Benzo-2-azaspiro[4.4]nonane compounds and their applications

Abstract

Disclosed are a series of benzo-2-azaspiro[4.4]nonane compounds, specifically a compound represented by formula (P) or a pharmaceutically acceptable salt thereof.

Description

[0001] The present invention claims the following priority:

[0002] CN202010144413.2, application date: March 4, 2020;

[0003] CN202010464132.5, application date: May 27, 2020;

[0004] CN202010144397.7, application date: March 4, 2020;

[0005] CN202010464155.6, application date: May 27, 2020;

[0006] CN202010902712.8, application date: September 1, 2020. Technical Field

[0007] The present invention relates to a series of benzo-2-azaspiro[4.4]nonane compounds, and in particular to a compound represented by formula (P) or a pharmaceutically acceptable salt thereof. Background Art

[0008] Sphingosine-1-phosphate (S1P) is a cell membrane-derived lysophospholipid signaling molecule that exerts physiological functions mainly by stimulating some members of the G protein-coupled receptor family, mainly the sphingosine-1-phosphate receptors (S1PRs) family. Currently, five different S1PR subtypes have been identified in mammals, including sphingosine-1-phosphate receptor 1 (S1PR1 or EDG1), sphingosine-1-phosphate receptor 2 (S1PR2 or EDG5), sphingosine-1-phosphate receptor 3 (S1PR3 or EDG3), sphingosine-1-phosphate receptor 4 (S1PR4 or EDG6), and sphingosine-1-phosphate receptor 5 (S1PR5 or EDG8). S1PR1-3 are widely expressed in various tissues, S1PR4 is mainly expressed in the lymphatic system and blood system, and S1PR5 is mainly expressed in the central nervous system. Lymphocytes sense S1P concentration gradients through S1PR1, thereby regulating lymphocytes from secondary lymphoid organs into lymphatic and blood circulation. S1PR1 agonists can trigger the endocytosis of S1PR1 on the surface of lymphocytes, making lymphocytes unable to sense S1P concentration gradients, preventing lymphocytes from migrating to lymphatic and blood circulation, triggering lymphocyte homing, reducing the number of lymphocytes in the peripheral circulatory system, preventing lymphocytes from reaching the location of inflammatory lesions or transplants, reducing excessive inflammation, and having an immune regulatory effect.

[0009] Autoimmune diseases are a general term for a class of diseases caused by the body's immune response to its own antigens, which causes the immune system to mistakenly attack its own tissues. Currently, there are more than 80 types of diseases that have been precisely defined, and excessive inflammatory response is a common feature. S1PR1 agonists can effectively reduce excessive inflammation and can be used to treat or prevent autoimmune diseases, including multiple sclerosis, inflammatory bowel disease (divided into Crohn's disease and ulcerative colitis), systemic lupus erythematosus and psoriasis.

[0010] At present, the in vivo efficacy studies of S1PR1 agonists are used to treat or prevent autoimmune diseases. Novartis' first-generation non-selective S1PRs agonist Fingolimod was approved by the FDA for relapsing multiple sclerosis (RMS) in September 2010, and Novartis' second-generation selective S1PR1 and S1PR5 agonist Siponimod was also approved by the FDA for relapsing multiple sclerosis (RMS) in March 2019. The discovery and application of new S1PR agonists has broad prospects. Summary of the invention

[0011] The present invention provides a compound represented by formula (P) or a pharmaceutically acceptable salt thereof,

[0012]

[0013] in,

[0014] T0 is selected from CH-E-R3 and N;

[0015] T1 is selected from CR4 and N;

[0016] E is absent or selected from O and NH;

[0017] Ring A is selected from oxazolyl, 1,2,4-oxadiazolyl, thiazolyl, 1,3,4-thiadiazole, 1,2,4-thiadiazolyl, pyrimidinyl and pyrazinyl;

[0018] R2 is selected from H, F, Cl, Br, CN, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with 1, 2 or 3 R b replace;

[0019] R3 is selected from C 1-6 Alkyl, cyclopentyl and cyclohexyl, the C 1-6 Alkyl, cyclopentyl and cyclohexyl are optionally substituted with 1, 2 or 3 R c replace;

[0020] R4 is selected from H and cyclopentyl;

[0021] R5 is selected from

[0022] R 51 Selected from H, OH, NH2, CN, COOH, CH2COOH, CH2OH, C 1-3 Alkoxy and -S(O)2-C 1-3 Alkyl, the C 1-3 Alkoxy and C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a replace;

[0023] R 52 is selected from OH, CN, NH2 and COOH;

[0024] R 53 Selected from H and OH;

[0025] R a , R b and R c are independently selected from F, Cl and Br;

[0026] n is selected from 0 and 1.

[0027] In some embodiments of the present invention, the ring A is selected from Other variables are as defined in the present invention.

[0028] In some embodiments of the present invention, the above R2 is selected from H, F, Cl, Br, CN, CH3 and OCH3, and the CH3 and OCH3 are optionally replaced by 1, 2 or 3 R b The other variables are as defined in the present invention.

[0029] In some embodiments of the present invention, the above R2 is selected from H, Br, Cl, CN, CHF2, CF3 and OCH3, and other variables are as defined in the present invention.

[0030] In some embodiments of the present invention, the above R3 is selected from C 1-4 alkyl, The C 1-4 alkyl, Optional 1, 2 or 3 R c The other variables are as defined in the present invention.

[0031] In some embodiments of the present invention, the above R3 is selected from CH(CH3)2, CHF2, CH2CH(CH3)2 Other variables are as defined herein.

[0032] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined herein.

[0033] In some embodiments of the present invention, the above R 51 is selected from H, OH, NH2, CN, COOH, CH2COOH, CH2OH, OCH3 and -S(O)2CH3, wherein OCH3 and -S(O)2CH3 are optionally replaced by 1, 2 or 3 R a The other variables are as defined in the present invention.

[0034] In some embodiments of the present invention, the above R 51 is selected from OH, NH2, CN, CH2COOH, CH2OH, OCH3 and -S(O)2CH3, and the other variables are as defined herein.

[0035] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined herein.

[0036] In some embodiments of the present invention, the above R 52 is selected from the group consisting of CN, NH2 and COOH, and other variables are as defined herein.

[0037] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined herein.

[0038] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from:

[0039]

[0040] Among them, T0, T1, R 53 , n, ring A, R2, R 51 and R 52 As defined in the present invention.

[0041] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from:

[0042]

[0043] in,

[0044] R2, R3, T1, E and n are as defined in the present invention;

[0045] T2 is selected from O and S;

[0046] T3 is selected from CH and N;

[0047] T4 is selected from CH, T5 is selected from N, or T4 is selected from N, T5 is selected from CH.

[0048] Some other solutions of the present invention are obtained by any combination of the above variables.

[0049] The present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof:

[0050]

[0051]

[0052]

[0053] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from:

[0054]

[0055] The present invention also provides use of the compound or a pharmaceutically acceptable salt thereof in preparing a drug for treating diseases associated with S1PR1.

[0056] The present invention also provides the following solutions:

[0057] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0058]

[0059] in,

[0060] T1 is selected from CH and N;

[0061] E is selected from O and NH;

[0062] Ring A is selected from oxazolyl, 1,2,4-oxadiazolyl, thiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazolyl, pyrimidinyl and pyrazinyl;

[0063] R1 is selected from H, OH, NH2, CN, COOH, CH2COOH, C 1-3 Alkoxy and -S(O)2-C 1-3 Alkyl, the C 1-3 Alkoxy and C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R a replace;

[0064] R2 is selected from F, Cl, Br, CN and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace;

[0065] R3 is selected from C 1-6 Alkyl and cyclopentyl, the C 1-6 The alkyl and cyclopentyl groups are optionally substituted with 1, 2 or 3 R c replace;

[0066] R a , R b and R c are independently selected from F, Cl and Br.

[0067] In some embodiments of the present invention, the ring A is selected from Other variables are as defined herein.

[0068] In some embodiments of the present invention, the above R1 is selected from H, OH, NH2, CN, COOH, CH2COOH, OCH3 and -S(O)2CH3, wherein OCH3 and -S(O)2CH3 are optionally replaced by 1, 2 or 3 R a The other variables are as defined in the present invention.

[0069] In some embodiments of the present invention, the above R1 is selected from OH, NH2, CN, CH2COOH, OCH3 and -S(O)2CH3, and other variables are as defined in the present invention.

[0070] In some embodiments of the present invention, the above R2 is selected from F, Cl, Br, CN and CH3, and the CH3 is optionally replaced by 1, 2 or 3 R b The other variables are as defined in the present invention.

[0071] In some embodiments of the present invention, the above R2 is selected from Cl, Br, CN and CHF2, and other variables are as defined in the present invention.

[0072] In some embodiments of the present invention, the above R3 is selected from C 1-3 Alkyl and The C 1-3 Alkyl and Optional 1, 2 or 3 R c The other variables are as defined in the present invention.

[0073] In some embodiments of the present invention, the above R3 is selected from CHF2, CH(CH3)2 and Other variables are as defined herein.

[0074] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined herein.

[0075] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from:

[0076]

[0077] in,

[0078] R1, R2, R3, T1 and E are as defined in the present invention;

[0079] T2 is selected from O and S;

[0080] T3 is selected from CH and N;

[0081] T4 is selected from CH, T5 is selected from N, or T4 is selected from N, T5 is selected from CH.

[0082] Some other solutions of the present invention are obtained by any combination of the above variables.

[0083] The present invention also provides the following solutions:

[0084] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0085]

[0086] in,

[0087] T1 is selected from CH and N;

[0088] E is selected from O and NH;

[0089] Ring A is selected from oxazolyl, 1,2,4-oxadiazolyl, thiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazolyl, pyrimidinyl and pyrazinyl;

[0090] R1 is selected from OH, CN, NH2 and COOH;

[0091] R2 is selected from F, Cl, Br, CN and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace;

[0092] R3 is selected from C 1-6 Alkyl and cyclopentyl, the C 1-6 The alkyl and cyclopentyl groups are optionally substituted with 1, 2 or 3 R c replace;

[0093] R b and R c are independently selected from F, Cl and Br;

[0094] n is selected from 0 or 1.

[0095] In some embodiments of the present invention, the ring A is selected from and, other variables are as defined in the present invention

[0096] In some embodiments of the present invention, the above R1 is selected from CN, NH2 and COOH, and other variables are as defined in the present invention.

[0097] In some embodiments of the present invention, the above R2 is selected from F, Cl, Br, CN and CH3, and the CH3 is optionally replaced by 1, 2 or 3 R b The other variables are as defined in the present invention.

[0098] In some embodiments of the present invention, the above R2 is selected from Br, CN and CHF2, and other variables are as defined in the present invention.

[0099] In some embodiments of the present invention, the above R3 is selected from C 1-3 Alkyl and The C 1-3 Alkyl and Optional 1, 2 or 3 R c The other variables are as defined in the present invention.

[0100] In some embodiments of the present invention, the above R3 is selected from CH(CH3)2, CHF2 and Other variables are as defined herein.

[0101] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined herein.

[0102] In some embodiments of the present invention, the above compound or a pharmaceutically acceptable salt thereof is selected from:

[0103]

[0104] in,

[0105] R2, R3, T1, E and n are as defined in the present invention;

[0106] T2 is selected from O and S;

[0107] T3 is selected from CH and N.

[0108] Some other solutions of the present invention are obtained by any combination of the above variables.

[0109] The present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0110]

[0111] in,

[0112] T1 is selected from CH and N;

[0113] E is selected from O and NH;

[0114] Ring A is selected from oxazolyl, 1,2,4-oxadiazolyl, thiazole, 1,3,4-thiadiazole, 1,2,4-thiadiazolyl, pyrimidinyl and pyrazinyl;

[0115] R1 is selected from OH, CN, NH2 and COOH;

[0116] R2 is selected from F, Cl, Br, CN and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R b replace;

[0117] R3 is selected from C 1-6 Alkyl and cyclopentyl, the C 1-6 The alkyl and cyclopentyl groups are optionally substituted with 1, 2 or 3 R c replace;

[0118] R b and R c are independently selected from F, Cl and Br;

[0119] n is selected from 0 or 1.

[0120] In some embodiments of the present invention, the ring A is selected from and, other variables are as defined in the present invention

[0121] In some embodiments of the present invention, the above R1 is selected from COOH, and other variables are as defined in the present invention.

[0122] In some embodiments of the present invention, the above R2 is selected from F, Cl, Br, CN and CH3, and the CH3 is optionally replaced by 1, 2 or 3 R b The other variables are as defined in the present invention.

[0123] In some embodiments of the present invention, the above R2 is selected from Br, CN and CHF2, and other variables are as defined in the present invention.

[0124] In some embodiments of the present invention, the above R3 is selected from C 1-3 Alkyl and The C 1-3 Alkyl and Optional 1, 2 or 3 R c The other variables are as defined in the present invention.

[0125] In some embodiments of the present invention, the above R3 is selected from CH(CH3)2, CHF2 and Other variables are as defined herein.

[0126] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined herein.

[0127] Some other solutions of the present invention are obtained by any combination of the above variables.

[0128] Technical Effects

[0129] The compounds of the present invention have significant and even unexpected S1PR1 agonistic activity, good bioavailability, and can significantly inhibit lymphocytes.

[0130] Related definitions

[0131] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0132] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0133] The term "pharmaceutically acceptable salt" refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases. When the compounds of the 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 the 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, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.

[0134] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

[0135] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0136] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up 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 another example, deuterium can be used to replace hydrogen to form a deuterated drug. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

[0137] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0138] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include a variant of deuterium and hydrogen, as long as 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 be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be arbitrary on the basis of chemical achievable.

[0139] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0140] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0141] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0142] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds to become a group with the corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy line For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0143] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-3 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6 and C5 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as 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, and the like.

[0144] Unless otherwise specified, the term “C 1-4 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 Alkyl groups include C 1-2 , C 1-3 and C 2-3 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 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), and the like.

[0145] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C2-3 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0146] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. 1-3 Alkoxy includes C 1-2 , C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0147] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including 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 , also includes any range from n to n+m, such as C1- 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 Etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.

[0148] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis 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.

[0149] The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0150] The solvent used in the present invention is commercially available.

[0151] Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names. DETAILED DESCRIPTION

[0152] The present invention is described in detail below by way of examples, but it is not intended to impose any adverse limitations on the present invention. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications may be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0153] Example 1

[0154]

[0155] Synthesis route:

[0156]

[0157] first step

[0158] Compound 1a (500 g, 2.50 mol) and isopropanol (180 g, 3.00 mol) were dissolved in N,N-dimethylformamide (2500 mL), sodium hydroxide (281 g, 5.00 mol) was added to the reaction solution, and then the reaction solution was stirred at 25°C for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with water (10 L), extracted with ethyl acetate (2 L × 3), the combined organic phases were washed with saturated brine (2 L × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1b.

[0159] MS-ESI calculated value [M+H] + 240 and 242, measured values ​​240 and 242.

[0160] Step 2

[0161] Compound 1b (180 g, 750 mmol) was dissolved in N, N-dimethylformamide (180 mL) and methanol (720 mL), potassium acetate (147 g, 1.50 mol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (16.46 g, 22.49 mmol) were added to the reaction solution, and then the gas in the reaction system was replaced with carbon monoxide. The reaction solution was stirred at 80°C for 19 hours under a carbon monoxide (50 PSI) atmosphere. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the residue was diluted with water (3 L), extracted with ethyl acetate (1 L × 3), the combined organic phases were washed with saturated brine (1 L × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (5:1, petroleum ether / ethyl acetate, Rf = 0.45) to obtain compound 1c.

[0162] 1 H NMR (400MHz, CDCl3) δ=8.23 (d, J=1.7Hz, 1H), 8.20-8.14 (m, 1H), 6.99 (d, J=9.0Hz, 1H), 4.81-4.69 (m, 1H), 3.91 (s, 3H), 1.43 (d, J=6.0Hz, 6H).

[0163] Step 3

[0164] Compound 1c (432 g, 1.91 mol) was dissolved in methanol (860 mL), and a solution of lithium hydroxide monohydrate (161 g, 3.83 mol) in water (860 mL) was added to the above reaction solution in batches, and the reaction solution was stirred at 25°C for 4 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and the residue was washed with ethyl acetate (800 mL×2). The pH value of the aqueous phase was adjusted to 3 with 1M hydrochloric acid aqueous solution, extracted with ethyl acetate (1000 mL×3), and the combined organic phases were washed with saturated brine (1000 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was added to a mixed solution of ethyl acetate (160 mL) and n-heptane (960 mL), stirred at 20°C for 16 hours, filtered, and the filter cake was dried under vacuum to obtain compound 1d.

[0165] 1 H NMR (400MHz, CDCl3) δ=8.32 (d, J=2.2Hz, 1H), 8.25 (dd, J=2.2, 8.9Hz, 1H), 7.04 (d, J=9.2Hz, 1H), 4.84-4.73 (m, 1H), 1.47 (d, J=6.1Hz, 6H).

[0166] Step 4

[0167] Compound 1f (56.0 g, 308 mmol) was dissolved in N, N-dimethylformamide (200 mL), potassium tert-butoxide (34.6 g, 308 mmol) was added, the reaction solution was stirred at 25°C for 2 hours, and then compound 1e (50.0 g, 237 mmol) was slowly added, and the reaction solution was stirred at 25°C for 12 hours. Water (800 mL) was added to the reaction solution, and it was extracted with ethyl acetate (400 mL×3), the organic phases were combined, and the organic phases were washed with water (500 mL×1) and saturated brine (500 mL×1), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by column chromatography (10:1, petroleum ether / ethyl acetate, Rf=0.6, 0.7) to obtain compound 1g.

[0168] MS-ESI calculated value [M+H] + 267 and 269, measured values ​​267 and 269.

[0169] 1 H NMR (400MHz, CDCl3) δ = 7.57-7.48 (m, 1H), 7.39-7.29 (m, 1H), 7.24-7.10 (m, 1H) ), 6.55-6.27(m, 1H), 3.81-3.70(m, 3H), 3.63-3.37(m, 2H), 3.33-3.00(m, 2H).

[0170] Step 5

[0171] Compound 1g (100 g, 374 mmol) was dissolved in dimethyl sulfoxide (400 mL), cesium carbonate (97.6 g, 299 mmol) was added, and nitromethane (68.6 g, 1.12 mol) was slowly added dropwise, and the reaction solution was stirred at 70°C for 16 hours. Water (1600 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (800 mL×3), and the organic phases were combined and washed with water (1000 mL×1) and saturated brine (1000 mL×1), respectively, dried over anhydrous sodium sulfate, and concentrated to obtain compound 1h.

[0172] 1 H NMR (400MHz, CDCl3) δ=7.41 (dd, J=7.2, 1.6Hz, 1H), 7.12-7.04 (m, 2H), 4.89 (d, J=11.6Hz, 1H), 4.81 (d, J=1 1.6Hz, 1H), 3.86 (s, 3H), 3.04-2.96 (m, 3H), 2.78 (d, J=16.4Hz, 1H), 2.44-2.35 (m, 1H), 2.26-2.16 (m, 1H).

[0173] Step 6

[0174] Compound 1h (100 g, 305 mmol) was dissolved in a mixed solvent of ethanol (300 mL) and water (100 mL), and ammonium chloride (48.90 g, 914 mmol) and iron powder (51.1 g, 914 mmol) were added, and the reaction solution was stirred at 80°C for 15 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was diluted with water (1000 mL), extracted with ethyl acetate (500 mL×3), the combined organic phases were washed with saturated brine (500 mL×1), dried over anhydrous sodium sulfate, concentrated, and the crude product was added to a mixed solution of ethyl acetate / n-heptane (1:6, 1180 mL), stirred at 25°C for 3 days, filtered, and the filter cake was dried in vacuo to obtain compound 1i.

[0175] MS-ESI calculated value [M+H] + 266 and 268, measured values ​​266 and 268.

[0176] 1 H NMR (400MHz, CDCl3) δ=7.52-7.32(m, 1H), 7.25-7.06(m, 2H), 7.06-6.87(m, 1H ), 3.63-3.32(m, 2H), 3.08-2.83(m, 2H), 2.69-2.41(m, 2H), 2.36-2.10(m, 2H).

