, CD3OD) δ=7.77-7.45(m,5H),7.22-7.07(m,1H),5.17(s,2H),4.96(br s,2H),3.19(br s,3H),3.10-2.97(m,1H),2.65-2.56(m,1H),2.46-2.32(m,1H),2.25(s,3H),2.01-1.74(m,6H),1.66(br s,2H),1.51-1.23(m,3H),1.17-0.98(m,2H).

[0591] Example 16

[0592]

[0593] Synthesis route:

[0594]

[0595] Step 1: Synthesis of Compound 16-1

[0596] Intermediate O (155 mg, 415 μmol) was dissolved in methanol (10 mL), and ethyl acetate hydrochloride (1.04 mL, 4 M) was added dropwise. The mixture was stirred at 20 °C for 30 minutes. Then, triethylamine (524.94 mg, 5.19 mmol) and intermediate U (75 mg, 208 μmol) were added, and the mixture was stirred at 60 °C for 12.5 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were concentrated under reduced pressure, and the residue was separated by thin-layer chromatography (petroleum ether / ethyl acetate, 3 / 1, V / V) to obtain compound 16-1.

[0597] MS-ESI calculated value [M+H] + 605, measured value 605.

[0598] Step 2: Synthesis of Compound 16-2

[0599] Compound 16-1 (120 mg, 198.5 μmol) was dissolved in ethyl acetate hydrochloride (4 M, 1.85 mL), and the reaction solution was stirred at 15 °C for 1 hour. The reaction solution was then concentrated under reduced pressure to obtain compound 16-2.

[0600] MS-ESI calculated value [M+H] + 505, measured value 505.

[0601] Step 3: Synthesis of Compound 16

[0602] Compound 16-2 (80 mg, 159 μmol) was dissolved in tetrahydrofuran (0.5 mL), water (0.5 mL), and ethanol (0.25 mL). Sodium hydroxide (12.7 mg, 317 μmol) was added, and the mixture was stirred at 55 °C for 4 hours. The reaction solution was adjusted to pH 7 with saturated sodium carbonate aqueous solution, and the crude product was concentrated under reduced pressure. Compound 16 was obtained by high performance liquid chromatography (HPLC) (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 37%-67%, 10 min).

[0603] MS-ESI calculated value [M+Na] + 499, measured value 499.

[0604] 1H NMR (400MHz, CD3OD) δ = 7.65-7.54 (m, 5H), 7.12 (d, J = 12Hz, 1H), 5.17 (s, 2H), 4.83-4.79 (m, 1H), 4.60-4.56 (m, 1H), 3.97 (d, J = 8Hz, 2H), 3.54-3. 47(m,2H),3.23-3.13(m,1H),3.03-2.95(m,1H),2.61-2.52(m,1H),2.2 8-2.21(m,4H),1.34-1.23(m,2H),0.64-0.59(m,2H),0.41-0.37(m,2H).

[0605] Example 17

[0606]

[0607] Synthesis route:

[0608]

[0609] Step 1: Synthesis of Compound 17-1

[0610] Intermediate N (185 mg, 553 μmol) was dissolved in methanol (5 mL), and ethyl acetate hydrochloride (1.38 mL, 4 M) was added dropwise. The mixture was stirred at 20 °C for 0.5 h. Then, triethylamine (700 mg, 6.92 mmol) and intermediate U (0.100 g, 277 μmol) were added, and the mixture was stirred at 60 °C for 1 h. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were concentrated under reduced pressure to obtain the crude product, which was then separated by thin-layer chromatography (petroleum ether / ethyl acetate, 3 / 1, V / V) to give compound 17-1.

[0611] MS-ESI calculated value [M+H] + 507, measured value 507.

[0612] Step 2: Synthesis of Compound 17

[0613] Compound 17-1 (80 mg, 158 μmol) was dissolved in tetrahydrofuran (0.5 mL), water (0.5 mL), and ethanol (0.25 mL). Sodium hydroxide (12.6 mg, 316 μmol) was added, and the reaction solution was reacted at 55 °C for 0.5 h. After adjusting the pH of the reaction solution to 7 with saturated sodium carbonate aqueous solution, the crude product was concentrated under reduced pressure and separated by high performance liquid chromatography (HPLC) (column: Phenomenex lμna C18 150*25 mm*10 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 43%-73%, 10 min) to obtain compound 17.

[0614] MS-ESI calculated value [M+Na] + 501, measured value 501.

[0615] 1 H NMR (400MHz, CD3OD) δ = 7.68-7.53 (m, 5H), 7.12 (d, J = 8Hz, 1H), 5.17 (s, 2H), 4.83-4.78 (m, 1H), 3.86 (d, J = 4Hz, 2H), 3.53-3.34 (m, 2H), 3.28-3.13(m,1H),3.05-2.93(m,1H),2.61-2.51(m,1H),2.28-2.20(m,4H),2.15-2.01(m,1H),1.40-1.21(m,2H),1.07-1.03(m,6H).

[0616] Example 18

[0617]

[0618] Synthesis route:

[0619]

[0620] Step 1: Synthesis of Compound 18-1

[0621] Intermediate Q (134 mg, 387 μmol) was dissolved in methanol (5 mL), and ethyl acetate hydrochloride (968 μL, 4 M) was added dropwise. The reaction mixture was stirred at 20 °C for 30 minutes. Then, triethylamine (490 mg, 4.84 mmol) and intermediate U (70.0 mg, 194 μmol) were added, and the reaction mixture was stirred at 60 °C for 5.5 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phase was concentrated under reduced pressure to give compound 18-1.

[0622] MS-ESI calculated value [M+H] + 619, measured value 619.

[0623] Step 2: Synthesis of Compound 18-2

[0624] Compound 18-1 (110 mg, 178 μmol) was dissolved in ethyl acetate hydrochloride (4 M, 1.65 mL), and the reaction solution was stirred at 15 °C for 1 hour. The reaction solution was concentrated under reduced pressure to give compound 18-2.

[0625] MS-ESI calculated value [M+Na] + 541, measured value 541.

[0626] Step 3: Synthesis of Compound 18

[0627] Compound 18-2 (90 mg, 174 μmol) was dissolved in tetrahydrofuran (0.5 mL), water (0.5 mL), and ethanol (0.25 mL). Sodium hydroxide (13.9 mg, 347 μmol) was added, and the mixture was stirred at 55 °C for 4 hours. The reaction solution was adjusted to pH 7 with saturated sodium carbonate aqueous solution. The crude product, concentrated under reduced pressure, was separated by high performance liquid chromatography (HPLC) (column: Unisil 3-100C18 Ultra 150*50 mm*3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 43%-73%, 10 min) to obtain compound 18.

[0628] MS-ESI calculated value [M+Na] + 513, measured value 513.

[0629] 1 H NMR (400MHz, CD3OD) δ = 7.69-7.50 (m, 5H), 7.13 (d, J = 8Hz, 1H), 5.21-5.13 (m, 2H), 4.99-4.94 (m, 1H), 4.84-4.80 (m, 1H), 3.58-3.35 (m, 2H) ),3.27-3.10(m,1H),3.08-2.89(m,1H),2.63-2.39(m,1H),2.25-2.24(m,4H),1.99-1.77(m,6H),1.71-1.48(m,2H),0.92-0.82(m,2H).

