Benzoxazinone derivative

Abstract

The invention relates to a benzoxazinone derivative and a preparation method thereof, in particular to a compound as shown in a formula (II), and a stereoisomer or pharmaceutically acceptable salt thereof. # imgabs0 #

Description

[0001] This application is a divisional application based on the Chinese invention patent application with application date of June 14, 2022, application number 202280037711.9, and invention name “Benzoxazinone derivatives”.

[0002] This application claims the following priority:

[0003] CN202110661381.8, June 15, 2021;

[0004] CN202111341577.5, November 12, 2021;

[0005] CN202210421052.0, April 20, 2022.

[0006] CN202210626997.6, June 02, 2022. Technical Field

[0007] The present application relates to a class of benzoxazinone derivatives and a preparation method thereof, and specifically to a compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. Background Art

[0008] Aldosterone is a mineralocorticoid hormone mainly secreted by the zona glomerulosa of the adrenal cortex. It is an important substance for regulating water-sodium balance and maintaining homeostasis in the body. The latest research has found that excessive aldosterone can promote inflammation, cause myocardial remodeling and fibrosis, and can also directly lead to renal tissue damage, increase proteinuria, and participate in the occurrence and development of various diseases such as chronic kidney disease, hypertension, and heart failure. Mineralocorticoid receptor antagonists antagonize the binding of aldosterone and mineralocorticoid receptor (MR), preventing the excessive activation of the aldosterone-MR complex, thereby delaying disease progression. Although early clinical trials have shown that MR antagonists can improve the prognosis of patients with heart failure, increase survival rates, and have kidney protection effects in addition to lowering blood pressure, the first-generation drug spironolactone has poor nuclear receptor selectivity, and long-term use can cause adverse reactions such as male breast development, impotence, and female menstrual disorders. Although the second-generation drug eplerenone improves nuclear receptor selectivity, its activity is weak and difficult to synthesize. Both spironolactone and eplerenone have the risk of hyperkalemia in clinical use, which limits the application of MR antagonists.

[0009] AZD9977 (WO2016001631) is a mineralocorticoid receptor modulator developed by AstraZeneca. Studies have shown that AZD9977 has partial antagonist activity on mineralocorticoid receptors. In the completed Phase I clinical trial of healthy people, it was demonstrated that AZD9977 has almost no effect on the sodium-potassium excretion ratio in urine and almost no effect on blood potassium, which may avoid the key clinical risk of hyperkalemia. Currently, AstraZeneca is conducting a Phase II clinical trial of AZD9977 and the SGLT-2 inhibitor dapagliflozin for the treatment of heart failure and chronic kidney disease.

[0010] Summary of the invention

[0011] In one aspect, the present application provides a compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0012]

[0013] in,

[0014] R 1 Selected from R 11 and R 12 ;

[0015] R 11 Select from -OR a 、-C(=O)NR b R c and -S(=O) 2 C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R aa replaced by;

[0016] R 12 is selected from 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted by 1, 2 or 3 R d replaced by;

[0017] R 2 , R 3 and R 4 are independently selected from H, F, Cl, Br, I, -CN, -NH 2 , -OH and C 1-4 alkyl;

[0018] R 5 and R 6 are independently selected from H, D, F, Cl, Br and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R ab Replaced by; R 7and R 8 are independently selected from H, F, Cl, Br, I, -CN, -NH 2 , -OH and C 1-4 alkyl;

[0019] R a , R b and R c are independently selected from H, C 1-4 Alkyl and C 3-4 Cycloalkyl, wherein the C 1-4 Alkyl and C 3-4 The cycloalkyl group is optionally substituted with 1, 2 or 3 R groups independently;

[0020] R d are independently selected from H, F, Cl, Br, I, -CN, -NH 2 , -OH and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R ac replaced by;

[0021] R aa , R ab and R ac Each independently selected from D, F, Cl, Br, I, -CN, -NH 2 and -OH;

[0022] R is independently selected from F, Cl, Br, I, -CN, -NH 2 and -OH;

[0023] The "hetero" in the 5-membered heteroaryl group represents 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and -N-.

[0024] In one aspect, the present application provides a compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0025]

[0026] in,

[0027] R 1 Selected from R 11 and R 12 ;

[0028] R 11 Select from -OR a 、-C(=O)NR b R c and -S(=O) 2 C 1-4 Alkyl, wherein the C1-4 The alkyl group is optionally substituted with 1, 2 or 3 R aa replaced by;

[0029] R 12 is selected from 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted by 1, 2 or 3 R d replaced by;

[0030] R 2 , R 3 and R 4 are independently selected from H, F, Cl, Br, I, -CN, -NH 2 , -OH and C 1-4 alkyl;

[0031] R 5 and R 6 are independently selected from H, D, F, Cl, Br and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R ab Replaced by; R 7 and R 8 are independently selected from H, F, Cl, Br, I, -CN, -NH 2 and -OH;

[0032] R a , R b and R c are independently selected from H, C 1-4 Alkyl and C 3-4 Cycloalkyl, wherein the C 1-4 Alkyl and C 3-4 The cycloalkyl group is optionally substituted with 1, 2 or 3 R groups independently;

[0033] R d are independently selected from H, F, Cl, Br, I, -CN, -NH 2 , -OH and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R ac replaced by;

[0034] R aa , R ab and R ac Each independently selected from D, F, Cl, Br, I, -CN, -NH 2 and -OH;

[0035] R is independently selected from F, Cl, Br, I, -CN, -NH 2 and -OH;

[0036] The "hetero" in the 5-membered heteroaryl group represents 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -N-, -O-, -S- and -NH-.

[0037] On the other hand, the present application provides a compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0038]

[0039] in,

[0040] R 1 Selected from R 11 and R 12 ;

[0041] R 11 Select from -OR a 、-C(=O)NR b R c and -S(=O) 2 C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R aa replaced by;

[0042] R 12 is selected from 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted by 1, 2 or 3 R d replaced by;

[0043] R 2 , R 3 and R 4 are independently selected from H, F, Cl, Br, I, -CN, -NH 2 , -OH and C 1-4 alkyl;

[0044] R 5 and R 6 are independently selected from H, F, Cl, Br and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R ab Replaced by; R a , R b and R c are independently selected from H, C 1-4 Alkyl and C 3-4 Cycloalkyl, wherein the C 1-4 Alkyl and C 3-4 The cycloalkyl group is optionally substituted with 1, 2 or 3 R groups independently;

[0045] R d are independently selected from H, F, Cl, Br, I, -CN, -NH2 , -OH and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R ac replaced by;

[0046] R aa , R ab and R ac are independently selected from F, Cl, Br, I, -CN, -NH 2 and -OH;

[0047] R is independently selected from F, Cl, Br, I, -CN, -NH 2 and -OH;

[0048] The "hetero" in the 5-membered heteroaryl group represents 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -N-, -O-, -S- and -NH-.

[0049] In some embodiments of the present application, the above compound has a structure shown in formula (II-1) or (II-2):

[0050]

[0051] Among them, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 and R 12 As defined in this application.

[0052] In some embodiments of the present application, the above compounds have structures shown in formula (I-1) and (I-2):

[0053]

[0054] Among them, R 2 , R 3 , R 4 , R 5 , R 6 , R 11 and R 12 As defined in this application.

[0055] In some embodiments of the present application, the above compound has a structure shown in formula (II-3), (II-4), (II-5) or (II-6):

[0056]

[0057] Among them, R2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 11 and R 12 As defined in this application.

[0058] In some embodiments of the present application, the above compound has a structure shown in formula (I-3), (I-4), (I-5) or (I-6):

[0059]

[0060] Among them, R 2 , R 3 , R 4 , R 5 , R 6 , R 11 and R 12 As defined in this application.

[0061] In some embodiments of the present application, the above R a is selected from H, and the other variables are as defined in this application.

[0062] In some embodiments of the present application, the above R b and R c are independently selected from H, -CH 3 、-CH 2 CH 3 and Other variables are as defined in this application.

[0063] In some embodiments of the present application, the above R d are independently selected from H, F, Cl, Br and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R ac Replaced by R ac and other variables are as defined in this application.

[0064] In some embodiments of the present application, the above R d are independently selected from H, F, Cl, Br and -CH 3 , wherein the -CH 3 Optional 1, 2 or 3 R ac Replaced by R ac and other variables are as defined in this application.

[0065] In some embodiments of the present application, the above R ac is selected from D and -OH, and the other variables are as defined herein.

[0066] In some embodiments of the present application, the above R d are independently selected from H, F, Cl, Br, -CH 3 , Other variables are as defined in this application.

[0067] In some embodiments of the present application, the above R d are independently selected from H, F, Cl, Br and -CH 3 , other variables are as defined in this application.

[0068] In some embodiments of the present application, the above R d are independently selected from H, -CH 3 , Other variables are as defined in this application.

[0069] In some embodiments of the present application, the above R 11 Selected from -OH, -C(=O)NH 2 、-C(=O)NHCH 3 、-C(=O)NHCH 2 CH 3 , and -S(=O) 2 CH 3 , other variables are as defined in this application.

[0070] In some embodiments of the present application, the above R 11 Selected from -OH, -C(=O)NHCH 3 、-C(=O)NHCH 2 CH 3 , and -S(=O) 2 CH 3 , other variables are as defined in this application.

[0071] In some embodiments of the present application, R 12 is selected from 5-membered heteroaryl, wherein "hetero" in the 5-membered heteroaryl represents 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -N-, -O- and -NH-, wherein the 5-membered heteroaryl is optionally substituted by 1, 2 or 3 R d The other variables are as defined in this application.

[0072] In some embodiments of the present application, R 12 is selected from 5-membered heteroaryl, wherein "hetero" in the 5-membered heteroaryl represents 3 or 4 heteroatoms or heteroatom groups independently selected from -N-, -O- and -NH-, wherein the 5-membered heteroaryl is optionally substituted by 1, 2 or 3 R dThe other variables are as defined in this application.

[0073] In some embodiments of the present application, the above R 12 Selected from It is stated are independently optionally substituted by 1, 2 or 3 R d Replaced by R d and other variables are as defined in this application.

[0074] In some embodiments of the present application, the above R 12 Selected from

[0075] wherein n is selected from 1, 2 and 3, R d and other variables are as defined in this application.

[0076] In some embodiments of the present application, the above R 12 Selected from

[0077] wherein n is selected from 1, 2 and 3, R d and other variables are as defined in this application.

[0078] In some embodiments of the present application, the above R 12 Selected from

[0079] R d and other variables are as defined in this application.

[0080] In some embodiments of the present application, the above R 12 Selected from

[0081] R d and other variables are as defined in this application.

[0082] In some embodiments of the present application, the above R 12 Selected from

[0083] Other variables are as defined in this application.

[0084] In some embodiments of the present application, the above R 12 Selected from

[0085] Other variables are as defined in this application.

[0086] In some embodiments of the present application, the above R 12 Selected from

[0087] Other variables are as defined in this application.

[0088] In some embodiments of the present application, the above R 1 Selected from -OH, -C(=O)NH 2 、--C(=O)NHCH 3 、-C(=O)NHCH 2 CH 3 , -S(=O) 2 CH 3 , Other variables are as defined in this application.

[0089] In some embodiments of the present application, the above R 1 Selected from -OH, -C(=O)NHCH 3 、-C(=O)NHCH 2 CH 3 , -S(=O) 2 CH 3 ,

[0090] Other variables are as defined in this application.

[0091] In some embodiments of the present application, the above R 1 Selected from -OH, -C(=O)NH 2 、-C(=O)NHCH 3 、-C(=O)NHCH 2 CH 3 , -S(=O) 2 CH 3 , Other variables are as defined in this application.

[0092] In some embodiments of the present application, the above R 1 Selected from -OH, -C(=O)NHCH 3 、-C(=O)NHCH 2 CH 3 , -S(=O) 2 CH 3 ,

[0093] Other variables are as defined in this application.

[0094] In some embodiments of the present application, the above R 1 Selected from -OH, -C(=O)NHCH 3 、-C(=O)NHCH 2 CH 3 , -S(=O) 2 CH 3 and Other variables are as defined in this application.

[0095] In some embodiments of the present application, the above R 2 and R 3 are independently selected from H, F and Cl, and other variables are as defined in the present application.

[0096] In some embodiments of the present application, the above R 2 Selected from F, R 3 is selected from H and F, and the other variables are as defined in this application.

[0097] In some embodiments of the present application, the above R 2 is selected from F, and the other variables are as defined in this application.

[0098] In some embodiments of the present application, the above R 3 is selected from H and F, and the other variables are as defined in this application.

[0099] In some embodiments of the present application, the above R 4 Selected from H, F, Cl and C 1-4 Alkyl, and other variables are as defined herein.

[0100] In some embodiments of the present application, the above R 4 Selected from H, F, Cl and -CH 3 , other variables are as defined in this application.

[0101] In some embodiments of the present application, the above R 4 is selected from H, and the other variables are as defined in this application.

[0102] In some embodiments of the present application, the above R 5 and R 6 are independently selected from H, D and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 Rab Replaced by R ab and other variables are as defined in this application.

[0103] In some embodiments of the present application, the above R 5 Selected from H, D and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R ab Replaced by R ab and other variables are as defined in this application.

[0104] In some embodiments of the present application, the above R 5 and R 6 are independently selected from H, D and -CH 3 , other variables are as defined in this application.

[0105] In some embodiments of the present application, the above R 5 Selected from H, D and -CH 3 , other variables are as defined in this application.

[0106] In some embodiments of the present application, the above R 6 is selected from H and D, and the other variables are as defined in this application.

[0107] In some embodiments of the present application, the above R 5 and R 6 are independently selected from H and -CH 3 , other variables are as defined in this application.

[0108] In some embodiments of the present application, the above R 5 Selected from H and -CH 3 , other variables are as defined in this application.

[0109] In some embodiments of the present application, the above R 6 is selected from H, and the other variables are as defined in this application.

[0110] In some embodiments of the present application, the above R 7 is selected from H and F, and the other variables are as defined in this application.

[0111] In some embodiments of the present application, the above R 7 is selected from H, and the other variables are as defined in this application.

[0112] In some embodiments of the present application, the above R 8 Selected from H, F, Cl and C 1-4 Alkyl, and other variables are as defined herein.

[0113] In some embodiments of the present application, the above R 8Selected from H, F, Cl and -CH 3 , other variables are as defined in this application.

[0114] Some other solutions of the present application are obtained by any combination of the above variables.

[0115] The present application also provides a compound of the following formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0116]

[0117]

[0118]

[0119]

[0120] The present application also provides a compound of the following formula, a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128] The present application also provides a pharmaceutical composition, which contains a therapeutically effective amount of the compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0129] The present application also provides the use of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of drugs for treating diseases related to mineralocorticoid receptor antagonists.

[0130] The present application also provides the use of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of a drug for treating diabetic nephropathy.

[0131] The present application also provides a method for treating a disease associated with a mineralocorticoid receptor antagonist in a subject in need thereof, comprising providing an effective dose of the above compound, its stereoisomer or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition to the subject.

[0132] The present application also provides the use of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in treating diseases related to mineralocorticoid receptor antagonists.

[0133] The present application also provides the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition for treating diseases associated with mineralocorticoid receptor antagonists.

[0134] In some embodiments of the present application, the mineralocorticoid receptor antagonist-related disease is selected from diabetic nephropathy.

[0135] The present application also provides a biological experimental test method for the above compounds:

[0136] Technical Effects

[0137] The compound of the present application has good antagonistic activity on mineralocorticoid receptors. In addition, the compound exhibits excellent pharmacokinetic and pharmacodynamic properties, and has good membrane permeability and solubility.

[0138] Definition and Description

[0139] 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.

[0140] 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.

[0141] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application, prepared from a compound with a specific substituent found in the present application and a relatively non-toxic acid or base. When the compound of the present application contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of a 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 compound of the present application contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent. Certain specific compounds of the present application contain basic and acidic functional groups and can be converted into either a base or acid addition salt.

[0142] The pharmaceutically acceptable salts of the present application 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.

[0143] The compounds of the present application may exist in specific geometric or stereoisomeric forms. The present application 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 mixtures enriched in enantiomers or diastereomers, all of which fall within the scope of the present application. Additional asymmetric carbon atoms may exist in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present application.

[0144] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0145] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability of a ring to rotate freely about double bonds or single bonds of ring carbon atoms.

[0146] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0147] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0148] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Represents a straight solid bond and straight dashed key For example express express

[0149] Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can rapidly interconvert. If tautomerism is possible (such as in solution), chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0150] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0151] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0152] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate is generated from an amine).

[0153] The compounds of the present application may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). 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 application, whether radioactive or not, are included in the scope of the present application.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] When the number of a linking group is 0, such as -(CRR) 0 -, indicating that the connecting group is a single bond.

[0158] 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.

[0159] When a substituent is vacant, it means that the substituent does not exist. For example, when the × in A-× is vacant, it means that the structure is actually A. When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom of it. For example, pyridyl as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0160] When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of the reading order from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0161] 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, -OCH 3 The straight solid bond in the group 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 lines in the phenyl group represent the connection 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.

[0162] When the chemical bond of a substituent intersects the chemical bond connecting two atoms on a ring, it means that the substituent can form a bond with any atom on the ring. When the atom to which a substituent is attached is not specified, the substituent can form a bond with any atom. If the atom to which the substituent is attached is in a bicyclic or tricyclic ring system, it means that the substituent can form a bond with any atom in any ring in the system. Combinations of substituents and / or variables are allowed only if the combination results in a stable compound. For example, the structural unit It means that it can be substituted at any position on the cyclohexyl group or the cyclopentyl group.

[0163] 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.

[0164] Unless otherwise specified, the term “C 3-4 The term "cycloalkyl" is used to denote any stable cyclic alkyl group containing 3 to 4 carbon atoms, which is a monocyclic ring system and can be monovalent, divalent or polyvalent. 3-4 Examples of cycloalkyl groups include cyclopropyl and cyclobutyl.

[0165] Unless otherwise specified, the terms "5-membered heteroaromatic ring" and "5-membered heteroaryl" can be used interchangeably. The term "5-membered heteroaryl" refers to a monocyclic group with a conjugated π electron system consisting of 5 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). The 5-6 membered heteroaryl may be attached to the rest of the molecule via a heteroatom or a carbon atom. Examples of the 5-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2 H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.).

[0166] 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 C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 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.

[0167] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., an affinity substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-brosylate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.

[0168] The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS), 2-(trimethylsilyl)ethoxymethyl (SEM) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0169] The compounds of the present application 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 substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0170] The structure of the compounds of the present application can be confirmed by conventional methods known to those skilled in the art. If the present application involves 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 (S×RD) 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 (Shel×s97) to confirm the absolute configuration.

[0171] The solvents used in this application are commercially available.

[0172] The following abbreviations are used in this application: MR stands for mineralocorticoid receptor; ACEI stands for angiotensin converting enzyme inhibitor; ARB stands for angiotensin receptor blocker; UACR stands for urine albumin / creatinine ratio; RAAS stands for renin-angiotensin-aldosterone system. g stands for gram; mg stands for milligram; μL stands for microliter; mL stands for milliliter; mol stands for mole; mmol stands for millimole; μmol stands for micromole; M stands for mole / liter; mM stands for millimole / liter; μM stands for micromole / liter; nM stands for nanomole / liter. Me stands for methyl; Boc stands for tert-butyloxycarbonyl; DMSO-d 6 CD stands for deuterated dimethyl sulfoxide; 3 OD stands for deuterated methanol; CDCl 3 stands for deuterated chloroform; DEA stands for diethanolamine; SFC stands for supercritical fluid chromatography. DETAILED DESCRIPTION

[0173] The present application is described in detail below by way of examples, but this does not mean any adverse limitation to the present application. The present application has been described in detail herein, and its specific embodiments are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0174] Intermediate A

[0175] Synthesis route:

[0176]

[0177] first step

[0178] Compound A-1 (50.0 g, 318 mmol) was dissolved in methanol (500 mL). Palladium / carbon (6.00 g, 10% purity) was added to the reaction solution under nitrogen protection. The reaction mixture was replaced with hydrogen several times and stirred at 50 psi hydrogen atmosphere at 20 degrees Celsius for 24 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain crude compound A-2. MS-ESI calculated value [M+H] + 128, measured value 128.