[0177] Step 7

[0178] Compound 1i (2.00 g, 7.52 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and lithium aluminum hydride (570 mg, 15.0 mmol) was slowly added to the reaction solution in batches, and the reaction solution was stirred at 70°C for 3 hours. The reaction solution was quenched by adding saturated ammonium chloride solution (50 mL), filtered, and the filtrate was collected and concentrated under reduced pressure. The residue was diluted with water (100 mL), extracted with ethyl acetate (100 mL×2), and the combined organic phase was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 1j.

[0179] MS-ESI calculated value [M+H] + 252 and 254, measured values ​​252 and 254.

[0180] Step 8

[0181] Compound 1j (1.22 g, 4.84 mmol) was dissolved in anhydrous dichloromethane (20 mL), di-tert-butyl dicarbonate (1.27 g, 5.81 mmol) and triethylamine (1.18 g, 11.6 mmol) were added to the mixture, and the reaction solution was stirred at 25° C. for 2 hours. The reaction solution was concentrated, and the crude product was separated and purified by silica gel column chromatography (5:1, petroleum ether / ethyl acetate, Rf=0.7) to obtain compound 1k.

[0182] MS-ESI calculated values ​​[M+H- t Bu] + 296 and 298, measured values ​​296 and 298.

[0183] Step 9

[0184] Compound 1k (1.44 g, 4.09 mmol), zinc cyanide (720 mg, 6.13 mmol) and 2-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (156 mg, 327 μmol) were dissolved in anhydrous N,N-dimethylformamide (20 mL). Tris(dibenzylideneacetone)dipalladium (150 mg, 164 μmol) was added to the mixture under nitrogen protection, and the reaction solution was stirred at 90°C for 12 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL×2), the combined organic phase was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (5:1, petroleum ether / ethyl acetate, Rf=0.25) to obtain compound 11.

[0185] MS-ESI calculated values ​​[M+H- t Bu] + 243, measured value 243.

[0186] Step 10

[0187] Compound 11 (720 mg, 2.41 mmol) was dissolved in anhydrous ethanol (10 mL), hydroxylamine hydrochloride (502 mg, 7.22 mmol) and triethylamine (731 mg, 7.22 mmol) were added to the mixture, and the reaction solution was stirred at 80° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and water (25 mL) was added to the residue for dilution. The reaction solution became turbid, and was filtered, and the filter cake was vacuum dried to obtain a crude compound 1m.

[0188] MS-ESI calculated value [M+H] + 332, measured value 332.

[0189] Step 11

[0190] Compound 1d (495 mg, 2.41 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), 1-hydroxybenzotriazole (391 mg, 2.90 mmol) and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (555 mg, 2.90 mmol) were added to the mixture, and the reaction solution was stirred at 25°C for 1 hour. Compound 1m (800 mg, 2.41 mmol) was added to the mixture, and the reaction solution was stirred at 25°C for 1 hour and at 80°C for 16 hours. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (500 mL×3), the combined organic phase was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography (3:1, petroleum ether / ethyl acetate, Rf=0.4) to obtain compound 1n.

[0191] MS-ESI calculated values ​​[M+H- t Bu] + 445, measured value 445.

[0192] Step 12

[0193] Compound 1n (750 mg, 1.50 mmol) was dissolved in ethyl acetate (5 mL), hydrochloric acid / ethyl acetate (4 M, 1.87 mL) was added to the mixture, and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of crude compound 1o.

[0194] MS-ESI calculated value [M+H] + 401, measured value 401.

[0195] 1 H NMR (400MHz, CDCl3) δ=8.41 (d, J=2.1Hz, 1H), 8.34 (dd, J=2.1, 8.9Hz, 1H), 8.10 (d, J=7.7Hz, 1H), 7.60-7.40 ( m, 2H), 7.13 (d, J=9.0Hz, 1H), 4.88-4.73 (m, 1H), 3.91-3.35 (m, 6H), 2.51-2.19 (m, 4H), 1.48 (d, J=6.1Hz, 6H).

[0196] Step 13

[0197] Compound 1o (7.83 mg, 103 μmol) was dissolved in anhydrous dichloromethane (2 mL), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (65.3 mg, 172 μmol) was added to the mixture, and the reaction solution was stirred at 25°C for 0.5 hours. Compound 1p hydrochloride (50 mg, 114 μmol) and triethylamine (34.7 mg, 343 μmol) were added to the mixture, and the reaction solution was stirred at 25°C for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 57%-77%, 6.5 minutes} to obtain compound 1.

[0198] MS-ESI calculated value [M+H] + 459, measured value 459.

[0199] 1 H NMR(400 MHz, DMSO-d6) δ=8.51 (d, J=2.4Hz, 1H), 8.41 (dd, J=9.2, 2.4Hz, 1H), 8.01-7.98 (m, 1H), 7.56 (d, J=8.8Hz, 1H), 7.53-7.49 ( m, 1H), 7.48-7.44 (m, 1H), 5.02-4.95 (m, 1H), 4.15-3.95 (m, 2H), 3.72-3.25 (m, 7H), 2.19-2.04 (m, 4H), 1.41-1.38 (m, 6H).

[0200] Example 3

[0201]

[0202] Synthesis route:

[0203]

[0204] Compound 3a (9.28 mg, 103 μmol) was dissolved in anhydrous dichloromethane (2 mL), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (65.3 mg, 172 μmol) was added to the mixture, and the reaction solution was stirred at 25° C. for 0.5 hours, and the hydrochloride of compound 1o (50.0 mg, 114 μmol) and triethylamine (34.7 mg, 343 μmol) were added to the mixture, and the reaction solution was stirred at 25° C. for 0.5 hours. The reaction solution was concentrated, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 60%-80%, 7.5 minutes} to obtain compound 3.

[0205] MS-ESI calculated value [M+H] + 473, measured value 473.

[0206] 1 H NMR(400 MHz, DMSO-d6) δ=8.53 (d, J=2.2Hz, 1H), 8.42 (dd, J=2.3, 8.9Hz, 1H), 8.04-7.98 (m, 1H), 7.59-7.43 (m, 3H), 5 .03-4.94(m, 1H), 4.13-3.97(m, 2H), 3.73-3.34(m, 6H), 3.30(s, 3H), 2.23-2.01(m, 4H), 1.42-1.37(m, 6H).

[0207] Example 4

[0208]

[0209] Synthesis route:

[0210]

[0211] Compound 4a (8.76 mg, 103 μmol) was dissolved in anhydrous dichloromethane (2 mL), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (65.3 mg, 172 μmol) was added to the mixture, and the reaction solution was stirred at 25° C. for 0.5 hours. Compound 1o hydrochloride (50.0 mg, 114 μmol) and triethylamine (34.7 mg, 343 μmol) were added to the mixture, and the reaction solution was stirred at 25° C. for 0.5 hours. The reaction solution was concentrated, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 57%-77%, 7.5 minutes} to obtain compound 4.

[0212] MS-ESI calculated value [M+H] + 468, measured value 468.

[0213] 1 H NMR(400 MHz, DMSO-d6) δ=8.53 (d, J=2.2Hz, 1H), 8.42 (dd, J=2.3, 9.0Hz, 1H), 8.06-7.97 (m, 1H), 7.61-7.44 (m, 3H), 5.0 4-4.94 (m, 1H), 4.07-3.89 (m, 2H), 3.74-3.42 (m, 4H), 3.36-3.25 (m, 2H), 2.23-2.03 (m, 4H), 1.42-1.37 (m, 6H).

[0214] Example 5

[0215]

[0216] Synthesis route:

[0217]

[0218] Compound 5a (13.5 mg, 103 μmol) was dissolved in anhydrous dichloromethane (2 mL), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (65.3 mg, 172 μmol), hydrochloride of compound 1o (50.0 mg, 114 μmol), triethylamine (34.7 mg, 343 μmol) were added to the mixture, and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was concentrated, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C1875*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 52%-72%, 6.5 minutes} to obtain compound 5.

[0219] MS-ESI calculated value [M+H] + 501, measured value 501.

[0220] 1 H NMR(400 MHz, DMSO-d6)δ=8.55-8.51(m, 1H), 8.45-8.40(m, 1H), 8.03-7.98(m, 1H), 7.59-7.43(m, 3H), 5.04-4.95 (m, 1H), 3.79-3.25 (m, 6H), 2.59-242 (m, 4H), 2.25-2.04 (m, 4H), 1.42-1.37 (m, 6H).

[0221] Example 6

[0222]

[0223] Synthesis route:

[0224]

[0225] first step

[0226] Compound 6a (18.0 mg, 103 μmol) was dissolved in anhydrous dichloromethane (2 mL), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (65.3 mg, 172 μmol) was added to the mixture, the reaction solution was stirred at 25°C for 0.5 hours, and the hydrochloride of compound 1o (50.0 mg, 114 μmol) and triethylamine (34.7 mg, 343 μmol) were added to the mixture. Water (20 mL) was added to the reaction solution, and it was extracted with dichloromethane (10 mL×3), the organic phases were combined, and the organic phases were washed with water (10 mL) and saturated brine (10 mL) in turn, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain compound 6b, and the crude product was used directly in the next step without purification.

[0227] MS-ESI calculated value [M+H] + 558, measured value 558.

[0228] Step 2

[0229] Compound 6b (81.0 mg, 145 μmol) was dissolved in anhydrous methanol (2 mL), and methanol hydrochloric acid (4 M, 363 μL) was added to the mixture, and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was concentrated, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 29%-49%, 7.5 minutes} to obtain the hydrochloride of compound 6.

[0230] MS-ESI calculated value [M+H] + 458, measured value 458.

[0231] 1 H NMR (400MHz, DMSO-d6) δ = 8.53 (d, J = 2.2Hz, 1H), 8.42 (dd, J = 2.2, 8.9Hz, 1H), 8.14 (brs, 3H), 8.06-9.00 (m, 1H), 7.61-7.44 (m, 3H), 5.05-4.93 (m, 1H), 3.92-3.25 (m, 8H), 2.26-1.98 (m, 4H), 1.42-1.37 (m, 6H).

[0232] Example 7

[0233]

[0234] Synthesis route:

[0235]

[0236] Compound 7a (15.8 mg, 114 μmol) was dissolved in anhydrous dichloromethane (2 mL), 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate (65.3 mg, 172 μmol) was added to the mixture, and the reaction solution was stirred at 25°C for 0.5 hours, and the hydrochloride of compound 1o (50.0 mg, 114 μmol) and triethylamine (34.7 mg, 343 μmol) were added to the mixture, and the reaction solution was stirred at 25°C for 0.5 hours. The reaction solution was concentrated, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 32%-52%, 6.5 minutes} to obtain compound 7.

[0237] MS-ESI calculated value [M+H] + 521, measured value 521.

[0238] 1 H NMR (400MHz, DMSO-d6) δ = 8.56-8.52 (m, 1H), 8.46-8.40 (m, 1H), 8.04-7.99 (m, 1H), 7.61-7.44 (m, 3H), 5.05-4.94 (m, 1 H), 4.45-4.35(m, 2H), 3.92-3.44(m, 4H), 3.34-3.28(m, 2H), 3.18-3.11(m, 3H), 2.26-1.96(m, 4H), 1.42-1.37(m, 6H).

[0239] Example 8

[0240]

[0241] Synthesis route:

[0242]

[0243] first step

[0244] Compound 8a (68.0 g, 653 mmol) and imidazole (200 mL) were dissolved in dichloromethane (500 mL) and cooled to 0°C. Tert-butyldimethylsilyl chloride (103 g, 686 mmol) was dissolved in dichloromethane (200 mL) and added to the above reaction solution. The reaction solution was stirred at 0°C under nitrogen protection for 3 hours. The reaction solution was concentrated under reduced pressure, diluted with petroleum ether (1500 mL), washed with water (300 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8b.

[0245] 1H NMR (400MHz, CDCl3) δ=4.24 (s, 2H), 4.20 (q, J=7.2Hz, 2H), 1.28 (t, J=7.2Hz, 3H), 0.93 (s, 9H), 0.11 (s, 6H).

[0246] Step 2

[0247] Compound 8b (12.0 g, 55.0 mmol) was dissolved in ethanol (120 mL) and cooled to 0°C. Potassium hydroxide (4.62 g, 82.4 mmol) in ethanol (120 mL) was added to the reaction solution, and the reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (100 mL). 1 M hydrochloric acid was slowly added dropwise at 0°C to adjust the pH to 4. The mixture was extracted with ethyl acetate (50 mL × 4), and the organic phases were combined and washed with water (30 mL × 1) and saturated brine (30 mL × 2), respectively, dried over anhydrous sodium sulfate, and concentrated to obtain compound 8c.

[0248] 1 H NMR (400MHz, CDCl3) δ = 4.24 (s, 2H), 0.94 (s, 9H), 0.15 (s, 6H)

[0249] Step 3

[0250] Compound 8d (1.00 g, 4.31 mmol) and 2-iodopropane (1.47 g, 8.62 mmol) were dissolved in toluene (8 mL), and then silver carbonate (3.57 g, 12.9 mmol) was added, and the reaction solution was stirred at 50° C. for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (100 mL), extracted with ethyl acetate (100 mL×3), and the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 8e.

[0251] MS-ESI calculated value [M+H] + 274 and 276, measured values ​​274 and 276.

[0252] 1 H NMR (400MHz, CDCl3) δ=8.72 (d, J=2.1Hz, 1H), 8.38 (d, J=2.1Hz, 1H), 5.48-5.37 (m, 1H), 3.92 (s, 3H), 1.42 (d, J=6.2Hz, 6H).

[0253] Step 4

[0254] Compound 8e (1.00 g, 3.65 mmol) was dissolved in anhydrous N, N-dimethylformamide (15 mL), zinc cyanide (857 mg, 7.30 mmol), tris(dibenzylideneacetone)dipalladium (334 mg, 365 μmol), 2-di-tert-butylphosphine-2′,4′,6′-triisopropylbiphenyl (348 mg, 730 μmol) were added, and the reaction solution was stirred at 90° C. for 12 hours under nitrogen protection. The reaction solution was concentrated, the residue was diluted with water (50 mL), extracted with ethyl acetate (30 mL×3), the combined organic phases were washed with saturated brine (40 mL×1), dried over anhydrous sodium sulfate, concentrated, and the crude product was separated and purified by silica gel column chromatography (10:1, petroleum ether / ethyl acetate, Rf=0.4) to obtain compound 8f.

[0255] MS-ESI calculated values ​​[M+H- i Pr] + 179, measured value 179.

[0256] Step 5

[0257] Compound 8f (100 mg, 454 μmol) was dissolved in tetrahydrofuran (1 mL) and methanol (0.5 mL), and a solution of lithium hydroxide monohydrate (57.2 mg, 1.36 mmol) in water (0.5 mL) was added dropwise to the reaction solution, and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and the residue was adjusted to pH 6 with 1N hydrochloric acid aqueous solution, then diluted with water (50 mL), extracted with ethyl acetate (50 mL×3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was separated and purified by thin layer silica gel chromatography (10:1, dichloromethane / methanol, Rf=0.21) to obtain compound 8g.

[0258] 1 H NMR (400MHz, CDCl3) δ = 9.18-8.74 (m, 1H), 8.70-8.23 (m, 1H), 5.60-5.38 (m, 1H), 1.43 (d, J = 6.1Hz, 6H).

[0259] Step 6

[0260] Compound 1j (8.20 g, 32.5 mmol), compound 8c (7.43 g, 39.0 mmol) and diisopropylethylamine (12.6 g, 97.6 mmol) were dissolved in N, N-dimethylformamide (80 mL) and then 2-(7-azobenzotriazole)-N, N, N, N-tetramethyluronium hexafluorophosphate (14.8 g, 39.0 mmol) was added. The reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, diluted with water (200 mL), extracted with ethyl acetate (100 mL×3), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was separated and purified by column chromatography (2:1, petroleum ether / ethyl acetate, Rf=0.3) to obtain compound 8h.

[0261] MS-ESI calculated value [M+H] + 310 and 312, measured values ​​310 and 312.

[0262] Step 7

[0263] Compound 8h (5.00 g, 16.1 mmol) was dissolved in anhydrous N,N-dimethylformamide (50 mL), and zinc cyanide (3.79 g, 32.2 mmol), tris(dibenzylideneacetone)dipalladium (738 mg, 806 μmol), and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (768 mg, 1.66 mmol) were added. The atmosphere was replaced with nitrogen three times. Under nitrogen protection, the reaction solution was stirred at 90°C for 12 hours. After the reaction was completed, the reaction solution was concentrated. The residue was diluted with water (200 mL), extracted with ethyl acetate (100 mL×3), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and separated and purified by silica gel column chromatography (2:1, petroleum ether / ethyl acetate, Rf=0.3) to obtain a crude product. The crude product was purified by HPLC {hydrochloric acid conditions, column model: Phenomenex luna C18 250*50mm*10μm; fluidity: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 10%-40%, 20 minutes} to obtain compound 8i.

[0264] MS-ESI calculated value [M+H] + 257, measured value 257.

[0265] Step 8

[0266] Compound 8i (700 mg, 2.73 mmol) and diisopropylethylamine (706 mg, 5.46 mmol) were dissolved in ethanol (15 mL), and then hydroxylamine hydrochloride (380 mg, 5.46 mmol) was added, and the reaction solution was stirred at 60° C. for 12 hours. The reaction solution was cooled to room temperature, concentrated, and the residue was diluted with ethanol (10 mL), stirred at 25° C. for 12 hours, filtered, and the filter cake was washed with ethanol (5 mL×2), and the filter cake was vacuum dried to obtain compound 8j.

[0267] MS-ESI calculated value [M+H] + 290, measured value 290.

[0268] Step 9

[0269] Compound 8g (43.9 mg, 213 μmol) was dissolved in N,N-dimethylformamide (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44.5 mg, 232 μmol) and 1-hydroxybenzotriazole (31.4 mg, 232 μmol) were added to the reaction solution. The reaction solution was stirred at 25°C for 15 minutes, and then compound 8j (56.0 mg, 194 μmol) was added. The reaction was stirred at 25°C for 1 hour and then at 80°C for 12 hours. The reaction solution was concentrated under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate (20 mL×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 57%-77%, 7 minutes} to obtain compound 8.

[0270] MS-ESI calculated value [M+H] + 460, measured value 460.

[0271] 1 H NMR (400MHz, CDCl3) δ=9.16 (d, J=2.3Hz, 1H), 8.65 (d, J=2.3Hz, 1H), 8.14-8.07 (m, 1H), 7.42 (t, J=8.0Hz, 1H), 7.32 ( d, J=8.0Hz, 1H), 5.62-5.51 (m, 1H), 4.25-4.06 (m, 2H), 3.97-3.33 (m, 6H), 2.32-2.01 (m, 4H), 1.48 (d, J=6.0Hz, 1H).

[0272] Example 9

[0273]

[0274] Synthesis route:

[0275]

[0276] first step

[0277] Compound 1a (1.00 g, 5.00 mmol) and cyclopentanol (517 mg, 6.00 mmol) were dissolved in N,N-dimethylformamide (10 mL) at 0°C, and sodium hydride (600 mg, 15.0 mmol, 60% purity) was added to the reaction solution after stirring for 15 minutes, and then the reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated, the residue was diluted with water (50 mL), extracted with ethyl acetate (50 mL×3), the combined organic phases were washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 9a.

[0278] MS-ESI calculated value [M+H] + 266 and 268, measured values ​​266 and 268.

[0279] Step 2

[0280] Compound 9a (1.30 g, 4.88 mmol) was dissolved in N, N-dimethylformamide (3 mL) and methanol (9 mL), potassium acetate (1.44 g, 14.7 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (357 mg, 488 μmol) were added to the reaction solution, and then the gas in the reaction system was replaced with argon and carbon monoxide in turn, and the reaction solution was stirred at 80°C for 19 hours under a carbon monoxide (50 PSI) atmosphere. The reaction solution was concentrated under reduced pressure, the residue was diluted with water (200 mL), extracted with ethyl acetate (200 mL×2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (10:1, petroleum ether / ethyl acetate, Rf=0.20) to obtain compound 9b.

[0281] MS-ESI calculated value [M+H] + 246, measured value 246.

[0282] Step 3

[0283] Compound 9b (1.00 g, 4.08 mmol) was dissolved in tetrahydrofuran (10 mL) and methanol (2 mL), and a solution of lithium hydroxide monohydrate (513 mg, 12.2 mmol) in water (1 mL) was added dropwise to the reaction solution, and the reaction solution was stirred at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water (100 mL), washed with ethyl acetate (100 mL×3), and the aqueous phase was adjusted to a pH of less than 6 with a 1N hydrochloric acid aqueous solution. It was extracted with ethyl acetate (50 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 9c.