[0630] Example 19

[0631]

[0632] Synthesis route:

[0633]

[0634] Step 1: Synthesis of Compound 19-1

[0635] Compound O (1.29 g, 3.46 mmol) was dissolved in methanol (40 mL). A hydrogen chloride / ethyl acetate solution (4 M, 10.8 mL) was added to the reaction mixture, and the reaction mixture was stirred at 20 °C for 0.5 h. Then, triethylamine (34.6 mmol, 4.81 mL) and intermediate V (500 mg, 1.73 μmol) were added sequentially to the reaction mixture, and the reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated sodium bicarbonate aqueous solution (100 mL). Extraction was performed with ethyl acetate (100 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1–0 / 1, V / V) to obtain compound 19-1.

[0636] MS-ESI calculated value [M+H] + 533, measured value 533.

[0637] Step 2: Synthesis of Compound 19

[0638] Compound 19-1 (380 mg, 713 μmol) was dissolved in tetrahydrofuran (3 mL), ethanol (1.5 mL), and water (3 mL). Sodium hydroxide (57.08 mg, 1.43 mmol) was added to the reaction mixture, and the mixture was stirred at 55 °C for 1.5 hours. The pH of the reaction mixture was adjusted to 4–5 by adding 4 M hydrochloric acid solution, and the mixture was concentrated under reduced pressure. The crude product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 38%–68%, 7 min) to obtain compound 19.

[0639] MS-ESI calculated value [M+H] + 491, measured value 491.

[0640] 1 H NMR (400MHz, CD3Cl) δ=9.83-9.43(m,2H),7.66-7.56(m,2H),7.56-7.45(m,3H),6.95(d,J=8.4Hz,1H),5.15(s,2H),4.74(br s,1H),3.93(d,J=6.4Hz,2H),3.24-2.83(m,4H),2.65-2.26(m,4H),2.20(s,3H),1.35-1.22(m,1H),0.70-0.57(m,2H),0.46-0.33(m,2H).

[0641] Example 20

[0642]

[0643] Synthesis route:

[0644]

[0645] Step 1: Synthesis of Compound 20-1

[0646] Intermediate A (712 mg, 2.07 mmol) was dissolved in methanol (10 mL). An ethyl acetate solution of hydrogen chloride (4 M, 6.48 mL) was added to the reaction mixture, and the reaction mixture was stirred at 20 °C for 0.5 h. Then, triethylamine (20.7 mmol, 2.89 mL) and intermediate V (300 mg, 1.04 μmol) were added sequentially to the reaction mixture, and the reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated sodium bicarbonate aqueous solution (100 mL). Extraction was performed with ethyl acetate (100 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin-layer chromatography (dichloromethane / methanol, 20 / 1, V / V) to obtain compound 20-1.

[0647] MS-ESI calculated value [M+H] + 545, measured value 545.

[0648] Step 2: Synthesis of Compound 20

[0649] Compound 20-1 (320 mg, 588 μmol) was dissolved in tetrahydrofuran (2 mL), ethanol (1 mL), and water (2 mL). Sodium hydroxide (47.0 mg, 1.18 mmol) was added to the reaction mixture, and the mixture was stirred at 55 °C for 1.5 h. The pH of the reaction mixture was adjusted to 5–6 by adding 1 M hydrochloric acid solution, followed by extraction with ethyl acetate (100 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 38%–68%, 7 min) to obtain compound 20.

[0650] MS-ESI calculated value [M+H] + 503, measured value 503.

[0651] 1H NMR (400MHz, CD3Cl) δ=7.66-7.57(m,2H),7.55-7.46(m,3H),7.45-7.42(m,1H),5.20(s,2H),4.74(br s,1H),3.21-2.83(m,5H),2.65-2.26(m,4H),2.22(s,3H),1.88-1.73(m,5H),1.53-1.20(m,6H).

[0652] Example 21

[0653]

[0654] Synthesis route:

[0655]

[0656] Step 1: Synthesis of Compound 21-1

[0657] Hydrochloric acid / ethyl acetate (4M, 2.43 mL, 9.72 mmol) was added to a methanol (5 mL) solution of intermediate O (118 mg, 389 μmol), and the reaction was carried out at 20 °C for 0.5 h. Triethylamine (787 mg, 7.78 mmol) was added dropwise to the reaction solution, followed by intermediate M (118 mg, 389 μmol), and the reaction was carried out at 60 °C for 3 h. The mixture was concentrated under reduced pressure, and the residue was diluted with 20 mL of water, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel thin-layer chromatography (dichloromethane / methanol, 20 / 1, V / V) to obtain compound 21-1.

[0658] MS-ESI calculated value [M+H] + 547, measured value 547.

[0659] Step 2: Synthesis of Compound 21

[0660] Compound 21-1 (104 mg, 190 μmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL), ethanol (1 mL), and water (2 mL). Sodium hydroxide (15.2 mg, 381 μmol) was added, and the mixture was reacted at 50 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated, diluted with 5 mL of water, and the pH was adjusted to 6 with 1 M hydrochloric acid aqueous solution. The solution was then concentrated under reduced pressure. The concentrated crude product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 30%-60%, 7 min) to obtain compound 21.

[0661] MS-ESI calculated value [M+H] + 505, measured value 505.

[0662] 1 H NMR (400MHz, CD3OD) δ = 7.74-7.53 (m, 5H), 7.19-7.11 (m, 1H), 5.19 (s, 2H), 5.13-5.07 (m, 1H), 3.99 (d, J = 6.8Hz, 2H), 3. 28-2.99(m,4H),2.69(s,3H),2.65-2.37(m,4H),2.27(s,3H),1.40-1.17(m,1H),0.68-0.57(m,2H),0.44-0.38(m,2H).

[0663] Example 22

[0664]

[0665] Synthesis route:

[0666]

[0667] Step 1: Synthesis of Compound 22-1

[0668] Hydrochloric acid / ethyl acetate (4M, 1.24 mL, 4.94 mmol) was added to a methanol (5 mL) solution of intermediate N (165 mg, 494 μmol), and the reaction was carried out at 20 °C for 0.5 h. Triethylamine (400 mg, 3.96 mmol) was added dropwise to the reaction solution, followed by intermediate M (150 mg, 494 μmol), and the reaction was carried out at 60 °C for 9 h. The mixture was concentrated under reduced pressure, and the residue was diluted with 20 mL of water, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel thin-layer chromatography (dichloromethane / methanol, 20 / 1, V / V) to give compound 22-1.

[0669] MS-ESI calculated value [M+H] + 549, measured value 549.

[0670] Step 2: Synthesis of the formate of compound 22

[0671] Compound 22-1 (88 mg, 160 μmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL), ethanol (1 mL), and water (2 mL). Sodium hydroxide (12.8 mg, 321 μmol) was added, and the mixture was reacted at 50 °C for 3 hours. After the reaction was complete, the reaction solution was concentrated, diluted with 5 mL of water, and the pH was adjusted to 6 with 1 M hydrochloric acid aqueous solution. The solution was then concentrated under reduced pressure. The concentrated crude product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 42%-52%, 7 min) to obtain the formate salt of compound 22.

[0672] MS-ESI calculated value [M+H] + 507, measured value 507.

[0673] 1 H NMR (400MHz, CD3OD) δ = 8.43 (br s,1H),7.71-7.51(m,5H),7.11(d,J=8.4Hz,1H),5.17(s,2H),5.12-5.03(m,1H),3.92-3.77(m,2H),3 .28-2.96(m,4H),2.67(s,3H),2.63-2.35(m,4H),2.25(s,3H),2.17-1.98(m,1H),1.12-1.00(m,6H).