[0179] Step 2

[0180] Ethyl 4-chloroacetoacetate (47.0 g, 286 mmol) was dissolved in tetrahydrofuran (340 mL), compound A-2 (33.0 g, 260 mmol) was added to the reaction solution, and the reaction mixture was heated to 50 degrees Celsius. At 50 degrees Celsius, N, N-diisopropylethylamine (33.6 g, 260 mmol) was added to the reaction solution, and the reaction mixture was stirred at 50 degrees Celsius for 12 hours. The reaction solution was diluted with water (200 mL), extracted with ethyl acetate (300 mL × 3), and the combined organic phase was washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 20 / 1~10 / 1, V / V) to obtain compound A-3.

[0181] MS-ESI calculated value [M+H] + 238, measured value 238.

[0182] Step 3

[0183] Compound A-3 (15.0 g, 63.2 mmol) was dissolved in ethanol (200 mL). Palladium / carbon (2.00 g, 10% purity) was added to the reaction solution under nitrogen protection. The reaction mixture was replaced with hydrogen several times and stirred at 20 degrees Celsius for 12 hours under a 50 psi hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 50 / 1 to 2 / 1, V / V) to obtain compound A-4. MS-ESI calculated value [M+H] + 240, measured value 240.

[0184] Step 4

[0185] Compound A-4 (12.0 g, 50.2 mmol) was dissolved in ethanol (50 mL), and an ethanol solution of methylamine (35.5 g, 343 mmol) was added to the reaction solution. The reaction mixture was stirred at 25 degrees Celsius for 12 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (200 mL×3), and the combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate A. MS-ESI calculated value [M+H] + 225, measured value 225.

[0186] Intermediate B

[0187] Synthesis route:

[0188]

[0189] first step

[0190] Compound B-1 (25.0 g, 160 mmol) was dissolved in glacial acetic acid (200 mL), and 60% nitric acid solution (22.5 g, 232 mmol) was slowly added to the reaction solution at 0 degrees Celsius. The reaction mixture was stirred at 25 degrees Celsius for 5 hours. 400 mL of ice water was added to the reaction solution, the mixed solution was filtered, and the filter cake was collected and dried to obtain a crude compound B-2.

[0191] Step 2

[0192] Compound B-2 (17.1 g, 84.8 mmol) was dissolved in methanol (150 mL). Sodium borohydride (6.42 g, 170 mmol) was slowly added to the reaction solution in batches at 0 degrees Celsius. The reaction mixture was stirred at 25 degrees Celsius for 1 hour. Water (200 mL) was added to the reaction solution, and the mixture was adjusted to pH = 4 with 12M hydrochloric acid, stirred for 1 hour, and extracted with ethyl acetate (200 mL × 5). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound B-3.

[0193] Step 3

[0194] Compound B-3 (22.0 g, 108 mmol) and methyl bromoacetate (19.8 g, 130 mmol) were dissolved in N, N-dimethylformamide (200 mL), potassium carbonate (22.0 g, 162 mmol) was added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 1.5 hours. The reaction solution was diluted with water (500 mL), extracted with ethyl acetate (200 mL × 3), and the combined organic phase was washed with saturated brine (300 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound B-4. MS-ESI calculated value [M+H] + 276, measured value 276.

[0195] Step 4

[0196] Compound B-4 (22.1 g, 80.2 mmol) was dissolved in anhydrous dichloromethane (200 mL), phosphorus tribromide (32.6 g, 120 mmol) was slowly added to the reaction solution at 0 degrees Celsius, and the reaction mixture was stirred at 25 degrees Celsius for 2 hours. The reaction solution was diluted with ice water (500 mL), extracted with ethyl acetate (400 mL × 3), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 3 / 1, V / V) to obtain intermediate B. 1 H NMR (400 MHz, CDCl 3)δ7.79(d,J=2.4Hz,1H),7.68(d,J=2.4Hz,1H),4.81(s,2H),4.43(s,2H),3.83(s,3H)ppm.

[0197] Intermediate C

[0198] Synthesis route:

[0199]

[0200] first step

[0201] Compound C-1 (0.5 g, 2.96 mmol) and methyl bromoacetate (543 mg, 3.55 mmol) were dissolved in N,N-dimethylformamide (7.5 mL), potassium carbonate (613 mg, 4.43 mmol) was added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 0.5 hours. Water (10 mL) was added to the reaction solution, and it was extracted with ethyl acetate (10 mL × 3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound C-2.

[0202] Step 2

[0203] Compound C-2 (0.72 g, 2.99 mmol) was dissolved in anhydrous dichloromethane (11 mL), phosphorus tribromide (889 mg, 3.28 mmol) was slowly added dropwise to the reaction solution at 0 degrees Celsius, and the reaction mixture was stirred at 20 degrees Celsius for 1 hour. The reaction solution was slowly poured into a saturated sodium bicarbonate aqueous solution (20 mL), extracted with dichloromethane (10 mL×2), the organic phase was washed with saturated brine (50 mL), 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 (eluent: petroleum ether / ethyl acetate, 5 / 1, V / V) to obtain intermediate C. 1 H NMR (400 MHz, CDCl 3 )δ7.93(d,J=2.4Hz,1H),7.60-7.54(m,1H),6.96(d,J=8.8Hz,1H),4.81(s,2H),4.47(s,2H),3.82(s,3H)ppm.

[0204] Intermediate D

[0205] Synthesis route:

[0206]

[0207] first step

[0208] Compound A-3 (30.0 g, 126 mmol) and (+)-1,2-bis((2S,5S)-2,5-diphenylphosphinoethane)ethane(1,5-cyclooctadiene)tetrafluoroborate rhodium (I) (2.24 g, 2.78 mmol) were dissolved in ethanol (300 mL). Zinc trifluoromethanesulfonate (4.60 g, 12.7 mmol) was added to the reaction solution under nitrogen protection. The reaction mixture was replaced with hydrogen several times and stirred at 60 degrees Celsius for 16 hours under a 50 psi hydrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 200 / 1-2 / 1, V / V) to obtain intermediate D. MS-ESI calculated value [M+H] + 240, measured value 240.

[0209] Intermediate E

[0210] Synthesis route:

[0211]

[0212] first step

[0213] Dissolve (S)-glycidol (10.6 g, 143 mmol, 9.47 mL) in tetrahydrofuran (150 mL), add triphenylphosphine (37.6 g, 143 mmol) and compound A-1 (15.0 g, 95.5 mmol), lower the temperature to 0 degrees Celsius, slowly add diethyl azodicarboxylate (24.9 g, 143 mmol, 26.0 mL), and stir at 20 degrees Celsius for 14 hours. Concentrate the reaction solution under reduced pressure. The crude product obtained by concentration is separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1 to 1 / 1, V / V) to obtain compound E-1.

[0214] Step 2

[0215] E-1 (5.00 g, 23.5 mmol) was dissolved in ethanol (920 mL), water (154 mL) and glacial acetic acid (12.7 g, 211 mmol, 12.1 mL), iron powder (7.86 g, 141 mmol) was added, and the reaction solution was stirred at 80 degrees Celsius for 14 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The crude product obtained by concentration was added with saturated sodium carbonate aqueous solution (100 mL), and ethyl acetate (100 mL×3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained by concentration was separated and purified by silica gel column chromatography (dichloromethane / methanol, 100 / 0~20 / 1, V / V) to obtain compound E-2. MS-ESI calculated value [M+H] + 184, measured value 184.

[0216] Step 3

[0217] E-2 (25.0 g, 136 mmol), imidazole (16.7 g, 24.6 mmol) and triphenylphosphine (50.1 g, 191 mmol) were dissolved in dichloromethane (250 mL), and iodine (52.0 g, 205 mmol) was added to the reaction solution at 0 degrees Celsius. The reaction mixture was stirred at 20 degrees Celsius for 0.5 hours. A saturated sodium sulfite solution (300 mL) was added to the reaction solution, and it was extracted with dichloromethane (500 mL×2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was stirred with methyl tert-butyl ether (1 L), filtered, and the collected filter cake was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 10 / 1~10 / 1, V / V) to obtain the compound intermediate E-3.

[0218] Step 4

[0219] The compound intermediate E-3 (20g, 68.2mmol) and 1H-1,2,3-triazole (18.9g, 273mmol) were dissolved in acetonitrile (400mL), potassium carbonate (18.9g, 136mmol) was added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 18 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The crude product obtained by concentration was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 15 / 1~8 / 1, V / V) to obtain intermediate E. MS-ESI calculated value [M+H] + 235, measured value 235.

[0220] Intermediate F

[0221] Synthesis route:

[0222]

[0223] first step

[0224] Intermediate D (20 g, 83.6 mmol) was dissolved in methanol (200 mL), lithium hydroxide monohydrate (17.5 g, 418 mmol) was dissolved in water (50 mL) and added to the reaction solution, and the reaction mixture was stirred at 20 degrees Celsius for 12 hours. The reaction solution was adjusted to pH 4 with 12M hydrochloric acid, water (200 mL) was added, and it was extracted with ethyl acetate (200 mL×2), and the combined organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound F-1. MS-ESI calculated value [M+H] + 212, measured value 212.

[0225] Step 2

[0226] Compound F-1 (17.5 g, 82.9 mmol) was dissolved in N,N-dimethylformamide (200 mL), 1,1'-carbonyldiimidazole (16.1 g, 99.4 mmol) was added to the reaction solution, and the reaction mixture was stirred at 20 degrees Celsius for 1 hour. N-hydroxyacetamidine (7.37 g, 99.4 μmol) was added to the reaction solution, and the reaction mixture was stirred at 20 degrees Celsius for 1 hour. The reaction mixture was then stirred at 80 degrees Celsius for 24 hours. Water (500 mL) was added to the reaction solution, and it was extracted with ethyl acetate (500 mL×3). The combined organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained by concentration was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 20 / 1~3 / 1, V / V) to obtain intermediate F. MS-ESI calculated value [M+H] + 250, measured value 250.

[0227] Intermediate G

[0228] Synthesis route:

[0229]

[0230] first step

[0231] F-1 (3.00 g, 14.2 mmol) was dissolved in N, N-dimethylformamide (30 mL), 1,1'-carbonyldiimidazole (3.46 g, 21.3 mmol) was added to the reaction solution, and the reaction mixture was stirred at 25 degrees Celsius for 0.5 hours. Then, ammonium chloride (2.28 g, 42.6 mmol) and N, N-diisopropylethylamine (5.51 g, 42.6 mmol) were added to the reaction solution, and the reaction mixture was stirred at 25 degrees Celsius for 12 hours. The reaction solution was diluted with water (200 mL), extracted with ethyl acetate (150 mL×2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound G-1. MS-ESI calculated value [M+H] + 211, measured value 211.

[0232] Step 2

[0233] Palladium dichloride (1.05 g, 5.95 mmol) was added to a mixed solution of acetonitrile (10 mL) and water (10 mL) of compound G-1 (2.50 g, 1.13 mmol), and the reaction solution was stirred at 50 degrees Celsius 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, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 3:1 to 3:1, V / V) to obtain compound G-2. MS-ESI calculated value [M+H] + 193, measured value 193.

[0234] Step 3

[0235] Compound G-2 (1.30 g, 6.76 mmol), trimethylsilyl azide (3.28 g, 27.1 mmol, 3.75 mL) and dibutyltin oxide (1.04 g, 4.19 mmol) were dissolved in toluene (5 mL), and the reaction solution was stirred at 100 degrees Celsius for 2.5 hours under a nitrogen environment. Saturated KF aqueous solution (100 mL) was first added to the reaction solution, stirred for at least one hour, and then saturated sodium bicarbonate solution (100 mL) was added, and extracted with ethyl acetate (100 mL×2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound G-3. MS-ESI calculated value [M+H] + 236, measured value 236.

[0236] Step 4

[0237] Compound G-3 (200 mg, 505 μmol) was dissolved in tetrahydrofuran (3 mL) and methanol (10 mL). Trimethylsilylated diazomethane (2 M, 11.1 mmol, 5.53 mL) was added to the reaction solution and stirred at 25 degrees Celsius for 1.5 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 5:1 to 1:1, V / V) to obtain intermediate G. MS-ESI calculated value [M+H] + 250, measured value 250. 1 H NMR (400 MHz, CDCl 3 )δppm 6.66-6.44(m,3H),4.41-4.22(m,5H),4.09-3.98(m,1H),3.89-3.79(m,1H),3.20-2.99(m,2H).

[0238] Intermediate H

[0239] Synthesis route:

[0240]

[0241] first step

[0242] Compound H-1 (25 g, 203 mmol) and potassium carbonate (84.2 g, 609 mmol) were dissolved in N,N-dimethylformamide (200 mL), chloroacetyl chloride (17.0 mL, 213 mmol) was added at 0 degrees Celsius, and the mixture was reacted at 20 degrees Celsius for 2 hours. Water (1.5 L) was added to the reaction solution, and the mixture was stirred for 20 minutes and then filtered. The filter cake was dried to obtain compound H-2. MS-ESI calculated value [M+H] + 164, measured value 164.

[0243] Step 2

[0244] Compound H-2 (25.6 g, 157 mmol) was dissolved in N,N-dimethylformamide (250 mL), N-bromosuccinimide (30.7 g, 173 mmol) was added, and the mixture was stirred at 20 degrees Celsius for 0.5 hours. Water (1500 mL) was added to the reaction solution and stirred for 30 minutes, filtered, and the filter cake was dried under reduced pressure to obtain compound H-3. MS-ESI calculated value [M+H] + 242, 244, measured values ​​242, 244.

[0245] Step 3

[0246] Compound H-3 (1 g, 4.13 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (302 mg, 413 μmol) were dissolved in methanol (20 mL) and N,N-dimethylformamide (10 mL), triethylamine (1.25 g, 12.4 mmol, 1.72 mL) was added, and stirred at 80 degrees Celsius for 16 hours under a carbon monoxide atmosphere (50 psi). The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 5 / 1 to 1 / 1, V / V) to obtain compound H-4. MS-ESI calculated value [M+H] + 222, measured value 222.

[0247] Step 4

[0248] Compound H-4 (500 mg, 2.26 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), lithium hydroxide monohydrate (948 mg, 22.6 mmol) was dissolved in water (2 mL) and added to the reaction solution, and the reaction solution was stirred at 65 degrees Celsius for 1 hour. Water (20 mL) was added to the reaction solution, and the pH was adjusted to about 5 with concentrated hydrochloric acid, filtered, and the filter cake was dried to obtain a crude compound H-5. MS-ESI calculated value [M+H] + 208, measured value 208.

[0249] Step 5

[0250] Compound H-5 (400 mg, 1.93 mmol) was dissolved in acetonitrile (15 mL), 1,1'-carbonyldiimidazole (626 mg, 3.86 mmol) was added to the reaction solution, and the reaction mixture was stirred at 20 degrees Celsius for 1 hour. Sodium borohydride (361 mg, 9.54 mmol) was dissolved in water (5 mL) and added to the reaction solution, and the reaction solution was stirred at 20 degrees Celsius for 0.5 hours. 2M hydrochloric acid was used to adjust the pH to 2, water (20 mL) was added, and ethyl acetate (30 mL×2) was used for extraction. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate H. MS-ESI calculated value [M+H] + 194, measured value 194. 1 H NMR (400 MHz, DMSO-d 6 )δppm 10.25-10.06(m,1H),7.02-6.85(m,1H),6.83-6.70(m,1H),5.06-4.88(m,1H),4.50-4.33(m,4H),2.22-2.06(m,3H).

[0251] Intermediate I

[0252] Synthesis route:

[0253]

[0254] first step

[0255] Compound I-1 (3 g, 20.9 mmol) and potassium carbonate (8.66 g, 62.69 mmol) were dissolved in N, N-dimethylformamide (540 mL), chloroacetyl chloride (2 mL, 25.15 mmol) was added at 0 degrees Celsius, and the reaction solution was reacted at 50 degrees Celsius for 16 hours. The reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate aqueous solution (50 mL) was added to the reaction solution, and ethyl acetate (50 mL×2) was used for extraction. The combined organic phase was washed with saturated brine (50 mL×2), filtered, and the filter cake was dried under reduced pressure to obtain compound I-2. MS-ESI calculated value [M+H]+ 184, measured value 184.

[0256] Step 2

[0257] Compound I-2 (3.7 g, 20.15 mmol) was dissolved in acetonitrile (80 mL), N-bromosuccinimide (3.95 g, 20.17 mmol) was added, and stirred at 30 degrees Celsius for 14 hours. The reaction solution was filtered, and the filter cake was dried under reduced pressure to obtain compound I-3. MS-ESI calculated value [M+H] + 262, 264, measured values ​​262, 264.

[0258] Step 3

[0259] Compound I-3 (4 g, 15.24 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (1.12 g, 1.53 mmol) were dissolved in methanol (120 mL), triethylamine (4.65 g, 45.98 mmol, 6.4 mL) was added, and stirred at 80 degrees Celsius for 16 hours under a carbon monoxide atmosphere (50 psi). The reaction solution was concentrated under reduced pressure to obtain compound I-4. MS-ESI calculated value [M+H] + 242, measured value 242.

[0260] Step 4

[0261] Lithium aluminum tetrahydride (314.16 mg, 8.28 mmol) was dissolved in tetrahydrofuran (5 mL), and compound I-4 (800 mg, 3.31 mmol) was dissolved in tetrahydrofuran (5 mL) and added to the reaction solution under a nitrogen atmosphere at 0 degrees Celsius. The reaction solution was stirred at 20 degrees Celsius for 2 hours. The reaction solution was cooled to 0 degrees Celsius, and water (10 mL) and sodium hydroxide aqueous solution (1M, 4 mL) were added successively to quench the reaction. The pH was adjusted to about 5 with concentrated hydrochloric acid, filtered, and the filter cake was dried to obtain a crude compound I-5. MS-ESI calculated value [M+H] + 214, measured value 214

[0262] Step 5

[0263] Compound I-5 (50 mg, 234.06 μmol) was dissolved in dichloromethane (5 mL), phosphorus tribromide (76.03 mg, 280.88 μmol) was added dropwise to the reaction solution at 0 degrees Celsius, and the reaction mixture was stirred at 20 degrees Celsius for 1 hour. Water (5 mL) was added to the reaction solution, and the pH was adjusted to 8 with saturated sodium bicarbonate, extracted with ethyl acetate (30 mL×3), and 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 the crude intermediate I. MS-ESI calculated value [M+H] +276, 278, measured values ​​276, 278.

[0264] Intermediate J

[0265] Synthesis route:

[0266]

[0267] first step

[0268] Lithium tetrahydrogen aluminum (7.14 g, 188.09 mmol) was dispersed in tetrahydrofuran (200 mL). Intermediate D (30 g, 125.40 mmol) was dissolved in 100 mL of tetrahydrofuran under an ice-water bath and added dropwise to the dispersed system of lithium tetrahydrogen aluminum. After the addition was completed, the temperature was raised to 25 degrees Celsius, and the reaction mixture was stirred at 25 degrees Celsius for 2 hours. Water (7 mL) and 15% aqueous sodium hydroxide solution (7 mL) were added to the reaction solution, and diluted with water (21 mL). Filter, and the filtrate was concentrated under reduced pressure to obtain compound J-1. MS-ESI calculated value [M+H] + 198, measured value 198.

[0269] Step 2

[0270] Add dimethyl tert-butyl chlorosilane (82.54 g, 547.65 mmol) and imidazole (49.71 g, 730.20 mmol) to a solution of compound J-1 (72 g, 365.10 mmol) in N,N-dimethylformamide (500 mL). The reaction solution was stirred at 25 degrees Celsius for 3 hours. The reaction solution was diluted with water (5000 mL), extracted with ethyl acetate (800 mL × 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 0 to 100 / 5, V / V) to obtain compound J-2. MS-ESI calculated value [M+H] + 312, measured value 312.

