Pyrimidine tricyclic compounds and uses thereof

Abstract

This application discloses pyrimidine tricyclic compounds and their uses, particularly pyrimidine tricyclic compounds and their applications in the preparation of medicaments for the treatment of related diseases. Specifically, the present application discloses a compound represented by formula (II), its stereoisomers, and pharmaceutically acceptable salts thereof: [C1] TIFF2023523830000173.tif42156

Description

[Technical field]

[0001] This application claims priority to Chinese patent application CN202010361013.7 filed on April 30, 2020 and Chinese patent application CN202110390228.6 filed on April 12, 2021. This application cites the above Chinese patent applications in their entirety.

[0002] <Technical field> The present application relates to pyrimidine tricyclic compounds and their use in the preparation of medicaments for the treatment of related diseases, specifically, the compounds represented by formula (I) and (II) or stereoisomers or pharmaceutically acceptable salts thereof: [Background technology]

[0003] Soluble guanylate cyclase (sGC) is widely present in the cytosol of mammals and is a heterodimer consisting of two subunits, α and β. Soluble guanylate cyclase is an important signaling substance of the NO-sGC-cGMP signaling pathway. When activated in vivo, sGC catalyzes the conversion of guanosine triphosphate (GTP) to guanosine cyclic phosphate (cGMP). cGMP is an important second messenger molecule that activates various effector molecules downstream, such as cGMP-dependent protein kinase G and cGMP-gated ion channels, triggering a series of downstream cascade reactions. sGC exerts important physiological functions in the gastrointestinal system, cardiovascular system, and central nervous system, such as promoting the dilation of blood vessels and smooth muscles, suppressing platelet coagulation, vascular remodeling, apoptosis, and inflammation, and participating in neurotransmission. Under pathophysiological conditions, inhibition of the NO / cGMP system can lead to, for example, hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke, sexual dysfunction, etc. In addition, research over the past two years has revealed that abnormalities in the sGC-mediated signaling pathway are also closely related to the development of fibrotic diseases such as chronic kidney disease and systemic sclerosis.

[0004] sGC stimulators have two mechanisms of action, which are NO-independent and Fe 2+ It can rely on direct activation of the sGC-cGMP signaling pathway by hemoglobin-containing cofactors, or it can increase the sensitivity of sGC to endogenous NO and act synergistically with NO. Thus, sGC stimulators are heme-dependent and NO-independent. Stimulating sGC to produce more cGMP can regulate various important physiological processes, such as promoting vascular smooth muscle dilation and inhibiting platelet aggregation. At the same time, activation of sGC can regulate other signaling pathways, such as TGF-β, and exert anti-fibrotic and anti-tumor effects. Therefore, sGC stimulators can be used as a potential therapeutic tool for cardiovascular diseases (heart failure, pulmonary arterial hypertension, angina pectoris, myocardial infarction) and fibrotic diseases (renal fibrosis, systemic sclerosis).

[0005] In response to the current unmet need in the market and in clinical practice for such soluble guanylate cyclase stimulators, the present application provides novel compounds that can be used as stimulators of soluble guanylate cyclase, have excellent in vitro stimulatory activity for soluble guanylate cyclase, and have good pharmacokinetic properties. Summary of the Invention [Means for solving the problem]

[0006] The present application provides a compound of formula (II), or a stereoisomer or a pharma- ceutically acceptable salt thereof: [ka] however, R 1 teeth, [ka] Selected from; R 2 each independently represents one or two R d as a substituent [ka] 1 or 2 R d as a substituent [ka] and 1, 2 or 3 R d C having as a substituent 1-3 Selected from alkyl groups; R 3 are each independently selected from H and halogen; R 4 H, and C 1-3 Selected from alkyl groups; E 1 is -(CH 2 ) m - Selected from; m is selected from 0, 1, and 2; E 2 is -(CH 2 ) n -, -(CH 2 ) p C(O)-, -O(CH 2 ) q -, -O(CH 2 ) r C(O)-, -CH 2 CH=CH- and -(CH 2 ) s NHC(O)-, wherein each CH 2 is optionally 1 or 2 R b Replaced by; E 3 is 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; T 1 N, and CR a Selected from; R aare each independently H, OH, -OC(=O)NHEt, -CO 2 Et, -NHCO 2 CH 3 , -C(=O)NH(CH 2 ) 2 OCH 3 , and C 1-3 Selected from alkyl groups; R b are each independently F, and CH 3 Selected from; R c are each independently H and CH 3 Selected from; R d are each independently a halogen, and CF 3 Selected from.

[0007] In some embodiments of the present application, the R a are each independently H, OH, -OC(=O)NHEt, -CO 2 Et, -C(=O)NH(CH 2 ) 2 OCH 3 , -NHCO 2 CH 3 , and C.H. 3 and the other symbols are as defined herein.

[0008] In some embodiments of the present application, the R d are each independently F, and CF 3 and the other symbols are as defined herein.

[0009] In some embodiments of the present application, the R 2 each independently represents one or two R d as a substituent [ka] 1 or 2 R d as a substituent [ka] and 1, 2 or 3 R d C having as a substituent 1-3 The alkyl group is selected from the group consisting of alkyl groups, and the other symbols are as defined herein.

[0010] In some embodiments of the present application, each R 2 are each independently [ka] and the other symbols are as defined herein.

[0011] In some embodiments of the present application, each R 2 teeth, [ka] and the other symbols are as defined herein.

[0012] In some embodiments of the present application, each R 2 teeth, [ka] and the other symbols are as defined herein.

[0013] In some embodiments of the present application, each R 3 is selected from H and F, and other symbols are as defined herein.

[0014] In some embodiments of the present application, the R 1 teeth, [ka] and the other symbols are as defined herein.

[0015] In some embodiments of the present application, the R 1 teeth, [ka] and the other symbols are as defined herein.

[0016] In some embodiments of the present application, the R 1 teeth, [ka] and the other symbols are as defined herein.

[0017] In some embodiments of the present application, the E 1 is a single bond, -CH 2 - and -(CH 2 ) 2 -, and other symbols are as defined herein.

[0018] In some embodiments of the present application, the E 2 is -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -CH 2 CH=CH-, -CH 2 CO-, -(CH 2 ) 2 CO-, -O(CH 2 ) 2 -, -OCH 2 C(O)- and -CH 2 NHC(O)-, wherein each CH 2 is optionally 1 or 2 R b and other symbols are as defined herein.

[0019] In some embodiments of the present application, the E 2 is -CH 2 -, -(CH 2 ) 2 -, -CF 2 CH 2 -, -(CH 2 ) 3 -, -CH 2CH=CH-, -CH 2 CO-, -CO-, -C(CH 3 ) 2 CO-, -CF 2 CO-, -(CH 2 ) 2 CO-, -O(CH 2 ) 2 -, -OCH 2 C(O)- and -CH 2 NHC(O)-, and other symbols are as defined herein.

[0020] In some embodiments of the present application, the E 3 is a single bond, NH, N(CH 3 ), and O, and other symbols are as defined herein.

[0021] In some embodiments of the present application, the T 1 are N, CH, C(OH), C(OC(=O)NHEt), C(CO 2 Et), C(NHCO 2 CH 3 ), C[C(=O)NH(CH 2 ) 2 OCH 3 ], and C(CH 3 ) and the other symbols are as defined herein.

[0022] In some embodiments of the present application, the structural unit: [ka] and the other symbols are as defined herein.

[0023] In some embodiments of the present application, the structural unit: [ka] and the other symbols are as defined herein.

[0024] The present application provides a compound of formula (I), or a stereoisomer or a pharma- ceutically acceptable salt thereof: [ka] however, R 1 teeth, [ka] Selected from; Each R 2 each independently has 1 or 2 substituents [ka] Has 1 or 2 substituents [ka] and C having 1, 2 or 3 substituents 1-3 alkyl groups, the substituents being halogen, and CF 3 Selected from; Each R 3 are each independently selected from H and halogen; E 1 is -(CH 2 ) m - Selected from; m is selected from 0, 1, and 2; E 2 is -(CH 2 ) n - and -(CH 2 ) p C(O)-; each n is selected from 1, 2, and 3; each p is selected from 0, 1, and 2; T 1 N, and CR a Selected from; R a H, and C 1-3 It is selected from alkyl groups.

[0025] In some embodiments of the present application, each R 2each independently has 1 or 2 substituents [ka] Has 1 or 2 substituents [ka] and C having 1, 2 or 3 substituents 1-3 alkyl groups, the substituents being selected from F, and CF 3 and the other symbols are as defined herein.

[0026] In some embodiments of the present application, each R 2 teeth, [ka] and the other symbols are as defined herein.

[0027] In some embodiments of the present application, each R 3 is selected from H and F, and other symbols are as defined herein.

[0028] In some embodiments of the present application, the R 1 teeth, [ka] and the other symbols are as defined herein.

[0029] In some embodiments of the present application, the E 1 is a single bond, -CH 2 - and -(CH 2 ) 2 -, and other symbols are as defined herein.

[0030] In some embodiments of the present application, the E 2 is -CH 2 -, -(CH 2 ) 2-, -(CH 2 ) 3 -, -CH 2 CO- and -(CH 2 ) 2 CO-, and other symbols are as defined herein.

[0031] In some embodiments of the present application, the T 1 is N, and -C(CH 3 )-, and the other symbols are as defined herein.

[0032] In some embodiments of the present application, the structural unit: [ka] and the other symbols are as defined herein.

[0033] The present application provides a compound of formula (II), or a stereoisomer or a pharma- ceutically acceptable salt thereof: [ka] however, R 1 teeth, [ka] Selected from; R 2 each independently represents one or two R d as a substituent [ka] 1 or 2 R d as a substituent [ka] and 1, 2 or 3 R d C having as a substituent 1-3 Selected from alkyl groups; R 3are each independently selected from H and halogen; R 4 H, and C 1-3 Selected from alkyl groups; E 1 is -(CH 2 ) m - Selected from; m is selected from 0, 1, and 2; E 2 is -(CH 2 ) n -, -(CH 2 ) p C(O)-, -O(CH 2 ) q -, -O(CH 2 ) r C(O)- and -(CH 2 ) s NHC(O)-, 2 is optionally 1 or 2 R b Replaced by; E 3 is 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; T 1 N, and CR a Selected from; R a are each independently H, OH, -OC(=O)NHEt, -CO 2 Et, -NHCO 2 CH 3 , and C 1-3 Selected from alkyl groups; R b are each independently F, and CH 3 Selected from; R c are each independently H and CH 3 Selected from; R d are each independently a halogen, and CF3 Selected from.

[0034] In some embodiments of the present application, the R a are each independently H, OH, -OC(=O)NHEt, -CO 2 Et, -NHCO 2 CH 3 , and C.H. 3 and the other symbols are as defined herein.

[0035] In some embodiments of the present application, the R d are each independently F, and CF 3 and the other symbols are as defined herein.

[0036] In some embodiments of the present application, the R 2 each independently represents one or two R d as a substituent [ka] 1 or 2 R d as a substituent [ka] and 1, 2 or 3 R d C having as a substituent 1-3 The alkyl group is selected from the group consisting of alkyl groups, and the other symbols are as defined herein.

[0037] In some embodiments of the present application, each R 2 teeth, [ka] and the other symbols are as defined herein.

[0038] In some embodiments of the present application, each R 3 is selected from H and F, and other symbols are as defined herein.

[0039] In some embodiments of the present application, the R 1 teeth [ka] and the other symbols are as defined herein.

[0040] In some embodiments of the present application, the E 1 is a single bond, -CH 2 - and -(CH 2 ) 2 -, and other symbols are as defined herein.

[0041] In some embodiments of the present application, the E 2 is -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -CH 2 CO-, -(CH 2 ) 2 CO-, -O(CH 2 ) 2 -, -OCH 2 C(O)- and -CH 2 NHC(O)-, wherein each CH 2 is optionally 1 or 2 R b and other symbols are as defined herein.

[0042] In some embodiments of the present application, the E 2 is -CH 2 -, -(CH 2 ) 2 -, -CF 2 CH 2 -, -(CH 2 ) 3 -, -CH 2 CO-, -CO-, -C(CH 3 ) 2 CO-, -CF 2 CO-, -(CH 2 ) 2 CO-, -O(CH2 ) 2 -, -OCH 2 C(O)- and -CH 2 NHC(O)-, and other symbols are as defined herein.

[0043] In some embodiments of the present application, the E 3 is a single bond, NH, N(CH 3 ), and O, and other symbols are as defined herein.

[0044] In some embodiments of the present application, the T 1 are N, CH, C(OH), C(OC(=O)NHEt), C(CO 2 Et), C(NHCO 2 CH 3 ), and C(CH 3 ) and the other symbols are as defined herein.

[0045] In some embodiments of the present application, the structural unit: [ka] and the other symbols are as defined herein.

[0046] In some embodiments of the present application, the compound, or a stereoisomer or a pharma- ceutically acceptable salt thereof, is [ka] Selected from However, R 2 , R 4 , T 1 , E 1 , E 2 , and E 3 is as defined anywhere in this application.

[0047] Furthermore, some embodiments of the present application may include any combination of the above symbols.

[0048] The present application further provides a compound selected from the following compounds, or a stereoisomer or a pharma- ceutically acceptable salt thereof: [ka] [ka] [ka] [ka]

[0049] The present application further provides a compound selected from the following compounds, or a stereoisomer or a pharma- ceutically acceptable salt thereof: [ka] [ka] [ka] [ka] [ka]

[0050] The present application also provides a pharmaceutical composition comprising the compound of the present application, or a stereoisomer or a pharma- ceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present application further comprises a pharma- ceutically acceptable excipient.

[0051] Meanwhile, the present application also provides the use of the above-mentioned compound, its stereoisomer or its pharma- ceutically acceptable salt, or its pharmaceutical composition in the preparation of a medicament for treating an sGC agonist-related disease.

[0052] On the other hand, the present application provides a method for treating an sGC agonist-related disease in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the present application, its stereoisomer or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0053] On the other hand, the present application provides the use of the present compound, its stereoisomer or its pharma- ceutically acceptable salt, or its pharmaceutical composition in the treatment of an sGC agonist-related disease.

[0054] On the other hand, the present application provides the present compound, its stereoisomer or its pharma- ceutically acceptable salt, or a pharmaceutical composition thereof for treating an sGC agonist-related disease.

[0055] In some embodiments of the present application, the sGC agonist-related disease is selected from heart failure or hypertension.

[0056] <Definitions and Explanations> The following terms and words used in this application shall have the following meanings unless otherwise specified: Certain terms and words should not be considered unclear or indefinite, but should be understood in their ordinary sense, unless otherwise defined. When trade names appear herein, it is intended to refer to the corresponding product or its active ingredients.

[0057] The term "pharmacologically acceptable" as used herein contemplates those corresponding compounds, materials, compositions and / or dosage forms which are within the scope of sound medical judgment and are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0058] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared from a compound having certain substituents found herein and a relatively non-toxic acid or base. In cases where a compound of the present invention has a relatively acidic functional group, a 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 in a suitable inert solvent. In cases where a compound of the present invention contains a relatively basic functional group, an 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 in a suitable inert solvent. Certain compounds of the present invention contain both basic and acidic functional groups and therefore can be converted into either base addition salts or acid addition salts.

[0059] The pharma- ceutically acceptable salts of the present application can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with the stoichiometrically appropriate base or acid in water or an organic solvent or a mixture of both.

[0060] Unless otherwise specified, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, rotamers, diastereoisomers and tautomers.

[0061] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All of these isomers and mixtures thereof are within the scope of the present invention.

[0062] Unless otherwise specified, the terms "enantiomers" or "rotamers" refer to stereoisomers that are mirror images of one another.

[0063] Unless otherwise specified, the terms "cis-trans isomers" or "geometric isomers" refer to the inability to freely rotate about a double bond or a single bond of carbon atoms that form a ring.

[0064] Unless otherwise specified, "diastereoisomer" refers to a stereoisomer that has two or more centers of chirality in the molecule and the relationship between the molecules is not that of mirror images.

[0065] Unless otherwise noted, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemization.

[0066] Solid wedge connections unless otherwise noted [ka] and dotted wedge connection [ka] represents the absolute configuration of the stereocenter, and a straight solid bond [ka] and line-dotted line connection [ka] indicates the relative configuration of stereocenters, and the wavy line [ka] is a solid wedge connection [ka] or wedge-shaped dotted line bond [ka] or a wavy line [ka] is a straight solid line connection [ka] and line-dotted bond [ka] Used to indicate

[0067] The compounds of the present invention may exist in specific forms. Unless otherwise specified, the term "tautomer" or "tautomeric form" means that isomers of different functional groups are in dynamic equilibrium at room temperature and can rapidly interconvert. If interconversion is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton transfer, such as keto-enol isomerization, imino-enamine isomerization, etc. Valence tautomers include interconversions via any recombination of bonded electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0068] Unless otherwise specified, the terms "enriched in one isomer," "enriched in an isomer," "enriched in one enantiomer," or "enantiomer-enriched" refer to less than 100% isomer or enantiomer and having at least 60% of that isomer or enantiomer, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%.

[0069] Unless otherwise specified, the term "isomeric excess" or "enantiomeric excess" refers to the relative percentage difference between two isomers or enantiomers. For example, if one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, the isomeric or enantiomeric excess (ee value) is 80%.

[0070] Optically active (R)- and (S)-isomers, as well as D- and L-isomers, can be prepared by chiral synthesis or chiral reagents or other conventional methods. If a certain enantiomer of the present compounds is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, and the resulting diastereomeric mixture can be isolated and the auxiliary cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, the salt of the diastereoisomer can be formed with an appropriate optically active acid or base, which can then be separated and collected by conventional methods well known in the art to provide the pure enantiomers. Furthermore, separation of enantiomers and diastereoisomers is usually achieved by the use of chromatography, which employs a chiral stationary phase, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).

[0071] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) to label the compound. As another example, deuterium can be substituted for hydrogen to form a deuterated drug. The bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon, and compared to non-deuterated drugs, deuterated drugs have the advantages of reduced toxicity, increased drug stability, enhanced efficacy, and a longer biological half-life. All variations in the isotopic composition of the compounds of the present application, whether radioactive or not, are all within the scope of the present application.

[0072] Unless otherwise noted, "C 1-3 The term "alkyl group" is used to refer to a saturated hydrocarbon group consisting of a straight or branched chain having 1 to 3 carbon atoms. 1-3 Alkyl groups are C 1-2 and C. 2-3 It may be monovalent (e.g., a methyl group), divalent (e.g., a methylene group), or polyvalent (e.g., a methine group). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl, isopropyl), and the like.

[0073] Unless otherwise stated, the terms "halogenated element" or "halogen" by themselves or as part of another substituent refer to a fluorine, chlorine, bromine, or iodine atom.

[0074] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and the terms include instances where the event or circumstance occurs and instances where the event or circumstance does not occur.

[0075] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced with a substituent, and the substituent can include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the compound is stable after substitution. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur in aromatics. "Optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents are optional within the range that is chemically feasible. "When each group is optionally substituted" means that any of the groups in the structure are optionally substituted. For example, "E 2 is -(CH 2 ) n -, -(CH 2 ) p C(O)-, -O(CH2 ) q -, -O(CH 2 ) r C(O)-, -CH 2 CH=CH- and -(CH 2 ) s NHC(O)-, wherein each CH 2 is optionally 1 or 2 R b "Replaced by" means E 2 Any CH in the selectable range 2 , optionally with one or two R b is meant to be replaced by

[0076] When any symbol (e.g., R) occurs more than one time in a compound composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with up to 2 R, and each occurrence of R is an independent option. Furthermore, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0077] The number of linking groups is 0, for example -(CRR) 0 In the case of -, it means that the linking group is a single bond.