[0674] Example 23

[0675]

[0676] Synthesis route:

[0677]

[0678] Step 1: Synthesis of Compound 23-1

[0679] Intermediate Q (191 mg, 514 μmol) was dissolved in methanol (20 mL), and then ethyl acetate hydrochloride (1.60 mL, 4 M) was added dropwise. The mixture was stirred at 20 °C for 0.5 h, followed by the addition of triethylamine (519 mg, 5.13 mmol) and intermediate R (100 mg, 257 μmol). The mixture was stirred at 60 °C for 12 h. The solvent was removed under reduced pressure, and then water (10 mL) was added. The pH was adjusted to 8 with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then analyzed by thin-plate chromatography (dichloromethane:

[0680] Compound 23-1 was obtained by purification with methanol (20:1, V:V).

[0681] MS-ESI calculated value [M+H] + 547, measured value 547.

[0682] Step 2: Synthesis of Compound 23

[0683] Compound 23-1 (130 mg, 238 μmol) was dissolved in a mixed solvent of anhydrous tetrahydrofuran (2 mL), water (1 mL), and anhydrous ethanol (2 mL), and sodium hydroxide (28.5 mg, 713 μmol) was added. The reaction mixture was reacted at 25 °C for 12 hours. The pH of the reaction solution was adjusted to 6 with 1 M hydrochloric acid, and the solution was concentrated under reduced pressure. The concentrated crude product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 38%-48%, 7 min) to obtain compound 23.

[0684] MS-ESI calculated value [M+H] + 533, measured value 533.

[0685] 1 H NMR (400MHz, CD3OD) δ=7.57-7.28(m,4H),7.15-7.03(m,2H),4.98-4.92(m,3H),4.42(br s,1H),3.25-3.15(m,1H),3.15-3.05(m,1H),2.72-2.50(m,2H),2.49- 2.41(m,2H),2.19-2.02(m,5H),1.98-1.73(m,11H),1.72-1.61(m,2H).

[0686] Example 24

[0687]

[0688] Synthesis route:

[0689]

[0690] Step 1: Synthesis of Compound 24-1

[0691] Intermediate O (191 mg, 514 μmol) was dissolved in methanol (12 mL). Hydrogen chloride / ethyl acetate solution (4 M, 1.60 mL) was added to the reaction mixture, and the reaction mixture was stirred at 20 °C under nitrogen protection for 0.5 h. Then, triethylamine (5.13 mmol, 715 μL) and intermediate R (100 mg, 257 μmol) were added sequentially to the reaction mixture, and the reaction mixture was stirred at 60 °C for 12 h. The residue after concentration under reduced pressure was diluted with water (10 mL), and the pH was adjusted to 8 with saturated sodium bicarbonate solution. Extraction was performed with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then separated by thin-layer chromatography (petroleum ether / ethyl acetate, 3 / 1, V / V) to obtain compound 24-1.

[0692] MS-ESI calculated value [M+H] + 633, measured value 633.

[0693] Step 2: Synthesis of the hydrochloride salt of compound 24-2

[0694] Compound 24-1 (140 mg, 221 μmol) was dissolved in ethyl acetate (4 mL). A hydrogen chloride / ethyl acetate solution (4 M, 4 mL) was added to the reaction solution, and the mixture was stirred at 15 °C for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain crude hydrochloride of compound 24-2.

[0695] MS-ESI calculated value [M+H] + 533, measured value 533.

[0696] Step 3: Synthesis of Compound 24

[0697] The crude hydrochloride salt of compound 24-2 (128 mg, 225 μmol) was dissolved in tetrahydrofuran (2 mL), ethanol (1 mL), and water (2 mL). Sodium hydroxide (18.0 mg, 450 μmol) was added to the reaction mixture, and the mixture was stirred at 55 °C for 0.5 h. The pH was adjusted to 6 by adding 1 M hydrochloric acid solution at 0 °C. The crude product was concentrated under reduced pressure and separated by high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 38%-48%, 7 min) to obtain compound 24.

[0698] MS-ESI calculated value [M+H] + 519, measured value 519.

[0699] 1H NMR (400MHz, CD3OD) δ=7.61-7.57(m,1H),7.57-7.48(m,2H),7.35-7.29(m,1H),7.26-7.21(m,1 H),7.16-7.10(m,1H),5.16-5.09(m,2H),4.50-4.39(m,1H),4.02-3.95(m,2H),3.23-3.14(m,1H ),3.13-3.04(m,1H),2.74-2.65(m,1H),2.63-2.53(m,1H),2.48-2.41(m,2H),2.19-2.15(m,3H) ,2.14-2.01(m,2H),1.94-1.71(m,4H),1.33-1.22(m,1H),0.65-0.58(m,2H),0.42-0.36(m,2H).

[0700] Example 25

[0701]

[0702] Synthesis route:

[0703]

[0704] Step 1: Synthesis of Compound 25-1

[0705] Intermediate L (164 mg, 514 μmol) was dissolved in methanol (12 mL). Hydrogen chloride / ethyl acetate solution (4 M, 1.60 mL) was added to the reaction mixture, and the reaction mixture was stirred at 20 °C under nitrogen protection for 0.5 h. Then, triethylamine (5.14 mmol, 715 μL) and intermediate R (100 mg, 257 μmol) were added sequentially to the reaction mixture, and the reaction mixture was stirred at 60 °C for 12 h. The residue after concentration under reduced pressure was diluted with water (10 mL), and the pH was adjusted to 8 with saturated sodium bicarbonate solution. Extraction was performed with ethyl acetate (15 mL × 3). The bound organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin-layer chromatography (petroleum ether / ethyl acetate, 3 / 1, V / V) to obtain compound 25-1.

[0706] MS-ESI calculated value [M+H] + 621, measured value 621.

[0707] Step 2: Synthesis of the hydrochloride salt of compound 25-2

[0708] Compound 25-1 (114 mg, 184 μmol) was dissolved in ethyl acetate (4 mL). A hydrogen chloride / ethyl acetate solution (4 M, 4 mL) was added to the reaction solution, and the mixture was stirred at 15 °C for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain crude hydrochloride of compound 25-2.

[0709] MS-ESI calculated value [M+H] + 521, measured value 521.

[0710] Step 3: Synthesis of Compound 25

[0711] The crude hydrochloride salt of compound 25-2 (105 mg, 189 μmol) was dissolved in tetrahydrofuran (2 mL), ethanol (1 mL), and water (2 mL). Sodium hydroxide (18.0 mg, 450 μmol) was added to the reaction mixture, and the mixture was stirred at 55 °C for 0.5 h. The pH was adjusted to 6 by adding 1 M hydrochloric acid solution to the reaction mixture at 0 °C. The crude product was concentrated under reduced pressure and separated by high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 35%-45%, 7 min) to obtain compound 25.

[0712] MS-ESI calculated value [M+H] + 507, measured value 507.

[0713] 1 H NMR(400MHz, CD3OD)δ=7.61-7.47(m,3H),7.36-7.29(m,1H),7.27-7.21(m,1H),7 .20-7.14(m,1H),5.15-5.08(m,2H),4.80-4.69(m,1H),4.48-4.39(m,1H),3.24-3 .15(m,1H),3.13-3.04(m,1H),2.76-2.65(m,1H),2.63-2.54(m,1H),2.49-2.39(m ,2H),2.22-2.15(m,3H),2.14-1.99(m,2H),1.96-1.73(m,4H),1.40-1.29(m,6H).