[0271] Step 3

[0272] Compound J-2 (50 g, 160.53 mmol) and Boc anhydride (210.21 g, 963.19 mmol) were dissolved in tetrahydrofuran (300 mL), 4-dimethylaminopyridine (58.84 g, 481.59 mmol) was added, and the reaction solution was stirred at 70 degrees Celsius for 4 hours under nitrogen environment. The reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 0-100 / 3, V / V) to obtain compound J-3. MS-ESI calculated value [M-56+H] + 356, measured value [M-56+H]+ 356.

[0273] Step 4

[0274] Compound J-3 (60 g, 145.78 mmol) was dissolved in tetrahydrofuran (700 mL), and tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 145.78 mmol, 145.78 mL) was added to the reaction solution, and the reaction solution was stirred at 25 degrees Celsius for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 0~5 / 1, V / V) to obtain compound J-4. MS-ESI calculated value [M-56+H] + 242, measured value [M-56+H] + 242.

[0275] Step 5

[0276] Compound J-4 (40 g, 134.53 mmol) was dissolved in dichloromethane (450 mL), and Dess-Martin reagent (74.18 g, 174.90 mmol) was added in batches. The reaction solution was stirred at 25 degrees Celsius for 1 hour. The reaction solution was quenched with saturated sodium sulfite solution (450 mL), diluted with saturated sodium bicarbonate solution (300 mL), and extracted with ethyl acetate (200 mL×3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound J-5. MS-ESI calculated value [M-56+H] + 240, measured value [M-56+H] + 240.

[0277] Step 6

[0278] Compound J-5 (33 g, 111.75 mmol) was dissolved in methanol (85 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (42.94 g, 223.50 mmol) and potassium carbonate (46.33 g, 335.25 mmol) were added. The reaction solution was reacted at 25 degrees Celsius for 1 hour. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (80 mL × 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 0~10 / 1, V / V) to obtain compound J-6. MS-ESI calculated value [M-56+H] + 236, measured value [M-56+H] + 236.

[0279] Step 7

[0280] Compound J-6 (37 g, 127.01 mmol) was dissolved in dichloromethane (370 mL), and trifluoroacetic acid (113.96 g, 999.44 mmol, 74.00 mL) was added dropwise. The reaction solution was reacted at 25 degrees Celsius for 2 hours. The reaction solution was quenched with saturated sodium bicarbonate (300 mL) and diluted with water (500 mL). It was extracted with ethyl acetate (80 mL × 3), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate J. MS-ESI calculated value [M+H] + 192, measured value 192.

[0281] Example 1

[0282] Synthesis route:

[0283]

[0284] first step

[0285] Compound 1-1 (1.00 g, 5.98 mmol) and methyl bromoacetate (1.10 g, 7.18 mmol) were dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (1.24 g, 8.97 mmol) was added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 2 hours. Water (100 mL) was added to the reaction solution, and it was extracted with ethyl acetate (100 mL×2). 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 crude compound 1-2. MS-ESI calculated value [M+H] + 240, measured value 240.

[0286] Step 2

[0287] Compound 1-2 (250 mg, 1.05 mmol) and intermediate A (260 mg, 1.10 mmol) were dissolved in 1,2-dichloroethane (3 mL). Acetic acid (126 mg, 2.10 mmol) was added to the reaction solution. The reaction mixture was stirred at 20 degrees Celsius for 0.5 hours. Sodium acetate borohydride (267 mg, 1.26 mmol) was then added to the reaction solution. The reaction mixture was stirred at 20 degrees Celsius for 12 hours. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 2), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained by concentration was separated by thin layer chromatography (developing solvent: dichloromethane / methanol, 15 / 1, V / V) to obtain compound 1-3. MS-ESI calculated value [M+H] + 448, measured value 448.

[0288] Step 3

[0289] Compound 1-3 (120 mg, 0.268 mmol) was dissolved in acetic acid (3 mL), and iron powder (74.9 mg, 1.34 mmol) was added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 1 hour. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL×3), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained by concentration was separated by preparative high performance liquid chromatography (chromatographic column: Waters Xbridge 150×25mm×10μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 27%-57%, 10min) to obtain compound 1. MS-ESI calculated value [M+H] + 386, measured value 386. 1 H NMR (400 MHz, DMSO-d 6 )δ10.62(s,1H),7.99-7.81(m,1H),6.94-6.76(m,3H),6.70-6.62(m,1H),6.60-6.51(m,1H),6.51-6.38(m,1H),4.53(s,2H),4.39(d,J=1 6.4Hz,1H),4.28(d,J=16.4Hz,1H),4.23-4.14(m,1H),4.09-3.91(m,1H),3.86-3.75(m,1H),2.56(d,J=4.4Hz,3H),2.41-2.22(m,2H)ppm.

[0290] Example 2

[0291] Synthesis route:

[0292]

[0293] first step

[0294] Compound 2-1 (4.00 g, 24.1 mmol) was dissolved in acetic acid (40 mL), nitric acid (2.36 g, 37.5 mmol) was added to the reaction solution at 0 degrees Celsius, and the reaction mixture was stirred at 20 degrees Celsius for 2 hours. Water (400 mL) was added to the reaction solution, filtered, and the filter cake was collected and dried to obtain crude compound 2-2. MS-ESI calculated value [M+H] + 212, measured value 212.

[0295] Step 2

[0296] Compound 2-2 (2.20 g, 10.4 mmol) was dissolved in dichloromethane (30 mL). A toluene solution of diisobutylaluminum hydride (1 M, 31.3 mL) was slowly added to the reaction solution at -65 degrees Celsius. The reaction mixture was stirred at -65 to 20 degrees Celsius for 5 hours. 1M hydrochloric acid (100 mL) was added to the reaction solution, and it was 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 by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 100 / 1 to 10 / 1, V / V) to obtain compound 2-3.

[0297] Step 3

[0298] Compound 2-3 (2.50 g, 13.7 mmol) and methyl bromoacetate (2.51 g, 16.4 mmol) were dissolved in N,N-dimethylformamide (25 mL), potassium carbonate (2.45 g, 17.7 mmol) was added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 1 hour. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL×2), and the combined organic phase was washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 2-4. MS-ESI calculated value [M+H] + 256, measured value 256.

[0299] Step 4

[0300] Compound 2-4 (3.10 g, 12.2 mmol) was dissolved in dichloromethane (30 mL), phosphorus tribromide (3.62 g, 13.4 mmol) was added to the reaction solution at 0 degrees Celsius, and the reaction mixture was stirred at 20 degrees Celsius for 1 hour. The reaction solution was adjusted to pH 7 with a saturated sodium bicarbonate solution, extracted with dichloromethane (100 mL×2), 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 a crude compound 2-5. MS-ESI calculated value [M+H] + 318, 320. Actual measured values: 318, 320.

[0301] Step 5

[0302] Intermediate A (1.20 g, 5.35 mmol) and compound 2-5 (2.04 g, 6.42 mmol) were dissolved in acetonitrile (12 mL), sodium iodide (802 mg, 5.35 mmol) and potassium carbonate (2.22 g, 16.1 mmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 10 / 1 to 1 / 2, V / V) to obtain compound 2-6. MS-ESI calculated value [M+H] + 462, measured value 462.

[0303] Step 6

[0304] Compound 2-6 (1.80 g, 3.90 mmol) was dissolved in acetic acid (18 mL), and iron powder (1.09 g, 19.50 mmol) was added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 2 hours. Water (200 mL) and a saturated solution of sodium bicarbonate (100 mL) were added to the reaction solution, extracted with ethyl acetate (200 mL×2), 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. The crude product was separated by silica gel column chromatography (eluent: ethyl acetate) to obtain compound 2. MS-ESI calculated value [M+H] + 400, measured value 400. 1 H NMR (400 MHz, DMSO-d 6 )δ10.53(s,1H),7.93-7.84(m,1H),6.73(s,1H),6.69-6.60(m,2H),6.60-6.52(m,1H),6.51-6.42(m,1H),4.54(s,2H),4.39-4.30(m,1H ),4.29-4.15(m,2H),4.15-4.01(m,1H),3.86-3.74(m,1H),2.56(d,J=4.4Hz,3H),2.40-2.33(m,1H),2.32-2.25(m,1H),2.13(s,3H)ppm.

[0305] Example 3

[0306] Synthesis route:

[0307]

[0308] first step

[0309] Compound 3-1 (5.60 g, 40 mmol) and acetic acid (65 mL) were added to the reaction flask, nitrogen was replaced three times, nitric acid (8.09 g, 128 mmol, 5.78 mL) was slowly added dropwise under stirring, and the reaction solution was stirred at 20 degrees Celsius for 1 hour. The reaction solution was poured into ice water (30 mL), filtered, and the filter cake was washed with water (50 mL), and the filter cake was collected to obtain a crude compound 3-2.

[0310] Step 2

[0311] Compound 3-2 (2.00 g, 10.8 mmol), methyl bromoacetate (1.98 g, 13.0 mmol, 1.22 mL), potassium carbonate (2.24 g, 16.2 mmol) and N,N-dimethylformamide (20 mL) were added to the reaction flask, and the temperature was slowly raised to 80 degrees Celsius, and the reaction was stirred for 1 hour. The reaction solution was slowly poured into water (20 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 3-3.

[0312] Step 3

[0313] 3-3 (0.8 g, 3.11 mmol) was dissolved in acetonitrile (1 mL), nitrogen was replaced three times, the temperature was lowered to -78 degrees Celsius, sodium borohydride (235 mg, 6.22 mmol) was added, and the reaction was carried out at -78 degrees Celsius for 2 hours. The reaction was slowly poured into a saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3-4.

[0314] Step 4

[0315] Add 3-4 (0.75 g, 2.89 mmol) and dichloromethane (11.5 mL) to the reaction flask, replace nitrogen three times, cool to 0 degrees Celsius, add phosphorus tribromide (3.15 g, 11.64 mmol), heat to 20 degrees Celsius and stir for 1 hour. Slowly pour the reaction solution into a saturated sodium bicarbonate solution (20 mL), extract with dichloromethane (20 mL × 3), wash the combined organic phase with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product is subjected to silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 1 / 1, V / V) to obtain compound 3-5.

[0316] Step 5

[0317] Intermediate A (50.0 mg, 223 μmol), compound 3-5 (108 mg, 335 μmol), sodium iodide (33.4 mg, 223 μmol), potassium carbonate (92.5 mg, 669 μmol) and acetonitrile (1.5 mL) were added to the reaction flask, nitrogen was replaced three times, the temperature was raised to 80 degrees Celsius and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude compound 3-6.

[0318] Step 6

[0319] 3-6 (350 mg, 752 μmol), reduced iron powder (420 mg, 7.52 mmol) and glacial acetic acid (8 mL) were added to the reaction flask, nitrogen was replaced three times, the temperature was raised to 80 degrees Celsius and stirred for 1 hour. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with methanol (20 mL), and the filtrate was concentrated under reduced pressure. The crude product obtained by vacuum concentration was dissolved in ethyl acetate (50 mL), washed with water (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained by concentration was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: [10mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient: acetonitrile 20%-45%, 6 minutes) to obtain compound 3. MS-ESI calculated value [M+H] + 404, measured value 404. 1 HNMR (400 MHz, DMSO-d 6 )δ10.80(s,1H),7.89(d,J=4.4Hz,1H),6.90-6.78(m,1H),6.71-6.62(m,2H),6.62-6.51(m,1H),6.49-6.41(m,1H),4.63(s,2 H),4.38-4.27(m,2H),4.23-4.17(m,1H),4.10-4.02(m,1H),3.84-3.77(m,1H),2.56(d,J=4.4Hz,3H),2.40-2.25(m,2H)ppm.

[0320] Example 4

[0321] Synthesis route:

[0322]

[0323] first step

[0324] Intermediate A (0.700 g, 3.12 mmol) and intermediate B (2.05 g, 6.06 mmol) were dissolved in acetonitrile (10 mL), sodium iodide (468 mg, 3.12 mmol) and potassium carbonate (1.29 g, 9.36 mmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 4-1. MS-ESI calculated value [M+H] + 482, measured value 482.

[0325] Step 2

[0326] Compound 4-1 (1.30 g, 2.70 mmol) was dissolved in acetic acid (10 mL), and iron powder (1.51 g, 27.0 mmol) was added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 0.5 hours. The reaction solution was quenched by adding water (100 mL) and a saturated solution of sodium bicarbonate (100 mL), extracted with ethyl acetate (100 mL×2), and the combined organic phase was washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: ethyl acetate), and then separated by preparative high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 250×50mm×10μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 35%-65%,, 14 minutes) to obtain compound 4. MS-ESI calculated value [M+H] + 420, measured value 420. 1 H NMR (400 MHz, DMSO-d 6 )δ10.79(s,1H),7.93-7.83(m,1H),6.97(d,J=1.6Hz,1H),6.77(d,J=1.6Hz,1H),6.69-6.63(m,1H),6.60-6.54(m,1H),6.49-6.43(m,1H), 4.66(s,2H),4.41-4.26(m,2H),4.23-4.16(m,1H),4.11-4.01(m,1H),3.81(d,J=1.6Hz,1H),2.56(d,J=4.4Hz,3H),2.46-2.25(m,2H)ppm.

[0327] Example 5

[0328] Synthesis route:

[0329]

[0330] first step

[0331] Compound 5-1 (1.00 g, 5.71 mmol) was dissolved in ethanol (5 mL), palladium / carbon (100 mg, 10% purity) was added, and the reaction mixture was stirred for 4 hours under a hydrogen atmosphere (15 psi) at 20 degrees Celsius. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 5-2. MS-ESI calculated value [M+H] + 146, measured value 146.

[0332] Step 2

[0333] Compound 5-2 (820 mg, 5.65 mmol) and ethyl 4-chloroacetoacetate (1.12 g, 6.78 mmol) were dissolved in tetrahydrofuran (10 mL), heated to 50 degrees Celsius, triethylamine (787 μL, 5.65 mmol) was added to the reaction solution, and stirred at 50 degrees Celsius for 4 hours. After the reaction was completed, ethyl acetate (50 mL) was added to the reaction solution for extraction, the organic phase was washed with water (50 mL), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate, 100 / 1~10 / 1, V / V) to obtain compound 5-3. MS-ESI calculated value [M+H] + 256, measured value 256.

[0334] Step 3

[0335] Compound 5-3 (500 mg, 1.96 mmol) was dissolved in ethanol (5 mL), palladium / carbon (100 mg, 10% purity) was added to the reaction solution, and the reaction mixture was stirred for 14 hours under a hydrogen atmosphere (15 psi) and 20 degrees Celsius. The reaction solution was filtered, concentrated under reduced pressure, and the resulting crude product was dissolved in ethanol (10 mL), palladium / carbon (200 mg, 10% purity) was added, and the reaction mixture was stirred for 14 hours under a hydrogen atmosphere (15 psi) and 20 degrees Celsius, and the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 5-4. MS-ESI calculated value [M+H] + 258, measured value 258.

[0336] Step 4

[0337] Compound 5-4 (400 mg, 1.56 mmol) was dissolved in ethanol (10 mL), and an ethanol solution of methylamine (4.78 g, 46.2 mmol) was added to the reaction solution. The reaction mixture was stirred at 20 degrees Celsius for 14 hours. The reaction solution was diluted with water (20 mL), 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 to obtain compound 5-5. MS-ESI calculated value [M+H] + 243, measured value 243.

[0338] Step 5

[0339] Compound 5-5 (150 mg, 619 μmol) and intermediate C (188 mg, 619 μmol) were dissolved in acetonitrile (5 mL). Sodium iodide (93 mg, 619 μmol) and potassium carbonate (257 mg, 1.86 mmol) were added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure. The crude product was separated by column chromatography (eluent: dichloromethane / methanol, 200 / 1 to 20 / 1, V / V) to obtain compound 5-6. MS-ESI calculated value [M+H] + 466, measured value 466.

[0340] Step 6

[0341] Compound 5-6 (75.0 mg, 161 μmol) was dissolved in acetic acid (2 mL), and iron powder (90.0 mg, 1.61 mmol) was added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 14 hours. The reaction solution was concentrated under reduced pressure, and the crude product obtained by concentration was subjected to preparative high performance liquid chromatography (chromatographic column: Waters Xbridge 150×25mm×5μm; mobile phase: 10mM ammonium bicarbonate aqueous solution-acetonitrile; gradient: acetonitrile: 26%-56%, 9 minutes) to obtain compound 5. MS-ESI calculated value [M+H] + 404, measured value 404. 1 H NMR (400 MHz, DMSO-d 6 )δ10.68(s,1H),7.69(d,J=4.4Hz,1H),6.95(s,1H),6.90(s,2H),6.87-6.79(m,1H),6.69-6.61(m,1H),4.5 5(s,2H),4.15-4.01(m,2H),3.97-3.78(m,2H),3.51-3.48(m,1H),2.52-2.50(m,3H),2.16-1.92(m,2H)ppm.

[0342] Example 6

[0343] Synthesis route:

[0344]

[0345] first step

[0346] Compound 6-1 (2.23 g, 12.3 mmol) and methyl bromoacetate (1.88 g, 12.3 mmol) were dissolved in acetonitrile (10 mL), potassium carbonate (1.70 g, 12.3 mmol) was added to the reaction solution, and the reaction solution was stirred at 80 degrees Celsius for 4 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6-2. MS-ESI calculated value [M+H] + 254, measured value 254.

[0347] Step 2

[0348] Compound 6-2 (2.70 g, 10.7 mmol) was dissolved in methanol (30 mL). Sodium borohydride (448 mg, 11.9 mmol) was slowly added to the reaction solution at -20 degrees Celsius. The reaction mixture was stirred at -20 degrees Celsius for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (150 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 10 / 1 to 1 / 1, V / V) to obtain compound 6-3. MS-ESI calculated value [MH] - 254, measured value 254.

[0349] Step 3

[0350] Compound 6-3 (428 mg, 1.68 mmol) and intermediate A (220 mg, 932 μmol) were dissolved in toluene (5 mL), and ferrous bromide (10.1 mg, 46.6 μmol) and potassium hydrogen sulfate (127 mg, 932 μmol) were added to the reaction solution. The reaction mixture was stirred at 120 degrees Celsius for 16 hours. After the reaction was completed, the reaction solution was 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 (eluent: dichloromethane / methanol, 200 / 1~20 / 1, V / V) to obtain compound 6-4. MS-ESI calculated value [M+H] + 462, measured value 462.

[0351] Step 4

[0352] Compound 6-4 (150 mg, 325 μmol) was dissolved in ethanol (3 mL) and water (3 mL), iron powder (182 mg, 3.25 mmol) and ammonium chloride (348 mg, 6.50 mmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 2 hours. The reaction solution was concentrated, and the residue was stirred in a methanol / ethyl acetate mixture (1 / 10, 50 mL, V / V) at 25 degrees Celsius for 0.5 hours, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained by concentration was separated by preparative high performance liquid chromatography (chromatographic column: Waters Xbridge 150×25mm×5μm; mobile phase: [10mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient: acetonitrile: 26%-56%) to obtain compound 6. MS-ESI calculated value [M+H] + 400, measured value 400. 1 H NMR (400 MHz, DMSO-d 6 )δ10.59(s,1H),7.98-7.52(m,1H),6.99-6.78(m,4H),6.70-6.58(m,2H),4.98-4.81(m,1H),4.61-4.48(m,2H),4.15-3.98(m,1H ),3.81-3.72(m,1.5H),3.38-3.35(m,0.5H),2.60-2.52(m,3H),2.36-2.10(m,1.5H),1.96-1.85(m,0.5H),1.52-1.37(m,3H)ppm.