[0078] When one of the symbols is selected from a single bond, it means that the two groups to which it is attached are directly connected, for example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0079] When a substituent is vacant, it means that the substituent does not exist. For example, when X of AX is vacant, it means that the structure is actually A. Also, when the direction of the listed linking group is not specified, the linking direction is arbitrary. For example, [ka] When the linking group L in the formula is -MW-, the ring A and the ring B are bonded in the same direction as the -MW- is read from left to right. [ka] In the opposite direction to the left-to-right reading, ring A and ring B may be bonded to each other. [ka] Combinations of the above linking groups, substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0080] Unless otherwise noted, C n-n+m Or C n -C n+m includes any one of the specific options in which the number of carbon atoms is n to n+m. For example, C 1-12 is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 Including any one of the ranges n to n+m. For example, C 1-12 is 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.

[0081] The compounds of the present application can be prepared by a variety of synthetic methods known to those of skill in the art, including the specific embodiments listed below, embodiments consisting of combinations with other chemical synthetic methods, and equivalent substitutions known to those of skill in the art, and preferred embodiments include, but are not limited to, the examples of the present application.

[0082] The structure of the compound of the present application can be confirmed by a conventional method known to those skilled in the art. When the present application relates to the absolute configuration of a compound, the absolute configuration can be confirmed by a conventional method in the art. For example, in single crystal X-ray diffraction (SXRD), a Bruker D8 venture diffractometer with CuKα radiation as a light source is used, and the diffraction intensity data is collected from the cultivated single crystal by a scanning method: φ / ω scan, and after collecting related data, the crystal structure is further analyzed by a direct method (Shelxs 97) to confirm the absolute configuration.

[0083] The solvents used here are commercially available. The following abbreviations are used in this application: aq is water, eq is equivalent / equivalent, min is minute, M is mol / L, DCM is dichloromethane, PE is petroleum ether, DMF is N,N-dimethylformamide, DMSO is dimethylsulfoxide, EtOAc is ethyl acetate, EtOH is ethanol, MeOH is methanol, CBz is benzyloxycarbonyl, an amine protecting group, Boc is tert-butoxycarbonyl, an amine protecting group, rt is room temperature, O / N is overnight, THF is tetrahydrofuran, Boc is tetrahydrofuran, and 2 O is di-tert-butyl dicarbonate, TFA is trifluoroacetic acid, DIPEA is diisopropylethylamine, SOCl 2 indicates sulfoxide chloride, IPAm indicates isopropylamine, and mp indicates melting point. Effect of the Invention

[0084] The compound of the present invention has a significant stimulating activity against guanylate cyclase, and has good pharmacokinetic properties such as clearance, half-life, and bioavailability after intragastric administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0085] The present application will be described in detail below through examples, but is not intended to be limiting to the present application. The present application has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various modifications and improvements can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0086] Example 1 [ka]

[0087] Synthesis Route: [ka]

[0088] Step 1: Synthesis of compound 001_2 (Ethoxycarbonylmethylene)triphenylphosphorane (112.51 g, 322.96 mmol) and compound 001_1 (25 g, 215.30 mmol) were dissolved in chloroform (250 mL) at room temperature under nitrogen protection, and the reaction mixture was heated to 70°C and reacted with stirring for 12 hours. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to remove the solvent, and 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 to 50 / 1, v / v). Compound 001_2 was obtained. 1 H NMR (400MHz, DMSO-d 6 )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).

[0089] Step 2: Synthesis of compound 001_3 Compound 001_2 (23 g, 123.52 mmol) was dissolved in ethanol (150 mL) at room temperature, and wet palladium / carbon (15 g, purity: 10%) was added. The reaction mixture was stirred and reacted under a hydrogen (15 psi) atmosphere at 15°C for 12 hours. After the reaction was completed, filtration was performed, and the filtrate was collected and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 20 / 1, v / v) to obtain compound 001_3.

[0090] Step 3: Synthesis of compound 001_4 Compound 001_3 (8.6 g, 45.69 mmol) was dissolved in carbon tetrachloride (180 mL) at room temperature, and N-bromosuccinimide (8.13 g, 45.69 mmol) and benzoyl peroxide (553.38 mg, 2.28 mmol) were added. The reaction mixture was heated to 75°C and stirred for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 50 / 1, v / v) to obtain compound 001_4. 1 H NMR (400 MHz, DMSO-d 6 )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).

[0091] Step 4: Synthesis of compound 001_5 Malononitrile (2.6 g, 39.31 mmol) was dissolved in tetrahydrofuran (50 mL) at room temperature, potassium tert-butoxide (44.92 mL, 1M tetrahydrofuran solution) was added, and the reaction mixture was reacted at 15°C for 0.5 hours while stirring. Compound 001_4 (10 g, 37.44 mmol) was dissolved in tetrahydrofuran (100 mL) at room temperature, the reaction mixture was heated to 75°C, and the above reaction mixture was added dropwise while stirring. The reaction mixture was stirred at 75°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and adjusted to pH = 3-4 with 2M dilute hydrochloric acid, and then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed successively with saturated saline (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 to 0 / 1, v / v) to obtain compound 001_5. 1 H NMR (400MHz, DMSO-d 6 )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).

[0092] Step 5: Synthesis of intermediate 001_9 Compound 001_8 (250 g, 1.42 mol) was dissolved in acetonitrile (2.5 L) at room temperature under nitrogen protection, 1-hydroxypyrrolidine-2,5-dione (172.10 g, 1.50 mol) and N,N'-dicyclohexylcarbodiimide (299.71 g, 1.45 mol) were added, and the reaction mixture was reacted at 20°C for 4 hours with stirring. After the reaction was completed, the reaction solution was filtered, the filter cake was rinsed with acetonitrile (3 L), and the filtrate was collected. The filtrate was concentrated under reduced pressure to remove the solvent, and compound 001_9 was obtained. 1 H NMR (400 MHz, CDCl 3 )δ: 8.53(d, J=3.2 Hz, 1 H), 8.16(dd, J=3.0, 7.4 Hz, 1 H), 2.93(s, 4 H).

[0093] Step 6: Synthesis of intermediate 001_10 Compound 001_9 (155 g, 568.56 mmol) was dissolved in tetrahydrofuran (300 mL) under nitrogen protection at room temperature, and aqueous ammonia (564.20 g, 4.02 mol, purity: 25%) was added, and the reaction mixture was reacted at 20°C for 5 hours with stirring. After the reaction was completed, ethyl acetate (300 mL x 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-d 6 )δ:8.52(d, J=2.8 Hz, 1 H), 8.10(s, 1 H), 7.99(dd, J=2.8, 8.0 Hz, 1 H), 7.88(s, 1 H).

[0094] Step 7: Synthesis of intermediate 001_11 Compound 001_10 (99 g, 567.14 mmol) was dissolved in dichloromethane (200 mL) at room temperature under nitrogen protection, 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, and the reaction mixture was reacted at 0°C for 2 hours while stirring. After the reaction was completed, a saturated aqueous solution of sodium bicarbonate was added to the reaction mixture to adjust the pH to 7-8, and the liquids were separated. The aqueous phase was extracted with dichloromethane (1500 mL × 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 50 / 1-10 / 1, v / v) to obtain compound 001_11.

[0095] Step 8: Synthesis of intermediate 001_12 Compound 001_11 (104 g, 664.35 mmol) was dissolved in n-butanol (1 L) under nitrogen protection at room temperature, 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 to react. After the reaction was completed, the mixture was cooled to room temperature to precipitate a solid. Water (1 L) was added to the reaction mixture, which was stirred for 1 hour and then filtered to collect the filter cake. The filter cake was concentrated under reduced pressure to remove the solvent, and intermediate 001_12 was obtained.

[0096] Step 9: Synthesis of intermediate 001_13 Compound 001_12 (137 g, 900.55 mmol) was dissolved in tetrahydrofuran (3 L) at room temperature under nitrogen protection, the reaction mixture was cooled to 0°C, boron trifluoride ethyl etherate (383.44 g, 2.70 mol, 333.43 mL) was slowly added dropwise, cooled to -10°C, and then a solution of isoamyl nitrite (137.14 g, 1.17 mol) in tetrahydrofuran (358 mL) was slowly added, and the reaction mixture was stirred at -10°C for 1 hour. Next, methyl tert-butyl ether (3 L) was added to the reaction mixture to precipitate a solid, and the filter cake was collected by filtration. The filter cake was added in batches to a solution of sodium iodide (175.48 g, 1.17 mol) in acetone (3 L) at 0°C, and the reaction mixture was reacted with stirring at 20°C for 1 hour. After the reaction was completed, the reaction solution was poured into ice water (3 L), extracted with ethyl acetate (800 mL × 3), and the organic phases were combined. The 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 to 10 / 1, v / v) to obtain intermediate 001_13. 1 H NMR (400 MHz, DMSO_d 6 )δ: 14.24(s, 1 H), 8.60-8.64(m, 1 H), 7.86(dd, J=2.6, 8.4 Hz, 1 H).

[0097] Step 10: Synthesis of intermediate 001_14 Compound 001_13 (97 g, 368.81 mmol) was dissolved in N,N-dimethylformamide (1 L) at room temperature, o-fluorobenzyl chloride (53.32 g, 368.81 mmol) and cesium carbonate (132.18 g, 405.69 mmol) were added, and the reaction mixture was heated to 80°C and reacted with stirring for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and half-saturated saline (1 L) was added to the reaction solution, and the mixture was stirred for 10 minutes, and then ethyl acetate (1.2 L) was added. The organic phase was separated and collected. The organic phase was washed with half-saturated saline (1 L x 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, and intermediate 001_14 was obtained. 1 H NMR (400 MHz, DMSO_d 6 )δ: 8.65-8.73(m, 1 H), 7.91(dd, J =2.8, 8.0 Hz, 1 H), 7.32-7.40(m, 1 H), 7.11-7.25(m, 3 H), 5.72(s, 2 H).

[0098] Step 11: Synthesis of intermediate 001_15 Compound 001_14 (25 g, 67.36 mmol) was dissolved in N,N-dimethylformamide (750 mL) and methanol (250 mL) at room temperature, triethylamine (30.72 g, 303.63 mmol) and cyclopentane-2,4-dien-1-yl(diphenyl)phosphine dichloromethane dichloropalladium ferrocene (3.45 g, 4.72 mmol) were added, and the mixture was replaced with carbon monoxide three times. The reaction mixture was reacted under carbon monoxide atmosphere (15 psi) at 80°C for 12 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the solvent, and the obtained crude product was dissolved in methyl tert-butyl ether (200 mL) and stirred for 30 minutes. The mixture was filtered, the filter cake was collected, and the solvent was removed by concentration under reduced pressure to obtain intermediate 001_15. 1 H NMR (400 MHz, DMSO_d 6)δ: 8.74-8.80(m, 1 H), 8.25(dd, J=2.8, 8.4 Hz, 1 H), 7.34-7.41(m, 1 H), 7.20-7.31(m, 2 H), 7.13-7.20(m, 1 H), 5.84(s, 2 H), 3.92(s, 3H).

[0099] Step 12: Synthesis of the hydrochloride salt of compound 001_6 Ammonium chloride (33.51 g, 626.52 mmol) was suspended in toluene (580 mL) at room temperature, and a solution of trimethylaluminum (2M, 300.73 mL) in toluene was added. The reaction mixture was heated to 80°C, and then 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, and methanol (73.02 mL) was added, followed by dilute hydrochloric acid (3M, 801.94 mL) (below 40°C), heated to 80°C and stirred for 30 minutes, cooled to 0°C and stirred for 30 minutes, filtered to collect the filter cake. 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_d 6 )δ: 9.40-9.78(d, J=24.4 Hz, 4 H), 8.85(m, 1 H), 8.57(dd, J=2.4, 8.8 Hz, 1 H), 7.35-7.43(m, 1 H), 7.28-7.35(m, 1 H), 7.20-7.28(m, 1H), 7.13-7.20(m, 1H), 5.89(s, 2H).

[0100] Step 13: Synthesis of compound 001_7 At room temperature, the hydrochloride salt of compound 001_6 (450 mg, 1.39 mmol) was dissolved in tert-butanol (13 mL), and compound 001_5 (554.03 mg, 2.20 mmol) and potassium carbonate (768.46 mg, 5.56 mmol) were added. The reaction mixture was heated to 80°C and reacted with stirring for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed successively with saturated saline (20 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: dichloromethane / ethanol = 1 / 0 to 20 / 1, v / v) to obtain compound 001_7.

[0101] Step 14: Synthesis of Compound 001 Compound 001_7 (600 mg, 1.22 mmol) was dissolved in toluene (12 mL) at room temperature, trimethylaluminum (1.82 mL, 2 M toluene solution) was added, and the reaction mixture was heated to 80°C and reacted with stirring for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and methanol (738.05 μL) was added dropwise at less than 40°C, followed by the addition of 3N dilute hydrochloric acid (825.80 μL). The mixture was heated to 80°C and stirred for 10 minutes. The reaction mixture was then cooled to 0-5°C, stirred for 30 minutes, filtered, and the filter cake was collected. The filter cake was rinsed with water (5 mL) and concentrated under reduced pressure to remove the solvent. The obtained crude product was dissolved in dimethyl sulfoxide (6 mL), and the filtrate was analyzed by preparative HPLC (mobile phase: acetonitrile / water; neutral system: 10 mM NH 4 HCO 3 ) and the resulting 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 (400MHz, DMSO-d 6)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).

[0102] Example 2 [ka]

[0103] Synthesis Route: [ka]

[0104] Step 1: Synthesis of compound 002_2 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 drop by drop. The reaction mixture was reacted at 100°C for 4 hours with stirring. Then, it was cooled to 25°C and reacted for 12 hours with stirring. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with water (30 mL) and methanol (15 mL) in that order, and the filter cake was collected. Compound 002_2 was obtained.

[0105] Step 2: Synthesis of compound 002_3 At 25°C, wet palladium on carbon (6 g, purity: 10%) was placed in a pre-dried reaction flask, N,N-dimethylformamide (90 mL) was added to wet the flask, and then compound 002_2 (12 g, 26.23 mmol) was added. The mixture was replaced with hydrogen three times, and reacted under hydrogen (15 psi) for 12 hours with stirring. After the reaction was completed, the reaction solution was filtered, the filter cake was rinsed with methanol (150 mL × 3), the organic phases were combined, and the solvent was removed by concentration under reduced pressure. Ethanol (30 mL) was added to the obtained crude product, stirred for 30 minutes, filtered, the filter cake was collected, and the solvent was removed by concentration under reduced pressure to obtain compound 002_3. 1 H NMR (400MHz, DMSO-d 6 )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).

[0106] Step 3: Synthesis of compound 002_4 Compound 002_3 (1.8 g, 4.89 mmol) was dissolved in ethanol (40 mL) at room temperature, 1,4-dioxolane-2,3-diol (1.17 g, 9.77 mmol) was added, and the reaction mixture was reacted at 15° C. for 12 hours with stirring. 1,4-dioxane-2,3-diol (0.6 g) was added, and the reaction mixture was reacted at 15° C. for 12 hours with stirring. After the reaction was completed, the mixture was concentrated under reduced pressure to remove the solvent, and methyl tert-butyl ether (20 mL) was added to the resulting residue, stirred for 10 minutes, filtered, the filter cake was collected, and concentrated under reduced pressure to remove the solvent. Compound 002_4 was obtained. 1 H NMR (400MHz, DMSO-d 6)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).

[0107] Step 4: Synthesis of the hydrochloride salt of compound 002_5 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, sodium borohydride (1.26 g, 3.330 mmol) was added, and the reaction mixture was reacted at 15°C for 0.5 hours while stirring. The reaction mixture was then cooled to 0°C, sodium borohydride (377.99 mg, 9.99 mmol) was added, and the reaction mixture was reacted at 15°C for 2 hours while stirring. After the reaction was completed, the reaction solution was cooled to 0°C, concentrated hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 3-4, and the solvent was removed by concentration under reduced pressure. The obtained residue was separated by preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.05% HCl) to obtain the hydrochloride salt of compound 002_5.

[0108] Step 5: Synthesis of compound 002 The hydrochloride salt of compound 002_5 (58 mg, 134.62 μmol, HCl) was dissolved in tetrahydrofuran (2 mL) at room temperature under nitrogen protection, the reaction mixture was lowered to 0°C, and a solution of p-nitrophenylmethyl chloroformate (27.13 mg, 134.62 μmol) dissolved in tetrahydrofuran (1 mL) was added dropwise at 0°C, and the reaction mixture was reacted at 0°C for 2 hours while stirring. Next, 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 oily product, N,N-dimethylformamide (1 mL) was added, and the atmosphere was replaced with nitrogen three times, and the reaction system was heated to 120°C and reacted with stirring for 12 hours. After that, the reaction was further heated to 140°C and reacted with stirring for 16 hours. After the reaction was completed, the mixture was cooled to room temperature. The compound was dissolved in dimethyl sulfoxide and 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-d 6 )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).

[0109] Example 3 [ka]

[0110] Synthesis Route: [ka]

[0111] Step 1: Synthesis of compound 003_2 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) at room temperature under nitrogen protection, and the reaction mixture was heated to 110°C and reacted with stirring for 12 hours. Then, toluene was removed by concentration under reduced pressure, and 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, and the reaction solution was heated to 85°C and reacted with stirring for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was added to water (800 mL), washed with methyl tert-butyl ether (500 mL × 3), and the organic phase was discarded. The aqueous phase was adjusted to pH 2 with 12 N concentrated hydrochloric acid, and then extracted with dimethyltetrahydrofuran (800 mL x 2). The organic phases were combined, washed successively with saturated saline (800 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. Compound 003_2 was obtained. 1 H NMR (400 MHz, CDCl 3 )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).

[0112] Step 2: Synthesis of compound 003_3 Compound 003_2 (117 g, 491.02 mmol) was dissolved in dichloromethane (1 L) at room temperature under nitrogen protection, and then ethanol (226.21 g, 4.91 mol), 1-((3-dimethylaminopropyl)-3-acetaldehyde hydrochloride (112.95 g, 589.23 mmol) and 4-dimethylaminopyridine (7.20 g. 58.92 mmol) were added in sequence, and the reaction mixture was reacted at 20°C for 12 hours with stirring. The solvent was then removed by concentration under reduced pressure. The resulting residue was diluted with ethyl acetate (100 mL), washed with water (100 mL), and then washed with 10% citric acid aqueous solution (150 mL × 3), saturated saline (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 2 / 3, v / v) to obtain compound 003_3. 1 H NMR (400 MHz, CDCl 3 )δ: 7.26(d, J=8.8 Hz, 2H), 6.88(d, J=8.8 Hz, 2H), 4.42(s, 2H), 4.11(q, J=7.2 Hz, 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, 14.0 Hz, 1H), 1.24(t, J=7.2 Hz, 3H), 1.17(d, J=7.2 Hz, 3H).

