Pyrimidine tricyclic compounds and their applications

Abstract

The present application discloses a pyrimidine tricyclic compound and its application, specifically a pyrimidine tricyclic compound and its application in the preparation of drugs for treating related diseases. Specifically disclosed are the compounds shown in formula (II), their stereoisomers and pharmaceutically acceptable salts thereof.

Description

[0001] This application claims the priority of Chinese Patent Application CN202010361013.7 with an application date of April 30, 2020, and Chinese Patent Application CN202110390228.6 with an application date of April 12, 2021. This application incorporates the entire texts of the above-mentioned Chinese patent applications by reference. Technical Field

[0002] This application relates to a pyrimidine tricyclic compound and its application in the preparation of drugs for treating related diseases. Specifically, it relates to the compounds shown in formula (I) and formula (II), their stereoisomers or their pharmaceutically acceptable salts. Background Art

[0003] Soluble guanylate cyclase (sGC) is widely present in the cytosol of mammalian cells and is a heterodimer composed of two subunits, α and β. Soluble guanylate cyclase is a key signal transduction enzyme in the NO-sGC-cGMP signaling pathway. After being activated in vivo, sGC catalyzes the conversion of guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP). cGMP is an important secondary messenger molecule that triggers a series of downstream cascade reactions by activating various downstream effector molecules, such as cGMP-dependent protein kinase G and cGMP-gated ion channels. It plays important physiological functions in the gastrointestinal system, cardiovascular system, and central nervous system, such as promoting vasodilation and smooth muscle relaxation, inhibiting platelet aggregation, vascular remodeling, apoptosis, and inflammation, and participating in neurotransmission. Under pathophysiological conditions, the NO / cGMP system can be inhibited, which can lead to, for example, hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke, and sexual dysfunction. In the past two years, studies have also shown that abnormal sGC-mediated signaling pathways are closely related to the occurrence of fibrotic diseases such as chronic kidney disease and systemic sclerosis.

[0004] sGC stimulators have a dual mechanism of action: they can directly activate the sGC-cGMP signaling pathway without relying on NO but relying on a heme cofactor containing Fe 2+ ; they can also enhance the sensitivity of sGC to endogenous NO and thus synergize with NO. Therefore, sGC stimulators are heme-dependent and NO-independent sGC stimulators. Stimulating sGC to generate more cGMP can regulate a variety of important physiological processes: promoting vasorelaxation and inhibiting platelet aggregation, etc. At the same time, activating sGC can also regulate other signaling pathways, such as TGF-β, to exert anti-fibrotic and anti-tumor effects. Therefore, sGC stimulators can be used as potential therapeutic means for treating cardiovascular diseases (heart failure, pulmonary hypertension, angina pectoris, myocardial infarction) and fibrotic diseases (renal fibrosis, systemic sclerosis).

[0005] In view of the unmet market and clinical needs for such soluble guanylate cyclase stimulators, the present application provides a class of new compounds. Such compounds can act as stimulators of soluble guanylate cyclase, have excellent in vitro stimulating activity on soluble guanylate cyclase, and have good pharmacokinetic properties. SUMMARY OF THE INVENTION

[0006] The present application provides a compound represented by formula (II), its stereoisomer or its pharmaceutically acceptable salt,

[0007]

[0008] wherein,

[0009] R1 is selected from

[0010] R2 are each independently selected from C1 or C2 d substituted and C1, C2 or C3 d substituted 1-3 alkyl;

[0011] R3 are each independently selected from H and halogen;

[0012] R4 is selected from H and C 1-3 alkyl;

[0013] E1 is selected from -(CH2) m -;

[0014] m is selected from 0, 1 and 2;

[0015] E2 is selected from -(CH2) n -, -(CH2) p C(O)-, -O(CH2) q -, -O(CH2) r C(O)-, -CH2CH=CH- and -(CH2) s NHC(O)-, and each CH2 is optionally substituted by 1 or 2 R b substituents;

[0016] E3 is selected from a single bond, NR c and O;

[0017] n is selected from 1, 2 and 3;

[0018] p is selected from 0, 1 and 2;

[0019] q is selected from 1 and 2;

[0020] r is selected from 1 and 2;

[0021] s is selected from 1 and 2;

[0022] T1 is selected from N and CR a ;

[0023] R a are each independently selected from H, OH, -OC(=O)NHEt, -CO2Et, -NHCO2CH3, -C(=O)NH(CH2)2OCH3, and C 1-3 alkyl;

[0024] R b are each independently selected from F and CH3;

[0025] R c are each independently selected from H and CH3;

[0026] R d are each independently selected from halogen and CF3.

[0027] In some embodiments of the present application, the above-mentioned R a are each independently selected from H, OH, -OC(=O)NHEt, -CO2Et, -C(=O)NH(CH2)2OCH3, -NHCO2CH3, and CH3, and other variables are as defined in the present application.

[0028] In some embodiments of the present application, the above-mentioned R d are each independently selected from F and CF3, and other variables are as defined in the present application.

[0029] In some embodiments of the present application, the above-mentioned R2 are each independently selected from C d substituted with 1 or 2 R and C d substituted with 1, 2, or 3 R 1-3 alkyl, and other variables are as defined in the present application.

[0030] In some embodiments of the present application, each of the above-mentioned R2 is independently selected from other variables are as defined in the present application.

[0031] In some embodiments of the present application, each of the above-mentioned R2 is selected from other variables are as defined in the present application.

[0032] In some embodiments of the present application, each of the above-mentioned R2 is selected from other variables are as defined in the present application.

[0033] In some embodiments of the present application, each of the above-mentioned R3 is selected from H and F, and other variables are as defined in the present application.

[0034] In some embodiments of the present application, the above R1 is selected from Other variables are as defined in the present application.

[0035] In some embodiments of the present application, the above R1 is selected from Other variables are as defined in the present application.

[0036] In some embodiments of the present application, the above R1 is selected from Other variables are as defined in the present application.

[0037] In some embodiments of the present application, the above E1 is selected from a single bond, -CH2-, and -(CH2)2-, and other variables are as defined in the present application.

[0038] In some embodiments of the present application, the above E2 is selected from -CH2-, -(CH2)2-, -(CH2)3-, -CH2CH=CH-, -CH2CO-, -(CH2)2CO-, -O(CH2)2-, -OCH2C(O)-, and -CH2NHC(O)-, and each of the CH2 is optionally substituted by 1 or 2 Rs b and other variables are as defined in the present application.

[0039] In some embodiments of the present application, the above E2 is selected from -CH2-, -(CH2)2-, -CF2CH2-, -(CH2)3-, -CH2CH=CH-, -CH2CO-, -CO-, -C(CH3)2CO-, -CF2CO-, -(CH2)2CO-, -O(CH2)2-, -OCH2C(O)-, and -CH2NHC(O)-, and other variables are as defined in the present application.

[0040] In some embodiments of the present application, the above E3 is selected from a single bond, NH, N(CH3), and O, and other variables are as defined in the present application.

[0041] In some embodiments of the present application, the above T1 is selected from N, CH, C(OH), C(OC(=O)NHEt), C(CO2Et), C(NHCO2CH3), C[C(=O)NH(CH2)2OCH3], and C(CH3), and other variables are as defined in the present application.

[0042] In some embodiments of the present application, the above structural unit is selected from Other variables are as defined in the present application.

[0043] In some embodiments of the present application, the above structural unit is selected from Other variables are as defined in the present application.

[0044] The present application provides a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0045]

[0046] wherein,

[0047] R1 is selected from

[0048] Each R2 is independently selected from a with 1 or 2 substituents and a C 1-3 alkyl with 1, 2 or 3 substituents, and the substituents are selected from halogen and CF3;

[0049] Each R3 is independently selected from H and halogen;

[0050] E1 is selected from -(CH2) m -;

[0051] m is selected from 0, 1 and 2;

[0052] E2 is selected from -(CH2) n - and -(CH2) p C(O)-;

[0053] Each n is selected from 1, 2 and 3;

[0054] Each p is selected from 0, 1 and 2;

[0055] T1 is selected from N and CR a ;

[0056] R a is selected from H and C 1-3 alkyl.

[0057] In some embodiments of the present application, each of the above R2s is independently selected from a with 1 or 2 substituents and a C 1-3 alkyl with 1, 2 or 3 substituents, the substituents are selected from F and CF3, and other variables are as defined in the present application.

[0058] In some embodiments of the present application, each of the above R2s is selected from Other variables are as defined in the present application.

[0059] In some embodiments of the present application, each of the above R3 is selected from H and F, and other variables are as defined in the present application.

[0060] In some embodiments of the present application, the above R1 is selected from Other variables are as defined in the present application.

[0061] In some embodiments of the present application, the above E1 is selected from a single bond, -CH2-, and -(CH2)2-, and other variables are as defined in the present application.

[0062] In some embodiments of the present application, the above E2 is selected from -CH2-, -(CH2)2-, -(CH2)3-, -CH2CO-, and -(CH2)2CO-, and other variables are as defined in the present application.

[0063] In some embodiments of the present application, the above T1 is selected from N and -C(CH3)-, and other variables are as defined in the present application.

[0064] In some embodiments of the present application, the above structural unit is selected from Other variables are as defined in the present application.

[0065] The present application provides a compound represented by formula (II), its stereoisomers or its pharmaceutically acceptable salts,

[0066]

[0067] wherein,

[0068] R1 is selected from

[0069] R2 are each independently selected from C having 1 or 2 R d substituted and C having 1, 2 or 3 R d substituted 1-3 alkyl;

[0070] R3 are each independently selected from H and halogen;

[0071] R4 is selected from H and C 1-3 alkyl;

[0072] E1 is selected from -(CH2) m -;

[0073] m is selected from 0, 1 and 2;

[0074] E2 is selected from -(CH2)n -, -(CH2) p C(O)-, -O(CH2) q -, -O(CH2) r C(O)- and -(CH2) s NHC(O)-, wherein the CH2 is optionally substituted by 1 or 2 R b substituted;

[0075] E3 is selected from a single bond, NR c and O;

[0076] n is selected from 1, 2, and 3;

[0077] p is selected from 0, 1, and 2;

[0078] q is selected from 1 and 2;

[0079] r is selected from 1 and 2;

[0080] s is selected from 1 and 2;

[0081] T1 is selected from N and CR a ;

[0082] R a are each independently selected from H, OH, -OC(=O)NHEt, -CO2Et, -NHCO2CH3, and C 1-3 alkyl;

[0083] R b are each independently selected from F and CH3;

[0084] R c are each independently selected from H and CH3;

[0085] R d are each independently selected from halogen and CF3.

[0086] In some embodiments of the present application, the above R a are each independently selected from H, OH, -OC(=O)NHEt, -CO2Et, -NHCO2CH3, and CH3, and other variables are as defined in the present application.

[0087] In some embodiments of the present application, the above R d are each independently selected from F and CF3, and other variables are as defined in the present application.

[0088] In some embodiments of the present application, the above R2 are each independently selected from C d substituted with 1 or 2 R and C d substituted with 1, 2, or 3 R 1-3 alkyl, and other variables are as defined in the present application.

[0089] In some embodiments of the present application, each of the above R2 is selected from Other variables are as defined in the present application.

[0090] In some embodiments of the present application, each of the above R3 is selected from H and F, and other variables are as defined in the present application.

[0091] In some embodiments of the present application, the above R1 is selected from Other variables are as defined in the present application.

[0092] In some embodiments of the present application, the above E1 is selected from a single bond, -CH2-, and -(CH2)2-, and other variables are as defined in the present application.

[0093] In some embodiments of the present application, the above E2 is selected from -CH2-, -(CH2)2-, -(CH2)3-, -CH2CO-, -(CH2)2CO-, -O(CH2)2-, -OCH2C(O)-, and -CH2NHC(O)-, and each of the CH2 is optionally substituted by 1 or 2 Rs b and other variables are as defined in the present application.

[0094] In some embodiments of the present application, the above E2 is selected from -CH2-, -(CH2)2-, -CF2CH2-, -(CH2)3-, -CH2CO-, -CO-, -C(CH3)2CO-, -CF2CO-, -(CH2)2CO-, -O(CH2)2-, -OCH2C(O)-, and -CH2NHC(O)-, and other variables are as defined in the present application.

[0095] In some embodiments of the present application, the above E3 is selected from a single bond, NH, N(CH3), and O, and other variables are as defined in the present application.

[0096] In some embodiments of the present application, the above T1 is selected from N, CH, C(OH), C(OC(=O)NHEt), C(CO2Et), C(NHCO2CH3), and C(CH3), and other variables are as defined in the present application.

[0097] In some embodiments of the present application, the above structural unit is selected from Other variables are as defined in the present application.

[0098] In some embodiments of the present application, the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt is selected from:

[0099]

[0100]

[0101] Wherein, R2, R4, T1, E1, E2 and E3 are as defined in any one of the present application.

[0102] Some embodiments of the present application are formed by any combination of the above variables.

[0103] The present application also provides the following compound, its stereoisomer or its pharmaceutically acceptable salt, which is selected from:

[0104]

[0105]

[0106]

[0107]

[0108] The present application also provides the following compound, its stereoisomer or its pharmaceutically acceptable salt, which is selected from:

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115] On the other hand, the present application provides a pharmaceutical composition comprising the compound, its stereoisomer or its pharmaceutically acceptable salt of the present application. In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

[0116] On the other hand, the present application also provides the use of the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating sGC agonist-related diseases.

[0117] On the other hand, the present application provides a method for treating sGC agonist-related diseases in mammals, including administering to a mammal in need of such treatment, preferably a human, a therapeutically effective amount of a compound of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0118] On the other hand, the present application provides the use of a compound of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of sGC agonist-related diseases.

[0119] On the other hand, the present application provides a compound of the present application, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating sGC agonist-related diseases.

[0120] In some embodiments of the present application, the sGC agonist-related diseases are selected from heart failure or hypertension.

[0121] Definitions and Explanations

[0122] 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 indeterminate or unclear without a specific definition, but should be understood in its ordinary meaning. When a trade name appears in this application, it is intended to refer to the corresponding product or its active ingredient.

[0123] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that 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.

[0124] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application, prepared from a compound having specific substituents 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, the base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. When the compound of the present application contains a relatively basic functional group, the acid addition salt can be obtained by contacting the neutral form of 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 both basic and acidic functional groups and can thus be converted into either a base or acid addition salt.

[0125] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compounds containing acid radicals or basic groups by conventional chemical methods. Generally, the preparation method of such salts is to react these compounds in the form of free acids or bases with stoichiometric appropriate bases or acids in water or organic solvents or a mixture of both.

[0126] Unless otherwise specified, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereoisomers and tautomers.

[0127] 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, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereoisomer-enriched mixtures, all of which mixtures are within the scope of the present application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present application.

[0128] Unless otherwise specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.

[0129] Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" are caused by the inability of double bonds or single bonds of ring carbon atoms to rotate freely.

[0130] Unless otherwise specified, the term "diastereoisomer" refers to stereoisomers that have two or more chiral centers and are not mirror images of each other.

[0131] Unless otherwise specified, "(+)" represents dextrorotation, "(-)" represents levorotation, and "(±)" represents racemization.

[0132] Unless otherwise specified, a solid wedge bond and a dashed wedge bond represent the absolute configuration of a stereocenter, a solid straight bond and a dashed straight bond represent the relative configuration of a stereocenter, and a wavy line represents a solid wedge bond or a dashed wedge bond or a wavy line represents a solid straight bond and a dashed straight bond

[0133] The compounds of the present application may exist in specific forms. Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to different functional group isomers that are in dynamic equilibrium at room temperature and can rapidly interconvert. If tautomers are possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0134] Unless otherwise specified, the terms "enriched in one isomer", "isomer enrichment", "enriched in one enantiomer", or "enantiomer enrichment" mean that the content of one isomer or enantiomer is less than 100%, and the content of this 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%.

[0135] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" refer 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%, then the isomer or enantiomer excess (ee value) is 80%.

[0136] The optically active (R)- and (S)-isomers as well as D and L isomers can be prepared by chiral synthesis, 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 mixture of diastereomers 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), it forms a diastereomeric salt with a suitable optically active acid or base, and then the diastereomers are resolved by conventional methods well 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 employs a chiral stationary phase and optionally in combination with chemical derivatization (such as formation of carbamates from amines).

[0137] The compounds of the present application may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound can be labeled with a radioactive isotope, 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 deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with the non-deuterated drugs, deuterated drugs have advantages such as reducing toxic and side effects, increasing drug stability, enhancing efficacy, and prolonging the biological half-life of the drug. All transformations of the isotopic composition of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.

[0138] Unless otherwise specified, the term "C 1-3 alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl includes C 1-2 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C 1-3 alkyl include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0139] Unless otherwise specified, the term "halogen" or "halogen atom" by itself or as part of another substituent represents a fluorine, chlorine, bromine or iodine atom.

[0140] The term "optionally" or "optionally" means that the subsequent described event or condition may but does not necessarily occur, and the description includes the case where the described event or condition occurs and the case where the described event or condition does not occur.

[0141] The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, and the substituent may include a variant of deuterium and hydrogen, as long as the valence state of the specific 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, and unless otherwise specified, the type and number of substituents may be arbitrary based on what is chemically feasible. The "when each certain group is optionally substituted" means that any of the groups in the aforementioned structure is optionally substituted; for example, when "E2 is selected from -(CH2) n -、-(CH2) p C(O)-, -O(CH2) q -、-O(CH2) r C(O)-, -CH2CH=CH- and -(CH2) s NHC(O)-, each CH2 is optionally replaced by 1 or 2 R b "Substituted" means that any CH2 in the optional group of E2 is optionally replaced by 1 or 2 R b replace.

[0142] 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, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0143] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0144] 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.

[0145] When a substituent is vacant, it means that the substituent is not present, for example, when X in AX is vacant, it means that the structure is actually A. When the listed linking group does not specify its connection direction, its connection 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 reading from left to right to form Combinations of said linking groups, substituents and / or their variants are only permitted if such combinations result in stable compounds.

[0146] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including from n to n + m carbons, such as C 1-12 including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 , also includes any range from n to n + m, such as 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.

[0147] 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, the embodiments formed by their combination with other chemical synthesis methods, and equivalent replacement methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present application.

[0148] The structures of the compounds of the present application can be confirmed by conventional methods well-known to those skilled in the art. If the present application relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the diffraction intensity data of the cultivated single crystal is collected with a Bruker D8 venture diffractometer, the light source is CuKα radiation, scanning mode: scanning, after collecting the relevant data, the crystal structure is further analyzed by the direct method (Shelxs97), and the absolute configuration can be confirmed.

[0149] The solvents used in this application are commercially available. The following abbreviations are used in this application: aq represents water; eq represents equivalent; min represents minute; M represents mol / L; DCM represents dichloromethane; PE represents petroleum ether; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, an amine protecting group; Boc represents tert-butoxycarbonyl, an amine protecting group; r.t. represents room temperature; O / N represents overnight; THF represents tetrahydrofuran; Boc2O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; SOCl2 represents thionyl chloride; IPAm represents isopropylamine; mp represents melting point.

[0150] Technical effects

[0151] The compounds of this application have significant stimulatory activity on guanylate cyclase and have good pharmacokinetic properties including clearance rate, half-life and oral bioavailability by gavage. Specific embodiments

[0152] The present application will be 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 specific embodiments thereof have also been disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0153] Example 1

[0154]

[0155] Synthesis route:

[0156]

[0157] Step 1: Synthesis of compound 001_2

[0158] Under room temperature and nitrogen protection, ethyl ethoxymethylenephosphonate (112.51 g, 322.96 mmol) and compound 001_1 (25 g, 215.30 mmol) were dissolved in chloroform (250 mL). The reaction mixture was heated to 70 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. Methyl tert-butyl ether (100 mL) was added to the obtained residue, stirred for 10 minutes, filtered, and the filtrate was collected. The solvent was removed by concentration under reduced pressure. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 50 / 1, volume ratio). Compound 001_2 was obtained. 11H NMR (400 MHz, DMSO-d6) δ: 6.64 (d, J = 1.6 Hz, 1H), 4.22 - 4.14 (m, 4H), 2.18 (d, J = 1.6 Hz, 3H), 1.24 (q, J = 7.2 Hz, 6H).

[0159] Step 2: Synthesis of Compound 001_3

[0160] At room temperature, dissolve Compound 001_2 (23 g, 123.52 mmol) in ethanol (150 mL), add wet palladium / carbon (15 g, purity: 10%), and stir the reaction mixture at 15 °C for 12 hours under a hydrogen atmosphere (15 psi). After completion of the reaction, filter. Collect the filtrate and concentrate it under reduced pressure to remove the solvent. The obtained crude product is separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 20 / 1, v / v) to obtain Compound 001_3.

[0161] Step 3: Synthesis of Compound 001_4

[0162] At room temperature, dissolve Compound 001_3 (8.6 g, 45.69 mmol) in carbon tetrachloride (180 mL), add N-bromosuccinimide (8.13 g, 45.69 mmol) and benzoyl peroxide (553.38 mg, 2.28 mmol), and heat the reaction mixture to 75 °C and stir for 12 hours. After completion of the reaction, cool to room temperature, filter, collect the filtrate, and concentrate it under reduced pressure to remove the solvent. The obtained crude product is separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 50 / 1, v / v) to obtain Compound 001_4. 1 1H NMR (400 MHz, DMSO-d6) δ: 4.23 - 4.13 (m, 2H), 4.12 - 4.00 (m, 2H), 3.31 (q, J = 16.8 Hz, 2H), 1.96 (s, 3H), 1.27 - 1.15 (m, 6H).

[0163] Step 4: Synthesis of Compound 001_5

[0164] At room temperature, malononitrile (2.6 g, 39.31 mmol) was dissolved in tetrahydrofuran (50 mL), and potassium tert-butoxide (44.92 mL, 1 M tetrahydrofuran solution) was added. The reaction mixture was stirred at 15 °C for 0.5 h. At room temperature, compound 001_4 (10 g, 37.44 mmol) was dissolved in tetrahydrofuran (100 mL). The reaction mixture was heated to 75 °C, and the above reaction mixture was added dropwise with stirring. The reaction mixture was stirred at 75 °C for 12 h. After the reaction was completed, it was cooled to room temperature, and the pH was adjusted to 3 - 4 with 2 M dilute hydrochloric acid aqueous solution, and then extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed successively with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 0 / 1, volume ratio) to obtain compound 001_5. 1 H NMR (400 MHz, DMSO-d6) δ: 5.35 (s, 1H), 4.20 (q, J = 7.2 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 2.96 - 2.76 (m, 2H), 1.46 (s, 3H), 1.23 - 1.17 (m, 6H).

[0165] Step 5: Synthesis of intermediate 001_9

[0166] Under room temperature and nitrogen protection, compound 001_8 (250 g, 1.42 mol) was dissolved in acetonitrile (2.5 L), and 1-hydroxypyrrolidine-2,5-dione (172.10 g, 1.50 mol) and N,N′-dicyclohexylmethanediimine (299.71 g, 1.45 mol) were added. The reaction mixture was stirred at 20 °C for 4 h. After the reaction was completed, the reaction solution was filtered, and the filter cake was rinsed with acetonitrile (3 L). The filtrate was collected and concentrated under reduced pressure to remove the solvent to obtain compound 001_9. 1 H NMR (400 MHz, CDCl3) δ: 8.53 (d, J = 3.2 Hz, 1H), 8.16 (dd, J = 3.0, 7.4 Hz, 1H), 2.93 (s, 4H).

[0167] Step 6: Synthesis of intermediate 001_10

[0168] Under room temperature and nitrogen protection, compound 001_9 (155 g, 568.56 mmol) was dissolved in tetrahydrofuran (300 mL), and ammonia water (564.20 g, 4.02 mol, purity: 25%) was added. The reaction mixture was stirred at 20 °C for 5 hours. After the reaction was completed, ethyl acetate (300 mL × 3) was added to the reaction solution for extraction, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. Intermediate compound 001_10 was obtained. 1 H NMR (400 MHz, DMSO-d6) δ: 8.52 (d, J = 2.8 Hz, 1H), 8.10 (s, 1H), 7.99 (dd, J = 2.8, 8.0 Hz, 1H), 7.88 (s, 1H).

[0169] Step 7: Synthesis of intermediate 001_11

[0170] Under room temperature and nitrogen protection, compound 001_10 (99 g, 567.14 mmol) was dissolved in dichloromethane (200 mL). The reaction mixture was cooled to 0 °C, triethylamine (126.26 g, 1.25 mol) was added, and then trifluoroacetic anhydride (190.59 g, 907.42 mmol) was slowly added dropwise. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 7 - 8, and liquid separation was performed. The aqueous phase was extracted with dichloromethane (1500 mL × 3), and the organic phases were combined. The organic phase was successively dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 50 / 1 - 10 / 1, volume ratio) to obtain compound 001_11.

[0171] Step 8: Synthesis of intermediate 001_12

[0172] Under room temperature and nitrogen protection, compound 001_11 (104 g, 664.35 mmol) was dissolved in n-butanol (1 L), and hydrazine hydrate (339.59 g, 6.65 mol, purity: 98%) was added. The reaction mixture was heated to 120 °C and stirred for 2 hours. After the reaction was completed, it was cooled to room temperature, and a solid precipitated. Water (1 L) was added to the reaction solution, and it was stirred for 1 hour. Then it was filtered, and the filter cake was collected. The filter cake was concentrated under reduced pressure to remove the solvent, and intermediate 001_12 was obtained.

[0173] Step 9: Synthesis of intermediate 001_13

[0174] Under room temperature and nitrogen protection, compound 001_12 (137 g, 900.55 mmol) was dissolved in tetrahydrofuran (3 L). The reaction mixture was cooled to 0 °C, and boron trifluoride diethyl etherate (383.44 g, 2.70 mol, 333.43 mL) was slowly added dropwise. After cooling to -10 °C, a solution of isoamyl nitrite (137.14 g, 1.17 mol) in tetrahydrofuran (358 mL) was slowly added. The reaction mixture was stirred at -10 °C for 1 hour. Then, methyl tert-butyl ether (3 L) was added to the reaction mixture, and a solid precipitated. The solid was filtered, and the filter cake was collected. The filter cake was added portionwise to a solution of sodium iodide (175.48 g, 1.17 mol) in acetone (3 L) at 0 °C. The reaction mixture was stirred at 20 °C for 1 hour. After the reaction was completed, the reaction solution was poured into ice water (3 L), and extracted with ethyl acetate (800 mL × 3). The organic phases were combined. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 20 / 1 - 10 / 1, volume ratio) to obtain intermediate 001_13. 1 H NMR (400 MHz, DMSO_d6) δ: 14.24 (s, 1H), 8.60 - 8.64 (m, 1H), 7.86 (dd, J = 2.6, 8.4 Hz, 1H).