[0284] MS-ESI calculated value [M+H] + 232, measured value 232.

[0285] 1 H NMR (400MHz, CDCl3) δ=8.32 (d, J=2.1Hz, 1H), 8.25 (dd, J=9.0, 2.1Hz, 1H), 7.04 (d, J=9 .0Hz, 1H), 5.00-4.92(m, 1H), 2.07-1.94(m, 4H), 1.92-1.83(m, 2H), 1.75-1.63(m, 2H).

[0286] Step 4

[0287] Compound 9c (52.8 mg, 228 μmol) was dissolved in N,N-dimethylformamide (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47.7 mg, 249 μmol) and 1-hydroxybenzotriazole (33.6 mg, 249 μmol) were added to the reaction solution. The reaction solution was stirred at 25°C for 15 minutes, and then compound 8j (60.0 mg, 207 μmol) was added. The reaction was stirred at 25°C for 1 hour and then at 80°C for 12 hours. After the reaction, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (30 mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC {hydrochloric acid conditions, column model: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 53%-83%, 10 minutes} to obtain compound 9.

[0288] MS-ESI calculated value [M+H] + 485, measured value 485.

[0289] 1H NMR (400MHz, CDCl3) δ = 8.45-8.41 (m, 1H), 8.37-8.32 (m, 1H), 8.13-8.07 (m, 1H), 7.457.38 (m, 1H), 7.34-7.29 (m, 1H), 7.18-7.11 (m, 1H) , 5.06-4.93(m, 1H), 4.30-4.20(m, 1H), 4.20-4.03(m, 1H), 3.96-3.52(m, 4H), 3.47-3.33(m, 3H), 2.34-1.98(m, 8H), 1.94-1.69(m, 4H).

[0290] Example 10

[0291]

[0292] first step

[0293] Compound 10a (2.00 g, 8.66 mmol) was dissolved in N, N-dimethylformamide (20 mL), 2-bromopropane (1.60 g, 13.0 mmol) and potassium carbonate (2.39 g, 17.3 mmol) were added, and the reaction solution was stirred at 80°C for 12 hours. The reaction solution was diluted with water (200 mL), extracted with ethyl acetate (200 mL×2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel column chromatography (3:1, petroleum ether / ethyl acetate, Rf=0.74) to obtain compound 10b.

[0294] MS-ESI calculated value [M+H] + 273 and 275, measured values ​​273 and 275.

[0295] Step 2

[0296] Compound 10b (900 mg, 3.30 mmol) was dissolved in tetrahydrofuran (10 mL) and methanol (2 mL), and a solution of lithium hydroxide monohydrate (415 mg, 9.89 mmol) in water (3 mL) was added dropwise to the reaction solution, and the reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated, and the pH was adjusted to about 6 with a 1N hydrochloric acid solution. Then, the solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 10c.

[0297] MS-ESI calculated value [M+H] + 259 and 261, measured values ​​259 and 261.

[0298] 1H NMR (400MHz, CDCl3) δ=8.30 (d, J=2.0Hz, 1H), 8.02 (dd, J=8.8, 2.0Hz, 1H), 694 (d, J=8.8Hz, 1H), 4.76-4.64 (m, 1H), 1.44 (d, J=6.0Hz, 6H).

[0299] Step 3

[0300] Compound 10c (64.5 mg, 249 μmol) was dissolved in N,N-dimethylformamide (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55.7 mg, 290 μmol) and 1-hydroxybenzotriazole (39.2 mg, 290 μmol) were added to the reaction solution. The reaction solution was stirred at 25°C for 15 minutes, and then compound 8j (60.0 mg, 207 μmol) was added. The reaction was stirred at 25°C for 1 hour and then at 80°C for 16 hours. The reaction solution was concentrated under reduced pressure, diluted with water (100 mL), extracted with ethyl acetate (50 mL×3), the combined organic phases were washed with water (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC {hydrochloric acid conditions, column model: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 60%-90%, 10 minutes} to obtain compound 10.

[0301] MS-ESI calculated value [M+H] + 512 and 514, measured values ​​512 and 514.

[0302] 1 H NMR (400MHz, CDCl3) δ = 8.43 (d, J = 2.1Hz, 1H), 8.14-8.08 (m, 2H), 7.44-7.37 (m, 1H), 7.32-7.28 (m, 1H), 7.07-7.01 (m, 1H), 4.77- 4.68 (m, 1H), 4.23-4.17 (m, 1H), 4.14-4.08 (m, 1H), 3.95-3.49 (m, 3H), 3.47-3.37 (m, 3H), 2.32-1.98 (m, 4H), 1.49-1.44 (m, 6H).

[0303] Embodiment 11

[0304]

[0305] first step

[0306] Compound 11a (0.500 g, 2.68 mmol) was dissolved in N, N-dimethylformamide (10 mL), 2-bromopropane (494 mg, 4.02 mmol) and potassium carbonate (741 mg, 5.36 mmol) were added, and the reaction solution was stirred at 80°C for 12 hours. The reaction solution was diluted with water (200 mL), extracted with ethyl acetate (200 mL×2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by chromatography (3:1, petroleum ether / ethyl acetate, Rf=0.62) to obtain compound 11b.

[0307] MS-ESI calculated value [M+H] + 229, measured value 229.

[0308] Step 2

[0309] Compound 11b (500 mg, 2.19 mmol) was dissolved in tetrahydrofuran (5 mL) and methanol (1 mL), and a solution of lithium hydroxide monohydrate (275 mg, 6.56 mmol) in water (1 mL) was added dropwise to the reaction solution, and the reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated to remove the organic solvent, and the pH was adjusted to about 6 with 1N hydrochloric acid solution. Then, the solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 11c.

[0310] MS-ESI calculated value [M+H] + 215, measured value 215.

[0311] 1 H NMR (400MHz, CDCl3) δ=8.13 (d, J=2.0Hz, 1H), 7.98 (dd, J=8.8, 2.0Hz, 1H), 697 (d, J=8.8Hz, 1H), 4.83-4.59 (m, 1H), 1.44 (d, J=6.1Hz, 6H)

[0312] Step 3

[0313] Compound 11c (44.5 mg, 207 μmol) was dissolved in N,N-dimethylformamide (2 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47.7 mg, 249 μmol) and 1-hydroxybenzotriazole (33.6 mg, 249 μmol) were added to the reaction solution, the reaction solution was stirred at 25°C for 15 minutes, and then compound 8j (60.0 mg, 207 μmol) was added, the reaction solution was stirred at 25°C for 1 hour, and then stirred at 80°C for 12 hours. The reaction solution was concentrated under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate (30 mL×3), and the combined organic phases were washed with water (20 mL×2) and saturated brine (20 mL×2), respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC {hydrochloric acid conditions, column model: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.05% HCl)-acetonitrile]; B%: 52%-82%, 10 minutes} to obtain compound 11.

[0314] MS-ESI calculated value [M+H] + 468, measured value 468.

[0315] 1 H NMR (400MHz, CDCl3) δ=8.25 (d, J=2.1Hz, 1H), 8.13-8.04 (m, 2H), 7.45-7.37 (m, 1H), 7.32-7.28 (m, 1H), 7.07 (d, J=8.7Hz, 1H), 4.7 8-4.66 (m, 1H), 4.25-4.17 (m, 1H), 4.16-4.04 (m, 1H), 3.98-3.50 (m, 3H), 3.46-3.37 (m, 3H), 2.33-2.04 (m, 4H), 1.49-1.44 (m, 6H).

[0316] Example 12

[0317]

[0318] Synthesis route:

[0319]

[0320] first step

[0321] Compound 12a (100 mg, 555 μmol) was dissolved in anhydrous N,N-dimethylformamide (1 mL). Anhydrous potassium carbonate (307 mg, 2.22 mmol) and 2-iodopropane (189 mg, 111 μmol) were added to the mixture. The reaction solution was stirred at 60°C for 18 hours. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with 10 mL of water and 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 12b.

[0322] MS-ESI calculated values ​​[M+H- i Pr] + 181, measured value 181.

[0323] 1 H NMR (400MHz, CDCl3) δ=10.40 (s, 1H), 8.42 (d, J=2.3Hz, 1H), 8.13 (dd, J=8.9, 2.3, Hz, 1H), 6.96 (d, J=8.9Hz, 1H), 4.71 (p, J=6.1Hz, 1H), 3.83 (s, 3H), 1.37 (d, J=6.1Hz, 6H).

[0324] Step 2

[0325] Compound 12b (140 mg, 630 μmol) was dissolved in anhydrous dichloromethane (4 mL), and (diethylamino)sulfur trifluoride (609 mg, 3.78 mmol) was added dropwise to the mixture. The reaction solution was stirred at 25°C for 15 hours, 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL×2). The organic phases were combined, washed with 10 mL of water and 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by thin layer silica gel chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound 12c.

[0326] MS-ESI calculated value [M+H] + 245, measured value 245.

[0327] 1 H NMR (400MHz, CDCl3) δ=8.18 (d, J=2.0Hz, 1H), 8.03 (dd, J=8.8, 2.0Hz, 1H), 688 (d, J=8.8H z, 1H), 8.50 (t, J=55.4Hz, 1H), 4.63 (p, J=6.1Hz, 1H), 3.83 (s, 3H), 1.32 (d, J=6.1Hz, 6H).

[0328] Step 3

[0329] Compound 12c (89.0 mg, 440 μmol) was dissolved in anhydrous tetrahydrofuran (3 mL) and anhydrous methanol (1.5 mL). A solution of lithium hydroxide monohydrate (45.9 mg, 1.09 mmol) in water (0.75 mL) was added to the reaction solution. The reaction solution was stirred at 25°C for 12 hours. The organic solvent was removed under reduced pressure. 1N hydrochloric acid aqueous solution was added to adjust the pH to 1. The solution was filtered with suction and the filter cake was dried to obtain compound 12d.

[0330] MS-ESI calculated value [M+H] + 231, measured value 231.

[0331] Step 4

[0332] Compound 12d (47.7 mg, 207 μmol) was dissolved in N,N-dimethylformamide (2 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47.7 mg, 249 μmol) and 1-hydroxybenzotriazole (33.6 mg, 249 μmol) were added to the reaction solution, the reaction solution was stirred at 25°C for 15 minutes, and then compound 8j (60.0 mg, 207 μmol) was added, the reaction solution was stirred at 25°C for 1 hour, and then stirred at 80°C for 12 hours. The reaction solution was concentrated under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate (30 mL×3), and the combined organic phases were washed with water (20 mL×2) and saturated brine (40 mL×1), respectively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC {hydrochloric acid conditions, column model: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 50%-80%, 10 minutes} to obtain compound 12.

[0333] MS-ESI calculated value [M+H] + 484, measured value 484.

[0334] 1 H NMR (400MHz, CDCl3) δ = 8.44 (s, 1H), 8.31-8.24 (m, 1H), 8.178.08 (m, 1H), 7.46-7.37 (m, 1H), 7.33-7.28 (m, 1H), 7.14-6.84 (m, 2H), 4 .83-4.69 (m, 1H), 4.24-4.17 (m, 1H), 4.16-4.05 (m, 1H), 3.99-3.50 (m, 3H), 3.46-3.37 (m, 3H), 2.38-2.07 (m, 4H), 1.49-1.39 (m, 6H).

[0335] Embodiment 13

[0336]

[0337]

[0338] first step

[0339] Compound 13a (3.00 g, 12.0 mmol) was dissolved in isopropylamine (10 mL), triethylamine (1.31 g, 12.9 mmol) was added to the mixture, and the reaction solution was stirred at 90°C for 12 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with water (20 mL×1) and saturated brine (20 mL×1), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by silica gel column chromatography (10:1, petroleum ether / ethyl acetate, Rf=0.50) to obtain compound 13b.

[0340] MS-ESI calculated value [M+H] + 273 and 275, measured values ​​273 and 275.

[0341] 1 H NMR (400MHz, CDCl3) δ=8.62 (d, J=1.9Hz, 1H), 8.09 (d, J=1.9Hz, 1H), 4.35-4.19 (m, 1H), 3.79 (s, 3H), 1.20 (d, J=6.5Hz, 6H).

[0342] Step 2

[0343] Compound 13b (1.53 g, 5.60 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL), and zinc cyanide (1.32 g, 11.2 mmol), tris(dibenzylideneacetone)dipalladium (513 mg, 560 μmol), and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (534 mg, 1.12 mmol) were added to the mixture. Under nitrogen protection, the reaction solution was stirred at 90° C. for 12 hours. The reaction solution was concentrated, and water (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with water (50 mL×1) and saturated brine (50 mL×1), respectively, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by silica gel column chromatography (10:1, petroleum ether / ethyl acetate, Rf=0.35) to obtain compound 13c.

[0344] MS-ESI calculated value [M+H] + 220, measured value 220.

[0345] 1 H NMR (400MHz, CDCl3) δ=8.89 (d, J=2.3Hz, 1H), 8.25 (d, J=2.3Hz, 1H), 4.49-4.38 (m, 1H), 3.90 (s, 3H), 1.30 (d, J=6.6Hz, 6H).

[0346] Step 3

[0347] Compound 13c (100 mg, 456 μmol) was dissolved in anhydrous tetrahydrofuran (4 mL) and anhydrous methanol (2 mL), and a solution of lithium hydroxide monohydrate (55.4 mg, 1.32 mmol) in water (2 mL) was added to the reaction solution. The reaction solution was stirred at 25°C for 12 hours, concentrated under reduced pressure to remove the organic solvent, and the residue was diluted with water (10 mL). The pH was adjusted to 1 with 1N hydrochloric acid, filtered, and the filter cake was dried to obtain compound 13d.

[0348] MS-ESI calculated value [M+H] + 206, measured value 206.

[0349] Step 4

[0350] Compound 13d (35.5 mg, 173 μmol) was dissolved in N,N-dimethylformamide (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (39.8 mg, 207 μmol) and 1-hydroxybenzotriazole (28.0 mg, 207 μmol) were added to the reaction solution. The reaction solution was stirred at 25°C for 15 minutes, and then compound 8j (50.0 mg, 173 μmol) was added. The reaction was stirred at 25°C for 1 hour and then at 80°C for 12 hours. Water (50 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC {hydrochloric acid conditions, column model: 3_Phenomenex luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 50%-70%, 7 minutes} to obtain compound 13.

[0351] MS-ESI calculated value [M+H] + 459, measured value 459.

[0352] 1H NMR (400MHz, CDCl3) δ=9.10 (d, J=2.3Hz, 1H), 8.42 (d, J=2.3Hz, 1H), 8.14-8.04 (m, 1H), 7.45-7.38 (m, 1H), 7.3 4-7.28 (m, 1H), 5.54-5.39 (m, 1H), 4.54-4.04 (m, 2H), 3.97-3.34 (m, 6H), 2.33-1.99 (m, 4H), 1.39-1.31 (m, 6H).

[0353] Embodiment 14

[0354]

[0355] Synthesis route:

[0356]

[0357] first step

[0358] Compound 1j (3.00 g, 9.67 mmol) and imidazole (856 mg, 12.6 mmol) were dissolved in dichloromethane (100 mL). A solution of tert-butyldimethylsilyl chloride (856 mg, 12.6 mmol) in dichloromethane (20 mL) was added to the above reaction solution at 0°C. The reaction solution was stirred at 25°C under nitrogen protection for 3 hours. Diluted with dichloromethane (200 mL), washed with water (100 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (10:1, petroleum ether / ethyl acetate, Rf=0.5) to obtain compound 14a. MS-ESI calculated value [M+H] + 424 and 426, measured values ​​424 and 426.

[0359] Step 2

[0360] Compound 14a (1.50 g, 3.53 mmol) and bis-naphthalene borate (987 mg, 3.89 mmol) were dissolved in 1,4-dioxane (20 mL), and then 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (259 mg, 353 μmol) and potassium acetate (1.04 g, 10.6 mmol) were added. The reaction solution was stirred at 80 ° C for 15 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, diluted with water (200 mL), extracted with ethyl acetate (100 mL×3), and the combined organic phase was washed with saturated brine (200 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (5:1, petroleum ether / ethyl acetate, Rf=0.70) to obtain compound 14b.

[0361] MS-ESI calculated value [M+H]+ 472, measured value 472.

[0362] Step 3

[0363] Compound 1b (10.0 g, 41.7 mmol), bis-naphthalene borate (12.7 g, 50.0 mmol) and potassium acetate (8.18 g, 83.3 mmol) were dissolved in anhydrous N, N-dimethylformamide (100 mL). Under nitrogen protection, 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (1.83 g, 2.50 mmol) was added to the reaction solution, and the reaction solution was stirred at 120° C. for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with water (500 mL), extracted with ethyl acetate (300 mL×2), the combined organic phase was washed with saturated brine (300 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (5:1, petroleum ether / ethyl acetate, Rf=0.49) to obtain compound 14c.

[0364] MS-ESI calculated value [M+H] + 288, measured value 288.

[0365] Step 4

[0366] Compound 14c (1.00 g, 3.48 mmol), compound 14d (685 mg, 4.18 mmol) and sodium carbonate (738 mg, 6.96 mmol) were dissolved in ethylene glycol dimethyl ether (10 mL) and water (10 mL). Under nitrogen protection, 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (255 mg, 348 μmol) was added to the reaction solution, and the reaction solution was stirred at 100° C. for 12 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL×2), and the combined organic phase was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography (5:1, petroleum ether / ethyl acetate, Rf=0.53) and purified to obtain compound 14e.

[0367] MS-ESI calculated value [M+H] + 245, measured value 245.

[0368] Step 5

[0369] Compound 14e (480 mg, 1.96 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL), N-bromosuccinimide (699 mg, 3.93 mmol) was added to the reaction solution at 0°C, and the reaction solution was stirred at 20°C for 3 hours. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL×2), and the combined organic phase was washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (5:1, petroleum ether / ethyl acetate, Rf=0.64) to obtain compound 14f.

[0370] MS-ESI calculated value [M+H] + 323 and 325, measured values ​​323 and 325.

[0371] Step 6

[0372] Compound 14f (50.0 mg, 155 μmol), compound 14b (72.9 mg, 155 μmol) and potassium phosphate (65.7 mg, 309 μmol) were dissolved in anhydrous dioxane (1.5 mL) and water (0.5 mL). Under nitrogen protection, 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (11.3 mg, 15.5 μmol) was added to the reaction solution, and the reaction solution was stirred at 80°C for 12 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with water (15 mL), extracted with ethyl acetate (15 mL×2), the combined organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 14g.

[0373] MS-ESI calculated value [M+H] + 588, measured value 588.

[0374] Step 7

[0375] Compound 14g (69.0 mg, 117 μmol) was dissolved in ethyl acetate (1 mL), hydrochloric acid / ethyl acetate (4 M, 1 mL) was added to the mixture, and the reaction solution was stirred at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 52%-72%, 7 minutes} to obtain compound 14.

[0376] MS-ESI calculated value [M+H] + 474, measured value 474.

[0377] 1H NMR (400MHz, CDCl3) δ = 8.26-809 (m, 2H), 8.05-7.85 (m, 1H), 7.54-7.40 (m, 1H), 7.39-7.29 (m, 1H), 7.25-6. 98 (m, 2H), 4.82-4.69 (m, 1H), 4.30-4.07 (m, 2H), 3.93-3.08 (m, 6H), 2.26-2.07 (m, 4H), 1.56-1.37 (m, 6H).

[0378] Embodiment 15

[0379]

[0380] Synthesis route:

[0381]

[0382] first step

[0383] Compound 1d (1.00 g, 4.87 mmol) and compound 15a (666 mg, 7.31 mmol) were slowly dissolved in phosphorus oxychloride (5 mL), and the reaction solution was stirred at 90° C. for 3 hours. The reaction solution was slowly quenched with a 5M NaOH aqueous solution, and the pH was adjusted to 10. The reaction solution was stirred at 25° C. for 30 minutes, and the reaction solution became turbid and filtered. The filter cake was dissolved with dichloromethane (100 mL) and methanol (10 mL), and the organic phase was washed with water (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 15b.

[0384] MS-ESI calculated value [M+H] + 261, measured value 261.