[0113] Step 3: Synthesis of compound 003_4 Diisopropylamine (16.93 g, 167.27 mmol) was added to anhydrous tetrahydrofuran (450 mL) at 20°C under nitrogen protection, and then the reaction solution was cooled to -78°C, and then a solution of n-butyllithium in tetrahydrofuran (72.99 mL, 2.5 M tetrahydrofuran solution) was slowly added dropwise, and the reaction mixture was warmed to 0°C and reacted with stirring for 0.5 hours. Next, after cooling to -78°C, compound 003_3 (40.5 g, 152.07 mmol) was dissolved in anhydrous tetrahydrofuran (160 mL) and added dropwise to the above reaction solution, and the reaction mixture was stirred at -78°C for 1 hour. Next, carbon tetrabromide (75.64 g, 228.10 mmol) was dissolved in anhydrous tetrahydrofuran (220 mL) and then added dropwise to the reaction system. The reaction mixture was warmed to 20°C and reacted with stirring for 10.5 hours. After the reaction was completed, the reaction solution was poured into an aqueous solution of ammonium chloride (1.5 L) and extracted with ethyl acetate (600 mL x 2). The organic phases were combined, washed with saturated saline (800 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 8 / 1, v / v) to obtain compound 003_4.

[0114] Step 4: Synthesis of compound 003_5 To a solution of malononitrile (11.48 g, 173.80 mmol) in tetrahydrofuran (100 mL), potassium tert-butoxide (191.18 mL, 1 M tetrahydrofuran solution) was added under nitrogen protection at 20°C, and 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 reacted at 75°C for 12 hours while stirring. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained residue was diluted with water (100 mL), and then 1 N dilute hydrochloric acid was added to adjust the pH to 6. Next, it was extracted with 2-methyltetrahydrofuran (200 mL × 3), and the organic phases were combined, washed successively with saturated saline (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 6 / 1, v / v) to obtain compound 003_5.

[0115] Step 5: Synthesis of compound 003_6 The hydrochloride salt of compound 001_6 (3.76 g, 13.09 mmol) was dissolved in tert-butanol (40 mL) at room temperature under nitrogen protection, 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 reacted at 80°C for 12 hours with stirring. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Water (100 mL) was added to the residue, and ethyl acetate (100 mL) was added to dilute it, and the organic phase was collected by separation, and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed successively with saturated saline (100 mL x 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 to 1 / 1, v / v) to obtain compound 003_6.

[0116] Step 6: Synthesis of compound 003_7 Compound 003_6 (3 g, 5.25 mmol) was dissolved in dichloromethane (30 mL) and water (3 mL) under nitrogen protection at room temperature, 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 reacted with stirring 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 organic phases were combined, washed successively with half-saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by reversed-phase MPLC (mobile phase: methanol / hydrochloric acid aqueous solution = 2:1 to 1:2, v / v) to obtain compound 003_7. 1 H NMR (400 MHz, DMSO-d 6 )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).

[0117] Step 7: Synthesis of compound 003_8 Compound 003_7 (330 mg, 676.38 μmol) was dissolved in anhydrous tetrahydrofuran (3 mL) at room temperature under nitrogen protection, diisopropylethylamine (349.66 mg, 2.71 mmol) and 4-dimethylaminopyridine (8.26 mg, 67.64 μmol) were added, and methylsulfonyl chloride (116.22 mg, 1.01 mmol) was added dropwise to the reaction mixture at 0°C. The reaction mixture was reacted with stirring at 0°C for 2 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (20 mL) at 0°C, and ethyl acetate (30 mL × 3) was added for extraction, and the organic phase was combined. The organic phase was washed successively with half-saturated saline (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: 2-methyltetrahydrofuran / ethyl acetate = 1 / 0 to 4 / 1, v / v) to obtain compound 003_8.

[0118] Step 8: Synthesis of Compound 003 At room temperature, compound 003_8 (240 mg, 453.24 mmol) was dissolved in tetrahydrofuran (6 mL), the reaction mixture was cooled to -65°C, lithium bis(trimethylsilyl)amide (1.36 mL, 1 M tetrahydrofuran solution) was added, and the reaction mixture was reacted with stirring at -65°C to 15°C for 12 hours. After the reaction was completed, 3 M dilute hydrochloric acid aqueous solution was added dropwise to the reaction solution to adjust the pH to 5-6, then water (5 mL) was added, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phases were combined, washed sequentially with saturated saline (3 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was subjected to preparative HPLC (mobile phase: acetonitrile / water, neutral system: 10 mM NH 4 HCO 3 ) to obtain compound 003. MS-ESI m / z: 434.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )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).

[0119] Example 4 [ka]

[0120] Synthesis Route: [ka]

[0121] Step 1: Synthesis of compound 004_1 Compound 002_3 (1 g, 2.71 mmol) was dissolved in N,N-dimethylformamide (30 mL) at room temperature under nitrogen protection, and ethyl bromoacetate (476.05 mg, 2.85 mmol) and N,N-diisopropylethylamine (350.87 mg, 2.71 mmol) were added. The reaction mixture was reacted at 15°C for 8 hours with stirring. The reaction mixture was then heated to 50°C and reacted for 4 hours with stirring. After the reaction was completed, the mixture was cooled to room temperature, half-saturated saline (30 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed successively with half-saturated saline (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: dichloromethane / methanol = 1 / 0 to 10 / 1, v / v) to obtain compound 004_1.

[0122] Step 2: Synthesis of compound 004_2 Compound 004_1 (0.6 g, 1.32 mmol) was dissolved in THF (10 mL) at room temperature under nitrogen protection, the reaction mixture was lowered to 0 ° C., triphosgene (129.30 mg, 435.71 μmol), triethylamine (400.81 mg, 3.96 mmol) were added, the reaction mixture was reacted with stirring at 0 ° C. for 0.5 hours, then the temperature was raised to 25 ° C. and the reaction was continued for 2 hours. After the reaction, the reaction mixture was quenched by adding a saturated aqueous sodium bicarbonate solution (15 mL) to the reaction mixture, diluted with ethyl acetate (20 mL) and separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phase was combined, 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 was separated by column chromatography (eluent: dichloromethane / methanol = 1 / 0 to 10 / 1, v / v) to obtain compound 004_2.

[0123] Step 3: Synthesis of compound 004 Compound 004_2 (0.58 g, 1.21 mmol) was dissolved in acetic acid (8 mL) and xylene (8 mL) under nitrogen protection at room temperature, and the reaction mixture was heated to 160°C and reacted at 160°C for 24 hours with stirring. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The obtained crude product was 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 H NMR (400MHz, DMSO-d 6 )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).

[0124] Examples 5 and 6 [ka]

[0125] Synthesis Route: [ka]

[0126] Synthesis of Compounds 005 and 006 Compound 001 (200 mg, 447.03 μmol) was purified on a chiral column (column type: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 μm); mobile phase: [Neu-ACN]; B(ACN)%: 50%-50%, 8 min) to give compounds 005 and 006. 005 (retention time: 1.80 min): MS-ESI m / z: 448.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6)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). 006 (Retention time: 1.93 min): MS-ESI m / z: 448.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )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).

[0127] Example 7

Chemical Structure

[0128] Synthesis Route:

Chemical Structure

[0129] Step 1: Synthesis of Compound 007_2 Compound 007_1 (1 g, 7.68 mmol, 970.87 μL) was dissolved in toluene (20 mL) at room temperature under nitrogen protection, and further added 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), and the reaction mixture was stirred at 20°C for 12 hours. Malononitrile (101.52 mg, 1.54 mmol) was added, and the reaction mixture was heated to 50°C and reacted with stirring for 12 hours. After the reaction was completed, the reaction solution was poured into water (50 mL), diluted with ethyl acetate (50 mL), separated, and the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate=1 / 0 to 10 / 1, v / v) to obtain compound 007_2. 1 H NMR (400MHz, DMSO-d 6 )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).

[0130] Step 2: Synthesis of compound 007_3 Ethyl bromoacetate (1.87 g, 11.22 mmol) was dissolved in anhydrous tetrahydrofuran (12 mL) under nitrogen protection at room temperature, and compound 007_2 (500 mg, 2.81 mmol), titanocene dichloride (72.69 mg, 280.60 μmol) and activated zinc powder (366.97 mg, 5.61 mmol) were added to the reaction mixture, which was stirred at 25°C for 12 hours. After the reaction was completed, 1 N dilute hydrochloric acid (15 mL) was added to the reaction system to quench the reaction, and ethyl acetate (25 mL) was added to dilute the mixture, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (25 mL x 3), and the organic phases were combined, washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 6 / 1, v / v) to obtain compound 007_3. 1 H NMR (400 MHz, CDCl 3 )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).

[0131] Step 3: Synthesis of compound 007 Compound 007_3 (24 mg, 90.13 μmol) was dissolved in tert-butanol (1 mL) under nitrogen protection at room temperature, and the hydrochloride salt of 001_6 (29.18 mg, 90.13 μmol) and potassium carbonate (24.91 mg, 180.25 μmol) were added, and the reaction mixture was reacted at 85° C. for 12 hours with stirring. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. 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 (400MHz, DMSO-d 6)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).

[0132] Example 8 [ka]

[0133] Synthesis Route: [ka]

[0134] Step 1: Synthesis of compound 008_2 Compound 008_1 (10 g, 69.36 mmol) was dissolved in anhydrous toluene (200 mL) at room temperature, 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, and the reaction mixture was reacted at 15°C for 12 hours with stirring. After the reaction was completed, water (200 mL) was added to the reaction solution, and the pH was adjusted to 3-4 with 3 M dilute hydrochloric acid, extracted with ethyl acetate (200 mL x 3), and the organic phase was combined. The organic phase was washed successively with saturated saline (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 / 0-3 / 1, v / v) to obtain compound 008_2. 1 H NMR (400MHz, DMSO-d 6 )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).

[0135] Step 2: Synthesis of compound 008_3 Ethyl bromoacetate (1.66 g, 9.97 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL) at room temperature under nitrogen protection, and compound 008_2 (958 mg, 4.98 mmol) and titanocene dichloride (129.11 mg, 498.40 μmol) were added, followed by activated zinc powder (651.81 mg, 9.97 mmol). The reaction mixture was reacted at 25°C for 12 hours with stirring. After completion of the reaction, the reaction was quenched by adding 1 N dilute hydrochloric acid (20 mL), and the mixture was separated into water (50 mL) and ethyl acetate (50 mL). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, 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 to 3 / 1, v / v) to obtain compound 008_3.

[0136] Step 3: Synthesis of compound 008_4 Compound 008_3 (100 mg, 356.74 μmol) and compound 001_6 hydrochloride (57.74 mg, 178.37 μmol) were dissolved in tert-butanol (3.5 mL) at room temperature under nitrogen protection, 1,8-diazabicyclo[5.4.0]undec-7-ene (67.89 mg, 445.92 μmol) was added, and the reaction mixture was heated to 85° C. and reacted with stirring for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product of two batches was combined, and the obtained crude product was diluted with ethyl acetate (25 mL) and water (15 mL), extracted with ethyl acetate (25 mL × 3), and the organic phase was combined, washed successively 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 thin layer chromatography (developer: DCM:MeOH=15:1, v / v) to obtain compound 008_4.

[0137] Step 4: Synthesis of compound 008 Intermediate 008_4 (42 mg, 80.53 μmol) was dissolved in anhydrous toluene (1 mL) at room temperature under nitrogen protection, and a toluene solution of trimethylaluminum (2.5 M, 96.64 μL) was added, and the reaction mixture was heated to 110° C. and reacted with stirring for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and 1 N dilute hydrochloric acid (1 mL) and methanol (5 mL) were added to dilute the reaction mixture, and the reaction mixture was reacted with stirring at 25° C. for 0.5 hours. The mixture was concentrated under reduced pressure to remove the solvent, 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 again separated by preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.04% HCl) to obtain compound 008. MS-ESI m / z: 476.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )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).

[0138] Example 9 [ka]

[0139] Synthesis Route: [ka]

[0140] Step 1: Synthesis of intermediate 009_1 Compound 012_3 (4.2 g, 11.61 mmol, hydrochloride salt) was dissolved in tert-butanol (84 mL) at room temperature, 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 reacted with stirring for 12 hours. After the reaction was completed, it was cooled to room temperature, water (200 mL) was added to quench the reaction, and the mixture 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 to 3 / 2, v / v) to obtain compound 009_1.

[0141] Step 2: Synthesis of intermediate 009_2 Compound 009_1 (2.4 g, 3.94 mmol) was dissolved in dichloromethane (12 mL) and water (1.2 mL) at room temperature, and the reaction mixture was cooled to 0°C. Dichlorodicyanobenzoquinone (1.07 g, 4.73 mmol) was then slowly added, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, a saturated aqueous solution of sodium bicarbonate (30 mL) was added, and the mixture was extracted with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 4, v / v) to obtain compound 009_2.

[0142] Step 3: Synthesis of intermediate 009_3 009_2 (1.08 g, 2.04 mmol, purity: 93%) was dissolved in tetrahydrofuran (20 mL) and dichloromethane (20 mL) at 0°C, then 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) were added, and the reaction mixture was warmed to room temperature and reacted with stirring for 1 hour. After completion of the reaction, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution (30 mL), and extracted with ethyl acetate (40 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 to 1 / 4, v / v) to obtain compound 009_3.

[0143] Step 4: Synthesis of intermediate 009 Compound 009_3 (500 mg, 2.73 mmol) was dissolved in tetrahydrofuran (5 mL) at room temperature, then cooled to -78°C, and a solution of lithium bis(trimethylsilyl)amide (2.73 mL, 1 M, 2.73 mmol) in tetrahydrofuran was added. The reaction mixture was warmed to 25°C, and then hexamethylphosphoryltriamine (489.98 mg, 2.73 mmol) was added. The reaction mixture was stirred at 25°C for 12 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The resulting residue was purified by preparative HPLC (mobile phase: acetonitrile / water; neutral system: 10 mM NH 4 HCO 3 ) to obtain compound 009. MS-ESI m / z: 472.0 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6)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).

[0144] Example 10 [ka]

[0145] Synthesis Route: [ka]

[0146] Step 1: Synthesis of compound 010_2 Compound 001_13 (10 g, 38.02 mmol) was dissolved in N,N-dimethylformamide (20 mL) at room temperature, and then cesium carbonate (37.16 g, 114.06 mmol) and 2,6-difluorobenzyl bromide (7.87 g, 38.02 mmol) were added. The reaction mixture was heated to 80°C and reacted with stirring for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, water (200 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 3 / 2, v / v) to obtain compound 010_2.

[0147] Step 2: Synthesis of compound 010_3 Compound 010_2 (8.5 g, 21.84 mmol) was dissolved in N,N-dimethylformamide (100 mL) and methanol (40 mL) at room temperature, then [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.12 g, 1.53 mmol) was added, and the reaction solution was stirred at 80°C under carbon monoxide atmosphere (15 psi) for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the solvent was removed from the filtrate under reduced pressure. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 7 / 3, v / v) to obtain compound 010_3.

[0148] Step 3: Synthesis of the hydrochloride salt of compound 010_4 Ammonium chloride (298.04 mg, 5.57 mmol) was suspended in toluene (4 mL) at room temperature under nitrogen protection, then a toluene solution of trimethylaluminum (2.67 mL, 2M, 5.35 mmol) was added, and the reaction mixture was heated to 80°C. Compound 010_3 (358 mg, 1.11 mmol) was then added, and the reaction mixture was reacted at 80°C for 0.5 hours with stirring, then the temperature was raised to 110°C and the reaction was reacted with stirring for 1.5 hours. After the reaction was completed, the temperature was lowered to 30°C, methanol (639.34 μL, 16.05 mmol) and 3 N diluted hydrochloric acid aqueous solution (7.13 mL, 21.34 mmol) were added, and the temperature was further raised to 80°C and stirred for 0.5 hours, then the temperature was lowered to 0°C and stirred for 0.5 hours. The reaction mixture was filtered, the filter cake was rinsed with toluene (10 mL), and the solvent was removed under reduced pressure to obtain the hydrochloride salt of compound 010_4.

[0149] Step 4: Synthesis of compound 010 Compound 007_3 (76.00 mg, 285.40 μmol) was dissolved in tert-butanol (2.5 mL) under nitrogen protection at room temperature, and compound 010_4 (97.53 mg, 285.40 μmol, hydrochloride) and potassium carbonate (78.89 mg, 570.80 μmol) were added in sequence. The reaction mixture was heated to 85° C. and reacted with stirring for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The obtained crude product was separated by preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.04% HCl) to obtain compound 010. MS-ESI m / z: 480.1 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ: 11.25(s, 2H), 9.00(dd, J=2.8, 9.0 Hz, 1H), 8.72(dd, J=1.6, 2.8 Hz, 1H), 7.53-7.41(m, 1H), 7.23-7.03(m, 2H), 5.84(s, 2H), 2.80(d, J=16.0 Hz, 2H), 2.58-2.52(m, 2H), 1.12(s, 3H).

[0150] Example 11 [ka]

[0151] Synthesis Route: [ka]

[0152] Step 1: Synthesis of compound 011 Compound 010_4 (250 mg, 731.60 μmol, hydrochloride salt) and compound 008_3 (328.13 mg, 1.17 mmol) were dissolved in tert-butanol (5 mL) at room temperature under nitrogen protection, 1,8-diazabicyclo[5.4.0]undec-7-ene (278.44 mg, 1.83 mmol) was added, and the reaction mixture was heated to 95°C and reacted with stirring for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.04% HCl) to obtain compound 011. MS-ESI m / z: 494.2 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 )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).

[0153] Example 12 [ka]

[0154] Synthesis Route: [ka]

[0155] Step 1: Synthesis of compound 012_1 Compound 001_13 (10 g, 38.02 mmol) was dissolved in N,N-dimethylformamide (50 mL) at room temperature, and then potassium carbonate (15.76 g, 114.06 mmol) and 1,1,1,2,2-pentafluoro-4-iodobutane (52.08 g, 190.11 mmol) were added. The reaction mixture was heated to 40°C and reacted with stirring for 2 hours. After the reaction was completed, it was cooled to room temperature, water (200 mL) was added to quench the reaction, and the mixture 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 to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1, v / v) to obtain compound 012_1.

[0156] Step 2: Synthesis of compound 012_2 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]dichloropalladium(II) (936.76 mg, 1.28 mmol), and the reaction solution was reacted under carbon monoxide (15 psi) atmosphere at 80°C for 12 hours with stirring. After the reaction was completed, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 7 / 3, v / v) to obtain compound 012_2.

[0157] Step 3: Synthesis of the hydrochloride salt of compound 012_3 Ammonium chloride (4.31 g, 80.60 mmol) was suspended in toluene (55 mL) at room temperature under nitrogen protection, followed by the addition of a toluene solution of trimethylaluminum (38.69 mL, 2M, 77.37 mmol), and the reaction mixture was heated to 80°C, followed by the addition of compound 012_2 (5.5 g, 16.12 mmol), and the reaction mixture was reacted with stirring for 0.5 hours, then heated to 110°C and reacted with stirring for 1.5 hours. The temperature was then lowered to 30°C, and methanol (9.39 mL, 232.12 mmol) and 3 M dilute hydrochloric acid (103.16 mL, 309.49 mmol) were added in sequence, then heated to 80°C and stirred for 0.5 hours, then lowered to 0°C and stirred for 0.5 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was rinsed with toluene (20 mL), and concentrated under reduced pressure to obtain compound 012_3.