[0714] Example 26

[0715]

[0716] Synthesis route:

[0717]

[0718] Step 1: Synthesis of Compound 26-1

[0719] Intermediate N (171 mg, 514 μmol) was dissolved in methanol (12 mL). Hydrogen chloride / ethyl acetate solution (4 M, 1.60 mL) was added to the reaction mixture, and the reaction mixture was stirred at 20 °C under nitrogen protection for 0.5 h. Then, triethylamine (5.14 mmol, 715 μL) and intermediate R (100 mg, 257 μmol) were added sequentially to the reaction mixture, and the reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (10 mL). The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was separated by thin-layer chromatography (petroleum ether / ethyl acetate, 3 / 1, V / V) to obtain compound 26-1.

[0720] MS-ESI calculated value [M+H] + 635, measured value 635.

[0721] Step 2: Synthesis of the hydrochloride salt of compound 26-2

[0722] Compound 26-1 (110 mg, 173 μmol) was dissolved in ethyl acetate (4 mL). A 4 M, 4 mL solution of hydrogen chloride / ethyl acetate was added to the reaction mixture, and the mixture was stirred at 15 °C for 0.5 hours. The reaction mixture was then concentrated under reduced pressure to obtain crude hydrochloride of compound 26-2.

[0723] MS-ESI calculated value [M+H] + 535, measured value 535.

[0724] Step 3: Synthesis of Compound 26

[0725] The crude hydrochloride salt of compound 26-2 (100 mg, 175 μmol) was dissolved in tetrahydrofuran (2 mL), ethanol (1 mL), and water (2 mL). Sodium hydroxide (14.0 mg, 350 μmol) was added to the reaction mixture, and the mixture was stirred at 55 °C for 0.5 h. The pH of the reaction mixture was adjusted to 6 by adding 1 M hydrochloric acid solution at 0 °C, and the mixture was concentrated under reduced pressure. The crude product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: 10 mmol / L ammonium bicarbonate aqueous solution-acetonitrile; gradient: acetonitrile 32%-62%, 8 min) to obtain compound 26.

[0726] MS-ESI calculated value [M+H] + 521, measured value 521.

[0727] 1H NMR(400MHz, CD3OD)δ=7.61-7.54(m,2H),7.53-7.48(m,1H),7.34-7.28(m,1H),7.24 -7.20(m,1H),7.16-7.11(m,1H),5.14-5.09(m,2H),4.41-4.34(m,1H),3.90-3.84(m, 2H),3.21-3.12(m,1H),3.09-3.00(m,1H),2.73-2.63(m,1H),2.63-2.51(m,1H),2.4 5-2.40(m,2H),2.17(s,3H),2.14-2.00(m,3H),1.92-1.70(m,4H),1.10-1.02(m,6H).

[0728] Example 27

[0729]

[0730] Synthesis route:

[0731]

[0732] Step 1: Synthesis of Compound 27-1

[0733] Intermediate A (176 mg, 514 μmol) was dissolved in methanol (12 mL). A hydrogen chloride / ethyl acetate solution (4 M, 1.60 mL) was added to the reaction mixture, and the reaction mixture was stirred at 20 °C under nitrogen protection for 0.5 h. Then, triethylamine (5.14 mmol, 715 μL) and intermediate R (100 mg, 257 μmol) were added sequentially to the reaction mixture, and the reaction mixture was stirred at 60 °C for 12 h. The residue after concentration under reduced pressure was diluted with water (20 mL), and the pH was adjusted to 8 with saturated sodium bicarbonate solution. Extraction was performed with ethyl acetate (15 mL × 3). The bound organic phase was dried over anhydrous sodium sulfate, filtered, and the crude product after concentration under reduced pressure was separated by thin-layer chromatography (petroleum ether / ethyl acetate, 3 / 1, V / V) to obtain compound 27-1.

[0734] MS-ESI calculated value [M+H] + 645, measured value 645.

[0735] Step 2: Synthesis of the hydrochloride salt of compound 27-2

[0736] Compound 27-1 (134 mg, 208 μmol) was dissolved in ethyl acetate (4 mL). A hydrogen chloride / ethyl acetate solution (4 M, 4 mL) was added to the reaction solution, and the mixture was stirred at 15 °C for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain crude hydrochloride of compound 27-2.

[0737] MS-ESI calculated value [M+H] + 545, measured value 545.

[0738] Step 3: Synthesis of Compound 27

[0739] The crude hydrochloride salt of compound 27-2 (123 mg, 212 μmol) was dissolved in tetrahydrofuran (2 mL), ethanol (1 mL), and water (2 mL). Sodium hydroxide (16.9 mg, 423 μmol) was added to the reaction mixture, and the mixture was stirred at 55 °C for 3 hours. The pH was adjusted to 6 by adding 1 M hydrochloric acid solution at 0 °C, and the mixture was concentrated under reduced pressure. The crude product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 40%-50%, 7 min) to obtain compound 27.

[0740] MS-ESI calculated value [M+H] + 531, measured value 531.

[0741] 1 H NMR(400MHz, CD3OD)δ=7.65-7.60(m,1H),7.59-7.47(m,3H),7.36-7.29(m,1H),7 .27-7.21(m,1H),5.22-5.13(m,2H),4.52-4.38(m,1H),3.24-3.14(m,1H),3.13-3 .04(m,1H),2.98-2.88(m,1H),2.75-2.65(m,1H),2.64-2.53(m,1H),2.49-2.41(m ,2H),2.24-2.16(m,3H),2.16-2.00(m,2H),1.94-1.72(m,9H),1.62-1.35(m,5H).

[0742] Example 28

[0743]

[0744] Synthesis route:

[0745]

[0746] Step 1: Synthesis of Compound 28-1

[0747] Intermediate P (143 mg, 438 μmol) was dissolved in methanol (2 mL). A hydrogen chloride / ethyl acetate solution (4 M, 1.37 mL) was added to the reaction mixture, and the reaction mixture was stirred at 20 °C under nitrogen protection for 0.5 h. Then, triethylamine (4.38 mmol, 610 μL) and intermediate S (100 mg, 219 μmol) were added sequentially to the reaction mixture, and the reaction mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated sodium bicarbonate aqueous solution (100 mL), extracted with ethyl acetate (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 28-1.

[0748] MS-ESI calculated value [M+H] + 513, measured value 513.

[0749] Step 2: Synthesis of Compound 28

[0750] Compound 28-1 (70.0 mg, 137 μmol) was dissolved in tetrahydrofuran (2 mL), ethanol (1 mL), and water (2 mL). Sodium hydroxide (10.9 mg, 273 μmol) was then added to the reaction mixture, which was stirred at 55 °C for 3 hours. The pH was adjusted to 4–5 by adding 4 M hydrochloric acid solution. The crude product, concentrated under reduced pressure, was separated by high-performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 35%–45%, 7 min) to obtain compound 28.

[0751] MS-ESI calculated value [M+H] + 499, measured value 499.

[0752] 1 H NMR (400MHz, CD3Cl) δ = 7.70 (s, 1H), 7.63-7.39 (m, 4H), 7.30 (br d, J = 8.4Hz, 1H), 6.77-6.30 (m, 1H), 5.21 (s, 2H), 4.51 (br s,1H),4.40-4.26(m,1H),4.18(br d,J=2.1Hz,1H),3.89(br d,J=9.3Hz,2H),3.21(br s,2H),2.95-2.82(m,1H),2.33(br d,J=4.0Hz,2H),2.24(s,3H).