[0175] Step 10: Synthesis of intermediate 001_14

[0176] At room temperature, compound 001_13 (97 g, 368.81 mmol) was dissolved in N,N-dimethylformamide (1 L). o-Fluorobenzyl chloride (53.32 g, 368.81 mmol) and cesium carbonate (132.18 g, 405.69 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature. Half-saturated brine (1 L) was added to the reaction solution, and after stirring for 10 minutes, ethyl acetate (1.2 L) was added. The layers were separated, and the organic phase was collected. The organic phase was washed with half-saturated brine (1 L × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was dispersed in methyl tert-butyl ether (240 mL), stirred for 30 minutes, filtered, and the filter cake was collected. The filter cake was concentrated under reduced pressure to remove the solvent to obtain intermediate 001_14. 1 H NMR (400 MHz, DMSO_d6) δ: 8.65 - 8.73 (m, 1H), 7.91 (dd, J = 2.8, 8.0 Hz, 1H), 7.32 - 7.40 (m, 1H), 7.11 - 7.25 (m, 3H), 5.72 (s, 2H).

[0177] Step 11: Synthesis of intermediate 001_15

[0178] At room temperature, compound 001_14 (25 g, 67.36 mmol) was dissolved in N,N-dimethylformamide (750 mL) and methanol (250 mL). Triethylamine (30.72 g, 303.63 mmol) and cyclopent-2,4-dien-1-yl(diphenyl)phosphine dichloromethane dichloropalladium ferrocene (3.45 g, 4.72 mmol) were added. The reaction mixture was purged with carbon monoxide three times, and then reacted at 80 °C for 12 hours under a carbon monoxide atmosphere (15 psi). After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the solvent. The obtained crude product was dissolved in methyl tert-butyl ether (200 mL) and stirred for 30 minutes. The mixture was filtered, and the filter cake was collected and concentrated under reduced pressure to remove the solvent, obtaining intermediate 001_15. 1 H NMR (400 MHz, DMSO_d6) δ: 8.74 - 8.80 (m, 1H), 8.25 (dd, J = 2.8, 8.4 Hz, 1H), 7.34 - 7.41 (m, 1H), 7.20 - 7.31 (m, 2H), 7.13 - 7.20 (m, 1H), 5.84 (s, 2H), 3.92 (s, 3H).

[0179] Step 12: Synthesis of the hydrochloride salt of compound 001_6

[0180] At room temperature, ammonium chloride (33.51 g, 626.52 mmol) was suspended in toluene (580 mL). A toluene solution of trimethylaluminum (2 M, 300.73 mL) was added. After the reaction mixture was heated to 80 °C, compound 001_15 (38 g, 125.30 mmol) was added. The reaction mixture was stirred at 80 °C for 30 minutes, then heated to 110 °C and stirred for 1.5 hours. The reaction mixture was cooled to 20 - 40 °C, methanol (73.02 mL) was added, and then dilute hydrochloric acid (3 M, 801.94 mL) (below 40 °C) was added. The mixture was heated to 80 °C and stirred for 30 minutes, then cooled to 0 °C and stirred for 30 minutes. The mixture was filtered, and the filter cake was collected. The filter cake was rinsed with water (85 mL) and concentrated under reduced pressure to remove the solvent, obtaining the hydrochloride salt of intermediate 001_6. 1 H NMR (400 MHz, DMSO_d6) δ: 9.40 - 9.78 (d, J = 24.4 Hz, 4H), 8.85 (m, 1H), 8.57 (dd, J = 2.4, 8.8 Hz, 1H), 7.35 - 7.43 (m, 1H), 7.28 - 7.35 (m, 1H), 7.20 - 7.28 (m, 1H), 7.13 - 7.20 (m, 1H), 5.89 (s, 2H).

[0181] Step 13: Synthesis of compound 001_7

[0182] At room temperature, the hydrochloride of compound 001_6 (450 mg, 1.39 mmol) was dissolved in tert-butanol (13 mL), compound 001_5 (554.03 mg, 2.20 mmol) and potassium carbonate (768.46 mg, 5.56 mmol) were added, and the reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, water (20 mL) was added to the reaction solution, and it was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The obtained crude product was separated by column chromatography (eluent: dichloromethane / ethanol = 1 / 0 - 20 / 1, volume ratio) to obtain compound 001_7.

[0183] Step 14: Synthesis of compound 001

[0184] At room temperature, compound 001_7 (600 mg, 1.22 mmol) was dissolved in toluene (12 mL), trimethylaluminum (1.82 mL, 2 M toluene solution) was added, and the reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, methanol (738.05 μL) was added dropwise below 40 °C, and then 3 N aqueous hydrochloric acid solution (825.80 μL) was added dropwise. The mixture was heated to 80 °C and stirred for 10 minutes. Then the reaction mixture was cooled to 0 - 5 °C and stirred for 30 minutes, filtered, the filter cake was collected, the filter cake was rinsed with water (5 mL), and the solvent was removed by concentration under reduced pressure. The obtained crude product was dissolved in dimethyl sulfoxide (6 mL), and the filtrate was separated by preparative HPLC (mobile phase: acetonitrile / water; neutral system: 10 mM NH4HCO3), and the obtained crude product was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). Compound 001 was obtained. MS-ESI m / z: 448.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 11.36 (s, 1H), 11.12 (s, 1H), 8.77 - 8.66 (m, 2H), 7.41 - 7.33 (m, 1H), 7.28 - 7.20 (m, 2H), 7.18 - 7.13 (m, 1H), 5.84 (s, 2H), 2.99 (d, J = 15.6 Hz, 1H), 2.54 (d, J = 2.0 Hz, 1H), 1.38 (s, 3H).

[0185] Example 2

[0186]

[0187] Synthetic route:

[0188]

[0189] Step 1: Synthesis of Compound 002_2

[0190] At room temperature, the hydrochloride salt of Compound 001_6 (8.5 g, 26.26 mmol) was dissolved in N,N-dimethylformamide (40 mL), and triethylamine (3.99 g, 39.39 mmol) was added. The reaction mixture was heated to 85 °C, and a solution of Compound E-2-(phenylazo)malononitrile (8.94 g, 52.52 mmol) dissolved in N,N-dimethylformamide (40 mL) was added dropwise. The reaction mixture was stirred at 100 °C for 4 hours. Then it was cooled to 25 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed successively with water (30 mL) and methanol (15 mL), and the filter cake was collected. Compound 002_2 was obtained.

[0191] Step 2: Synthesis of Compound 002_3

[0192] At 25 °C, wet palladium-carbon (6 g, purity: 10%) was placed in a pre-dried reaction flask, then N,N-dimethylformamide (90 mL) was added to moisten it, and then Compound 002_2 (12 g, 26.23 mmol) was added. Hydrogen was displaced three times, and the reaction was stirred for 12 hours under hydrogen (15 psi). After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with methanol (150 mL × 3). The organic phases were combined and concentrated under reduced pressure to remove the solvent. Ethanol (30 mL) was added to the obtained crude product and stirred for 30 minutes, then filtered, and the filter cake was collected. The solvent was removed by concentration under reduced pressure to obtain Compound (002_3). 1 H NMR (400 MHz, DMSO-d6) δ: 8.85 (dd, J = 2.8, 8.8 Hz, 1H), 8.62 (s, 1H), 7.95 (s, 1H), 7.39 - 7.31 (m, 1H), 7.26 - 7.10 (m, 2H), 5.86 (s, 2H), 5.74 (s, 1H), 4.04 (s, 1H), 2.91 - 2.87 (m, 1H), 2.89 (s, 1H), 2.73 (s, 2H).

[0193] Step 3: Synthesis of Compound 002_4

[0194] At room temperature, compound 002_3 (1.8 g, 4.89 mmol) was dissolved in ethanol (40 mL), and 1,4-dioxane-2,3-diol (1.17 g, 9.77 mmol) was added. The reaction mixture was stirred at 15 °C for 12 hours. 1,4-Dioxane-2,3-diol (0.6 g) was added additionally, and the reaction mixture was stirred at 15 °C for 12 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. Methyl tert-butyl ether (20 mL) was added to the obtained residue, and the mixture was stirred for 10 minutes, filtered, and the filtrate was collected. The solvent was removed by concentration under reduced pressure. Compound 002_4 was obtained. 1 H NMR (400 MHz, DMSO-d6) δ: 9.10 (d, J = 1.6 Hz, 1H), 8.90 (dd, J = 2.8, 8.8 Hz, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.77 - 8.73 (m, 1H), 8.61 (s, 1H), 8.46 (s, 1H), 7.43 - 7.33 (m, 1H), 7.30 - 7.21 (m, 2H), 7.19 - 7.14 (m, 1H), 5.88 (s, 2H).

[0195] Step 4: Synthesis of the hydrochloride salt of compound 002_5

[0196] At room temperature, compound 002_4 (1.3 g, 3.33 mmol) was dissolved in ethanol (60 mL). The reaction mixture was cooled to 0 °C, and sodium borohydride (1.26 g, 3.330 mmol) was added. The reaction mixture was stirred at 15 °C for 0.5 hour. Subsequently, the reaction mixture was cooled to 0 °C, and sodium borohydride (377.99 mg, 9.99 mmol) was added additionally. The reaction mixture was stirred at 15 °C for 2 hours. After the reaction was completed, the reaction solution was cooled to 0 °C, and then concentrated hydrochloric acid was added dropwise to adjust the pH to 3 - 4. The solvent was removed by concentration under reduced pressure. The obtained residue was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.05% HCl) to obtain the hydrochloride salt of compound 002_5.

[0197] Step 5: Synthesis of compound 002

[0198] Under room temperature and nitrogen protection, the hydrochloride of compound 002_5 (58 mg, 134.62 μmol, HCl) was dissolved in tetrahydrofuran (2 mL). The reaction mixture was cooled to 0 °C, and a solution of methyl chloroformate p-nitrophenyl ester (27.13 mg, 134.62 μmol) dissolved in tetrahydrofuran (1 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours. Then N,N-diisopropylethylamine (34.80 mg, 269.24 μmol) was added, and the reaction mixture was stirred at 15 °C for 2 hours. The reaction system was concentrated under reduced pressure to obtain an oil. N,N-dimethylformamide (1 mL) was added, and nitrogen was displaced three times. The reaction system was heated to 120 °C and stirred for 12 hours. Then it was further heated to 140 °C and stirred for 16 hours. After the reaction was completed, it was cooled to room temperature. After dissolving with dimethyl sulfoxide, it was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.05% HCl) to obtain compound 002. MS-ESI m / z: 421.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 11.39 (s, 1H), 8.69 (d, J = 1.6 Hz, 1H), 8.64 (dd, J = 2.6, 8.8 Hz, 1H), 7.67 (s, 1H), 7.40 - 7.31 (m, 1H), 7.27 - 7.20 (m, 2H), 7.18 - 7.11 (m, 1H), 5.79 (s, 2H), 3.84 (t, J = 5.0 Hz, 2H), 3.60 (s, 2H).

[0199] Example 3

[0200]

[0201] Synthetic route:

[0202]

[0203] Step 1: Synthesis of compound 003_2

[0204] Under room temperature and nitrogen protection, compound 003_1 (50 g, 499.42 mmol), p-methoxybenzyl chloride (312.86 g, 2.00 mol, 272.05 mL), and potassium hydroxide (140.11 g, 2.50 mol) were dissolved in toluene (900 mL). The reaction mixture was heated to 110 °C and stirred for 12 hours. Then, toluene was removed by concentration under reduced pressure. The resulting residue was dissolved in methanol (1 L), and then a solution of potassium hydroxide (49.88 g, 888.97 mmol) in water (500 mL) was added. Then, the reaction solution was heated to 85 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. Water (800 mL) was added to the residue, and it was washed with methyl tert-butyl ether (500 mL × 3). The organic phase was discarded. The aqueous phase was adjusted to pH 2 with 12N concentrated hydrochloric acid and then extracted with dimethyltetrahydrofuran (800 mL × 2). The combined organic phases were washed successively with saturated brine (800 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. Compound 003_2 was obtained. 1 H NMR (400 MHz, CDCl3) δ: 7.29 (s, 2H), 6.90 (d, J = 8.8 Hz, 2H), 4.41 - 4.52 (m, 2H), 3.83 (s, 3H), 3.55 (t, J = 6.0 Hz, 2H), 2.65 - 2.76 (m, 1H), 2.01 - 2.12 (m, 1H), 1.69 - 1.79 (m, 1H), 1.23 (d, J = 7.2 Hz, 3H).

[0205] Step 2: Synthesis of compound 003_3

[0206] Under room temperature and nitrogen protection, compound 003_2 (117 g, 491.02 mmol) was dissolved in dichloromethane (1 L). Then, ethanol (226.21 g, 4.91 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (112.95 g, 589.23 mmol), and 4-dimethylaminopyridine (7.20 g, 58.92 mmol) were added successively. The reaction mixture was stirred at 20 °C for 12 hours. Then, the solvent was removed by concentration under reduced pressure. The resulting residue was diluted with ethyl acetate (100 mL), washed with water (100 mL), then washed with 10% aqueous citric acid solution (150 mL × 3), and then washed with saturated brine (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 2 / 3, volume ratio) to obtain compound 003_3. 1H NMR (400MHz, CDCl3) δ: 7.26 (d, J=8.8Hz, 2H), 6.88 (d, J=8.8Hz, 2H), 4.42 (s, 2H), 4.11 (q, J=7.2Hz, 2H), 3.81 (s, 3H), 3.519-3 .432 (m, 2H), 2.68-2.57 (m, 1H), 2.07-1.95 (m, 1H), 1.69 (dd, J=6.4, 14.0Hz, 1H), 1.24 (t, J=7.2Hz, 3H), 1.17 (d, J=7.2Hz, 3H).

[0207] Step 3: Synthesis of Compound 003_4

[0208] Under nitrogen at 20°C, diisopropylamine (16.93 g, 167.27 mmol) was added to anhydrous tetrahydrofuran (450 mL). The reaction solution was then cooled to -78°C, followed by the slow dropwise addition of a 2.5 M solution of n-butyllithium in tetrahydrofuran (72.99 mL). The reaction mixture was warmed to 0°C and stirred for 0.5 hours. The reaction mixture was then cooled to -78°C, and compound 003_3 (40.5 g, 152.07 mmol) was dissolved in anhydrous tetrahydrofuran (160 mL) and added dropwise to the reaction solution. The reaction mixture was stirred at -78°C for 1 hour, and carbon tetrabromide (75.64 g, 228.10 mmol) was dissolved in anhydrous tetrahydrofuran (220 mL) and added dropwise to the reaction system. The reaction mixture was warmed to 20°C and stirred for 10.5 hours. After completion of the reaction, the reaction mixture was poured into an aqueous ammonium chloride solution (1.5 L) and extracted with ethyl acetate (600 mL x 2). The organic phases were combined, washed sequentially with saturated brine (800 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 8 / 1, volume ratio) to obtain compound 003_4.

[0209] Step 4: Synthesis of Compound 003_5

[0210] Under 20 °C and nitrogen protection, potassium tert-butoxide (191.18 mL, 1 M solution in tetrahydrofuran) was added to a solution of malononitrile (11.48 g, 173.80 mmol) in tetrahydrofuran (100 mL). Then the reaction solution was heated to 75 °C. A solution of compound 003_4 (30 g, 86.90 mmol) in tetrahydrofuran (250 mL) was added dropwise to the above reaction solution. The reaction mixture was stirred at 75 °C for 12 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The resulting residue was diluted with water (100 mL), and the pH was adjusted to 6 with 1 N dilute hydrochloric acid. Then it was extracted with 2-methyltetrahydrofuran (200 mL × 3). The combined organic phases were successively washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 6 / 1, volume ratio) to obtain compound 003_5.

[0211] Step 5: Synthesis of compound 003_6

[0212] At room temperature and under nitrogen protection, the hydrochloride of compound 001_6 (3.76 g, 13.09 mmol) was dissolved in tert-butanol (40 mL), and compound 003_5 (6.83 g, 20.68 mmol) and potassium carbonate (5.95 g, 43.06 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. The residue was added with water (100 mL) and diluted with ethyl acetate (100 mL). The organic phase was collected by liquid separation, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The combined organic phases were successively washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate was removed by concentration under reduced pressure. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1, volume ratio) to obtain compound 003_6.

[0213] Step 6: Synthesis of compound 003_7

[0214] At room temperature and under nitrogen protection, compound 003_6 (3 g, 5.25 mmol) was dissolved in dichloromethane (30 mL) and water (3 mL). The reaction mixture was cooled to 0 °C, and 2,3-dichloro-5,6-dicyano-p-benzoquinone (2.38 g, 10.50 mmol) was added. The reaction mixture was stirred at 20 °C for 12 hours. After the reaction was completed, the reaction solution was poured into water (50 mL), and extracted with ethyl acetate (40 mL × 3). The combined organic phases were successively washed with semi-saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The obtained crude product was separated by reverse-phase MPLC (mobile phase: methanol / hydrochloric acid aqueous solution = 2∶1 - 1∶2, volume ratio) to obtain compound 003_7.1 1H NMR (400 MHz, DMSO-d6) δ: 11.02 (s, 1H), 8.91 - 8.69 (m, 2H), 7.42 - 7.32 (m, 1H), 7.29 - 7.10 (m, 4H), 5.83 (s, 2H), 3.23 - 3.01 (m, 2H), 2.37 - 2.25 (m, 1H), 2.01 - 1.87 (m, 1H), 1.32 (s, 3H).

[0215] Step 7: Synthesis of Compound 003_8

[0216] Under nitrogen protection at room temperature, dissolve Compound 003_7 (330 mg, 676.38 μmol) in anhydrous tetrahydrofuran (3 mL), add diisopropylethylamine (349.66 mg, 2.71 mmol) and 4-dimethylaminopyridine (8.26 mg, 67.64 μmol), and dropwise add methanesulfonyl chloride (116.22 mg, 1.01 mmol) to the reaction mixture at 0 °C. Stir the reaction mixture at 0 °C for 2 hours. After the reaction is completed, pour the reaction solution into saturated sodium bicarbonate aqueous solution (20 mL) at 0 °C, extract with ethyl acetate (30 mL × 3), combine the organic phases, wash the organic phases successively with semi-saturated brine (30 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. The obtained crude product is separated by column chromatography (eluent: 2-methyltetrahydrofuran / ethyl acetate = 1 / 0 - 4 / 1, volume ratio) to obtain Compound 003_8.

[0217] Step 8: Synthesis of Compound 003

[0218] Dissolve Compound 003_8 (240 mg, 453.24 mmol) in tetrahydrofuran (6 mL) at room temperature, cool the reaction mixture to -65 °C, add lithium bis(trimethylsilyl)amide (1.36 mL, 1 M tetrahydrofuran solution), and stir the reaction mixture at -65 °C to -15 °C for 12 hours. After the reaction is completed, add 3 M dilute hydrochloric acid aqueous solution dropwise to the reaction solution until pH = 5 - 6. Then add water (5 mL), extract with ethyl acetate (25 mL × 3), combine the organic phases, wash the organic phases successively with saturated brine (3 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. The obtained crude product is separated by preparative HPLC (mobile phase: acetonitrile / water; neutral system: 10 mM NH4HCO3). Compound 003 is obtained. MS-ESI m / z: 434.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ: 10.82 (s, 1H), 8.81 - 8.58 (m, 2H), 7.64 (s, 1H), 7.32 - 7.41 (m, 1H), 7.29 - 7.09 (m, 3H), 5.81 (s, 2H), 3.53 - 3.43 (m, 1H), 1.84 (d, J = 12.0 Hz, 1H), 1.39 - 1.19 (m, 4H).

[0219] Example 4

[0220]

[0221] Synthetic route:

[0222]

[0223] Step 1: Synthesis of compound 004_1

[0224] Under room temperature and nitrogen protection, dissolve compound 002_3 (1 g, 2.71 mmol) in N,N-dimethylformamide (30 mL), add ethyl bromoacetate (476.05 mg, 2.85 mmol) and N,N-diisopropylethylamine (350.87 mg, 2.71 mmol). Stir the reaction mixture at 15 °C for 8 hours. Then heat the reaction mixture to 50 °C and stir for 4 hours. After the reaction is completed, cool to room temperature, add semi-saturated brine (30 mL) to the reaction system, extract with ethyl acetate (50 mL × 3), combine the organic phases, wash successively with semi-saturated brine (30 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. The obtained crude product is separated by column chromatography (eluent: dichloromethane / methanol = 1 / 0 - 10 / 1, volume ratio) to obtain compound 004_1.

[0225] Step 2: Synthesis of compound 004_2

[0226] Under room temperature and nitrogen protection, dissolve compound 004_1 (0.6 g, 1.32 mmol) in THF (10 mL). Cool the reaction mixture to 0 °C, add triphosgene (129.30 mg, 435.71 μmol) and triethylamine (400.81 mg, 3.96 mmol). Stir the reaction mixture at 0 °C for 0.5 h, then warm it up to 25 °C and continue the reaction for 2 h. After the reaction is completed, quench the reaction by adding saturated aqueous sodium bicarbonate solution (15 mL), dilute with ethyl acetate (20 mL), separate the layers, collect the organic phase, extract the aqueous phase with ethyl acetate (30 mL × 3), combine the organic phases, wash successively with saturated brine (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. The obtained crude product is separated by column chromatography (eluent: dichloromethane / methanol = 1 / 0 - 10 / 1, v / v) to obtain compound 004_2.

[0227] Step 3: Synthesis of compound 004

[0228] Under room temperature and nitrogen protection, dissolve compound 004_2 (0.58 g, 1.21 mmol) in acetic acid (8 mL) and xylene (8 mL). Heat the reaction mixture to 160 °C and stir the reaction system at 160 °C for 24 h. After the reaction is completed, cool to room temperature and concentrate under reduced pressure to remove the solvent. The obtained crude product is separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) to obtain compound 004. MS-ESI m / z: 435.1 [M + H] + . 1 1H NMR (400 MHz, DMSO-d6) δ: 11.90 (s, 1H), 11.70 (s, 1H), 8.78 - 8.59 (m, 2H), 7.37 (q, J = 7.2 Hz, 1H), 7.32 - 7.12 (m, 3H), 5.81 (s, 2H), 4.59 (s, 2H).

[0229] Examples 5 and 6

[0230]

[0231] Synthesis route:

[0232]

[0233] Synthesis of compounds 005 and 006

[0234] Compound 001 (200 mg, 447.03 μmol) was purified by a chiral column (column type: DAICEL CHIRALCEL OJ (250 mm * 30 mm, 10 μm); mobile phase: [Neu-ACN]; B(ACN) %: 50% - 50%, 8 min). Compounds 005 and 006 were obtained.

[0235] 005 (retention time: 1.80 min): MS-ESI m / z: 448.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 11.37 (s, 1H), 11.13 (s, 1H), 8.87 - 8.61 (m, 2H), 7.41 - 7.34 (m, 1H), 7.29 - 7.19 (m, 2H), 7.19 - 7.14 (m, 1H), 5.84 (s, 2H), 3.00 (d, J = 15.6 Hz, 1H), 2.53 (s, 1H), 1.37 (s, 3H).

[0236] 006 (retention time: 1.93 min): MS-ESI m / z: 448.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 11.37 (s, 1H), 11.13 (s, 1H), 8.87 - 8.61 (m, 2H), 7.41 - 7.34 (m, 1H), 7.29 - 7.19 (m, 2H), 7.19 - 7.13 (m, 1H), 5.84 (s, 2H), 3.00 (d, J = 15.6 Hz, 1H), 2.53 (s, 1H), 1.37 (s, 3H).

[0237] Example 7

[0238]

[0239] Synthesis route:

[0240]

[0241] Step 1: Synthesis of compound 007_2

[0242] Under room temperature and nitrogen protection, dissolve compound 007_1 (1 g, 7.68 mmol, 970.87 μL) in toluene (20 mL), then add malononitrile (507.61 mg, 7.68 mmol), glacial acetic acid (461.44 mg, 7.68 mmol) and ammonium acetate (592.30 mg, 7.68 mmol). Stir the reaction mixture at 20 °C for 12 hours. Add additional malononitrile (101.52 mg, 1.54 mmol), and heat the reaction mixture to 50 °C and stir for 12 hours. After the reaction is completed, pour the reaction solution into water (50 mL), dilute with ethyl acetate (50 mL), separate the layers, and collect the organic phase. Extract the aqueous phase with ethyl acetate (50 mL × 3). Combine the organic phases, wash with saturated brine (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. The obtained crude product is separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 10 / 1, volume ratio) to obtain compound 007_2. 1 H NMR (400 MHz, DMSO-d6) δ: 4.14 (q, J = 7.2 Hz, 2H), 3.74 (s, 2H), 2.34 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H).

[0243] Step 2: Synthesis of compound 007_3

[0244] Under room temperature and nitrogen protection, dissolve ethyl bromoacetate (1.87 g, 11.22 mmol) in anhydrous tetrahydrofuran (12 mL), add compound 007_2 (500 mg, 2.81 mmol), dichlorotitanocene (72.69 mg, 280.60 μmol), and activated zinc powder (366.97 mg, 5.61 mmol). Stir the reaction mixture at 25 °C for 12 hours. After the reaction is completed, add 1 N dilute hydrochloric acid (15 mL) to the reaction system to quench the reaction, dilute with ethyl acetate (25 mL), separate the layers, and collect the organic phase. Extract the aqueous phase with ethyl acetate (25 mL × 3). Combine the organic phases, wash with saturated brine (30 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. The obtained crude product is separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 6 / 1, volume ratio) to obtain compound 007_3. 1 H NMR (400 MHz, CDCl3) δ: 5.00 (s, 1H), 4.17 (d, J = 7.2 Hz, 4H), 2.75 (s, 4H), 1.43 (s, 3H), 1.29 (t, J = 7.2 Hz, 6H).