[0158] Step 4: Synthesis of compound 012 Compound 012_3 (100 mg, 276.49 μmol, hydrochloride) and compound 007_3 (117.80 mg, 442.39 μmol) were dissolved in tert-butanol (2 mL) at room temperature under nitrogen protection, potassium carbonate (95.53 mg, 691.23 μmol) was added, and the reaction mixture was heated to 85° C. and reacted with stirring 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] + . 1 H NMR (400MHz, DMSO-d 6 )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).

[0159] Example 13 [ka]

[0160] Synthesis Route: [ka]

[0161] Step 1: Synthesis of intermediate 013_2 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, a solution of n-butyllithium (129.85 mL, 2.5 M) in n-hexane was added, the reaction mixture was heated to 0°C and stirred for 0.5 hours. Next, the reaction mixture was cooled to -78°C, and a solution of ethyl propionate (32.09 g, 317.13 mmol) and compound 013_1 (25 g, 249.71 mmol) in tetrahydrofuran (30 mL) was added in sequence, and the reaction mixture was reacted at -78°C for 1 hour while stirring. After the reaction was completed, the reaction mixture was poured into a saturated aqueous ammonium chloride solution (800 mL), separated, and the aqueous phase was extracted with ethyl acetate (500 mL x 3). The organic phases were combined, washed successively with saturated saline (500 mL x 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 to 10 / 1, v / v) to obtain intermediate 013_2. 1 H NMR (400 MHz, CDCl 3 )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).

[0162] Step 2: Synthesis of intermediate 013_3 Intermediate 013_2 (10.2 g, 50.43 mmol) was dissolved in chlorobenzene (200 mL) at room temperature, N-bromosuccinimide (8.98 g, 50.43 mmol) and azodiisobutyronitrile (828.16 mg, 5.04 mmol) were added, and the reaction mixture was heated to 75°C and reacted with stirring for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered. The filtrate was collected and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 24 / 1, v / v) to obtain intermediate 013_3. 1 H NMR (400 MHz, CDCl 3 )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).

[0163] Step 3: Synthesis of intermediate 013_4 Compound malononitrile (3.45 g, 52.29 mmol) was dissolved in tetrahydrofuran (260 mL) under nitrogen protection at 20 ° C., potassium tert-butoxide (59.76 mL, 1 M) in tetrahydrofuran solution was added, and the reaction mixture was reacted at 20 ° C. with stirring for 0.5 hours, then the temperature was raised to 75 ° C., and a solution of intermediate 013_3 (14 g, 49.80 mmol) in tetrahydrofuran (20 mL) was added dropwise, and the reaction mixture was reacted at 75 ° C. with stirring 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), separated, and the organic phase was collected. The aqueous phase was adjusted to pH 3-5 with 1N diluted hydrochloric acid, and then extracted with ethyl acetate (300 mL × 2). The organic phases were combined, washed successively with saturated saline (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 to 50 / 1, v / v) 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).

[0164] Step 4: Synthesis of intermediate 013_5 Compound 010_4 (1.0 g, 2.93 mmol, hydrochloride salt) and intermediate 013_4 (1.25 g, 4.68 mmol) were dissolved in tert-butanol (10 mL) at room temperature under nitrogen protection, potassium carbonate (2.02 g, 14.63 mmol) was added, and the reaction mixture was heated to 80°C and reacted with stirring for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent, and the resulting residue was diluted with water (40 mL) and ethyl acetate (40 mL), separated to collect the organic phase, and the aqueous phase was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated saline (50 mL x 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 / 2-methyltetrahydrofuran = 1 / 0 to 1 / 1, v / v) to obtain intermediate 013_5. 1 H NMR (400 MHz, DMSO_d 6 )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).

[0165] Step 5: Synthesis of compound 013 At room temperature, intermediate 013_5 (180 mg, 342.54 μmol) was dissolved in toluene (4 mL), and a toluene solution of trimethylaluminum (513.81 μL, 2 M) was added. The reaction mixture was heated to 110° C. and reacted with stirring for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and dilute hydrochloric acid aqueous solution (2.19 mL, 3 M) was added dropwise at less than 40° C. The mixture was stirred at room temperature for 1 hour, then 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 organic phases were combined, washed successively with saturated saline (20 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, acidic system: 0.04% HCl). Compound 013 was obtained. MS-ESI m / z: 480.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 )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).

[0166] Example 14 [ka]

[0167] Synthesis Route: [ka]

[0168] Synthesis of Compound 014 Intermediate 008_3 (223.22 mg, 796.30 μmol) and intermediate 012_3 (180 mg, 497.69 μmol, hydrochloride salt) were dissolved in tert-butanol (3.6 mL) under nitrogen protection at room temperature, 1,8-diazabicyclo[5.4.0]undec-7-ene (189.42 mg, 1.24 mmol) was added, and the reaction mixture was heated to 95°C and reacted with stirring for 36 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. 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 H NMR (400MHz, DMSO_d 6 )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).

[0169] Example 15 [ka]

[0170] Synthesis Route: [ka]

[0171] Step 1: Synthesis of intermediate 015_1 010_4 (2.5 g, 7.32 mmol, hydrochloride salt) and 003_5 (3.87 g, 11.71 mmol) were dissolved in tert-butanol (50 mL) under nitrogen protection at room temperature, potassium carbonate (4.04 g, 29.28 mmol) was added, and the reaction mixture was heated to 80°C and reacted with stirring for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. Water (80 mL) and ethyl acetate (80 mL) were added to the resulting residue to separate the layers, and the aqueous phase was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed successively with saturated saline (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was 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 1 / 1, v / v) to obtain compound 015_1. 1 H NMR (400MHz, DMSO_d 6 )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).

[0172] Step 2: Synthesis of intermediate 015_2 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, dichlorodicyanobenzoquinone (831.68 mg, 3.66 mmol) was added in batches, and the reaction mixture was reacted at 15°C for 12 hours with stirring. After the reaction was completed, the solvent was removed by concentration under reduced pressure. A saturated aqueous solution of sodium bicarbonate (100 mL) was added to the residue, and 2-methyltetrahydrofuran (100 mL) was added to dilute it. After separation, the organic phase was collected, and the aqueous phase was extracted with 2-methyltetrahydrofuran (100 mL x 2). The organic phases were combined, washed successively with a saturated aqueous solution of sodium bicarbonate (100 mL x 2) and saturated saline (100 mL x 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 to 3 / 2, v / v) to obtain intermediate 015_2. 1 H NMR (400MHz, DMSO_d 6 )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).

[0173] Step 3: Synthesis of intermediate 015_3 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, and then N,N-diisopropylethylamine (825.98 mg, 6.39 mmol) and 4-dimethylaminopyridine (26.03 mg, 213.03 μmol) were added, and the reaction mixture was reacted at 20°C for 1 hour with stirring. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (100 mL) at 0°C and extracted with ethyl acetate (100 mL). The organic phases were combined, 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 to 3 / 2, v / v) to obtain intermediate 015_3. 1 H NMR (400MHz, DMSO_d 6 )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).

[0174] Step 4: Synthesis of Compound 015 At room temperature, intermediate 015_3 (500 mg, 913.23 μmol) was dissolved in tetrahydrofuran (10 mL), hexamethylphosphoryltriamine (507.32 mg, 2.83 mmol) was added, the reaction mixture was cooled to -78°C, a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (2.83 mL, 1 M) was added, the reaction mixture was heated to 20°C, and the reaction was stirred for 5 hours. After the reaction was completed, the reaction mixture was poured into ice water (30 mL), diluted with ethyl acetate (30 mL), and after separation, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed successively with saturated saline (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained crude product was purified by preparative HPLC (mobile phase: acetonitrile / water, neutral system: 10 mM NH 4 HCO 3 ) to obtain compound 015. MS-ESI m / z: 452.1 [M+H] + . 1 H NMR (400MHz, DMSO_d 6 )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).

[0175] Example 16 [ka]

[0176] Synthesis Route: [ka]

[0177] Step 1: Synthesis of intermediate 016_1 Compound 012_3 (750 mg, 2.07 mmol, hydrochloride) was dissolved in tert-butanol (15 mL) at room temperature, compound 001_5 (784.68 mg, 3.11 mmol) and potassium carbonate (1.15 g, 8.29 mmol) were added, and the reaction mixture was heated to 80°C and reacted with stirring for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed successively with saturated saline (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the resulting residue was separated by column chromatography (eluent: dichloromethane / methanol = 1 / 0 to 50 / 1, v / v) to obtain compound 016_1. 1 H NMR(400MHz, 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).

[0178] Step 2: Synthesis of compound 0016 Compound 016_1 (50 mg, 94.09 μmol) was dissolved in toluene (1 mL) at room temperature and added to a toluene solution of trimethylaluminum (141.13 μL, 2 M). The reaction mixture was heated to 80° C. and reacted with stirring for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and dilute hydrochloric acid aqueous solution (602.17 μL, 3 M) was added dropwise at less than 40° C. The mixture was stirred at 15° C. for 10 minutes. Next, water (3 mL) was added to the mixture, and it was extracted with 2-methyltetrahydrofuran (3 mL × 3). The organic phases were combined, washed successively with saturated saline (3 mL), 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: 0.04% M HCl) to obtain compound 016. MS-ESI m / z: 486.1 [M+H] + . 1 H NMR (400MHz, DMSO_d 6 )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).

[0179] Example 17 [ka]

[0180] Synthesis Route: [ka]

[0181] Step 1: Synthesis of intermediate 017_1 Compound 010_4 (1.1 g, 3.22 mmol, hydrochloride) was dissolved in tert-butanol (20 mL) at room temperature, compound 001_5 (1.22 g, 4.83 mmol) and potassium carbonate (1.78 g, 12.88 mmol) were added, and the reaction mixture was heated to 80°C and reacted with stirring for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed successively with saturated saline (30 mL), 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: petroleum ether / ethyl acetate = 1 / 0 to 2 / 1, v / v) to obtain compound 017_1. 1 H NMR (400MHz, DMSO_d 6 )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).

[0182] Step 2: Synthesis of intermediate 017 Compound 017_1 (300 mg, 568.37 μmol) was dissolved in toluene (6 mL) at room temperature, and a toluene solution of trimethylaluminum (852.55 μL, 2 M) was added. The reaction mixture was heated to 80° C. and reacted with stirring for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and a dilute aqueous hydrochloric acid solution (3.64 mL, 3 M) was added dropwise at less than 40° C. The mixture was stirred at 15° C. for 10 minutes. Then, water (10 mL) was added to the mixture, and the mixture was extracted with 2-methyltetrahydrofuran (20 mL × 3). The organic phases were combined, washed successively with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The obtained residue was subjected to preparative HPLC (mobile phase: acetonitrile / water, neutral system: 10 mM NH4 HCO 3 ) to obtain compound 017. MS-ESI m / z: 466.0 [M+H] + . 1 H NMR(400MHz, DMSO_d6)δ: 11.36(s, 1H), 11.12(s, 1H), 8.76(s, 1H), 8.70(dd, J=3.2, 9.6 Hz, 1H), 7.52-7.43(m, 1H), 7.15(t, J=8.0 Hz, 2H), 5.84(s, 2H), 2.98(d, J=16.0 Hz, 1H), 2.52(s, 1H), 1.36(s, 3H).

[0183] Example 18 [ka]

[0184] Synthesis Route: [ka]

[0185] Step 1: Synthesis of intermediate 018_1 Intermediate 012_3 (750 mg, 2.07 mmol, hydrochloride salt) and intermediate 013_4 (883.53 mg, 3.32 mmol) were dissolved in tert-butanol (20 mL) at room temperature under nitrogen protection, potassium carbonate (1.15 g, 8.29 mmol) was added, and the reaction mixture was heated to 80°C and reacted with stirring for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue obtained was diluted with water (100 mL) and ethyl acetate (100 mL), and after separation, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed successively with saturated saline (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: dichloromethane / ethanol = 1 / 0 to 19 / 1, v / v) to obtain intermediate 018_1. 1H NMR (400 MHz, DMSO_d 6 )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).

[0186] Step 2: Synthesis of compound 018 At room temperature, intermediate 018_1 (300 mg, 513.17 μmol, purity: 93.3%) was dissolved in toluene (8 mL), a toluene solution of trimethylaluminum (769.75 μL, 2 M) was added, and the reaction mixture was heated to 110°C and reacted with stirring for 12 hours. After the reaction was completed, the mixture was cooled to 0°C, a dilute aqueous hydrochloric acid solution (3.28 mL, 3 M) was added dropwise, and the reaction mixture was stirred at 0°C for 0.5 hours. The reaction mixture was then poured into water (30 mL), diluted with 2-methyltetrahydrofuran (30 mL), and the organic phase was collected after separation. The aqueous phase was extracted with 2-methyltetrahydrofuran (30 mL × 3). The organic phases were combined, washed successively with saturated saline (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 purified by preparative HPLC (mobile phase: acetonitrile / water, neutral system: 10 mM NH 4 HCO 3 ) to obtain compound 018. MS-ESI m / z: 500.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6)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).

[0187] Example 19 [ka]

[0188] Synthesis Route: [ka]

[0189] Step 1: Synthesis of intermediate 019_1 The hydrochloride salt of intermediate 001_6 (1 g, 3.09 mmol) was dissolved in tert-butanol (20 mL) under nitrogen protection at room temperature, and intermediate 013_4 (1.23 g, 4.63 mmol) and potassium carbonate (1.07 g, 7.72 mmol) were added. The reaction mixture was heated to 80°C and reacted with stirring for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and saturated saline (30 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL x 3). The organic phases were combined, washed successively with saturated saline (30 mL x 3), 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: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1, ethyl acetate / 2-methyltetrahydrofuran = 20 / 1, v / v) to obtain intermediate 019_1. 1 H NMR (400MHz, DMSO_d 6)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).

[0190] Step 2: Synthesis of compound 019 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 reacted with stirring for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with 2-methyltetrahydrofuran (10 mL), and the pH was adjusted to 5-6 with 1 M dilute hydrochloric acid, water was added (5 mL), and extracted with 2-methyltetrahydrofuran (30 mL × 3). The organic phases were combined, washed successively with saturated saline (30 mL × 3), 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, acidic system: 0.04% HCl). Compound 019 was obtained. MS-ESI m / z: 462.1 [M+H] + 1 H NMR (400MHz, DMSO_d 6 )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).

[0191] Examples 20 and 21 [Chemical]

[0192] Synthesis route: [Chemical]

[0193] Synthesis of Compounds 020 and 021 Compound 016 (65 mg, 133.93 μmol) was separated on a 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. 020 (retention time: 1.087 min): MS - ESI m / z: 486.1 [M + H] + . 1 H 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). 021 (retention time: 1.204 min): MS - ESI m / z: 486.0 [M + H] + . 1 H 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).

[0194] Example 22 [Chemical]

[0195] Synthesis route: [ka]

[0196] Step 1: Synthesis of intermediate 022_2 022_1 (5 g, 56.75 mmol, 4.90 mL) was placed in a dry reaction flask under nitrogen protection at room temperature, 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, and 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, the solution was allowed to stand and separated, and ethyl acetate (50 mL) and 10% aqueous sodium hydrogen sulfate solution (50 mL) were added to dilute, separate, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated saline (75 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 8 / 1, v / v). The target intermediate 022_2 was obtained. 1 H NMR (400 MHz, CDCl 3 )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).

[0197] Step 2: Synthesis of intermediate 022_3 Intermediate 022_2 (5 g, 24.01 mmol) and malononitrile (1.59 g, 24.01 mmol) were dissolved in toluene (50 mL) at room temperature under nitrogen protection, acetic acid (1.44 g, 24.01 mmol, 1.37 mL) and ammonium acetate (1.85 g, 24.01 mmol) were added, and the reaction system was heated to 50 °C and stirred for 12 hours. The reaction system was cooled to room temperature, and ethyl acetate (50 mL) and saturated saline (50 mL) were added to separate the liquids, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the combined organic phase was washed with saturated saline (65 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 8 / 1, v / v) to obtain intermediate 022_3. 1 H NMR (400 MHz, CDCl 3 )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).

[0198] Step 3: Synthesis of intermediate 022_4 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) at room temperature under nitrogen protection, titanocene dichloride (343.63 mg, 1.33 mmol, 214.77 μL) was added, activated zinc powder (2.60 g, 39.80 mmol) was added, and the reaction mixture was reacted at room temperature for 12 hours with stirring. After the reaction was completed, 40 mL of 1 M dilute hydrochloric acid was added to quench the reaction, ethyl acetate (80 mL) was added to dilute the reaction solution, the liquid was separated, the aqueous phase was extracted with ethyl acetate (100 mL × 3), and the organic phase was combined. The organic phase was washed with saturated saline (80 mL × 2), 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 to 10 / 3, v / v) to obtain intermediate 022_4. 1 H NMR (400 MHz, CDCl 3 )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).

[0199] Step 4: Synthesis of intermediate 022_5 Intermediate 022_4 (1.40 g, 4.06 mmol) was dissolved in tert-butanol (25 mL) at room temperature under nitrogen protection, 010_4 (868.18 mg, 2.54 mmol, hydrochloride) and potassium carbonate (877.85 mg, 6.35 mmol) were added, and the reaction mixture was heated to 85°C and reacted with stirring for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, 50 mL of saturated saline was added to the reaction system to quench the reaction, ethyl acetate (80 mL) was added to dilute, the liquid was separated, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (80 mL x 3), and the organic phase was combined. The organic phase was washed with saturated saline (50 mL x 3), 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 to 2 / 1, ethyl acetate / 2-methyltetrahydrofuran = 10 / 1, v / v). Intermediate 022_5 was obtained. 1 H NMR (400 MHz, DMSO_d 6 )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).

[0200] Step 5: Synthesis of intermediate 022_6 Intermediate 022_5 (620.00 mg, 1.03 mmol) was dissolved in dichloromethane (6 mL) and water (0.6 mL) under nitrogen protection at room temperature, and dichlorodicyanobenzoquinone (349.76 mg, 1.54 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (20 mL), extracted with dichloromethane (30 mL × 3), and the organic phase was collected. The organic phase was 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 to 5 / 4, ethyl acetate / 2-methyltetrahydrofuran = 10 / 1 to 5 / 1, v / v) to obtain intermediate 022_6. 1 H NMR (400 MHz, DMSO_d 6 )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).

[0201] Step 6: Synthesis of intermediate 022_7 Intermediate 022_6 (0.3 g, 620.55 μmol) was dissolved in dichloromethane (3 mL) and tetrahydrofuran (3 mL) under nitrogen protection at room temperature, and 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, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (30 mL) at 0°C, extracted with ethyl acetate (50 mL × 3), and the organic phases were combined. The organic phase was washed with saturated saline (30 mL × 3), 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 to 2 / 1, ethyl acetate / 2-methyltetrahydrofuran=10 / 1, v / v) to obtain intermediate 022_7. 1 H NMR (400 MHz, DMSO_d 6 )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).

[0202] Step 7: Synthesis of Compound 022 Intermediate 022_7 (0.28 g, 498.63 μmol) was dissolved in tetrahydrofuran (6 mL) at room temperature under nitrogen protection, hexamethylphosphoric triamide (277.00 mg, 1.55 mmol, 271.57 μL) was added, the reaction system was cooled to -78°C, 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), the aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The organic phase was washed with saturated saline (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The obtained residue was purified by preparative HPLC (mobile phase: acetonitrile / water, neutral system: 0.01% NH 4 HCO 3 ) to obtain compound 022. MS-ESI m / z: 466.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 )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).