[0353] Example 7

[0354] Synthesis route:

[0355]

[0356] first step

[0357] Dissolve glycidol (2.59 g, 35.0 mmol) in tetrahydrofuran (50 mL), add triphenylphosphine (8.35 g, 31.8 mmol) and compound A-1 (5.00 g, 31.8 mmol), lower the temperature to 0 degrees Celsius, slowly add diethyl azodicarboxylate (5.54 g, 31.8 mmol), and stir at 15 degrees Celsius for 2 hours. Add saturated aqueous ammonium chloride solution (20 mL), extract with ethyl acetate (50 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 1 / 1, V / V) to obtain compound 7-1. MS-ESI calculated value [M+H] + 214, measured value 214.

[0358] Step 2

[0359] Compound 7-1 (4 g, 18.8 mmol) was dissolved in ethanol (20 mL) and water (40 mL), and iron powder (5.24 g, 93.8 mmol) and acetic acid (20 mL) were added under nitrogen atmosphere, and the reaction mixture was stirred at 80 degrees Celsius for 16 hours. The reaction solution was filtered, and water (20 ml) and ethyl acetate (30 mL) were added to the filtrate for extraction. The 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 (eluent: petroleum ether / ethyl acetate, 1 / 1, V / V) to obtain compound 7-2. MS-ESI calculated value [M+H] + 184, measured value 184.

[0360] Step 3

[0361] Compound 7-2 (1.40 g, 7.64 mmol) was dissolved in dichloromethane (15 mL), triethylamine (2.13 mL, 15.3 mmol) and methanesulfonyl chloride (887 μL, 11.5 mmol) were added, and stirred at 25 degrees Celsius for 16 hours. Saturated aqueous ammonium chloride solution (10 mL) was added to quench, and the mixture was extracted with dichloromethane (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained by concentration was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 1 / 1, V / V) to obtain compound 7-3. MS-ESI calculated value [M+H] + 202, measured value 202.

[0362] Step 4

[0363] Potassium iodide (395 mg, 2.38 mmol) and sodium methylsulfenyl salt (486 mg, 4.76 mmol) were added to a solution of compound 7-3 (0.48 g, 2.38 mmol) in N, N-dimethylformamide (4 mL) and microwaved at 100 degrees Celsius for 1 hour. Saturated ammonium chloride (10 mL) was added to quench, and then water (10 mL) and ethyl acetate (10 mL) were added to extract. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained by concentration was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 1 / 1, V / V) to obtain compound 7-4. MS-ESI calculated value [M+H] + 246, measured value 246.

[0364] Step 5

[0365] Compound 7-4 (0.2 g, 815 μmol), intermediate C (372 mg, 1.22 mmol), sodium iodide (122 mg, 815 μmol), potassium carbonate (338 mg, 2.45 mmol) and acetonitrile (3 mL) were added to the reaction flask, nitrogen was replaced three times, the temperature was raised to 80 degrees Celsius and stirred for 16 hours. The reaction solution was directly concentrated under reduced pressure to obtain compound 7-5.

[0366] Step 6

[0367] Add 7-5 (0.50 g, 1.07 mmol), reduced iron powder (596 mg, 10.7 mmol) and glacial acetic acid (5 mL) to the reaction flask, replace nitrogen three times, heat to 80 degrees Celsius and stir for 1 hour. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (20 mL), the filtrate was concentrated under reduced pressure, the crude product was dissolved in ethyl acetate (10 mL), washed with water (10 mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrated crude product was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [10 mM ammonium bicarbonate aqueous solution-acetonitrile]; gradient: acetonitrile: 25%-45%, 6 minutes) to obtain compound 7. MS-ESI calculated value [M+H] + 407, measured value 407. 1 HNMR (400 MHz, DMSO-d 6 )δ10.61(s,1H),6.92-6.88(m,1H),6.88-6.85(m,1H),6.84(s,1H),6.70(d,J=9.2Hz,1H),6.63-6.58(m,2H),4.53(s,2H),4.5 2-4.46(m,1H),4.44-4.38(m,1H),4.32-4.24(m,1H),4.10-4.05(m,1H),4.04-3.97(m,1H),3.40-3.36(m,2H),3.05(s,3H)ppm.

[0368] Example 8

[0369] Synthesis route:

[0370]

[0371] first step

[0372] Compound 2-5 (0.220 g, 0.692 mmol) and compound 5-5 (0.168 g, 0.692 mmol) were dissolved in acetonitrile (10 mL), and sodium iodide (149 mg, 0.691 mmol) and anhydrous potassium carbonate (286 mg, 2.07 mmol) were added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained by concentration was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 1:1, V / V) to obtain compound 8-1. Calculated value [M+H] + 480, measured value 480.

[0373] Step 2

[0374] Compound 8-1 (250 mg, 2.70 mmol) was dissolved in acetic acid (6 mL), iron powder (582 mg, 10.4 mmol) was added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 14 hours. The reaction solution was filtered and concentrated, quenched by adding water (100 mL) and a saturated solution of sodium bicarbonate (100 mL), extracted with ethyl acetate (100 mL×2), 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 a crude product. The crude product was purified by preparative high performance liquid chromatography (chromatographic column: Waters Xbridge 150×25mm×5μm; mobile phase: 10mM ammonium bicarbonate aqueous solution-acetonitrile; gradient: acetonitrile: 33%-63%, 10 minutes) to obtain the compound, and then subjected to SFC (chromatographic column: DAICEL CHIRALPAK AS (250mm×30mm×10μm); mobile phase: [supercritical CO 2 -methanol]; gradient: methanol 60%-60%, 4.1 minutes, 30 minutes) to separate compounds 8a (first main peak) and 8b (second main peak). The compounds were subjected to SFC (chromatographic column: Chiralpak AS-3 50×4.6mm ID, 3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in methanol solution; gradient: 0.05% diethylamine in methanol solution: 5%-40%; flow rate: 3 mL / min; detector: DAD; column temperature: 35 degrees Celsius; back pressure: 100 Bar) to measure the ee% value.

[0375] Compound 8a: MS-ESI calculated value [M+H] + 418, measured value 418. ee%=100%, RT=1.477min. 1 HNMR (400MHz, CD 3OD)δ6.83-6.81(m,1H),6.80-6.78(m,1H),6.61-6.51(m,1H),6.49-6.42(m,1H),4.54(s,2H),4.16(d,J=14.4Hz,1H),4.09-4 .02(m,1H),3.87-3.80(m,1H),3.77(d,J=14.4Hz,1H),3.49-3.42(m,1H),2.56(s,3H),2.17(s,3H),2.09(d,J=7.6Hz,2H)ppm.

[0376] Compound 8b: MS-ESI calculated value [M+H] + 418, measured value 418. ee% = 100%, RT = 2.443min. 1 HNMR (400MHz, CD 3 OD)δ6.88-6.85(m,1H),6.84-6.81(m,1H),6.63-6.56(m,1H),6.52-6.46(m,1H),4.58(s,2H),4.20(d,J=14.4Hz,1H),4.13-4 .06(m,1H),3.91-3.84(m,1H),3.81(d,J=14.4Hz,1H),3.52-3.46(m,1H),2.60(s,3H),2.21(s,3H),2.13(d,J=7.6Hz,2H)ppm.

[0377] Example 9

[0378] Synthesis route:

[0379]

[0380] first step

[0381] Intermediate D (0.50 g, 2.09 mmol) was dissolved in methanol (3 mL), ethylamine (471 mg, 10.5 mmol) was added to the reaction solution, and the reaction mixture was stirred at 25 degrees Celsius for 12 hours. Water (100 mL) was added to the reaction solution for dilution, and it was extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 9-1. MS-ESI calculated value [M+H] + 239, measured value 239.

[0382] Step 2

[0383] Compound 9-1 (200 mg, 839 μmol) and intermediate C (306 mg, 1.01 mmol) were dissolved in acetonitrile (5 mL), sodium iodide (126 mg, 839 μmol) and potassium carbonate (348 mg, 2.52 mmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 9-2. MS-ESI calculated value [M+H] + 462, measured value 462.

[0384] Step 3

[0385] Compound 9-2 (300 mg, 650 μmol) was dissolved in acetic acid (3 mL), and iron powder (363 mg, 6.50 mmol) was added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 2 hours. The reaction solution was quenched by adding water (10 mL) and a saturated solution of sodium bicarbonate (20 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phase was washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained by concentration was separated and purified by high performance liquid chromatography (chromatographic column: WatersXbridge 150 × 25 mm × 5 μm; mobile phase: 10 mM aqueous ammonium bicarbonate solution-acetonitrile; gradient: acetonitrile: 32%-62%, 10 minutes) to obtain compound 9. MS-ESI calculated value [M+H] + 400, measured value 400. 1 H NMR (400 MHz, DMSO-d 6 )δ10.62(s,1H),8.02-7.93(m,1H),6.97-6.76(m,3H),6.72-6.62(m,1H),6.61-6.51(m,1H),6.51-6.41(m,1H),4.53(s,2H),4.45-4.2 5(m,2H),4.19(d,J=9.8Hz,1H),4.11-3.97(m,1H),3.87-3.74(m,1H),3.15-2.96(m,2H),2.42-2.20(m,2H),0.99(t,J=7.2Hz,3H)ppm.

[0386] Example 10

[0387] Synthesis route:

[0388]

[0389] first step

[0390] Intermediate D (500 mg, 2.09 mmol) and intermediate B (920 mg, 2.72 mmol) were dissolved in acetonitrile (10 mL), sodium iodide (313 mg, 2.09 mmol) and potassium carbonate (867 mg, 6.27 mmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 200 / 1 to 8 / 1, V / V) to obtain compound 10-1. MS-ESI calculated value [M+H] + 497, measured value 497.

[0391] Step 2

[0392] Compound 10-1 (900 mg, 1.81 mmol) was dissolved in acetic acid (10 mL), and iron powder (1.01 g, 18.1 mmol) was added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 0.5 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was diluted with ethyl acetate (250 mL), washed with a saturated solution of sodium bicarbonate (250 mL×2) and saturated brine (250 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 10-2. MS-ESI calculated value [M+H] + 435, measured value 435.

[0393] Step 3

[0394] Compound 10-2 (0.500 g, 1.15 mmol) was dissolved in methanol (5 mL), lithium hydroxide monohydrate (386 mg, 9.20 mmol) was dissolved in water (1 mL) and added to the reaction solution, and the reaction mixture was stirred at 20 degrees Celsius for 12 hours. Water (20 mL) was added to the reaction solution, and the pH was adjusted to 4 with 1M hydrochloric acid, and extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 10-3. MS-ESI calculated value [M+H] + 407, measured value 407.

[0395] Step 4

[0396] Compound 10-3 (60.0 mg, 0.148 mmol) was dissolved in N,N-dimethylformamide (2 mL), 1,1'-carbonyldiimidazole (28.7 mg, 0.177 mmol) was added to the reaction solution, and the reaction mixture was stirred at 20 degrees Celsius for 0.5 hours. N-hydroxyacetamidine (32.3 mg, 0.442 mmol) was then added to the reaction solution, and the reaction mixture was stirred at 20 degrees Celsius for 0.5 hours, and then the reaction solution was stirred at 80 degrees Celsius for 11 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL×2), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by thin layer chromatography (developing solvent: petroleum ether / ethyl acetate / ethanol, 4 / 3 / 1, V / V / V) to obtain compound 10. MS-ESI calculated value [M+H] + 445, measured value 445. 1 H NMR (400MHz, CD 3 OD)δ6.89(s,1H),6.74 -6.64(m,2H),6.63-6.52(m,2H),4.63(s,2H),4.34-4.17(m,3H),4.11-4.02(m,1H),3.92-3.82(m,1H),3.05(d,J=6.8Hz,2H),2.27(s,3H)ppm.

[0397] Embodiment 11

[0398] Synthesis route:

[0399]

[0400] first step

[0401] 7-2 (0.2 g, 1.09 mmol), intermediate C (498 mg, 1.64 mmol), sodium iodide (164 mg, 1.09 mmol), potassium carbonate (453 mg, 3.28 mmol) and acetonitrile (3 mL) were added to the reaction flask, and the nitrogen was replaced three times. Under the nitrogen atmosphere, the temperature was raised to 80 degrees Celsius and stirred for 16 hours. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 11-1. MS-ESI calculated value [M+H] + 407, measured value 407.

[0402] Step 2

[0403] Compound 11-1 (0.5 g, 1.23 mmol), iron powder (68.7 mg, 1.23 mmol) and acetic acid (5 mL) were added to the reaction flask, and nitrogen was replaced three times. Under a nitrogen atmosphere, the temperature was raised to 80 degrees Celsius and stirred for 1 hour. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (20 mL), the filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (10 mL) and washed with water (10 mL×3). The organic phase was 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 high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: 10mM ammonium bicarbonate aqueous solution-acetonitrile; gradient: acetonitrile: 25%-50%, 6 minutes) to obtain compound 11. MS-ESI calculated value [M+H] + 344, measured value 344. 1 H NMR (400 MHz, DMSO-d 6 )δ10.61(s,1H),6.94-6.87(m,1H),6.86-6.79(m,2H),6.65-6.59(m,1H),6.54-6.46(m,1H),6.42-6.34(m,1H), 4.94-4.91(m,1H),4.53(s,2H),4.47-4.34(m,2H),3.97-3.92(m,1H),3.50-3.43(m,1H),3.40-3.30(m,2H)ppm.

[0404] Example 12

[0405] Synthesis route:

[0406]

[0407] first step

[0408] Add intermediate D (720 mg, 3.01 mmol), intermediate C (763 mg, 2.51 mmol), potassium carbonate (1.04 g, 7.52 mmol), sodium iodide (376 mg, 2.51 mmol) and acetonitrile (10 mL) to the reaction flask, and heat to 80 degrees Celsius for 5 hours. Filter the reaction solution, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product is separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 20 / 1 to 2 / 1, V / V) to obtain compound 12-1. MS-ESI calculated value [M+H] + 463, measured value 463.

[0409] Step 2

[0410] Compound 12-1 (1 g, 2.16 mmol), iron powder (1.09 g, 19.5 mmol) and acetic acid (10 mL) were added to the reaction flask, nitrogen was replaced three times, the temperature was raised to 80 degrees Celsius and stirred for 16 hours. The reaction solution was filtered under reduced pressure, filtered and concentrated under reduced pressure. Ethyl acetate (25 mL) was added to the resulting residue, stirred for 0.5 h, and washed with saturated sodium carbonate solution (15 mL). The organic phase was concentrated under reduced pressure to obtain the crude compound 12-2. MS-ESI calculated value [M+H] + 401, measured value 401.

[0411] Step 3

[0412] Compound 12-2 (920 mg, 2.30 mmol) was dissolved in tetrahydrofuran (6 mL) and water (6 mL), and lithium hydroxide (275 mg, 11.5 mmol) was added. The reaction solution was stirred at 20 degrees Celsius for 2 hours. Water (30 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 2). 1M hydrochloric acid aqueous solution was added to the aqueous phase to adjust the pH to about 4, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 12-3.

[0413] Step 4

[0414] Compound 12-3 (250 mg, 671 μmol) was dissolved in N,N-dimethylformamide (2.5 mL), 1,1'-carbonyldiimidazole (131 mg, 806 μmol) was added, and the reaction solution was stirred at 20 degrees Celsius for 1 hour. 12-4 (149 mg, 2.01 mmol) was added to the reaction solution, and the reaction solution was stirred at 20 degrees Celsius for 1 hour. The reaction solution was heated to 80 degrees Celsius and continued to stir for 14 hours. Water (20 mL) was added to the reaction solution to quench, and extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated brine (50 mL), 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 (petroleum ether / ethyl acetate, 2 / 1~1 / 1, V / V) to obtain compound 12. MS-ESI calculated value [M+H] + 411, measured value 411. 1 H NMR (400 MHz, DMSO-d 6)δ10.59(s,1H),6.91-6.83(m,1H),6.82-6.74(m,2H),6.70(d,J=8.8Hz,1H),6.64-6.59(m,2H),4.53(s,2H ), 4.41-4.21 (m, 3H), 4.04 (d, J = 10.8Hz, 1H), 3.92 (t, J = 6.8Hz, 1H), 3.07 (d, J = 6.8Hz, 2H), 2.27 (s, 3H) ppm.

[0415] Example 13

[0416] Synthesis route:

[0417]

[0418] Compound 12-3 (50 mg, 134 μmol) was dissolved in dichloromethane (1 mL), 1,1'-carbonyldiimidazole (65 mg, 403 μmol) was added, and the reaction solution was stirred at 25 degrees Celsius for 0.5 hours. Cyclopropylamine (31 mg, 571 μmol) was added to the reaction solution, and the reaction solution was stirred for 1.5 hours. Water (20 mL) was added to the reaction solution to quench, and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (20 mL), 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 preparative high performance liquid chromatography (chromatographic column: Waters Xbridge 150×25mm×5μm; mobile phase: 10mM ammonium bicarbonate aqueous solution-acetonitrile; gradient: acetonitrile: 28%-58%, 8 minutes) to obtain compound 13. MS-ESI calculated value [M+H] + 412, measured value 412. 1 H NMR (400 MHz, DMSO-d 6 )δ10.60(s,1H),8.01(d,J=4.0Hz,1H),6.91-6.86(m,1H),6.85-6.79(m,2H) ,6.64(dd,J=2.8,9.6Hz,1H),6.59-6.51(m,1H),6.48-6.42(m,1H),4.53(s,2 H),4.42-4.24(m,2H),4.18(d,J=9.6Hz,1H),4.03(dd,J=1.8,10.8Hz,1H),2. 64-2.53(m,2H),2.37-2.21(m,2H),0.63-0.55(m,2H),0.39-0.30(m,2H)ppm.

[0419] Embodiment 14

[0420] Synthesis route:

[0421]

[0422] first step

[0423] Compound E-2 (3.00 g, 16.4 mmol) and intermediate C (5.48 g, 18.0 mmol) were dissolved in acetonitrile (40 mL), sodium iodide (2.45 g, 16.4 mmol) and potassium carbonate (6.79 g, 49.1 mmol) were added, and the reaction solution was stirred at 80 degrees Celsius for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 8 / 1 to 1 / 2, V / V) to obtain compound 14-1. MS-ESI calculated value [M+H] + 407, measured value 407.

[0424] Step 2

[0425] Compound 14-1 (6.4 g, 15.8 mmol) and triphenylphosphine (6.2 g, 23.6 mmol) were dissolved in N,N-dimethylformamide (64 mL), and N-bromosuccinimide (4.20 g, 23.6 mmol) was added at 20 degrees Celsius. The reaction solution was stirred at 50 degrees Celsius for 1 hour. Water (600 mL) was added to the reaction solution to quench it, and it was extracted with ethyl acetate (200 mL×2). The combined organic phase was washed with saturated brine (200 mL×2), 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 (petroleum ether / ethyl acetate, 8 / 1~4 / 1, V / V) to obtain compound 14-2. MS-ESI calculated value [M+H] + 469, 471. Measured values: 469, 471.

[0426] Step 3

[0427] Compound 14-2 (200 mg, 426 μmol) and 14-3 (108 mg, 1.28 mmol) were dissolved in acetonitrile (4 mL), sodium carbonate (70.8 mg, 852 μmol) was added, and the reaction solution was stirred at 70 degrees Celsius for 12 hours. The reaction solution was 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 (petroleum ether / ethyl acetate, 1 / 1, V / V) to obtain compound 14-4. MS-ESI calculated value [M+H] + 473, measured value 473.

[0428] Step 4

[0429] Compound 14-4 (50 mg, 106 μmol) was dissolved in glacial acetic acid (2 mL), iron powder (59 mg, 1.06 mmol) was added, and the reaction solution was stirred at 80 degrees Celsius for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin layer chromatography (developing solvent: dichloromethane / methanol, 20 / 1, V / V) to obtain compound 14. MS-ESI calculated value [M+H] + 411, measured value 411. 1 H NMR (400 MHz, CDCl 3 )δ6.88-6.83(m,1H),6.80-6.69(m,3H),6.67-6.56(m,2H),4.66(d,J=7.2H z,2H),4.55(s,2H),4.31-4.14(m,3H),4.07-3.95(m,2H),2.42(s,3H)ppm.