[0245] Step 3: Synthesis of compound 007

[0246] Under room temperature and nitrogen protection, compound 007_3 (24 mg, 90.13 μmol) was dissolved in tert-butanol (1 mL), and the hydrochloride of 001_6 (29.18 mg, 90.13 μmol) and potassium carbonate (24.91 mg, 180.25 μmol) were added. The reaction mixture was stirred at 85 °C for 12 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. The obtained crude product was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) to obtain compound 007. MS-ESI m / z: 462.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 11.25 (s, 2H), 9.00 (dd, J = 2.8, 8.8 Hz, 1H), 8.77 - 8.63 (m, 1H), 7.41 - 7.32 (m, 1H), 7.28 - 7.09 (m, 3H), 5.82 (s, 2H), 2.80 (d, J = 16.0 Hz, 2H), 2.54 (d, J = 15.6 Hz, 2H), 1.12 (s, 3H).

[0247] Example 8

[0248]

[0249] Synthetic route

[0250]

[0251] Step 1: Synthesis of compound 008_2

[0252] At room temperature, compound 008_1 (10 g, 69.36 mmol) was dissolved in anhydrous toluene (200 mL), and malononitrile (5.04 g, 76.30 mmol), glacial acetic acid (4.17 g, 69.36 mmol) and ammonium acetate (5.35 g, 69.36 mmol) were added. The reaction mixture was stirred at 15 °C for 12 hours. After the reaction was completed, water (200 mL) was added to the reaction solution, and then it was adjusted to pH = 3 - 4 with 3 M dilute hydrochloric acid, and then extracted with ethyl acetate (200 mL × 3). The organic phases were combined. The organic phase was washed successively with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 1, volume ratio) to obtain compound 008_2. 11H NMR (400 MHz, DMSO-d6) δ: 4.08 (q, J = 7.2 Hz, 2H), 2.84 - 2.76 (m, 2H), 2.72 - 2.64 (m, 2H), 2.26 (s, 3H), 1.19 (t, J = 6.8 Hz, 3H).

[0253] Step 2: Synthesis of Compound 008_3

[0254] Under nitrogen protection at room temperature, ethyl bromoacetate (1.66 g, 9.97 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), and compound 008_2 (958 mg, 4.98 mmol) and titanocene dichloride (129.11 mg, 498.40 μmol) were added. Activated zinc powder (651.81 mg, 9.97 mmol) was added, and the reaction mixture was stirred at 25 °C for 12 hours. After the reaction was completed, 1 N dilute hydrochloric acid (20 mL) was added to quench the reaction. The mixture was separated with water (50 mL) and ethyl acetate (50 mL), and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 1, v / v) to obtain compound 008_3.

[0255] Step 3: Synthesis of Compound 008_4

[0256] Under nitrogen protection at room temperature, compound 008_3 (100 mg, 356.74 μmol) and the hydrochloride salt of compound 001_6 (57.74 mg, 178.37 μmol) were dissolved in tert-butanol (3.5 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (67.89 mg, 445.92 μmol) was added. The reaction mixture was heated to 85 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude products from two batches were combined. Ethyl acetate (25 mL) and water (15 mL) were added to the obtained crude product for dilution, and it was extracted with ethyl acetate (25 mL × 3). The combined organic phases were successively washed with saturated brine (35 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by preparative thin-layer chromatography (developing agent: DCM∶MeOH = 15∶1, v / v) to obtain compound 008_4.

[0257] Step 4: Synthesis of Compound 008

[0258] Under room temperature and nitrogen protection, intermediate 008_4 (42 mg, 80.53 μmol) was dissolved in anhydrous toluene (1 mL), and a toluene solution of trimethylaluminum (2.5 M, 96.64 μL) was added. The reaction mixture was heated to 110 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, 1 N dilute hydrochloric acid (1 mL) and methanol (5 mL) were added to the reaction solution for dilution, and the reaction mixture was stirred at 25 °C for 0.5 hour. The solvent was removed by concentration under reduced pressure, and the obtained crude product was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) to obtain the crude product of compound 008. The crude product was separated by preparative HPLC again (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) to obtain compound 008. MS-ESI m / z: 476.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 11.21 (s, 1H), 10.57 (s, 1H), 9.32 (dd, J = 2.8, 9.2 Hz, 1H), 8.70 (s, 1H), 7.35 (d, J = 3.2 Hz, 1H), 7.28 - 7.19 (m, 1H), 7.17 - 7.08 (m, 2H), 5.84 (s, 2H), 2.77 - 2.65 (m, 2H), 2.54 (s, 2H), 2.01 (d, J = 10.8 Hz, 1H), 1.89 (s, 1H), 1.19 (s, 3H).

[0259] Example 9

[0260]

[0261] Synthetic route:

[0262]

[0263] Step 1: Synthesis of intermediate 009_1

[0264] At room temperature, compound 012_3 (4.2 g, 11.61 mmol, hydrochloride) was dissolved in tert-butanol (84 mL), and then potassium carbonate (6.42 g, 46.45 mmol) and 003_5 (6.14 g, 18.58 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, water (200 mL) was added to quench the reaction, and it was extracted with ethyl acetate (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 2, volume ratio) to obtain compound 009_1.

[0265] Step 2: Synthesis of Intermediate 009_2

[0266] At room temperature, dissolve compound 009_1 (2.4 g, 3.94 mmol) in dichloromethane (12 mL) and water (1.2 mL). Cool the reaction mixture to 0 °C, and then slowly add 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (1.07 g, 4.73 mmol). Stir the reaction mixture at room temperature for 12 hours. After completion of the reaction, add saturated aqueous sodium bicarbonate solution (30 mL), and extract with dichloromethane (50 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. The obtained residue is separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 4, v / v) to obtain compound 009_2.

[0267] Step 3: Synthesis of Intermediate 009_3

[0268] At 0 °C, dissolve 009_2 (1.08 g, 2.04 mmol, purity: 93%) in tetrahydrofuran (20 mL) and dichloromethane (20 mL). Then add methanesulfonyl chloride (234.08 mg, 2.04 mmol), N,N-diethylacetamide (792.30 mg, 6.13 mmol), and 4-dimethylaminopyridine (24.96 mg, 204.34 μmol). Warm the reaction mixture to room temperature and stir for 1 hour. After completion of the reaction, quench the reaction with saturated aqueous sodium bicarbonate solution (30 mL), and extract with ethyl acetate (40 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. The obtained residue is separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 4, v / v) to obtain compound 009_3.

[0269] Step 4: Synthesis of Intermediate 009

[0270] At room temperature, dissolve compound 009_3 (500 mg, 2.73 mmol) in tetrahydrofuran (5 mL). Then cool to -78 °C and add a solution of lithium bis(trimethylsilyl)amide (2.73 mL, 1 M, 2.73 mmol) in tetrahydrofuran. Warm the reaction mixture to 25 °C, and then add hexamethylphosphoric triamide (489.98 mg, 2.73 mmol). Stir the reaction mixture at 25 °C for 12 hours. After completion of the reaction, quench the reaction with saturated aqueous ammonium chloride solution (20 mL), and extract with ethyl acetate (40 mL). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. The obtained residue is separated by preparative HPLC (mobile phase: acetonitrile / water; neutral system: 10 mM NH4HCO3) to obtain compound 009. MS-ESI m / z: 472.0 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ: 8.74 - 8.68 (s, 1H), 8.68 - 8.63 (m, 1H), 7.67 - 7.59 (m, 1H), 4.91 - 4.80 (m, 2H), 3.58 - 3.42 (m, 2H), 3.05 - 2.89 (m, 2H), 1.89 - 1.82 (m, 1H), 1.37 - 1.33 (m, 3H), 1.32 - 1.23 (m, 1H).

[0271] Example 10

[0272]

[0273] Synthesis route:

[0274]

[0275] Step 1: Synthesis of compound 010_2

[0276] At room temperature, dissolve compound 001_13 (10 g, 38.02 mmol) in N,N-dimethylformamide (20 mL), then add cesium carbonate (37.16 g, 114.06 mmol) and 2,6-difluorobenzyl bromide (7.87 g, 38.02 mmol). Heat the reaction mixture to 80 °C and stir for 2 hours. After completion of the reaction, cool to room temperature, add water (200 mL) to quench the reaction, and extract with ethyl acetate (200 mL). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 2, v / v) to obtain compound 010_2.

[0277] Step 2: Synthesis of compound 010_3

[0278] At room temperature, dissolve compound 010_2 (8.5 g, 21.84 mmol) in N,N-dimethylformamide (100 mL) and methanol (40 mL), then add 1,1-bis(diphenylphosphino)ferrocene palladium chloride (1.12 g, 1.53 mmol). Stir the reaction solution under a carbon monoxide atmosphere (15 psi) at 80 °C for 12 hours. After completion of the reaction, cool to room temperature, filter, and remove the solvent under reduced pressure from the filtrate. The obtained crude product is separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 7 / 3, v / v) to obtain compound 010_3.

[0279] Step 3: Synthesis of the hydrochloride salt of compound 010_4

[0280] Under nitrogen at room temperature, ammonium chloride (298.04 mg, 5.57 mmol) was suspended in toluene (4 mL). A toluene solution of trimethylaluminum (2.67 mL, 2 M, 5.35 mmol) was then added. The reaction mixture was heated to 80°C, followed by the addition of compound 010_3 (358 mg, 1.11 mmol). The reaction mixture was stirred at 80°C for 0.5 hour, then heated to 110°C and stirred for 1.5 hours. After completion, the temperature was lowered to 30°C, methanol (639.34 μL, 16.05 mmol) and 3N dilute hydrochloric acid (7.13 mL, 21.34 mmol) were added, and the temperature was raised to 80°C, stirred for 0.5 hour, and then cooled to 0°C, stirred for 0.5 hour. The reaction mixture was filtered, the filter cake rinsed with toluene (10 mL), and the solvent removed under reduced pressure to provide the hydrochloride salt of compound 010_4.

[0281] Step 4: Synthesis of Compound 010

[0282] Under nitrogen at room temperature, compound 007_3 (76.00 mg, 285.40 μmol) was dissolved in tert-butanol (2.5 mL). Compound 010_4 (97.53 mg, 285.40 μmol, hydrochloride) and potassium carbonate (78.89 mg, 570.80 μmol) were added sequentially. The reaction mixture was heated to 85°C and stirred at 85°C for 16 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) to yield compound 010. MS-ESI m / z: 480.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ: 11.25 (s, 2H), 9.00 (dd, J=2.8, 9.0Hz, 1H), 8.72 (dd, J=1.6, 2.8Hz, 1H), 7.53 -7.41 (m, 1H), 7.23-7.03 (m, 2H), 5.84 (s, 2H), 2.80 (d, J=16.0Hz, 2H), 2.58-2.52 (m, 2H), 1.12 (s, 3H).

[0283] Example 11

[0284]

[0285] Synthesis route:

[0286]

[0287] Step 1: Synthesis of compound 011

[0288] Under nitrogen at room temperature, compound 010_4 (250 mg, 731.60 μmol, hydrochloride) and compound 008_3 (328.13 mg, 1.17 mmol) were dissolved in tert-butanol (5 mL). 1,8-diazabicycloundec-7-ene (278.44 mg, 1.83 mmol) was added. The reaction mixture was heated to 95°C and stirred for 2 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The crude product was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) to yield compound 011. MS-ESI m / z: 494.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ: 11.20 (s, 1H), 10.56 (s, 1H), 9.41-9.17 (m, 1H), 8.70 (s, 1H), 7.55-7.36 (m, 1H), 7.29-6.92 (m, 2H), 5.95 -5.70 (m, 2H), 2.82-2.61 (m, 2H), 2.58-2.53 (m, 1H), 2.44-2.32 (m, 1H), 2.08-1.97 (m, 1H), 1.90-1.79 (m, 1H), 1.25-1.15 (m, 3H).

[0289] Example 12

[0290]

[0291] Synthesis route:

[0292]

[0293] Step 1: Synthesis of compound 012_1

[0294] At room temperature, compound 001_13 (10 g, 38.02 mmol) was dissolved in N,N-dimethylformamide (50 mL), followed by the addition of potassium carbonate (15.76 g, 114.06 mmol) and 1,1,1,2,2-pentafluoro-4-iodobutane (52.08 g, 190.11 mmol). The reaction mixture was heated to 40°C and stirred for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, quenched with water (200 mL), and extracted with ethyl acetate (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to remove the solvent to obtain a crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-3 / 1, volume ratio) to obtain compound 012_1.

[0295] Step 2: Synthesis of compound 012_2

[0296] At room temperature, compound 012_1 (7.5 g, 18.29 mmol) was dissolved in N,N-dimethylformamide (60 mL) and methanol (20 mL). Then, triethylamine (7.4 g, 73.16 mmol) was added, followed by 1,1-bis(diphenylphosphino)ferrocene palladium chloride (936.76 mg, 1.28 mmol). The reaction mixture was stirred at 80 °C for 12 hours under a carbon monoxide atmosphere (15 psi). After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 7 / 3, v / v) to obtain compound 012_2.

[0297] Step 3: Synthesis of the hydrochloride salt of compound 012_3

[0298] At room temperature and under nitrogen protection, ammonium chloride (4.31 g, 80.60 mmol) was suspended in toluene (55 mL). Then, a toluene solution of trimethylaluminum (38.69 mL, 2 M, 77.37 mmol) was added. The reaction mixture was heated to 80 °C, and then compound 012_2 (5.5 g, 16.12 mmol) was added. The reaction mixture was stirred for 0.5 hour and then heated to 110 °C and stirred for 1.5 hours. Subsequently, the temperature was lowered to 30 °C, and methanol (9.39 mL, 232.12 mmol) and 3 M aqueous hydrochloric acid solution (103.16 mL, 309.49 mmol) were added in sequence. Then, the mixture was heated to 80 °C and stirred for 0.5 hour, and then cooled to 0 °C and stirred for 0.5 hour. After the reaction was completed, the reaction mixture was filtered, and the filter cake was washed with toluene (20 mL) and concentrated under reduced pressure to obtain compound 012_3.

[0299] Step 4: Synthesis of compound 012

[0300] At room temperature and under nitrogen protection, compound 012_3 (100 mg, 276.49 μmol, hydrochloride salt) and compound 007_3 (117.80 mg, 442.39 μmol) were dissolved in tert-butanol (2 mL). Potassium carbonate (95.53 mg, 691.23 μmol) was added, and the reaction mixture was heated to 85 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature. The solvent was removed by concentration under reduced pressure, and the obtained crude product was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) to obtain compound 012. MS-ESI m / z: 500.1 [M + H] + . 11H NMR (400 MHz, DMSO-d6) δ: 11.27 (s, 2H), 9.01 (dd, J = 2.8, 9.2 Hz, 1H), 8.73 (s, 1H), 4.90 (t, J = 6.4 Hz, 2H), 3.06 - 2.90 (m, 2H), 2.82 (d, J = 16.0 Hz, 2H), 2.57 (d, J = 16.0 Hz, 2H), 1.14 (s, 3H).

[0301] Example 13

[0302]

[0303] Synthetic route:

[0304]

[0305] Step 1: Synthesis of Intermediate 013_2

[0306] At room temperature, N,N-diisopropylethylamine (32.09 g, 317.13 mmol) was dissolved in tetrahydrofuran (400 mL). The reaction mixture was cooled to -78 °C, and a solution of n-butyllithium (129.85 mL, 2.5 M) in n-hexane was added. The reaction mixture was warmed to 0 °C and stirred for 0.5 h. Then the reaction mixture was cooled to -78 °C, and ethyl propionate (32.09 g, 317.13 mmol) and a solution of compound 013_1 (25 g, 249.71 mmol) in tetrahydrofuran (30 mL) were added successively. The reaction mixture was stirred at -78 °C for 1 h. After completion of the reaction, the reaction solution was poured into saturated aqueous ammonium chloride solution (800 mL), and liquid separation was carried out. The aqueous phase was extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed successively with saturated brine (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 10 / 1, volume ratio). Intermediate 013_2 was obtained. 1 1H NMR (400 MHz, CDCl3) δ: 4.14 (qd, J = 7.2, 2.0 Hz, 4H), 2.48 (dd, J = 14.0, 7.2 Hz, 1H), 2.30 - 2.37 (m, 2H), 1.92 - 2.04 (m, 1H), 1.73 - 1.84 (m, 1H), 1.24 - 1.29 (m, 6H), 1.18 (d, J = 6.8 Hz, 3H).

[0307] Step 2: Synthesis of Intermediate 013_3

[0308] At room temperature, intermediate 013_2 (10.2 g, 50.43 mmol) was dissolved in chlorobenzene (200 mL). N-Bromosuccinimide (8.98 g, 50.43 mmol) and azobisisobutyronitrile (828.16 mg, 5.04 mmol) were added. The reaction mixture was heated to 75 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filtrate was collected and the solvent was removed by concentration under reduced pressure. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 24 / 1, volume ratio) to obtain intermediate 013_3. 1 H NMR (400 MHz, CDCl3) δ: 4.25 (q, J = 7.2 Hz, 2H), 4.15 - 4.19 (m, 2H), 2.45 - 2.55 (m, 3H), 2.35 - 2.41 (m, 1H), 1.91 (s, 3H), 1.28 - 1.36 (m, 6H).

[0309] Step 3: Synthesis of intermediate 013_4

[0310] Under nitrogen protection at 20 °C, malononitrile (3.45 g, 52.29 mmol) was dissolved in tetrahydrofuran (260 mL). A solution of potassium tert-butoxide (59.76 mL, 1 M) in tetrahydrofuran was added. The reaction mixture was stirred at 20 °C for 0.5 hour, then heated to 75 °C, and a solution of intermediate 013_3 (14 g, 49.80 mmol) in tetrahydrofuran (20 mL) was added dropwise. The reaction mixture was stirred at 75 °C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (400 mL), diluted with ethyl acetate (200 mL), and the organic phase was separated by liquid-liquid extraction. The aqueous phase was adjusted to pH 3 - 5 with 1 N dilute hydrochloric acid aqueous solution and then extracted with ethyl acetate (300 mL × 2). The combined organic phases were washed successively with saturated brine (400 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 50 / 1, volume ratio) to obtain intermediate 013_4. 1 H NMR (400 MHz, CDCl3) δ: 4.28 (q, J = 6.8 Hz, 2H), 4.22 (s, 1H), 4.16 (q, J = 7.2 Hz, 2H), 2.34 - 2.40 (m, 2H), 2.15 - 2.21 (m, 2H), 1.56 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H).

[0311] Step 4: Synthesis of intermediate 013_5

[0312] Under room temperature and nitrogen protection, compound 010_4 (1.0 g, 2.93 mmol, hydrochloride) and intermediate 013_4 (1.25 g, 4.68 mmol) were dissolved in tert-butanol (10 mL), potassium carbonate (2.02 g, 14.63 mmol) was added, and the reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, the solvent was removed by concentration under reduced pressure, water (40 mL) and ethyl acetate (40 mL) were added to the obtained residue for dilution, the organic phase was collected after liquid separation, and the aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed successively with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by concentration under reduced pressure. The obtained crude product was separated by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0 - 1 / 1, volume ratio) to obtain intermediate 013_5. 1 H NMR (400 MHz, DMSO_d6) δ: 11.09 (s, 1H), 8.85 (dd, J = 2.8, 8.8 Hz, 1H), 8.71 (s, 1H), 7.51 - 7.42 (m, 1H), 7.29 - 7.22 (m, 1H), 7.19 - 7.16 (m, 1H), 6.90 (s, 2H), 5.80 (s, 2H), 3.91 (q, J = 7.2 Hz, 2H), 2.44 - 2.35 (m, 1H), 1.98 - 1.81 (m, 3H), 1.34 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H).

[0313] Step 5: Synthesis of compound 013

[0314] At room temperature, intermediate 013_5 (180 mg, 342.54 μmol) was dissolved in toluene (4 mL), a toluene solution of trimethylaluminum (513.81 μL, 2 M) was added, and the reaction mixture was heated to 110 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and a dilute hydrochloric acid aqueous solution (2.19 mL, 3 M) was added dropwise below 40 °C. The mixture was stirred at room temperature for 1 hour, then the mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL), and the aqueous phase was further extracted with 2-methyltetrahydrofuran (20 mL × 3). The combined organic phases were washed successively with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate by concentration under reduced pressure. The obtained crude product was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). Compound 013 was obtained. MS-ESI m / z: 480.1 [M + H] + [[ID=ON]]. 11H NMR (400 MHz, DMSO-d6) δ: 11.48 (s, 1H), 10.90 (s, 1H), 9.09 (dd, J = 2.8, 9.2 Hz, 1H), 8.74 - 8.72 (m, 1H), 7.53 - 7.43 (m, 1H), 7.15 (t, J = 8.0 Hz, 2H), 5.83 (d, J = 3.2 Hz, 2H), 2.80 (t, J = 6.4 Hz, 2H), 2.16 - 2.08 (m, 1H), 2.02 - 1.92 (m, 1H), 1.32 (s, 3H).

[0315] Example 14

[0316]

[0317] Synthetic route:

[0318]

[0319] Synthesis of Compound 014

[0320] Under room temperature and nitrogen protection, Intermediate 008_3 (223.22 mg, 796.30 μmol) and Intermediate 012_3 (180 mg, 497.69 μmol, hydrochloride) were dissolved in tert-butanol (3.6 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (189.42 mg, 1.24 mmol) was added. The reaction mixture was heated to 95 °C and stirred for 36 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. The obtained crude product was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) to obtain Compound 014. MS-ESI m / z: 514.1 [M + H] + . 1 1H NMR (400 MHz, DMSO-d6) δ: 11.20 (s, 1H), 10.55 (s, 1H), 9.29 (dd, J = 2.8, 9.2 Hz, 1H), 8.69 (s, 1H), 4.87 (t, J = 6.8 Hz, 2H), 3.02 - 2.86 (m, 3H), 2.80 - 2.64 (m, 2H), 2.26 (d, J = 15.6 Hz, 1H), 2.08 - 1.96 (m, 1H), 1.90 - 1.80 (m, 1H), 1.18 (s, 3H).

[0321] Example 15

[0322]

[0323] Synthetic route:

[0324]

[0325] Step 1: Synthesis of Intermediate 015_1

[0326] Under room temperature and nitrogen protection, 010_4 (2.5 g, 7.32 mmol, hydrochloride) and 003_5 (3.87 g, 11.71 mmol) were dissolved in tert-butanol (50 mL), potassium carbonate (4.04 g, 29.28 mmol) was added, and the reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, the solvent was removed by reduced pressure concentration, water (80 mL) and ethyl acetate (80 mL) were added to the obtained residue for liquid separation, and the aqueous phase was extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed successively with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate was removed by reduced pressure concentration. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1, volume ratio) to obtain Compound 015_1. 1 H NMR (400 MHz, DMSO_d6) δ: 10.92 (s, 1H), 8.85 (dd, J = 2.8, 8.8 Hz, 1H), 8.72 (s, 1H), 7.51 - 7.42 (m, 1H), 7.14 (t, J = 8.0 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.79 (s, 2H), 6.67 (d, J = 8.4 Hz, 2H), 5.81 (s, 2H), 4.20 (d, J = 11.6 Hz, 1H), 4.06 (d, J = 11.6 Hz, 1H), 3.51 (s, 3H), 3.16 - 3.09 (m, 1H), 3.07 - 2.99 (m, 1H), 2.43 - 2.35 (m, 1H), 2.13 - 2.02 (m, 1H), 1.31 (s, 3H).

[0327] Step 2: Synthesis of Intermediate 015_2

[0328] At room temperature, intermediate 015_1 (1.8 g, 3.05 mmol) was dissolved in dichloromethane (36 mL) and water (3.6 mL). The reaction mixture was cooled to 0 °C, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (831.68 mg, 3.66 mmol) was added portionwise. The reaction mixture was stirred at 15 °C for 12 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. Saturated aqueous sodium bicarbonate solution (100 mL) was added to the residue, and it was diluted with 2-methyltetrahydrofuran (100 mL). After liquid separation, the organic phase was collected. The aqueous phase was extracted with 2-methyltetrahydrofuran (100 mL × 2). The combined organic phases were washed successively with saturated aqueous sodium bicarbonate solution (100 mL × 2) and saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 2, volume ratio) to obtain intermediate 015_2. 1 H NMR (400 MHz, DMSO_d6) δ: 10.88 (s, 1H), 8.85 (dd, J = 2.8, 8.8 Hz, 1H), 8.71 (dd, J = 1.6, 2.8 Hz, 1H), 7.52 - 7.42 (m, 1H), 7.19 - 7.11 (m, 2H), 6.81 (s, 2H), 5.80 (s, 1H), 3.11 - 3.16 (m, 1H), 3.07 - 2.99 (m, 1H), 2.35 - 2.22 (m, 1H), 1.85 - 1.75 (m, 1H), 1.30 (s, 3H).

[0329] Step 3: Synthesis of intermediate 015_3

[0330] At room temperature, intermediate 015_2 (1 g, 2.13 mmol) was dissolved in dichloromethane (10 mL) and tetrahydrofuran (10 mL). The reaction mixture was cooled to 0 °C, methylsulfonyl chloride (248.91 mg, 2.17 mmol) was added, then N,N-diisopropylethylamine (825.98 mg, 6.39 mmol) and 4-dimethylaminopyridine (26.03 mg, 213.03 μmol) were added. The reaction mixture was stirred at 20 °C for 1 hour. After completion of the reaction, the reaction solution was poured into saturated aqueous sodium bicarbonate solution (100 mL) at 0 °C, and it was extracted with ethyl acetate (100 mL). The combined organic phases were washed successively with saturated brine (400 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 2, volume ratio) to obtain intermediate 015_3. 11H NMR (400 MHz, DMSO-d6) δ: 11.08 (s, 1H), 8.85 (dd, J = 2.8, 8.8 Hz, 1H), 8.71 (dd, J = 1.2, 2.8 Hz, 1H), 7.52 - 7.42 (m, 1H), 7.14 (t, J = 8.0 Hz, 2H), 6.93 (s, 2H), 5.81 (s, 2H), 4.03 - 3.95 (m, 1H), 3.84 - 3.75 (m, 1H), 2.98 (s, 3H), 2.60 - 2.53 (m, 1H), 2.24 - 2.15 (m, 1H), 1.34 (s, 3H).