[0753] Example 29

[0754]

[0755] Synthesis route:

[0756]

[0757] Step 1: Synthesis of Compound 29-1

[0758] Under nitrogen protection, intermediate N (148 mg, 444 μmol) was dissolved in methanol (20 mL). A hydrogen chloride / ethyl acetate solution (4 M, 1.39 mL) was added to the reaction mixture, and the reaction mixture was stirred at 20 °C for 0.5 h. Then, triethylamine (4.44 mmol, 619 μL) and intermediate S (100 mg, 222 μmol) were added sequentially to the reaction mixture, and the reaction mixture was stirred at 60 °C for 5 h. The residue after concentration under reduced pressure was diluted with saturated sodium bicarbonate aqueous solution (50 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by thin-layer chromatography (dichloromethane / methanol, 20 / 1, V / V) to obtain the crude product of compound 29-1.

[0759] MS-ESI calculated value [M+H] + 533, measured value 533.

[0760] Step 2: Synthesis of Compound 29

[0761] The crude compound 29-1 (140 mg, 263 μmol) was dissolved in tetrahydrofuran (2 mL), ethanol (1 mL), and water (2 mL). Sodium hydroxide (10.5 mg, 263 μmol) was added to the reaction mixture, and the mixture was stirred at 55 °C for 3 hours. The pH of the reaction mixture was adjusted to 4–5 by adding 4 M hydrochloric acid solution, and the mixture was concentrated under reduced pressure. The crude product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 42%–52%, 7 min) to obtain compound 29.

[0762] MS-ESI calculated value [M+H] + 505, measured value 505.

[0763] 1H NMR (400MHz, CD3Cl) δ = 7.61 (s, 1H), 7.58-7.39 (m, 4H), 6.94 (d, J = 8.4Hz, 1H), 5.14 (s, 2H), 4.50 (br s, 1H), 4.25 (br s,1H),4.19-4.00(m,1H),3.98-3.83(m,2H),3.80(d,J=6.4Hz,2H),3.28-3.14(m,2H),2. 95-2.79(m,1H),2.42-2.26(m,2H),2.20(s,3H),2.17-2.06(m,1H),1.04(d,J=6.6Hz,6H).

[0764] Example 30

[0765]

[0766] Synthesis route:

[0767]

[0768] Step 1: Synthesis of Compound 30-1

[0769] Intermediate A (153 mg, 444 μmol) was dissolved in methanol (20 mL). A hydrogen chloride / ethyl acetate solution (4 M, 1.39 mL) was added to the reaction mixture, and the reaction mixture was stirred at 20 °C under nitrogen protection for 0.5 h. Then, triethylamine (4.44 mmol, 619 μL) and intermediate S (100 mg, 222 μmol) were added sequentially to the reaction mixture, and the reaction mixture was stirred at 60 °C for 5 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated sodium bicarbonate aqueous solution (50 mL). Extraction was performed with ethyl acetate (50 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by thin-layer chromatography (dichloromethane / methanol, 20 / 1, V / V) to obtain the crude product of compound 30-1.

[0770] MS-ESI calculated value [M+H] + 543, measured value 543.

[0771] Step 2: Synthesis of Compound 30

[0772] The crude compound 30-1 (140 mg, 258 μmol) was dissolved in tetrahydrofuran (2 mL), ethanol (1 mL), and water (2 mL). Sodium hydroxide (20.6 mg, 516 μmol) was added to the reaction mixture, and the mixture was stirred at 55 °C for 3 hours. The pH of the reaction mixture was adjusted to 4–5 by adding 4 M hydrochloric acid solution, and the mixture was concentrated under reduced pressure. The crude product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 38%–68%, 7 min) to obtain compound 30.

[0773] MS-ESI calculated value [M+H] + 515, measured value 515.

[0774] 1 H NMR (400MHz, CD3Cl) δ = 7.63 (s, 1H), 7.57 (s, 1H), 7.55-7.47 (m, 2H), 7.47-7 .40(m,2H),5.21(s,2H),4.67-4.56(m,1H),4.36-4.20(m,1H),4.19-4.09(m ,1H),4.09-3.96(m,2H),3.43-3.30(m,1H),3.30-3.11(m,1H),3.01-2.83(m ,2H),2.50-2.30(m,2H),2.24(s,3H),1.92-1.70(m,5H),1.49-1.25(m,5H).

[0775] Example 31

[0776]

[0777] Synthesis route:

[0778]

[0779] Step 1: Synthesis of compound 31-1

[0780] Intermediate Q (166 mg, 444 μmol) was dissolved in methanol (20 mL), and then hydrochloric acid / ethyl acetate (1.39 mL, 4 M) was added dropwise to the reaction solution. The mixture was stirred at 20 °C for 0.5 h, and then triethylamine (450 mg, 4.44 mmol) and intermediate S (100 mg, 222 μmol) were added. The mixture was stirred at 60 °C for 5 h. The solvent was removed under reduced pressure, and water (10 mL) was added to the residue. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (15 × 3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by thin-plate chromatography (dichloromethane:methanol = 20:1, V:V) to obtain the crude product of compound 31-1.

[0781] MS-ESI calculated value [M+H] + 545, measured value 545.

[0782] Step 2: Synthesis of Compound 31

[0783] The crude compound 31-1 (170 mg, 226 μmol) was dissolved in a mixed solvent of anhydrous tetrahydrofuran (2 mL), water (1 mL), and anhydrous ethanol (2 mL). Sodium hydroxide (18.1 mg, 451 μmol) was added, and the reaction solution was stirred at 25 °C for 12 hours. The pH of the reaction solution was adjusted to 6 with 1 M hydrochloric acid aqueous solution, and the solution was concentrated under reduced pressure. The concentrated crude product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 32%-62%, 7 min) to obtain compound 31.

[0784] MS-ESI calculated value [M+H] + 517, measured value 517.

[0785] 1H NMR (400MHz, CD3OD) δ = 7.66 (s, 1H), 7.64-7.51 (m, 4H), 7.13 (d, J = 8.4Hz, 1H), 5.16 (s, 2H), 4.98-4.93 (m, 1H), 4.90 (br d,J=2.5Hz,1H),4.43-4.35(m,2H),4.29-4.21(m,2H),3.45(m,J=8.4Hz,1H),3.21-3.10(m,1H),3.04-2.95(m,1 H),2.57-2.45(m,1H),2.24(s,3H),2.22-2.14(m,1H),1.99-1.89(m,2H),1.89-1.76(m,4H),1.72-1.61(m,2H).

[0786] Example 32

[0787]

[0788] Synthesis route:

[0789]

[0790] Step 1: Synthesis of Compound 32-1

[0791] Under nitrogen protection, intermediate L (95.1 mg, 298 μmol) was dissolved in methanol (20 mL). A hydrogen chloride / ethyl acetate solution (4 M, 931 μL) was added to the reaction mixture, and the reaction mixture was stirred at 20 °C for 0.5 h. Then, triethylamine (2.98 mmol, 415 μL) and intermediate S (100 mg, 149 μmol) were added sequentially to the reaction mixture, and the reaction mixture was stirred at 60 °C for 5 h. The batches of intermediate S (50 mg) were combined, and the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL), and the pH was adjusted to 8 with saturated sodium bicarbonate solution. Extraction was performed with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by thin-layer chromatography (dichloromethane / methanol, 20 / 1, V / V) to obtain compound 32-1.

[0792] MS-ESI calculated value [M+H] + 519, measured value 519.

[0793] Step 2: Synthesis of Compound 32

[0794] Compound 32-1 (100 mg, 193 μmol) was dissolved in tetrahydrofuran (2 mL), ethanol (1 mL), and water (2 mL). Sodium hydroxide (15.4 mg, 386 μmol) was added to the reaction mixture, and the mixture was stirred at 55 °C for 3 hours. The pH was adjusted to 6 by adding 1 M hydrochloric acid solution at 0 °C, and the mixture was concentrated under reduced pressure. The crude product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 30%-60%, 7 min) to obtain compound 32-1.