[0385] Step 2

[0386] Copper bromide (601 mg, 2.69 mmol) and tert-butyl nitrite (277 mg, 2.69 mmol) were dissolved in acetonitrile (10 mL), and the reaction solution was stirred at 25°C for 30 minutes. Compound 15b (350 mg, 1.34 mmol) was slowly added to the reaction solution, and the reaction solution was stirred at 25°C for 1 hour and at 70°C for 2 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (20 mL), the filtrate was washed with 1M hydrochloric acid aqueous solution (30 mL), and concentrated under reduced pressure. The residue was diluted with water (20 mL), extracted with dichloromethane (30 mL×2), the combined organic phases were washed with water (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (3:1, petroleum ether / ethyl acetate, Rf=0.53) to obtain compound 15c.

[0387] MS-ESI calculated value [M+H] + 324 and 326, measured values ​​324 and 326.

[0388] Step 3

[0389] Compound 15c (50.0 mg, 154 μmol), compound 14b (72.7 mg, 154 μmol) and potassium phosphate (65.5 mg, 308 μmol) were dissolved in anhydrous dioxane (1.5 mL) and water (0.5 mL). Under nitrogen protection, 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (11.3 mg, 15.4 μmol) was added to the reaction solution, and the reaction solution was stirred at 80°C for 12 hours. The reaction solution was concentrated under reduced pressure, the crude product was diluted with water (15 mL), extracted with ethyl acetate (15 mL×2), the combined organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 15d.

[0390] MS-ESI calculated value [M+H] + 589, measured value 589.

[0391] Step 4

[0392] Compound 15d (86.0 mg, 146 μmol) was dissolved in ethyl acetate (1 mL), hydrochloric acid / ethyl acetate (4 M, 1 mL) was added to the mixture, and the reaction solution was stirred at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 45%-65%, 8 minutes} to obtain compound 15.

[0393] MS-ESI calculated value [M+H] + 475, measured value 475.

[0394] 1 H NMR(400 MHz, CDCl3) δ=8.24 (d, J=8.0Hz, lH), 8.17 (s, lH), 7.81 (d, J=7.2Hz, 1H), 7.42-7.36 (m, 1H), 7.33-7.28 (m, 1H), 7.1 1(d, J=8.4Hz, 1H), 4.82-4.73(m, 1H), 4.25-4.06(m, 2H), 3.96-3.38(m, 6H), 2.25-2.06(m, 4H), 1.49-1.45(m, 6H).

[0395] Example 16

[0396]

[0397] Synthesis route:

[0398]

[0399] first step

[0400] Compound 14b (150 mg, 318 μmol) and compound 16a (63.5 mg, 318 μmol) were dissolved in 1,4-dioxane (3 mL), and then 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (23.3 mg, 31.8 μmol), potassium phosphate (135 mg, 636 μmol) and water (0.6 mL) were added. The reaction solution was stirred at 100° C. for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, diluted with water (80 mL), extracted with ethyl acetate (50 mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by thin layer silica gel chromatography (1:1, petroleum ether / ethyl acetate, Rf=0.50) to obtain compound 16b.

[0401] MS-ESI calculated value [M+H] + 508 and 510, measured values ​​508 and 510.

[0402] Step 2

[0403] Compound 16b (96.0 mg, 189 μmol) and compound 14c (65.1 mg, 227 μmol) were dissolved in 1,4-dioxane (1 mL), and then 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (13.8 mg, 18.9 μmol), potassium phosphate (160 mg, 755 μmol) and water (0.2 mL) were added. The reaction solution was stirred at 80°C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, diluted with water (80 mL), extracted with ethyl acetate (40 mL×4), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the phase product compound 16c.

[0404] MS-ESI calculated value [M+H] + 589, measured value 589.

[0405] Step 3

[0406] Compound 16c (123 mg, 209 μmol) was dissolved in hydrochloric acid / methanol (4 M, 3 mL), and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_PhenomenexLuna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 60%-80%, 7 minutes} to obtain compound 16.

[0407] MS-ESI calculated value [M+H] + 475, measured value 475.

[0408] 1 H NMR (400MHz, CDCl3) δ=8.62 (d, J=2.1Hz, 1H), 8.53 (dd, J=8.8, 2.1Hz, 1H), 8.05 (d, J=7.6Hz, 1H), 7.44 (t, J=7.6Hz, 1H), 7.34 (d, J=8.0Hz, 1H) , 7.09 (d, J=9.0Hz, 1H), 4.84-4.71 (m, 1H), 4.25-4.05 (m, 2H), 3.98-3. 50 (m, 3H), 3.49-3.33 (m, 3H), 2.39-2.05 (m, 4H), 1.47 (d, J=6.0Hz, 6H).

[0409] Embodiment 17

[0410]

[0411] Synthesis route:

[0412]

[0413] first step

[0414] Compound 10a (1.00 g, 4.33 mmol) was dissolved in anhydrous N,N-dimethylformamide (15 mL), and zinc cyanide (1.02 g, 8.66 mmol), tris(dibenzylideneacetone)dipalladium (396 mg, 433 μmol), and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (412 mg, 866 μmol) were added to the mixture. Under nitrogen protection, the reaction solution was stirred at 90° C. for 12 hours. The reaction solution was concentrated to remove the N,N-dimethylformamide solvent, and the crude product was separated and purified by silica gel column chromatography (2:1, petroleum ether / ethyl acetate, Rf=0.24) to obtain compound 17a.

[0415] 1H NMR (400MHz, CDCl3) δ=8.16 (d, J=2.0Hz, 1H), 8.08 (dd, J=2.0, 8.7Hz, 1H), 697 (d, J=8.7Hz, 1H), 3.85 (s, 3H).

[0416] Step 2

[0417] Compound 17a (523 mg, 2.80 mmol) was dissolved in N,N-dimethylformamide (15 mL) and water (1.5 mL). Potassium carbonate (969 mg, 7.01 mmol) and sodium difluorochloroacetate (2.21 g, 11.2 mmol) were added to the mixture. The reaction solution was stirred at 100°C for 2 hours. The reaction solution was cooled to 25°C. 1.6 mL of concentrated hydrochloric acid and 3.2 mL of water were added to the mixture. The reaction solution was stirred at 25°C for 12 hours. 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with 20 mL of water and 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 17b.

[0418] Step 3

[0419] Compound 17b (100 mg, 440 μmol) was dissolved in anhydrous tetrahydrofuran (4 mL) and anhydrous methanol (2 mL), and a solution of lithium hydroxide monohydrate (55.4 mg, 1.32 mmol) in water (2 mL) was added to the mixture. The reaction solution was stirred at 25°C for 12 hours, and the organic solvent was removed under reduced pressure. 1N hydrochloric acid aqueous solution was added to adjust the pH to 1. The mixture became turbid and was filtered. The filter residue was dried in vacuo to obtain compound 17c. 1 H NMR (400MHz, CDCl3) δ=8.35 (d, J=2.1Hz, 1H), 8.26 (dd, J=2.1, 8.7Hz, 1H), 7.38 (d, J=8.8Hz, 1H), 6.76 (t, J=70.4Hz, 1H).

[0420] Step 4

[0421] Compound 17c (44.2 mg, 207 μmol) was dissolved in N,N-dimethylformamide (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47.7 mg, 249 μmol) and 1-hydroxybenzotriazole (33.6 mg, 249 μmol) were added to the reaction solution. The reaction solution was stirred at 25°C for 15 minutes, and then compound 8j (60.0 mg, 207 μmol) was added. The reaction was stirred at 25°C for 1 hour and then at 80°C for 12 hours. Water (50 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC (hydrochloric acid conditions, column model: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 44%-74%, 10 minutes) to obtain compound 17.

[0422] MS-ESI calculated value [M+H] + 467, measured value 467.

[0423] 1 H NMR (400MHz, CDCl3) δ = 8.60-8.54 (m, 1H), 8.48-8.43 (m, 1H), 8.15-8.07 (m, 1H), 7.56 (d, J = 8.8Hz, 1H), 7.43 (t, J = 7.6Hz, 1H) , 7.33 (d, J=7.6Hz, 1H), 6.78 (t, J=70.8Hz, 1H), 4.33-4.08 (m, 2H), 3.99-3.51 (m, 4H), 3.48-3.39 (m, 3H), 2.31-2.04 (m, 4H).

[0424] Embodiment 18

[0425]

[0426] Synthesis route:

[0427]

[0428] first step

[0429] Compound 14c (200 mg, 696 μmol), compound 18a (198 mg, 696 μmol) and potassium phosphate (296 mg, 1.39 mmol) were dissolved in anhydrous dioxane (4 mL) and water (1 mL). Under nitrogen protection, 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (51.0 mg, 70 μmol) was added to the reaction solution, and the reaction solution was stirred at 80°C for 12 hours. The reaction solution was concentrated under reduced pressure, the crude product was diluted with water (30 mL), extracted with ethyl acetate (30 mL×2), the combined organic phase was washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by thin layer silica gel chromatography (5:1, petroleum ether / ethyl acetate, Rf=0.31) to obtain compound 18b. MS-ESI calculated value [M+H] + 318 and 320, measured values ​​318 and 320.

[0430] Step 2

[0431] Compound 18b (50.0 mg, 157 μmol), compound 14b (74.1 mg, 157 μmol) and potassium phosphate (66.7 mg, 314 μmol) were dissolved in anhydrous dioxane (1.5 mL) and water (0.5 mL). Under nitrogen protection, 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (11.5 mg, 15.7 μmol) was added to the reaction solution, and the reaction solution was stirred at 80°C for 12 hours. The reaction solution was concentrated under reduced pressure, the crude product was diluted with water (10 mL), extracted with ethyl acetate (10 mL×2), the combined organic phase was washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 18c.

[0432] MS-ESI calculated value [M+H] + 583, measured value 583.

[0433] Step 3

[0434] Compound 18c (78.0 mg, 134 μmol) was dissolved in ethyl acetate (1 mL), and hydrochloric acid / ethyl acetate (4 M, 1 mL) was added to the mixture, and the reaction solution was stirred at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 51%-71%, 7 minutes} to obtain compound 18.

[0435] MS-ESI calculated value [M+H] + 469, measured value 469.

[0436] 1 H NMR (400MHz, CDCl3) δ = 8.88 (s, 2H), 8.76 (br s, 1H), 8.68 (d, J = 8.9Hz, 1H), 7.44-7.38 (m, 1H), 7.36-7.32 (m, 1H), 7.26-7.22 (m, 1H), 7.10 (d, J = 8.9Hz, 1H), 4. 82-4.75 (m, 1H), 4.27-4.08 (m, 2H), 3.99-3.42 (m, 4H), 3.14-3.03 (m, 2H), 2.24-2.09 (m, 4H), 1.49-1.46 (m, 6H).

[0437] Embodiment 19

[0438]

[0439] Synthesis route:

[0440]

[0441] first step

[0442] Compound 14c (200 mg, 696 μmol), compound 19a (198 mg, 696 μmol) and potassium phosphate (296 mg, 1.39 mmol) were dissolved in anhydrous dioxane (4 mL) and water (1 mL). Under nitrogen protection, 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (51.0 mg, 69.7 μmol) was added to the reaction solution, and the reaction solution was stirred at 60°C for 12 hours. The reaction solution was concentrated under reduced pressure, the crude product was diluted with water (30 mL), extracted with ethyl acetate (30 mL×2), the combined organic phase was washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by thin layer silica gel chromatography (5:1, petroleum ether / ethyl acetate, Rf=0.09) to obtain compound 19b. MS-ESI calculated value [M+H] + 318 and 320, measured values ​​318 and 320.

[0443] Step 2

[0444] Compound 19b (61.0 mg, 192 μmol), compound 14b (90.4 mg, 192 μmol) and potassium phosphate (81.4 mg, 383 μmol) were dissolved in anhydrous dioxane (1.5 mL) and water (0.5 mL). Under nitrogen protection, 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (14.0 mg, 19.2 μmol) was added to the reaction solution, and the reaction solution was stirred at 80°C for 12 hours. The reaction solution was concentrated under reduced pressure, the crude product was diluted with water (15 mL), extracted with ethyl acetate (10 mL×2), the combined organic phase was washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 19c.

[0445] MS-ESI calculated value [M+H] + 583, measured value 583.

[0446] Step 3

[0447] Compound 19c (90.0 mg, 154 μmol) was dissolved in ethyl acetate (1 mL), hydrochloric acid / ethyl acetate (4 M, 1 mL) was added to the mixture, and the reaction solution was stirred at 20° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 51%-71%, 7 minutes} to obtain compound 19.

[0448] MS-ESI calculated value [M+H] + 469, measured value 469.

[0449] 1 H NMR (400MHz, CDCl3) δ = 9.13 (br s, 1H), 8.99 (br s, 1H), 8.39-8.30 (m, 2H), 7.70 (d, J=7.2Hz, 1H), 7.45 (t, J=7.4Hz, 1H), 7.31 (d, J=7.6Hz, 1H), 7.16 (d, J=8 .4Hz, 1H), 4.83-4.75(m, 1H), 4.23-4.10(m, 2H), 3.97-3.18(m, 6H), 2.36-2.04(m, 4H), 1.51-1.45(m, 6H).

[0450] Embodiment 20

[0451]

[0452] Synthesis route:

[0453]

[0454] first step

[0455] Compound 14c (300 mg, 1.04 mmol), compound 20a (208 mg, 1.04 mmol) and potassium phosphate (554 mg, 2.61 mmol) were dissolved in ethylene glycol dimethyl ether (4 mL) and water (1 mL). Tetrakistriphenylphosphine palladium (121 mg, 104 μmol) was added to the mixture under nitrogen protection. The reaction solution was stirred at 120°C in a microwave for 1 hour. 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was separated and purified by silica gel column chromatography (5:1, petroleum ether / ethyl acetate, Rf=0.30) to obtain compound 20b.

[0456] MS-ESI calculated value [M+H] + 324 and 326, measured values ​​324 and 326.

[0457] Step 2

[0458] Compound 20b (50.0 mg, 154 μmol), compound 14b (72.7 mg, 154 μmol), potassium phosphate (65.5 mg, 308 μmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (11.3 mg, 154 μmol) were dissolved in dioxane (1.5 mL) and water (0.5 mL). Under nitrogen protection, the reaction solution was stirred at 80°C for 12 hours. The reaction solution was concentrated, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with saturated brine (30 mL), and concentrated to obtain compound 20c.

[0459] MS-ESI calculated value [M+H] + 589, measured value 589.

[0460] Step 3

[0461] Compound 20c (83.0 mg, 141 μmol) was dissolved in ethyl acetate (2 mL), and hydrochloric acid / ethyl acetate (4 M, 353 μL) was added to the mixture, and the reaction solution was stirred at 25°C for 2 hours. Water (10 mL) was added to the reaction solution for dilution, and it was extracted with ethyl acetate (10 mL×2), and the combined organic phases were washed with water (10 mL) and saturated brine (10 mL) in sequence, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 58%-78%, 7 minutes} to obtain compound 20.

[0462] MS-ESI calculated value [M+H] + 475, measured value 475.

[0463] 1 H NMR (400MHz, DMSO-d6) δ=8.52 (d, J=2.2Hz, 1H), 8.38 (dd, J=8.8, 2.2Hz, 1H), 8.20 (d, J=7.2Hz, 1H), 7.54-7.41 (m, 3H ), 5.02-4.91(m, 1H), 4.61-4.52(m, 1H), 4.12-3.94(m, 2H), 3.73-3.38(m, 6H), 2.19-1.97(m, 4H), 1.42-1.37(m, 6H).

[0464] Embodiment 21

[0465]

[0466] Synthesis route:

[0467]

[0468] first step

[0469] Compound 1d (100 g, 487 mmol) was dissolved in dichloromethane (500 mL), thionyl chloride (116 g, 975 mmol, 70.7 mL) was slowly added, and then N, N-dimethylformamide (35.6 mg, 487 μmol) was added. The reaction solution was stirred at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was added to a mixed solution of n-heptane / ethyl acetate (1:10, 220 mL) and stirred at 25°C for 3 hours. Filter, wash the filter cake with n-heptane (50 mL×2), and dry under reduced pressure to obtain compound 21a.

[0470] Step 2

[0471] Compound 21a (2.00 g, 8.94 mmol), triethylamine (2.71 g, 26.8 mmol) and 2-aminoethanol (1.09 g, 17.88 mmol) were dissolved in dichloromethane (30 mL), and nitrogen was replaced three times. Then the reaction solution was stirred at 25 ° C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (200 mL), extracted with ethyl acetate (200 mL×2), and the combined organic phases were washed with 1N hydrochloric acid aqueous solution (50 mL×2). Drying over anhydrous sodium sulfate, filtering, and the filtrate was concentrated under reduced pressure to obtain compound 21b.

[0472] MS-ESI calculated value [M+H] + 249, measured value 249.

[0473] Step 3

[0474] Compound 21b (2.00 g, 8.06 mmol) was dissolved in dichloromethane (60 mL), and dichlorothionyl (2.88 g, 24.2 mmol) was added dropwise to the solution, and the reaction solution was stirred at 25°C for 12 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (50 mL), extracted with dichloromethane (50 mL×3), and the combined organic phases were washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 21c.

[0475] MS-ESI calculated value [M+H] + 231, measured value 231.

[0476] Step 4

[0477] Compound 21c (1.20 g, 5.21 mmol), N-bromosuccinimide (1.86 g, 10.4 mmol) and azobisisobutyronitrile (42.8 mg, 261 μmol) were dissolved in carbon tetrachloride (30 mL), and nitrogen was replaced three times. The reaction solution was stirred at 80° C. for 16 hours under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was diluted with water (100 mL), extracted with dichloromethane (100 mL×3), and the combined organic phases were washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (10:1, petroleum ether / ethyl acetate, Rf=0.14) to obtain compound 21d.

[0478] MS-ESI calculated value [M+H] + 307 and 309, measured values ​​307 and 309.

[0479] 1H NMR (400MHz, CDCl3) δ=8.18 (d, J=2.0Hz, 1H), 8.13 (dd, J=88, 2.0Hz, 1H), 7.09 (s, 1H), 7.04 (d, J=8.8Hz, 1H), 4.74 (p, J=6.1, 1H), 1.45 (d, J=6.1Hz, 6H).

[0480] Step 5

[0481] Compound 21d (50.0 mg, 162 μmol), compound 14b (76.8 mg, 163 μmol), potassium carbonate (67.5 mg, 488 μmol) and tetrakis(triphenylphosphine)palladium (18.8 mg, 16.3 μmol) were accurately weighed in a microwave tube, and then water (0.5 mL) and ethylene glycol dimethyl ether (1.5 mL) were added to the microwave tube. The reaction solution was stirred for 40 minutes under microwave heating at 100°C. The reaction solution was concentrated under reduced pressure, the residue was diluted with water (50 mL), extracted with dichloromethane (50 mL×3), the combined organic phases were washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 21e.

[0482] MS-ESI calculated value [M+H] + 572, measured value 572.

[0483] Step 6

[0484] Compound 21e (50.0 mg, 87.5 mmol) was dissolved in ethyl acetate (2 mL) and hydrochloric acid / ethyl acetate (4 M, 2 mL), and the nitrogen was replaced three times. The reaction solution was stirred at 25 ° C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure, the residue was diluted with water (50 mL), extracted with dichloromethane (50 mL×3), the combined organic phases were washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was then purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 48%-68%, 7 minutes} to obtain compound 21. MS-ESI calculated value [M+H] + 458, measured value 458.

[0485] 1H NMR (400MHz, DMSO-d6) δ = 8.41-8.36 (m, 1H), 8.33-8.27 (m, 1H), 7.84-7.79 (m, 1H), 7.66 (d, J = 2.4Hz, 1H), 7.48 (d, J = 9.0Hz, 1H), 7.41-7.34 (m, 1H), 7.33-7.27(m, 1H), 4.96-4.87(m, 1H), 4.12-3.94(m, 2H), 3.72-3. 49 (m, 5H), 3.21-3.13 (m, 2H), 2.20-1.91 (m, 4H), 1.38 (d, J=6.4Hz, 6H).

[0486] Embodiment 22

[0487]

[0488] Synthesis route:

[0489]

[0490] first step

[0491] Compound 22a (200 mg, 1.39 mol) was dissolved in dichloromethane (2 mL), and Dess-Martin periodinane (1.30 g, 3.07 mmol) was added to the reaction solution, and the reaction solution was stirred at 25° C. for 1 hour. Saturated sodium bicarbonate aqueous solution (50 mL) was added to the reaction solution, and extracted with dichloromethane (20 mL×4), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (10 / 1, petroleum ether / ethyl acetate) to obtain compound 22b.