[0331] Step 4: Synthesis of Compound 015

[0332] At room temperature, dissolve intermediate 015_3 (500 mg, 913.23 μmol) in tetrahydrofuran (10 mL), add hexamethylphosphoric triamide (507.32 mg, 2.83 mmol), cool the reaction mixture to -78 °C, add a solution of lithium bis(trimethylsilyl)amide (2.83 mL, 1 M) in tetrahydrofuran, warm the reaction mixture to 20 °C and stir for 5 hours. After completion of the reaction, pour the reaction solution into ice water (30 mL), dilute with ethyl acetate (30 mL), separate the layers and collect the organic phase. Extract the aqueous phase with ethyl acetate (30 mL × 3). Combine the organic phases, wash successively with saturated brine (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent. The obtained crude product was separated by preparative HPLC (mobile phase: acetonitrile / water; neutral system: 10 mM NH4HCO3). Compound 015 was obtained. MS-ESI m / z: 452.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ: 8.72 (dd, J = 1.6, 2.8 Hz, 1H), 8.65 (dd, J = 2.8, 8.8 Hz, 1H), 7.65 (d, J = 4.4 Hz, 1H), 7.52 - 7.42 (m, 1H), 7.15 (t, J = 8.0 Hz, 2H), 5.80 (s, 2H), 3.57 - 3.39 (m, 2H), 1.83 (d, J = 12.0 Hz, 1H), 1.32 (s, 3H), 1.29 - 1.19 (m, 1H).

[0333] Example 16

[0334]

[0335] Synthetic route:

[0336]

[0337] Step 1: Synthesis of Intermediate 016_1

[0338] At room temperature, dissolve compound 012_3 (750 mg, 2.07 mmol, hydrochloride) in tert-butanol (15 mL), add compound 001_5 (784.68 mg, 3.11 mmol) and potassium carbonate (1.15 g, 8.29 mmol). Heat the reaction mixture to 80 °C and stir for 12 hours. After completion of the reaction, cool to room temperature, add water (30 mL) to the reaction solution, and extract with ethyl acetate (30 mL × 3). Combine the organic phases, wash the organic phases successively with saturated brine (30 mL), dry over anhydrous sodium sulfate, and filter. Concentrate the filtrate under reduced pressure to remove the solvent. The resulting residue is separated by column chromatography (eluent: dichloromethane / methanol = 1 / 0 - 50 / 1, volume ratio) to obtain compound 016_1. 1 1H NMR (400 MHz, DMSO-d6) δ: 11.04 (s, 1H), 8.84 (dd, J = 2.8, 8.8 Hz, 1H), 8.72 - 8.69 (m, 1H), 6.88 (s, 2H), 4.87 (t, J = 6.4 Hz, 2H), 3.92 - 3.82 (m, 2H), 3.37 (d, J = 16.4 Hz, 1H), 3.06 - 2.90 (m, 2H), 2.80 (d, J = 16.4 Hz, 1H), 1.33 (s, 3H), 0.99 (t, J = 7.1 Hz, 3H).

[0339] Step 2: Synthesis of Compound 0016

[0340] At room temperature, dissolve compound 016_1 (50 mg, 94.09 μmol) in toluene (1 mL), add a toluene solution of trimethylaluminum (141.13 μL, 2 M). Heat the reaction mixture to 80 °C and stir for 12 hours. After completion of the reaction, cool to room temperature, and dropwise add dilute hydrochloric acid aqueous solution (602.17 μL, 3 M) below 40 °C. Stir the mixture at 15 °C for 10 minutes. Then add water (3 mL) to the mixture and extract with 2-methyltetrahydrofuran (3 mL × 3). Combine the organic phases, wash successively with saturated brine (3 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent. The resulting residue is separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% M HCl) to obtain compound 016. MS-ESI m / z: 486.1 [M + H] + . 11H NMR (400 MHz, DMSO-d6) δ: 11.39 (s, 1H), 11.13 (s, 1H), 8.76 - 8.74 (m, 1H), 8.73 - 8.69 (m, 1H), 4.91 (t, J = 6.8 Hz, 2H), 3.08 - 2.82 (m, 1H), 2.54 (s, 1H), 1.39 (s, 3H).

[0341] Example 17

[0342]

[0343] Synthetic route:

[0344]

[0345] Step 1: Synthesis of intermediate 017_1

[0346] At room temperature, dissolve compound 010_4 (1.1 g, 3.22 mmol, hydrochloride) in tert-butanol (20 mL), add compound 001_5 (1.22 g, 4.83 mmol) and potassium carbonate (1.78 g, 12.88 mmol). The reaction mixture is heated to 80 °C and stirred for 12 hours. After the reaction is completed, it is cooled to room temperature. Water (30 mL) is added to the reaction solution, and the mixture is extracted with ethyl acetate (30 mL × 3). The combined organic phases are washed successively with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to remove the solvent. The resulting residue is separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 2 / 1, volume ratio) to obtain compound 017_1. 1 1H NMR (400 MHz, DMSO-d6) δ: 11.02 (s, 1H), 8.83 (dd, J = 2.8, 8.8 Hz, 1H), 8.72 - 8.70 (m, 1H), 7.53 - 7.41 (m, 1H), 7.14 (t, J = 8.0 Hz, 2H), 6.86 (s, 2H), 5.80 (s, 2H), 3.85 (t, J = 6.8 Hz, 2H), 3.37 (s, 1H), 2.77 (d, J = 16.8 Hz, 1H), 1.30 (s, 3H), 0.97 (t, J = 7.2 Hz, 3H).

[0347] Step 2: Synthesis of intermediate 017

[0348] At room temperature, compound 017_1 (300 mg, 568.37 μmol) was dissolved in toluene (6 mL), and a toluene solution of trimethylaluminum (852.55 μL, 2 M) was added. The reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, and aqueous hydrochloric acid solution (3.64 mL, 3 M) was added dropwise below 40 °C. The mixture was stirred at 15 °C for 10 minutes. Then water (10 mL) was added to the mixture, and it was extracted with 2-methyltetrahydrofuran (20 mL × 3). The organic phases were combined, washed successively with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate was removed by concentration under reduced pressure. The obtained residue was separated by preparative HPLC (mobile phase: acetonitrile / water; neutral system: 10 mM NH4HCO3) to obtain compound 017. MS-ESI m / z: 466.0 [M+H] + . 1 HNMR(400MHz, DMSO_d6) δ: 11.36(s, 1H), 11.12(s, 1H), 8.76(s, 1H), 8.70(dd, J = 3.2, 9.6Hz, 1H), 7.52 - 7.43(m, 1H), 7.15(t, J = 8.0Hz, 2H), 5.84(s, 2H), 2.98(d, J = 16.0Hz, 1H), 2.52(s, 1H), 1.36(s, 3H).

[0349] Example 18

[0350]

[0351] Synthetic route:

[0352]

[0353] Step 1: Synthesis of intermediate 018_1

[0354] Under room temperature and nitrogen protection, intermediate 012_3 (750 mg, 2.07 mmol, hydrochloride) and intermediate 013_4 (883.53 mg, 3.32 mmol) were dissolved in tert-butanol (20 mL), potassium carbonate (1.15 g, 8.29 mmol) was added, and the reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, the solvent was removed by concentration under reduced pressure, water (100 mL) and ethyl acetate (100 mL) were added to the obtained residue for dilution, the organic phase was collected after liquid separation, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed successively with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate was removed by concentration under reduced pressure. The obtained crude product was separated by column chromatography (eluent: dichloromethane / ethanol = 1 / 0 - 19 / 1, volume ratio) to obtain intermediate 018_1.1 H NMR (400 MHz, DMSO-d6) δ: 11.11 (s, 1H), 8.85 (dd, J = 2.8, 8.8 Hz, 1H), 8.71 - 8.69 (m, 1H), 6.92 (s, 2H), 4.87 (t, J = 6.8 Hz, 2H), 3.95 - 3.87 (m, 2H), 3.06 - 2.87 (m, 2H), 2.46 - 2.39 (m, 1H), 1.99 - 1.86 (m, 3H), 1.37 (s, 3H), 1.07 (t, J = 6.8 Hz, 3H).

[0355] Step 2: Synthesis of Compound 018

[0356] At room temperature, intermediate 018_1 (300 mg, 513.17 μmol, purity: 93.3%) was dissolved in toluene (8 mL), and a toluene solution of trimethylaluminum (769.75 μL, 2 M) was added. The reaction mixture was heated to 110 °C and stirred for 12 hours. After the reaction was completed, it was cooled to 0 °C, and dilute hydrochloric acid aqueous solution (3.28 mL, 3 M) was added dropwise. The reaction mixture was stirred at 0 °C for 0.5 hours, then the reaction mixture was poured into water (30 mL), diluted with 2-methyltetrahydrofuran (30 mL), and the organic phase was collected after liquid separation. The aqueous phase was extracted with 2-methyltetrahydrofuran (30 mL × 3). The combined organic phases were washed successively with saturated brine (40 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by preparative HPLC (mobile phase: acetonitrile / water; neutral system: 10 mM NH4HCO3). Compound 018 was obtained. MS-ESI m / z: 500.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 11.49 (s, 1H), 10.90 (s, 1H), 9.09 (dd, J = 2.8, 9.2 Hz, 1H), 8.73 - 8.71 (m, 1H), 4.90 (t, J = 6.8 Hz, 2H), 3.07 - 2.91 (m, 2H), 2.85 - 2.79 (m, 2H), 2.19 - 2.10 (m, 1H), 2.05 - 1.93 (m, 1H), 1.35 (s, 3H).

[0357] Example 19

[0358]

[0359] Synthetic route:

[0360]

[0361] Step 1: Synthesis of Intermediate 019_1

[0362] Under room temperature and nitrogen protection, the hydrochloride of intermediate 001_6 (1 g, 3.09 mmol) was dissolved in tert-butanol (20 mL), intermediate 013_4 (1.23 g, 4.63 mmol) and potassium carbonate (1.07 g, 7.72 mmol) were added, and the reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, saturated brine (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed successively with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1, ethyl acetate / 2-methyltetrahydrofuran = 20 / 1, volume ratio) to obtain intermediate 019_1. 1 H NMR (400 MHz, DMSO_d6) δ: 11.08 (s, 1H), 8.85 (dd, J = 2.6, 8.8 Hz, 1H), 8.70 (dd, J = 1.6, 2.6 Hz, 1H), 7.42 - 7.31 (m, 1H), 7.28 - 7.09 (m, 3H), 6.90 (s, 2H), 5.87 - 5.77 (m, 2H), 3.99 - 3.86 (m, 2H), 2.46 - 2.35 (m, 1H), 2.04 - 1.90 (m, 3H), 1.36 (s, 3H), 1.07 (t, J = 7.2 Hz, 3H).

[0363] Step 2: Synthesis of compound 019

[0364] At room temperature, intermediate 019_1 (260 mg, 512.32 μmol) was dissolved in toluene (6 mL), a toluene solution of trimethylaluminum (768.49 μL, 2 M) was added, and the reaction mixture was heated to 110 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, diluted with 2-methyltetrahydrofuran (10 mL), the pH was adjusted to 5 - 6 with 1 M dilute hydrochloric acid, water (5 mL) was added, and the mixture was extracted with 2-methyltetrahydrofuran (30 mL×3). The organic phases were combined, washed successively with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The obtained crude product was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). Compound 019 was obtained. MS-ESI m / z: 462.1 [M+H] +1¹H NMR (400 MHz, DMSO-d6) δ: 11.45 (s, 1H), 10.87 (s, 1H), 9.06 (dd, J = 2.8, 9.0 Hz, 1H), 8.68 (dd, J = 1.6, 2.8 Hz, 1H), 7.41 - 7.29 (m, 1H), 7.24 - 7.07 (m, 3H), 5.84 - 5.76 (m, 2H), 2.85 - 2.71 (m, 2H), 2.15 - 2.03 (m, 1H), 2.02 - 1.90 (m, 1H), 1.30 (s, 3H).

[0365] Examples 20 and 21

[0366]

[0367] Synthetic route:

[0368]

[0369] Synthesis of Compounds 020 and 021

[0370] Compound 016 (65 mg, 133.93 μmol) was separated by chiral column (column type: DAICEL CHIRALCEL OJ (250 mm * 30 mm, 10 μm); mobile phase: [Neu-ACN]; B(ACN)%: 30% - 30%, 10 min). Compounds 020 and 021 were obtained.

[0371] 020 (retention time: 1.087 min): MS-ESI m / z: 486.1 [M+H] + . 1 ¹H NMR (400 MHz, DMSO-d6) δ: 11.14 (s, 2H), 8.76 - 8.71 (m, 1H), 8.71 (dd, J = 2.0, 8.8 Hz, 1H), 4.90 (t, J = 7.2 Hz, 2H), 3.09 - 2.89 (m, 3H), 2.55 - 2.52 (m, 1H), 1.38 (s, 3H).

[0372] 021 (retention time: 1.204 min): MS-ESI m / z: 486.0 [M+H] + . 1 ¹H NMR (400 MHz, DMSO-d6) δ: 11.15 (s, 2H), 8.78 - 8.65 (m, 2H), 4.91 (t, J = 6.4 Hz, 2H), 3.08 - 2.91 (m, 3H), 2.56 - 2.52 (m, 1H), 1.38 (s, 3H).

[0373] Example 22

[0374]

[0375] Synthesis route:

[0376]

[0377] Step 1: Synthesis of intermediate 022_2

[0378] Under room temperature and nitrogen protection, 022_1 (5 g, 56.75 mmol, 4.90 mL) was placed in a dry reaction flask, and p-methoxybenzyl chloride (9.78 g, 62.43 mmol, 8.50 mL) and N,N-diisopropylethylamine (14.67 g, 113.50 mmol, 19.77 mL) were added. The reaction system was heated to 150 °C and stirred for 2 hours. After the reaction was completed, the reaction system was cooled to room temperature, allowed to stand, and the solution was separated into layers. Ethyl acetate (50 mL) and 10% sodium bisulfate solution (50 mL) were added for dilution, and the organic phase was collected by liquid separation. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (75 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 8 / 1, volume ratio). The target intermediate 022_2 was obtained. 1 H NMR (400 MHz, CDCl3) δ: 7.24 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.44 (s, 2H), 3.79 (s, 3H), 3.70 (t, J = 6.4 Hz, 2H), 2.69 (t, J = 6.2 Hz, 2H), 2.16 (s, 3H).

[0379] Step 2: Synthesis of intermediate 022_3

[0380] Under room temperature and nitrogen protection, intermediate 022_2 (5 g, 24.01 mmol) and malononitrile (1.59 g, 24.01 mmol) were dissolved in toluene (50 mL), acetic acid (1.44 g, 24.01 mmol, 1.37 mL) and ammonium acetate (1.85 g, 24.01 mmol) were added. The reaction system was heated to 50 °C and stirred for 12 hours. The reaction system was cooled to room temperature, ethyl acetate (50 mL) and saturated brine (50 mL) were added for liquid separation, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (65 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 8 / 1, volume ratio). Intermediate 022_3 was obtained. 11H NMR (400 MHz, CDCl3) δ: 7.23 (d, J = 8.8 Hz, 2H), 6.93 - 6.87 (m, 2H), 4.45 (s, 2H), 3.82 (s, 3H), 3.67 (t, J = 6.0 Hz, 2H), 2.84 (t, J = 5.8 Hz, 2H), 2.29 (s, 3H).

[0381] Step 3: Synthesis of Intermediate 022_4

[0382] Under room temperature and nitrogen protection, Intermediate 022_3 (3.40 g, 13.27 mmol), ethyl bromoacetate (4.43 g, 26.53 mmol, 2.93 mL) were dissolved in tetrahydrofuran (30 mL), dichlorotitanocene (343.63 mg, 1.33 mmol, 214.77 μL) was added, and activated zinc powder (2.60 g, 39.80 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, 40 mL of 1 M dilute hydrochloric acid was added to quench the reaction, and ethyl acetate (80 mL) was added to dilute the reaction solution. The layers were separated, and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined. The combined organic phase was washed with saturated brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 10 / 3, v / v). Intermediate 022_4 was obtained. 1 1H NMR (400 MHz, CDCl3) δ: 7.26 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.83 (s, 1H), 4.38 (s, 2H), 4.19 - 4.08 (m, 2H), 3.82 (s, 3H), 3.58 (t, J = 5.6 Hz, 2H), 2.69 - 2.54 (m, 2H), 2.13 - 1.91 (m, 2H), 1.33 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H).

[0383] Step 4: Synthesis of Intermediate 022_5

[0384] Under room temperature and nitrogen protection, intermediate 022_4 (1.40 g, 4.06 mmol) was dissolved in tert-butanol (25 mL), and 010_4 (868.18 mg, 2.54 mmol, hydrochloride), potassium carbonate (877.85 mg, 6.35 mmol) were added. The reaction mixture was heated to 85 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature. 50 mL of saturated brine was added to the reaction system to quench the reaction, and ethyl acetate (80 mL) was added for dilution. The layers were separated, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (80 mL × 3), and the organic phases were combined. The combined organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure from the filtrate. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 2 / 1, ethyl acetate / 2-methyltetrahydrofuran = 10 / 1, volume ratio). Intermediate 022_5 was obtained. 1 H NMR (400 MHz, DMSO_d6) δ: 10.62 (s, 1H), 9.06 (dd, J = 2.8, 9.2 Hz, 1H), 8.69 (dd, J = 1.6, 2.8 Hz, 1H), 7.51 - 7.43 (m, 1H), 7.17 - 7.11 (m, 4H), 6.80 - 6.77 (m, 2H), 6.65 (s, 2H), 5.81 (s, 2H), 4.28 (s, 2H), 3.63 (s, 3H), 3.45 - 3.39 (m, 2H), 2.70 - 2.65 (m, 1H), 2.45 - 2.41 (m, 1H), 1.78 - 1.71 (m, 1H), 2.23 - 2.17 (m, 1H), 1.35 (s, 3H).

[0385] Step 5: Synthesis of intermediate 022_6

[0386] Under room temperature and nitrogen protection, intermediate 022_5 (620.00 mg, 1.03 mmol) was dissolved in dichloromethane (6 mL) and water (0.6 mL). At 0 °C, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (349.76 mg, 1.54 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate aqueous solution (20 mL), and dichloromethane (30 mL × 3) was added for extraction. The organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure from the filtrate. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 5 / 4, ethyl acetate / 2-methyltetrahydrofuran = 10 / 1 - 5 / 1, volume ratio), and intermediate 022_6 was obtained. 11H NMR (400 MHz, DMSO-d6) δ: 10.60 (s, 1H), 9.05 (dd, J = 2.8, 9.2 Hz, 1H), 8.68 (dd, J = 1.6, 2.8 Hz, 1H), 7.53 - 7.39 (m, 1H), 7.16 - 7.10 (m, 2H), 6.65 (d, J = 2.8 Hz, 2H), 5.80 (s, 2H), 4.51 (t, J = 4.8 Hz, 1H), 3.43 - 3.37 (m, 2H), 2.62 (d, J = 16.0 Hz, 1H), 2.42 (d, J = 16.0 Hz, 1H), 2.05 - 1.97 (m, 1H), 1.68 - 1.60 (m, 1H), 1.35 (s, 3H).

[0387] Step 6: Synthesis of Intermediate 022_7

[0388] Under room temperature and nitrogen protection, Intermediate 022_6 (0.3 g, 620.55 μmol) was dissolved in dichloromethane (3 mL) and tetrahydrofuran (3 mL). Methanesulfonyl chloride (106.63 mg, 930.82 μmol, 72.04 μL), N,N-diisopropylethylamine (240.60 mg, 1.86 mmol, 324.26 μL), and 4-dimethylaminopyridine (7.58 mg, 62.05 μmol) were added at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate aqueous solution (30 mL) at 0 °C, and extracted with ethyl acetate (50 mL × 3). The organic phases were combined. The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure from the filtrate. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 2 / 1, ethyl acetate / 2-methyltetrahydrofuran = 10 / 1, volume ratio) to obtain Intermediate 022_7. 1 1H NMR (400 MHz, DMSO-d6) δ: 10.73 (s, 1H), 9.05 (dd, J = 2.8, 9.0 Hz, 1H), 8.69 (dd, J = 1.4, 2.8 Hz, 1H), 7.50 - 7.42 (m, 1H), 7.15 - 7.10 (m, 1H), 6.86 (s, 2H), 6.77 (s, 2H), 5.80 (s, 1H), 4.20 - 4.15 (m, 2H), 3.34 - 3.32 (m, 2H), 2.75 - 2.66 (m, 1H), 2.43 (d, J = 7.2 Hz, 2H), 2.08 - 2.07 (m, 3H), 1.62 - 1.55 (m, 2H).

[0389] Step 7: Synthesis of Compound 022

[0390] Under room temperature and nitrogen protection, intermediate 022_7 (0.28 g, 498.63 μmol) was dissolved in tetrahydrofuran (6 mL), and hexamethylphosphoric triamide (277.00 mg, 1.55 mmol, 271.57 μL) was added. The reaction system was cooled to -78 °C, and lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 1.55 mL) was added. The reaction mixture was warmed to room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was poured into ice water (30 mL), extracted with ethyl acetate (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined. The combined organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by preparative HPLC (mobile phase: acetonitrile / water; neutral system: 0.01% NH4HCO3). Compound 022 was obtained. MS-ESI m / z: 466.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 10.65 (s, 1H), 8.91 (dd, J = 2.8, 9.0 Hz, 1H), 8.68 (dd, J = 1.2, 2.4 Hz, 1H), 7.80 (s, 1H), 7.50 - 7.42 (m, 1H), 7.17 - 7.10 (m, 2H), 5.79 (s, 2H), 3.38 (d, J = 9.0 Hz, 2H), 2.43 - 2.32 (m, 1H), 1.81 (d, J = 12.8 Hz, 1H), 1.63 - 1.55 (m, 1H), 1.10 (s, 3H).

[0391] Example 23

[0392]

[0393] Synthetic route:

[0394]

[0395] Step 1: Synthesis of intermediate 023_1

[0396] Under room temperature and nitrogen protection, intermediate 022_4 (1.52 g, 4.42 mmol) was dissolved in tert-butanol (20 mL), and intermediate 012_3 (1.00 g, 2.76 mmol, hydrochloride) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.05 g, 6.91 mmol, 1.04 mL) were added. The reaction mixture was heated to 85 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, saturated brine (50 mL) and ethyl acetate (80 mL) were added to the reaction system, and the layers were separated. The organic phase was collected. The aqueous phase was extracted with ethyl acetate (80 mL × 3), and the organic phases were combined. The combined organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, and filtered. The solvent in the filtrate was removed under reduced pressure, and the resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 2 / 1, ethyl acetate / 2-methyltetrahydrofuran = 10 / 1, volume ratio). Intermediate 023_1 was obtained. MS-ESI m / z: 624.5 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.54 - 8.51 (m, 2H), 7.21 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.49 (s, 2H), 5.00 - 4.91 (m, 2H), 4.45 - 4.34 (m, 2H), 3.79 (s, 3H), 2.87 - 2.80 (m, 2H), 2.68 - 2.61 (m, 2H), 1.60 (s, 3H).

[0397] Step 2: Synthesis of intermediate 023_2

[0398] Under room temperature and nitrogen protection, intermediate 023_1 (0.67 g, 1.07 mmol) was dissolved in dichloromethane (6 mL) and water (0.6 mL), and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (365.87 mg, 1.61 mmol) was added at 0 °C. The reaction mixture was stirred at 25 °C for 12 hours. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate aqueous solution (20 mL), and extracted with dichloromethane (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent in the filtrate was removed under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 5 / 4, ethyl acetate / 2-methyltetrahydrofuran = 10 / 1 - 5 / 1, volume ratio). Intermediate 023_2 was obtained. MS-ESI m / z: 504.4 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ: 10.61 (s, 1H), 9.06 (dd, J = 2.8, 9.0 Hz, 1H), 8.68 (s, 1H), 6.69 - 6.65 (m, 2H), 4.94 - 4.84 (m, 2H), 4.53 (s, 1H), 3.42 (s, 2H), 3.00 - 2.90 (m, 2H), 2.64 (d, J = 16.4 Hz, 1H), 2.43 (s, 1H), 1.81 - 1.68 (m, 2H), 1.38 (s, 3H).

[0399] Step 3: Synthesis of Intermediate 023_3

[0400] Under room temperature and nitrogen protection, Intermediate 023_2 (0.46 g, 913.79 μmol) was dissolved in dichloromethane (5 mL) and tetrahydrofuran (5 mL). 4-Dimethylaminopyridine (11.16 mg, 91.38 μmol) was added at 0 °C, followed by methanesulfonyl chloride (157.01 mg, 1.37 mmol, 106.0 μL) and N,N-diisopropylethylamine (354.29 mg, 2.74 mmol, 477.5 μL). The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction solution was poured into saturated aqueous sodium bicarbonate (30 mL) at 0 °C, and extracted with ethyl acetate (50 mL × 3). The organic layers were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 2 / 1, ethyl acetate / 2-methyltetrahydrofuran = 10 / 1, v / v). Intermediate 023_3 was obtained. 1 1H NMR (400 MHz, DMSO-d6) δ: 10.74 (s, 1H), 9.08 - 9.04 (m, 2H), 8.69 (s, 2H), 6.80 (s, 2H), 4.87 (t, J = 6.6 Hz, 2H), 4.21 (brs, 2H), 3.14 (s, 3H), 2.78 - 2.66 (m, 2H), 2.45 - 2.42 (m, 2H), 1.37 (s, 2H).

[0401] Step 4: Synthesis of Compound 023

[0402] Under room temperature and nitrogen protection, intermediate 023_3 (0.4 g, 687.89 μmol) was dissolved in tetrahydrofuran (8 mL), hexamethylphosphoric triamide (382.14 mg, 2.13 mmol, 374.64 μL) was added, the reaction system was cooled to -78 °C, and lithium bis(trimethylsilyl)amide (1 M solution in tetrahydrofuran, 2.13 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was poured into ice water (30 mL) for quenching, extracted with ethyl acetate (30 mL), and the aqueous phase was further extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure from the filtrate. The resulting residue was purified by preparative HPLC twice (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). The target compound 023 was obtained. MS-ESI m / z: 486.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 10.84 (s, 1H), 8.89 (dd, J = 2.6, 8.8 Hz, 1H), 8.73 - 8.71 (m, 1H), 7.99 (s, 1H), 4.88 (t, J = 6.8 Hz, 2H), 3.05 - 2.93 (m, 2H), 2.67 - 2.58 (m, 2H), 2.45 (s, 1H), 1.87 (d, J = 12.8 Hz, 1H), 1.67 - 1.57 (m, 1H), 1.14 (s, 3H).