[0430] Embodiment 15

[0431] Synthesis route:

[0432]

[0433] first step

[0434] Compound 12-3 (680 mg, 1.83 mmol) was dissolved in N, N-dimethylformamide (10 mL), 1,1'-carbonyldiimidazole (355 mg, 2.19 mmol) was added to the reaction solution, the reaction mixture was stirred at 20 degrees Celsius for 1 hour, and compound 15-1 (723 mg, 5.48 mmol) was added. The reaction mixture was stirred at 20 degrees Celsius for 1 hour, and the temperature was raised to 80 degrees Celsius and stirred for 14 hours. Water (20 mL) was added to the reaction solution, and it was extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained by concentration was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1 to 1 / 1, V / V) to obtain compound 15-2. MS-ESI calculated value [M+H] + 469, measured value 469.

[0435] Step 2

[0436] Compound 15-2 (600 mg, 1.28 mmol) was dissolved in tetrahydrofuran (3 mL) and anhydrous ethanol (15 mL), and sodium borohydride (97.0 mg, 2.56 mmol) was added to the reaction solution in batches. After the reaction mixture was stirred at 25 degrees Celsius for 2 hours, a saturated ammonium chloride solution (100 mL) was added to the reaction solution, and extracted with ethyl acetate (60 mL×3). The combined organic phase was washed with saturated brine (50 mL), 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 preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 40%-50%, 7min) to obtain compound 15. MS-ESI calculated value [M+H] + 427, measured value 427. 1 H NMR (400 MHz, DMSO-d 6 )δ10.58(s,1H),6.89-6.85(m,1H),6.81-6.76(m,2H),6.73-6.68(m,1H),6.64-6.59(m,2H),5.71-5.57(m,1H),4.53(s,2 H), 4.49 (d, J = 4.4Hz, 2H), 4.41-4.34 (m, 1H), 4.33-4.21 (m, 2H), 4.08-4.02 (m, 1H), 3.95 (s, 1H), 3.12 (d, J = 6.8Hz, 2H) ppm.

[0437] Example 16

[0438] Synthesis route:

[0439]

[0440] first step

[0441] Compound 10-3 (200 mg, 492 mmol) and acetic acid hydrazide (182 mg, 2.46 mmol) were dissolved in ethyl acetate (5 mL), and tri-n-propyl cyclophosphoric anhydride 50% ethyl acetate solution (1.56 g, 2.46 mmol) and triethylamine (249 mg, 2.46 mmol) were added to the reaction solution. The reaction mixture was stirred at 20 degrees Celsius for 0.5 hours. Water (20 mL) was added to the reaction solution, and it was extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude compound 16-1. MS-ESI calculated value [M+H] + 463, measured value 463.

[0442] Step 2

[0443] Compound 16-1 (200 mg, 432 μmol) was dissolved in acetonitrile (3 mL), and N,N-diisopropylethylamine (168 mg, 1.30 mmol) and p-toluenesulfonyl chloride (165 mg, 864 μmol) were added to the reaction solution. The reaction mixture was stirred at 60 degrees Celsius for 12 hours. Water (20 mL) was added to the reaction solution, and it was extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (chromatographic column: Waters Xbridge 150×25 mm×10 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 38%-38%, 2 min) to obtain compound 16. MS-ESI calculated value [M+H] + 445, measured value 445. 1 H NMR (400 MHz, DMSO-d 6 )δ10.84-10.72(m,1H),6.99-6.89(m,1H),6.79-6.67(m,2H),6.67-6.55(m,2H),4.70-4.62(m,2H) ,4.40-4.21(m,3H),4.14-4.02(m,1H),3.94-3.84(m,1H),3.08-2.92(m,2H),2.42-2.36(m,3H)ppm.

[0444] Embodiment 17

[0445] Synthesis route:

[0446]

[0447] first step

[0448] Lithium aluminum tetrahydride (209 mg, 5.52 mmol) was dissolved in tetrahydrofuran (10 mL), and compound 10-2 (2.00 g, 4.60 mmol) was dissolved in tetrahydrofuran (5 mL) and added to the reaction solution at 0 degrees Celsius under nitrogen protection. The reaction mixture was stirred at 20 degrees Celsius for 12 hours. Water (100 mL) was added to the reaction solution, and the pH was adjusted to 2 with 2M hydrochloric acid. It was extracted with ethyl acetate (100 mL×2), and the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 2 / 1 to 1 / 2, V / V) to obtain compound 17-1. MS-ESI calculated value [M+H] + 393, measured value 393.

[0449] Step 2

[0450] Compound 17-1 (200 mg, 489 μmol) was dissolved in dichloromethane (2 mL), and Dess-Martin periodinane (311 mg, 733 μmol) was added to the reaction solution. The reaction mixture was stirred at 20 degrees Celsius for 12 hours. Saturated sodium bicarbonate solution (30 mL) and saturated sodium sulfite solution (30 mL) were added to the reaction solution, extracted with ethyl acetate (50 mL×2), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 5 / 1~1 / 1, V / V) to obtain compound 17-2. MS-ESI calculated value [M+H] + 391, measured value 391.

[0451] Step 3

[0452] Compound 17-2 (260 mg, 665 μmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (256 mg, 1.33 mmol) were dissolved in methanol (5 mL), potassium carbonate (276 mg, 2.00 mmol) was added to the reaction solution, and the reaction mixture was stirred at 20 degrees Celsius for 12 hours. Water (20 mL) was added to the reaction solution, and it was extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was separated by thin layer chromatography (developing solvent: petroleum ether / ethyl acetate, 1 / 1, V / V) to obtain compound 17-3. MS-ESI calculated value [M+H] + 387, measured value 387.

[0453] Step 4

[0454] Compound 17-3 (200 mg, 517 μmol), anhydrous copper sulfate (82.5 mg, 517 mmol) and sodium ascorbate (205 mg, 1.03 mmol) were dissolved in tert-butyl alcohol (15 mL) and water (5 mL). Trimethylsilyl azide (179 mg, 1.55 mmol) was added to the reaction solution at 20 degrees Celsius, and the reaction mixture was stirred at 90 degrees Celsius for 12 hours. Water (100 mL) was added to the reaction solution, and the pH was adjusted to 8 with a saturated sodium bicarbonate solution. It was extracted with ethyl acetate (100 mL×2), and the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by thin layer chromatography (developing solvent: dichloromethane / methanol, 10 / 1, V / V) to obtain compound 17. MS-ESI calculated value [M+H] + 430, measured value 430. 1HNMR (400MHz, CD 3 OD)δ7.64-7.48(m,1H),7.03-6.88(m,1H),6.83-6.70(m,1H),6.67-6.46(m,3H),4.64(s,2H) ,4.28(s,2H),4.21-4.13(m,1H),4.09-4.01(m,1H),3.71-3.61(m,1H),3.02-2.88(m,2H)ppm.

[0455] Embodiment 18

[0456] Synthesis route:

[0457]

[0458] first step

[0459] Compound 3-5 (300 mg, 1.25 mmol) and intermediate D (444 mg, 2.72 mmol) were dissolved in acetonitrile (3 mL), sodium iodide (188 mg, 1.25 mmol) and potassium carbonate (520 mg, 3.76 mmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 18-1. MS-ESI calculated value [M+H] + 481, measured value 481.

[0460] Step 2

[0461] Compound 18-1 (500 mg, 1.04 mmol) was dissolved in acetic acid (5 mL), and iron powder (581 mg, 10.4 mmol) was added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 3 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by thin layer chromatography (developing solvent: petroleum ether / ethyl acetate, 1 / 1, V / V) to obtain compound 18-2. MS-ESI calculated value [M+H] + 419, measured value 419.

[0462] Step 3

[0463] Compound 18-2 (370 mg, 884 μmol) was dissolved in methanol (3 mL), lithium hydroxide monohydrate (297 mg, 7.07 mmol) was dissolved in water (0.5 mL) and added to the reaction solution, and the reaction mixture was stirred at 25 degrees Celsius for 1 hour. Water (20 mL) was added to the reaction solution, and the pH was adjusted to about 3 with 1M hydrochloric acid, and extracted with ethyl acetate (20 mL×2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 18-3. MS-ESI calculated value [M+H] + 391, measured value 391.

[0464] Step 4

[0465] Compound 18-3 (300 mg, 769 μmol) was dissolved in N,N-dimethylformamide (3 mL), 1,1'-carbonyldiimidazole (150 mg, 922 μmol) was added to the reaction solution, and the reaction mixture was stirred at 20 degrees Celsius for 0.5 hours. N-hydroxyacetamidine (114 mg, 1.54 mmol) was added to the reaction solution, and the reaction mixture was stirred at 20 degrees Celsius for 0.5 hours. The reaction mixture was then stirred at 80 degrees Celsius for 11 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (chromatographic column: Waters Xbridge 150 × 25 mm × 10 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 42%-72%, 10 min) to obtain compound 18. MS-ESI calculated value [M+H] + 429, measured value 429. 1 HNMR (400 MHz, DMSO-d 6 )δ10.94-10.65(m,1H),6.81-6.67(m,2H),6.67-6.54(m,3H),4.68-4.57(m,2H),4.37-4. 21(m,3H),4.13-4.03(m,1H),3.97-3.89(m,1H),3.13-3.01(m,2H),2.31-2.22(m,3H)ppm.

[0466] Embodiment 19

[0467] Synthesis route:

[0468]

[0469] first step

[0470] Compound 19-1 (3.00 g, 21.4 mmol) was dissolved in sulfuric acid (25 mL), and 65% nitric acid solution (4.7 g, 48.5 mmol) was dissolved in sulfuric acid (5 mL) and added to the reaction solution at -20 degrees Celsius. The reaction mixture was stirred at -20 degrees Celsius for 2 hours. 300 mL of ice water was added to the reaction solution, the mixed solution was filtered, and the filter cake was collected and dried to obtain a crude compound 19-2.

[0471] Step 2

[0472] Compound 19-2 (2.10 g, 11.3 mmol) was dissolved in tetrahydrofuran (15 mL), and sodium borohydride (1.00 g, 26.4 mmol) was dissolved in water (5 mL) and added to the reaction solution at 20 degrees Celsius. The reaction mixture was stirred at 20 degrees Celsius for 1 hour. The reaction solution was adjusted to a pH of about 3 with 2M hydrochloric acid, water (50 mL) was added, and it was extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 19-3.

[0473] Step 3

[0474] Compound 19-3 (1.90 g, 10.2 mmol) and methyl bromoacetate (2.33 g, 15.2 mmol) were dissolved in N,N-dimethylformamide (20 mL), potassium carbonate (2.11 g, 15.2 mmol) was added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 0.5 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL×2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 19-4.

[0475] Step 4

[0476] Compound 19-4 (2.70 g, 10.4 mmol) was dissolved in dichloromethane (30 mL), phosphorus tribromide (3.10 g, 11.5 mmol) was slowly added to the reaction solution at 0 degrees Celsius, and the reaction mixture was stirred at 20 degrees Celsius for 0.5 hours. The reaction solution was diluted with water (100 mL), adjusted to a pH of about 7 with a saturated sodium bicarbonate solution, extracted with dichloromethane (100 mL×2), and the combined organic phase was washed with saturated brine, 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 (eluent: petroleum ether / ethyl acetate, 20 / 1~10 / 1, V / V) to obtain compound 19-5. MS-ESI calculated value [M+H] + 322, 324. Actual values: 322, 324.

[0477] Step 5

[0478] Intermediate D (150 mg, 627 μmol) and compound 19-5 (242 mg, 752 μmol) were dissolved in acetonitrile (3 mL), sodium iodide (94.0 mg, 627 μmol) and potassium carbonate (260 mg, 1.88 mmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 1 hour. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain compound 19-6. MS-ESI calculated value [M+H] + 481, measured value 481.

[0479] Step 6

[0480] Compound 19-6 (400 mg, 833 μmol) was dissolved in acetic acid (5 mL), and iron powder (465 mg, 8.33 mmol) was added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 1 hour. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was added with water (20 mL) and a saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (50 mL×2), and the combined organic phase was washed with saturated brine, 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 thin layer chromatography (developing solvent: petroleum ether / ethyl acetate, 2 / 1, VV) to obtain compound 19-7. MS-ESI calculated value [M+H] + 419, measured value 419.

[0481] Step 7

[0482] Compound 19-7 (250 mg, 598 μmol) was dissolved in methanol (3 mL), lithium hydroxide monohydrate (201 mg, 4.78 mmol) was dissolved in water (0.5 mL) and added to the reaction solution, and the reaction mixture was stirred at 25 degrees Celsius for 1 hour. Water (20 mL) was added to the reaction solution, and the pH was adjusted to about 4 with 2M hydrochloric acid. The reaction solution was filtered, and the filter cake was concentrated under reduced pressure to obtain crude compound 19-8. MS-ESI calculated value [M+H] + 391, measured value 391.

[0483] Step 8

[0484] Compound 19-8 (160 mg, 410 μmol) was dissolved in N,N-dimethylformamide (3 mL), 1,1'-carbonyldiimidazole (79.8 mg, 492 μmol) was added to the reaction solution, and the reaction mixture was stirred at 20 degrees Celsius for 0.5 hours. N-hydroxyacetamidine (60.7 mg, 820 μmol) was added to the reaction solution, and the reaction mixture was stirred at 20 degrees Celsius for 0.5 hours. The reaction mixture was stirred at 80 degrees Celsius for 11 hours. Water (20 mL) was added to the reaction solution, and it was extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by thin layer chromatography (developing solvent: petroleum ether / ethyl acetate, 1 / 1, V / V) to obtain compound 19. MS-ESI calculated value [M+H] + 429, measured value 429. 1 H NMR (400 MHz, DMSO-d 6 )δ10.68-10.42(m,1H),6.93-6.84(m,1H),6.80-6.70(m,2H),6.70-6.58(m,2H),4.60-4.52(m,2H) ,4.46-4.24(m,3H),4.08-3.99(m,1H),3.98-3.90(m,1H),3.14-3.03(m,2H),2.33-2.19(m,3H)ppm.

[0485] Embodiment 20

[0486] Synthesis route:

[0487]

[0488] first step

[0489] Compound 19-4 (50.0 g, 833 μmol) and iron powder (86.2 g, 1.54 mmol) were dissolved in ethanol (500 mL), and ammonium chloride (82.6 g, 1.54 mmol) was dissolved in water (150 mL) and added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 3 hours. The reaction solution was filtered through diatomaceous earth, and water (1 L) was added to the filtrate, and extracted with ethyl acetate (1 L × 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 20-1. MS-ESI calculated value [M+H] + 198, measured value 198.

[0490] Step 2

[0491] Compound 20-1 (35.0 g, 178 mmol) was dissolved in dichloromethane (400 mL), phosphorus tribromide (57.7 g, 213 mmol) was slowly added to the reaction solution at 0 degrees Celsius, and the reaction mixture was stirred at 20 degrees Celsius for 0.5 hours. The reaction solution was diluted with water (400 mL), extracted with dichloromethane (300 mL×4), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was added with ethyl acetate (600 mL), stirred at 25 degrees Celsius for 30 minutes, filtered, and the filter cake was dried to obtain compound 20-2. MS-ESI calculated value [M+H] + 260,262,measured value 260,262.

[0492] Step 3

[0493] Compound 20-2 (18.3 g, 70.4 mmol) and intermediate E (11.0 g, 47.0 mmol) were dissolved in acetonitrile (220 mL), sodium iodide (7.04 g, 47.0 mmol) and sodium bicarbonate (7.89 g, 93.9 mmol) were added to the reaction solution, and the reaction mixture was stirred at 75 degrees Celsius for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 10 / 1 to 1 / 1, V / V) to obtain compound 20. MS-ESI calculated value [M+H] + 414, measured value 414. 1 H NMR (400 MHz, DMSO-d 6 )δ10.60-10.43(m,1H),7.89-7.72(m,2H),6.92-6.82(m,1H),6.80-6.69(m,2H),6.69-6.59(m,1H),6.58-6. 47(m,1H),4.64-4.44(m,4H),4.38-4.26(m,1H),4.25-4.15(m,1H),4.06-3.95(m,2H),3.90-3.79(m,1H)ppm.

[0494] Embodiment 21

[0495] Synthesis route:

[0496]

[0497] first step

[0498] Compound 14-2 (750 mg, 1.60 mmol) was dissolved in acetic acid (8 mL), and iron powder (893 mg, 16.0 mmol) was added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 1 hour. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was washed with a saturated sodium bicarbonate solution (50 mL × 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 20 / 1 to 5 / 1, V / V) to obtain compound 21-1. MS-ESI calculated value [M+H] + 407,409,measured value 407,409.

[0499] Step 2

[0500] Compound 21-1 (200 mg, 491 μmol) and 1H-1,2,3-triazole (170 mg, 18.0 mmol) were dissolved in acetonitrile (2 mL), and sodium iodide (73.6 mg, 491 μmol) and potassium carbonate (204 mg, 1.47 mmol) were added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained by concentration was separated by thin layer chromatography (developing solvent: petroleum ether / ethyl acetate, 1 / 1, V / V) to obtain compound 21. MS-ESI calculated value [M+H] + 396, measured value: 396. 1 H NMR (400 MHz, DMSO-d 6 )δ10.66-10.48(m,1H),7.90-7.71(m,2H),6.90-6.81(m,1H),6.78-6.68(m,3H),6.66-6.57(m,1H),6.57-6. 49(m,1H),4.63-4.43(m,4H),4.31-4.21(m,1H),4.20-4.11(m,1H),4.07-3.93(m,2H),3.92-3.79(m,1H)ppm.

[0501] Embodiment 22

[0502] Synthesis route:

[0503]

[0504] first step

[0505] Compound 22-1 (25.0 g, 147 mmol) was dissolved in acetic acid (400 mL), and liquid bromine (8.33 mL, 162 mmol) was dissolved in acetic acid (40 mL). The mixture was added to the reaction solution, and the reaction solution was stirred at 20 degrees Celsius for 12 hours. The reaction solution was poured into water (2.5 L), filtered, and the filter cake was dried to obtain the crude compound 22-2. MS-ESI calculated value [M+H] + 249, 251. Actual measured values: 249, 251.

[0506] Step 2

[0507] Compound 22-2 (22.5 g, 90.4 mmol) was dissolved in acetic acid (160 mL) and trifluoroacetic acid (80 mL), and nitric acid (8.36 mL, 121 mmol, 65% purity) was added, and the mixture was reacted at 20 degrees Celsius for 2 hours. Water (500 mL) was added to the reaction solution, filtered, and the filter cake was dried to obtain the crude compound 22-3. MS-ESI calculated value [MH] - 292, 294. Actual values: 292, 294.

[0508] Step 3

[0509] Compound 22-3 (86 g, 292 mmol) was dissolved in ethanol (800 mL), wet palladium / carbon (15 g, 57.5 mmol, 10% content) was added, and stirred at 25 degrees Celsius for 16 hours under a hydrogen atmosphere (50 psi). The reaction solution was filtered and the filtrate was concentrated to obtain the crude compound 22-4. MS-ESI calculated value [M+H] + 186, measured value 186.

[0510] Step 4

[0511] Compound 22-4 (54 g, 292 mmol) and potassium carbonate (121 g, 875 mmol) were dissolved in N,N-dimethylformamide (600 mL), chloroacetyl chloride (25.5 mL, 321 mmol) was added at 0 degrees Celsius, and the mixture was reacted at 20 degrees Celsius for 5 hours. Water (1.5 L) was added to the reaction solution, and the mixture was stirred for 10 minutes and then filtered. The filter cake was dried to obtain the crude compound 22-5. MS-ESI calculated value [M+H] + 226, measured value 226.