[0492] Step 2

[0493] Compound 1o (100 mg, 229 μmol) and compound 22b (97.6 mg, 687 μmol) were dissolved in dichloromethane (20 mL), acetic acid (27.5 mg, 458 μmol) was added to the reaction solution, followed by sodium triacetoxyborohydride (97.0 mg, 457 μmol), and the reaction solution was stirred at 25° C. for 12 hours. The reaction solution was concentrated under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate (30 mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by thin layer silica gel chromatography (15 / 1, dichloromethane / methanol) to obtain compound 22c.

[0494] MS-ESI calculated value [M+H] + 527, measured value 527.

[0495] Step 3

[0496] Compound 22c (110 mg, 209 μmol) was dissolved in a mixed solvent of tetrahydrofuran (4 mL) and methanol (2 mL), and a solution of lithium hydroxide monohydrate (26.3 mg, 627 μmol) in water (1 mL) was added to the reaction solution, and the reaction solution was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure, and the residue was diluted with water (15 mL), and the pH value was adjusted to 5 with a 1M aqueous hydrochloric acid solution, and extracted with ethyl acetate (10 mL×4), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 33%-53%, 6.5 minutes} to obtain the hydrochloride of compound 22.

[0497] MS-ESI calculated value [M+H] + 499, actual measured value 499.

[0498] 1 H NMR (400MHz, DMSO-d6) δ = 8.52 (d, J = 2.2Hz, 1H), 8.45-8.37 (m, 1H), 8.06-8.00 (m, 1H), 7.76-7.70 (m, 1H), 7.60-7.49 (m, 2H), 5.06-4.85 (m, 1H), 3.88-3.46(m, 4H), 3.29-3.20(m, 2H), 2.57-2.52(m, 4H), 2.27-2 .18(m, 2H), 1.41-1.36(m, 6H), 1.35-1.28(m, 2H), 1.25-1.19(m, 2H).

[0499] Step 4

[0500] The hydrochloride of compound 22 was chirally separated. Chromatographic column: CHIRALPAK IG 50×4.6mm×3μm; mobile phase A: CO2, mobile phase B: ethanol (0.05% diethylamine); gradient B%: 40%-40%, 9min. Compound 22A (ee%=99.62%, SFC retention time: 6.567 minutes) and compound 22B (ee%=99.4%, SFC retention time: 5.084 minutes) were obtained.

[0501] Compound 22A: MS-ESI calculated value [M+H] + 499, actual measured value 499.

[0502] 1H NMR (400MHz, CD3OD) δ = 8.47-8.41 (m, 2H), 8.11 (d, J = 7.6Hz, 1H), 7.60 (d, J = 7.6Hz, 1H), 7.52-7.43 (m, 2H), 5.00-4.92 (m, 2H), 3.76- 3.57 (m, 3H), 3.45-3.36 (m, 4H), 2.50-2.41 (m, 1H), 2.40-2.32 (m, 3H), 1.48 (d, J=6.0Hz, 6H), 1.32-1.29 (m, 2H), 0.88-0.84 (m, 2H).

[0503] Compound 22B: MS-ESI calculated value [M+H] + 499, actual measured value 499.

[0504] 1 H NMR (400MHz, CD3OD) δ = 8.39-8.33 (m, 2H), 8.04 (dd, J = 0.8, 7.6Hz, 1H), 7.55 ( d, J=6.8Hz, 1H), 7.47-7.37(m, 2H), 4.96-4.85(m, 2H), 3.74-3.52(m, 3H), 3. 39-3.33(m, 3H), 3.32-3.31(m, 1H), 3.32-3.30(m, 1H), 2.47-2.37(m, 1H), 2. 36-2.28 (m, 3H), 1.44 (d, J=6.0Hz, 6H), 1.26-1.21 (m, 2H), 0.81-0.74 (m, 2H).

[0505] Embodiment 23

[0506]

[0507] Synthesis route:

[0508]

[0509] first step

[0510] Compound 1o (100 mg, 229 μmol) and compound 23a (99.9 mg, 458 μmol) were dissolved in dichloromethane (8 mL), acetic acid (27.5 mg, 458 μmol) was added to the reaction solution, the reaction solution was stirred at 25 ° C for 12 hours, sodium triacetoxyborohydride (97.0 mg, 458 μmol) was added, and the reaction solution was stirred at 25 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate (30 mL×3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product compound 23b. MS-ESI calculated value [M+H] + 603, measured value 603.

[0511] Step 2

[0512] Compound 23b (120 mg, 199 μmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and ethanol (1 mL), and a solution of lithium hydroxide monohydrate (25.1 mg, 597 μmol) in water (1 mL) was added to the reaction solution, and the reaction solution was stirred at 15°C for 48 hours. The mixture was concentrated under reduced pressure, and the residue was diluted with 0.5 M aqueous hydrochloric acid solution (30 mL) and stirred at 15°C for 10 minutes. The mixture was extracted with ethyl acetate (20 mL×3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30 mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 35%-55%, 7 minutes} to obtain the hydrochloride of compound 23.

[0513] MS-ESI calculated value [M+H] + 513, measured value 513.

[0514] 1 H NMR (400MHz, CDCl3) δ = 8.38-8.26 (m, 2H), 8.03 (d, J = 7.4Hz, 1H), 7.77 (br s, 1H), 7.41 (t, J=6.8Hz, 1H), 7.13 (d, J=9.0Hz, 1H), 4.87-4.75 (m, 1H), 4.09-3.09 (m, 8H), 2.80-1.95 (m, 10H), 1.49 (d, J=6.0Hz, 6H).

[0515] Embodiment 24

[0516]

[0517]

[0518] first step

[0519] Compound 1j (4.0 g, 15.9 mmol) and compound 22b (2.93 g, 20.6 mmol) were dissolved in dichloromethane (100 mL), acetic acid (953 mg, 15.9 mmol) was added to the reaction solution, and the reaction solution was stirred at 15°C for 13 hours, and then sodium triacetoxyborohydride (6.72 g, 31.7 mmol) was added, and the reaction solution was stirred at 15°C for 1 hour. The reaction solution was concentrated under reduced pressure, diluted with water (200 mL), extracted with ethyl acetate (100 mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (1:1, petroleum ether / ethyl acetate) to obtain compound 24a.

[0520] MS-ESI calculated value [M+H] + 378 and 380, measured values ​​378 and 380.

[0521] Step 2

[0522] Compound 24a (2.35 g, 6.21 mmol), bis(triphenylphosphino)ferrocenepalladium chloride (2.37 g, 9.32 mmol), potassium acetate (1.22 g, 12.42 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (454 mg, 621 μmol) were dissolved in dioxane (20 mL). Under nitrogen protection, the reaction solution was stirred at 80° C. for 12 hours and concentrated under reduced pressure. 50 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed with (30 mL*2) saturated brine, and dried over anhydrous sodium sulfate. The crude product was separated and purified by column chromatography (5:1, petroleum ether / ethyl acetate) to obtain compound 24b.

[0523] MS-ESI calculated value [M+H] + 426, measured value 426.

[0524] Step 3

[0525] Compound 20b (195 mg, 601 μmol), compound 24b (256 mg, 601 μmol), potassium phosphate (255 mg, 1.20 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (44.0 mg, 60.1 μmol) were dissolved in dioxane (6 mL) and water (3 mL). Under nitrogen protection, the reaction solution was stirred at 80° C. for 12 hours. The reaction solution was concentrated under reduced pressure, 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (50 mL*2). The organic phases were combined, washed with 30 mL of water and 30 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by thin layer chromatography (1:1, petroleum ether / ethyl acetate) to obtain compound 24c.

[0526] MS-ESI calculated value [M+H] + 543, measured value 543.

[0527] Step 4

[0528] Compound 24c (140 mg, 258 μmol) was dissolved in tetrahydrofuran (4 mL) and methanol (2 mL), and a solution of lithium hydroxide monohydrate (43.3 mg, 1.03 mmol) in water (1 mL) was added to the mixture, and the reaction solution was stirred at 20°C for 12 hours. A 1M aqueous hydrochloric acid solution was added to the reaction solution to adjust the pH value to about 5. The mixture was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 38%-58%, 7 minutes} to obtain the hydrochloride of compound 24.

[0529] MS-ESI calculated value [M+H] + 515, measured value 515.

[0530] 1H NMR (400MHz, MeOH-d4) δ = 8.39-8.21 (m, 3H), 7.56 (d, J = 7.5Hz, 1H), 7.50-7.41 (m, 1H), 7.41-7.33 (m, 1H), 4.98-4. 89(m, 1H), 4.09-3.77(m, 2H), 3.74-3.43(m, 6H), 2.61-2.22(m, 4H), 1.57-1.48(m, 2H), 1.47-1.43(m, 6H), 1.22(br s, 2H).

[0531] Embodiment 25

[0532]

[0533] Synthesis route:

[0534]

[0535] first step

[0536] Compound 18b (66.9 mg, 157 μmol), compound 24b (50 mg, 157 μmol) and potassium phosphate (66.7 mg, 314 μmol) were dissolved in anhydrous dioxane (3 mL) and water (1 mL). 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (11.5 mg, 15.7 μmol) was added to the reaction solution under nitrogen atmosphere, and the reaction solution was stirred at 80°C for 12 hours. The reaction solution was diluted with water (15 mL), extracted with ethyl acetate (15 mL×2), and the combined organic phase was washed with saturated sodium chloride (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 25a.

[0537] MS-ESI calculated value [M+H] + 537, measured value 537.

[0538] Step 2

[0539] Compound 25a (75 mg, 140 μmol) was dissolved in anhydrous tetrahydrofuran (3 mL), methanol (1 mL) and water (1 mL), lithium hydroxide monohydrate (11.7 mg, 280 μmol) was added to the mixture, and the reaction solution was stirred at 50° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 34%-54%, 7 minutes} to obtain the hydrochloride of compound 25.

[0540] MS-ESI calculated value [M+H] + 509, measured value 509.

[0541] 1H NMR (400MHz, MeOH-d4) δ = 8.96-8.94 (m, 2H), 8.73-8.69 (m, 2H), 7.55-7.47 (m, 2 H), 7.45-7.42 (m, 1H), 7.34 (d, J=8.7Hz, 1H), 4.92-4.90 (m, 1H), 4.04-3.91 (m, 2 H), 3.71-3.59(m, 2H), 3.57-3.44(m, 2H), 3.17-3.07(m, 2H), 2.42-2.35(m, 2H), 2.34-2.20 (m, 2H), 1.55-1.49 (m, 2H), 1.45 (d, J=6.0Hz, 6H), 1.24-1.19 (m, 2H).

[0542] Embodiment 26

[0543]

[0544] Synthesis route:

[0545]

[0546] first step

[0547] Compound 24b (184 mg, 433 μmol), compound 14f (140 mg, 433 μmol) and potassium phosphate (184 mg, 866 μmol) were dissolved in anhydrous dioxane (3 mL) and water (1 mL). Under nitrogen protection, 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (31.7 mg, 43.3 μmol) was added to the reaction solution, and the reaction solution was stirred at 80°C for 12 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (15 mL×2), and the combined organic phase was washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (10:1, dichloromethane / methanol) to purify compound 26a.

[0548] MS-ESI calculated value [M+H] + 542, measured value 542.

[0549] Step 2

[0550] Compound 26a (160 mg, 295 μmol) was dissolved in anhydrous tetrahydrofuran (3 mL), methanol (1 mL) and water (1 mL), lithium hydroxide monohydrate (24.8 mg, 591 μmol) was added to the mixture, and the reaction solution was stirred at 50° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 34%-54%, 7 minutes} to obtain the hydrochloride of compound 26.

[0551] MS-ESI calculated value [M+H] + 514, measured value 514.

[0552] 1 H NMR (400MHz, MeOH-d4) δ = 8.24 (d, J = 2.3Hz, 1H), 8.21 (dd, J = 8.9, 2.4Hz, 1H), 8.10 (s, 1H), 7 .59-7.55(m, 1H), 7.52-7.47(m, 1H), 7.45-7.40(m, 1H), 7.36(d, J=8.9Hz, 1H), 4.93-4.90( m, 1H), 4.03-3.89 (m, 2H), 3.70-3.60 (m, 2H), 3.59-3.44 (m, 2H), 3.25-3.20 (m, 2H), 2.56-2 .37 (m, 2H), 2.35-2.23 (m, 2H), 1.54-1.50 (m, 2H), 1.44 (d, J=6.1Hz, 6H), 1.26-1.22 (m, 2H).

[0553] Embodiment 27

[0554]

[0555] Synthesis route:

[0556]

[0557] first step

[0558] Compound 24b (138 mg, 326 μmol), compound 21d (100 mg, 326 μmol) and potassium phosphate (138 mg, 651 μmol) were dissolved in anhydrous dioxane (3 mL) and water (1 mL). Under nitrogen protection, 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (23.8 mg, 43.3 μmol) was added to the reaction solution, and the reaction solution was stirred at 80° C. for 12 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (15 mL×2), and the combined organic phase was washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (1:1, petroleum ether / ethyl acetate) to purify compound 27a.

[0559] MS-ESI calculated value [M+H] + 526, measured value 526.

[0560] Step 2

[0561] Compound 27a (150 mg, 285 μmol) was dissolved in anhydrous tetrahydrofuran (3 mL), methanol (1 mL) and water (1 mL), lithium hydroxide monohydrate (24.0 mg, 570 μmol) was added to the mixture, and the reaction solution was stirred at 50° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 31%-51%, 7 minutes} to obtain the hydrochloride of compound 27.

[0562] MS-ESI calculated value [M+H] + 498, measured value 498.

[0563] 1 H NMR (400MHz, MeOH-d4) δ = 8.30-8.24 (m, 2H), 7.80-7.75 (m, 1H), 7.51-7.49 (m, 1 H), 7.47-7.41 (m, 2H), 7.36 (d, J=8.9Hz, 1H), 4.92-4.89 (m, 1H), 4.02-3.88 (m, 2 H), 3.70-3.60(m, 2H), 3.58-3.43(m, 2H), 3.27-3.20(m, 2H), 2.56-2.38(m, 2H), 2.37-2.26 (m, 2H), 1.54-1.50 (m, 2H), 1.44 (d, J=6.0Hz, 6H), 1.27-1.21 (m, 2H).

[0564] Embodiment 28

[0565]

[0566] Synthesis route:

[0567]

[0568] first step

[0569] Compound 1d (1.00 g, 4.87 mmol) was dissolved in phosphorus oxychloride (6 mL), and thiosemicarbazide monohydrochloride (666 mg, 7.31 mmol) was added to the mixture, and the reaction solution was stirred at 90°C for 8 hours. The reaction solution was slowly dripped into a 6 M NaOH (40 mL) aqueous solution, extracted with ethyl acetate (30 mL×2), and the organic phases were combined, washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 28a.

[0570] MS-ESI calculated value [M+H] + 261, measured value 261.

[0571] Step 2

[0572] Compound 28a (210 mg, 807 mmol) was dissolved in acetonitrile (5 mL), and tert-butyl nitrite (166 mg, 1.61 mmol) and copper bromide (360 mg, 1.61 mmol) were added to the mixture at 0°C, and the reaction solution was stirred at 20°C for 1 hour and at 70°C for 2 hours. 1M aqueous hydrochloric acid solution (10 mL) was added to the reaction solution, and extracted with ethyl acetate (30 mL×2), and the organic phases were combined, washed with 20 mL of water and 20 mL of saturated brine, and dried over anhydrous sodium sulfate. The crude product was separated and purified by silica gel thin layer chromatography (3 / 1, petroleum ether / ethyl acetate) to obtain compound 28b.

[0573] MS-ESI calculated value [M+H] + 324 and 326, measured values ​​324 and 326.

[0574] Step 3

[0575] Compound 24b (87.9 mg, 207 μmol), compound 28b (67.0 mg, 207 μmol), potassium phosphate (87.7 mg, 413 μmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (15.1 mg, 20.7 μmol) were dissolved in dioxane (3 mL) and water (1.5 mL). Under nitrogen protection, the reaction solution was stirred at 80°C for 12 hours. The reaction solution was concentrated under reduced pressure, 20 mL of water was added to the crude product, and the mixture was extracted with ethyl acetate (50 mL*2). The organic phases were combined, washed with 30 mL of water and 30 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 28c.

[0576] MS-ESI calculated value [M+H] + 543, measured value 543.

[0577] Step 4

[0578] Compound 28c (124 mg, 228 μmol) was dissolved in tetrahydrofuran (4 mL) and methanol (2 mL), and a solution of lithium hydroxide monohydrate (28.8 mg, 685 μmol) in water (1 mL) was added to the mixture, and the reaction solution was stirred at 20°C for 12 hours. A 1M aqueous hydrochloric acid solution was added to the reaction solution to adjust the pH to about 5. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75×30mm×3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 30%-50%, 7 minutes} to obtain the hydrochloride of compound 28.

[0579] MS-ESI calculated value [M+H] + 515, measured value 515.

[0580] 1 H NMR (400MHz, MeOH-d4) δ = 8.32-8.25 (m, 2H), 7.92-7.87 (m, 1H), 7.61 (d, J = 7.2Hz, 1H), 7.50 (t, J = 7.7Hz, 1H), 7.39 (d, J = 8.9Hz, 1H), 4.95-4.91 ( m, 1H), 4.13-3.80 (m, 2H), 3.71-3.46 (m, 4H), 3.44-3.37 (m, 2H), 2.55-2 .25(m, 4H), 1.55-1.49(m, 2H), 1.45(d, J=6.0Hz, 6H), 1.22-1.19(m, 2H).

[0581] Embodiment 29

[0582]

[0583] Synthesis route:

[0584]

[0585] first step

[0586] Compound 12d (139 mg, 603 μmol) was dissolved in anhydrous N, N-dimethylformamide (3 mL), 1-hydroxybenzotriazole (97.9 mg, 724 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (138 mg, 724 μmol) were added to the mixture, the reaction solution was stirred at 25°C for 1 hour, compound 1m (200 mg, 603 μmol) was added to the reaction solution, the reaction solution was stirred at 25°C for 1 hour, and the reaction solution was further stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure, water (100 mL) was added to the residue, and the mixture was extracted with dichloromethane (50 mL×3), the organic phases were combined, the organic phases were washed with saturated brine (30 mL×3), and dried over anhydrous sodium sulfate. The crude product was purified by thin layer chromatography (1:1, petroleum ether / ethyl acetate) to obtain compound 29a.

[0587] MS-ESI calculated value [M+H-tBu] + 470, measured value 470.

[0588] 1 H NMR(400 MHz, CDCl3) δ=8.44 (s, 1H), 8.27 (dd, J=8.8, 2.2Hz, 1H), 8.09 (dd, J=7.6, 1.2Hz, 1H), 7.39 (t, J=7.6Hz, 1H), 7.33 (d, J=7.2Hz, 1H), 7.09 (d, J=8.8Hz , 1H), 6.99 (t, J=55.4Hz, 1H), 4.84-4.71 (m, 1H), 3.74-3.36 (m, 6H), 2.28- 2.09 (m, 3H), 2.02-1.94 (m, 1H), 1.54-1.47 (m, 9H), 1.44 (d, J=5.9Hz, 6H).

[0589] Step 2

[0590] Compound 29a (200 mg, 380 μmol) was dissolved in dioxane (1 mL), and dioxane hydrochloride solution (4 M, 2.85 mL) was added to the mixture. The reaction solution was stirred at 25 degrees Celsius for 1 hour, concentrated under reduced pressure, and dried under reduced pressure to obtain the hydrochloride of compound 29b.

[0591] MS-ESI calculated value [M+H] + 426, measured value 426.

[0592] Step 3

[0593] The hydrochloride of compound 29b (156 mg, 367 μmol) and compound 22b (78.3 mg, 551 μmol) were dissolved in dichloromethane (2 mL), glacial acetic acid (22.1 mg, 367 μmol) was added to the mixture, and the reaction solution was stirred at 15° C. for 13 hours, sodium triacetoxyborohydride (156 mg, 735 μmol) was added to the reaction solution, and the reaction solution was stirred at 15° C. for 1 hour. 10% sodium bicarbonate solution was used to adjust the pH to about 9, and water (100 mL) was added to the reaction solution for dilution, followed by extraction with dichloromethane (50 mL×3), and the organic phases were combined, washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, and concentrated to obtain compound 29c.

[0594] MS-ESI calculated value [M+H] + 552, measured value 552.