[0403] Example 24

[0404]

[0405] Synthetic route:

[0406]

[0407] Step 1: Synthesis of intermediate 024_2

[0408] Under room temperature and nitrogen protection, compound 024_1 (50 g, 314.29 mmol) was dissolved in dichloromethane (500 mL), then thionyl chloride (186.95 g, 1.57 mol) and N,N-dimethylformamide (2.3 g, 31.43 mmol) were added to the reaction system, and the reaction mixture was heated to 40 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and then concentrated again after adding toluene (200 mL). Intermediate 024_2 was obtained.

[0409] Step 2: Synthesis of intermediate 024_4

[0410] Under room temperature and nitrogen protection, lithium bis(trimethylsilyl)amide (1 M, 11.27 mL) was dissolved in tetrahydrofuran (18 mL). After cooling to -78 °C, a solution of compound 024_3 (26.05 g, 154.90 mmol) in tetrahydrofuran (150 mL) was added dropwise. After stirring at -78 °C for 1 hour, a solution of compound 024_2 (33 g, 185.88 mmol) in tetrahydrofuran (150 mL) was added dropwise. After stirring at -78 °C for 1 hour, the reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The reaction solution was quenched by pouring it into a saturated ammonium chloride aqueous solution (600 mL), and extracted with ethyl acetate (500 mL × 3). The organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 1, v / v). Intermediate 024_4 was obtained.

[0411] Step 3: Synthesis of intermediate 024_5

[0412] Under room temperature and nitrogen protection, intermediate 024_4 (17.5 g, 56.56 mmol) was dissolved in dimethyl sulfoxide (52.5 mL) in a microwave tube. Sodium chloride (3.64 g, 62.23 mmol) and water (11.2 mL) were added. The reaction was carried out at 150 °C and 12 bar for 30 minutes. The solvent was removed by concentration under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1, v / v). Intermediate 024_5 was obtained.

[0413] Step 4: Synthesis of intermediate 024_6

[0414] Under room temperature and nitrogen protection, intermediate 024_5 (11.5 g, 45.78 mmol) and aminoguanidine hydrochloride (10.12 g, 91.56 mmol, hydrochloride) were dissolved in ethylene glycol (120 mL). Then boron trifluoride diethyl etherate (14.6 g, 103.00 mmol) was added to the reaction system. The reaction mixture was heated to 120 °C and stirred for 2 hours. After the reaction was completed, it was cooled to room temperature. Water (100 mL) was added to the reaction solution, and the pH was adjusted to 11 with 1 N aqueous sodium hydroxide solution. It was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. Intermediate 024_6 was obtained.

[0415] Step 5: Synthesis of intermediate 024_7

[0416] At room temperature, intermediate 024_6 (3 g, 9.76 mmol) was dissolved in isopropanol (30 mL), and intermediate 001_5 (4.93 g, 19.53 mmol) and potassium hydroxide (821.66 mg, 14.64 mmol) were added. The reaction mixture was stirred at 80 °C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The resulting residue was separated by preparative HPLC (mobile phase: acetonitrile / water; hydrochloric acid system: 0.05% HCl). Intermediate 024_7 was obtained.

[0417] Step 6: Synthesis of Compound 024

[0418] At room temperature, intermediate 024_7 (430 mg, 0.871 mmol) was dissolved in toluene (8 mL), and a toluene solution of trimethylaluminum (2 M, 1.31 mL) was added. The reaction mixture was heated to 120 °C and reacted for 12 hours. After the reaction was completed, 1 N hydrochloric acid (8 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The resulting residue was separated by preparative HPLC (mobile phase: acetonitrile / water; hydrochloric acid system: 0.05% HCl). Compound 024 was obtained. MS-ESI m / z: 448.4 [M+H] + . 1 H NMR (400 MHz, CD3CN) δ: 9.10 - 8.97 (m, 2H), 8.83 (dd, J = 2.4, 10.0 Hz, 1H), 8.61 - 8.53 (m, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.31 - 7.25 (m, 1H), 7.14 - 7.09 (m, 2H), 4.48 (s, 2H), 2.81 - 2.66 (m, 2H), 1.47 (s, 3H).

[0419] Example 25

[0420]

[0421] Synthesis route:

[0422]

[0423] Step 1: Synthesis of Intermediate 025_1

[0424] Under room temperature and nitrogen protection, intermediate 024_6 (2 g, 6.51 mmol) was dissolved in tetrahydrofuran (25 mL) and ethanol (25 mL), then compound 013_4 (2.6 g, 9.76 mmol) and sodium ethoxide (1.11 g, 16.27 mmol) were added to the reaction system. The reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was concentrated. The obtained residue was subjected to column chromatography (eluent: dichloromethane / methanol = 1 / 0 - 9 / 1, volume ratio). Intermediate 025_1 was obtained.

[0425] Step 2: Synthesis of intermediate 025_2

[0426] Under room temperature, intermediate 025_1 (0.5 g, 0.948 mmol) was dissolved in pyridine (10 mL). The reaction mixture was stirred at 90 °C for 36 hours. After the reaction was completed, the reaction solution was concentrated. The obtained residue was subjected to preparative HPLC (mobile phase: acetonitrile / water; hydrochloric acid system: 0.05% HCl). Intermediate 025_2 was obtained. 1 H NMR (400 MHz, DMSO_d6) δ: 11.23 (s, 1H), 9.03 - 9.00 (m, 1H), 8.67 (s, 1H), 7.37 - 7.28 (m, 1H), 7.20 - 7.18 (m, 1H), 7.16 - 7.10 (m, 3H), 4.42 (s, 2H), 3.95 - 3.89 (m, 2H), 2.50 - 2.40 (m, 2H), 1.96 - 1.90 (m, 3H), 1.36 (s, 3H), 1.09 - 1.05 (m, 3H).

[0427] Step 3: Synthesis of compound 025

[0428] Under room temperature and nitrogen protection, intermediate 025_2 (39 mg, 76.85 μmol) was dissolved in a mixed solution of xylene (0.8 mL) and acetic acid (2.4 mL). The reaction mixture was heated to 140 °C and stirred for 48 hours. After the reaction was completed, the reaction solution was cooled to room temperature and the solvent was removed under reduced pressure. The obtained residue was subjected to preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.05% HCl). Compound 025 was obtained. MS-ESI m / z: 462.4 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ: 11.63 (s, 1H), 11.03 (s, 1H), 9.24 (dd, J = 10.2, 2.6 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 7.40 - 7.36 (m, 1H), 7.32 - 7.26 (m, 1H), 7.21 - 7.11 (m, 2H), 4.44 (s, 2H), 2.83 (t, J = 6.8 Hz, 2H), 2.16 - 2.09 (m, 1H), 2.00 - 1.93 (m, 1H), 1.33 (s, 3H).

[0429] Example 26

[0430]

[0431] Synthetic route:

[0432]

[0433] Step 1: Synthesis of intermediate 026_1

[0434] Under nitrogen protection, dissolve intermediate 001_7 (50 mg, 101.32 μmol) in a mixed solution of tetrahydrofuran (1 mL) and water (1 mL), then add lithium hydroxide monohydrate (8.50 mg, 202.65 μmol). The reaction mixture is reacted at room temperature for 12 hours. After the reaction is completed, the solvent is removed by concentration under reduced pressure. Then, the pH is adjusted to 4 - 5 with 3M dilute hydrochloric acid aqueous solution, and after dilution with acetonitrile, it is subjected to preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.4% HCl). Intermediate 026_1 is obtained. MS-ESI m / z: 466.1 [M + H] + . 1 1H NMR (400 MHz, DMSO-d6) δ: 10.96 (s, 1H), 8.83 (dd, J = 8.8, 2.8 Hz, 1H), 8.70 (dd, J = 2.8, 1.6 Hz, 1H), 7.41 - 7.32 (m, 1H), 7.26 - 7.11 (m, 3H), 6.98 - 6.61 (m, 2H), 5.81 (s, 2H), 3.29 (d, J = 16.8 Hz, 1H), 2.72 (d, J = 16.8 Hz, 1H), 1.30 (s, 3H).

[0435] Step 2: Synthesis of compound 026

[0436] Under room temperature and nitrogen protection, intermediate 026_1 (500 mg, 1.07 mmol) was dissolved in dioxane (8 mL), and triethylamine (166.33 mg, 1.64 mmol) and diphenylphosphoryl azide (452.35 mg, 1.64 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. It was separated by preparative HPLC (mobile phase: acetonitrile / water; neutral system: 10 mM NH4HCO3) and preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.05% HCl) successively. Compound 026 was obtained. MS-ESI m / z: 463.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 11.47 (s, 1H), 10.36 (s, 1H), 9.21 (dd, J = 9.2, 2.8 Hz, 1H), 8.68 (d, J = 1.6 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.25 - 7.18 (m, 2H), 7.17 - 7.12 (m, 1H), 5.82 (d, J = 2.4 Hz, 2H), 3.23 (d, J = 12.8 Hz, 1H), 3.12 - 3.03 (m, 1H), 1.33 (s, 3H).

[0437] Example 27

[0438]

[0439] Synthetic route:

[0440]

[0441] Step 1: Synthesis of intermediate 027_2

[0442] Under room temperature and nitrogen protection, compound 027_1 (25 g, 143.52 mmol) was dissolved in ethyl acetate (100 mL) and chloroform (100 mL), and copper(II) bromide (64.11 g, 287.04 mmol) was added. The reaction mixture was heated to 100 °C and stirred for 36 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 50 / 1, v / v). Intermediate 027_2 was obtained. 1 H NMR (400 MHz, CDCl3) δ: 4.29 (q, J = 7.2 Hz, 4H), 2.09 (s, 3H), 1.31 (t, J = 7.2 Hz, 6H).

[0443] Step 2: Synthesis of intermediate 027_3

[0444] Under room temperature and nitrogen protection, a solution of potassium tert-butoxide (1 M, 47.41 mL) in tetrahydrofuran was added dropwise to a solution of malononitrile (2.74 g, 41.49 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred at room temperature for 0.5 hour. Then the reaction mixture was added dropwise to a solution of intermediate 027_2 (10 g, 39.51 mmol) in tetrahydrofuran (100 mL) at 75 °C. The reaction mixture was stirred at 75 °C for 12 hours. After the reaction was completed, it was cooled to room temperature. Water (100 mL) was added to the reaction solution, and the pH was adjusted to 3 - 4 with 3 M dilute hydrochloric acid. It was extracted with ethyl acetate (100 mL × 3), and the organic phases were combined. The organic phase was washed successively with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 10 / 1, volume ratio). Intermediate 027_3 was obtained. 1 H NMR (400 MHz, DMSO_d6) δ: 5.72 (s, 1H), 4.30 - 4.34 (m, 4H), 1.61 (s, 3H), 1.22 (t, J = 7.2 Hz, 6H).

[0445] Step 3: Synthesis of intermediate 027_4

[0446] Under room temperature and nitrogen protection, intermediate 001_6 (2 g, 6.18 mmol, hydrochloride) was dissolved in tert-butanol (20 mL), and then intermediate 027_3 (2.33 g, 9.76 mmol) and potassium carbonate (3.42 g, 24.71 mmol) were added to the reaction system. The reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The obtained residue was separated by column chromatography (eluent: dichloromethane / ethanol = 1 / 0 - 2 / 1, volume ratio). Intermediate 027_4 was obtained.

[0447] Step 4: Synthesis of intermediate 027_5

[0448] Under room temperature and nitrogen protection, intermediate 027_4 (1.25 g, 2.61 mmol) was dissolved in methanol (5 mL) and 25% aqueous ammonia (5 mL). The reaction was stirred in a sealed vessel at 50 °C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and then anhydrous toluene (20 mL) was added for secondary concentration. Intermediate 027_5 was obtained.

[0449] Step 5: Synthesis of intermediate 027_6

[0450] Under room temperature and nitrogen protection, intermediate 027_5 (0.5 g, 1.11 mmol) was dissolved in ethyl glycolate (5.46 mL, 56.62 mmol), then N-bromosuccinimide (434.69 mg, 2.44 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.67 mL, 4.44 mmol) were added. The reaction mixture was stirred at 80 °C for 0.5 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The obtained residue was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). Intermediate 027_6 was obtained. MS-ESI m / z: 510.5 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 11.24 (s, 1H), 8.87 - 8.84 (m, 1H), 8.71 - 8.70 (m, 1H), 7.38 - 7.36 (m, 1H), 7.25 - 7.15 (m, 3H), 7.13 (br.s, 1H), 5.82 (s, 2H), 4.04 (q, J = 7.2 Hz, 2H), 3.84 (s, 2H), 1.60 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H).

[0451] Step 6: Synthesis of intermediate 027_7

[0452] Under room temperature and nitrogen protection, intermediate 027_6 (300 mg, 0.589 mmol) was dissolved in methanol (0.75 mL) and water (2.25 mL), then lithium hydroxide monohydrate (123.54 mg, 2.94 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, methanol was removed by concentration under reduced pressure, then water (20 mL) was added, and the mixture was extracted with ethyl acetate (40 mL). The organic phase was discarded, and the aqueous phase was adjusted to pH about 4 with 1 M dilute hydrochloric acid, then extracted with 2-methyltetrahydrofuran (60 mL). The organic phase was concentrated under reduced pressure to obtain intermediate 027_7.

[0453] Step 7: Synthesis of compound 027

[0454] Under room temperature and nitrogen protection, intermediate 027_7 (0.15 g, 0.312 mmol) was dissolved in dioxane (5 mL), then thionyl chloride (3 mL, 41.35 mmol) was added. The reaction mixture was stirred at 80 °C for 2 h. After the reaction ended, the reaction solution was concentrated. The obtained residue was separated by preparative HPLC (mobile phase: acetonitrile / water; hydrochloric acid system: 0.05% HCl). Compound 027 was obtained. MS-ESI m / z: 464.4 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ: 11.62 (s, 1H), 11.45 (s, 1H), 9.00 (dd, J = 2.8, 9.2 Hz, 1H), 8.74 (s, 1H), 7.39 - 7.36 (m, 1H), 7.25 - 7.21 (m, 2H), 7.18 - 7.14 (m, 1H), 5.85 (s, 2H), 4.61 (d, J = 16 Hz, 1H), 4.44 (d, J = 16 Hz, 1H), 1.57 (s, 3H).

[0455] Example 28

[0456]

[0457] Synthesis route:

[0458]

[0459] Step 1: Synthesis of Intermediate 028_1

[0460] Under room temperature and nitrogen protection, Intermediate 026_1 (4.6 g, 9.88 mmol) was dissolved in acetonitrile (50 mL), N-hydroxysuccinimide (1.19 g, 10.38 mmol) and N,N-dicyclohexylcarbodiimide (2.08 g, 10.08 mmol) were added, and the reaction mixture was stirred at room temperature for 4 hours. N-hydroxysuccinimide (227.50 mg, 1.98 mmol) and N,N-dicyclohexylcarbodiimide (407.86 mg, 1.98 mmol) were added additionally, and the reaction mixture was stirred at room temperature for another 12 hours. After the reaction was completed, the mixture was filtered, the filter cake was washed with ice-cold acetonitrile (20 mL), the filtrate was collected, and the solvent was removed by concentration under reduced pressure. Intermediate 028_1 was obtained.

[0461] Step 2: Synthesis of Intermediate 028_2

[0462] Under nitrogen protection, Intermediate 028_1 (5.5 g, 9.78 mmol) was dissolved in tetrahydrofuran (80 mL), ammonia water (6.85 g, 48.89 mmol) was slowly added dropwise, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure from the reaction solution, diluted with water (100 mL), extracted with 2-methyltetrahydrofuran (200 mL × 3), and the organic phases were combined. The solvent was removed by concentration under reduced pressure, and the obtained solid was suspended in anhydrous toluene (20 mL × 2), and the organic solvent was removed by concentration under reduced pressure. Methyl tert-butyl ether (50 mL) was added to the obtained residue, and the mixture was stirred by pulping for 10 minutes. The mixture was filtered, the filter cake was collected, and the organic solvent was removed by concentration under reduced pressure. Intermediate 028_2 was obtained.

[0463] Step 3: Synthesis of Intermediate 028_3

[0464] Under room temperature and nitrogen protection, dissolve intermediate 028_2 (3.3 g, 7.11 mmol) in dioxane (60 mL), add isoamyl nitrite (4.16 g, 35.53 mmol) and methylene iodide (5.71 g, 21.32 mmol), and heat the reaction mixture to 85 °C and stir for 4 hours. After the reaction is completed, cool the reaction solution to room temperature and concentrate it under reduced pressure to remove the solvent. Add a mixture of ethyl acetate:dichloromethane = 1:1 (5 mL) to the obtained residue, stir for 10 minutes, and filter. Collect the filter cake and concentrate it under reduced pressure to remove the solvent. Intermediate 028_3 is obtained.

[0465] Step 4: Synthesis of intermediate 028_4

[0466] Under room temperature and nitrogen protection, dissolve intermediate 028_3 (2.1 g, 3.65 mmol) in N,N-dimethylformamide (12 mL) and methanol (5 mL), then add 1,1-bis(diphenylphosphino)ferrocene palladium chloride (186.96 mg, 255.52 μmol) and N,N-diisopropylethylamine (10.4 mL), displace with carbon monoxide three times, and heat the reaction mixture to 80 °C under carbon monoxide (15 psi) and stir for 12 hours. Add 1,1-bis(diphenylphosphino)ferrocene palladium chloride (186.96 mg, 255.52 μmol) again, and continue to stir the reaction mixture at 80 °C for 12 hours. After the reaction is completed, cool the reaction to room temperature and concentrate it under reduced pressure to remove the solvent. The obtained residue is separated by column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1, dichloromethane:methanol = 1 / 0 - 10 / 1, volume ratio). Intermediate 028_4 is obtained.

[0467] Step 5: Synthesis of intermediate 028_5

[0468] Under room temperature and nitrogen protection, dissolve intermediate 028_4 (300 mg, 591.19 μmol) in acetonitrile (4 mL) and water (0.8 mL), slowly add bis(trifluoroacetoxy)iodobenzene (1.27 g, 2.96 mmol) at 0 °C, and stir the reaction mixture at room temperature for 12 hours. Add bis(trifluoroacetoxy)iodobenzene (1.27 g, 2.96 mmol) again at 0 °C, and heat the reaction mixture to 35 °C and stir for 12 hours. After the reaction is completed, cool the reaction solution to room temperature. Adjust the pH to 3 - 4 with 1 M dilute hydrochloric acid aqueous solution, extract with 2-methyltetrahydrofuran (20 mL × 3), and combine the organic phases. The organic phase is washed successively with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue is separated by column chromatography (eluent: dichloromethane / methanol = 1 / 0 - 10 / 1, volume ratio). Intermediate 028_5 is obtained.

[0469] Step 6: Synthesis of Intermediate 028_6

[0470] Under room temperature and nitrogen protection, dissolve Intermediate 028_5 (45 mg, 93.86 μmol) in tetrahydrofuran (1 mL) and water (0.2 mL), then add lithium hydroxide monohydrate (7.88 mg, 187.72 μmol). The reaction mixture is stirred at room temperature for 12 hours. After the reaction is completed, adjust the pH to 5 - 7 with 3M dilute hydrochloric acid, then extract with 2-methyltetrahydrofuran (10 mL × 4), and combine the organic phases. The organic phase is successively washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. Intermediate 028_6 is obtained.

[0471] Step 7: Synthesis of Compound 028

[0472] Under room temperature and nitrogen protection, dissolve Intermediate 028_6 (160 mg, 343.78 μmol) in thionyl chloride (2 mL) and dioxane (2 mL). The reaction mixture is heated to 75 °C and stirred for 2 hours. After the reaction is completed, cool the reaction solution to room temperature and concentrate under reduced pressure to remove the solvent. The obtained residue is purified by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). Compound 028 is obtained. MS-ESI m / z: 448.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 11.73 (s, 1H), 8.77 (s, 1H), 8.61 (d, J = 7.6 Hz, 1H), 8.35 (d, J = 4.0 Hz, 1H), 7.37 (d, J = 6.4 Hz, 1H), 7.10 - 7.30 (m, 3H), 5.87 (s, 2H), 3.68 (d, J = 12.4 Hz, 1H), 3.28 - 3.29 (m, 1H), 1.54 (s, 3H).

[0473] Examples 29 and 30

[0474]

[0475] Synthetic route:

[0476]

[0477] Under room temperature and nitrogen protection, compound 001 (300 mg, 670.55 μmol) was dissolved in tetrahydrofuran (5 mL). The temperature was lowered to -65 °C, and a hexane solution of lithium bis(trimethylsilyl)amide (1 M, 1.41 mL) was added. The reaction mixture was stirred at -65 °C for 0.5 h, then iodomethane (99.94 mg, 704.07 μmol) was added dropwise. The reaction mixture was stirred at room temperature for 12 h. Additional iodomethane (95.18 mg, 670.55 μmol) was added, and the reaction mixture was stirred at room temperature for 3 h. After the reaction was completed, 1 M aqueous hydrochloric acid solution (0.2 mL) was added to the reaction solution, and the solvent was removed by concentration under reduced pressure. The resulting residue was separated by preparative HPLC (mobile phase: acetonitrile / water; neutral system: 10 mM NH4HCO3). Compounds 029 and 030 were obtained.

[0478] 029: MS-ESI m / z: 462.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 11.46 (s, 1H), 8.75 (d, J = 0.8 Hz, 1H), 8.56 (dd, J = 8.4, 2.8 Hz, 1H), 7.31 - 7.41 (m, 1H), 7.23 (t, J = 8.8 Hz, 2H), 7.15 (t, J = 7.6 Hz, 1H), 5.87 (s, 2H), 3.39 (s, 3H), 3.07 (d, J = 15.2 Hz, 1H), 2.68 (d, J = 15.2 Hz, 1H), 1.38 (s, 3H).

[0479] 030: MS-ESI m / z: 462.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 11.18 (s, 1H), 8.70 - 8.80 (m, 2H), 7.33 - 7.40 (m, 1H), 7.19 - 7.27 (m, 1H), 7.11 - 7.19 (m, 2H), 5.88 (s, 2H), 3.21 (s, 3H), 2.96 (d, J = 15.2 Hz, 1H), 2.55 - 2.58 (m, 1H), 1.39 (s, 3H).

[0480] Example 31

[0481]

[0482] Synthetic route:

[0483]

[0484]

[0485] Step 1: Synthesis of Intermediate 031_2

[0486] Under room temperature and nitrogen protection, dissolve 031_1 (20 g, 95.17 mmol) in water (150 mL), then add dilute hydrochloric acid (1 M, 70 mL), and stir the reaction mixture at room temperature for 10 minutes. After the reaction is completed, extract the reaction solution with ethyl acetate (50 mL × 3). Combine the organic phases, wash with saturated brine (150 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent. Intermediate 031_2 is obtained.

[0487] Step 2: Synthesis of Intermediate 031_3

[0488] Under room temperature and nitrogen protection, dissolve Intermediate 031_2 (13 g, 69.08 mmol) in acetone (400 mL), add potassium carbonate (19.10 g, 138.17 mmol), stir the reaction mixture at room temperature for 20 minutes, then add methyl iodide (58.83 g, 414.50 mmol), and stir the reaction mixture at 60 °C for 12 hours. After the reaction is completed, concentrate the reaction solution under reduced pressure to remove the solvent, and separate the obtained residue by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 10 / 1, volume ratio). Intermediate 031_3 is obtained. 1 H NMR (400 MHz, CDCl3) δ: 4.32 (q, J = 7.2 Hz, 2H), 4.19 (q, J = 7.2 Hz, 2H), 1.56 (s, 6H), 1.37 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H).

[0489] Step 3: Synthesis of Intermediate 031_4

[0490] Under room temperature and nitrogen protection, dissolve Intermediate 031_3 (2.46 g, 11.38 mmol) and malononitrile (3.01 g, 45.51 mmol) in ethanol (25 mL), add pyridine (4.50 g, 56.88 mmol, 4.59 mL), heat the reaction system to 70 °C, and stir the reaction for 12 hours. After the reaction is completed, cool the reaction system to room temperature, adjust the pH value to 3 - 4 with 1 M hydrochloric acid solution, dilute with ethyl acetate (50 mL) and water (30 mL), separate the layers, and collect the organic phase. Extract the aqueous phase with ethyl acetate (50 mL × 3), combine the organic phases. Wash successively with 1 N hydrochloric acid solution (50 mL × 3) and saturated brine (50 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. Separate the obtained residue by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1, volume ratio). Intermediate 031_4 is obtained.

[0491] Step 4: Synthesis of Intermediate 031_5

[0492] Dissolve Intermediate 031_4 (3 g, 11.35 mmol) in chloroform (15 mL) and ethanol (15 mL), then add diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (3.16 g, 12.49 mmol). Heat the reaction system to 50 °C and stir for 12 hours. Add additional diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (862.60 mg, 3.41 mmol), heat the reaction system to 50 °C and stir for 12 hours. Add additional diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (2.88 g, 11.35 mmol), heat the reaction system to 50 °C and stir for 12 hours. After the reaction is completed, cool the reaction solution to room temperature and concentrate it under reduced pressure to remove the solvent. The resulting residue is separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 7 / 1, v / v). Intermediate 031_5 is obtained. 1 H NMR (400 MHz, CDCl3) δ: 4.34 - 4.19 (m, 5H), 3.66 (d, J = 7.0 Hz, 1H), 1.38 - 1.29 (m, 12H).

[0493] Step 5: Synthesis of Intermediate 031_6

[0494] Under room temperature and nitrogen protection, dissolve Intermediate 031_5 (1.73 g, 6.50 mmol) and 001_6 (1.31 g, 4.06 mmol, hydrochloride) in tert-butanol (20 mL), then add potassium carbonate (1.40 g, 10.15 mmol). Heat the reaction system to 85 °C and stir at 85 °C for 12 hours. After the reaction is completed, cool the reaction system to room temperature, add water (35 mL) to quench the reaction, dilute with ethyl acetate (50 mL), separate the layers, collect the organic phase, and extract the aqueous phase with ethyl acetate (40 mL × 3). Combine the organic phases, wash with saturated brine (40 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The resulting crude product is separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 0 / 1, v / v). Intermediate 031_6 is obtained.