[0795] MS-ESI calculated value [M+H] + 491, measured value 491.

[0796] 1 H NMR (400MHz, CD3OD) δ = 7.66 (s, 1H), 7.63-7.55 (m, 3H), 7.55-7.51 (m, 1H), 7 .16(d,J=8.5Hz,1H),5.16(s,2H),4.86-4.70(m,2H),4.38-4.30(m,2H),4. 21(t,J=8.9Hz,2H),3.43-3.35(m,1H),3.20-3.09(m,1H),3.04-2.95(m,1H ),2.56-2.44(m,1H),2.24(s,3H),2.22-2.13(m,1H),1.34(d,J=6.0Hz,6H).

[0797] Step 3: Synthesis of compounds 32A and 32B

[0798] Compound 32 was separated into compounds 32A and 32B by SFC (separation column: DAICL CHIRALPAK IC 250 mm × 30 mm, 10 μm; mobile phase: 0.1% ammonia-methanol; gradient: methanol 35%-35%, 4.3 min; 140 min). The retention time of 32A was 1.27 min, ee% = 100%, and the retention time of 32B was 1.68 min, ee% = 98.21%.

[0799] Example 33

[0800]

[0801] Synthesis route:

[0802]

[0803] Step 1: Synthesis of compound 33-1

[0804] Under nitrogen protection, intermediate O (165 mg, 444 μmol) was dissolved in methanol (20 mL). A hydrogen chloride / ethyl acetate solution (4 M, 1.39 mL) was added to the reaction mixture, and the mixture was stirred at 20 °C for 0.5 h. Triethylamine (4.44 mmol, 619 μL) and intermediate S (100 mg, 222 μmol) were added sequentially to the reaction mixture, and the reaction mixture was stirred at 60 °C for 3 h. The residue after concentration under reduced pressure was diluted with water (10 mL), the pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was then separated by thin-layer chromatography (dichloromethane / methanol, 20 / 1, V / V) to obtain compound 33-1.

[0805] MS-ESI calculated value [M+H] + 531, measured value 531.

[0806] Step 2: Synthesis of Compound 33

[0807] Compound 33-1 (114 mg, 215 μmol) was dissolved in tetrahydrofuran (2 mL), ethanol (1 mL), and water (2 mL). Sodium hydroxide (17.2 mg, 430 μmol) was added to the reaction mixture, and the mixture was stirred at 55 °C for 3 hours. The pH of the reaction solution was adjusted to 6 by adding 1 M hydrochloric acid solution at 0 °C. The crude product, concentrated under reduced pressure, was separated by high performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 30%-60%, 7 min) to obtain compound 33.

[0808] MS-ESI calculated value [M+H] + 503, measured value 503.

[0809] 1H NMR (400MHz, CD3OD) δ=7.66-7.64(m,1H),7.62-7.55(m,3H),7.54-7.50(m,1H),7.15-7.09 (m,1H),5.22-5.12(m,2H),4.86-4.82(m,1H),4.41-4.30(m,2H),4.26-4.15(m,2H),4.00-3 .92(m,2H),3.44-3.33(m,1H),3.21-3.10(m,1H),3.04-2.93(m,1H),2.55-2.43(m,1H),2.2 5-2.22(m,3H),2.21-2.13(m,1H),1.34-1.18(m,1H),0.64-0.57(m,2H),0.43-0.34(m,2H).

[0810] Example 34

[0811]

[0812] Synthesis route:

[0813]

[0814] Step 1: Synthesis of Compound 34-1

[0815] Hydrochloric acid / ethyl acetate (4M, 1.24 mL, 4.94 mmol) was added to a methanol (2 mL) solution of intermediate Q (170.75 mg, 494.40 μmol), and the reaction was carried out at 20 °C for 0.5 h. Triethylamine (400 mg, 3.96 mmol) was added dropwise to the reaction solution, followed by intermediate M (150 mg, 494 μmol), and the reaction was carried out at 60 °C for 3 h. The pH of the reaction solution was adjusted to 8 with a saturated sodium bicarbonate aqueous solution, diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel thin-layer chromatography (dichloromethane / methanol, 20 / 1, V / V) to obtain compound 34-1.

[0816] MS-ESI calculated value [M+H] + 561, measured value 561.

[0817] Step 2: Synthesis of Compound 34

[0818] Compound 34-1 (140 mg, 262.86 μmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL), ethanol (1 mL), and water (2 mL). Sodium hydroxide (42.06 mg, 1.05 mmol) was added, and the mixture was reacted at 60 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated, diluted with 3 mL of water, and the pH was adjusted to 5 with 1 M hydrochloric acid aqueous solution. The solution was then concentrated under reduced pressure. The concentrated crude product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 34%-64%, 10 min) to obtain compound 34.

[0819] MS-ESI calculated value [M+H] + 519, measured value 519.

[0820] 1 H NMR(400MHz, CD3OD)δ=7.68-7.52(m,5H),7.16-7.09(m,1H),5.19-5.14(m,2H),5.12-5.05(m,1H),4.98-4 .92(m,1H),3.29-2.98(m,4H),2.70-2.65(m,3H),2.64-2.36(m,4H),2.29-2.20(m,3H),2.01-1.57(m,9H).

[0821] Example 35

[0822]

[0823] Synthesis route:

[0824]

[0825] Step 1: Synthesis of Compound 35-1

[0826] Hydrochloric acid / ethyl acetate (4M, 1.24 mL, 4.94 mmol) was added to a methanol (5 mL) solution of intermediate L (157.87 mg, 494.40 μmol), and the reaction was carried out at 20 °C for 0.5 h. Triethylamine (400 mg, 3.96 mmol) was added dropwise to the reaction solution, followed by intermediate M (150 mg, 494 μmol), and the reaction was carried out at 60 °C for 3 h. The reaction solution was diluted with water (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL × 1). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated by silica gel thin-layer chromatography (dichloromethane / methanol, 10 / 1, V / V) to obtain compound 35-1.

[0827] MS-ESI calculated value [M+H] + 535, measured value 535.

[0828] Step 2: Synthesis of Compound 35

[0829] Compound 35-1 (86 mg, 160.87 μmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL), ethanol (1 mL), and water (2 mL). Sodium hydroxide (12.87 mg, 321.73 mmol) was added, and the mixture was reacted at 60 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated, diluted with 2 mL of water, and the pH was adjusted to 6 with 1 M hydrochloric acid aqueous solution. The solution was then concentrated under reduced pressure. The concentrated crude product was separated by high performance liquid chromatography (HPLC) (column: Phenomenex luna C18 75 × 30 mm × 3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 40%-50%, 7 min) to obtain compound 35.

[0830] MS-ESI calculated value [M+H] + 493, measured value 493.

[0831] 1 H NMR (400MHz, CD3OD) δ = 7.73-7.49 (m, 5H), 7.16 (d, J = 8.4Hz, 1H), 5.16 (s, 2H), 5.11-5.05 (m, 1H), 4.79 -4.68(m,1H),3.29-2.98(m,4H),2.67(s,3H),2.64-2.36(m,4H),2.25(s,3H),1.34(d,J=6.1Hz,6H).

[0832] Biological activity:

[0833] Test Example 1: In vitro evaluation of the S1P1 agonist activity of the compounds of this invention

[0834] Experimental objective: To detect the agonistic activity of the compound on S1P1.