[0512] Step 5

[0513] Compound 22-5 (40 g, 178 mmol) was dissolved in methanol (350 mL), lithium hydroxide monohydrate (29.8 g, 711 mmol) was dissolved in water (150 mL), mixed and added to the reaction solution, and the reaction solution was stirred at 20 degrees Celsius for 4 hours. Water (1.5 L) was added to the reaction solution, and the pH was adjusted to about 1 with concentrated hydrochloric acid, filtered, and the filter cake was dried to obtain a crude compound 22-6. MS-ESI calculated value [M+H] + 212, measured value 212.

[0514] Step 6

[0515] Compound 22-6 (16 g, 75.8 mmol) was dissolved in acetonitrile (400 mL), 1,1'-carbonyldiimidazole (24.6 g, 152 mmol) was added to the reaction solution, and the reaction mixture was stirred at 20 degrees Celsius for 1 hour. Sodium borohydride (5.76 g, 152 mmol) was dissolved in water (130 mL) and slowly added dropwise to the reaction solution, and the reaction solution was stirred at 20 degrees Celsius for 2 hours. Concentrated hydrochloric acid was used to adjust the pH to 2-3, water (500 mL) was added, and ethyl acetate (400+300 mL) was used for extraction. The organic phases were combined and concentrated to obtain a residue. The residue was dissolved in sodium hydroxide solution (1 M, 100 mL), the pH was adjusted to about 7 with hydrochloric acid, filtered, and the filter cake was dried to obtain a crude compound 22-7. MS-ESI calculated value [M+H] + 198, measured value 198.

[0516] Step 7

[0517] Compound 22-7 (15 g, 70.0 mmol) was dissolved in dichloromethane (400 mL), phosphorus tribromide (22.7 g, 84.0 mmol) was added to the reaction solution at 0 degrees Celsius, and the reaction solution was stirred at 20 degrees Celsius for 1 hour. Water (200 mL) was added to the reaction solution, filtered, and the filtrate was separated and the organic phase was concentrated to obtain a residue, which was combined with the filter cake and dried to obtain a crude compound 22-8. MS-ESI calculated value [M+H] + 260, 262. Actual measured values: 260, 262.

[0518] Step 8

[0519] Intermediate F (10 g, 40.1 mmol) was dissolved in acetonitrile (200 mL), potassium carbonate (11.1 g, 80.2 mmol), sodium iodide (6.01 g, 40.1 mmol) were added to the reaction solution, and then compound 22-8 (13.6 g, 52.2 mmol) was added, and the reaction solution was stirred at 70 degrees Celsius for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography (eluent: petroleum ether / dichloromethane, 3 / 1-0 / 1, V / V) to obtain an oily substance, which was stirred with ethyl acetate / n-heptane (2V / 15V) for 30 minutes, filtered, and the filter cake was dried to obtain compound 22. MS-ESI calculated value [M+H] + 429, measured value 429. 1 H NMR (400MHz, CD 3 OD)δ6.87-6.82(m,2H),6.73-6.70(m,1H),6.62-6.58(m,2H),4.60(s,2H),4.37-4. 26(m,3H),4.03-3.99(m,1H),3.88-3.84(m,1H),3.01(d,J=7.2Hz,2H),2.27(s,3H).

[0520] Embodiment 23

[0521] Synthesis route:

[0522]

[0523] first step

[0524] Compound 23-1 (1 g, 4.83 mmol) was dissolved in a mixed solution of tetrahydrofuran (10 mL), water (10 mL) and methanol (10 mL). Lithium hydroxide (1.16 g, 48.3 mmol) was added to the reaction solution, and the reaction mixture was stirred at 25 degrees Celsius for 1 hour. Water (50 mL) was added to the reaction solution and then extracted with ethyl acetate (50 mL × 2). The aqueous phase was adjusted to pH 4 with 1M hydrochloric acid solution and extracted with ethyl acetate (50 mL × 2). 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 crude compound 23-2. MS-ESI calculated value [M+H] + 194, measured value 194.

[0525] Step 2

[0526] Compound 23-2 (500 mg, 2.59 mmol) was dissolved in acetonitrile (10 mL), 1,1'-carbonyldiimidazole (839 mg, 5.18 mmol) was added to the reaction solution, the reaction mixture was stirred at 20 degrees Celsius for 0.5 hours, sodium borodeuteride (195 mg, 5.18 mmol) dissolved in water (5 mL) was added to the reaction solution, and stirred at 20 degrees Celsius for 1 hour. Water (50 mL) was added to the reaction solution, the reaction solution was adjusted to pH about 4 with 1M hydrochloric acid solution, extracted with ethyl acetate (50 mL×2), 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 crude compound 23-3. MS-ESI calculated value [M+H] + 182, measured value 182.

[0527] Step 3

[0528] Compound 23-3 (100 mg, 0.55 mmol) was dissolved in anhydrous dichloromethane (3 mL), and phosphorus tribromide solution (164 mg, 0.60 mmol) was slowly added dropwise to the reaction solution at 0 degrees Celsius, and the reaction mixture was stirred at 25 degrees Celsius for 2 hours. Ice water (50 mL) was added to the reaction solution, and it was extracted with ethyl acetate (40 mL×3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude compound 23-4.

[0529] Step 4

[0530] Compound 23-4 (102 mg, 0.42 mmol) and intermediate F (69 mg, 0.28 mmol) were dissolved in acetonitrile (1.5 mL), sodium iodide (42 mg, 0.42 mmol) and anhydrous potassium carbonate (115 mg, 0.84 mmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 16 hours. The reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1 to 2 / 1, V / V) to obtain compound 23. MS-ESI calculated value [M+H] + 413, measured value 413. 1 H NMR (400 MHz, DMSO-d 6)δ10.59(s,1H),6.91-6.85(m,1H),6.82-6.75(m,2H),6.70(d,J=8.8Hz,1H),6.65-6.58(m,2H),4.53( s,2H),4.36-4.24(m,1H),4.11-3.97(m,1H),3.96-3.86(m,1H),3.07(d,J=6.8Hz,2H),2.27(s,3H)ppm.

[0531] Embodiment 24

[0532] Synthesis route:

[0533]

[0534] first step

[0535] Compound E-2 (0.40 mg, 2.18 mmol) and compound 20-2 (0.68 g, 2.62 mmol) were dissolved in acetonitrile (15 mL), sodium iodide (327 mg, 2.18 mmol) and anhydrous sodium carbonate (0.91 g, 6.55 mmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 16 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1 to 2 / 1, V / V) to obtain compound 24-1. MS-ESI calculated value [M+H] + 363, measured value 363.

[0536] Step 2

[0537] Compound 24-1 (1.06 g, 2.31 mmol) was dissolved in N,N-dimethylformamide (20 mL), triphenylphosphine (0.91 g, 3.47 mmol) was added to the reaction solution, and N-bromosuccinimide (0.62 g, 3.47 mmol) was added in batches at 0 degrees Celsius, and the reaction mixture was stirred at 50 degrees Celsius for 1 hour. Water (100 mL) was added to the reaction solution, and it was extracted with ethyl acetate (100 mL×2), and the combined organic phase was washed with saturated brine (200 mL), 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 (petroleum ether / ethyl acetate, 200 / 1~5 / 1, V / V) to obtain compound 24-2.

[0538] Step 3

[0539] Compound 24-2 (100 mg, 0.24 mmol) and compound 14-3 (59.3 mg, 0.71 mmol) were dissolved in acetonitrile (3 mL), anhydrous sodium carbonate (39.0 mg, 0.47 mmol) was added to the reaction solution, and the reaction mixture was stirred at 20 degrees Celsius for 2 hours. Water (30 mL) was added to the reaction solution and extracted with ethyl acetate (20 mL×2), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, and the crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1~1 / 1, V / V) to obtain compound 24. MS-ESI calculated value [M+H] + 429, measured value 429. 1 H NMR (400 MHz, DMSO-d 6 )δ10.55(s,1H),6.87(d,J=10.6Hz,1H),6.79-6.74(m,1H),6.72-6.62(m,3H),4.71(d,J=6.0H z,1H),4.66-4.59(m,1H),4.56(s,2H),4.37-4.26(m,2H),4.10-3.97(m,3H),2.40(s,3H)ppm.

[0540] Embodiment 25

[0541] Synthesis route:

[0542]

[0543] first step

[0544] Compound 10-3 (830 mg, 2.04 mmol) and 4-methylmorpholine (289 mg, 2.86 mmol, 314 μL) were dissolved in tetrahydrofuran (8 mL), and isobutyl chloroformate (334 mg, 2.45 mmol, 322 μL) was added, and then ammonia water (511 mg, 4.08 mmol, 561 μL, 28% purity) was added. The reaction solution was stirred at 0 degrees Celsius for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol, 100:1-20:1, V / V) to obtain compound 25-1. MS-ESI calculated value [M+H] + 406, measured value 406.

[0545] Step 2

[0546] Palladium dichloride (60.3 mg, 340 μmol) was added to a mixed solution of compound 25-1 (460 mg, 1.13 mmol) in acetonitrile (5 mL) and water (5 mL), and the reaction solution was stirred at 50 degrees Celsius for 5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol, 100:1-20:1, V / V) to obtain compound 25-2.

[0547] Step 3

[0548] Compound 25-2 (440 mg, 1.13 mmol) and hydroxylamine hydrochloride (315 mg, 4.54 mmol) were dissolved in ethanol (10 mL) and triethylamine (689 mg, 6.81 mmol, 948 μL) was added. The reaction solution was stirred at 80 degrees Celsius for 3 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography (dichloromethane / methanol, 100:1-10:1, V / V) to obtain compound 25-3. MS-ESI calculated value [M+H] + 421, measured value 421.

[0549] Step 4

[0550] Compound 25-3 (120 mg, 285 μmol) and ethyl acetate (75.4 mg, 855 μmol, 83.8 μL) were dissolved in dimethyl sulfoxide (2 mL), sodium hydroxide (34.2 mg, 855 μmol) was added, and the reaction solution was stirred at 15 degrees Celsius for 2 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (10 mL×3), and the combined organic phase was washed with saturated brine (20 mL), 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 preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75×30mm×3μm; mobile phase: 10mM ammonium bicarbonate aqueous solution-acetonitrile; gradient: acetonitrile 32%-62%, 8min) to obtain compound 25. MS-ESI calculated value [M+H] + 445, measured value 445. 1 H NMR (400MHz, CD 3 OD)δ6.95-6.91(m,1H),6.77-6.73(m,1H),6.68-6.52(m,3H),4.65(s,2H),4.36-4.21(m, 3H), 4.07 (dd, J = 2.0, 11.0Hz, 1H), 3.83-3.74 (m, 1H), 2.96-2.82 (m, 2H), 2.50 (s, 3H) ppm.

[0551] Embodiment 26

[0552] Synthesis route:

[0553]

[0554] first step

[0555] Compound 25-2 (200 mg, 516 μmol), trimethylsilyl azide (238 mg, 2.06 mmol, 271 μL) and dibutyltin oxide (20 mg, 80.3 μmol) were dissolved in toluene (3 mL), and the reaction solution was stirred for 14 hours at 10 degrees Celsius in a nitrogen environment. Saturated KF aqueous solution (20 mL) was first added to the reaction solution, stirred for at least one hour, and then saturated sodium bicarbonate (50 mL) was added, extracted with ethyl acetate (20 mL×3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate (2:1) ~ dichloromethane / methanol (20:1), V / V) to obtain compound 26-1. MS-ESI calculated value [M+H] + 431, measured value 431.

[0556] Step 2

[0557] Compound 26-1 (50 mg, 116 μmol), iodomethane (165 mg, 1.16 mmol, 72.3 μL) and triethylamine (58.7 mg, 580 μmol, 80.8 μL) were dissolved in acetonitrile (1 mL), and the reaction solution was stirred at 85 degrees Celsius for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated by thin layer chromatography (developing solvent: dichloromethane / methanol, 10 / 1, V / V) to obtain compound 26. MS-ESI calculated value [M+H] + 445, measured value 445. 1 H NMR (400 MHz, CDCl 3 )δ9.51(s,1H),6.89(s,1H),6.69-6.59(m,2H),6.56-6.45(m,2H),4.69(s,2H),4.32 -4.21(m,6H),4.09(dd,J=2.0,11.0Hz,1H),3.84-3.71(m,1H),3.18-3.05(m,2H)ppm.

[0558] Embodiment 27

[0559] Synthesis route:

[0560]

[0561] first step

[0562] Compound 12-3 (220 mg, 591 μmol) and 4-methylmorpholine (83.7 mg, 827 mmol, 91.0 μL) were dissolved in tetrahydrofuran (6 mL), and isobutyl chloroformate (96.8 mg, 709 μmol, 93.1 μL) was added, and then ammonia water (148 mg, 1.18 mmol, 163 μL, 28% purity) was added. The reaction solution was stirred at 0 degrees Celsius for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was separated by silica gel column chromatography (dichloromethane / methanol, 100:1-20:1, V / V) to obtain compound 27-1. MS-ESI calculated value [M+H] + 372, measured value 372.

[0563] Step 2

[0564] Palladium dichloride (37.2 mg, 210 μmol) was added to a mixed solution of compound 27-1 (260 mg, 1.13 mmol) in acetonitrile (5 mL) and water (5 mL), and the reaction solution was stirred at 50 degrees Celsius for 11 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography (dichloromethane / methanol, 100:1-20:1, V / V) to obtain compound 27-2. MS-ESI calculated value [M+H] + 354, measured value 354.

[0565] Step 3

[0566] Compound 27-2 (230 mg, 651 μmol), trimethylsilane (300 mg, 2.60 mmol, 342 μL) and dibutyltin oxide (110 mg, 442 μmol) were dissolved in toluene (5 mL), and the reaction solution was stirred at 80 degrees Celsius for 30 hours under a nitrogen environment. Saturated KF aqueous solution (20 mL) was first added to the reaction solution, stirred for at least one hour, and then saturated sodium bicarbonate solution (50 mL) was added, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate (2:1) ~ dichloromethane / methanol (20:1), V / V) to obtain compound 27-3. MS-ESI calculated value [M+H] + 397, measured value 397.

[0567] Step 4

[0568] Compound 27-3 (200 mg, 505 μmol) and trimethylsilylated diazomethane (2M, 706 μmol, 353 μL) were dissolved in tetrahydrofuran (2 mL) and methanol (0.5 mL), and the reaction solution was stirred at 10 degrees Celsius for 0.5 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated by thin layer chromatography (developing solvent: dichloromethane / methanol, 10 / 1, V / V) to obtain compound 27. MS-ESI calculated value [M+H] + 411, measured value 411. 1 H NMR (400 MHz, CDCl 3 )δ8.04(s,1H),6.96-6.89(m,1H),6.88-6.82(m,1H),6.73-6.60(m,2H),6.60-6.48(m,2H), 4.61(s,2H),4.36-4.24(m,6H),4.17-3.98(m,1H),3.92-3.70(m,1H),3.22-3.08(m,2H)ppm.

[0569] Embodiment 28

[0570] Synthesis route:

[0571]

[0572] first step

[0573] Sodium methoxide (400 mg, 7.41 mmol) was added to a solution of hydroxylamine hydrochloride (500 mg, 7.20 mmol) in methanol (5 mL), the reaction solution was stirred at 0 degrees Celsius for one hour, and then compound 28-1 (430 mg, 9.77 mmol, 0.51 mL) was added, the reaction solution was heated to 15 degrees Celsius and stirred for 15 hours, and then heated to 40 degrees Celsius and stirred for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, ethyl acetate (50 mL×3) was added to the crude product, the organic phases were combined, and the organic phases were concentrated under reduced pressure to obtain a crude compound 28-2.

[0574] Step 2

[0575] Compound 12-3 (300 mg, 806 μmol) was dissolved in N,N-dimethylformamide (3 mL), 1,1'-carbonyldiimidazole (157 mg, 967 μmol) was added, and the reaction solution was stirred at 15 degrees Celsius for 1 hour. 28-2 (182 mg, 2.36 mmol) was added to the reaction solution, and the reaction solution was stirred at 15 degrees Celsius for 1 hour. The reaction solution was heated to 90 degrees Celsius and continued to stir for 64 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was separated and purified by thin layer chromatography (developing solvent: petroleum ether / ethyl acetate, 1 / 2, V / V) to obtain compound 28. MS-ESI calculated value [M+H] + 414, measured value 414. 1 H NMR (400 MHz, DMSO-d 6 )δ10.59(s,1H),6.92-6.83(m,1H),6.83-6.75(m,2H),6.74–6.67(m,1H),6.65-6.57(m,2H),4.53(s ,2H),4.40-4.21(m,3H),4.04(dd,J=2.2,11.0Hz,1H),3.98-3.86(m,1H),3.08(d,J=6.8Hz,2H)ppm.

[0576] Embodiment 29

[0577] Synthesis route:

[0578]

[0579] first step

[0580] Compound 19-8 (95 mg, 243 μmol) was dissolved in N,N-dimethylformamide (1 mL), 1,1'-dicarbonyl imidazole (48 mg, 296 μmol) was added, and the reaction solution was stirred at 15 degrees Celsius for 1 hour. Compound 28-2 (60 mg, 778 μmol) was then added, and the reaction solution was stirred at 15 degrees Celsius for 1 hour, and then heated to 90 degrees Celsius for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, and the crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1:2, V / V) to obtain compound 29. MS-ESI calculated value [M+H] + 432, measured value 432. 1 HNMR (400 MHz, DMSO-d 6)δ10.54(s,1H),6.88(d,J=10.8Hz,1H),6.79-6.69(m,2H),6.69-6.51(m,2H),4.56(s,2H),4.46-4. 37(m,1H),4.37-4.24(m,2H),4.02(dd,J=2.0,11.0Hz,1H),3.98-3.71(m,1H),3.18-2.99(m,2H)ppm.

[0581] Embodiment 30

[0582] Synthesis route:

[0583]

[0584] first step

[0585] Compound 19-8 (250 mg, 640 μmol) and 4-methylmorpholine (129 mg, 1.27 mmol, 140 μL) were dissolved in tetrahydrofuran (5 mL), and isobutyl chloroformate (130 mg, 952 μmol, 125 μL) was added, and then ammonia water (241 mg, 1.93 mmol, 265 μL, 28% purity) was added, and the reaction solution was stirred at 0 degrees Celsius for 2 hours. Ethyl acetate (20 mL) was added to the reaction solution for dilution, and the organic phase was washed with 10% citric acid aqueous solution (10 mL), 10% sodium bicarbonate solution (10 mL) and saturated brine (10 mL) in turn, and concentrated under reduced pressure to obtain crude compound 30-1. MS-ESI calculated value [MH] - 388, measured value 388.

[0586] Step 2

[0587] Palladium dichloride (45.5 mg, 257 μmol) was added to a mixed solution of compound 30-1 (200 mg, 514 μmol) in acetonitrile (0.5 mL) and water (0.5 mL), and the reaction solution was stirred at 50 degrees Celsius for 1 hour. The reaction solution was extracted with ethyl acetate (20 mL×3), and the combined organic phase was washed with saturated brine (20 mL), 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 (dichloromethane / methanol, 100:1-20:1, V / V) to obtain compound 30-2.

[0588] Step 3

[0589] Compound 30-2 (200 mg, 539 μmol), trimethylsilyl azide (263 mg, 2.17 mmol, 300 μL) and dibutyltin oxide (20 mg, 80.3 μmol) were dissolved in toluene (5 mL), and the reaction solution was stirred at 100 degrees Celsius for 14 hours under a nitrogen environment. Saturated KF aqueous solution (20 mL) was first added to the reaction solution, stirred for at least one hour, and then saturated sodium bicarbonate (50 mL) was added, extracted with ethyl acetate (20 mL×3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (dichloromethane / methanol, 100:1~20:1, V / V) to obtain compound 30-3. MS-ESI calculated value [M+H] + 415, measured value 415.