[0595] Step 4

[0596] Compound 29c (137 mg, 248 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and a solution of sodium hydroxide (39.7 mg, 993 μmol) in water (0.5 mL) was added to the mixture, and the reaction solution was stirred at 20° C. for 12 hours. The pH of the reaction solution was adjusted to about 5 using 1N hydrochloric acid solution, and the reaction solution was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 37%-57%, 7 minutes} to obtain the hydrochloride of compound 29.

[0597] MS-ESI calculated value [M+H] + 524, measured value 524.

[0598] 1 H NMR (400MHz, CDCl3) δ = 8.38 (s, 1H), 8.22 (d, J = 8.6Hz, 1H), 8.08 (d, J = 7.1Hz, 1H), 7.88 (br s, 1H), 7.42 (br s, 1H), 7.07 (d, J=8.8Hz, 1H), 6.96 (t, J=55.5Hz, 1H), 4.82-4.67 (m, 1H), 4.3 6-3.15 (m, 10H), 2.83-2.06 (m, 4H), 1.77-1.48 (m, 2H), 1.43 (d, J=8.6Hz, 6H).

[0599] Embodiment 30

[0600]

[0601] Synthesis route:

[0602]

[0603] first step

[0604] Compound 10c (156 mg, 603 μmol) was dissolved in anhydrous N, N-dimethylformamide (3 mL), 1-hydroxybenzotriazole (97.9 mg, 724 μmol), 1-(3-dimethylamino)-3-ethylcarbodiimide hydrochloride (138 mg, 724 μmol) were added to the mixture, the reaction solution was stirred at 25°C for 1 hour, compound 1m (200 mg, 603 μmol) was added to the reaction solution, the reaction solution was stirred at 25°C for 1 hour, and the reaction solution was further stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure, water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL×3), the organic phases were combined, the organic phases were washed with saturated brine (30 mL×3), and dried over anhydrous sodium sulfate. The crude product was purified by thin layer chromatography (1:1, petroleum ether / ethyl acetate) to obtain compound 30a.

[0605] MS-ESI calculated values ​​[M+H- t Bu] + 498 and 500, measured values ​​498 and 500.

[0606] 1 H NMR (400MHz, CDCl3) δ = 8.43 (d, J = 2.0Hz, 1H), 8.16-8.01 (m, 2H), 7.44-7.30 (m, 2H), 7.03 (d, J=8.8Hz, 1H), 4.78-4.68 (m, 1H), 3.75-3.31 (m, 6H), 2.31-1.94 (m, 4H), 1.58-1.41 (m, 15H).

[0607] Step 2

[0608] Compound 30a (100 mg, 180 μmol) was dissolved in dioxane (1 mL), and dioxane hydrochloride solution (4 M, 1.35 mL) was added to the mixture. The reaction mixture was stirred at 25° C. for 1 hour and concentrated under reduced pressure to obtain the hydrochloride salt of compound 30b.

[0609] MS-ESI calculated value [M+H] + 454 and 456, measured values ​​454 and 456.

[0610] Step 3

[0611] The hydrochloride of compound 30b (70.0 mg, 143 μmol) and compound 22b (30.4 mg, 214 μmol) were dissolved in dichloromethane (1 mL), glacial acetic acid (8.56 mg, 143 μmol) was added to the mixture, and the reaction solution was stirred at 15° C. for 13 hours, sodium triacetoxyborohydride (60.4 mg, 343 μmol) was added to the reaction solution, and the reaction solution was stirred at 15° C. for 1 hour. 10% sodium bicarbonate solution was used to adjust the pH to about 9, and water (100 mL) was added to the reaction solution to dilute it, followed by extraction with dichloromethane (50 mL×3), and the organic phases were combined, washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, and concentrated to obtain compound 30c.

[0612] MS-ESI calculated value [M+H] + 580 and 582, measured values ​​580 and 582.

[0613] Step 4

[0614] Compound 30c (60 mg, 248 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and a solution of sodium hydroxide (16.5 mg, 413 μmol) in water (0.5 mL) was added to the mixture, and the reaction solution was stirred at 20°C for 12 hours. The pH of the reaction solution was adjusted to about 5 with 1N hydrochloric acid solution, and the mixture was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_PhenomenexLuna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 43%-63%, 7 aliquots} to obtain the hydrochloride of compound 30.

[0615] MS-ESI calculated value [M+H] + 552 and 554, measured values ​​552 and 554.

[0616] 1 H NMR (400MHz, CDCl3) δ=8.37 (s, 1H), 8.12-8.03 (m, 2H), 7.98-7.78 (m, 1H), 7.50-7.36 (m, 1H), 7.01 (d, J=8.6 Hz, 1H), 4.81-4.65 (m, 1H), 4.32-2.79 (m, 10H), 2.60-2.08 (m, 4H), 1.75-1.42 (m, 2H), 1.46 (d, J=5.8Hz, 6H).

[0617] Embodiment 31

[0618]

[0619] Synthesis route:

[0620]

[0621] first step

[0622] Compound 9c (140 mg, 603 μmol) was dissolved in anhydrous N, N-dimethylformamide (3 mL), 1-hydroxybenzotriazole (97.9 mg, 724 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (138 mg, 724 μmol) were added to the mixture, the reaction solution was stirred at 25°C for 1 hour, compound 1m (200 mg, 603 μmol) was added to the reaction solution, the reaction solution was stirred at 25°C for 1 hour, and the reaction solution was further stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure, water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL×3), the organic phases were combined, the organic phases were washed with saturated brine (30 mL×3), and dried over anhydrous sodium sulfate. The crude product was purified by thin layer chromatography (1:1, petroleum ether / ethyl acetate, Rf=0.80) to obtain compound 31a.

[0623] MS-ESI calculated values ​​[M+H- t Bu] + 471, measured value 471.

[0624] Step 2

[0625] Compound 31a (300 mg, 570 μmol) was dissolved in dioxane (2 mL), and dioxane hydrochloride solution (4 M, 4.27 mL) was added to the mixture. The reaction mixture was stirred at 25° C. for 1 hour and concentrated under reduced pressure to obtain the hydrochloride of compound 31b.

[0626] MS-ESI calculated value [M+H] + 427, measured value 427.

[0627] Step 3

[0628] The hydrochloride of compound 31b (200 mg, 431 μmol) and compound 22b (123 mg, 864 μmol) were dissolved in dichloromethane (2 mL), glacial acetic acid (25.9 mg, 431 μmol) was added to the mixture, and the reaction solution was stirred at 15° C. for 13 hours, sodium triacetoxyborohydride (183 mg, 864 μmol) was added to the reaction solution, and the reaction solution was stirred at 15° C. for 1 hour. 10% sodium bicarbonate solution was used to adjust the pH to about 9, and water (100 mL) was added to the reaction solution for dilution, followed by extraction with dichloromethane (50 mL×3), and the organic phases were combined, washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, and concentrated to obtain compound 31c.

[0629] MS-ESI calculated value [M+H] + 553, measured value 553.

[0630] Step 4

[0631] Compound 31c (20 mg, 36.2 μmol) was dissolved in anhydrous dioxane (0.8 mL), and anhydrous lithium hydroxide (3.04 mg, 72.4 μmol) in water (0.2 mL) was added to the mixture, and the reaction solution was stirred at 28°C for 2 hours. The pH of the reaction solution was adjusted to about 5, and the reaction solution was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: Phenomenex lunaC18 150*25mm*10μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 29%-59%, 10 minutes} to obtain the hydrochloride of compound 31.

[0632] MS-ESI calculated value [M+H] + 525, measured value 525.

[0633] 1 H NMR (400MHz, CDCl3) δ = 8.42-8.28 (m, 2H), 807 (d, J = 7.8Hz, 1H), 7.49-7.38 (m, 1H) , 7.14 (d, J=8.8Hz, 1H), 5.04-4.95 (m, 1H), 3.53-3.19 (m, 6H), 2.49-0.73 (m, 18H).

[0634] Embodiment 32

[0635]

[0636] Synthesis route:

[0637]

[0638] first step

[0639] Compound 8g (790 mg, 3.83 mmol) was dissolved in anhydrous N, N-dimethylformamide (10 mL), 1-hydroxybenzotriazole (621 mg, 4.60 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (881 mg, 4.60 mmol) were added to the mixture, the reaction solution was stirred at 25°C for 1 hour, compound 1m (1.27 g, 3.83 mmol) was added to the reaction solution, the reaction solution was stirred at 25°C for 1 hour, and the reaction solution was stirred at 80°C for 8 hours. 80 mL of water was added to the reaction solution, extracted with ethyl acetate (60 mL×3), the organic phases were combined, the organic phases were washed with saturated brine (60 mL×2), dried over anhydrous sodium sulfate, and concentrated to obtain compound 32a.

[0640] MS-ESI calculated value [M+H-tBu] + 446, measured value 446.

[0641] Step 2

[0642] Compound 32a (1.93 g, 2.74 mmol) was dissolved in ethyl acetate (30 mL). To the mixture was added hydrochloric acid / ethyl acetate (4 M, 6.85 mL). The reaction mixture was stirred at 25° C. for 1 hour and concentrated under reduced pressure to obtain the hydrochloride of compound 32b.

[0643] MS-ESI calculated value [M+H] + 402, measured value 402.

[0644] Step 3

[0645] The hydrochloride of compound 32b (100 mg, 228 μmol) and compound 22b (48.7 mg, 343 μmol) were dissolved in dichloromethane (5 mL), glacial acetic acid (13.7 mg, 228 μmol) was added to the mixture, and the reaction solution was stirred at 20° C. for 8 hours, sodium triacetoxyborohydride (96.8 mg, 457 μmol) was added to the reaction solution, and the reaction solution was stirred at 20° C. for 10 hours. The solvent was removed under reduced pressure, and a 10% aqueous solution of sodium bicarbonate (20 mL) was added to the residue, and extracted with dichloromethane (30 mL×2), and the organic phases were combined, washed with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 32c.

[0646] MS-ESI calculated value [M+H] + 528, measured value 528.

[0647] Step 4

[0648] Compound 32c (125 mg, 237 μmol) was dissolved in anhydrous tetrahydrofuran (6 mL), and a methanol (3 mL) solution containing sodium hydroxide (37.9 mg, 948 μmol) was added to the mixture, and the reaction solution was stirred at 20°C for 12 hours. The pH of the reaction solution was adjusted to 5 using 12N HCl solution, and the solvent was removed by concentration. The crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 43%-63%, 7 minutes} to obtain the hydrochloride of compound 32.

[0649] MS-ESI calculated value [M+H] + 500, measured value is 500.

[0650] 1 H NMR(400 MHz, CDCl3) δ=9.16 (d, J=2.5Hz, 1H), 8.64 (d, J=2.3Hz, 1H), 8.10 (d, J=7.8Hz, 1H), 7.52-7.42 (m, 1H), 7.28-7 .25 (m, 1H), 5.63-5.54 (m, 1H), 3.68-320 (m, 6H), 2.63-1.55 (m, 8H), 1.49 (d, J=6.3Hz, 6H), 1.41-1.19 (m, 2H).

[0651] Embodiment 33

[0652]

[0653] Synthesis route:

[0654]

[0655] first step

[0656] Compound 13d (150 mg, 731 μmol) was dissolved in anhydrous N, N-dimethylformamide (15 mL), 1-hydroxybenzotriazole (118 mg, 877 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (168 mg, 877 μmol) were added to the mixture, the reaction solution was stirred at 25°C for 1 hour, compound 1m (242 mg, 730 μmol) was added to the reaction solution, the reaction solution was stirred at 25°C for 2 hours, and the reaction solution was further stirred at 80°C for 8 hours. The solvent was removed under reduced pressure, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×2), the organic phases were combined, the organic phases were washed with water (20 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate, and the crude product was subjected to silica gel column chromatography (2:1, petroleum ether / ethyl acetate) to obtain compound 33a.

[0657] MS-ESI calculated value [M+H-tBu] + 445, measured value 445.

[0658] Step 2

[0659] Compound 33a (208 mg, 415 μmol) was dissolved in ethyl acetate (2 mL), and hydrochloric acid / ethyl acetate (4 M, 0.52 mL) was added to the mixture. The reaction solution was stirred at 25° C. for 1 hour, and the solvent was removed under reduced pressure and dried to obtain the hydrochloride of compound 33b.

[0660] MS-ESI calculated value [M+H] + 401, measured value 401.

[0661] Step 3

[0662] The hydrochloride of compound 33b (50 mg, 0.11 mmol) and compound 22b (40.6 mg, 286 μmol) were dissolved in dichloromethane (5 mL), glacial acetic acid (6.87 mg, 114 μmol) was added to the mixture, and the reaction solution was stirred at 25°C for 8 hours. Sodium triacetoxyborohydride (48.5 mg, 228 μmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 6 hours. A 10% aqueous sodium bicarbonate solution (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL×3). The organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by thin layer silica gel chromatography (0:1, petroleum ether / ethyl acetate) to obtain compound 33c. MS-ESI calculated value [M+H] + 527, measured value 527.

[0663] Step 4

[0664] Compound 33c (53 mg, 0.10 mmol) was dissolved in anhydrous tetrahydrofuran (6 mL) and anhydrous methanol (3 mL), and a solution of lithium hydroxide monohydrate (12.6 mg, 301 μmol) in water (1.5 mL) was added to the mixture, and the reaction solution was stirred at 25° C. for 12 hours. The pH of the reaction solution was adjusted to 5 with 12 N HCl, and the mixture was concentrated under reduced pressure to obtain compound 33d.

[0665] MS-ESI calculated value [M+H] + 517, measured value 517.

[0666] Step 5

[0667] Compound 33d (51 mg, 99 μmol) was dissolved in anhydrous dichloromethane (3 mL), triethylamine (19.9 mg, 197 μmol) and trifluoroacetic anhydride (20.8 mg, 108 μmol) were added to the mixture, and the reaction solution was stirred at 0°C for 1 hour. 1M HCl aqueous solution was added to the reaction solution to adjust the pH to 5, and the reaction solution was concentrated under reduced pressure. The crude product was purified by HPLC {hydrochloric acid conditions, column model: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 32%-62%, 8 minutes} to obtain the hydrochloride of compound 33.

[0668] MS-ESI calculated value [M+H] + 499, actual measured value 499.

[0669] 1 H NMR (400MHz, CDCl3) δ = 11.86-11.55 (m, 1H), 9.08 (s, 1H), 8.40 (s, 1H), 8.05 (d, J = 7.5Hz, 1H), 7.92 (d, J = 7.0Hz, 1H), 7.48-7.37 (m, 1H), 5 .64-5.48 (m, 1H), 4.58-4.44 (m, 1H), 4.31-3.84 (m, 2H), 3.65-3.10 (m, 6H), 2.60-2.07 (m, 4H), 1.86-1.48 (m, 4H), 1.35 (d, J=6.5Hz, 6H).

[0670] Embodiment 34

[0671]

[0672] Synthesis route:

[0673]

[0674] first step

[0675] Compound 17c (100 mg, 469 μmol) was dissolved in anhydrous N, N-dimethylformamide (10 mL), 1-hydroxybenzotriazole (76.1 mg, 563 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107 mg, 563 μmol) were added to the mixture, the reaction solution was stirred at 25°C for 1 hour, compound 1m (155 mg, 469 μmol) was added to the reaction solution, the reaction solution was stirred at 25°C for 2 hours, and the reaction solution was further stirred at 80°C for 8 hours. The mixture was concentrated under reduced pressure, 20 mL of water was added to the residue for dilution, and the mixture was extracted with ethyl acetate (30 mL×2), the organic phases were combined, the organic phases were washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 34a.

[0676] MS-ESI calculated value [M+H-tBu] + 453, measured value 453.

[0677] Step 2

[0678] Compound 34a (314 mg, 617 μmol) was dissolved in ethyl acetate (2 mL), and hydrochloric acid / ethyl acetate (4 M, 0.77 mL) was added to the mixture. The reaction mixture was stirred at 25° C. for 1 hour and concentrated under reduced pressure to obtain the hydrochloride of compound 34b.

[0679] MS-ESI calculated value [M+H] + 409, measured value 409.

[0680] Step 3

[0681] The hydrochloride of compound 34b (70 mg, 0.16 mmol) and compound 22b (44.7 mg, 314 μmol) were dissolved in dichloromethane (5 mL), glacial acetic acid (9.5 mg, 0.16 mmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 8 hours. Sodium triacetoxyborohydride (133 mg, 629 μmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 6 hours. A 10% sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL×3). The organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by thin layer silica gel chromatography (0:1, petroleum ether / ethyl acetate) to obtain compound 34c. MS-ESI calculated value [M+H] + 535, measured value 535.

[0682] Step 4

[0683] Compound 34c (88 mg, 0.16 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and a solution of lithium hydroxide monohydrate (20.7 mg, 493 μmol) in water (2.5 mL) was added to the mixture, and the reaction solution was stirred at 25° C. for 12 hours. The pH of the reaction solution was adjusted to 5 using 12N HCl, and the mixture was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography {hydrochloric acid conditions, column model: VenusilASB Phenyl 150*30mm*5μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 42%-52%, 9 minutes} to obtain the hydrochloride of compound 34.

[0684] MS-ESI calculated value [M+H] + 507, measured value 507.

[0685] 1 H NMR(400 MHz, CDCl3) δ = 1211-11.84 (m, 1H), 8.53 (d, J = 7.5Hz, 1H), 8.43 (d, J = 8.0Hz, 1H), 8.14-8.05 (m, 1H), 8.04-7.92 (m, 1H), 7.60-7.5 3 (m, 1H), 7.50-7.42 (m, 1H), 6.79 (t, J=70.8Hz, 1H), 4.36-3.83 (m, 2H), 3.65-3.18 (m, 6H), 2.62-2.21 (m, 4H), 1.75-1.56 (m, 4H).

[0686] Embodiment 35

[0687]

[0688] Synthesis route:

[0689]

[0690] first step

[0691] Compound 35a (50 mg, 0.27 mmol) was dissolved in anhydrous dichloromethane (5 mL), Dess-Martin periodinane (181 mg, 427 μmol) was added to the mixture, the reaction solution was stirred at 20°C for 1 hour, 10% sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by thin layer silica gel chromatography (2:1, petroleum ether / ethyl acetate) to obtain compound 35b.

[0692] 1H NMR (400MHz, CDCl3) δ=9.15 (s, 1H), 5.24 (s, 1H), 1.53-1.42 (m, 4H), 1.48 (s, 9H).

[0693] Step 2

[0694] The hydrochloride of compound 1o (100 mg, 228 μmol) and compound 35b (63.6 mg, 343 μmol) were dissolved in dichloromethane (10 mL), glacial acetic acid (13.7 mg, 228 μmol) was added to the mixture, and the reaction solution was stirred at 25° C. for 8 hours, sodium triacetoxyborohydride (194 mg, 915 μmol) was added to the reaction solution, and the reaction solution was stirred at 25° C. for 6 hours. 10% sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, and extracted with dichloromethane (10 mL×3), the organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by thin layer silica gel chromatography (0:1, petroleum ether / ethyl acetate) to obtain compound 35c.

[0695] MS-ESI calculated value [M+H] + 570, measured value 570.

[0696] Step 3

[0697] Compound 35c (100 mg, 175 μmol) was dissolved in ethyl acetate (5 mL), and hydrochloric acid / ethyl acetate (4 M, 219 μL) solution was added to the mixture, and the reaction solution was stirred at 25°C for 2 hours. After concentration, the crude product was purified by HPLC {hydrochloric acid conditions, column model: Boston Green ODS 150*30mm*5μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 17%-47%, 8 minutes} to obtain the hydrochloride of compound 35.

[0698] MS-ESI calculated value [M+H] + 470, measured value 470.

[0699] 1 H NMR(400 MHz, DMSO-d6) δ = 8.78-8.66 (m, 1H), 8.63-8.54 (m, 1H), 8.41 (dd, J = 9.0, 2.1Hz, 1H), 8.08-7.98 (m, 1H) ), 7.61-7.47 (m, 2H), 5.05-4.92 (m, 1H), 4.38-3.08 (m, 8H), 2.65-1.84 (m, 8H), 1.39 (d, J=6.0Hz, 6H).

[0700] Embodiment 36

[0701]

[0702] Synthesis route:

[0703]

[0704] first step

[0705] Compound 36a (100 mg, 1.03 mmol) was dissolved in anhydrous dichloromethane (10 mL), Dess-Martin periodinane (699 mg, 1.65 mmol) was added to the mixture, the reaction solution was stirred at 20°C for 1 hour, 10% sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, extracted with dichloromethane (10 mL×3), the organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by thin-plate silica gel chromatography (1:1, petroleum ether / ethyl acetate) to obtain compound 36b.

