Pyrimidine tri-fused ring derivative and pharmaceutical application thereof

Abstract

The invention discloses a pyrimidine tri-fused ring derivative and a pharmaceutical application thereof, and particularly discloses a compound as shown in a formula (I), and a stereoisomer and a pharmaceutically acceptable salt thereof. # imgabs0 #

Description

[0001] This application is a divisional application based on the Chinese invention patent application with application date of October 13, 2022, application number 202280067441.6, and invention name “Pyrimidine tricyclic derivatives and their applications in medicine”.

[0002] This application claims the following priority

[0003] This application claims 1) the priority and benefits of Chinese Patent Application No. 2021111941776 filed with the State Intellectual Property Office of China on October 13, 2021, 2) the priority and benefits of Chinese Patent Application No. 2021115653068 filed with the State Intellectual Property Office of China on December 20, 2021, and 3) the priority and benefits of Chinese Patent Application No. 2022111609592 filed with the State Intellectual Property Office of China on September 22, 2022, and the contents disclosed in said applications are incorporated herein by reference in their entirety. Technical Field

[0004] The present application relates to a pyrimidine tricyclic derivative and its pharmaceutical application, and specifically to a compound represented by formula (I), its stereoisomers and pharmaceutically acceptable salts thereof. Background Art

[0005] Soluble guanylate cyclase (sGC) is widely present in the cytosol of mammals and is a heterodimer composed of two subunits, α and β. Soluble guanylate cyclase is a key signal transduction enzyme in the NO-sGC-cGMP signaling pathway. After being activated in vivo, sGC catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP is an important secondary messenger molecule that activates a variety of downstream effector molecules, such as cGMP-dependent protein kinase G and cGMP-gated ion channels, thereby triggering a series of downstream cascade reactions. It plays an important physiological function in the gastrointestinal system, cardiovascular system, and central nervous system, such as promoting vascular and smooth muscle relaxation, inhibiting platelet aggregation, vascular remodeling, cell apoptosis and inflammation, and participating in neurotransmission. Under pathophysiological conditions, the NO / cGMP system can be inhibited, which can lead to, for example, hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, atherosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke, and sexual dysfunction. In the past two years, studies have shown that abnormal sGC-mediated signaling pathways are also closely related to the occurrence of fibrotic diseases such as chronic kidney disease and systemic sclerosis.

[0006] sGC stimulators have a dual mechanism of action: they are independent of NO but dependent on Fe 2+The heme cofactor of sGC directly activates the sGC-cGMP signaling pathway; it can also enhance the sensitivity of sGC to endogenous NO, thereby producing a synergistic effect with NO. Therefore, sGC stimulator is a heme-dependent, NO-independent sGC stimulator. Stimulating sGC to produce more cGMP can regulate a variety of important physiological processes: promoting vascular smooth muscle relaxation, inhibiting platelet aggregation, etc. At the same time, activating sGC can also regulate other signaling pathways, such as TGF-β, to exert anti-fibrosis and anti-tumor effects. Therefore, sGC stimulators can be used as a potential therapeutic method for the treatment of cardiovascular diseases (heart failure, pulmonary hypertension, angina pectoris, myocardial infarction) and fibrotic diseases (renal fibrosis, systemic sclerosis).

[0007] In view of the unmet market and clinical demand for such soluble guanylate cyclase stimulators, the present application provides a new class of compounds. Such compounds can be used as stimulators of soluble guanylate cyclase, have excellent in vitro stimulatory activity on soluble guanylate cyclase, and have good pharmacokinetic properties. Summary of the invention

[0008] The present application provides a compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0009]

[0010] in,

[0011] R1 is selected from H, -OH, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Alkylamino;

[0012] R2 is selected from benzyl or C 1-8 Alkyl, benzyl or C 1-8 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 halogen atoms;

[0013] R3 and R4 are each independently selected from H or C 1-3 alkyl;

[0014] Or R3 and R4 and the atoms they are connected to form C 3-6 Cycloalkyl;

[0015] Provided that the compound is not selected from the following structures, stereoisomers thereof or pharmaceutically acceptable salts thereof:

[0016]

[0017] In some embodiments of the present application, the above R1 is selected from H, -OH, C 1-3 Alkyl or C 1-3Alkoxy and other variables are as defined herein.

[0018] In some embodiments of the present application, the above R1 is selected from H, -OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy, and other variables are as defined in the present application.

[0019] In some embodiments of the present application, the above R1 is selected from H, -OH, methyl or methoxy, and other variables are as defined in the present application.

[0020] In some embodiments of the present application, the above R2 is selected from benzyl or C 1-6 Alkyl, benzyl or C 1-6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 halogen atoms, and the other variables are as defined herein.

[0021] In some embodiments of the present application, the above R2 is selected from benzyl or C 1-4 Alkyl, benzyl or C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 halogen atoms, and the other variables are as defined herein.

[0022] In some embodiments of the present application, the above R2 is selected from benzyl or C 1-4 Alkyl, benzyl or C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 F, Cl or Br atoms, and the other variables are as defined herein.

[0023] In some embodiments of the present application, the above R2 is selected from benzyl or C 1-4 Alkyl, benzyl or C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 F atoms, and the other variables are as defined herein.

[0024] In some embodiments of the present application, the above R2 is selected from C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 halogen atoms, and the other variables are as defined herein.