[0590] Step 4

[0591] Compound 30-3 (180 mg, 434 μmol) and trimethylsilylated diazomethane (2M, 608 μmol, 304 μL) were dissolved in tetrahydrofuran (4 mL) and methanol (1 mL), and the reaction solution was stirred at 10 degrees Celsius for 2 hours. The reaction solution was quenched by adding water (20 mL), extracted with ethyl acetate (20 mL×2), and the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by thin layer chromatography (developing solvent: dichloromethane / methanol, 10 / 1, V / V) to obtain compound 30. MS-ESI calculated value [M+H] + 429, measured value 429. 1 H NMR (400 MHz, CDCl 3 )δ9.23-8.93(m,1H),6.73-6.67(m,2H),6.64-6.59(m,1H),6.56-6.51(m,2H),4.60-4.5 4(m,2H),4.42-4.21(m,6H),4.11-4.00(m,1H),3.85-3.74(m,1H),3.16-3.09(m,2H)ppm.

[0592] Embodiment 31

[0593] Synthesis route:

[0594]

[0595] first step

[0596] Compound 5-4 (1.00 g, 3.89 mmol) and compound intermediate C (1.42 g, 4.67 mmol) were dissolved in acetonitrile (20 mL), sodium iodide (583 mg, 3.89 mmol) and potassium carbonate (1.61 g, 11.66 mmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 31-1. MS-ESI calculated value [M+H] + 481, measured value 481.

[0597] Step 2

[0598] Compound 31-1 (2.00 g, 4.16 mmol) was dissolved in acetic acid (20 mL), iron powder (2.33 g, 41.63 mmol) was added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 6 / 1 to 2 / 1) to obtain compound 31-2. MS-ESI calculated value [M+H] + 419, measured value 419.

[0599] Step 3

[0600] Compound 31-2 (900 mg, 2.15 mmol) was dissolved in methanol (10 mL), lithium hydroxide monohydrate (903 mg, 21.51 mmol) was dissolved in water (2 mL) and added to the reaction solution, and the reaction mixture was stirred at 25 degrees Celsius for 12 hours. The reaction solution was adjusted to pH 2 with 12M hydrochloric acid, water (50 mL) was added, and it was extracted with ethyl acetate (50 mL×2), and the combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 31-3. MS-ESI calculated value [M+H] + 391, measured value 391.

[0601] Step 4

[0602] Compound 31-3 (400 mg, 1.02 mmol) was dissolved in N,N-dimethylformamide (2 mL), 1,1-carbonyldiimidazole (199 mg, 1.23 mmol) was added to the reaction solution, and the reaction mixture was stirred at 20 degrees Celsius for 0.5 hours. N-hydroxyacetamidine (152 mg, 2.05 mmol) was added to the reaction solution, and the reaction mixture was stirred at 20 degrees Celsius for 0.5 hours. The reaction mixture was then stirred at 80 degrees Celsius for 15 hours. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (chromatographic column: Waters Xbridge 150 × 25 mm × 10 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 42%-72%) to obtain compound 31-4. MS-ESI calculated value [M+H] + 429, measured value 429.

[0603] Step 5

[0604] Compound 31-4 was purified by SFC (separation column: DAICEL CHIRALPAK AD 250 mm × 30 mm × 10 μm; mobile phase: supercritical CO 2 -0.1% ammonia in isopropanol solution; gradient: 0.1% ammonia in isopropanol solution 25%-25%) to separate compounds 31b (first main peak) and 31a (second main peak). The compounds were then subjected to SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol solution; gradient: 0.05% diethylamine in ethanol solution: 5%-40%) to measure the ee value.

[0605] Compound 31a: ee% = 98%, RT = 1.569 min. MS-ESI calculated value [M+H] + 429, measured value 429; 1 HNMR (400 MHz, DMSO-d 6)δ10.63(s,1H),6.96-6.85(m,1H),6.84-6.79(m,1H),6.76(s,1H),6.74-6.68(m,2H),4.54(d,J=3.2Hz,2H),4.29(d,J=10 .8Hz,1H),4.16-3.94(m,2H),3.71(d,J=14.4Hz,1H),3.52-3.41(m,1H),2.93-2.81(m,1H),2.69-2.60(m,1H),2.19(s,3H).

[0606] Compound 31b: ee% = 100%, RT = 1.336 min. MS-ESI calculated value [M+H] + 429, measured value 429; 1 H NMR (400 MHz, DMSO-d 6 )δ10.63(s,1H),6.96-6.85(m,1H),6.84-6.79(m,1H),6.76(s,1H),6.74-6.68(m,2H),4.54(d,J=3.2Hz,2H),4.29(d,J=10 .8Hz,1H),4.16-3.94(m,2H),3.71(d,J=14.4Hz,1H),3.52-3.41(m,1H),2.93-2.81(m,1H),2.69-2.60(m,1H),2.19(s,3H).

[0607] Embodiment 32

[0608] Synthesis route:

[0609]

[0610] first step

[0611] Intermediate D (3g, 12.54mmol) and compound 22-8 (3.59g, 13.79mmol) were dissolved in acetonitrile (50mL), sodium iodide (1.88g, 12.54mmol) and potassium carbonate (5.20g, 37.62mmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was concentrated under reduced pressure and diluted with water (50mL), extracted with ethyl acetate (50mL×3), and the combined organic phase was washed with saturated brine (30mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 1 / 0~3 / 1) to obtain compound 32-1. MS-ESI calculated value [M+H] + 419, measured value 419.

[0612] Step 2

[0613] Lithium aluminum tetrahydride (68.58 mg, 1.81 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), and a solution of compound 32-1 (0.63 g, 1.51 mmol) in anhydrous tetrahydrofuran (5 mL) was added to the reaction solution under a nitrogen atmosphere at 0 degrees Celsius. The reaction mixture was stirred at 20 degrees Celsius for 1 hour. After the reaction was completed, a saturated aqueous solution of ammonium chloride (20 mL) was added to quench the reaction, and then water (30 mL) was added to dilute it, and it was extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 32-2. MS-ESI calculated value [M+H] + 377, measured value 377.

[0614] Step 3

[0615] Compound 32-2 (550 mg, 1.46 mmol) was dissolved in dichloromethane (10 mL), and DMP (929.76 mg, 2.19 mmol) was added to the reaction solution. The reaction mixture was stirred at 20 degrees Celsius for 1 hour. After the reaction was completed, a saturated aqueous sodium sulfite solution (20 mL) was added to the reaction solution to quench the reaction, and then a saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8, and water (30 mL) was added to dilute, and extracted with dichloromethane (50 mL × 3). The combined organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 32-3. MS-ESI calculated value [M+H] + 375, measured value 375.

[0616] Step 4

[0617] Compound 32-3 (460 mg, 1.23 mmol) and compound 32-4 were dissolved in methanol (10 mL), and potassium carbonate (509.5 mg, 3.69 mmol) was added to the reaction solution. The reaction mixture was stirred at 20 degrees Celsius for 1 hour. After the reaction was completed, water (20 mL) was added to the reaction solution, and it was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 1 / 0 to 3 / 1) to obtain compound 32-5. MS-ESI calculated value [M+H] + 371, measured value 371.

[0618] Step 5

[0619] Compound 32-5 (150 mg, 405.02 μmol), anhydrous copper sulfate (64.65 mg, 405.02 μmol) and sodium ascorbate (160.48 mg, 810.05 μmol) were dissolved in tert-butyl alcohol (10 mL) and water (4 mL), the mixed liquid was replaced with nitrogen three times, and trimethylsilyldiazomethane (139.99 mg, 1.22 mmol) was added under a nitrogen atmosphere at 20 degrees Celsius. The reaction mixture was stirred at 90 degrees Celsius for 12 hours. After the reaction, aqueous ammonia (2 mL) was added at 25 degrees Celsius, the mixture was stirred for 30 minutes at 25 degrees Celsius, and then water (20 mL) was added, extracted with ethyl acetate (50 mL × 3), the combined organic phase was washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by high performance liquid chromatography (chromatographic column: Unisil 3-100 C18 Ultra 150 × 25 mm × 3 μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 26%-56%) to obtain compound 32. MS-ESI calculated value [M+H] + 414, measured value 414. 1 H NMR (400 MHz, DMSO-d 6 )δ10.62-11.35(m,1H),7.62(s,1H),6.80-6.89(m,1H),6.74(d,J=8.6Hz,1H),6.66-6.71(m,1H),6.57-6.63(m,2H) ,4.59(s,2H),4.41-4.50(m,1H),4.27-4.34(m,1H),4.14(m,1H),3.95(m,1H),3.66-3.73(m,1H),2.79-2.92(m,2H).

[0620] Embodiment 33

[0621] Synthesis route:

[0622]

[0623] Intermediate G (200 mg, 802 μmol) and compound 22-8 (313 mg, 1.20 mmol) were dissolved in acetonitrile (4 mL), sodium iodide (120 mg, 802 μmol) and potassium carbonate (333 mg, 2.41 mmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by thin layer chromatography (developing solvent: petroleum ether / ethyl acetate, 1 / 1, V / V) to obtain the compound. Compound 33 was separated by preparative high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 150×25mm×10μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 34%-64%). MS-ESI calculated value [M+H] + 429, measured value 429. 1 H NMR (400MHz, CD 3 OD)δ6.88-6.65(m,3H),6.64-6.46(m,2H),4.60(s,2H),4.32(s,2H),4.29-4.17(m,4H),4.08-3.92(m,1H),3.85-3.73(m,1H),3.01(m,2H).

[0624] Embodiment 34

[0625] Synthesis route:

[0626]

[0627] first step

[0628] Compound G-2 (750 mg, 3.90 mmol) was dissolved in acetonitrile (20 mL), sodium iodide (585 mg, 3.90 mmol) and sodium bicarbonate (983 mg, 11.71 mmol), intermediate C (1.78 g, 5.85 mmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 5 / 1 to 1 / 1, V / V) to obtain compound 34-1. MS-ESI calculated value [M+Na] + 438, measured value 438.

[0629] Step 2

[0630] Compound 34-1 (1.20 g, 2.89 mmol) and dibutyltin oxide (321 mg, 1.29 mmol) were dissolved in toluene (15 mL). Azide trimethylsilane (1.40 g, 11.56 mmol, 1.60 mL) was added to the reaction solution at 25 degrees Celsius in a nitrogen environment. The reaction solution was stirred for 12 hours at 100 degrees Celsius in a nitrogen environment. Saturated potassium fluoride aqueous solution (50 mL) was first added to the reaction solution, stirred for at least one hour, and then saturated sodium bicarbonate solution (30 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 10 / 1 to 1 / 2, V / V) to obtain compound 34-2. MS-ESI calculated value [M+H] + 459, measured value 459.

[0631] Step 3

[0632] Compound 34-2 (450 mg, 982 μmol) and potassium carbonate (204 mg, 1.47 mmol) were dissolved in tetrahydrofuran (5 mL), deuterated iodomethane (209 mg, 1.47 mmol) was added to the reaction solution, and the reaction solution was stirred at 25 degrees Celsius for 12 hours. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL×2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 34-3. MS-ESI calculated value [M+H] + 476, measured value 476.

[0633] Step 4

[0634] Compound 34-3 (400 mg, 841 μmol) was dissolved in acetic acid (5 mL), and iron powder (376 mg, 6.73 mmol) was added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (chromatographic column: Phenomenex Luna 150×25mm×10μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 33%-63%) to obtain compound 34. MS-ESI calculated value [M+H] + 414, measured value 414. 1 H NMR (400 MHz, CDCl 3)δ8.19(s,1H),6.96-6.88(m,1H),6.88-6.82(m,1H),6.73-6.62(m,2H),6.56-6.48(m,2H),4 .65-4.55(m,2H),4.35-4.21(m,3H),4.11-4.03(m,1H),3.82-3.70(m,1H),3.20-3.06(m,2H).

[0635] Embodiment 35

[0636] Synthesis route:

[0637]

[0638] first step

[0639] Compound 6-3 (3 g, 11.14 mmol) was dissolved in ethanol (10 mL) and water (5 mL), and reduced iron powder (4.98 g, 89.14 mmol) and ammonium chloride (4.77 g, 89.14 mmol) were added to the reaction solution. The reaction mixture was stirred at -80 degrees Celsius for 3 hours. After the reaction was completed, it was filtered, and water (30 mL) was added to the filtrate, extracted with ethyl acetate (30 mL × 2), washed with saturated brine (30 mL), and the organic phases were combined and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 100 / 1~1 / 1, V / V) to obtain 35-1. MS-ESI calculated value [MH] - 192, measured value 192.

[0640] Step 2

[0641] Compound 35-1 (1.00 g, 4.01 mmol) and intermediate F (1.16 g, 6.02 mmol) were dissolved in 1,2-dichloroethane (20 mL), and hypophosphorous acid (52.2 mg, 802 μmol) was added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (chromatographic column: Phenomenex luna 250×50mm×10μm; mobile phase: 0.1% ammonia solution-ethanol; gradient: 35%-65%, 20min) to obtain the compound, and then SFC (separation column: Agela Innoval ODS-2 250mm×100mm×10μm; mobile phase: supercritical CO 2-0.1% ammonia in ethanol; gradient: 0.1% ammonia in ethanol 30%-30%) to separate compounds 35a (first main peak) and 35b (second main peak). The compounds were then subjected to SFC (chromatographic column: Chiralcel OD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol solution; gradient: 0.05% diethylamine in ethanol solution: 5%-40%) to measure the ee value.

[0642] Compound 35a: ee% = 98%, RT = 1.344 min. 1 H NMR (400 MHz, DMSO-d 6 )δ10.55(s,1H),6.99-6.89(m,1H),6.86(d,J=8.2Hz,1H),6.80-6.62(m,4H),4.93-4.75(m,1H),4.53(s,2H),4.09(d,J=10.4Hz,1H),3.88(m,1H),3.29-3.21(m,1H),3.08-2.97(m,1H),2.94-2.83(m,1H),2.31(s,3H),1.32(d,J=7.0Hz,3H). MS-ESI calculated value [M+H] + 425, measured value 425.

[0643] Compound 35b: ee% = 98%, RT = 1.515 min. 1 H NMR (400 MHz, DMSO-d 6 )δ10.58(s,1H),7.23-7.08(m,1H),6.97-6.82(m,3H),6.80-6.68(m,2H),5.03-4.89(m,1H),4.65-4.45(m,2H),4.23(d,J=10.6Hz,1H),3.93-3.67(m,2H),2.92-2.74(m,1H),2.59-2.53(m,1H),2.19(s,3H),1.34(m,3H). MS-ESI calculated value [M+H] + 425, measured value 425.

[0644] Embodiment 36

[0645] Synthesis route:

[0646]

[0647] Intermediate H (200 mg, 1.04 mmol) and intermediate F (387 mg, 1.55 mmol) were dissolved in 1,2-dichloroethane (5 mL), and hypophosphorous acid (67.3 mg, 1.04 mmol) was added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated by thin layer chromatography (developing solvent: dichloromethane / methanol, 15 / 1, V / V) to obtain the compound, which was separated by preparative high performance liquid chromatography (chromatographic column: Phenomenex luna 150×25mm×10μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 42%-72%, 10min) to obtain compound 36. MS-ESI calculated value [M+H] + 425, measured value 425. 1 HNMR (400 MHz, DMSO-d 6 )δ10.24(s,1H),6.84-6.57(m,5H),4.49(d,J=1.8Hz,2H),4.37-4.14(m,3H), 4.12-3.99(m,1H),3.72(m,1H),3.09-2.96(m,2H),2.24(s,3H),2.12(s,3H).

[0648] Embodiment 37

[0649] Synthesis route:

[0650]

[0651] Intermediate H (200 mg, 802 μmol) and intermediate G (233 mg, 1.20 mmol) were dissolved in 1,2-dichloroethane (5 mL), and hypophosphorous acid (52.2 mg, 802 μmol) was added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 24 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated by thin layer chromatography (developing solvent: petroleum ether / ethyl acetate, 1 / 1, V / V) to obtain the compound, and then separated by preparative high performance liquid chromatography (chromatographic column: Phenomenex luna 150×25mm×10μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 38%-68%) to obtain compound 37. MS-ESI calculated value [M+H] + 425, measured value 425. 1 H NMR (400 MHz, DMSO-d 6)δ10.25(s,1H),6.82-6.66(m,3H),6.66-6.55(m,2H),4.49(d,J=1.2Hz,2H),4.36(d,J=15.6Hz,1H),4.2 6(s,3H),4.22-4.12(m,2H),4.07-3.97(m,1H),3.70-3.58(m,1H),3.13-2.88(m,2H),2.16-2.04(m,3H).

[0652] Embodiment 38

[0653] Synthesis route:

[0654]

[0655] Intermediate I (50.0 mg, 181 μmol) and intermediate G (54.1 mg, 217 μmol) were dissolved in acetonitrile (3 mL), sodium iodide (27.1 mg, 181 μmol) and potassium carbonate (75.0 mg, 542 μmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated by thin layer chromatography (developing solvent: petroleum ether / ethyl acetate, 1 / 1, V / V) to obtain the compound, and the compound 38 was separated by preparative high performance liquid chromatography (chromatographic column: Phenomenex luna 150×25mm×10μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 39%-69%, 10min). MS-ESI calculated value [M+H] + 445, measured value 445. 1 H NMR (400 MHz, DMSO-d 6 )δ10.49(s,1H),6.93-6.87(m,1H),6.87-6.78(m,1H),6.76-6.66(m,1H),6.66-6.54(m,1H),6.53-6.42(m,1H ),4.67-4.55(m,2H),4.46-4.33(m,1H),4.31-4.20(m,5H),4.14-4.06(m,1H),3.82(m,1H),3.14-2.94(m,2H).

[0656] Embodiment 39

[0657] Synthesis route:

[0658]

[0659] first step

[0660] Intermediate H (500 mg, 2.59 mmol) and intermediate J (594 mg, 3.11 mmol) were dissolved in 1,2-dichloroethane (20 mL), and hypophosphorous acid (168 mg, 2.59 mmol) was added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 24 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 10 / 1 to 2 / 1, V / V) to obtain compound 39-1. MS-ESI calculated value [M+H] + 367, measured value 367.

[0661] Step 2

[0662] Compound 39-1 (270 mg, 737 μmol), sodium ascorbate (292 mg, 1.47 mmol), anhydrous copper sulfate (118 mg, 737 μmol) were dissolved in tert-butyl alcohol (20 mL) and water (8 mL), and trimethylsilyl azide (255 mg, 2.21 mmol) was added to the reaction solution under nitrogen protection at 20 degrees Celsius, and the reaction mixture was stirred at 90 degrees Celsius for 12 hours. The reaction solution was diluted with water (50 mL) and ammonia water (20 mL), extracted with ethyl acetate (50 mL×2), 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 a crude product. The crude product was separated by high performance liquid chromatography (chromatographic column: Phenomenex luna 150×25mm×10μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 29%-59%) to obtain compound 39. MS-ESI calculated value [M+H] + 410, measured value 410. 1 HNMR (400 MHz, DMSO-d 6 )δ10.31-10.12(m,1H),7.66-7.47(m,1H),6.72(br s,2H),6.71-6.63(m,1H),6.63-6.55(m,1H),6.54-6.45(m,1H),4.54-4.45(m,2H),4.45-4.36(m,1H),4.28- 4.15(m,1H),4.15-4.04(m,1H),4.04-3.93(m,1H),3.56-3.52(m,1H),2.98-2.74(m,2H),2.20-2.08(m,3H).

[0663] Embodiment 40

[0664] Synthesis route:

[0665]

[0666] first step

[0667] Compound 5-4 (5.5 g, 21.38 mmol) was dissolved in methanol (60 mL), and water and a solution of lithium hydroxide (1.35 g, 32.07 mmol) dissolved in water (15 mL) were added to the reaction solution. The reaction mixture was stirred at 20 degrees Celsius for 12 hours. After the reaction was completed, the methanol was removed by evaporation under reduced pressure, and water (50 mL) was added to dilute it. The pH was adjusted to 4 with aqueous hydrochloric acid solution (2 M), and extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 40-1. MS-ESI calculated value [M+H] + 230, measured value 230.