[0706] 1 H NMR (400MHz, CDCl3) δ=9.33 (s, 1H), 1.82-1.72 (m, 4H).

[0707] Step 2

[0708] Compound 1o (70 mg, 0.16 mmol) and compound 36b (22.8 mg, 240 μmol) were dissolved in dichloromethane (8 mL), glacial acetic acid (1.92 mg, 32.0 μmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 8 hours. Sodium triacetoxyborohydride (136 mg, 640 μmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 6 hours. To the reaction solution was added 10% aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (10 mL×3), the organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by HPLC {hydrochloric acid conditions, column model: Venusil ASB Phenyl 150*30mm*5μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 45%-55%, 9 minutes} to obtain the hydrochloride of compound 36.

[0709] MS-ESI calculated value [M+H] + 480, measured value 480.

[0710] Embodiment 37

[0711]

[0712] Synthesis route:

[0713]

[0714] first step

[0715] Compound 37a (2.00 g, 7.43 mmol), compound 37b (983 mg, 7.81 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (272 mg, 372 μmol) and potassium carbonate (2.06 g, 14.9 mmol) were dissolved in n-butanol (20 mL), and the reaction solution was stirred at 100° C. for 12 hours under nitrogen protection. The reaction mixture was filtered and concentrated, the crude product was diluted with water (40 mL), extracted with ethyl acetate (40 mL×2), the combined organic phase was washed with saturated brine (40 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by thin layer silica gel chromatography (10:1-3:1, petroleum ether / ethyl acetate, V / V) to obtain compound 37c.

[0716] MS-ESI calculated value [MH] + 269, measured value 269.

[0717] Step 2

[0718] Compound 37c (700 mg, 2.59 mmol) was dissolved in methanol (15 mL), wet palladium carbon (70.0 mg, 10% purity) was added to the reaction solution under nitrogen protection, and the reaction mixture was stirred at 50° C. under hydrogen (1 MPa) atmosphere for 16 hours. The reaction mixture was filtered and concentrated to obtain compound 37d.

[0719] MS-ESI calculated value [MH] + 271, measured value 271.

[0720] Step 3

[0721] Compound 11 (10.3 g, 34.5 mmol) was dissolved in ethyl acetate (50 mL), hydrochloric acid / ethyl acetate (4 M, 80 mL) was added to the mixture, and the reaction mixture was stirred at 25° C. for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride of compound 37e.

[0722] MS-ESI calculated value [M+H] + 199, measured value 199.

[0723] Step 4

[0724] The hydrochloride of compound 37e (10.0 g, 42.6 mmol) was dissolved in dichloromethane (100 mL), acetic acid (42.6 mmol, 2.44 mL) and compound 22b (18.2 g, 128 mmol) were added to the reaction solution, and the reaction solution was stirred at 25°C for 1 hour. Sodium acetate borohydride (27.1 g, 128 mmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 1 hour. The crude product was diluted with water (200 mL), extracted with dichloromethane (100 mL×2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by thin layer silica gel chromatography (200:1-20:1, dichloromethane / methanol, V / V) to obtain compound 37f.

[0725] MS-ESI calculated value [M+H] + 325, measured value 325.

[0726] Step 5

[0727] Compound 37f (12.7 g, 39.2 mmol) was dissolved in anhydrous ethanol (150 mL), hydroxylamine hydrochloride (8.16 g, 117 mmol) and triethylamine (16.4 mL, 117 mmol) were added to the mixture, and the reaction solution was stirred at 80° C. for 5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography (chromatographic column: Phenomenex Synergi Max-RP 250×50 mm×10 μm; mobile phase: [water (0.1% TFA)-acetonitrile]; acetonitrile%: 1%-20%, 20 min) to obtain trifluoroacetate of compound 37g.

[0728] MS-ESI calculated value [M+H] + 358, measured value 358.

[0729] Step 6

[0730] Compound 37d (693 mg, 2.55 mmol) was dissolved in N, N-dimethylformamide (20 mL), and 1-hydroxybenzotriazole (413 mg, 3.05 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (586 mg, 3.05 mmol) were added to the mixture. The reaction solution was stirred at 20°C for 1 hour, and trifluoroacetate of compound 37g (1.20 g, 2.55 mmol) was added to the mixture. The reaction solution was stirred at 20°C for 2 hours and at 80°C for 8 hours. Water (100 mL) was added for dilution, and the mixture was extracted with ethyl acetate (40 mL×2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by thin layer silica gel chromatography (1:0-20:1, dichloromethane / methanol, V / V) to obtain compound 37h.

[0731] MS-ESI calculated value [M+H] + 594, measured value 594.

[0732] Step 7

[0733] Compound 37h (400 mg, 416 μmol) was dissolved in tetrahydrofuran (5 mL), methanol (5 mL) and water (2 mL), and lithium hydroxide monohydrate (52.4 mg, 1.25 mmol) was added, and the reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and the residue was diluted with water (30 ml), and the pH was adjusted to 3 with 1N hydrochloric acid aqueous solution, and extracted with ethyl acetate (30 mL×2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75×30 mm×3 um; mobile phase: [water (0.225% FA)-acetonitrile]; acetonitrile%: 45%-75%, 7 min) to obtain the formate salt of compound 37.

[0734] MS-ESI calculated value [M+H] + 566, measured value 566.

[0735] 1 H NMR (400MHz, CD3OD) δ = 8.47-8.38 (m, 2H), 8.14-8.10 (m, 1H), 7.86 (d, J = 8.2Hz, 1H), 7.59 (d, J = 7.2Hz, 1H), 7.53-7.47 (m, 1H), 3.73-3.60 (m, 2 H), 3.46-3.35 (m, 4H), 3.04 (t, J=11.4Hz, 1H), 2.48-2.29 (m, 4H), 2.00 -1.74(m, 6H), 1.71-1.36(m, 6H), 1.33-1.26(m, 2H), 0.89-0.82(m, 2H).

[0736] Embodiment 38

[0737]

[0738] Synthesis route:

[0739]

[0740] first step

[0741] Compound 37a (2.00 g, 7.43 mmol), compound 38a (874 mg, 7.81 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (272 mg, 372 μmol), potassium carbonate (2.05 g, 14.9 mmol) were dissolved in n-butanol (20 mL), and the reaction solution was stirred at 100° C. for 12 hours under nitrogen protection. The reaction mixture was filtered and concentrated, the crude product was diluted with water (40 mL), extracted with ethyl acetate (40 mL×2), the combined organic phase was washed with saturated brine (40 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by thin layer silica gel chromatography (10:1-3:1, petroleum ether / ethyl acetate, V / V) to obtain compound 38b.

[0742] MS-ESI calculated value [MH] + 255, measured value 255.

[0743] Step 2

[0744] Compound 38b (700 mg, 2.73 mmol) was dissolved in methanol (15 mL), wet palladium carbon (70.0 mg, 10% purity) was added to the reaction solution under nitrogen protection, and the reaction mixture was stirred at 50° C. in a hydrogen atmosphere (1 MPa) for 16 hours. The reaction mixture was filtered and concentrated to obtain compound 38c.

[0745] MS-ESI calculated value [MH] + 257, measured value 257.

[0746] Step 3

[0747] Compound 38c (300 mg, 1.16 mmol) was dissolved in dichloromethane (6 mL), oxalyl chloride (305 μL, 3.49 mmol) and N,N-dimethylformamide (8.49 mg, 116 μmol) were added to the reaction solution, the reaction solution was stirred at 25°C for 0.5 hours, and the reaction solution was concentrated under reduced pressure to obtain compound 38d.

[0748] Step 4

[0749] Compound 38d (317 mg, 1.15 mmol) was dissolved in dichloromethane (8 mL), triethylamine (1.91 mmol, 333 μL) and trifluoroacetate of compound 37g (300 mg, 636 μmol) were added to the reaction solution, and the reaction solution was stirred at 25° C. for 12 hours. Water (20 mL) was added for dilution, and the mixture was extracted with dichloromethane (20 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 38e.

[0750] MS-ESI calculated value [M+H] +598, measured value 598.

[0751] Step 5

[0752] Compound 38e (522 mg, 873 μmol) was dissolved in acetonitrile (8 mL), sodium hydroxide (34.9 mg, 873 μmol) was added to the reaction solution, and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure, the crude product was diluted with water (20 mL), extracted with ethyl acetate (20 mL×2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 38f.

[0753] MS-ESI calculated value [M+H] + 580, actual measured value 580.

[0754] Step 6

[0755] Compound 38f (464 mg, 800 μmol) was dissolved in tetrahydrofuran (4 mL), methanol (4 mL) and water (2 mL), and lithium hydroxide monohydrate (101 mg, 2.40 mmol) was added, and the reaction solution was stirred at 25° C. for 12 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and the residue was diluted with water (30 ml), adjusted to pH=3 with 1N hydrochloric acid aqueous solution, extracted with ethyl acetate (30 mL×2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by high performance liquid chromatography (chromatographic column: 3_PhenomenexLuna C18 75×30 mm×3 μm; mobile phase: [water (0.05% HCl)-acetonitrile]; acetonitrile%: 48%-68%, 6.5 min) to obtain the hydrochloride of compound 38.

[0756] MS-ESI calculated value [M+H] + 552, measured value 552.

[0757] 1 H NMR (400MHz, CD3OD) δ = 8.46-8.39 (m, 2H), 8.17-8.11 (m, 1H), 7.87 (d, J = 8.4Hz, 1H), 7.61 (d, J = 7.4Hz, 1H), 7.54-7.48 (m, 1H), 3.97 (s, 2 H), 3.70-3.37 (m, 7H), 2.58-2.24 (m, 4H), 2.22-2.10 (m, 2H), 2.04-1.91 (m, 2H), 1.86-1.68 (m, 4H), 1.52 (d, J=2.4Hz, 2H), 1.20 (s, 2H).

[0758] Embodiment 39

[0759]

[0760] Synthesis route:

[0761]

[0762] first step

[0763] Compound 39a (400 mg, 1.86 mmol) was dissolved in dichloromethane (6 mL), oxalyl chloride (650 μL, 7.42 mmol) and N,N-dimethylformamide (27.1 mg, 371 μmol) were added to the reaction solution, the reaction solution was stirred at 25° C. for 0.5 hours, and the reaction solution was concentrated under reduced pressure to obtain compound 39b.

[0764] Step 2

[0765] The trifluoroacetate of compound 37g (550 mg, 1.17 mmol) and compound 39b (437 mg, 1.87 mmol) were dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (3.50 mmol, 610 μL) was added to the reaction solution, and the reaction solution was stirred at 25° C. for 1 hour. Water (30 mL) was added for dilution, and the mixture was extracted with dichloromethane (20 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 39c.

[0766] MS-ESI calculated value [M+H] + 555, actual measured value 555.

[0767] Step 3

[0768] Compound 39c (800 mg, 1.44 mmol) was dissolved in acetonitrile (15 mL), sodium hydroxide (115 mg, 2.88 mmol) was added to the reaction solution, and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure, the crude product was diluted with water (20 mL), extracted with ethyl acetate (20 mL×2), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 39d.

[0769] MS-ESI calculated value [M+H] + 537, measured value 537.

[0770] Step 4

[0771] Compound 39d (483 mg, 899 μmol) was dissolved in tetrahydrofuran (6 mL), methanol (3 mL) and water (3 mL), and lithium hydroxide monohydrate (113 mg, 2.70 mmol) was added, and the reaction solution was stirred at 25° C. for 12 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated by high performance liquid chromatography (chromatographic column: 3_Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 39%-59%, 6.5 min) to obtain the hydrochloride of compound 39.

[0772] MS-ESI calculated value [M+H] + 509, measured value 509.

[0773] 1 H NMR (400MHz, DMSO-d6) δ = 11.55-9.82 (m, 1H), 8.90 (d, J = 2.2Hz, 1H), 8.52 (d, J = 2.2Hz, 1H), 7.99 (d, J = 7.4Hz, 1H), 7.77 (d, J = 7.6Hz, 1H), 7.50 (t, J=7.6Hz, 1H), 5.47-5.39(m, 1H), 3.67-3.51(m, 3H), 3.26-3.16(m, 3H), 2.34 (s, 1H), 2.29-217 (m, 3H), 1.38 (d, J=6.2Hz, 7H), 1.33-1.28 (m, 3H).

[0774] Embodiment 40

[0775]

[0776] Synthesis route:

[0777]

[0778] first step

[0779] Compound 40a (4.00 g, 19.8 mmol) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane (810 mg, 992 μmol) were dissolved in tetrahydrofuran (20 mL), and the gas was replaced with nitrogen three times. Cyclopentylzinc bromide tetrahydrofuran solution (0.5 M, 39.7 mL) was added to the reaction solution at 60°C, and the reaction solution was stirred at 60°C for 12 hours. The reaction solution was concentrated under reduced pressure, the crude product was diluted with 1N hydrochloric acid solution (50 mL), extracted with methyl tert-butyl ether (50 mL×3), the combined organic phase was washed with 1N hydrochloric acid solution (50 mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by thin layer silica gel chromatography (1:0, petroleum ether / ethyl acetate, V / V) to obtain compound 40b. MS-ESI calculated value [M+H] + 236, measured value 236.

[0780] Step 2

[0781] Compound 40b (2.50 g, 10.6 mmol) was dissolved in ethanol (25 mL) and water (5 mL), sodium hydroxide (1.27 g, 31.9 mmol) was added, and the reaction solution was stirred at 90°C for 0.5 hours. The reaction solution was concentrated under reduced pressure to remove the organic solvent, and the residue was diluted with water (100 mL), adjusted to pH = 4 with 1N hydrochloric acid aqueous solution, extracted with dichloromethane (100 mL×2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated by thin layer silica gel chromatography (10:1-2:1, petroleum ether / ethyl acetate, V / V) to obtain compound 40c.

[0782] MS-ESI calculated value [M+H] + 222, measured value 222.

[0783] Step 3

[0784] Compound 40c (200 mg, 904 μmol) was dissolved in dichloromethane (5 mL), oxalyl chloride (237 μL, 2.71 mmol) and N,N-dimethylformamide (6.61 mg, 90.4 μmol) were added to the reaction solution, the reaction solution was stirred at 25°C for 1 hour, and the reaction solution was concentrated under reduced pressure to obtain compound 40d.

[0785] Step 4

[0786] Compound 37g (200 mg, 560 μmol) and compound 40d (201 mg, 839 μmol) were dissolved in dichloromethane (6 mL), and N, N-diisopropylethylamine (839 μmol, 146 μL) was added to the reaction solution. The reaction solution was stirred at 25°C for 2 hours. Saturated sodium bicarbonate aqueous solution (50 mL) was added for dilution, and the mixture was extracted with ethyl acetate (40 mL×3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by thin layer chromatography (dichloromethane / methanol, 10 / 1, V / V) to obtain compound 40e.

[0787] MS-ESI calculated value [M+H] + 543, measured value 543.

[0788] Step 5

[0789] Compound 40e (68.0 mg, 125 μmol) was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL), and 1 M sodium hydroxide aqueous solution (4.26 mL) was added. The reaction solution was stirred at 50°C for 3 hours. The reaction solution was cooled to 25°C, adjusted to pH 4-5 with 1N hydrochloric acid aqueous solution, diluted with water (10 mL), and concentrated under reduced pressure to remove the organic solvent. The aqueous phase was extracted with dichloromethane (40 mL×3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: 10 mmol / L ammonium bicarbonate aqueous solution-acetonitrile; gradient: acetonitrile 44%-74%, 10 min) to obtain compound 40.

[0790] MS-ESI calculated value [M+H] + 515, measured value 515.

[0791] 1 HNMR (400MHz, CD3OD) δ8.11-8.15 (m, 1H), 7.60-7.62 (m, 1H), 7.49-7.54 (m, 2H), 7.30-7.31 (m, 1H), 4.00 (s, 3H), 3.40-3.54 (m, 7H), 2.37-2.40 (m, 5H), 2.09-2.11 (m, 2H), 1.90-1.93 (m, 5H), 1.87-1.89 (m, 2H), 1.44-1.46 (m, 2H), 1.07-1.08 (m, 2H).

[0792] Embodiment 43

[0793]

[0794] Synthesis route:

[0795]

[0796] first step

[0797] Intermediate 43a (1000 mg, 5 mmol), iodopropane (927 mg, 6 mmol) and silver carbonate (1250 mg, 5 mmol) were added to toluene (10 mL). The reaction solution was heated to 50°C for 12 hours. The reaction solution was added to water (50 mL), extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 1 to 5 / 1, V / V) to obtain intermediate 43b.

[0798] MS-ESI calculated value [M+H] + 263, measured value 263.

[0799] Step 2

[0800] Intermediate 43b (1260 mg, 5 mmol) and hydrated lithium hydroxide (605 mg, 14 mmol) were added to tetrahydrofuran (12 mL) and water (3 mL). The reaction solution was reacted at room temperature for 12 hours. The reaction solution was added to water (20 mL), extracted with ethyl acetate (20 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 43c.

[0801] MS-ESI calculated value [M+H] + 249, measured value 249.

[0802] Step 3

[0803] Intermediate 11 (400 mg, 1 mmol), intermediate 43c (300 mg, 1 mmol), 1-hydroxybenzotriazole (196 mg, 1.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (278 mg, 1.5 mmol) were added to N-dimethylformamide (20 mL). The reaction solution was heated to 80° C. for 11 hours. The reaction solution was added to water (150 mL), extracted with ethyl acetate (40 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude compound 43d.

[0804] MS-ESI calculated value [M+Na] + 566, measured value 566.

[0805] Step 4

[0806] Compound 43d (815 mg, 1.5 mmol), 4M hydrochloric acid and ethyl acetate (1.87 mL) were added to ethyl acetate (6 mL), and the reaction solution was reacted at 25° C. for 1 hour. The mixture was concentrated under reduced pressure and separated by thin layer silica gel chromatography (20:1, petroleum ether / ethyl acetate, V / V) to obtain the hydrochloride of intermediate 43e.

[0807] MS-ESI calculated value [M+H] + 444, measured value 444.

[0808] Step 5

[0809] The hydrochloride of intermediate 43e (250 mg, 564 μmol), intermediate 22b (240 mg, 1.7 mmol) and acetic acid (34 mg, 564 μmol) were added to dichloromethane (20 mL). The reaction solution was stirred at 25°C for 1 hour, sodium acetate borohydride (478 mg, 2.3 mmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 13 hours. The reaction solution was added to 10% sodium bicarbonate solution (50 mL), extracted with dichloromethane (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 4 / 1 to 1 / 1, V / V) to obtain intermediate 43f.

[0810] MS-ESI calculated value [M+H] + 570, measured value 570.

[0811] Step 6

[0812] Compound 43f (100 mg, 176 μmol) and hydrated lithium hydroxide (22 mg, 527 μmol) were added to tetrahydrofuran (10 mL) and water (2.5 mL), and the reaction solution was reacted at 25°C for 12 hours. The crude product was concentrated under reduced pressure. The crude product was separated by high performance liquid chromatography (chromatographic column: 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 of compound 43.

[0813] MS-ESI calculated value [M+H] + 542, measured value 542.

[0814] 1H NMR (400MHz, CD3OD) δ8.42-8.33 (m, 2H), 8.10 (d, J=7.6Hz, 1H), 7.62 (br s, 1H), 7.53-7.40 (m, 2H), 4.05-3.85 (m, 2H), 3.69-3.55 (m, 3H), 3.53-3.35 (m, 4H), 2.66 (s, 1H), 2.54-2.24 (m, 4H), 1.52 (br s, 2H), 1.42 (d, J=6.0Hz, 6H), 1.30-1.21 (m, 2H).

[0815] Embodiment 44

[0816]

[0817] Synthesis route:

[0818]

[0819] first step

[0820] Intermediate 1j (3940 mg, 16 mmol) was added to intermediate 44a (3000 mg, 19 mmol). The reaction solution was heated to 25°C for 60 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane / methanol, 100 / 1 to 100 / 1, V / V) to obtain intermediate 44b.

[0821] MS-ESI calculated value [M+H] + 380, 382. Actual measured values: 380, 382.