[0495] Step 6: Synthesis of Compound 031

[0496] Under room temperature and nitrogen protection, intermediate 031_6 (0.9 g, 1.77 mmol) was dissolved in toluene (18 mL). Then, a toluene solution of trimethylaluminum (2 M, 2.84 mL) was added dropwise to the reaction system. The reaction solution was heated to 80 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was slowly poured into dilute hydrochloric acid (1 M, 30 mL) to quench the reaction, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). Compound 031 was obtained. MS-ESI m / z: 462.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 11.48 (s, 1H), 11.11 (s, 1H), 8.75 - 8.74 (m, 1H), 8.72 - 8.69 (m, 1H), 7.40 - 7.35 (m, 1H), 7.27 - 7.21 (m, 2H), 7.18 - 7.15 (m, 1H), 5.84 (s, 2H), 3.97 (s, 1H), 1.46 (s, 3H), 0.77 (s, 3H).

[0497] Examples 32 and 33

[0498]

[0499] Synthetic route:

[0500]

[0501] Step 1: Synthesis of intermediate 032_1

[0502] Under room temperature and nitrogen protection, intermediate 001_7 (3 g, 6.08 mmol) was dissolved in glacial acetic acid (20 mL). Then, a solution of sodium nitrite (1.26 g, 18.24 mmol) dissolved in water (10 mL) was added to the reaction system. The reaction mixture was heated to 90 °C and stirred for 2 hours. After the reaction ended, it was cooled to room temperature. The reaction solution was diluted with ethyl acetate (100 mL), then washed with saturated aqueous sodium bicarbonate solution (40 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 3, v / v). Intermediate 032_1 was obtained.

[0503] Step 2: Synthesis of intermediate 032_2

[0504] Intermediate 032_1 (0.3 g, 0.607 mmol) was dissolved in tetrahydrofuran (9 mL) at room temperature. Red aluminum (1.93 g, 6.67 mmol, 70% purity) was added at 5-10°C, and the reaction mixture was stirred at room temperature for 16 hours. After completion, the reaction solution was quenched with 1M hydrochloric acid (20 mL) and then extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: dichloromethane / methanol = 1 / 0-9 / 1, volume ratio) to obtain Intermediate 032_2.

[0505] Step 3: Synthesis of Intermediate 032_3

[0506] Intermediate 032_2 (120 mg, 0.265 mmol) was dissolved in tetrahydrofuran (2 mL) at room temperature. A solution of N,N,N',N'-tetramethylazodicarbonamide (205.52 mg, 1.19 mmol) in tetrahydrofuran (0.5 mL) was added at 0°C, followed by a solution of tri-tert-butylphosphine (241.49 mg, 1.19 mmol) in tetrahydrofuran (0.5 mL). The reaction mixture was heated to 70°C and stirred for 3 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The crude product was separated by preparative HPLC (mobile phase: acetonitrile / water; neutral system: 10 mM NH4HCO3) to obtain Intermediate 032_3. MS-ESI m / z: 435.4 [M+H] + . 1 H NMR (400MHz, DMSO_d6) δ: 11.24 (s, 1H), 8.74 (d, J=1.0Hz, 1H), 8.52-8.49 (m, 1H), 7.40-7.34 (m, 1H), 7.26-7.14(m, 3H), 5.84(s, 2H), 4.72-4.59(m, 2H), 2.00-1.97(m, 1H), 1.82-1.74(m, 1H), 1.46(s, 3H)

[0507] Step 3: Synthesis of compounds 032 and 033

[0508] The intermediate 032_3 was separated by chiral column (column type: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 μm); mobile phase: [Neu-ACN]%: 45%-45%, 12 min) to obtain 032 and 033.

[0509] 032 (retention time: 1.269 min): MS-ESI m / z: 435.1 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ: 11.23 (s, 1H), 8.73 (s, 1H), 8.50 (dd, J = 8.4, 2.8 Hz, 1H), 7.39 - 7.34 (m, 1H), 7.29 - 7.20 (m, 2H), 7.17 - 7.14 (m, 1H), 5.84 (s, 2H), 4.70 - 4.59 (m, 2H), 1.99 (d, J = 13.6 Hz, 1H), 1.81 - 1.73 (m, 1H), 1.46 (s, 3H).

[0510] 033 (Retention time: 1.554 min): MS-ESI m / z: 435.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ: 11.24 (s, 1H), 8.73 (s, 1H), 8.50 (dd, J = 8.4, 2.8 Hz, 1H), 7.39 - 7.34 (m, 1H), 7.29 - 7.20 (m, 2H), 7.17 - 7.14 (m, 1H), 5.84 (s, 2H), 4.70 - 4.59 (m, 2H), 1.99 (d, J = 13.6 Hz, 1H), 1.81 - 1.73 (m, 1H), 1.46 (s, 3H).

[0511] Example 34

[0512]

[0513] Synthetic route:

[0514]

[0515] Step 1: Synthesis of intermediate 034_2

[0516] Under room temperature and nitrogen protection, compound 001_1 (28.67 g, 246.87 mmol, 27.3 mL) and malononitrile (17.12 g, 259.21 mmol, 16.31 mL) were dissolved in tetrahydrofuran (300 mL), and the reaction was stirred for 1 hour. After the reaction was completed, a tetrahydrofuran solution of intermediate 034_2 was obtained.

[0517] Step 2: Synthesis of intermediate 034_3

[0518] Under room temperature and nitrogen protection, the zinc powder (48.32 g, 738.98 mmol) activated with dilute hydrochloric acid and titanocene dichloride (6.38 g, 24.63 mmol, 3.99 mL) were placed in a dry reaction flask, and tetrahydrofuran (340 mL) was added. One-tenth of the solution of ethyl bromodifluoroacetate (100 g, 492.65 mmol, 63.29 mL) dissolved in tetrahydrofuran (60 mL) was added to the reaction system. The reaction system was stirred at room temperature. After initiation, the tetrahydrofuran solution of the remaining ethyl bromodifluoroacetate was slowly added dropwise. After the reaction system was stirred at room temperature for 0.5 h, it was filtered, and the filter cake was washed with tetrahydrofuran (60 mL), and the filtrates were combined. At room temperature, the filtrate was added to the tetrahydrofuran solution of intermediate 034_2 (40.44 g, 246.33 mmol). The reaction system was stirred at room temperature for 12 h. After the reaction was completed, the pH was adjusted to about 3 with 1N hydrochloric acid solution, diluted with ethyl acetate (250 mL) and water (200 mL), separated by liquid-liquid extraction, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (150 mL×3). The combined organic phases were washed successively with saturated brine (250 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 9 / 1, volume ratio). Intermediate 034_3 was obtained. 1 H NMR (400 MHz, CDCl3) δ: 4.69 (s, 1H), 4.46 - 4.31 (m, 4H), 1.81 (s, 3H), 1.46 - 1.31 (m, 6H).

[0519] Step 3: Synthesis of intermediate 034_4

[0520] Under room temperature and nitrogen protection, intermediate 034_3 (7.6 g, 26.37 mmol) was dissolved in tert-butanol (110 mL), then potassium carbonate (5.69 g, 41.19 mmol) and 001_6 (5.33 g, 16.48 mmol, hydrochloride) were added. The reaction mixture was heated to 85 °C and stirred for 40 h. After the reaction was completed, it was cooled to room temperature, diluted with water (100 mL) and ethyl acetate (100 mL), separated by liquid-liquid extraction to collect the organic phase, and the aqueous phase was extracted with ethyl acetate (100 mL×3). The combined organic phases were washed successively with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The obtained residue was separated by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0 - 1 / 1, volume ratio). Intermediate 034_4 was obtained. 11H NMR (400 MHz, DMSO-d6) δ: 11.80 (d, J = 2.8 Hz, 1H), 9.01 (dd, J = 2.4, 8.8 Hz, 1H), 8.69 (dd, J = 1.6, 2.4 Hz, 1H), 7.38 - 7.33 (m, 1H), 7.24 - 7.11 (m, 3H), 6.94 (s, 1H), 5.81 (s, 2H), 4.23 - 4.09 (m, 2H), 1.81 (d, J = 2.8 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H).

[0521] Step 4: Synthesis of Compound 034

[0522] Under room temperature and nitrogen protection, dissolve intermediate 034_4 (300 mg, 566.63 μmol) in toluene (6 mL), add a toluene solution of trimethylaluminum (2 M, 849.95 μL, 1.70 mmol), and heat the reaction mixture to 80 °C and stir for 4 hours. After the reaction is completed, cool the reaction solution to room temperature, slowly add dilute hydrochloric acid (3 M, 3.68 mL) to quench, dilute with 2-methyltetrahydrofuran (10 mL) and then separate the layers. Extract the aqueous phase with 2-methyltetrahydrofuran (10 mL × 2). Combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. The crude product is separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). Compound 034 is obtained. MS-ESI m / z: 484.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ: 12.32 (d, J = 2.0 Hz, 1H), 12.02 (s, 1H), 8.77 (dd, J = 1.6, 2.8 Hz, 1H), 8.65 (dd, J = 2.8, 8.8 Hz, 1H), 7.41 - 7.35 (m, 1H), 7.30 - 7.15 (m, 3H), 5.86 (s, 2H), 1.55 (s, 3H).

[0523] Examples 35 and 36

[0524]

[0525] Synthetic route:

[0526]

[0527] Step 1: Synthesis of Intermediate 035_1

[0528] Under room temperature and nitrogen protection, intermediate 031_4 (2.1 g, 7.95 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). The reaction system was cooled to 0 °C, and methylmagnesium bromide solution (3 M, 3.97 mL) was added dropwise. The reaction system was stirred at 0 °C for 15 minutes. After the reaction was completed, the reaction solution was quenched with 1 N dilute hydrochloric acid (50 mL), diluted with water (30 mL), and then extracted with ethyl acetate (50 mL). The aqueous phase was further extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 9 / 1, v / v). Intermediate 035_1 was obtained. 1 H NMR (400 MHz, CDCl3) δ: 4.88 (s, 1H), 4.35 - 4.12 (m, 4H), 1.63 (s, 3H), 1.42 (s, 3H), 1.33 - 1.31 (m, 9H).

[0529] Step 2: Synthesis of intermediate 035_2

[0530] Under room temperature and nitrogen protection, intermediate 001_6 (608.22 mg, 1.88 mmol, hydrochloride) and intermediate 035_1 (790 mg, 2.82 mmol) were dissolved in tert-butanol (12 mL). Potassium carbonate (778.99 mg, 5.64 mmol) was added, and the reaction system was heated to 85 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (40 mL). The aqueous phase was again extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 4, v / v). Intermediate 035_2 was obtained.

[0531] Step 3: Synthesis of intermediate 035_3

[0532] Under room temperature and nitrogen protection, intermediate 035_2 (465 mg, 891.63 μmol) was dissolved in toluene (10 mL), and then a toluene solution of trimethylaluminum (2 M, 1.43 mL) was added. The reaction system was heated to 80 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and 3 M hydrochloric acid solution (6 mL) was added to quench the reaction. Then, ethyl acetate (40 mL) and water (20 mL) were added for dilution. The layers were separated, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). Intermediate 035_3 was obtained. MS-ESI m / z: 476.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 11.53 (s, 1H), 11.18 (s, 1H), 8.75 - 8.69 (m, 2H), 7.40 - 7.35 (m, 1H), 7.28 - 7.14 (m, 3H), 5.84 (s, 2H), 1.32 (d, J = 5.8 Hz, 6H), 0.76 (s, 3H).

[0533] Step 4: Synthesis of Compounds 035 and 036

[0534] The intermediate 035_3 was separated by a chiral column (column type: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 μm); mobile phase: [Neu-ACN]%: 50% - 50%, 12 min). Compounds 035 and 036 were obtained.

[0535] 035 (retention time: 1.696 min): MS-ESI m / z: 476.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 11.53 (s, 1H), 11.19 (s, 1H), 8.74 (dd, J = 1.6, 2.6 Hz, 1H), 8.70 (dd, J = 2.8, 8.8 Hz, 1H), 7.41 - 7.33 (m, 1H), 7.29 - 7.13 (m, 3H), 5.84 (s, 2H), 1.32 (d, J = 5.6 Hz, 6H), 0.76 (s, 3H).

[0536] 036 (retention time: 2.403 min): MS-ESI m / z: 476.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ: 11.53 (s, 1H), 11.18 (s, 1H), 8.74 (dd, J = 1.6, 2.6 Hz, 1H), 8.70 (dd, J = 2.8, 8.8 Hz, 1H), 7.42 - 7.32 (m, 1H), 7.31 - 7.12 (m, 3H), 5.84 (s, 2H), 1.32 (d, J = 5.6 Hz, 6H), 0.76 (s, 3H).

[0537] Examples 37 and 38

[0538]

[0539] Synthetic route:

[0540]

[0541] Step 1: Synthesis of Intermediate 037_1

[0542] Under room temperature and nitrogen protection, Intermediate 027_6 (690 mg, 1.35 mmol) was dissolved in trifluoroacetic acid (9 mL). The reaction mixture was cooled to 0 °C, and a solution of sodium nitrite (280.33 mg, 4.06 mmol) dissolved in water (0.9 mL) was added. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was completed, the reaction solution was diluted with water (30 mL), filtered to obtain a yellow solid, and azeotropically dried with toluene (20 mL). The solvent was removed under reduced pressure to obtain Intermediate 037_1.

[0543] Step 2: Synthesis of Intermediate 037_2

[0544] Under room temperature and nitrogen protection, Intermediate 037_1 (470 mg, 920.76 μmol) was dissolved in tetrahydrofuran (1.5 mL). The temperature was lowered to 10 °C, and a toluene solution of Red-Al (1.06 g, 3.68 mmol, purity: 70%) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to neutral. Water (20 mL) and 2-methyltetrahydrofuran (50 mL) were added for dilution, and then liquid separation was performed. The aqueous phase was extracted with 2-methyltetrahydrofuran (50 mL × 3), and the organic phases were combined. Dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The obtained residue was separated by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0 - 0 / 1, volume ratio). Intermediate 037_2 was obtained. 11H NMR (400 MHz, DMSO-d6) δ: 12.75 (s, 1H), 11.27 (s, 1H), 8.79 (dd, J = 1.2, 2.4 Hz, 1H), 8.55 (s, 1H), 7.41 - 7.35 (m, 2H), 7.26 - 7.14 (m, 2H), 5.86 (s, 2H), 4.52 (t, J = 5.6 Hz, 1H), 3.43 (q, J = 5.6 Hz, 2H), 3.27 - 3.22 (m, 1H), 3.18 - 3.13 (m, 1H), 1.50 (s, 3H).

[0545] Step 3: Synthesis of Intermediate 037_3

[0546] Under room temperature and nitrogen protection, dissolve Intermediate 037_2 (250 mg, 533.72 μmol) in tetrahydrofuran (5 mL). Cool the solution to 0 °C and add a solution of N,N,N′,N′-tetramethylazodicarboxamide (413.54 mg, 2.40 mmol) dissolved in tetrahydrofuran (1.25 mL). Finally, add a solution of triphenylphosphine (629.94 mg, 2.4 mmol) dissolved in tetrahydrofuran (1.25 mL) at 0 °C. Stir the reaction mixture at 70 °C for 5 hours. After the reaction is completed, cool the reaction solution to room temperature, filter, and remove the solvent under reduced pressure. The crude product is separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). Intermediate 037_3 is obtained. MS-ESI m / z: 451.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ: 11.58 (s, 1H), 8.76 (dd, J = 1.6, 2.8 Hz, 1H), 8.51 (dd, J = 2.8, 8.4 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.28 - 7.14 (m, 3H), 5.90 - 5.81 (m, 2H), 4.80 (s, 1H), 4.35 - 4.18 (m, 3H), 1.64 (s, 3H).

[0547] Step 4: Synthesis of Compounds 037 and 038

[0548] Intermediate 037_3 is separated by a chiral column (column type: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [Neu-ACN]%: 45% - 45%, 12 min) to obtain 037 and 038.

[0549] 037 (retention time: 1.215 min): MS-ESI m / z: 451.1 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ: 11.59 (s, 1H), 8.76 (s, 1H), 8.51 (dd, J = 2.8, 8.4 Hz, 1H), 7.38 - 7.35 (m, 1H), 7.28 - 7.14 (m, 3H), 5.90 - 5.81 (m, 2H), 4.81 (s, 1H), 4.36 (s, 1H), 4.29 - 4.17 (m, 2H), 1.64 (s, 3H).

[0550] 038 (retention time: 1.574 min): MS-ESI m / z: 451.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ: 11.58 (s, 1H), 8.76 (dd, J = 1.6, 2.4 Hz, 1H), 8.51 (dd, J = 2.8, 8.8 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.27 - 7.14 (m, 3H), 5.90 - 5.81 (m, 2H), 4.82 (d, J = 12 Hz, 1H), 4.35 - 4.29 (m, 1H), 4.25 - 4.18 (m, 2H), 1.64 (s, 3H).

[0551] Example 39

[0552]

[0553] Synthetic route:

[0554]

[0555] Step 1: Synthesis of intermediate 039_1

[0556] Under room temperature and nitrogen protection, dissolve intermediate 027_6 (200 mg, 392.57 mmol) in tetrahydrofuran (4 mL). Cool the reaction mixture to 10 °C and add Red-Al (453.50 mg, 1.57 mmol, purity: 70%). Restore the reaction mixture to room temperature and stir for 12 hours. After the reaction is completed, pour the reaction solution into dilute hydrochloric acid (1 M, 10 mL) to quench it. Dilute with 2-methyltetrahydrofuran (10 mL) and separate the layers. Extract the aqueous phase with 2-methyltetrahydrofuran (10 mL × 2). Combine the organic phases. Dry the organic phases over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. The resulting residue is separated by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0 - 5 / 4, volume ratio). Obtain intermediate 039_1.

[0557] Step 2: Synthesis of intermediate 039_2

[0558] Under room temperature and nitrogen protection, dissolve intermediate 039_1 (130 mg, 278.12 μmol) in tetrahydrofuran (1.1 mL) and dichloromethane (1.1 mL). Sequentially add N,N-diisopropylethylamine (71.89 mg, 556.24 μmol) and 4-dimethylaminopyridine (3.40 mg, 27.81 μmol). After cooling to 0 °C, add methanesulfonyl chloride (47.79 mg, 417.18 μmol). Stir the reaction mixture at room temperature for 1 hour. After the reaction is completed, pour the reaction solution into saturated sodium bicarbonate aqueous solution (10 mL) to quench, add 2-methyltetrahydrofuran (10 mL) for dilution and then separate the layers. Extract the aqueous phase with 2-methyltetrahydrofuran (10 mL × 2), and combine the organic phases. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. The obtained residue is separated by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0 - 5 / 4, volume ratio). Intermediate 039_2 is obtained. 1 H NMR (400 MHz, DMSO_d6) δ: 11.26 (s, 1H), 8.87 (dd, J = 2.8, 8.8 Hz, 1H), 8.71 (s, 1H), 7.39 - 7.34 (m, 1H), 7.25 - 7.20 (m, 2H), 7.17 - 7.13 (m, 1H), 6.64 (s, 2H), 5.82 (s, 2H), 4.29 - 4.27 (m, 2H), 3.20 (s, 3H), 1.57 (s, 3H).

[0559] Step 3: Synthesis of Compound 039

[0560] Under room temperature and nitrogen protection, dissolve intermediate 039_2 (60 mg, 109.99 μmol) in tetrahydrofuran (1 mL). Cool to -78 °C and sequentially add a hexane solution of lithium bis(trimethylsilyl)amide (1 M, 274.97 μL) and hexamethylphosphoric triamide (49.27 mg, 274.97 mmol). Stir the reaction mixture at room temperature for 2 hours. Cool to -78 °C and add a hexane solution of lithium bis(trimethylsilyl)amide (1 M, 274.97 μL) and hexamethylphosphoric triamide (49.27 mg, 274.97 mmol) again. Stir the reaction mixture at room temperature for 12 hours. After the reaction is completed, pour the reaction solution into saturated ammonium chloride aqueous solution (10 mL) to quench, add 2-methyltetrahydrofuran (10 mL) for dilution and then separate the layers. Extract the aqueous phase with 2-methyltetrahydrofuran (10 mL × 2), and combine the organic phases. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. The crude product is separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) to obtain Compound 039. MS-ESI m / z: 450.2 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ: 11.07 (s, 1H), 8.76 (dd, J = 2.8, 8.8 Hz, 1H), 8.71 (s, 1H), 7.68 (s, 1H), 7.37 - 7.35 (m, 1H), 7.24 - 7.21 (m, 2H), 7.17 - 7.13 (m, 1H), 5.82 (d, J = 3.6 Hz, 2H), 4.12 - 3.98 (m, 4H), 1.55 (s, 3H).

[0561] Examples 40 and 41

[0562]

[0563] Synthetic route:

[0564]

[0565] Step 1: Synthesis of Intermediate 040_1

[0566] Under room temperature and nitrogen protection, Intermediate 034_4 (2 g, 3.78 mmol) was dissolved in tetrahydrofuran (40 mL). The reaction mixture was cooled to 0 °C, and lithium aluminum hydride (286.75 mg, 7.56 mmol) was added. The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, the reaction solution was quenched to neutral with 1 M dilute hydrochloric acid, diluted with 2-methyltetrahydrofuran (50 mL), and separated by liquid-liquid extraction. The aqueous phase was extracted with 2-methyltetrahydrofuran (50 mL × 3). The combined organic phases were concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0 - 1 / 1, v / v). Intermediate 040_1 was obtained.

[0567] Step 2: Synthesis of Intermediate 040_2

[0568] Under room temperature and nitrogen protection, Intermediate 040_1 (720 mg, 1.48 mmol) was dissolved in trifluoroacetic acid (15 mL). After cooling to 0 °C, a solution of sodium nitrite (305.76 mg, 4.43 mmol) dissolved in water (1.5 mL) was added. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was completed, the reaction solution was diluted with water (50 mL), and the precipitate was collected by filtration. The filter cake was washed with water (2 mL), and the solvent was removed by concentration under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0 - 5 / 4, v / v). Intermediate 040_2 was obtained.

[0569] Step 3: Synthesis of Intermediate 040_3

[0570] Under room temperature and nitrogen protection, intermediate 040_2 (260 mg, 532.36 μmol) was dissolved in tetrahydrofuran (4 mL). The temperature was lowered to 0 °C, and a solution of N,N,N′,N′-tetramethylazodicarboxamide (412.49 mg, 2.40 mmol) dissolved in tetrahydrofuran (4 mL) was added. Finally, a solution of triphenylphosphine (628.33 mg, 2.40 mmol) dissolved in tetrahydrofuran (2 mL) was added at 0 °C. The reaction mixture was stirred at 75 °C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the solvent was removed under reduced pressure. The obtained residue was separated by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0 - 0 / 1, volume ratio). The crude product was obtained. The crude product was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). Intermediate 040_3 was obtained. MS-ESI m / z: 471.4 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 12.32 (d, J = 2.4 Hz, 1H), 8.76 (dd, J = 1.6, 2.8 Hz, 1H), 8.62 (dd, J = 2.8, 8.4 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.25 - 7.20 (m, 2H), 7.17 - 7.14 (m, 1H), 5.86 (s, 2H), 5.06 - 5.03 (m, 1H), 4.97 - 4.94 (m, 1H), 1.48 (s, 3H).

[0571] Step 4: Synthesis of Compounds 040 and 041

[0572] The chiral column separation of compound 040_3 was carried out (column type: REGIS (R,R) WHELK-O1 (250 mm * 25 mm, 10 μm); mobile phase: [Neu-ACN]; B%: 50% - 50%, 10 min). Compounds 040 and 041 were obtained.

[0573] 040 (retention time: 1.284 min): MS-ESI m / z: 471.4 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 12.33 (s, 1H), 8.75 (s, 1H), 8.61 (dd, J = 2.8, 8.8 Hz, 1H), 7.37 (m, 1H), 7.25 - 7.20 (m, 2H), 7.17 - 7.13 (m, 1H), 5.86 (s, 2H), 5.06 - 4.94 (m, 2H), 1.48 (s, 3H).

[0574] 041 (Retention time: 1.400 min): MS-ESI m / z: 471.4 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 12.33 (s, 1H), 8.76 (s, 1H), 8.63 - 8.61 (m, 1H), 7.37 (d, J = 5.2 Hz, 1H), 7.25 - 7.23 (m, 2H), 7.16 (t, J = 7.2 Hz, 1H), 5.86 (s, 2H), 5.06 - 4.94 (m, 2H), 1.48 (s, 3H).

[0575] Examples 42 and 43

[0576]

[0577] Synthetic route:

[0578]

[0579] Step 1: Synthesis of intermediate 042_1

[0580] Under room temperature and nitrogen protection, dissolve intermediate 040_1 (1.4 g, 2.87 mmol) in tetrahydrofuran (15 mL) and dichloromethane (15 mL), then successively add N,N-diisopropylethylamine (1.3 g, 10.05 mmol, 1.75 mL), p-toluenesulfonyl chloride (1.37 g, 7.18 mmol) and 4-dimethylaminopyridine (35.09 mg, 287.23 μmol). The reaction mixture is heated to 50 °C and stirred for 12 hours. After the reaction is completed, the reaction solution is cooled to room temperature, separated with saturated citric acid aqueous solution (50 mL) and 2-methyltetrahydrofuran (30 mL). The aqueous phase is extracted with 2-methyltetrahydrofuran (50 mL × 3), and the organic phases are combined. The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove the solvent. The obtained residue is separated by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0 - 1 / 1, volume ratio) and preparative HPLC separation (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). Intermediate 042_1 is obtained. 11H NMR (400 MHz, DMSO-d6) δ: 11.58 (d, J = 4.0 Hz, 1H), 9.02 (dd, J = 2.8, 8.8 Hz, 1H), 8.72 (dd, J = 1.6, 2.8 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.40 - 7.34 (m, 1H), 7.25 - 7.20 (m, 2H), 7.17 - 7.15 (m, 3H), 5.88 - 5.79 (m, 2H), 4.45 (t, J = 5.2 Hz, 2H), 1.97 (s, 3H), 1.51 - 1.47 (m, 3H).