[0668] Step 2

[0669] Compound 40-1 (4.66 g, 20.33 mmol) was dissolved in N, N-dimethylformamide (50 mL), 1,1'-carbonyldiimidazole (4.95 g, 30.05 mol) was added to the reaction solution, and the reaction mixture was stirred at 25 degrees Celsius for 30 minutes. Then ammonium chloride (3.26 g, 61 mmol) and DIPEA (7.88 g, 61 mmol) were added to the reaction solution, and the reaction mixture was stirred at 25 degrees Celsius for 12 hours. After the reaction was completed, water (250 mL) was added for dilution, and ethyl acetate (200 mL×2) was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate to ethyl acetate / methanol, 5 / 1 to 20 / 1, V / V) to obtain the compound, and compound 40-2 was isolated. MS-ESI calculated value [M+H] + 229, measured value 229.

[0670] Step 3

[0671] Compound 40-2 (6.58 g, 28.83 mmol) was dissolved in acetonitrile (70 mL) and water (70 mL), and palladium dichloride (2.56 g, 14.42 mmol) was added to the reaction solution. The reaction mixture was stirred at 50 degrees Celsius for 12 hours. After the reaction was completed, water (150 mL) was added to dilute it, and ethyl acetate (150 mL × 2) was used for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (eluent: petroleum ether / ethyl acetate, 10 / 1 to 3 / 1, V / V) to obtain the compound, and compound 40-3 was isolated. MS-ESI calculated value [M+H] + 211, measured value 211.

[0672] Step 4

[0673] Compound 40-3 (0.73 g, 3.47 mmol) was dissolved in toluene (20 mL), and trimethylsilane (1.60 g, 13.89 mmol) and dibutyltin oxide (899.20 mg, 3.61 mmol) were added to the reaction solution. The reaction mixture was replaced with gas under nitrogen protection and stirred at 100 degrees Celsius for 2.5 hours. After the reaction was completed, potassium fluoride aqueous solution (100 mL) was added, stirred for 1 hour, and then ethyl acetate (50 mL) was added and extracted with water (20 mL). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 40-4. MS-ESI calculated value [M+H] + 254, measured value 254.

[0674] Step 5

[0675] Compound 40-4 (1.4 g, 5.53 mmol) was dissolved in methanol (16 mL) and tetrahydrofuran (3 mL). Trimethylsilylated diazomethane (2 M, 8.85 mL) was added to the reaction solution. The reaction mixture was stirred at 5 degrees Celsius for 12 hours. After the reaction was completed, ethyl acetate (30 mL) was added and extracted with water (30 mL). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. The crude product was chromatographed on a silica gel column (petroleum ether / ethyl acetate: 10 / 1 to 2 / 1, V / V) to obtain compound 40-5. MS-ESI calculated value [M+H] + 268, measured value 268.

[0676] Step 6

[0677] Compound 40-5 (300 mg, 1.12 mmol) and intermediate C (682.76 mg, 2.25 mmol) were dissolved in acetonitrile (10 mL), sodium iodide (336.54 mg, 2.25 mmol) and sodium bicarbonate (282.93 mg, 3.37 mmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 40-6. MS-ESI calculated value [M+H] + 491, measured value 491.

[0678] Step 7

[0679] Compound 40-6 (1 g, 2.04 mmol) was dissolved in acetic acid (15 mL), and iron powder (1.51 g, 27.0 mmol) was added to the reaction solution. The reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by preparative high performance liquid chromatography (chromatographic column: Phenomenex Luna C18 250×50mm×10μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 35%-65%, 20 minutes) to obtain compound 40. MS-ESI calculated value [M+H] + 429, measured value 429. 1 H NMR (400MHz, CD 3 Cl)δ=8.48(s,1H),6.89-6.75(m,2H),6.67(d,J=1.2Hz,1H),6.56-6.43(m,2H),4.63(d,J=4.4Hz ,2H),4.35(s,1H),4.27(s,1H),4.21(s,3H),3.97-3.90(m,1H),3.59(d,J=14.4Hz,1H),3.40(br t,J=7.6Hz,1H),2.93-2.75(m,2H).

[0680] Embodiment 41

[0681] Synthesis route:

[0682]

[0683] Compound 40-5 (280 mg, 1.05 mmol) and compound 22-8 (817.45 mg, 3.14 mmol) were dissolved in acetonitrile (10 mL), sodium iodide (314.10 mg, 2.10 mmol) and sodium bicarbonate (264.07 mg, 3.14 mmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by preparative high performance liquid chromatography (chromatographic column: Phenomenex Synergi Max-RP 250×0mm*10μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: 40%-65%, 21min) to obtain compounds 41a (first main peak) and 41b (second main peak). The compound was separated by SFC (chromatographic column: Chiralpak AS-3 50×4.6mm ID, 3μm; mobile phase: supercritical CO 2 -0.05% DEA in methanol solution; gradient: 0.05% DEA in methanol solution: 5%-40%) to measure the ee value.

[0684] Compound 41a: ee% = 100%, RT = 1.214 min. 1 H NMR (400MHz, CD 3 Cl) δ = 8.30 (br s, 1H), 6.88 (t, J = 8.2 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 6.56-6.44 (m, 2H), 4.66 (d, J = 0.8, 2H), 4.28-4.09 (m, 5H), 4.06-3.97 (m, 1H), 3.94-3.87 (m, 1H), 3.47 (br t, J = 7.6 Hz, 1H), 2.97-2.75 (m, 2H). MS-ESI calculated value [M+H] + 447, measured value 447.

[0685] Compound 41b: ee% = 100%, RT = 1.517 min. 1 H NMR (400MHz, CD 3 Cl) δ = 8.30 (br s, 1H), 6.88 (t, J = 8.2 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 6.56-6.44 (m, 2H), 4.66 (d, J = 0.8, 2H), 4.28-4.09 (m, 5H), 4.06-3.97 (m, 1H), 3.94-3.87 (m, 1H), 3.47 (br t, J = 7.6 Hz, 1H), 2.97-2.75 (m, 2H). MS-ESI calculated value [M+H] + 447, measured value 447.

[0686] Embodiment 42

[0687] Synthesis route:

[0688]

[0689] first step

[0690] Intermediate H (14 g, 72.46 mmol) was dissolved in toluene (200 mL), and the reaction solution was stirred at 45 degrees Celsius for 0.5 hours. Phosphorus tribromide (33.35 g, 123.19 mmol) was slowly added dropwise to the reaction solution, and the reaction solution was stirred at 100 degrees Celsius for 1 hour. The reaction solution was added with water (1000 mL) and stirred for 30 minutes, filtered, and the filter cake was dried to obtain compound 42-1. 1H NMR (400MHz, MeOD) δ = 6.94 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 4.50-4.41 (m, 4H), 2.23 (s, 3H).

[0691] Step 2

[0692] Compound 42-1 (8.42 g, 32.87 mmol) and compound 40-2 (7.5 g, 32.87 mmol) were dissolved in acetonitrile (90 mL), sodium iodide (4.93 g, 32.87 mmol) and potassium carbonate (13.63 g, 98.60 mmol) were added to the reaction solution, and the reaction mixture was stirred at 80 degrees Celsius for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Methanol and water (methanol / water, 1 / 1, V / V, 65 mL) were added to the crude product, stirred at room temperature for 10 minutes, filtered to obtain a filter cake, and the filter cake was dried to obtain a compound, which was subjected to SFC (chromatographic column: DAICEL CHIRALPAKIG (250 mm×50 mm×10 um); mobile phase: supercritical CO 2 -0.1% ammonia ethanol solution; gradient: 50%-50%) to obtain 42a (the first main peak) and 42b (the second main peak). The compounds were subjected to SFC (chromatographic column: Chiralpak AS-3 50×4.6mm ID, 3μm; mobile phase: supercritical CO 2 -0.05% DEA in ethanol solution; gradient: 0.05% DEA in ethanol solution: 5%-40%) to measure the ee value.

[0693] Compound 42a: ee%=100%, RT=0.800min. 1 H NMR (400 MHz, DMSO-d 6 )δ=10.21(s,1H),7.24(s,1H),7.06(d,J=8.4Hz,1H),6.91-6.75(m,3H),6.72-6.60(m,1H),4.51(s,2H),4.23-3.90(m,4H),3.38-3.26(m,3H),2.24(s,3H). MS-ESI calculated value [M+H] + 404, measured value 404.

[0694] Compound 42b: ee% = 100%, RT = 1.129 min. 1 H NMR (400 MHz, DMSO-d 6)δ=10.21(s,1H),7.24(s,1H),7.06(d,J=8.4Hz,1H),6.91-6.75(m,3H),6.72-6.60(m,1H),4.51(s,2H),4.23-3.90(m,4H),3.38-3.26(m,3H),2.24(s,3H). MS-ESI calculated value [M+H] + 404, measured value 404.

[0695] Embodiment 43

[0696] Synthesis route:

[0697]

[0698] Compound 40-2 (204.25 mg, 895.07 μmol) and intermediate I (275 mg, 994.52 μmol) were dissolved in acetonitrile (10 mL), potassium carbonate (412.35 mg, 2.98 mmol) and sodium iodide (149.07 mg, 994.52 μmol) were added to the reaction solution, and the reaction mixture was stirred at 85 degrees Celsius for 2 hours. The reaction solution was filtered, the filtrate was extracted, and the crude product was concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150×25mm×10μm; mobile phase: 0.225% formic acid aqueous solution-acetonitrile; gradient: acetonitrile 34%-64%, 10min), and then separated by SFC (separation column: DAICEL CHIRALPAK AY-H 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ammonia in ethanol; gradient: 0.1% ammonia in ethanol 60%-60%) to separate compounds 43a (first main peak) and 43b (second main peak). The compounds were subjected to SFC (chromatographic column: Chiralpak AY-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethanolamine in isopropanol and acetonitrile solution; gradient: 40% 0.05% diethylamine in isopropanol and acetonitrile solution) to measure the ee value.

[0699] Compound 43a: ee%=100%, RT=0.497min. 1 H NMR (400 MHz, DMSO-d 6)δ=10.45(s,1H),7.30-7.23(m,2H),7.00(d,J=8.0Hz,1H),6.86-6.78(m,2H),6.67(d,J=10.0Hz,1H),4.61(s,2H),4.27-4.23(m,1H),4.16-4.12(m,2H),3.95-3.90(m,1H),3.43-3.40(m,1H),2.19-2.07(m,2H). MS-ESI calculated value [M+H] + 424, measured value 424.

[0700] Compound 43b: ee% = 99.74%, RT = 1.555 min. 1 H NMR (400 MHz, DMSO-d 6 )δ=10.45(s,1H),7.29-7.22(m,2H),7.00(d,J=8.4Hz,1H),6.86-6.78(m,2H),6.68-6.66(m,1H),4.61(s,2H),4.27-4.23(m,1H),4.15-4.12(m,2H),3.92-3.89(m,1H),3.41-3.40(m,1H),2.15-2.11(m,2H). MS-ESI calculated value [M+H] + 424, measured value 424.

[0701] Activity test

[0702] Experimental Example 1 Evaluation of MR antagonist activity in vitro

[0703] Experimental purpose: To test the MR antagonist activity of the compound

[0704] Experimental Materials:

[0705] DMEM medium was purchased from BI; fetal bovine serum was purchased from Biosera; HEK293 / Gal4 / MR cell line was provided by Wuhan Heyan Biopharmaceutical Technology Co., Ltd. Bright Glo was purchased from Promega; EnVision multi-label analyzer (PerkinElmer).

[0706] Experimental methods:

[0707] MR cells were seeded in a white 96-well plate, with 40,000 cells per well in 80 ml of cell suspension. The cell plate was placed in a carbon dioxide incubator for overnight culture.

[0708] The compound to be tested was diluted with a gun to 8 concentration points, 5-fold gradient dilution, and the compound concentration was 2 millimolar to 0.026 micromolar. 38 microliters of culture medium was added to the middle plate, and then 2 microliters of compound per well were added to the middle plate according to the corresponding position. After mixing, 10 microliters of compound solution per well were transferred to the cell plate, and the cell plate was placed in a carbon dioxide incubator for incubation for 1 hour. Aldosterone was diluted to 10 nanomolar using culture medium, that is, 20 microliters of aldosterone with a concentration of 1 micromolar was added to 1980 microliters of culture medium, and after mixing, 10 microliters of aldosterone solution were added to each well of the cell plate except the positive control well. The cell plate was placed in a carbon dioxide incubator and incubated for 24 hours. The final concentration of the compound was 10 micromolar to 0.128 nanomolar, and the final concentration of aldosterone was 1 nanomolar.

[0709] After the incubation, discard the cell supernatant, add 100 μl of Bright Glo reagent per well to the cell plate, and read immediately on the EnVision Multi-label Analyzer.

[0710] Data Analysis:

[0711] Using the equation %Inhibition = ((RFU Cmpd -AVER(RFU Neg.Ctrl )) / ((AVER(RFU Pos.Ctrl )-AVER(RFU Neg.Ctrl The raw data were converted into inhibition rate by 100% and the compound curve was fitted by log(inhibitor) vs.response-Variable slope of Graphpad Prism 5. IC 50 The value is calculated by the software using the formula Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)). Experimental results: See Table 1.

[0712] Table 1 MR antagonist activity test results

[0713] Compound <![CDATA[IC for MR 50 (nM)]]> 2 372 4 289 5 325 6 273 7 519 8a 130 9 403 10 15 12 27 14 78 15 107 18 62 19 66 20 27 21 50 22 9 23 29 24 32 25 72 26 32 27 80 28 35 29 22 30 68 31a 80 32 50.8 33 11 34 130 35a 251.1 35b 76.6 36 13.7 37 43.9 38 22.6 42a 29.14 43a 18.03

[0714] Experimental conclusion: The compound of the present application has a good antagonistic activity on mineralocorticoid receptors.

[0715] Experimental Example 2: Pharmacokinetic Evaluation

[0716] Experimental Materials:

[0717] SD rats (male, 7-9 weeks old, Beijing Weitonglihua)

[0718] Experimental operation:

[0719] The pharmacokinetic characteristics of rodents after intravenous (IV) and oral (PO) administration of the compound were tested using a standard protocol. Rats were given a single intravenous injection and oral administration in the experiment. The intravenous injection vehicle was water. The intravenous injection vehicle was a clear solution of 80% polyethylene glycol 400 / 20% water, and the oral solvent was a uniform suspension of 99.9% (0.5% HPMC: Solutol HS15 = 95:5) / 0.1% Tween 80. This project used four male SD rats, two rats were administered intravenously, and plasma samples were collected at 0h (before administration) and 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24h after administration. The other two rats were administered orally by gavage, and plasma samples were collected at 0h (before administration) and 0.25, 0.5, 1, 2, 4, 8, and 24h after administration, and whole blood samples were collected within 24 hours. All blood samples were immediately transferred to labeled commercial centrifuge tubes containing K2-EDTA. After blood samples were collected, they were centrifuged at 3200 g for 10 minutes at 4°C to obtain supernatant plasma, which was quickly placed in dry ice and then stored at -60°C or lower for LC-MS / MS analysis. The non-compartmental model was used to analyze the plasma drug concentration-time data and calculate pharmacokinetic parameters such as peak concentration (C max ), clearance (CL), tissue distribution (Vdss), area under the concentration-time curve (AUC 0-last ), bioavailability (F), etc.

[0720] The experimental results are shown in Table 2:

[0721] Table 2 Pharmacokinetic evaluation results of the compounds of the present application in rats

[0722]

[0723] Experimental conclusion: The compound of the present application has good pharmacokinetic properties.

[0724] Experimental Example 3: In vivo efficacy test in unilateral nephrectomized rats

[0725] Experimental Materials:

[0726] SD rats (male, Beijing Weitonglihua Experimental Animal Technology Co., Ltd.)

[0727] Experimental operation:

[0728] After 2-3 days of adaptive feeding, the right kidney of SD male rats was removed and fed with ordinary feed and drinking water. After one week of recovery, they were divided into groups according to their body weight. After grouping, an osmotic pump was implanted subcutaneously and aldosterone was injected at a concentration of 3 mg / mL (dissolved in 0.15% DMSO / prepared with sterile water) (Source Leaf Biology S30644-5mg), with a flow rate of 0.75 μg / hr (Alzet model 2004). At the same time, 6% NaCl high-salt feed (customized by Beijing Keao Xieli Feed Co., Ltd.) and 0.3% KCl drinking water (Source Leaf Biology S24120) were fed. While the osmotic pump was implanted subcutaneously, oral administration was performed. The dosage is detailed in the grouping. The control group was orally administered with a solvent (0.5% hydroxypropyl methylcellulose, polyethylene glycol stearate 15=95:5 (v / v, containing 0.1% Tween 80)) once a day for 4 consecutive weeks. Body weight was measured and recorded every day.

[0729] Experimental conclusion: The compound of the present application has a significant protective effect on the kidneys and can effectively reduce the ratio of albumin to creatinine in rat urine.

Claims

1. A compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, R1 is selected from R 11 and R 12 ; R 11 Select from -OR a 、-C(=O)NR b R c and -S(=O)2C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R aa replaced by; R 12 is selected from 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted by 1, 2 or 3 R d replaced by; R2, R3 and R4 are independently selected from H, F, Cl, Br, I, -CN, -NH2, -OH and C 1-4 alkyl; R5 and R6 are independently selected from H, D, F, Cl, Br and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R ab R7 and R8 are independently selected from H, F, Cl, Br, I, -CN, -NH2, -OH and C 1-4 alkyl; R a , R b and R c are independently selected from H, C 1-4 Alkyl and C 3-4 Cycloalkyl, wherein the C 1-4 Alkyl and C 3-4 The cycloalkyl group is optionally substituted with 1, 2 or 3 R groups independently; R d are independently selected from H, F, Cl, Br, I, -CN, -NH2, -OH and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R ac replaced by; R aa , R ab and R ac Each of the following is independently selected from D, F, Cl, Br, I, -CN, -NH2 and -OH; R is independently selected from F, Cl, Br, I, -CN, -NH2 and -OH; The "hetero" in the 5-membered heteroaryl group represents 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and -N-.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (II-1), (II-2), (II-3), (II-4), (II-5) or (II-6): in, R2, R3, R4, R5, R6, R7, R8, R 11 and R 12 As defined in claim 1.

3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R a Selected from H; Optionally, R b and R c are independently selected from H, -CH3, -CH2CH3 and Optionally, R d are independently selected from H, F, Cl, Br and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R ac or, R d are independently selected from H, F, Cl, Br and -CH3, wherein the -CH3 is optionally replaced by 1, 2 or 3 R ac replaced by; Or, R d are independently selected from H, F, Cl, Br, -CH3, 4. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R 11 Selected from -OH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)NHCH2CH3, and -S(=O)2CH3; Optionally, R 12 Selected from wherein n is selected from 1, 2 and 3; Or, R 12 Selected from Or, R 12 Selected from 5. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from -OH, -C(=O)NH2, -C(=O)NHCH3, -C(=O)NHCH2CH3, -S(=O)2CH3, 6. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R2 and R3 are independently selected from H, F and Cl; Optionally, R4 is selected from H, F, Cl and C 1-4 alkyl; Alternatively, R4 is selected from H, F, Cl and -CH3.

7. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R5 and R6 are independently selected from H, D and C 1-4 Alkyl, wherein the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R ab or, R5 and R6 are independently selected from H, D and -CH3; Optionally, R7 is selected from H and F; Optionally, R8 is selected from H, F, Cl and C 1-4 Alkyl; or, R8 is selected from H, F, Cl and -CH3.

8. The compound of the following formula, its stereoisomer or its pharmaceutically acceptable salt:

9. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1 to 8, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of drugs for mineralocorticoid receptor antagonist-related diseases; optionally, the mineralocorticoid receptor antagonist-related diseases are selected from diabetic nephropathy.

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