[0203] Example 23 [ka]

[0204] Synthesis Route: [ka]

[0205] Step 1: Synthesis of intermediate 023_1 Intermediate 022_4 (1.52 g, 4.42 mmol) was dissolved in tert-butanol (20 mL) at room temperature under nitrogen protection, and intermediate 012_3 (1.00 g, 2.76 mmol, hydrochloride salt) 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 reacted with stirring for 12 hours. After the reaction was completed, it was cooled to room temperature, and saturated saline (50 mL) and ethyl acetate (80 mL) were added to the reaction system, which was separated and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (80 mL x 3), and the organic phases were combined. The organic phase was washed with saturated saline (50 mL x 3), dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure, and the resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 2 / 1, ethyl acetate / 2-methyltetrahydrofuran = 10 / 1, v / v). Intermediate 023_1 was obtained. MS-ESI m / z: 624.5 [M+H] + . 1 H NMR (400 MHz, CDCl 3 )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).

[0206] Step 2: Synthesis of intermediate 023_2 Intermediate 023_1 (0.67 g, 1.07 mmol) was dissolved in dichloromethane (6 mL) and water (0.6 mL) under nitrogen protection at room temperature, dichlorodicyanobenzoquinone (365.87 mg, 1.61 mmol) was added at 0°C, and the reaction mixture was reacted at 25°C for 12 hours with stirring. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (20 mL) and extracted with dichloromethane (30 mL x 3). The organic phase was 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 to 5 / 4, ethyl acetate / 2-methyltetrahydrofuran = 10 / 1 to 5 / 1, v / v). Intermediate 023_2 was obtained. MS-ESI m / z: 504.4 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 )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).

[0207] Step 3: Synthesis of intermediate 023_3 Intermediate 023_2 (0.46 g, 913.79 μmol) was dissolved in dichloromethane (5 mL) and tetrahydrofuran (5 mL) under nitrogen protection at room temperature, and 4-dimethylaminopyridine (11.16 mg, 91.38 μmol), methanesulfonyl chloride (157.01 mg, 1.37 mmol, 106.09 μL), and N,N-diisopropylethylamine (354.29 mg, 2.74 mmol, 477.48 μL) were added at 0°C, and the reaction mixture was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (30 mL) at 0°C, extracted with ethyl acetate (50 mL × 3), and the organic phase was combined. The organic phase was washed with saturated saline (30 mL × 3), 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 to 2 / 1, ethyl acetate / 2-methyltetrahydrofuran = 10 / 1, v / v) to obtain intermediate 023_3. 1 H NMR (400 MHz, DMSO_d 6 )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(br s, 2H), 3.14(s, 3H), 2.78-2.66(m, 2H), 2.45-2.42(m, 2H), 1.37(s, 2H).

[0208] Step 4: Synthesis of compound 023 Intermediate 023_3 (0.4 g, 687.89 μmol) was dissolved in tetrahydrofuran (8 mL) at room temperature under nitrogen protection, hexamethylphosphoric triamide (382.14 mg, 2.13 mmol, 374.64 μL) was added, the reaction system was cooled to -78°C, lithium bis(trimethylsilyl)amide (1 M tetrahydrofuran solution, 2.13 mL) was added, the reaction mixture was returned to room temperature and stirred for 1 hour. After the reaction was completed, the reaction solution was poured into ice water (30 mL) to quench, extracted with ethyl acetate (30 mL), and the aqueous phase was further extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated saline (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed from the filtrate under reduced pressure. The obtained residue was separated twice by HPLC (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_d 6 )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).

[0209] Example 24 [ka]

[0210] Synthesis Route: [ka]

[0211] Step 1: Synthesis of intermediate 024_2 Compound 024_1 (50 g, 314.29 mmol) was dissolved in dichloromethane (500 mL) at room temperature under nitrogen protection, then dichlorosulfoxide (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 toluene (200 mL) was added and concentrated again. Intermediate 024_2 was obtained.

[0212] Step 2: Synthesis of intermediate 024_4 Lithium bis(trimethylsilyl)amide (1 M, 11.27 mL) was dissolved in tetrahydrofuran (18 mL) at room temperature under nitrogen protection, and then cooled to -78°C. Compound 024_3 (26.05 g, 154.90 mmol) in tetrahydrofuran (150 mL) was added dropwise and reacted at -78°C for 1 hour while stirring, then compound 024_2 (33 g. 185.88 mmol) in tetrahydrofuran (150 mL) was added dropwise and reacted at -78°C for 1 hour while stirring, then the temperature was returned to room temperature and stirred for 3 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution (600 mL) to quench the reaction, and ethyl acetate (500 mL × 3) was added for extraction, and the organic phase was 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 to 3 / 1, v / v). Intermediate 024_4 was obtained.

[0213] Step 3: Synthesis of intermediate 024_5 Intermediate 024_4 (17.5 g, 56.56 mmol) was dissolved in dimethyl sulfoxide (52.5 mL) in a microwave tube under nitrogen protection at room temperature, sodium chloride (3.64 g, 62.23 mmol) and water (11.2 mL) were added, and the mixture was reacted at 150°C and 12 bar for 30 minutes. The solvent was removed by concentration under reduced pressure, and the obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1, v / v). Intermediate 024_5 was obtained.

[0214] Step 4: Synthesis of intermediate 024_6 Intermediate 024_5 (11.5 g, 45.78 mmol) and aminoguanidine hydrochloride (10.12 g, 91.56 mmol, hydrochloride salt) were dissolved in ethylene glycol (120 mL) at room temperature under nitrogen protection, boron trifluoride ethyl ether (14.62 g, 103.00 mmol) was added to the reaction system, the reaction mixture was heated to 120°C, and the reaction was allowed to proceed with stirring for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (100 mL) was added to the reaction solution, the pH was adjusted to 11 with 1N aqueous sodium hydroxide solution, and the solution 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.

[0215] Step 5: Synthesis of intermediate 024_7 Intermediate 024_6 (3 g, 9.76 mmol) was dissolved in isopropanol (30 mL) at room temperature, and intermediate 001_5 (4.93 g, 19.53 mmol) and potassium hydroxide (821.66 mg, 14.64 mmol) were added, and 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 obtained residue was separated by preparative HPLC (mobile phase: acetonitrile / water, hydrochloric acid system: 0.05% HCl). Intermediate 024_7 was obtained.

[0216] Step 6: Synthesis of Compound 024 Intermediate 024_7 (430 mg, 0.871 mmol) was dissolved in toluene (8 mL) at room temperature, and a toluene solution of trimethylaluminum (2M, 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 concentrated under reduced pressure to remove the solvent. The obtained 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, CD3 CN)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).

[0217] Example 25 [ka]

[0218] Synthesis Route: [ka]

[0219] Step 1: Synthesis of intermediate 025_1 Intermediate 024_6 (2 g, 6.51 mmol) was dissolved in tetrahydrofuran (25 mL) and ethanol (25 mL) at room temperature under nitrogen protection, 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, and 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 separated by column chromatography (eluent: dichloromethane / methanol = 1 / 0 to 9 / 1, v / v). Intermediate 025_1 was obtained.

[0220] Step 2: Synthesis of intermediate 025_2 Intermediate 025_1 (0.5 g, 0.948 mmol) was dissolved in pyridine (10 mL) at room temperature, and the reaction mixture was stirred at 90° C. for 36 hours. After the reaction was completed, the reaction solution was concentrated. The resulting residue was separated by preparative HPLC (mobile phase: acetonitrile / water, hydrochloric acid system: 0.05% HCl). Intermediate 025_2 was obtained. 1 H NMR (400 MHz, DMSO_d 6)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).

[0221] Step 3: Synthesis of compound 025 Intermediate 025_2 (39 mg, 76.85 μmol) was dissolved in a mixture of xylene (0.8 mL) and acetic acid (2.4 mL) under nitrogen protection at room temperature, and the reaction mixture was heated to 140° C. and reacted with stirring for 48 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The resulting residue was separated by preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.05% HCl). Compound 025 was obtained. MS-ESI m / z: 462.4 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 )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).

[0222] Example 26 [ka]

[0223] Synthesis Route: [ka]

[0224] Step 1: Synthesis of intermediate 026_1 Intermediate 001_7 (50 mg, 101.32 μmol) was dissolved in a mixture of tetrahydrofuran (1 mL) and water (1 mL) under nitrogen protection, followed by the addition of lithium hydroxide monohydrate (8.50 mg, 202.65 μmol), and the reaction mixture was reacted at room temperature for 12 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. Then, the mixture was adjusted to pH=4-5 with 3M dilute hydrochloric acid aqueous solution, diluted with acetonitrile, and separated by preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.4% HCl). Intermediate 026_1 was obtained. MS-ESI m / z: 466.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 )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).

[0225] Step 2: Synthesis of compound 026 Intermediate 026_1 (500 mg, 1.07 mmol) was dissolved in dioxane (8 mL) at room temperature under nitrogen protection, triethylamine (166.33 mg, 1.64 mmol) and diphenylphosphoryl azide (452.35 mg, 1.64 mmol) were added, and the reaction mixture was heated to 80°C and reacted with stirring for 12 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. Sequentially, the product was purified by preparative HPLC (mobile phase: acetonitrile / water; neutral system: 10 mM NH 4 HCO 3 ) and preparative HPLC (mobile phase: acetonitrile / water; acidic system: 0.05% HCl). Compound 026 was obtained. MS-ESI m / z: 463.1 [M+H] + . 1H NMR (400 MHz, DMSO_d 6 )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).

[0226] Example 27 [ka]

[0227] Synthesis Route: [ka]

[0228] Step 1: Synthesis of intermediate 027_2 Compound 027_1 (25 g, 143.52 mmol) was dissolved in ethyl acetate (100 mL) and chloroform (100 mL) under nitrogen protection at room temperature, and copper bromide (64.11 g, 287.04 mmol) was added. The reaction mixture was heated to 100°C and stirred for 36 hours. The reaction mixture was then 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 to 50 / 1, v / v). Intermediate 027_2 was obtained. 1 H NMR (400 MHz, CDCl 3 )δ: 4.29(q, J=7.2 Hz, 4H), 2.09(s, 3H), 1.31(t, J=7.2 Hz, 6H).

[0229] Step 2: Synthesis of intermediate 027_3 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) at room temperature under nitrogen protection, and the reaction mixture was stirred at room temperature for 0.5 hours. Next, 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 reacted at 75°C for 12 hours with stirring. After the reaction was completed, the reaction mixture was cooled to room temperature, water (100 mL) was added to the reaction mixture, the pH was adjusted to 3-4 with 3M dilute hydrochloric acid, extracted with ethyl acetate (100 mL x 3), and the organic phase was combined. The organic phase was washed successively with saturated saline (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 to 10 / 1, v / v) to obtain intermediate 027_3. 1 H NMR (400 MHz, DMSO_d 6 )δ: 5.72(s, 1H), 4.30-4.34(m, 4H), 1.61(s, 3H), 1.22(t, J=7.2 Hz, 6H).

[0230] Step 3: Synthesis of intermediate 027_4 Intermediate 001_6 (2 g, 6.18 mmol, hydrochloride salt) was dissolved in tert-butanol (20 mL) at room temperature under nitrogen protection, 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 to 2 / 1, v / v). Intermediate 027_4 was obtained.

[0231] Step 4: Synthesis of intermediate 027_5 Intermediate 027_4 (1.25 g, 2.61 mmol) was dissolved in methanol (5 mL) and 25% aqueous ammonia (5 mL) at room temperature under nitrogen protection, and the reaction was stirred at 50°C for 12 hours in a soundproof tank. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and anhydrous toluene (20 mL) was added to perform a second concentration. Intermediate 027_5 was obtained.

[0232] Step 5: Synthesis of intermediate 027_6 Intermediate 027_5 (0.5 g, 1.11 mmol) was dissolved in ethyl hydroxyacetate (5.46 mL, 56.62 mmol) at room temperature under nitrogen protection, 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, and the reaction mixture was stirred at 80°C for 0.5 hours. 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_d 6 )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).

[0233] Step 6: Synthesis of intermediate 027_7 Intermediate 027_6 (300 mg, 0.589 mmol) was dissolved in methanol (0.75 mL) and water (2.25 mL) under nitrogen protection at room temperature, lithium hydroxide monohydrate (123.54 mg, 2.94 mmol) was added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to remove methanol, 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 4 with 1 M dilute hydrochloric acid, extracted with 2-methyltetrahydrofuran (60 mL), and the organic phase was concentrated under reduced pressure to obtain intermediate 027_7.

[0234] Step 7: Synthesis of Compound 027 Intermediate 027_7 (0.15 g, 0.312 mmol) was dissolved in dioxane (5 mL) under nitrogen protection at room temperature, dichlorosulfoxide (3 mL, 41.35 mmol) was added, and the reaction mixture was stirred at 80° C. for 2 hours. After the reaction was completed, the reaction solution was concentrated. The resulting 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] + . 1 H NMR (400 MHz, DMSO_ d 6 )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).

[0235] Example 28 [ka]

[0236] Synthesis Route: [ka]

[0237] Step 1: Synthesis of intermediate 028_1 Intermediate 026_1 (4.6 g, 9.88 mmol) was dissolved in acetonitrile (50 mL) at room temperature under nitrogen protection, 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, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, it was filtered, the filter cake was rinsed with ice-cold acetonitrile (20 mL), and the filtrate was collected and concentrated under reduced pressure to remove the solvent. Intermediate 028_1 was obtained.

[0238] Step 2: Synthesis of intermediate 028_2 Intermediate 028_1 (5.5 g, 9.78 mmol) was dissolved in tetrahydrofuran (80 mL) under nitrogen protection, and aqueous ammonia (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 reaction solution was concentrated under reduced pressure to remove the solvent, 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 resulting 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 resulting residue, and the mixture was slurried and stirred 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.

[0239] Step 3: Synthesis of intermediate 028_3 Intermediate 028_2 (3.3 g, 7.11 mmol) was dissolved in dioxane (60 mL) at room temperature under nitrogen protection, and isoamyl nitrite (4.16 g, 35.53 mmol) and diiodomethane (5.71 g, 21.32 mmol) were added. The reaction mixture was heated to 85° C. and reacted with stirring for 4 hours. After the reaction was completed, the reaction solution was returned to room temperature and concentrated under reduced pressure to remove the solvent. A mixture of ethyl acetate:dichloromethane=1:1 (5 mL) was added to the obtained residue, stirred for 10 minutes, and filtered. The filter cake was collected and concentrated under reduced pressure to remove the solvent. Intermediate 028_3 was obtained.

[0240] Step 4: Synthesis of intermediate 028_4 Intermediate 028_3 (2.1 g, 3.65 mmol) was dissolved in N,N-methylformamide (12 mL) and methanol (5 mL) under nitrogen protection at room temperature, and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (186.96 mg, 255.52 μmol) and N,N-diisopropylethylamine (10.4 mL) were added. The atmosphere was replaced with carbon monoxide three times, and the reaction mixture was heated to 80°C under carbon monoxide (15 psi) and stirred for 12 hours. [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (186.96 mg, 255.52 μmol) was added, and the reaction mixture was stirred at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate=2 / 1, dichloromethane:methanol=1 / 0-10 / 1, v / v) to obtain intermediate 028_4.

[0241] Step 5: Synthesis of intermediate 028_5 Intermediate 028_4 (300 mg, 591.19 μmol) was dissolved in acetonitrile (4 mL) and water (0.8 mL) under nitrogen protection at room temperature, and bis(trifluoroacetoxy)iodobenzene (1.27 g, 2.96 mmol) was added slowly at 0°C, and the reaction mixture was stirred at room temperature for 12 hours. Bis(trifluoroacetoxy)iodobenzene (1.27 g, 2.96 mmol) was added at 0°C, and the reaction mixture was warmed to 35°C and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature. The pH was adjusted to 3-4 with 1 M dilute hydrochloric acid, extracted with 2-methyltetrahydrofuran (20 mL × 3), and the organic phase was combined. The organic phase was washed with saturated saline (20 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: dichloromethane / methanol = 1 / 0 to 10 / 1, v / v) to obtain intermediate 028_5.

[0242] Step 6: Synthesis of intermediate 028_6 Intermediate 028_5 (45 mg, 93.86 μmol) was dissolved in tetrahydrofuran (1 mL) and water (0.2 mL) under nitrogen protection at room temperature, followed by the addition of lithium hydroxide monohydrate (7.88 mg, 187.72 μmol), and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the pH was adjusted to 5-7 with 3 M dilute hydrochloric acid, and then extracted with 2-methyltetrahydrofuran (10 mL x 4), and the organic phases were combined. The organic phases were successively washed with saturated saline (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. Intermediate 028_6 was obtained.

[0243] Step 7: Synthesis of Compound 028 Intermediate 028_6 (160 mg, 343.78 μmol) was dissolved in sulfoxide chloride (2 mL) and dioxane (2 mL) under nitrogen protection at room temperature, and the reaction mixture was heated to 75° C. and reacted with stirring for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature 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). Compound 028 was obtained. MS-ESI m / z: 448.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 )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).

[0244] Examples 29 and 30 [ka]

[0245] Synthesis Route: [ka]

[0246] Compound 001 (300 mg, 670.55 μmol) was dissolved in tetrahydrofuran (5 mL) at room temperature under nitrogen protection, and the temperature was lowered to -65°C, and a n-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 hours, and then iodomethane (99.94 mg, 704.07 μmol) was added dropwise, and the reaction mixture was stirred at room temperature for 12 hours. Iodomethane (95.18 mg, 670.55 μmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, 1M diluted hydrochloric acid aqueous solution (0.2 mL) was added to the reaction solution, and the solvent was removed by concentrating under reduced pressure. The obtained residue was subjected to preparative HPLC (mobile phase: acetonitrile / water, neutral system: 10 mM NH 4 HCO 3 ) to obtain compounds 029 and 030. 029: MS-ESI m / z: 462.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 )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). 030: MS-ESI m / z: 462.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 )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).

[0247] Example 31 [ka]

[0248] Synthesis Route: [ka]

[0249] Step 1: Synthesis of intermediate 031_2 031_1 (20 g, 95.17 mmol) was dissolved in water (150 mL) under nitrogen protection at room temperature, and dilute hydrochloric acid (1 M, 70 mL) was added, and the reaction mixture was stirred at room temperature for 10 minutes. After the reaction was completed, the reaction solution was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated saline (150 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. Intermediate 031_2 was obtained.

[0250] Step 2: Synthesis of intermediate 031_3 Intermediate 031_2 (13 g, 69.08 mmol) was dissolved in acetone (400 mL) under nitrogen protection at room temperature, potassium carbonate (19.10 g, 138.17 mmol) was added, and the reaction mixture was reacted at room temperature with stirring for 20 minutes, after which iodomethane (58.83 g, 414.50 mmol) was added. The reaction mixture was heated to 60°C and reacted with stirring for 12 hours. After completion of the reaction, 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 to 10 / 1, v / v). Intermediate 031_3 was obtained. 1 H NMR (400 MHz, CDCl 3 )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).

[0251] Step 3: Synthesis of intermediate 031_4 Intermediate 031_3 (2.46 g, 11.38 mmol) and malononitrile (3.01 g, 45.51 mmol) were dissolved in ethanol (25 mL) at room temperature under nitrogen protection, pyridine (4.50 g, 56.88 mmol, 4.59 mL) was added, the reaction system was heated to 70 ° C, and reacted with stirring for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, 1 M hydrochloric acid was added to adjust the pH to 3-4, ethyl acetate (50 mL) and water (30 mL) were added to dilute, and the organic phase was collected by separation. The aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was combined. It was washed successively with 1N hydrochloric acid aqueous solution (50 mL × 3), saturated saline (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 to 1 / 1, v / v) to obtain intermediate 031_4.