[0581] Step 2: Synthesis of Intermediate 042_2

[0582] Under room temperature and nitrogen protection, Intermediate 042_1 (70 mg, 109.10 μmol) was dissolved in tetrahydrofuran (2 mL). The temperature was lowered to -78 °C, and hexamethylphosphoric triamide (48.88 mg, 272.76 mmol, 47.92 μL) and a n-hexane solution of lithium bis(trimethylsilyl)amide (1 M, 272.76 μL) were added successively. The reaction mixture was allowed to return to room temperature and stirred for 12 hours. After the reaction was completed, the reaction solution was slowly poured into dilute hydrochloric acid (1 M, 5 mL), diluted with semi-saturated brine (5 mL) and 2-methyltetrahydrofuran (5 mL), and then separated by liquid-liquid extraction. The aqueous phase was extracted with 2-methyltetrahydrofuran (5 mL × 3), and the organic phases were combined. The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The resulting residue was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) to obtain Intermediate 042_2. MS-ESI m / z: 470.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ: 11.76 (s, 1H), 8.72 (s, 1H), 8.67 - 8.66 (m, 1H), 7.83 (s, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.25 - 7.23 (m, 2H), 7.17 - 7.13 (m, 1H), 5.82 (s, 2H), 4.03 (d, J = 10.0 Hz, 1H), 3.61 (d, J = 11.2 Hz, 1H), 1.34 (s, 3H).

[0583] Step 3: Synthesis of Compounds 042 and 043

[0584] The compound 042 was separated by a chiral column (column type: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH₃·H₂O in MeOH]%: 35% - 35%, 15 min). Compounds 042 and 043 were obtained.

[0585] 042 (retention time: 1.169 min): MS-ESI m / z: 470.1 [M + H] + . 1 ¹H NMR (400 MHz, DMSO-d₆) δ: 11.71 (s, 1H), 8.72 (s, 1H), 8.67 (d, J = 8.0 Hz, 1H), 7.83 (s, 1H), 7.36 (d, J = 6.0 Hz, 1H), 7.2 - 7.23 (m, 2H), 7.17 - 7.13 (m, 1H), 5.82 (s, 2H), 4.03 (d, J = 9.2 Hz, 1H), 3.62 (d, J = 10.8 Hz, 1H), 1.34 (s, 3H).

[0586] 043 (retention time: 1.190 min): MS-ESI m / z: 470.1 [M + H] + . 1 ¹H NMR (400 MHz, DMSO-d₆) δ: 11.71 (s, 1H), 8.72 (s, 1H), 8.66 (dd, J = 2.8, 8.8 Hz, 1H), 7.82 (s, 1H), 7.39 - 7.34 (m, 1H), 7.25 - 7.21 (m, 2H), 7.17 - 7.13 (m, 1H), 5.82 (s, 2H), 4.03 (d, J = 10.0 Hz, 1H), 3.62 (d, J = 12.0 Hz, 1H), 1.34 (s, 3H).

[0587] Examples 44 and 45

[0588]

[0589] Synthetic route:

[0590]

[0591] Step 1: Synthesis of intermediate 044_1

[0592] Under room temperature and nitrogen protection, intermediate 034_3 (9.37 g, 32.52 mmol) was dissolved in tert-butanol (40 mL), then potassium carbonate (5.24 g, 37.93 mmol) and intermediate 012_3 (3.92 g, 10.84 mmol, hydrochloride) were added. The reaction mixture was heated to 85 °C and stirred for 12 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: dichloromethane / methanol = 1 / 0 - 95 / 5, volume ratio). Intermediate 044_1 was obtained.

[0593] Step 2: Synthesis of intermediate 044_2

[0594] Under room temperature and nitrogen protection, intermediate 044_1 (1 g, 1.76 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0 °C, and then lithium aluminum hydride (133.79 mg, 3.52 mmol) was slowly added. The reaction mixture was stirred at 0 °C for 1 hour. The reaction solution was slowly poured into dilute hydrochloric acid (1 N, 20 mL) for quenching, and 2-methyltetrahydrofuran (10 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.1% TFA). Intermediate 044_2 was obtained.

[0595] Step 3: Synthesis of intermediate 044_3

[0596] Under room temperature and nitrogen protection, intermediate 044_2 (98 mg, 186.54 μmol) was dissolved in trifluoroacetic acid (2 mL), the reaction was cooled to 0 °C, and a solution of sodium nitrite (38.61 mg, 559.62 μmol) in water (0.2 mL) was added. The reaction mixture was stirred at 0 °C for 1 hour. After the reaction was completed, water (8 mL) was added to the reaction solution, and a solid precipitated out. The solid was filtered, and the filter cake was concentrated with anhydrous toluene (10 mL) to obtain intermediate 044_3.

[0597] Step 4: Synthesis of intermediate 044_4

[0598] Under room temperature and nitrogen protection, triphenylphosphine (73.25 mg, 279.29 μmol) was added into a reaction flask, then a solution of intermediate 044_3 (98 mg, crude product) in tetrahydrofuran (1.7 mL) was added to the reaction system, and finally a solution of N,N,N′,N′-tetramethylazodicarboxamide (56.47 mg, 279.29 μmol) in tetrahydrofuran (0.3 mL) was added to the reaction system. The reaction mixture was stirred at 70 °C for 12 hours. After the reaction was completed, the reaction solution was concentrated, and the obtained residue was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). Intermediate 044_4 was obtained. MS-ESI m / z: 509.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 12.33 (s, 1H), 8.77 (s, 1H), 8.63 (dd, J = 2.8, 8.4 Hz, 1H), 5.07 - 5.05 (m, 1H), 4.98 - 4.90 (m, 3H), 3.06 - 2.94 (m, 2H), 1.49 (s, 3H).

[0599] Step 5: Synthesis of Compounds 044 and 045

[0600] Intermediate 044_4 was subjected to chiral resolution (column type: REGIS (S,S) WHELK-O1 (250 mm * 25 mm, 10 μm); mobile phase: [Neu-ACN]%: 30% - 30%, 5 min) to obtain compounds 044 and 045. Chiral analysis method: OD_MeOH_IPAm, gradient: 5 - 50%, flow rate: 3.4 mL / min, column temperature: 35 °C_, time: 3 min.

[0601] 044 (retention time: 0.789 min): MS-ESI m / z: 509.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 12.34 (s, 1H), 8.78 (q, J = 1.6 Hz, 1H), 8.63 (dd, J = 2.8, 8.8 Hz, 1H), 5.07 - 5.05 (m, 1H), 4.98 - 4.90 (m, 3H), 3.05 - 2.95 (m, 2H), 1.49 (s, 3H).

[0602] 045 (retention time: 0.768 min): MS-ESI m / z: 509.1 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ: 12.34 (s, 1H), 8.77 (q, J = 1.2 Hz, 1H), 8.62 (dd, J = 2.8, 8.8 Hz, 1H), 5.07 - 5.05 (m, 1H), 4.98 - 4.90 (m, 3H), 3.06 - 2.95 (m, 2H), 1.49 (s, 3H).

[0603] Examples 46 and 47

[0604]

[0605] Synthetic route:

[0606]

[0607] Step 1: Synthesis of intermediate 046_1

[0608] Under room temperature and nitrogen protection, intermediate 044_1 (150 mg, 264.37 μmol) was dissolved in anhydrous toluene (2 mL), and a toluene solution of trimethylaluminum (2 M, 396.55 μL) was slowly added. The reaction mixture was stirred at 80 °C for 4 hours. After the reaction was completed, it was cooled to room temperature, adjusted to pH = 6 with 1 M dilute hydrochloric acid, and then extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The residue was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). Intermediate 046_1 was obtained. 1 1H NMR (400 MHz, DMSO-d6) δ: 12.34 (s, 1H), 12.05 (s, 1H), 8.79 - 8.78 (m, 1H), 8.66 (dd, J = 2.8, 8.8 Hz, 1H), 4.93 (t, J = 6.8 Hz, 2H), 3.05 - 2.95 (m, 2H), 1.57 (s, 3H).

[0609] Step 2: Synthesis of compounds 046 and 047

[0610] Intermediate 046_1 was separated by a chiral column (column type: REGIS (S,S) WHELK-O1 (250 mm * 25 mm, 10 μm); mobile phase: [Neu-MeOH]%: 20% - 20%, 4 min). Compounds 046 and 047 were obtained. Chiral analysis method: OD_MeOH_IPAm, gradient: 5 - 50%, flow rate: 3.4 mL / min, column temperature: 35 °C, time: 3 min.

[0611] 046 (retention time: 0.850 min): MS-ESI m / z: 522.0 [M+H] + .1 H NMR (400 MHz, DMSO-d6) δ: 12.40 - 12.25 (m, 1H), 12.12 - 11.98 (m, 1H), 8.78 (q, J = 1.2 Hz, 1H), 8.66 (dd, J = 3.2, 8.4 Hz, 1H), 4.93 (t, J = 6.8 Hz, 2H), 3.07 - 2.94 (m, 2H), 1.57 (s, 3H).

[0612] 047 (retention time: 0.847 min): MS-ESI m / z: 522.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 12.38 - 12.10 (m, 2H), 8.79 (q, J = 1.6 Hz, 1H), 8.67 (dd, J = 3.2, 8.8 Hz, 1H), 4.94 (t, J = 7.2 Hz, 2H), 3.06 - 2.95 (m, 2H), 1.57 (s, 3H).

[0613] Example 48

[0614]

[0615] Synthetic route:

[0616]

[0617] Step 1: Synthesis of intermediate 048_2

[0618] Under the protection of room temperature and nitrogen, dissolve compound 048_1 (50 g, 287.11 mmol) in anhydrous toluene (1000 mL), add malononitrile (18.02 g, 272.75 mmol), β-alanine (766.67 mg, 8.61 mmol) and acetic acid (3.17 g, 52.73 mmol) thereto, and heat the reaction system to 125 °C and stir for 12 hours. After the reaction is completed, the system is cooled to room temperature, and the solvent is removed by reduced pressure concentration. The obtained residue is separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 1, volume ratio). Intermediate 048_2 is obtained. 1 H NMR (400 MHz, DMSO-d6) δ: 4.39 (q, J = 7.2 Hz, 4H), 1.28 (t, J = 7.2 Hz, 6H).

[0619] Step 2: Synthesis of intermediate 048_3

[0620] Under room temperature and nitrogen protection, intermediate 048_2 (30 g, 135.02 mmol) was dissolved in tetrahydrofuran (300 mL), and the temperature was lowered to -78 °C. A solution of allylmagnesium bromide (1 M, 202.52 mL) in tetrahydrofuran was slowly added dropwise. The reaction system was stirred at -78 °C for 15 minutes. After the reaction was completed, saturated ammonium chloride solution (300 mL) was added to the reaction system to quench the reaction, and ethyl acetate (200 mL) and water (100 mL) were added for dilution, followed by liquid separation. The aqueous phase was extracted with ethyl acetate (300 mL × 3), and the organic phases were combined. The combined organic phase was washed with saturated brine (250 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 3 / 1, volume ratio). Intermediate 048_3 was obtained. 1 H NMR (400 MHz, DMSO_d6) δ: 5.81 - 5.67 (m, 1H), 5.64 - 5.58 (m, 1H), 5.34 - 5.23 (m, 2H), 4.36 - 4.22 (m, 4H), 2.81 (d, J = 7.2 Hz, 2H), 1.23 (t, J = 7.2 Hz, 6H).

[0621] Step 3: Synthesis of intermediate 048_4

[0622] Under room temperature and nitrogen protection, intermediate 048_3 (5.5 g, 20.81 mmol) was dissolved in tert-butanol (55 mL). Intermediate 001_6 (4.21 g, 13.01 mmol, hydrochloride) and potassium bicarbonate (3.26 g, 32.52 mmol) were added thereto, and the reaction system was heated to 85 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (50 ml), and extracted with ethyl acetate (60 mL × 3). The organic phases were combined and successively washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The obtained residue was added with methyl tert-butyl ether (30 mL), stirred at room temperature for 30 minutes, and a pale yellow solid precipitated out. It was filtered, the solid was collected, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was again added with acetonitrile (30 mL) and stirred at room temperature for 1 hour, and a white solid precipitated out. It was filtered, the solid was collected, and the filtrate was concentrated under reduced pressure to obtain intermediate 048_4. The filtrate was collected, the solvent was removed by concentration under reduced pressure from the filtrate, and the obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 7 / 3, volume ratio). Intermediate 048_4 was obtained. 11H NMR (400 MHz, DMSO-d6) δ: 11.37 (s, 1H), 8.87 (dd, J = 2.8, 8.8 Hz, 1H), 8.70 (dd, J = 1.6, 2.4 Hz, 1H), 7.41 - 7.33 (m, 1H), 7.27 - 7.19 (m, 2H), 7.18 - 7.12 (m, 1H), 6.92 (br s, 2H), 5.87 - 5.76 (m, 2H), 5.39 - 5.26 (m, 1H), 5.08 (dd, J = 1.6, 17.0 Hz, 1H), 4.95 (dd, J = 2.0, 10 Hz, 1H), 4.18 - 4.08 (m, 2H), 3.26 (dd, J = 7.2, 14.0 Hz, 1H), 2.80 (dd, J = 7.2, 14.0 Hz, 1H), 1.14 - 1.09 (m, 3H).

[0623] Step 4: Synthesis of Intermediate 048_5

[0624] Under room temperature and nitrogen protection, dissolve Intermediate 048_4 (1 g, 1.98 mmol) in dichloromethane (20 mL) and tetrahydrofuran (20 mL). Cool the reaction system to -40 °C, introduce ozone into the reaction system until the reaction system turns blue, and then introduce oxygen for 15 minutes. Add thiourea (451.78 mg, 5.94 mmol) into the reaction system and stir at room temperature for 12 hours. After the reaction is completed, detect that there is no peroxide residue with starch potassium iodide test paper, filter, collect the filtrate, and concentrate under reduced pressure to remove the solvent. Intermediate 048_5 is obtained.

[0625] Step 5: Synthesis of Intermediate 048_6

[0626] Under room temperature and nitrogen protection, dissolve Intermediate 048_5 (1 g, 1.97 mmol) in tetrahydrofuran (10 mL). Cool the reaction system to 0 °C, add sodium cyanoborohydride (123.84 mg, 1.97 mmol), stir the reaction system at 0 °C for 0.5 hour, warm up to 25 °C and stir for 11.5 hours. After the reaction is completed, dilute with water (50 mL), extract with 2-methyltetrahydrofuran (80 mL × 3), and combine the organic phases. The organic phase is washed successively with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product is separated by column chromatography (eluent: dichloromethane / methanol = 30 / 1 - 10 / 1, volume ratio). The crude product is obtained. The crude product is separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.1% TFA). Intermediate 048_6 is obtained. 11H NMR (400 MHz, DMSO-d6) δ: 11.04 (s, 1H), 8.90 - 8.78 (m, 1H), 8.71 (br s, 1H), 7.40 - 7.33 (m, 1H), 7.25 - 7.16 (m, 3H), 7.13 - 6.90 (m, 2H), 5.81 (br s, 2H), 4.17 - 4.06 (m, 2H), 3.99 (q, J = 7.2 Hz, 2H), 3.56 (dd, J = 3.6, 7.2 Hz, 1H), 2.33 (br s, 2H), 1.11 (t, J = 7.2 Hz, 3H).

[0627] Step 6: Synthesis of Compound 048

[0628] Under room temperature and nitrogen protection, dissolve intermediate 048_6 (250 mg, 490.71 μmol) in N,N-dimethylformamide (5 mL) in a pre-dried reaction flask. Add tert-butyl nitrite (759.03 mg, 7.36 mmol) and water (1.00 g, 55.51 mmol) thereto, and stir the reaction system at room temperature for 12 hours. After the reaction is completed, dilute with water (10 mL), extract with 2-methyltetrahydrofuran (10 mL × 3), and combine the organic phases. The organic phases are successively washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue is separated by column chromatography (eluent: dichloromethane / methanol = 1 / 0 - 9 / 1, volume ratio) and preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). Compound 048 is obtained. 1 1H NMR (400 MHz, DMSO-d6) δ: 11.67 (s, 1H), 8.78 - 8.74 (m, 1H), 8.51 (dd, J = 2.8, 8.4 Hz, 1H), 7.42 - 7.33 (m, 1H), 7.28 - 7.15 (m, 3H), 5.86 (s, 2H), 4.78 (br dd, J = 2.8, 12.0 Hz, 1H), 4.35 (br t, J = 11.6 Hz, 1H), 4.24 - 4.10 (m, 2H), 2.70 - 2.62 (m, 1H), 2.33 (s, 1H), 1.14 (t, J = 7.0 Hz, 3H).

[0629] Example 49

[0630]

[0631] Synthesis route:

[0632]

[0633] Step 1: Synthesis of Intermediate 049_1

[0634] Under room temperature and nitrogen protection, dissolve intermediate 048_4 (8.7 g, 17.21 mmol) in tetrahydrofuran (90 mL), add hydrazine hydrate (91.44 g, 1.79 mol, 88.78 mL, purity: 98%), heat the reaction system to 85 °C, and stir at 85 °C for 2 hours. After the reaction is completed, cool the reaction system to room temperature, solid precipitates, filter, collect the solid, and concentrate the solid under reduced pressure to remove the solvent. Intermediate 049_1 is obtained. At the same time, collect the filtrate, dilute it with water (80 mL) and 2-methyltetrahydrofuran (100 mL), separate the layers, and collect the organic phase. Extract the aqueous phase with 2-methyltetrahydrofuran (200 mL × 3), combine the organic phases. Wash with saturated brine (100 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Intermediate 049_1 is obtained.

[0635] Step 2: Synthesis of intermediate 049_2

[0636] Under room temperature and nitrogen protection, dissolve intermediate 049_1 (4.74 g, 9.64 mmol) in tetrahydrofuran (50 mL) and methanol (50 mL), add trifluoroacetic acid (1.65 g, 14.47 mmol, 1.07 mL), cool the reaction system to 0 °C, dropwise add tert-butyl nitrite (2.98 g, 28.93 mmol, 3.44 mL), and heat the reaction system to 85 °C and stir for 1.5 hours. After the reaction is completed, cool the reaction system to room temperature, solid precipitates, filter, and collect the filtrate. Concentrate the filtrate under reduced pressure to remove the solvent to obtain a residue. Dissolve the residue in methyl tert-butyl ether (20 mL) and stir for 30 minutes, yellow solid precipitates, filter, and collect the solid. Intermediate 049_2 is obtained. The filtrate is concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 0 / 1, volume ratio). Intermediate 049_2 is obtained.

[0637] Step 3: Synthesis of intermediate 049_3

[0638] Under room temperature and nitrogen protection, dissolve intermediate 049_2 in N-methylpyrrolidone (20 mL), tetrahydrofuran (5 mL) and dichloromethane (5 mL), cool the reaction system to -60 °C, introduce ozone into the reaction system for 30 minutes, and then introduce oxygen for 15 minutes. After the gas introduction is completed, raise the reaction system to 20 °C and add thiourea (1.35 g, 17.77 mmol), and stir at 20 °C for 12 hours. Pour the reaction solution into water (20 mL), and extract with 2-methyltetrahydrofuran (10 mL × 3). Wash the organic phase with saturated brine (5 mL), dry over anhydrous sodium sulfate, filter and concentrate to obtain intermediate 049_3.

[0639] Step 4: Synthesis of intermediate 049_4

[0640] Under room temperature and nitrogen protection, dissolve intermediate 049_3 (4 g, 7.87 mmol) in tetrahydrofuran (40 mL). Cool the reaction system to 0 °C, add sodium cyanoborohydride (494.39 mg, 7.87 mmol), stir the reaction system at 0 °C for 0.5 h, and then restore to room temperature and stir for 11.5 h. Add additional sodium cyanoborohydride (247.20 mg, 3.93 mmol), heat the reaction mixture to 50 °C, and stir for 3 h. After the reaction is completed, cool the reaction system to room temperature, and directly concentrate the reaction solution to remove the solvent. The obtained residue is separated by column chromatography (eluent: dichloromethane / methanol = 100 / 1 - 40 / 1, volume ratio). Intermediate 049_4 is obtained. 1 H NMR (400 MHz, DMSO_d6) δ: 10.93 (s, 1H), 8.81 (dd, J = 2.8, 8.8 Hz, 1H), 8.70 - 8.69 (m, 1H), 7.44 - 7.33 (m, 2H), 7.24 - 7.12 (m, 4H), 6.74 (br s, 1H), 5.81 (s, 2H), 4.62 (t, J = 5.0 Hz, 1H), 4.37 - 4.33 (m, 1H), 3.46 (s, 3H), 3.38 - 3.36 (m, 1H), 2.25 - 2.16 (m, 1H), 2.06 - 1.97 (m, 1H).

[0641] Step 5: Synthesis of Compound 049

[0642] Under room temperature and nitrogen protection, dissolve intermediate 049_4 (200 mg, 391.81 μmol) in N,N-dimethylformamide (4 mL) and water (0.4 mL) in a pre-dried reaction flask. Add tert-butyl nitrite (606.05 mg, 5.88 mmol, 699.02 μL) thereto at 20 °C, stir the reaction system at 20 °C for 2 h, and then heat to 60 °C and stir for 0.5 h. After the reaction is completed, directly filter the reaction solution through a filter head, and collect the filtrate. The filtrate is subjected to two preparative separations (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) and (mobile phase: acetonitrile / water; neutral system: 10 mM NH4HCO3). Compound 049 is obtained. MS-ESI m / z: 494.0 [M + H] +.1H NMR (400 MHz, DMSO-d6) δ: 11.46 (br s, 1H), 8.75 (d, J = 0.8 Hz, 1H), 8.51 (dd, J = 2.8, 8.4 Hz, 1H), 8.37 (br s, 1H), 7.39 - 7.34 (m, 1H), 7.23 (t, J = 9.0 Hz, 2H), 7.17 - 7.13 (m, 1H), 5.85 (s, 2H), 4.70 (br dd, J = 4.0, 12.0 Hz, 1H), 4.56 - 4.51 (m, 1H), 3.49 (s, 3H), 2.25 (br d, J = 13.6 Hz, 1H), 1.77 (dt, J = 4.4, 13.4 Hz, 1H).

[0643] Examples 50 and 51

[0644]

[0645] Synthetic route:

[0646]

[0647] Step 1: Synthesis of intermediate 050_2

[0648] Under room temperature and nitrogen protection, dissolve intermediate 050_1 (50 g, 580.79 mmol) in toluene (900 mL), add p-methoxybenzyl chloride (363.83 g, 2.32 mol) and potassium hydroxide (162.93 g, 2.90 mol), then gradually heat up to 110 °C (first heat to 60 °C, then to 85 °C, and finally to 110 °C). Stir the reaction mixture at 110 °C for 12 hours. Then concentrate under reduced pressure to remove toluene. Dissolve the residue in methanol (1000 mL), and then add a solution of potassium hydroxide (58.00 g, 1.03 mol) in water (500 mL). Stir and react at 85 °C for 12 hours. After the reaction is completed, concentrate under reduced pressure to remove the solvent. Add water (800 mL) to dilute the obtained residue, extract with methyl tert-butyl ether (600 mL × 3), and discard the organic phase; adjust the pH of the aqueous phase to 1 - 2 with concentrated hydrochloric acid, and extract with 2-methyltetrahydrofuran (800 mL × 3). Combine the organic phases. The organic phase is successively washed with saturated brine (800 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. Intermediate 050_2 is obtained. 11H NMR (400 MHz, CDCl3) δ: 9.92 (s, 1H), 7.28 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 4.47 (s, 2H), 3.83 (s, 3H), 3.53 (t, J = 6.0 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 1.96 (m, 2H).

[0649] Step 2: Synthesis of Intermediate 050_3

[0650] Under room temperature and nitrogen protection, dissolve Intermediate 050_2 (108.6 g, 484.28 mmol) in dichloromethane (1000 mL), add ethanol (223.10 g, 4.84 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (111.40 g, 581.13 mmol) and 4-dimethylaminopyridine (7.10 g, 58.11 mmol). The reaction mixture is stirred at room temperature for 12 hours. The reaction solution is concentrated under reduced pressure to remove the solvent. The obtained residue is diluted with water (1500 mL) and ethyl acetate (1000 mL) and then separated by liquid-liquid extraction. The aqueous phase is further extracted with ethyl acetate (800 mL × 2). The combined organic phases are successively washed with saturated aqueous citric acid solution (1000 mL × 3), saturated brine (1000 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained residue is separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1, v / v). Intermediate 050_3 is obtained. 1 1H NMR (400 MHz, CDCl3) δ: 7.28 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.45 (s, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.83 (s, 3H), 3.51 (t, J = 6.0 Hz, 2H), 2.43 (t, J = 7.6 Hz, 2H), 1.99 - 1.92 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H).

[0651] Step 3: Synthesis of Intermediate 050_4

[0652] Under room temperature and nitrogen protection, a solution of lithium diisopropylamide (2 M, 80.94 mL) in tetrahydrofuran was dissolved in tetrahydrofuran (450 mL). After cooling to -78 °C, a solution of intermediate 050_3 (37.13 g, 147.16 mmol) in tetrahydrofuran (150 mL) was slowly added. The mixture was stirred at -78 °C for 1 hour, and then a solution of carbon tetrabromide (73.20 g, 220.74 mmol) in tetrahydrofuran (200 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction solution was slowly poured into a saturated ammonium chloride aqueous solution (1000 mL), and extracted with ethyl acetate (600 mL × 3). The organic phases were combined, washed successively with saturated brine (600 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 7 / 3, volume ratio). Intermediate 050_4 was obtained. 1 H NMR (400 MHz, CDCl3) δ: 7.27 - 7.24 (m, 2H), 6.90 - 6.87 (m, 2H), 4.44 - 4.42 (m, 2H), 4.22 (q, J = 6.8 Hz, 2H), 3.81 (s, 3H), 3.74 (t, J = 6.4 Hz, 2H), 2.96 (t, J = 6.4 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H).

[0653] Step 4: Synthesis of intermediate 050_5

[0654] Under room temperature and nitrogen protection, intermediate 050_4 (14.7 g, 35.85 mmol) was dissolved in acetonitrile (150 mL). After cooling to 0 °C, triethylamine (3.63 g, 35.85 mmol) and diethyl phosphite (4.95 g, 35.85 mmol) were added successively. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 17 / 3, volume ratio). Intermediate 050_5 was obtained. 1 H NMR (400 MHz, CDCl3) δ: 7.25 (d, J = 8.8 Hz, 2H), 6.90 - 6.88 (m, 2H), 4.49 (m, 1H), 4.44 (s, 2H), 4.25 - 4.18 (m, 2H), 3.82 (s, 3H), 3.61 - 3.57 (m, 2H), 2.44 - 2.35 (m, 1H), 2.24 - 2.16 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H).