[0835] I. Cell Treatment

[0836] 1. Remove the U2OS-EDG1 cells (batch number: Invitrogen-K1520) from the liquid nitrogen tank and thaw them rapidly in a 37°C water bath;

[0837] 2. Aspirate the cell suspension into a 15 mL centrifuge tube, resuspend in 5 mL of preheated culture medium, and centrifuge at 1000 rpm for 5 min;

[0838] 3. Discard the supernatant, resuspend in 10 mL of culture medium, transfer to a T75 culture flask, and incubate at 37°C in a 5% CO2 incubator.

[0839] II. Agonist Assay

[0840] 1. Dilute the compound to the working concentration by performing a 3-fold dilution using an Echo 555 (manufacturer: Labcyte), resulting in 10 concentrations. Transfer 200 nL of each concentration to a cell plate and centrifuge at 1000 rpm for 15 seconds.

[0841] 2. Aspirate the culture medium from the culture flask, add 4 mL of DuPont phosphate buffer (DPBS, supplier: Coring, catalog number: 21-031-CVR, batch number: 03318006) to wash away residual serum, add 2 mL of trypsin, incubate at 37°C for 2 minutes to digest the cells, add 10 mL of seeding medium to resuspend the cells, and take 0.6 mL of the cell suspension for counting;

[0842] 3. Adjust the cell density to 1.88E+05 cells / mL using seeding plate medium, seeding 40 μL (7500 μL / well) into each well, and adding 40 μL of FreeStyle medium around the perimeter of the cell plate. TM Expression medium, incubated at room temperature for 15 minutes, then incubated at 37°C with 5% CO2 for 20 hours.

[0843] III. Signal Detection

[0844] 1. Configure LiveBLAzer according to the instruction manual. TM -FRET B / G Substrate (CCF4-AM) detection reagent;

[0845] 2. Add 8 μL of 6×Substrate Mixture to each well of the cell plate, centrifuge at 1000 rpm for 15 seconds, attach the membrane, incubate at 23°C for 2 hours, and detect with Envision chemiluminescence.

[0846] IV. Data Analysis

[0847] 1. Use equations to convert the raw data into %Effect, EC 50 The value can be obtained by curve fitting using four parameters [obtained in GraphPad Prism using the "log(agonist) vs. response--Variable slope" mode].

[0848] 2. Calculation formula:

[0849] Ratio=(460nm–blank) / (535nm–blank)

[0850] %Effect=(Sample) Ratio –Ave LCRatio ) / (Ave HC Ratio -Ave LC Ratio ) x 100%

[0851] The experimental results are shown in Table 1:

[0852] Table 1 Results of S1P1 agonist activity assay

[0853] Test sample <![CDATA[S1P1 agonist activity EC 50 , Emax]]> Trifluoroacetate of compound 1 41.56 nM, 88.4% Trifluoroacetate of compound 3 5.77 nM, 95% Hydrochloride salt of compound 10 57.18 nM, 84.2% Trifluoroacetate of compound 11 4.97 nM, 97.4% Hydrochloride salt of compound 13 14.06 nM, 102.2% Hydrochloride salt of compound 14 27.37 nM, 113.2% Compound 20 8.92 nM, 51.0% Compound 21 12.30 nM, 105.5% Formate of compound 22 19.23 nM, 107.3% Compound 28 23.09 nM, 120.7% Compound 29 8.62 nM, 102.8% Compound 30 16.50 nM, 63.4% Compound 31 10.27 nM, 105.0% Compound 32 2.30 nM, 98.6% Compound 32A 3.84 nM, 101.4% Compound 32B 1.15 nM, 103.4% Compound 33 2.98 nM, 109.9% Compound 35 6.88 nM, 100.7%

[0854] Conclusion: All compounds of the present invention exhibit significant and even unexpected S1P1 agonist activity.

[0855] Test Example 2: Pharmacokinetic Evaluation of Compounds in Rats

[0856] Experimental objective: To test the pharmacokinetics of the compound in SD rats.

[0857] Experimental materials:

[0858] Sprague Dawley rats (male, 200-300g, 7-9 weeks old, Shanghai Slack)

[0859] Experimental procedure:

[0860] The pharmacokinetic characteristics of the compound after intravenous and oral administration were tested in rodents using a standard protocol. In the experiment, the candidate compound was prepared into a clear solution and administered to rats via single intravenous injection and oral administration. The solvent for both intravenous and oral administration was DMSO:10% hydroxypropyl β-cyclodextrin aqueous solution = 5:95. Whole blood samples were collected within 48 hours, centrifuged at 3000g for 15 minutes, and the supernatant was separated to obtain plasma samples. Four volumes of acetonitrile solution containing internal standard were added to precipitate proteins. The supernatant was centrifuged again, and an equal volume of water was added. The supernatant was then injected, and the plasma concentration was quantitatively analyzed using LC-MS / MS. Pharmacokinetic parameters such as peak concentration, time to peak concentration, clearance, half-life, area under the curve, and bioavailability were calculated.

[0861] The experimental results are shown in Table 2:

[0862] Table 2 Pharmacokinetic Test Results

[0863]

[0864] ND: Undetermined; / : Undetermined due to lack of relevant testing.

[0865] *: Area under the curve (AUC) during drug administration 0-last iv(nM.hr)

[0866] Conclusion: The compounds of this invention exhibit good bioavailability, high area under the curve and low clearance rate in SD rat pharmacokinetics.

[0867] Test Example 3: Pharmacodynamic Evaluation of the Compound in a Male SD Rats with Ischemia-Reperfusion Infarction

[0868] Experimental Objective: To explore the ameliorative effect of compound 32 on a rat model of ischemia-reperfusion cerebral infarction.

[0869] Experimental materials: Male SD rats (250g-280g, SPF grade, Zhejiang Vital River Laboratory Animal Technology Co., Ltd.)

[0870] Experimental procedure:

[0871] 1) Anesthesia: The animals were kept under anesthesia using 2.5% isoflurane inhalation.

[0872] 2) Middle Cerebral Artery Occlusion (MCAO) Model: Animals weighed between 250-280g during the modeling surgery. After anesthesia, rats were placed in a supine, sterile position with the left common carotid artery exposed. A specially designed nylon suture was inserted through the left internal carotid artery to occlude the left middle cerebral artery, achieving a 90-minute temporary ischemia-reperfusion model in the left brain. In the Sham group, the left common carotid artery was exposed after anesthesia, but the suture was not inserted. Meloxicam was administered subcutaneously once daily for 3 consecutive days at a dose of 1 mg / kg. The test compound group (compound 32) was administered via tail vein injection after reperfusion at a dose of 1 mg / kg and a volume of 5 mL / kg.

[0873] 3) Model success criteria:

[0874] 1: Animals were included in the group if they scored 2-3 points according to the Bederson method within 60 minutes after surgery.

[0875] 2: Within 30-60 minutes of modeling, if the blood flow on the model side (left side) decreases by more than 30% compared to the right side, the model is considered successful and animals are included in the group; if the blood flow decreases by less than 30%, the model is considered unsuccessful and animals are removed.

[0876] 4) Detection indicator: Percentage of cerebral infarction at the end of the test

[0877] Evaluation of cerebral infarction area: On the endpoint of the experiment, animals were euthanized, and brains were harvested and coronally sectioned with equal thickness (3 mm per slice, 5 slices in total). The slices were stained with 2% TTC staining solution. Double-sided scanning imaging of the stained brain slices was performed for infarction area analysis. Brain tissue was subsequently fixed with 10% formalin. The percentage of left cerebral infarction area is shown below. Figure 1 As shown.

[0878] The experimental results are shown in Table 3. The T-test compound 32 showed a p-value of <0.05 compared to the model group.