[0252] Step 4: Synthesis of intermediate 031_5 Intermediate 031_4 (3 g, 11.35 mmol) was dissolved in chloroform (15 mL) and ethanol (15 mL), then 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate diethyl (3.16 g, 12.49 mmol) was added, the reaction system was heated to 50°C, and the reaction was allowed to proceed with stirring for 12 hours. 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate diethyl (862.60 mg, 3.41 mmol) was added, the reaction system was heated to 50°C, and the reaction was allowed to proceed with stirring for 12 hours. 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate diethyl (2.88 g, 11.35 mmol) was added, the reaction system was heated to 50°C, and the reaction was allowed to proceed with stirring for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 7 / 1, v / v) to obtain intermediate 031_5. 1 H NMR (400 MHz, CDCl 3)δ: 4.34-4.19(m, 5H), 3.66(d, J=7.0 Hz, 1H), 1.38-1.29(m, 12H).

[0253] Step 5: Synthesis of intermediate 031_6 Intermediate 031_5 (1.73 g, 6.50 mmol) and 001_6 (1.31 g, 4.06 mmol, hydrochloride salt) were dissolved in tert-butanol (20 mL) at room temperature under nitrogen protection, followed by the addition of potassium carbonate (1.40 g, 10.15 mmol), and the reaction system was heated to 85°C and stirred at 85°C for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature, water (35 mL) was added to quench the reaction, ethyl acetate (50 mL) was added to dilute, the organic phase was collected by liquid separation, and the aqueous phase was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated saline (40 mL x 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 to 0 / 1, v / v). Intermediate 031_6 was obtained.

[0254] Step 6: Synthesis of compound 031 Intermediate 031_6 (0.9 g, 1.77 mmol) was dissolved in toluene (18 mL) at room temperature under nitrogen protection, and then a toluene solution of trimethylaluminum (2M, 2.84 mL) was added dropwise to the reaction system, and 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 x 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 (400MHz, DMSO_d 6)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).

[0255] Examples 32 and 33 [ka]

[0256] Synthesis Route: [ka]

[0257] Step 1: Synthesis of intermediate 032_1 Intermediate 001_7 (3 g, 6.08 mmol) was dissolved in glacial acetic acid (20 mL) at room temperature under nitrogen protection, and then a solution of sodium nitrite (1.26 g, 18.24 mmol) dissolved in water (10 mL) was added to the reaction system, and the reaction mixture was heated to 90°C and reacted with stirring for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and diluted with ethyl acetate (100 mL), then washed with saturated aqueous sodium bicarbonate solution (40 mL), and the organic phase was 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 to 1 / 3, v / v). Intermediate 032_1 was obtained.

[0258] Step 2: Synthesis of intermediate 032_2 Intermediate 032_1 (0.3 g, 0.607 mmol) was dissolved in tetrahydrofuran (9 mL) at room temperature, Red-Al (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 of the reaction, the reaction solution was quenched with 1 M hydrochloric acid (20 mL), 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 obtained residue was separated by column chromatography (eluent: dichloromethane / methanol = 1 / 0-9 / 1, v / v). Intermediate 032_2 was obtained.

[0259] Step 3: Synthesis of intermediate 032_3 Intermediate 032_2 (120 mg, 0.265 mmol) was dissolved in tetrahydrofuran (2 mL) at room temperature, and a solution of N,N,N',N'-tetramethylazodicarboxamide (205.52 mg, 1.19 mmol) dissolved in tetrahydrofuran (0.5 mL) was added at 0°C, followed by a solution of tri-tert-butylphosphine (241.49 mg, 1.19 mmol) dissolved 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 obtained crude product was purified by preparative HPLC (mobile phase: acetonitrile / water, neutral system: 10 mM NH 4 HCO 3 ) to obtain intermediate 032_3. MS-ESI m / z: 435.4 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 )δ: 11.24(s, 1H), 8.74(d, J=1.0 Hz, 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)

[0260] Step 3: Synthesis of Compounds 032 and 033 The intermediate 032_3 was separated using a 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. 032 (retention time: 1.269 min): MS-ESI m / z: 435.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 ) 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). 033 (retention time: 1.554 min): MS-ESI m / z: 435.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 ) 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).

[0261] Example 34

Chemical Structure

[0262] Synthesis route:

Chemical Structure

[0263] Step 1: Synthesis of intermediate 034_2 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) under nitrogen protection at room temperature and reacted with stirring for 1 hour. After completion of the reaction, a tetrahydrofuran solution of intermediate 034_2 was obtained.

[0264] Step 2: Synthesis of intermediate 034_3 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 under nitrogen protection at room temperature, tetrahydrofuran (340 mL) was added, 1 / 10 of a solution of ethyl difluorobromoacetate (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, and after the start of the reaction, the remaining tetrahydrofuran solution of ethyl difluorobromoacetate was slowly added dropwise, and the reaction system was stirred at room temperature for 0.5 hours. Then, it was filtered, the filter cake was rinsed with tetrahydrofuran (60 mL), and the filtrate was combined. The filtrate was added to a tetrahydrofuran solution of intermediate 034_2 (40.44 g, 246.33 mmol) at room temperature, and the reaction system was stirred at room temperature for 12 hours. After the reaction was completed, the pH was adjusted to about 3 with 1N hydrochloric acid solution, and the mixture was diluted with ethyl acetate (250 mL) and water (200 mL), separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed successively with saturated saline (250 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 9 / 1, v / v). Intermediate 034_3 was obtained. 1 H NMR (400 MHz, CDCl 3 )δ: 4.69(s, 1H), 4.46-4.31(m, 4H), 1.81(s, 3H), 1.46-1.31(m, 6H).

[0265] Step 3: Synthesis of intermediate 034_4 Intermediate 034_3 (7.6 g, 26.37 mmol) was dissolved in tert-butanol (110 mL) at room temperature under nitrogen protection, then potassium carbonate (5.69 g, 41.19 mmol) and 001_6 (5.33 g, 16.48 mmol, hydrochloride) were added, and the reaction mixture was heated to 85°C and reacted with stirring for 40 hours. After the reaction was completed, it was cooled to room temperature, diluted with water (100 mL) and ethyl acetate (100 mL), separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed successively with saturated brine (50 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 / 2-methyltetrahydrofuran = 1 / 0 to 1 / 1, v / v). Intermediate 034_4 was obtained. 1 H NMR (400 MHz, DMSO_d 6 )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).

[0266] Step 4: Synthesis of compound 034 Intermediate 034_4 (300 mg, 566.63 μmol) was dissolved in toluene (6 mL) at room temperature under nitrogen protection, and a toluene solution of trimethylaluminum (2M, 849.95 μL, 1.70 mmol) was added. The reaction mixture was heated to 80°C and reacted with stirring for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, quenched by slowly adding dilute hydrochloric acid (3M, 3.68 mL), diluted with 2-methyltetrahydrofuran (10 mL), and then separated. The aqueous phase was extracted with 2-methyltetrahydrofuran (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, 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). Compound 034 was obtained. MS-ESI m / z: 484.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 )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).

[0267] Examples 35 and 36 [ka]

[0268] Synthesis Route: [ka]

[0269] Step 1: Synthesis of intermediate 035_1 Intermediate 031_4 (2.1 g, 7.95 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) at room temperature under nitrogen protection, the reaction system was lowered to 0°C, methylmagnesium bromide solution (3M, 3.97 mL) was added dropwise, and the reaction system was reacted at 0°C for 15 minutes while stirring. After the reaction was completed, the reaction solution was quenched with 1N dilute hydrochloric acid (50 mL), diluted with water (30 mL), extracted with ethyl acetate (50 mL), and the aqueous phase was further extracted with ethyl acetate (10 mL x 3), and the organic phase was combined. The organic phase was washed with saturated saline (40 mL x 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 to 9 / 1, v / v). Intermediate 035_1 was obtained. 1 H NMR (400 MHz, CDCl 3 )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).

[0270] Step 2: Synthesis of intermediate 035_2 Intermediate 001_6 (608.22 mg, 1.88 mmol, hydrochloride salt) and intermediate 035_1 (790 mg, 2.82 mmol) were dissolved in tert-butanol (12 mL) at room temperature under nitrogen protection, potassium carbonate (778.99 mg, 5.64 mmol) was added, and the reaction system was heated to 85°C and reacted with stirring for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (40 mL), the aqueous phase was extracted again with ethyl acetate (30 mL x 3), and the organic phases were combined. The organic phase was washed with saturated saline (30 mL x 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 to 1 / 4, v / v). Intermediate 035_2 was obtained.

[0271] Step 3: Synthesis of intermediate 035_3 Intermediate 035_2 (465 mg, 891.63 μmol) was dissolved in toluene (10 mL) under nitrogen protection at room temperature, followed by the addition of a toluene solution of trimethylaluminum (2M, 1.43 mL), and the reaction system was heated to 80°C and reacted with stirring for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and 3 M hydrochloric acid (6 mL) was added to the reaction solution to quench the reaction, and then ethyl acetate (40 mL) and water (20 mL) were added to dilute and separate the liquids, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated saline (50 mL x 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 (400MHz, DMSO_d 6 )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).

[0272] Step 4: Synthesis of Compounds 035 and 036 Intermediate 035_3 was separated on a chiral column (column type: DAICEL CHIRALCEL OD (250mm*30mm, 10μm); mobile phase: [Neu-ACN]%: 50%-50%, 12min). Compounds 035 and 036 were obtained. 035 (retention time: 1.696 min): MS-ESI m / z: 476.2 [M+H] + . 1 H NMR (400MHz, DMSO_d 6)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). 036 (retention time: 2.403 min):MS-ESI m / z: 476.2 [M+H] + . 1 H NMR (400MHz, DMSO_d 6 )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).

[0273] Examples 37 and 38 [ka]

[0274] Synthesis Route: [ka]

[0275] Step 1: Synthesis of intermediate 037_1 Intermediate 027_6 (690 mg, 1.35 mmol) was dissolved in trifluoroacetic acid (9 mL) at room temperature under nitrogen protection, the reaction mixture was cooled to 0° C., a solution of sodium nitrite (280.33 mg, 4.06 mmol) dissolved in water (0.9 mL) was added, and the reaction mixture was stirred at 0° C. for 1 hour. After the reaction was completed, the reaction mixture was diluted with water (30 mL) and filtered to obtain a yellow solid. Toluene (20 mL) was added to remove water by azeotropy, and the solvent was removed under reduced pressure to obtain intermediate 037_1.

[0276] Step 2: Synthesis of intermediate 037_2 Intermediate 037_1 (470 mg, 920.76 μmol) was dissolved in tetrahydrofuran (1.5 mL) under nitrogen protection at room temperature, and the temperature was lowered to 10°C, and a toluene solution of Red-Al (1.06 g, 3.68 mmoL, purity: 70%) was added, and the reaction mixture was reacted at room temperature for 12 hours while stirring. After the reaction was completed, 1M dilute hydrochloric acid was added to the reaction solution to adjust the pH to neutral, and water (20 mL) and 2-methyltetrahydrofuran (50 mL) were added to dilute it, and the aqueous phase was extracted with 2-methyltetrahydrofuran (50 mL × 3), and the organic phase was combined. The mixture was 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 / 2-methyltetrahydrofuran = 1 / 0 to 0 / 1, v / v). Intermediate 037_2 was obtained. 1 H NMR (400 MHz, DMSO_d 6 )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).

[0277] Step 3: Synthesis of intermediate 037_3 Intermediate 037_2 (250 mg, 533.72 μmol) was dissolved in tetrahydrofuran (5 mL) under nitrogen protection at room temperature, and the temperature was lowered to 0°C to add a solution of N,N,N',N'-tetramethylazodicarboxamide (413.54 mg, 2.40 mmol) dissolved in tetrahydrofuran (1.25 mL). Finally, a solution of triphenylphosphine (629.94 mg, 2.4 mmol) dissolved in tetrahydrofuran (1.25 mL) was added at 0°C, and the reaction mixture was reacted at 70°C for 5 hours while stirring. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, the filtrate was removed under reduced pressure, and the crude product was separated by preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.04% HCl). Intermediate 037_3 was obtained. MS-ESI m / z: 451.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 )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).

[0278] Step 4: Synthesis of Compounds 037 and 038 Intermediate 037_3 was separated using 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. 037 (retention time: 1.215 min): MS-ESI m / z: 451.1 [M+H] + . 1 H NMR (400 MHz, DMSO_ d 6)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). 038 (Retention time: 1.574 min): MS - ESI m / z: 451.1 [M + H] + . 1 H NMR(400 MHz, DMSO_d 6 )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).

[0279] Example 39

Chemical formula

[0280] Synthesis route:

Chemical formula

[0281] Step 1: Synthesis of Intermediate 039_1 Intermediate 027_6 (200 mg, 392.57 mmol) was dissolved in tetrahydrofuran (4 mL) at room temperature under nitrogen protection, the reaction mixture was cooled to 10°C, Red-Al (453.50 mg, 1.57 mmol, purity 70%) was added, and the reaction mixture was returned to room temperature and reacted with stirring for 12 hours. After the reaction was completed, the reaction solution was quenched by pouring dilute hydrochloric acid (1M, 10 mL) into it, diluted with 2-methyltetrahydrofuran (10 mL), separated, and the aqueous phase was extracted with 2-methyltetrahydrofuran (10 mL x 2). The organic phases were combined, 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 / 2-methyltetrahydrofuran = 1 / 0 to 5 / 4, v / v). Intermediate 039_1 was obtained.

[0282] Step 2: Synthesis of intermediate 039_2 Intermediate 039_1 (130 mg, 278.12 μmol) was dissolved in tetrahydrofuran (1.1 mL) and dichloromethane (1.1 mL) under nitrogen protection at room temperature, and N,N-diisopropylethylamine (71.89 mg, 556.24 μmol) and 4-dimethylaminopyridine (3.40 mg, 27.81 μmol) were added in sequence. The temperature was lowered to 0°C, and methanesulfonyl chloride (47.79 mg, 417.18 μmol) was added, and the reaction mixture was reacted at room temperature for 1 hour while stirring. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (10 mL) to quench the reaction, and 2-methyltetrahydrofuran (10 mL) was added to dilute the mixture, and the liquids were separated. The aqueous phase was extracted with 2-methyltetrahydrofuran (10 mL × 2), and 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 obtained residue was separated by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0 to 5 / 4, v / v) to obtain intermediate 039_2. 1 H NMR (400 MHz, DMSO_d 6)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).

[0283] Step 3: Synthesis of compound 039 Intermediate 039_2 (60 mg, 109.99 μmol) was dissolved in tetrahydrofuran (1 mL) under nitrogen protection at room temperature, and the temperature was lowered to -78°C, and a n-hexane solution of lithium bis(trimethylsilyl)amide (1 M, 274.97 μL) and hexamethylphosphoric triamide (49.27 mg, 274.97 mmol) were added, and the reaction mixture was reacted at room temperature with stirring for 2 hours. The temperature was lowered to -78°C, and a n-hexane solution of lithium bis(trimethylsilyl)amide (1 M, 274.97 μL) and hexamethylphosphoric triamide (49.27 mg, 274.97 mmol) were added, and the reaction mixture was reacted at room temperature with stirring for 12 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous solution of ammonium chloride (10 mL) to quench it, and then 2-methyltetrahydrofuran (10 mL) was added to dilute it, and the liquids were separated. The aqueous phase was extracted with 2-methyltetrahydrofuran (10 mL x 2), and 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 crude product was 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] + . 1 H NMR (400 MHz, DMSO_d 6)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).

[0284] Examples 40 and 41 [ka]

[0285] Synthesis Route: [ka]

[0286] Step 1: Synthesis of intermediate 040_1 Intermediate 034_4 (2 g, 3.78 mmol) was dissolved in tetrahydrofuran (40 mL) under nitrogen protection at room temperature, the reaction mixture was cooled to 0°C, lithium aluminum hydride (286.75 mg, 7.56 mmol) was added, and the reaction mixture was stirred at 0°C for 2 hours. After the reaction was completed, the reaction solution was quenched to neutral with 1M dilute hydrochloric acid, diluted with 2-methyltetrahydrofuran (50 mL), separated, and the aqueous phase was extracted with 2-methyltetrahydrofuran (50 mL x 3). The organic phases were combined and concentrated under reduced pressure to remove the solvent. The resulting residue was separated by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0 to 1 / 1, v / v). Intermediate 040_1 was obtained.

[0287] Step 2: Synthesis of intermediate 040_2 Intermediate 040_1 (720 mg, 1.48 mmol) was dissolved in trifluoroacetic acid (15 mL) under nitrogen protection at room temperature, and the temperature was lowered to 0°C. A solution of sodium nitrite (305.76 mg, 4.43 mmol) dissolved in water (1.5 mL) was added, and the reaction mixture was reacted at 0°C for 1 hour while stirring. After the reaction was completed, the reaction solution was diluted with water (50 mL), filtered to collect the filter cake, rinsed with water (2 mL), and concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0 to 5 / 4, v / v). Intermediate 040_2 was obtained.

[0288] Step 3: Synthesis of intermediate 040_3 Intermediate 040_2 (260 mg, 532.36 μmol) was dissolved in tetrahydrofuran (4 mL) under nitrogen protection at room temperature, and the temperature was lowered to 0°C to add a solution of N,N,N',N'-tetramethylazodicarboxamide (412.49 mg, 2.40 mmol) dissolved in tetrahydrofuran (4 mL), and finally a solution of triphenylphosphine (628.33 mg, 2.40 mmol) dissolved in tetrahydrofuran (2 mL) was added at 0°C, and the reaction mixture was reacted at 75°C for 12 hours with stirring. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the solvent was removed from the filtrate under reduced pressure. The obtained residue was separated by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0 to 0 / 1, v / v). 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_d 6)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).

[0289] Step 4: Synthesis of Compounds 040 and 041 Compound 040_3 was separated on a chiral column (column type: REGIS (R,R) WHELK - O1 (250 mm * 25 mm, 10 um); mobile phase: [Neu - ACN]; B%: 50% - 50%, 10 min). Compounds 040 and 041 were obtained. 040 (Retention time: 1.284 min): MS - ESI m / z: 471.4 [M + H] + . 1 H NMR (400 MHz, DMSO_d 6 )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). 041 (Retention time: 1.400 min): MS - ESI m / z: 471.4 [M + H] + . 1 H NMR (400 MHz, DMSO_d 6 )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).

[0290] Examples 42 and 43 [ka]

[0291] Synthesis Route: [ka]

[0292] Step 1: Synthesis of intermediate 042_1 Intermediate 040_1 (1.4 g, 2.87 mmol) was dissolved in tetrahydrofuran (15 mL) and dichloromethane (15 mL) under nitrogen protection at room temperature, and then 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) were added in sequence, and the reaction mixture was heated to 50°C and reacted with stirring for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and separated with saturated aqueous citric acid (50 mL) and 2-methyltetrahydrofuran (30 mL), the aqueous phase was extracted with 2-methyltetrahydrofuran (50 mL x 3), and the organic phase was combined. The organic phase was 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 / 2-methyltetrahydrofuran = 1 / 0 to 1 / 1, v / v) and preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.04% HCl). Intermediate 042_1 was obtained. 1 H NMR (400 MHz, DMSO_d 6 )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).