[0655] Step 5: Synthesis of intermediate 050_6

[0656] Under room temperature and nitrogen protection, a solution of potassium tert-butoxide (1 M, 40.94 mL) in tetrahydrofuran was added dropwise to a solution of malononitrile (11.3 g, 34.12 mmol) in tetrahydrofuran (80 mL), and the mixture was stirred at room temperature for 30 minutes. At 75 °C, the reaction mixture was added to a solution of intermediate 050_5 (11.3 g, 34.12 mmol) in tetrahydrofuran (80 mL), and stirring was continued for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into dilute hydrochloric acid (1 M, 100 mL), extracted with ethyl acetate (100 mL), and the aqueous phase was extracted again with ethyl acetate (100 mL × 2). The organic phases were combined. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 7 / 3, volume ratio). Intermediate 050_6 was obtained. 1 H NMR (400 MHz, CDCl3) δ: 7.26 - 7.24 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 4.44 (s, 2H), 4.35 (d, J = 6.4 Hz, 1H), 4.29 - 4.23 (m, 2H), 3.83 (s, 3H), 3.62 - 3.54 (m, 2H), 3.24 - 3.19 (m, 1H), 2.30 - 2.23 (m, 1H), 2.17 - 2.10 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H).

[0657] Step 6: Synthesis of intermediate 050_7

[0658] Under room temperature and nitrogen protection, intermediate 001_6 (1.02 g, 3.16 mmol, hydrochloride) was dissolved in ethanol (20 mL), sodium ethoxide (537.78 mg, 7.90 mmol) and intermediate 050_6 (1 g, 3.16 mmol) were added successively, and the reaction mixture was stirred at 80 °C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the solvent was removed by concentration under reduced pressure. The residue was extracted and separated with water (50 mL) and 2-methyltetrahydrofuran (50 mL), and the aqueous phase was extracted again with 2-methyltetrahydrofuran (50 mL × 2). The organic phases were combined. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0 - 3 / 7, volume ratio). Intermediate 050_7 was obtained. 11H NMR (400 MHz, DMSO-d6) δ: 10.93 (s, 1H), 8.84 (dd, J = 2.8, 8.8 Hz, 1H), 8.70 (dd, J = 1.6, 2.8 Hz, 1H), 7.39 - 7.33 (m, 1H), 7.27 - 7.22 (m, 2H), 7.17 - 7.13 (m, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.81 (s, 2H), 6.71 (d, J = 8.4 Hz, 2H), 5.81 (s, 2H), 4.28 (d, J = 11.6 Hz, 1H), 4.14 (d, J = 11.6 Hz, 1H), 3.85 - 3.67 (m, 2H), 3.54 (s, 3H), 3.52 - 3.49 (m, 1H), 2.44 (t, J = 7.2 Hz, 2H).

[0659] Step 7: Synthesis of Intermediate 050_8

[0660] Under room temperature and nitrogen protection, dissolve Intermediate 050_7 (5.5 g, 9.86 mmol) in 1,2-dichloroethane (110 mL). Cool the solution to 0 °C and add a toluene solution of aluminum trichloride (3.95 g, 29.59 mmol). Stir the reaction mixture at room temperature for 12 hours. After the reaction is completed, pour the reaction solution into dilute hydrochloric acid (1 M, 200 mL), extract with 2-methyltetrahydrofuran (200 mL), and extract the aqueous phase with 2-methyltetrahydrofuran (200 mL × 2). Combine the organic phases. Dry the organic phases over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. The obtained residue is separated by column chromatography (eluent: dichloromethane / methanol = 1 / 0 - 20 / 1, volume ratio). Intermediate 050_8 is obtained.

[0661] Step 8: Synthesis of Compound 051

[0662] Under room temperature and nitrogen protection, dissolve Intermediate 050_8 (800 mg, 1.83 mmol) in N,N-dimethylformamide (16 mL) and water (1.6 mL). Add tert-butyl nitrite (2.83 g, 27.43 mmol). Stir the reaction mixture at room temperature for 12 hours. After the reaction is completed, dilute the reaction solution with 2-methyltetrahydrofuran (80 mL) and wash with semi-saturated brine (50 mL × 3). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. The obtained residue is separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). Compound 051 is obtained. MS-ESI m / z: 437.0 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ: 11.23 (s, 1H), 8.75 (dd, J = 1.6, 2.8 Hz, 1H), 8.51 (dd, J = 2.8, 8.4 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.28 - 7.21 (m, 2H), 7.18 - 7.14 (m, 1H), 6.65 (s, 1H), 5.85 (s, 2H), 4.73 (dd, J = 3.2, 11.6 Hz, 1H), 4.64 - 4.55 (m, 1H), 2.05 (d, J = 14.0 Hz, 1H), 1.76 (dt, J = 4.8, 13.6 Hz, 1H).

[0663] Step 9: Synthesis of Compound 050

[0664] Under room temperature and nitrogen protection, dissolve Compound 051 (60 mg, 137.50 μmol) in tetrahydrofuran (2 mL), cool down to 0 °C and add sodium hydride (16.5 mg, 412.49 μmol, purity: 60%). Stir the reaction at 0 °C for 30 minutes, then add ethyl isocyanate (4.89 mg, 68.75 μmol). Stir the reaction mixture at room temperature for 2 hours. After the reaction is completed, add saturated ammonium chloride aqueous solution (5 mL), extract with 2-methyltetrahydrofuran (5 mL), and extract the aqueous phase again with 2-methyltetrahydrofuran (5 mL × 2). Combine the organic phases. Dry the organic phases over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. The obtained residue is separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). Compound 050 is obtained. MS-ESI m / z: 508.0 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ: 11.55 (s, 1H), 8.75 (s, 1H), 8.73 - 8.70 (m, 1H), 8.49 (t, J = 6.0 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.23 (t, J = 9.2 Hz, 2H), 7.17 - 7.13 (m, 1H), 5.86 (s, 2H), 4.72 (d, J = 12.8 Hz, 1H), 4.31 (t, J = 10.8 Hz, 1H), 3.18 - 3.08 (m, 2H), 2.43 (s, 2H), 1.01 (t, J = 7.2 Hz, 3H).

[0665] Examples 52 and 53

[0666]

[0667] Synthetic route:

[0668]

[0669] Step 1: Synthesis of Intermediate 052_1

[0670] Under room temperature and nitrogen protection, Intermediate 012_3 (300 mg, 0.829 mmol, hydrochloride) and Intermediate 035_1 (348.78 mg, 1.24 mmol) were dissolved in tert-butanol (6 mL), potassium carbonate (343.92 mg, 2.49 mmol) was added, and the reaction system was heated to 85 °C and stirred for 12 hours. The reaction system was cooled to room temperature, water (40 mL) and 2-methyltetrahydrofuran (30 mL) were added, and liquid separation was performed to collect the organic phase. The organic phase was successively washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The obtained residue was separated by column chromatography (eluent: dichloromethane / methanol = 1 / 0 - 98 / 2, volume ratio). Intermediate 052_1 was obtained.

[0671] Step 2: Synthesis of Intermediate 052_2

[0672] Under room temperature and nitrogen protection, Intermediate 052_1 (250 mg, 446.86 μmol) was dissolved in toluene (4 mL), and a toluene solution of trimethylaluminum (2 M, 0.715 mL) was added under nitrogen protection. The reaction system was heated to 80 °C and stirred for 12 hours. After the reaction was completed, 6 mL of 3 M hydrochloric acid solution was added, diluted with ethyl acetate (40 mL) and water (20 mL), and liquid separation was performed to collect the organic phase. The aqueous phase was extracted with ethyl acetate (40 mL × 3), and the organic phases were combined. The combined organic phase was successively washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The obtained residue was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl). The target intermediate 052_2 was obtained. MS-ESI m / z: 514.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 11.57 (s, 1H), 11.21 (s, 1H), 8.76 - 8.75 (m, 1H), 8.71 (dd, J = 2.8, 8.4 Hz, 1H), 4.91 (t, J = 6.8 Hz, 2H), 3.07 - 2.93 (m, 2H), 1.34 (d, J = 4 Hz, 6H), 0.78 (s, 3H).

[0673] Step 3: Synthesis of Compounds 052 and 053

[0674] Intermediate 052_2 (185 mg, 360.35 μmol) was separated by chiral column (column type: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 μm); mobile phase: [Neu-IPA]%: 25% - 25%, 4 min). The target compounds 052 and 053 were obtained.

[0675] 052 (retention time: 2.411 min): MS-ESI m / z: 514.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 11.55 (s, 1H), 11.18 (s, 1H), 8.76 - 8.75 (m, 1H), 8.71 (dd, J = 2.8, 8.4 Hz, 1H), 4.91 (t, J = 6.4 Hz, 2H), 3.06 - 2.93 (m, 2H), 1.33 (d, J = 6.4 Hz, 6H), 0.77 (s, 3H).

[0676] 053 (retention time: 2.642 min): MS-ESI m / z: 514.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) δ: 11.55 (s, 1H), 11.17 (s, 1H), 8.76 - 8.75 (m, 1H), 8.71 (dd, J = 2.8, 8.4 Hz, 1H), 4.91 (t, J = 6.4 Hz, 2H), 3.11 - 2.90 (m, 2H), 1.33 (d, J = 6.4 Hz, 6H), 0.77 (s, 3H).

[0677] Example 54

[0678]

[0679] Synthesis route:

[0680]

[0681] Step 1: Synthesis of intermediate 054_1

[0682] Under room temperature and nitrogen protection, 048_6 (1 g, 1.96 mmol) was dissolved in tetrahydrofuran (10 mL), and then 2-methoxyethylamine (4.42 g, 58.89 mmol) was added. The reaction system was stirred at 65 °C for 12 hours. After the reaction was completed, the temperature was lowered to room temperature, diluted with water (10 mL), adjusted to pH = 5 - 6 with 3 M dilute hydrochloric acid, extracted with 2-methyltetrahydrofuran (20 mL × 3), and the organic phases were combined. They were washed successively with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by concentration under reduced pressure. The obtained residue was separated by column chromatography (eluent: dichloromethane / methanol = 1 / 0 - 97 / 3, volume ratio) to obtain compound 054_1.

[0683] Step 2: Synthesis of compound 054

[0684] Under room temperature and nitrogen protection, 054_1 (188 mg, 349.11 μmol) was dissolved in N,N-dimethylformamide (2 mL) in a pre-dried reaction flask, and then tert-butyl nitrite (540 mg, 5.24 mmol) and water (200 mg, 11.10 mmol) were added. The reaction system was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.04% HCl) to obtain compound 054. MS-ESI m / z: 522.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ: 11.44 (s, 1H), 8.78 - 8.75 (m, 1H), 8.53 (dd, J = 2.8, 8.4 Hz, 1H), 8.01 (t, J = 5.6 Hz, 1H), 7.41 - 7.33 (m, 1H), 7.27 - 7.16 (m, 3H), 5.91 - 5.81 (m, 2H), 4.72 (d, J = 12.4 Hz, 1H), 4.13 - 4.05 (m, 1H), 3.29 - 3.16 (m, 7H), 2.72 (d, J = 13.4 Hz, 1H), 1.88 - 1.78 (m, 1H).

[0685] Example 55

[0686]

[0687] Synthetic route:

[0688]

[0689] Step 1: Synthesis of intermediate 055_1

[0690] Under room temperature and nitrogen protection, dissolve intermediate 048_4 (3.0 g, 5.94 mmol) in 1,4-dioxane (30 mL). Add isoamyl nitrite (3.48 g, 29.68 mmol, 4.00 mL) and diiodomethane (4.77 g, 17.81 mmol, 1.44 mL) to the reaction system. Heat the reaction system to 100 °C and stir for 2 hours. The reaction system changes from turbid to clear. Continue to stir the reaction at 100 °C for 4 hours. After the reaction is completed, directly concentrate the reaction solution to remove the solvent to obtain the crude product. The crude product is separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 0 / 1, volume ratio) to obtain intermediate 055_1.

[0691] Step 2: Synthesis of intermediate 055_2

[0692] Under room temperature and nitrogen protection, disperse intermediate 055_1 (800 mg, 1.30 mmol), vinyltributyltin (617.36 mg, 1.95 mmol, 566.39 μL) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (106.0 mg, 129.79 μmol) in 1,4-dioxane (10 mL). Place the reaction vessel in an oil bath at 80 °C and stir for 12 hours. After the reaction is completed, pour the reaction solution into water (100 mL), extract with ethyl acetate (40 mL × 3), and combine the organic phases. The organic phase is washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product is separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1, volume ratio) to obtain intermediate 055_2.

[0693] Step 3: Synthesis of compound 055

[0694] Under room temperature and nitrogen protection, dissolve intermediate 055_2 (300 mg, 580.83 μmol) in dichloromethane (5 mL), and add GRUBB'S second-generation catalyst (49.31 mg, 58.08 μmol). Then stir the reaction solution at room temperature for 15 hours. After the reaction is completed, directly concentrate the reaction solution to remove the solvent to obtain the residue. The residue is separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1, volume ratio) to obtain the crude product of the product. The crude product of the product is further separated by preparative HPLC (mobile phase: acetonitrile / water; hydrochloric acid system: 0.04% HCl) to obtain compound 055. MS-ESI m / z: 489.1 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ: 11.76 (s, 1H), 8.75 - 8.74 (m, 1H), 8.63 (dd, J = 3.2, 5.6 Hz, 1H), 7.41 - 7.35 (m, 1H), 7.29 - 7.21 (m, 2H), 7.19 - 7.15 (m, 1H), 6.74 (dd, J = 2.4, 9.6 Hz, 1H), 6.62 - 6.58 (m, 1H), 5.86 (s, 2H), 4.20 - 4.05 (m, 2H), 3.26 (dd, J = 5.6, 17.6 Hz, 1H), 2.75 (td, J = 2.4, 17.6 Hz, 1H), 1.08 (t, J = 7.2 Hz, 3H).

[0695] Example 56

[0696]

[0697] Synthesis route:

[0698]

[0699] Step 1: Synthesis of intermediate 056_1

[0700] Under room temperature and nitrogen protection, dissolve intermediate 049_2 (0.5 g, 987.24 μmol) in 1,4-dioxane (5 mL). Add isoamyl nitrite (578.27 mg, 4.94 mmol) and diiodomethane (793.24 mg, 2.96 mmol) to the reaction system. Heat the reaction system to 85 °C and stir for 2 hours. The reaction system changes from turbid to clear. After the reaction is completed, pour the reaction solution into water (50 mL), extract with ethyl acetate (20 mL × 3), and combine the organic phases. The organic phase is washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated. The obtained residue is separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 0 / 1, volume ratio) to obtain intermediate 056_1.

[0701] Step 2: Synthesis of intermediate 056_2

[0702] Under room temperature and nitrogen protection, intermediate 056_1 (500 mg, 809.92 μmol), vinyltributyltin (385.23 mg, 1.21 mmol) and dichloromethane complex of [1,1-bis(diphenylphosphino)ferrocene] palladium dichloride (66.14 mg, 80.99 μmol) were dissolved in 1,4-dioxane (10 mL). The reaction vessel was placed in an oil bath at 80 °C and stirred for 12 hours. After the reaction was completed, the reaction solution was poured into water (50 mL), extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1, volume ratio) to obtain intermediate 056_2.

[0703] Step 3: Synthesis of compound 056

[0704] Under room temperature and nitrogen protection, intermediate 056_2 (150 mg, 289.86 μmol) was dissolved in dichloromethane (3 mL), and GRUBB'S second-generation catalyst (24.61 mg, 28.99 μmol) was added. The reaction system was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was directly concentrated to remove the solvent to obtain a residue. The residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 2, volume ratio) to obtain a crude product. The crude product was separated by preparative HPLC (mobile phase: acetonitrile / water; hydrochloric acid system: 0.04% HCl) to obtain compound 056. MS-ESI m / z: 490.1 [M+H] + . 1 H NMR (400 MHz, MeOD_d4) δ: 8.65 - 8.60 (m, 2H), 7.33 (q, J = 7.2 Hz, 1H), 7.24 (br t, J = 7.6 Hz, 1H), 7.15 - 7.07 (m, 2H), 6.84 (dd, J = 2.8, 9.6 Hz, 1H), 6.71 (ddd, J = 2.0, 5.6, 9.6 Hz, 1H), 5.95 (s, 2H), 3.56 (s, 3H), 2.89 (dd, J = 5.6, 18.0 Hz, 1H), 2.64 (td, J = 2.4, 18.0 Hz, 1H).

[0705] Biological test

[0706] Experimental example 1: In vitro activity test

[0707] I. cGMP expression test based on lnCap cells

[0708] 1. Experimental procedure

[0709] 1) Solution preparation

[0710] ● 10% BSA (Bovine Serum Albumin)

[0711] Dissolve 10 g of BSA in 100 mL of double-distilled water (ddH2O) to obtain 10% BSA.

[0712] ● 5 mM DETA (Diethylenetriamine)-NO

[0713] Weigh 10 mg of DETA-NO and dissolve it in 12.2 mL of double-distilled water (ddH2O) to obtain 5 mM DETA-NO. Aliquot and store at -20 °C in a refrigerator.

[0714] ● Washing Buffer (50 mL)

[0715]

[0716] ● Assay Buffer (50 mL)

[0717]

[0718] ● Detection Buffer

[0719] a) Add 50 μL of cGMP-D2 (cyclic guanosine monophosphate labeled with D2) to 1 mL of lysis buffer and mix well.

[0720] b) Add 50 μL of anti-cGMP cryptate (Eu 3+ cryptate-labeled anti-cyclic guanosine monophosphate antibody) to 1 mL of lysis buffer and mix well.

[0721] 2) Compound dilution

[0722] (1) Dilute the compound to 5 mM with DMSO. Transfer 10 μL of the compound to a shallow-well plate for Echo.

[0723] (2) Use Echo to perform gradient dilution of the compound, dilute each compound by 10 concentration gradients and add 50 nL to a 384-well microplate respectively.

[0724] 3) Prepare LNCap cells

[0725] (1) LNCap medium: RPMI1640 + 10% fetal bovine serum + 1% double antibody.

[0726] (2) Preheat the phosphate buffer solution, trypsin, and medium used in the cell passage process in a 37 °C water bath.

[0727] (3) Remove the cells (passage 14) from the 37 °C, 5% CO2 incubator, and aspirate the old culture medium in the culture flask using a pipette.

[0728] (4) Aspirate 5 mL of phosphate buffer and add it to the culture flask to rinse the cells, then discard the liquid.

[0729] (5) Aspirate 3 mL of trypsin and add it to the culture flask. After shaking, discard the liquid and place the culture flask in the incubator.

[0730] (6) After approximately 2 minutes, take out the culture flask. After observing that the cells have detached, aspirate 9 mL of culture medium and add it to the culture flask, then pipette up and down several times. Transfer the cell suspension to a 50 mL centrifuge tube.

[0731] (7) Aspirate 0.7 mL of the cell suspension and add it to the counting chamber, then count on the ViCell XR. For the remaining cells, centrifuge at 1000 rpm for 5 minutes and discard the supernatant.

[0732] (8) Add 10 mL of washing buffer to wash the cells, centrifuge at 1000 rpm for 5 minutes, and discard the supernatant.

[0733] (9) Add assay buffer and adjust the cell concentration to 1.25×10 6 / mL. Add 8 μL per well to the microplate.

[0734] 4) Preparation and addition of DETA-NO

[0735] (1) Take 10 μL of 5 mM DETA-NO and add it to 1240 μL and 1657 μL of assay buffer respectively to obtain 40 μM and 30 μM DETA-NO.

[0736] (2) Use Bravo to transfer 2 μL per well of DETA-NO to the 384-well microplate.

[0737] (3) Centrifuge at 1500 rpm for 5 minutes. Incubate the microplate at 37 °C for 30 minutes.

[0738] 5) Prepare the cGMP standard curve

[0739] (1) Dilute the 1 mM cGMP stock solution to 10 μM with assay buffer. Then perform 11-fold serial dilutions with a 4-fold dilution factor.

[0740] (2) Add the diluted cGMP to the microplate at 10 μL per well.

[0741] 6) Add the detection reagent and read the plate

[0742] (1) Transfer 5 μL / well of cGMP-D2 into a 384-well microplate using Bravo. Centrifuge at 1500 rpm for 1 min.

[0743] (2) Transfer 5 μL / well of anti-cGMP cryptate into a 384-well microplate using Bravo. Centrifuge at 1500 rpm for 1 min.

[0744] (3) Incubate at room temperature for 1 h.

[0745] (4) Read 665 / 615 using Envision.

[0746] 7) Data analysis

[0747] (1) cGMP standard curve: Use Graphpad prism to create a standard curve based on the ratio of cGMP concentration to 665 / 615.

[0748] (2) Convert the HTRF (Homogeneous Time-Resolved Fluorescence) ratio (665 / 615) to cGMP concentration: In Graphpad prism, copy the HTRF ratio (665 / 615) into the ratio column of the cGMP standard curve, run the analysis "Log inhibitor vs response - variable slope", select "interpolate", and convert the HTRF ratio (665 / 615) to cGMP concentration.

[0749] (3) Compound activation curve: Use the "Log agonist vs response - variable slope" analysis method in Graphpad prism to create a curve based on the converted cGMP concentration and the compound concentration.

[0750] Table 1 MEC values of the compounds in this application for sGC stimulation activity

[0751] Compound Number MEC (nM) Compound Number MEC (nM) Compound Number MEC (nM) 001 6.38 016 17.51 034 31.53 002 81.22 017 3.46 035 10.08 003 7.97 018 13.12 036 ＜5.08 004 142.79 019 2.4 037 33.86 005 5.21 020 28.72 038 19.13 006 2.32 021 18.99 039 28.15 007 55.54 022 24.9 040 931.1 008 88.37 023 26.12 041 160.5 009 5.8 024 7.59 042 24.32 010 51.76 028 21.26 043 29.99 011 178.6 029 37.34 048 33.55 012 118.6 030 84.34 049 126.5 013 3.12 031 19.78 050 231.7 014 402.7 032 23.75 052 68.64 015 4.66 033 20.71 053 25.81

[0752] MEC: The minimum effective concentration that stimulates cGMP production (more than three times the basal value) in lnCap cells.

[0753] Experimental conclusion: The compounds in this application can effectively stimulate sGC and significantly increase the cGMP level.

[0754] Experimental Example 2: In vivo pharmacokinetic property study

[0755] Experimental purpose: The purpose of this study is to determine the pharmacokinetic parameters of the compound in male SD rats.

[0756] Experimental materials:

[0757] Sprague Dawley rats (male, 200 - 300 g, 7 - 9 weeks old, from Shanghai SLAC)

[0758] Experimental methods:

[0759] Four male SD rats were used in this project. Two SD rats in one group were given intravenous injection with a dosage of 0.3 mg / kg and a concentration of 0.15 mg / mL; two SD rats in another group were given oral administration with a dosage of 1 mg / kg and a concentration of 0.2 mg / mL. Plasma samples were collected at 0.083 (only for the intravenous group), 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 h after administration, and then the collected samples were analyzed by LC - MS / MS and data were collected. The collected analytical data were used to calculate relevant pharmacokinetic parameters with Phoenix WinNonlin 6.3 software.

[0760] The experimental results are shown in Table 2.

[0761] Table 2 Results of in - vivo pharmacokinetic experiments

[0762]

[0763] Conclusion: The compound of this application has good clearance rate, half - life and oral bioavailability after gavage.

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from R2 is independently selected from R-containing groups having 1 or 2 R d substituted and C-containing groups having 1, 2 or 3 R d substituted C 1-3 alkyl; R3 is independently selected from H and halogen; R4 is selected from H and C 1-3 alkyl; E1 is selected from -(CH2) m -; m is selected from 0, 1 and 2; E2 is selected from -(CH2) n -, -(CH2) p C(O)-, -O(CH2) q -, -O(CH2) r C(O)-, -CH2CH=CH- and -(CH2) s NHC(O)-, and each CH2 is optionally substituted with 1 or 2 R b substituents; E3 is selected from a single bond, NR c and O; n is selected from 1, 2 and 3; p is selected from 0, 1 and 2; q is selected from 1 and 2; r is selected from 1 and 2; s is selected from 1 and 2; T1 is selected from N and Cr a ; R a each independently selected from H, OH, -OC(=O)NHEt, -CO2Et, -NHCO2CH3, -C(=O)NH(CH2)2OCH3, and C 1-3 alkyl; R b each independently selected from F and CH3; R c each independently selected from H and CH3; R d Each independently selected from halogen and CF3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R a are each independently selected from H, OH, -OC(=O)NHEt, -CO2Et, -C(=O)NH(CH2)2OCH3, -NHCO2CH3 and CH3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R d Each independently selected from F and CF3.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R2 is independently selected from a group consisting of a group containing one or two R d substituted and a group containing one, two or three R d substituted C 1-3 alkyl groups.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, R2 is independently selected from 6. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein, R2 is independently selected from 7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R3 are each independently selected from H and F.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from 9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from 10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R1 is selected from 11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, E1 is selected from a single bond, -CH2- and -(CH2)2-.

12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, E2 is selected from -CH2-, -(CH2)2-, -(CH2)3-, -CH2CO-, -(CH2)2CO-, -O(CH2)2-, -OCH2C(O)-, and -CH2NHC(O)-, and each CH2 is optionally substituted with 1 or 2 Rs b substituted.

13. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein, E2 is selected from -CH2-, -(CH2)2-, -CF2CH2-, -(CH2)3-, -CH2CH=CH-, -CH2CO-, -CO-, -C(CH3)2CO-, -CF2CO-, -(CH2)2CO-, -O(CH2)2-, -OCH2C(O)- and -CH2NHC(O)-.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, E3 is selected from a single bond, NH, N(CH3) and O.

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, T1 is selected from N, CH, C(OH), C(OC(=O)NHEt), C(CO2Et), C(NHCO2CH3), C[C(=O)NH(CH2)2OCH3] and C(CH3).

16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from 17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Structural unit Selected from 18. The compound or a pharmaceutically acceptable salt thereof according to claims 1-16, wherein the compound is selected from wherein R2, R4, T1, E1, E2 and E3 are as defined in any one of claims 1-16.

19. A compound of the following formula or a pharmaceutically acceptable salt thereof:

20. A compound of the following formula or a pharmaceutically acceptable salt thereof:

21. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-20.

22. The pharmaceutical composition according to claim 21, wherein, It further comprises a pharmaceutically acceptable excipient. [[ID= ​

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