[0822] Step 2

[0823] Compound 44b (1120 mg, 3 mmol) was dissolved in anhydrous N, N-dimethylformamide (25 mL), zinc cyanide (660 mg, 5.6 mmol), tris(dibenzylideneacetone)dipalladium (81 mg, 88 μmol), 2-di-tert-butylphosphine-2′,4′,6′-triisopropylbiphenyl (84 mg, 177 μmol) were added, and the atmosphere was replaced with nitrogen three times. Under nitrogen protection, the reaction solution was stirred at 90°C for 12 hours. After the reaction, the reaction solution was concentrated. The residue was diluted with water (140 mL), extracted with ethyl acetate (50 mL×3), the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated, and separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 0 / 1, V / V) to obtain intermediate 44c. MS-ESI calculated value [M+H] + 327, measured value 327.

[0824] Step 3

[0825] Intermediate 44c (503 mg, 1.5 mmol), hydroxylamine hydrochloride (321 mg, 4.6 mmol) and triethylamine (468 mg, 4.6 mmol) were added to ethanol (10 mL). The reaction solution was reacted at 80° C. for 4 hours. The reaction solution was added to water (50 mL), extracted with ethyl acetate (60 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and separated by thin layer silica gel chromatography (20:1, petroleum ether / ethyl acetate, V / V) to obtain intermediate 44d.

[0826] MS-ESI calculated value [M+H] + 360, measured value 360.

[0827] Step 4

[0828] Intermediate 44d (452 ​​mg, 1 mmol), intermediate 1d (215 mg, 1 mmol), 1-hydroxybenzotriazole (170 mg, 1.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (241 mg, 1.3 mmol) were added to N,N-dimethylformamide (30 mL). The reaction solution was heated to 80° C. for 11 hours. The reaction solution was added to water (120 mL), extracted with ethyl acetate (40 mL×2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude compound 44e.

[0829] MS-ESI calculated value [M+H] + 529, measured value 529.

[0830] Step 5

[0831] Compound 44e (57 mg, 108 μmol) was added to acetic acid (149 mg, 2.5 mmol), and the reaction solution was reacted at 35°C for 12 hours. The crude product was concentrated under reduced pressure. The crude product was separated by high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 46%-66%, 6.5 min) to obtain the hydrochloride of compound 44.

[0832] MS-ESI calculated value [M+H]+489, found value 489.

[0833] 1H NMR (400MHz, CD3OD) δ8.36-8.27 (m, 2H), 8.00-7.91 (m, 1H), 7.48-7.29 (m, 3H), 4.96-4.8 8 (m, 2H), 4.63-4.42 (m, 1H), 4.04-3.51 (m, 7H), 2.33-198 (m, 4H), 1.44 (d, J=6.0Hz, 6H).

[0834] Embodiment 45

[0835]

[0836] Synthesis route:

[0837]

[0838] first step

[0839] Intermediate 1j (1500 mg, 5.2 mmol) was added to intermediate 45a (1140 mg, 7.1 mmol). The reaction solution was heated to 25°C for 30 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane / methanol, 100 / 1 to 5 / 1, V / V) to obtain intermediate 45b.

[0840] MS-ESI calculated value [M+H] + 380, 382. Actual measured values: 380, 382.

[0841] Step 2

[0842] Compound 45b (523 mg, 853 μmol) was dissolved in anhydrous N, N-dimethylformamide (6 mL), zinc cyanide (242 mg, 2.1 mmol), tris(dibenzylideneacetone)dipalladium (38 mg, 41 μmol) and 2-di-tert-butylphosphine-2′, 4′, 6′-triisopropylbiphenyl (39 mg, 83 μmol) were added, and the mixture was replaced with nitrogen three times. Under nitrogen protection, the reaction solution was stirred at 90°C for 12 hours. After the reaction, the reaction solution was concentrated. Water (10 mL) was added to the residue for dilution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated, and separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1 to 1 / 1, V / V) to obtain intermediate 45c. MS-ESI calculated value [M+H] + 327, measured value 327.

[0843] Step 3

[0844] Intermediate 45c (103 mg, 1.5 mmol), hydroxylamine hydrochloride (66 mg, 947 μmol) and triethylamine (96 mg, 947 μmol) were added to ethanol (4 mL). The reaction solution was reacted at 80°C for 12 hours. The reaction solution was added to water (30 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was separated by thin layer silica gel chromatography (20:1, dichloromethane / methanol, V / V) to obtain intermediate 45d.

[0845] MS-ESI calculated value [M+H] + 360, measured value 360.

[0846] Step 4

[0847] Intermediate 45d (98 mg, 215 μmol), intermediate 1d (44 mg, 215 μmol), 1-hydroxybenzotriazole (35 mg, 256 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mg, 259 mmol) were added to N,N-dimethylformamide (10 mL). The reaction solution was heated to 80° C. for 11 hours. The reaction solution was added to water (50 mL), extracted with ethyl acetate (20 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 45e.

[0848] MS-ESI calculated value [M+H] + 529, measured value 529.

[0849] Step 5

[0850] Compound 45e (70 mg, 132 μmol) was added to acetic acid (459 mg, 3.1 mmol), and the reaction solution was reacted at 35°C for 12 hours. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin layer silica gel chromatography (20:1, dichloromethane / methanol, V / V) to obtain compound 45.

[0851] MS-ESI calculated value [M+H]+489, found value 489.

[0852] 1H NMR (400MHz, CDCl3) δ8.44 (d, J=1.7Hz, 1H), 8.38-8.32 (m, 1H), 8.14-8.07 (m, 1H), 7.45-7.38 (m, 1H), 7.35-7.30 (m, 1H), 7.14 (d, J=9. 0Hz, 1H), 4.87-4.75 (m, 1H), 4.47-4.29 (m, 1H), 3.92-3.68 (m, 6H), 3.41 (brt, J=7.2Hz, 2H), 2.36-1.99 (m, 6H), 1.49 (d, J=6.1Hz, 6H).

[0853] Embodiment 46

[0854]

[0855] Synthesis route:

[0856]

[0857] first step

[0858] Intermediate 1mm (300 mg, 905 μmol), intermediate 46a (161 mg, 905 μmol), 1-hydroxybenzotriazole (147 mg, 1.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (208 mg, 1.1 mmol) were added to N,N-dimethylformamide (10 mL). The reaction solution was heated to 80°C and stirred for 11 hours. The reaction solution was added to water (20 mL), extracted with ethyl acetate (30 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 46b by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 1 to 10 / 1, V / V). MS-ESI calculated value [M+Na] + 496, measured value 496.

[0859] Step 2

[0860] Compound 46b (260 mg, 549 μmol), 4M hydrochloric acid and ethyl acetate (1 mL) were added to ethyl acetate (2 mL), and the reaction solution was reacted at 25° C. for 1 hour. The mixture was concentrated under reduced pressure and separated and purified by thin layer silica gel chromatography (20:1, dichloromethane / methanol) to obtain the hydrochloride salt of intermediate 46c.

[0861] MS-ESI calculated value [M+H] + 374, measured value 374.

[0862] Step 3

[0863] The hydrochloride of intermediate 46c (205 mg, 500 μmol), intermediate 22b (142 mg, 1 mmol) and acetic acid (30 mg, 500 μmol) were added to dichloromethane (15 mL), and the reaction solution was stirred at 25°C for 1 hour. Sodium acetate borohydride (424 mg, 2 mmol) was added to the reaction solution, and the reaction solution was stirred at 25°C for 13 hours. 10% sodium bicarbonate solution (20 mL) was added to the reaction solution, and extracted with dichloromethane (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by thin layer silica gel chromatography (0:1, petroleum ether / ethyl acetate, V / V) to obtain intermediate 46d.

[0864] MS-ESI calculated value [M+H] + 500, measured value is 500.

[0865] Step 4

[0866] Compound 46d (138 mg, 276 μmol) and hydrated lithium hydroxide (12 mg, 276 μmol) were added to tetrahydrofuran (20 mL) and water (5 mL), and the reaction solution was reacted at 25° C. for 12 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was separated by high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 75×30 mm×3 μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile 46%-66%, 6.5 min) to obtain the hydrochloride of compound 46.

[0867] MS-ESI calculated value [M+H] + 472, measured value 472.

[0868] 1 H NMR (400MHz, CD3OD) δ8.17-8.03 (m, 3H), 7.62 (d, J=7.6Hz, 1H), 7.49 (t, J=7.6Hz, 1H), 7.42 (d, J=8.3Hz, 2H), 7.03-7.00(m, 1H), 3.69-3.54(m, 3H), 3.41(d, J=5.6Hz, 2H), 2.66(s, 2H), 2.61( d, J=7.3Hz, 2H), 2.46-2.29(m, 2H), 255-2.24(m, 1H), 2.01-1.89(m, 1H), 1.56-1.48(m, 1H), 1. 51 (d, J=2.5Hz, 1H), 1.54-1.45 (m, 1H), 1.36-1.26 (m, 1H), 1.22 (s, 2H), 0.95 (d, J=6.5Hz, 6H).

[0869] Test Example 1: In vitro evaluation of the agonist activity of the compounds of the present invention on S1PR1

[0870] Experimental purpose: To detect the agonist activity of compounds on S1PR1

[0871] 1. Cell Treatment

[0872] 1. Thaw the PathHumter cell line according to standard procedures;

[0873] 2. Inoculate the cells in 20 μl of a 384-well microplate and incubate at 37°C for an appropriate time.

[0874] 2. Agonists

[0875] 1. For agonist assays, cells are incubated with the sample to be tested to induce a response;

[0876] 2. Dilute the stock solution to be tested 5-fold into the buffer solution;

[0877] 3.5 μl of the 5-fold dilution was added to the cells and incubated at 37°C for 90-180 minutes. The vehicle concentration was 1%.

[0878] 3. Signal Detection

[0879] 1. Add 12.5 μl or 15 μl of 50% volume ratio PathHunter detection reagent once, and then incubate at room temperature for 1 hour to generate detection signal;

[0880] 2. Read the microplate using a PerkinElmer EnvisionTM instrument to detect chemiluminescent signals.

[0881] 4. Data Analysis

[0882] 1. Use CBIS data analysis suite (ChemInnovation, CA) to analyze compound activity;

[0883] 2. Calculation formula:

[0884] % Activity = 100% x (mean test sample RLU - mean vehicle RLU) / (mean maximum control ligand - mean vehicle RLU)

[0885] The experimental results are shown in Table 1:

[0886] Table 1 S1PR1 agonist activity test results

[0887]

[0888]

[0889] Conclusion: The compounds of the present invention all have significant and even unexpected S1PR1 agonist activity.

[0890] Test Example 2: In vitro evaluation of the agonist activity of the compounds of the present invention on S1PR1

[0891] Experimental purpose: To detect the agonist activity of compounds on S1PR1

[0892] 1. Cell Treatment

[0893] 1. Take out the cells U2OS-EDG1 (lot number: Invitrogen-K1520) from the liquid nitrogen tank and thaw quickly in a 37°C water bath;

[0894] 2. Aspirate the cell suspension and place it in a 15 mL centrifuge tube, resuspend it in 5 mL of preheated culture medium, and centrifuge at 1000 rpm for 5 minutes;

[0895] 3. Discard the supernatant, resuspend in 10 mL of culture medium, transfer to a T75 culture flask, and culture in a 37°C, 5% CO2 incubator.

[0896] 2. Agonist Assay

[0897] 1. Dilute the compound to the working concentration, dilute the compound 3-fold, 10 concentrations by Echo 555 (manufacturer: Labcyte), transfer 200 nL of each concentration to the cell plate, and centrifuge at 1000 rpm for 15 seconds;

[0898] 2. Aspirate the culture medium in the culture flask, add 4 mL of Dulbecco's Phosphate Buffered Saline (DPBS, supplier: Coring, catalog number: 21-031-CVR, batch number: 03318006) to wash away the residual serum, add 2 mL of trypsin, incubate in a 37°C incubator for 2 minutes to digest the cells, add 10 mL of seed culture medium to resuspend the cells, and take out 0.6 mL of the cell suspension for counting;

[0899] 3. Use the seed plate medium to adjust the cell density to 1.88E+05 cells / mL, seed each well with 40μL (7500\well), and add 40μL FreeStyle around the cell plate. TM Expression medium, incubate at room temperature for 15 minutes, and culture at 37°C, 5% CO2 for 20 hours.

[0900] 3. Signal Detection

[0901] 1. Configure LiveBLAzer according to the instructions TM -FRET B / G Substrate (CCF4-AM) detection reagent;

[0902] 2. Add 8 μL of 6×Substrate Mixture to each well of the cell plate, centrifuge at 1000 rpm for 15 seconds, apply the membrane, incubate at 23°C for 2 hours, and detect with Envision chemiluminescence.

[0903] 4. Data Analysis

[0904] 1. Convert the raw data into % Effcct, EC using the equation 50 The value can be obtained by four-parameter curve fitting [obtained by the "log(agonist)vs.response--Variable slope" mode in GraphPad Prism];

[0905] 2. Calculation formula:

[0906] Ratio=(460nmblank) / (535nmblank)

[0907] %Effect=(Sample Ratio -Ave LC Ratio ) / (Ave HC Ratio -Ave LC Ratio )x100%

[0908] The experimental results are shown in Table 2:

[0909] Table 2 S1PR1 agonist activity test results

[0910] Test product <![CDATA[S1PR1 agonist activity EC 50 , Emax]]> Compound 22A 0.15nM, 84.2% Compound 22B 0.32nM, 74.0% Hydrochloride of compound 29 0.0211nM, 91.5% Hydrochloride of compound 30 0.132nM, 103% Hydrochloride of compound 31 0.456nM, 101% Hydrochloride of compound 32 1.45nM, 95.9% Hydrochloride of compound 33 10.2nM, 99.9% Hydrochloride of compound 34 6.07nM, 94.9%

[0911] Conclusion: The compounds of the present invention all have significant and even unexpected S1PR1 agonist activity.

[0912] Test Example 3: Pharmacokinetic Evaluation of Compounds in Rats

[0913] Experimental purpose: To test the pharmacokinetics of the compound in SD rats

[0914] Experimental Materials:

[0915] Sprague Dawley rats (male, 200-300 g, 7-9 weeks old, Shanghai Slake)

[0916] Experimental operation:

[0917] The pharmacokinetic characteristics of rodents after intravenous and oral administration of the compound were tested by standard protocols. In the experiment, the candidate compound was prepared into a clear solution and given a single intravenous injection and oral administration to rats. The intravenous solvent was a 5:95 DMSO and 10% hydroxypropyl β-cyclodextrin aqueous solution, and the oral solvent was a 0.5% w / v methylcellulose and 0.2% w / v Tween 80 aqueous solution. Whole blood samples were collected within 24 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, and the supernatant was centrifuged and added with an equal volume of water. The supernatant was centrifuged again and the supernatant was sampled. The blood drug concentration was quantitatively analyzed by LC-MS / MS analysis method, and pharmacokinetic parameters such as peak concentration, clearance, half-life, area under the drug-time curve, bioavailability, etc. were calculated.

[0918] Experimental results:

[0919] Table 3 Pharmacokinetic test results

[0920]

[0921] Conclusion: The compounds of the present invention show good bioavailability, higher area under the concentration-time curve and lower clearance in the pharmacokinetics of SD rats.

[0922] Test Example 4: Pharmacokinetic Evaluation of Compounds in Mice

[0923] Experimental purpose: To test the pharmacokinetics of compounds in CD-1 mice

[0924] Experimental Materials:

[0925] CD-1 mice (male, 20-40 g, 6-10 weeks old, Shanghai Bikai)

[0926] Experimental operation:

[0927] The pharmacokinetic characteristics of rodents after intravenous and oral administration of the compound were tested according to the standard protocol. In the experiment, the candidate compound was prepared into a clear solution or suspension and given a single intravenous injection and oral administration to two mice. The intravenous solvent was 5:95 DMSO and 10% hydroxypropyl β-cyclodextrin aqueous solution, and the oral solvent was 0.5% w / v methylcellulose and 0.2% w / v Tween 80 aqueous solution. Whole blood samples were collected within 24 hours, centrifuged at 3200g for 10 minutes, and the supernatant was separated to obtain plasma samples. Four volumes of acetonitrile solution containing internal standard were added to precipitate proteins, and the supernatant was centrifuged and added with an equal volume of water. The supernatant was centrifuged again and the supernatant was sampled. The blood drug concentration was quantitatively analyzed by LC-MS / MS analysis method, and pharmacokinetic parameters such as peak concentration, clearance, half-life, area under the drug-time curve, bioavailability, etc. were calculated.

[0928] Experimental results:

[0929] Table 4 Pharmacokinetic test results

[0930]

[0931]

[0932] Conclusion: The compounds of the present invention show good bioavailability, higher area under the concentration-time curve and lower clearance in the pharmacokinetics of CD-1 mice.

[0933] Test Example 5: Pharmacokinetic evaluation of compounds at different doses in rats

[0934] Experimental day: Pharmacokinetics of the test compound at different doses in SD rats

[0935] Experimental Materials:

[0936] Sprague Dawley rats (male, 200-300 g, 7-9 weeks old, Shanghai Slake)

[0937] Experimental operation:

[0938] The pharmacokinetic characteristics of the compounds in SD rats after oral administration were tested by the standard protocol. In the experiment, the candidate compounds were prepared into clear solutions and given to rats for a single oral administration. The solvent for compound 1 was DMSO: 10% hydroxypropyl β-cyclodextrin aqueous solution = 5:95. The solvent for compounds 1A and 1B was 0.5% carboxymethyl cellulose + 0.2% Tween 80. Whole blood samples within 48 hours were collected for compounds 1, 1A and 1B, centrifuged at 3000g for 15 minutes, and the supernatant was separated to obtain plasma samples. Four times the volume of acetonitrile solution containing internal standard was added to precipitate the protein, and the supernatant was centrifuged and added with an equal volume of water. The supernatant was centrifuged again and the supernatant was sampled. The blood drug concentration was quantitatively analyzed by LC-MS / MS analysis method, and pharmacokinetic parameters such as peak concentration, peak time, half-life, and area under the drug-time curve were calculated.

[0939] The experimental results are shown in Table 5:

[0940] Table 5 Pharmacokinetic test results

[0941]

[0942] Note: - means cannot be determined.

[0943] Conclusion: The increase in systemic exposure of the compounds of the present invention at different doses in the pharmacokinetics of SD rats conforms to the dose-related linear proportion; the compounds of the present invention show higher area under the concentration-time curve and peak concentration in the pharmacokinetics of SD rats.

Claims

1. A compound represented by formula (P) or a pharmaceutically acceptable salt thereof, in, T0 is selected from CH-E-R3 and N; T1 is selected from CR4 and N; E is absent or selected from O and NH; Ring A is selected from oxazolyl, 1,2,4-oxadiazolyl, thiazolyl, 1,3,4-thiadiazole, 1,2,4-thiadiazolyl, pyrimidinyl and pyrazinyl; R2 is selected from H, F, Cl, Br, CN, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy group is optionally substituted with 1, 2 or 3 R b replace; R3 is selected from C 1-6 Alkyl, cyclopentyl and cyclohexyl, the C 1-6 Alkyl, cyclopentyl and cyclohexyl are optionally substituted with 1, 2 or 3 R c replace; R4 is selected from H and cyclopentyl; R5 is selected from R 51 Selected from OH, NH2, CN, CH2COOH, CH2OH, C 1-3 Alkoxy and -S(O)2-C 1-3 alkyl; R 52 Selected from CN, NH2 and COOH; R 53 Selected from H and OH; R b and R c are independently selected from F, Cl and Br; n is selected from 0 and 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R2 is selected from H, F, Cl, Br, CN, CH3 and OCH3, wherein CH3 and OCH3 are optionally replaced by 1, 2 or 3 R b replace.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein: R2 is selected from H, Br, Cl, CN, CHF2, CF3 and OCH3.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R3 is selected from C 1-4 alkyl, The C 1-4 alkyl, Optional 1, 2 or 3 R c replace.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein: R3 is selected from CH(CH3)2, CHF2, CH2CH(CH3)2 7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1, 5 or 6, wherein: Structural unit Selected from 8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 51 Selected from OH, NH2, CN, CH2COOH, CH2OH, OCH3 and -S(O)2CH3.

9. The compound according to claim 1 or 8 or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from: in, R2 as defined in claim 1; R3 as defined in claim 1; T1, E and n are as defined in claim 1; T2 is selected from O and S; T3 is selected from CH and N; T4 is selected from CH, T5 is selected from N, or T4 is selected from N, T5 is selected from CH.

12. A compound represented by the following formula or a pharmaceutically acceptable salt thereof:

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, which is selected from:

14. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases associated with S1PR1.

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