[0293] Step 2: Synthesis of intermediate 042_2 Intermediate 042_1 (70 mg, 109.10 μmol) was dissolved in tetrahydrofuran (2 mL) under nitrogen protection at room temperature, and the temperature was lowered to -78°C. Hexamethylphosphoric triamide (48.88 mg, 272.76 mmol, 47.92 μL) and lithium bis(trimethylsilyl)amide (1 M, 272.76 μL) in n-hexane were added in sequence, the reaction mixture was returned to room temperature, and the reaction was allowed to proceed with stirring for 12 hours. After the reaction was completed, the reaction solution was slowly poured into dilute hydrochloric acid (1 M, 5 mL), and diluted with half-saturated saline (5 mL) and 2-methyltetrahydrofuran (5 mL), and the aqueous phase was extracted with 2-methyltetrahydrofuran (5 mL x 3), and the organic phase was combined. The organic phase was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the solvent was removed. 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 H NMR (400 MHz, DMSO_d 6 )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).

[0294] Step 3: Synthesis of Compounds 042 and 043 Compound 042_2 was purified using a chiral column (column type: DAICEL CHIRALPAKAS (250mm*30mm, 10μm); mobile phase: [0.1%NH 3 H 2 O MeOH]%: 35%-35%, 15 min) to obtain compounds 042 and 043. 042 (Retention time: 1.169 min): MS-ESI m / z: 470.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) 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). 043 (Retention time: 1.190 min): MS-ESI m / z: 470.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0295] Examples 44 and 45

Chemical formula

[0296] Synthesis route:

Chemical formula

[0297] Step 1: Synthesis of Intermediate 044_1 Intermediate 034_3 (9.37 g, 32.52 mmol) was dissolved in tert-butanol (40 mL) under nitrogen protection at room temperature, and 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 reacted with stirring 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 to 95 / 5, v / v). Intermediate 044_1 was obtained.

[0298] Step 2: Synthesis of intermediate 044_2 Intermediate 044_1 (1 g, 1.76 mmol) was dissolved in tetrahydrofuran (20 mL) under nitrogen protection at room temperature, cooled to 0°C, and 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 mixture was slowly quenched by pouring it into dilute hydrochloric acid (1 N, 20 mL), and extracted with 2-methyltetrahydrofuran (10 mL). 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.

[0299] Step 3: Synthesis of intermediate 044_3 Intermediate 044_2 (98 mg, 186.54 μmol) was dissolved in trifluoroacetic acid (2 mL) at room temperature under nitrogen protection, the reaction temperature was lowered to 0°C, a solution of sodium nitrite (38.61 mg, 559.62 μmol) in water (0.2 mL) was added, and 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 to precipitate a solid, which was then filtered. The obtained filter cake was concentrated with anhydrous toluene (10 mL) to obtain intermediate 044_3.

[0300] Step 4: Synthesis of intermediate 044_4 Triphenylphosphine (73.25 mg, 279.29 μmol) was added to the reaction flask under nitrogen protection at room temperature, followed by a solution of intermediate 044_3 (98 mg, crude product) in tetrahydrofuran (1.7 mL), 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, and the reaction mixture was stirred at 70°C for 12 hours. After the reaction was completed, the reaction solution was concentrated, and the resulting 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_d 6 )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).

[0301] Step 5: Synthesis of Compounds 044 and 045 Intermediate 044_4 was separated by chiral (column type: REGIS(S,S)WHELK-O1 (250mm*25mm, 10μm); mobile phase: [Neu-ACN]%: 30%-30%, 5min). Compounds 044 and 045 were obtained. Chiral analysis method: OD_MeOH_IPAm, gradient: 5-50%, flow rate: 3.4mL / min, column temperature: 35℃, time: 3min. 044 (retention time: 0.789 min): MS-ESI m / z: 509.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 )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). 045 (retention time: 0.768 min): MS-ESI m / z: 509.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 )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).

[0302] Examples 46 and 47 [ka]

[0303] Synthesis Route: [ka]

[0304] Step 1: Synthesis of intermediate 046_1 Intermediate 044_1 (150 mg, 264.37 μmol) was dissolved in anhydrous toluene (2 mL) at room temperature under nitrogen protection, and a toluene solution of trimethylaluminum (2M, 396.55 μL) was slowly added, and the reaction mixture was reacted at 80° C. for 4 hours with stirring. After the reaction was completed, it was cooled to room temperature, adjusted to pH=6 with 1M dilute hydrochloric acid, and then 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. The residue was separated by preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.04% HCl). Intermediate 046_1 was obtained. 1 H NMR (400 MHz, DMSO_d 6 )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).

[0305] Step 2: Synthesis of Compounds 046 and 047 Intermediate 046_1 was separated on a chiral column (column type: REGIS (S,S) WHELK-O1 (250 mm * 25 mm, 10 μm); mobile phase: [Neu-MeOH]%: 20% - 20%, 4 min) to obtain Compounds 046 and 047. Chiral analysis method: OD_MeOH_IPAm, gradient: 5 - 50%, flow rate: 3.4 mL / min, column temperature: 35 °C, time: 3 min. 046 (retention time: 0.850 min): MS-ESI m / z: 522.0 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 ) 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). 047 (retention time: 0.847 min): MS-ESI m / z: 522.0 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 ) 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).

[0306] Example 48

Chemical Structure

[0307] Synthesis Route:

Chemical Structure

[0308] Step 1: Synthesis of intermediate 048_2 Compound 048_1 (50 g, 287.11 mmol) was dissolved in anhydrous toluene (1000 mL) at room temperature under nitrogen protection, to which malononitrile (18.02 g, 272.75 mmol), β-aminopropionic acid (766.67 mg, 8.61 mmol) and acetic acid (3.17 g, 52.73 mmol) were added, and the reaction system was heated to 125°C and stirred for 12 hours. After the reaction was completed, the reaction system was returned to room temperature and concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1, v / v). Intermediate 048_2 was obtained. 1 H NMR (400MHz, DMSO_d 6 )δ : 4.39(q, J=7.2 Hz, 4H), 1.28(t, J=7.2 Hz, 6H).

[0309] Step 2: Synthesis of intermediate 048_3 Intermediate 048_2 (30 g, 135.02 mmol) was dissolved in tetrahydrofuran (300 mL) at room temperature under nitrogen protection, cooled to -78°C, and 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, the reaction system was quenched by adding saturated ammonium chloride solution (300 mL), and diluted with ethyl acetate (200 mL) and water (100 mL) to separate the liquid. The aqueous phase was extracted with ethyl acetate (300 mL x 3), and the organic phase was combined. The organic phase was washed with saturated saline (250 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 3 / 1, v / v). Intermediate 048_3 was obtained. 1 H NMR (400MHz, DMSO_d 6)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).

[0310] Step 3: Synthesis of intermediate 048_4 Intermediate 048_3 (5.5 g, 20.81 mmol) was dissolved in tert-butanol (55 mL) under nitrogen protection at room temperature, and intermediate 001_6 (4.21 g, 13.01 mmol, hydrochloride salt) 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, the mixture was returned to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed successively with saturated saline (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. Methyl tert-butyl ether (30 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 30 minutes to precipitate a pale yellow solid, which was then filtered, collected, and concentrated under reduced pressure to obtain a crude product. Acetonitrile (30 mL) was further added to the crude product, and the mixture was stirred at room temperature for 1 hour to precipitate a white solid. The mixture was filtered, the solid was collected, and concentrated under reduced pressure to obtain intermediate 048_4. The filtrate was collected and concentrated under reduced pressure to remove the solvent, and the obtained crude product was separated by column chromatography (solvent: petroleum ether / ethyl acetate = 1 / 0 to 7 / 3, v / v). Intermediate 048_4 was obtained. 1 H NMR (400MHz, DMSO_d 6)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).

[0311] Step 4: Synthesis of intermediate 048_5 Intermediate 048_4 (1 g, 1.98 mmol) was dissolved in dichloromethane (20 mL) and tetrahydrofuran (20 mL) under nitrogen protection at room temperature, and the reaction system was cooled to -40°C and ozone was added until the reaction system turned blue, and then oxygen was added for 15 minutes. Thiourea (451.78 mg, 5.94 mmol) was added to the reaction system and stirred at room temperature for 12 hours. After the reaction was completed, it was confirmed that no peroxide remained on starch-potassium iodide paper, and the mixture was filtered, and the filtrate was collected and concentrated under reduced pressure to remove the solvent. Intermediate 048_5 was obtained.

[0312] Step 5: Synthesis of intermediate 048_6 Intermediate 048_5 (1 g, 1.97 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature under nitrogen protection, the reaction system was lowered to 0 ° C, sodium cyanoborohydride (123.84 mg, 1.97 mmol) was added, the reaction system was stirred at 0 ° C for 0.5 hours, and the temperature was raised to 25 ° C and stirred for 11.5 hours. After the reaction was completed, water (50 mL) was added to dilute, extracted with 2-methyltetrahydrofuran (80 mL × 3), and the organic phase was combined. The organic phase was washed with saturated saline (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained crude product was separated by column chromatography (eluent: dichloromethane / methanol = 30 / 1 to 10 / 1, v / v). The crude product was obtained. The crude product was separated by preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.1% TFA). Intermediate 048_6 was obtained. 1 H NMR (400MHz, DMSO_d 6 )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).

[0313] Step 6: Synthesis of Compound 048 Intermediate 048_6 (250 mg, 490.71 μmol) was dissolved in N,N-dimethylformamide (5 mL) in a pre-dried reaction flask under nitrogen protection at room temperature, and tert-butyl nitrite (759.03 mg, 7.36 mmol) and water (1.00 g, 55.51 mmol) were added thereto, and the reaction system was stirred at room temperature for 12 hours. After the reaction was completed, water (10 mL) was added to dilute the mixture, and the mixture was extracted with 2-methyltetrahydrofuran (10 mL × 3), and the organic phases were combined. The organic phase was washed with saturated saline (10 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: dichloromethane / methanol = 1 / 0-9 / 1, v / v) and preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.04% HCl). Compound 048 was obtained. 1 H NMR (400MHz, DMSO_d 6 )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.

[0314] Example 49 [ka]

[0315] Synthesis Route: [ka]

[0316] Step 1: Synthesis of intermediate 049_1 Intermediate 048_4 (8.7 g, 17.21 mmol) was dissolved in tetrahydrofuran (90 mL) at room temperature under nitrogen protection, and hydrazine hydrate (91.44 g, 1.79 mol, 88.78 mL, purity 98%) was added, and the reaction system was heated to 85°C and stirred at 85°C for 2 hours. After the reaction was completed, the reaction system was cooled to room temperature, a solid was precipitated, filtered, the solid was collected, and the solid was concentrated under reduced pressure to remove the solvent. Intermediate 049_1 was obtained. Water (80 mL) and 2-methyltetrahydrofuran (100 mL) were added to dilute, and the organic phase was collected by liquid separation. The aqueous phase was extracted with 2-methyltetrahydrofuran (200 mL × 3), and the organic phases were combined. The mixture was washed with saturated saline (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Intermediate 049_1 was obtained.

[0317] Step 2: Synthesis of intermediate 049_2 Intermediate 049_1 (4.74 g, 9.64 mmol) was dissolved in tetrahydrofuran (50 mL) and methanol (50 mL) at room temperature under nitrogen protection, trifluoroacetic acid (1.65 g, 14.47 mmol, 1.07 mL) was added, the reaction system was cooled to 0°C, tert-butyl nitrite (2.98 g, 28.93 mmol, 3.44 mL) was added dropwise, the reaction system was heated to 85°C and stirred for 1.5 hours. After the reaction was completed, the reaction system was returned to room temperature, a solid was precipitated, filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to remove the solvent, and a residue was obtained. The residue was dissolved in methyl tert-butyl ether (20 mL), stirred for 30 minutes, a yellow solid was precipitated, filtered, and the solid was collected. Intermediate 049_2 was obtained. The filtrate was concentrated under reduced pressure and separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1, v / v) to obtain intermediate 049_2.

[0318] Step 3: Synthesis of intermediate 049_3 Intermediate 049_2 was dissolved in N-methylpyrrolidone (20 mL), tetrahydrofuran (5 mL) and dichloromethane (5 mL) under nitrogen protection at room temperature, and the reaction system was cooled to -60°C, and ozone was introduced into the reaction system for 30 minutes, followed by oxygen for 15 minutes. After the aeration was completed, the reaction system was warmed to 20°C, thiourea (1.35 g, 17.77 mmol) was added, and the mixture was stirred at 20°C for 12 hours. The reaction solution was poured into water (20 mL) and extracted with 2-methyltetrahydrofuran (10 mL × 3). The organic phase was washed with saturated saline (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain intermediate 049_3.

[0319] Step 4: Synthesis of intermediate 049_4 Intermediate 049_3 (4 g, 7.87 mmol) was dissolved in tetrahydrofuran (40 mL) under nitrogen protection at room temperature, the reaction system was cooled to 0°C, sodium cyanoborohydride (494.39 mg, 7.87 mmol) was added, the reaction system was stirred at 0°C for 0.5 hours, and the reaction system was returned to room temperature and stirred for 11.5 hours. Sodium cyanoborohydride (247.20 mg, 3.93 mmol) was added, and the reaction mixture was heated to 50°C and stirred for 3 hours. After the reaction was completed, the reaction system was returned to room temperature, and the reaction solution was concentrated directly to remove the solvent. The obtained residue was separated by column chromatography (eluent: dichloromethane / methanol = 100 / 1 to 40 / 1, v / v). Intermediate 049_4 was obtained. 1 H NMR (400MHz, DMSO_d 6 )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).

[0320] Step 5: Synthesis of Compound 049 Intermediate 049_4 (200 mg, 391.81 μmol) was dissolved in N,N-dimethylformamide (4 mL) and water (0.4 mL) in a pre-dried reaction flask under nitrogen protection at room temperature, and tert-butyl nitrite (606.05 mg, 5.88 mmol, 699.02 μL) was added to the solution at 20°C. The reaction system was stirred at 20°C for 2 hours, then heated to 60°C and stirred for 0.5 hours. After the reaction was completed, the reaction solution was directly filtered through a filter head, and the filtrate was collected. The filtrate was separated into 100 mL of acetonitrile / water (mobile phase: acetonitrile / water, acidic system: 0.04% HCl) and 10 mL of acetonitrile / water (mobile phase: acetonitrile / water, neutral system: 10 mM NH 4 HCO 3 Compound 049 was obtained by two separate fractions of 0.1% ethyl acetate (1H) and 0.2% ethyl acetate (2H). MS-ESI m / z: 494.0 [M+H] + . 1H NMR (400MHz, DMSO_d 6 )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).

[0321] Examples 50 and 51 [ka]

[0322] Synthesis Route: [ka]

[0323] Step 1: Synthesis of intermediate 050_2 Intermediate 050_1 (50 g, 580.79 mmol) was dissolved in toluene (900 mL) at room temperature under nitrogen protection, p-methoxybenzyl chloride (363.83 g, 2.32 mol) and potassium hydroxide (162.93 g, 2.90 mol) were added, and the reaction mixture was then heated to 110°C with a temperature gradient (first 60°C, then 85°C, and finally 110°C), and the reaction mixture was reacted at 110°C for 12 hours with stirring. After that, the mixture was concentrated under reduced pressure to remove toluene, and the residue was dissolved in methanol (1000 mL), and then a solution of potassium hydroxide (58.00 g, 1.03 mol) in water (500 mL) was added, and the mixture was reacted at 85°C for 12 hours with stirring. After the reaction was completed, the mixture was concentrated under reduced pressure to remove the solvent. The obtained residue was diluted with water (800 mL) and extracted with methyl tert-butyl ether (600 mL x 3), and the organic phase was discarded. The aqueous phase was adjusted to pH = 1-2 with concentrated hydrochloric acid, extracted with 2-methyltetrahydrofuran (800 mL x 3), and the organic phase was combined. The organic phase was washed successively with saturated saline (800 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. Intermediate 050_2 was obtained. 1 H NMR (400 MHz, CDCl 3 )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).

[0324] Step 2: Synthesis of intermediate 050_3 Intermediate 050_2 (108.6 g, 484.28 mmol) was dissolved in dichloromethane (1000 mL) at room temperature under nitrogen protection, and 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) were added, and the reaction mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue obtained was diluted with water (1500 mL) and ethyl acetate (1000 mL), and then separated. The aqueous phase was extracted with ethyl acetate (800 mL x 2), and the organic phase was combined. The organic phase was washed successively with saturated aqueous citric acid solution (1000 mL x 3), saturated saline (1000 mL x 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 to 1 / 1, v / v) to obtain intermediate 050_3. 1 H NMR (400 MHz, CDCl 3 )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).

[0325] Step 3: Synthesis of intermediate 050_4 A solution of lithium diisopropylamide (2M, 80.94 mL) in tetrahydrofuran was dissolved in tetrahydrofuran (450 mL) at room temperature under nitrogen protection, and the temperature was lowered to -78°C. Then, a solution of intermediate 050_3 (37.13 g, 147.16 mmol) in tetrahydrofuran (150 mL) was slowly added, and the mixture was reacted at -78°C for 1 hour with stirring. A solution of carbon tetrabromide (73.20 g. 220.74 mmol) in tetrahydrofuran (200 mL) was added, and the reaction mixture was returned to room temperature and stirred for 12 hours. The reaction mixture was slowly poured into a saturated aqueous ammonium chloride solution (1000 mL), extracted with ethyl acetate (600 mL x 3), and the organic phases were combined. The organic phases were washed successively with saturated saline (600 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 7 / 3, v / v). Intermediate 050_4 was obtained. 1 H NMR (400 MHz, CDCl 3 )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).

[0326] Step 4: Synthesis of intermediate 050_5 Intermediate 050_4 (14.7 g, 35.85 mmol) was dissolved in acetonitrile (150 mL) under nitrogen protection at room temperature, and the temperature was lowered to 0°C. Triethylamine (3.63 g, 35.85 mmol) and diethyl phosphite (4.95 g, 35.85 mmol) were added in sequence, and 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 resulting residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 17 / 3, v / v). Intermediate 050_5 was obtained. 1 H NMR (400 MHz, CDCl 3)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).

[0327] Step 5: Synthesis of intermediate 050_6 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) at room temperature under nitrogen protection, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to a solution of intermediate 050_5 (11.3 g, 34.12 mmol) in tetrahydrofuran (80 mL) at 75°C, 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), and extracted with ethyl acetate (100 mL). The aqueous phase was further extracted with ethyl acetate (100 mL x 2), and the organic phases were combined. The organic phase was 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 to 7 / 3, v / v). Intermediate 050_6 was obtained. 1 H NMR (400 MHz, CDCl 3 )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).

[0328] Step 6: Synthesis of intermediate 050_7 Intermediate 001_6 (1.02 g, 3.16 mmol, hydrochloride salt) was dissolved in ethanol (20 mL) at room temperature under nitrogen protection, sodium ethoxide (537.78 mg, 7.90 mmol) and intermediate 050_6 (1 g, 3.16 mmol) were added in sequence, 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 concentrated under reduced pressure to remove the solvent, and the residue was extracted with water (50 mL) and 2-methyltetrahydrofuran (50 mL) and separated, the aqueous phase was extracted again with 2-methyltetrahydrofuran (50 mL × 2), and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to remove the solvent. The obtained residue was separated by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0 ~ 3 / 7, v / v). Intermediate 050_7 was obtained. 1 H NMR (400 MHz, DMSO_d 6 )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).