[0879] Table 3

[0880] Group Percentage of left cerebral infarction area Sham Group 0 Model group 32.4％ Compound 32 21.0％

[0881] Experimental conclusion: Compared with the model group, the compound of the present invention can significantly improve the infarct area in the ischemia-reperfusion model.

[0882] Test Example 4: Analysis and Identification of Metabolites of Compounds in Human Liver Microsomes and Hepatocyte Incubation Systems

[0883] Experimental objective:

[0884] High-resolution mass spectrometry was used to identify the metabolites and structures of compound 32B produced by incubation in human liver microsomes and hepatocytes; LC-UV was used to calculate the percentage content of compound 32B and its metabolites; and possible biotransformation pathways of compound 32B in human liver microsomes and hepatocytes were investigated in vitro.

[0885] Experimental procedure:

[0886] Compound 32B (10 μM) was incubated in a system containing human liver microsomes and NADPH at 37 °C for 60 min. 7-ethoxycoumarin (7-EC, 10 μM) was used as a positive control to evaluate the enzyme metabolic activity in the liver microsome incubation system. The incubated samples were analyzed using LC-UV-HRMS. The structures of each metabolite were determined and identified based on the primary and secondary mass spectrometry signals and / or comparison with standards. Data was acquired using LC-UV-HRMS, and the relative percentage of the UV integrated peak area for each metabolite was provided. Based on the mass spectrometry information of the metabolites, the possible structures of the metabolites were inferred, and their possible metabolic pathways in various liver microsomes were also inferred.

[0887] Compound 32B (10 μM) was incubated at 37 °C for 120 min in mouse, rat, dog, monkey, and human hepatocyte systems. 7-ethoxycoumarin (7-EC, 30 μM) was used as a positive control to evaluate the enzyme metabolic activity in the hepatocyte incubation system. The incubated samples were analyzed by LC-UV-MS. The structures of each metabolite were elucidated and identified based on the primary and secondary mass spectrometric signals and / or comparison with standards. Data were acquired by HPLC-UV-MS, and the relative percentage of the UV integrated peak area for each metabolite was provided. Based on the mass spectrometric information of the metabolites, the possible structures of the metabolites were inferred, and their possible metabolic pathways in various hepatocyte genus were also predicted.

[0888] Experimental results: After incubation of compound 32B with human liver microsomes for 1 hour, the parent drug was the main component with a relative abundance of 100.00%; no other metabolites were detected. After incubation of compound 32B with human hepatocytes for 2 hours, it mainly existed in the parent drug form with a relative abundance of 100.00%, and no other metabolites were detected.

[0889] Experimental conclusion: The compounds of this invention have good metabolic stability.

[0890] Test Example 5: In vitro evaluation of the agonistic activity of the compounds of this invention against S1P2, S1P3, and S1P4. Objective: To detect the agonistic activity of the compounds against S1P2, S1P3, and S1P4.

[0891] I. Cell Treatment

[0892] 1. The PathHunter cell line was expanded from the cryopreservation facility according to standard procedures.

[0893] 2. Seed cells in a total volume of 20 μL into white 384-well microplates and incubate at 37°C for an appropriate time before testing.

[0894] II. Agonist assay

[0895] 1. To perform agonist assays, cells are incubated with the sample to induce a reaction.

[0896] 2. The stock solution is stored in buffer at 5 times the concentration to be tested.

[0897] 3. Add 5 μL of the stock solution sample (5 times the concentration to be tested) to the cells and incubate at 37°C or room temperature for 90-180 minutes. The solvent concentration is 1%.

[0898] III. Signal Detection

[0899] 1. A single addition of 12.5 or 15 μL (50% v / v) of the PathHunter Detection reagent mixture generates a detection signal, followed by incubation at room temperature for 1 hour.

[0900] 2. Use the PerkinElmer Envision™ instrument to detect the chemiluminescence signal and read the microplate after the signal is generated.

[0901] IV. Data Analysis

[0902] 1. Use the CBIS data analysis suite (ChemInnovation, CA) to analyze compound activity.

[0903] 2. For agonist mode assays, the percentage of activity is calculated using the following formula:

[0904] % activity = 100% x (mean RLU of test sample - mean RLU of blank control) / (mean MAX control ligand - mean RLU of blank control).

[0905] The experimental results are shown in Table 4.

[0906] Table 4

[0907] <![CDATA[S1P2 agonist activity EC 50 > <![CDATA[S1P3 agonist activity EC 50 > <![CDATA[S1P4 agonist activity EC 50 > Compound 32B >300nM >300nM >300nM

[0908] Conclusion: The compounds of this invention are effective against S1P2 and S1P. 3, S1P4 has weak agonistic activity.

Claims

1. A compound of formula (I) ###0001### or a pharmaceutically acceptable salt thereof, wherein, m is 1 ; T1 is selected from CR5; L1 is a single bond; R1 is selected from H, -NH-CH2-COOH and -NH-CH2CH2-COOH. L2 is selected from CH2, CH2CH2, C(CH3)2 and CH2CH2CH2. R3 is selected from H, F, Cl, Br, CN and CF3. R5 is selected from H and F. one of R1and R2is H, the other is selected from the group consisting of -L1-NR a -L2-COOH, -L1-NR a -L2-Cyclopropyl-COOH and -azetidinyl-COOH, said -L1-NR a -L2-COOH, -azetidinyl-COOH optionally substituted with 1, 2, or 3 R b substituents; 10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, selected from ###0003### wherein, m and T1 are as defined in claim 1 ; R1 is as defined in claim 1 or 2; R2 is as defined in any one of claims 1, 4 or 5; R3 is as defined in claim 1 or 6; R4 is as defined in any one of claims 1, 7 or 8. L2is selected from C 1-3 alkyl; R3and R5are each independently selected from the group consisting of H, F, Cl, Br, CN, and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2, or 3 R c substituents; R4is selected from -O-C 1-6 alkyl, -O-C 1-3 alkyl-cyclopropyl, -O-C 3-6 cycloalkyl and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-6 alkyl and C 3-6 cycloalkyl is optionally substituted with 1, 2, or 3 R d substituents; R a selected from H and CH3; R b selected from H, F, CI, Br, and I; R c and R d are each independently selected from H, F, Cl, Br, and I.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, 11. A compound according to claim 10, or a pharmaceutically acceptable salt thereof, selected from ###0004### wherein, m, T1, R3, R4 are as defined in claim 10; L2 is as defined in claim 1 or 3.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, 13. A compound according to claim 12, or a pharmaceutically acceptable salt thereof, selected from ###0006### 4. The compound or pharmaceutically acceptable salt thereof of claim 1 or 3, wherein, R2is selected from H, -NH-CH2-COOH, -NH-CH2CH2-COOH, -N(CH3)-CH2CH2-COOH, and said -NH-CH2-COOH, -NH-CH2CH2-COOH, -N(CH3)-CH2CH2-COOH, and optionally substituted by 1, 2, or 3 R b substituents.

5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein, R2is selected from H, -NH-CH2-COOH, -NH-CH2CH2-COOH, -N(CH3)-CH2CH2-COOH, 6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, 14. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of ischemic stroke.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, R4is selected from -O-C 1-4 alkyl, -O-C 1-3 alkyl, -O-C 1-4 alkyl, -O-C 1-3 alkyl, -O-C d substituted.

8. The compound or pharmaceutically acceptable salt thereof of claim 1 or 7, wherein, R4is selected from 9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ R a As defined in claim 1 ; ​ ​ 12. A compound as shown below, or a pharmaceutically acceptable salt thereof, ​ ​

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