[0329] Step 7: Synthesis of intermediate 050_8 Intermediate 050_7 (5.5 g, 9.86 mmol) was dissolved in 1,2-dichloroethane (110 mL) under nitrogen protection at room temperature, cooled to 0°C, and a toluene solution of aluminum trichloride (3.95 g, 29.59 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 dilute hydrochloric acid (1M, 200 mL), extracted with 2-methyltetrahydrofuran (200 mL), and the aqueous phase was further extracted with 2-methyltetrahydrofuran (200 mL x 2), and 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 obtained residue was separated by column chromatography (eluent: dichloromethane / methanol = 1 / 0 to 20 / 1, v / v). Intermediate 050_8 was obtained.

[0330] Step 8: Synthesis of Compound 051 Intermediate 050_8 (800 mg, 1.83 mmol) was dissolved in N,N-dimethylformamide (16 mL) and water (1.6 mL) under nitrogen protection at room temperature, tert-butyl nitrite (2.83 g, 27.43 mmol) was added, and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was diluted with 2-methyltetrahydrofuran (80 mL) and washed with half-saturated saline (50 mL × 3). The organic phase was 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). Compound 051 was obtained. MS-ESI m / z: 437.0 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6)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).

[0331] Step 9: Synthesis of Compound 050 Compound 051 (60 mg, 137.50 μmol) was dissolved in tetrahydrofuran (2 mL) at room temperature under nitrogen protection, cooled to 0°C, sodium hydride (16.5 mg, 412.49 μmol, purity: 60%) was added, and the reaction was stirred at 0°C for 30 minutes, after which ethyl isocyanate (4.89 mg, 68.75 μmol) was added and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, a saturated aqueous ammonium chloride solution (5 mL) was added, extracted with 2-methyltetrahydrofuran (5 mL), the aqueous phase was extracted again with 2-methyltetrahydrofuran (5 mL × 2), and 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 preparative HPLC (mobile phase: acetonitrile / water, acidic system: 0.04% HCl). Compound 050 was obtained. MS-ESI m / z: 508.0 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6)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=7.2Hz, 3H).

[0332] Examples 52 and 53 [ka]

[0333] Synthesis Route: [ka]

[0334] Step 1: Synthesis of intermediate 052_1 Intermediate 012_3 (300 mg, 0.829 mmol, hydrochloride salt) and intermediate 035_1 (348.78 mg, 1.24 mmol) were dissolved in tert-butanol (6 mL) under nitrogen protection at room temperature, 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 the organic phase was collected. The organic phase was washed successively with saturated saline (20 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: dichloromethane / methanol = 1 / 0 to 98 / 2, v / v). Intermediate 052_1 was obtained.

[0335] Step 2: Synthesis of intermediate 052_2 Intermediate 052_1 (250 mg, 446.86 μmol) was dissolved in toluene (4 mL) under nitrogen protection at room temperature, and a toluene solution of trimethylaluminum (2M, 0.715 mL) was added under nitrogen protection, and 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 was added, and the mixture was diluted with ethyl acetate (40 mL) and water (20 mL), separated, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (40 mL x 3), and the organic phase was combined. The organic phase was washed successively with saturated saline (50 mL x 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). The target intermediate 052_2 was obtained. MS-ESI m / z: 514.2[M+H] + . 1 H NMR (400MHz, DMSO_d 6 )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).

[0336] Step 3: Synthesis of Compounds 052 and 053 Intermediate 052_2 (185 mg, 360.35 μmol) was separated on a chiral column (column type: DAICEL CHIRALCEL OD (250mm*30mm, 10μm); mobile phase: [Neu-IPA]%: 25%-25%, 4min). Target compounds 052 and 053 were obtained. 052 (retention time: 2.411 min): MS-ESI m / z: 514.2 [M+H] + . 1 H NMR (400 MHz, DMSO_ d 6)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). 053 (Retention time: 2.642 min): MS-ESI m / z: 514.2 [M+H] + . 1 H NMR(400 MHz, DMSO_d 6 )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).

[0337] Example 54

Chem.

[0338] Synthesis route:

Chem.

[0339] Step 1: Synthesis of Intermediate 054_1 048_6 (1 g, 1.96 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature under nitrogen protection, then 2-methoxyethylamine (4.42 g, 58.89 mmol) was added, and the reaction system was stirred at 65°C for 12 hours. After the reaction was completed, the mixture was returned 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 x 3), and the organic phases were combined. Sequentially, the mixture was washed with saturated saline (15 mL x 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: dichloromethane / methanol=1 / 0-97 / 3, v / v) to obtain compound 054_1.

[0340] Step 2: Synthesis of compound 054 054_1 (188 mg, 349.11 μmol) was dissolved in N,N-dimethylformamide (2 mL) in a pre-dried reaction flask under nitrogen protection at room temperature, followed by the addition of tert-butyl nitrite (540 mg, 5.24 mmol) and water (200 mg, 11.10 mmol), and 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). Compound 054 was obtained. MS-ESI m / z: 522.2 [M+H] + . 1 H NMR (400MHz, DMSO_d 6 )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).

[0341] Example 55 [ka]

[0342] Synthesis Route: [ka]

[0343] Step 1: Synthesis of intermediate 055_1 Intermediate 048_4 (3.0 g, 5.94 mmol) was dissolved in 1,4-dioxane (30 mL) at room temperature under nitrogen protection, and isoamyl nitrite (3.48 g, 29.68 mmol, 4.00 mL) and diiodomethane (4.77 g, 17.81 mmol, 1.44 mL) were added to the reaction system. The reaction system was heated to 100°C and stirred for 2 hours. The reaction system changed from milky white to transparent. The reaction was continued with stirring at 100°C for 4 hours. After the reaction was completed, the reaction solution was concentrated as it was to remove the solvent, and the crude product was obtained. The crude product was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1, v / v) to obtain intermediate 055_1.

[0344] Step 2: Synthesis of intermediate 055_2 Intermediate 055_1 (800 mg, 1.30 mmol), vinyltri-n-butyltin (617.36 mg, 1.95 mmol, 566.39 μL) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (106.0 mg, 129.79 μmol) were dispersed in 1,4 dioxane (10 mL) at room temperature under nitrogen protection. 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 (100 mL), extracted with ethyl acetate (40 mL × 3), and the organic phase was combined. The organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and then concentrated by filtration. The crude product was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1, v / v) to obtain intermediate 055_2.

[0345] Step 3: Synthesis of compound 055 Intermediate 055_2 (300 mg, 580.83 μmol) was dissolved in dichloromethane (5 mL) under nitrogen protection at room temperature, and GRUBB'S second generation catalyst (49.31 mg, 58.08 μmol) was added. The reaction solution was then stirred at room temperature for 15 hours. After the reaction was completed, the reaction solution was concentrated as it was to remove the solvent and obtain a residue. The residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1, v / v) to obtain a crude product. The crude product was further separated by preparative HPLC (mobile phase: acetonitrile / water, hydrochloric acid system: 0.04% HCl). Compound 055 was obtained. MS-ESI m / z: 489.1 [M+H] + . 1 H NMR (400 MHz, DMSO_d 6 )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, 17.6Hz, 1H), 1.08(t, J=7.2 Hz, 3H).

[0346] Example 56 [ka]

[0347] Synthesis Route: [ka]

[0348] Step 1: Synthesis of intermediate 056_1 Intermediate 049_2 (0.5 g, 987.24 μmol) was dissolved in 1,4-dioxane (5 mL) at room temperature under nitrogen protection, and isoamyl nitrite (578.27 mg, 4.94 mmol) and diiodomethane (793.24 mg, 2.96 mmol) were added to the reaction system. The reaction system was heated to 85°C and stirred for 2 hours. The reaction system changed from milky white to transparent. 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 saline (50 mL), dried over anhydrous sodium sulfate, and then concentrated by filtration. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 0 / 1, v / v) to obtain intermediate 056_1.

[0349] Step 2: Synthesis of intermediate 056_2 Intermediate 056_1 (500 mg, 809.92 μmol), vinyltri-n-butyltin (385.23 mg, 1.21 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane adduct (66.14 mg, 80.99 μmol) were dissolved in 1,4-dioxane (10 mL) at room temperature under nitrogen protection. 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 phase was combined. The organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and then concentrated by filtration. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 1, v / v) to obtain intermediate 056_2.

[0350] Step 3: Synthesis of compound 056 Intermediate 056_2 (150 mg, 289.86 μmol) was dissolved in dichloromethane (3 mL) under nitrogen protection at room temperature, 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 concentrated as it was to remove the solvent and obtain a residue. The residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 to 1 / 2, v / v) to obtain a crude product. The crude product was separated by preparative HPLC (mobile phase: acetonitrile / water, hydrochloric acid system: 0.04% HCl). Compound 056 was obtained. MS-ESI m / z: 490.1 [M+H] + . 1 H NMR (400 MHz, MeOD_d 4 )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).

[0351] Biological Testing Experimental example 1: In vitro activity test 1. cGMP expression test using lnCap cells 1. Experimental Steps 1) Preparation of solutions ● 10% BSA (bovine serum protein) Dissolve 10 g BSA in 100 mL double distilled water (ddH2O). 2 O) to obtain 10% BSA.

[0352] ● 5mM DETA (diethylenetriamine)-NO 10 mg of DETA-NO was weighed and added to 12.2 mL of distilled water (ddH 2 O) to obtain 5 mM DETA-NO, which was then divided into small portions and frozen and stored in a -20°C refrigerator.

[0353] ● Washing Buffer (50mL) [Table 1]

[0354] ● Assay Buffer (50mL) [Table 2]

[0355] ● Detection Buffer a) 50 μL of cGMP-D2 (cyclic guanosine monophosphate labeled D2) was added to 1 mL of lysis buffer and mixed uniformly. b) 50 μL anti-cGMP cryptate (Eu 3+ The hole-shaped compound (anti-cyclic guanosine monophosphate antibody, labeled as such) was added to 1 mL of lysis buffer and mixed uniformly.

[0356] 2) Compound dilution (1) Compounds were diluted to 5 mM with DMSO. 10 μL of the compounds were transferred to an Echo shallow well plate. (2) The compounds were gradient-diluted using Echo. Each compound was diluted to 10 concentration gradients, and 50 nL of each was placed in a 384-well plate.

[0357] 3) Preparation of LNCap cells (1) LNCap medium: RPMI1640 + 10% fetal bovine serum + 1% bispecific antibody. (2) The phosphate buffer, pancreatin, and medium used in the cell passaging process were preheated in a 37°C water bath. (3) 37°C, 5% CO 2の The cells (14th passage) were removed from the incubator, and the old culture medium in the culture flask was aspirated with a pipette. (4) 5 mL of phosphate buffer was aspirated and placed in a culture bottle, the cells were washed, and the liquid was then discarded. (5) Aspirate 3 mL of pancreatin and place it in a culture bottle. After shaking, discard the liquid and place the culture bottle in an incubator. (6) After about 2 minutes, the culture bottle was removed, and after confirming that all the cells had been separated, 9 mL was sucked up and placed into the culture bottle. The cell suspension was then transferred to a 50 mL centrifuge tube after blowing several times. (7) 0.7 mL of the cell suspension was aspirated into a counting cup and counted using ViCell XR. The remaining cells were centrifuged at 1000 rpm for 5 minutes, and the supernatant was removed. (8) 10 mL washing buffer was added to wash the cells, centrifuged at 1000 rpm for 5 minutes, and the supernatant was removed. (9) Add assay buffer to adjust the cell concentration to 1.25 × 10 6 The solution was adjusted to 8 μL / mL and placed in a micropore plate at 8 μL / hole.

[0358] 4) Preparation and addition of DETA-NO (1) 10 μL of 5 mM DETA-NO was taken and added to 1240 μL and 1657 μL of assay buffer, respectively, to obtain 40 μM and 30 μM DETA-NO. (2) Using a Bravo, 2 μL / well of DETA-NO was transferred into a 384-well plate. (3) Centrifugation was performed at 1500 rpm for 5 minutes, and the micropore plate was incubated at 37° C. for 30 minutes.

[0359] 5) Preparation of cGMP standard curve (1) 1 mM cGMP stock solution in assay buffer was diluted to 10 μM, and then diluted 4-fold to give 11 concentration gradients. (2) The diluted cGMP was placed into a micropore plate at 10 μL / pore.

[0360] 6) Add detection reagent and read (1) 5 μL / well of cGMP-D2 was transferred into a 384-well plate using a Bravo. The plate was centrifuged at 1500 rpm for 1 minute. (2) Using a Bravo, 5 μL / well of anti-cGMP cryptate was transferred into a 384-well plate. The plate was centrifuged at 1500 rpm for 1 minute. (3) Incubate at room temperature for 1 hour. (4) 665 / 615 was read using envision.

[0361] 7) Data Analysis (1) cGMP standard curve: A standard curve was prepared using Graphpad prism based on the cGMP concentration and the 665 / 615 ratio. (2) The HTRF (homogeneous time-resolved fluorometry) ratio (665 / 615) was converted to cGMP concentration: In Graphpad Prism, the HTRF ratio (665 / 615) was copied into the ratio column of the cGMP standard curve, and run the analysis "Log inhibitor vs response-variable slope" and select "interpolate" to convert the HTRF ratio (665 / 615) to cGMP concentration. (3) Compound activation curve: Based on the converted cGMP concentration and compound concentration, a curve was generated using the “Log agonist vs response-variable slope” analysis method in Graphpad prism.

[0362] [Table 3]

[0363] Experimental conclusion: The compound of the present invention can effectively stimulate sGC and significantly increase cGMP level. Experimental Example 2: Pharmacokinetic properties test Experimental Objective: The objective of this study was to determine the pharmacokinetic parameters of this compound in SD male rats.

[0364] Test materials: Sprague Dawley rats (male, 200-300g, 7-9 weeks old, Shanghai Slac)

[0365] Testing Method: Four male SD rats were used, two in one group were intravenously administered with a dose of 0.3 mg / kg and a concentration of 0.15 mg / mL, and the other two were orally administered with a dose of 1 mg / kg and a concentration of 0.2 mg / mL. Plasma samples were collected at 0.083 (intravenous group only), 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration, and LC-MS / MS analysis was performed on the collected samples to collect data. The collected analytical data was used to calculate the relevant pharmacokinetic parameters using Phoenix WinNonlin 6.3 software.

[0366] The experimental results are shown in Table 2.

[0367] [Table 4]

[0368] Conclusion: The compound has good clearance, half-life and bioavailability following intragastric administration.

Claims

1. A compound represented by formula (II), or a stereoisomer or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, R 1 teeth, 【Chemistry 2】 Selected from; R 2 each independently represents one or two R d as a substituent 【Chemistry 3】 1 or 2 R d as a substituent 【Chemistry 4】 and 1, 2 or 3 R d C having as a substituent 1-3 Selected from alkyl groups; R 3 are each independently selected from H and halogen; R 4 H, and C 1-3 Selected from alkyl groups; E 1 is -(CH 2 ) m - selected from; m is selected from 0, 1, and 2; E 2 is -(CH 2 ) n -, -(CH 2 ) p C(O)-, -O(CH 2 ) q -, -O(CH 2 ) r C(O)-, -CH 2 CH=CH- and -(CH 2 ) s NHC(O)-, wherein each CH 2 is 1 or 2 R b may be substituted with; E 3 is 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; T 1 N, and CR a Selected from; R a are each independently H, OH, -OC(=O)NHEt, -CO 2 Et, -NHCO 2 CH 3 , -C(=O)NH(CH 2 ) 2 OCH 3 , and C 1-3 Selected from alkyl groups; R b are each independently F, and CH 3 Selected from; R c are each independently H and CH 3 Selected from; R d are each independently a halogen, and CF 3 are selected from.)

2. R a are each independently H, OH, -OC(=O)NHEt, -CO 2 Et, -C(=O)NH(CH 2 ) 2 OCH 3 , -NHCO 2 CH 3 , and C.H. 3 2. The compound according to claim 1, or a stereoisomer or a pharma- ceutically acceptable salt thereof, selected from:

3. R d are each independently F, and CF 3 2. The compound according to claim 1, or a stereoisomer or a pharma- ceutically acceptable salt thereof, selected from:

4. R 2 each independently represents one or two R d as a substituent 【Chemistry 5】 1 or 2 R d as a substituent 【Chemistry 6】 and 1, 2 or 3 R d C having as a substituent 1-3 2. The compound of claim 1, or a stereoisomer or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from the group consisting of alkyl groups.

5. R 2 are each independently 【Chemistry 7】 Selected from Or R 2 are each independently 【Chemistry 8】 Selected from 5. The compound of claim 4, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

6. R 3 are each independently selected from H and F, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

7. R 1 teeth, 【Chemistry 9】 Selected from Or R 1 teeth, 【Chemistry 10】 Selected from Or R 1 teeth, 【Chemistry 11】 Selected from 2. The compound of claim 1, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

8. E 1 is a single bond, -CH 2 - and -(CH 2 ) 2 2. The compound of claim 1, selected from: -, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

9. E 2 -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -CH 2 CO-, -(CH 2 ) 2 CO-, -O(CH 2 ) 2 -, -OCH 2 C(O)- and -CH 2 NHC(O)-, wherein each CH 2 is 1 or 2 R b Optionally substituted with 2. The compound of claim 1, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

10. E 2 -CH 2 -, -(CH 2 ) 2 -, -CF 2 CH 2 -, -(CH 2 ) 3 -, -CH 2 CH=CH-, -CH 2 CO-, -CO-, -C(CH 3 ) 2 CO-, -CF 2 CO-, -(CH 2 ) 2 CO-, -O(CH 2 ) 2 -, -OCH 2 C(O)- and -CH 2 10. The compound of claim 9, selected from NHC(O)-, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

11. E 3 is a single bond, NH, N(CH 3 2. The compound of claim 1, or a stereoisomer or pharma- ceutically acceptable salt thereof, selected from:

12. T 1 are N, CH, C(OH), C(OC(=O)NHEt), C(CO 2 Et), C(NHCO 2 CH 3 ), C[C(=O)NH(CH 2 ) 2 OCH 3 ], and C(CH 3 2. The compound according to claim 1, or a stereoisomer or a pharma- ceutically acceptable salt thereof, selected from:

13. Structural units: 【Chemistry 12】 teeth, 【Chemistry 13】 Selected from Or, the structural unit: 【Chemistry 14】 teeth, 【Chemistry 15】 Selected from 2. The compound of claim 1, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

14. The compound is 【Chemistry 16】 Selected from R 2 , R 4 , T 1 , E 1 , E 2 , and E 3 is as defined in any one of claims 1 to 12, 13. A compound according to claims 1 to 12, or a stereoisomer or a pharma- ceutically acceptable salt thereof.

15. 1. A compound of the formula: or a stereoisomer or a pharma- ceutically acceptable salt thereof. 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】

16. 1. A compound of the formula: or a stereoisomer or a pharma- ceutically acceptable salt thereof. 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 【Chemistry 24】

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, 15 to 16, or a stereoisomer or a pharma- ceutically acceptable salt thereof, optionally further comprising a pharma- ceutically acceptable auxiliary.

18. Use of a compound according to any one of claims 1 to 13, 15 to 16, or a stereoisomer or a pharma- ceutically acceptable salt thereof, in the preparation of a medicament for the treatment of an sGC agonist-related disease.

19. The use according to claim 18, wherein the sGC agonist-related disease is heart failure or hypertension.

Images