[0025] In some embodiments of the present application, the above R2 is selected from C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 F, Cl or Br atoms, and the other variables are as defined herein.

[0026] In some embodiments of the present application, the above R2 is selected from C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 F atoms, and the other variables are as defined herein.

[0027] In some embodiments of the present application, the above R2 is selected from benzyl or n-butyl, the benzyl is substituted by 1 fluorine, the n-butyl is substituted by 5 fluorines, and other variables are as defined in the present application.

[0028] In some embodiments of the present application, the above R2 is selected from Other variables are as defined in this application.

[0029] In some embodiments of the present application, the above R3 and R4 are each independently selected from H, methyl, ethyl, n-propyl or isopropyl, or R3 and R4 and the atoms to which they are connected together form a cyclopropane group, and other variables are as defined in the present application.

[0030] In some embodiments of the present application, the above R3 and R4 are each independently selected from H or methyl, or R3 and R4 and the atoms to which they are commonly connected form a cyclopropane group, and other variables are as defined in the present application.

[0031] In some embodiments of the present application, the above structural unit Selected from Other variables are as defined in this application.

[0032] Some other solutions of the present application are obtained by any combination of the above variables.

[0033] The present application also provides the following compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof, which are selected from:

[0034]

[0035] The present application also provides the following compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof, which are selected from:

[0036]

[0037]

[0038] On the other hand, the present application provides a pharmaceutical composition comprising the compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient.

[0039] On the other hand, the present application provides the use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a drug for treating diseases related to sGC agonists or stimulants.

[0040] On the other hand, the present application provides a method for treating a mammalian sGC agonist or stimulator-related disease, comprising administering a therapeutically effective amount of the compound of the present application, its stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0041] On the other hand, the present application provides the use of the compound of the present application, its stereoisomer or pharmaceutically acceptable salt, or its pharmaceutical composition in treating sGC agonist or stimulator related diseases.

[0042] In another aspect, the present application provides a compound of the present application, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating diseases associated with sGC agonists or stimulators.

[0043] In some embodiments of the present application, the sGC agonist or stimulator-related disease is selected from heart failure or hypertension.

[0044] Technical Effects

[0045] The compounds of the present application can effectively stimulate sGC, significantly increase cGMP levels, have a good apparent distribution volume and half-life, have a good cardiac distribution and have no risk of entering the brain.

[0046] Definition and Description

[0047] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0048] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0049] The term "pharmaceutically acceptable salt" refers to salts of compounds of the present application, prepared from compounds with specific substituents found in the present application and relatively non-toxic acids or bases. When the compounds of the present application contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of the present application contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of the present application contain basic and acidic functional groups and can be converted into either base or acid addition salts.

[0050] The pharmaceutically acceptable salts of the present application can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

[0051] Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

[0052] The compounds of the present application may exist in specific geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which fall within the scope of the present application. Additional asymmetric carbon atoms may exist in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present application.

[0053] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0054] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability of a ring to rotate freely about double bonds or single bonds of ring carbon atoms.

[0055] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0056] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0057] Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Represents a straight solid bond or straight dashed key

[0058] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0059] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0060] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate is generated from an amine).

[0061] The compounds of the present application may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For another example, deuterium can be used to replace hydrogen to form a deuterated drug. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present application, whether radioactive or not, are included in the scope of the present application.

[0062] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0063] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include a variant of deuterium and hydrogen, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be arbitrary on the basis of chemical achievable.

[0064] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0065] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0066] When the number of a substituent is 0, it means that the substituent does not exist, for example, -A-(R)0 means that the structure is actually -A.

[0067] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.

[0068] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0069] When a substituent has bonds that cross-link to two or more atoms in a ring, the substituent may be bonded to any atom in the ring, e.g. Indicates that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene. When the listed substituents do not specify which atom is connected to the substituted group, the substituent can be bonded through any atom thereof. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0070] When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of the reading order from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0071] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds to become a group with the corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy line For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0072] Unless otherwise specified, the term "alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group. In some embodiments, the alkyl group is C 1-8 In other embodiments, the alkyl group is C 1-4 In other embodiments, the alkyl group is C 1-3Alkyl. It may be monosubstituted (such as -CH2F) or polysubstituted (such as -CF3), and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

[0073] Unless otherwise specified, the term “C 1-4 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 Alkyl groups include C 1-2 , C 1-3 and C 2-3 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), and the like.

[0074] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0075] Unless otherwise specified, the term “C 1-3 "Alkylamino" means -NH-C 1-3 alkyl.

[0076] Unless otherwise specified, “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic system. 3-6 Cycloalkyl includes C 3-5 , C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0077]

[0043] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0078] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0079] The structure of the compounds of the present application can be confirmed by conventional methods known to those skilled in the art. If the present application involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data of the cultured single crystal using a Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is φ / ω scanning. After collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.

[0080] The solvents used in the present application can be obtained commercially. The following abbreviations are used in the present application: ACN represents acetonitrile; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; HPLC represents high performance liquid chromatography; LCMS represents liquid chromatography-mass spectrometry; °C represents degrees Celsius; h represents hours; mL represents milliliters; mM represents millimoles per liter; mmol represents millimoles; μmol represents micromoles; HNMR represents hydrogen nuclear magnetic resonance; MS represents mass spectrometry; min represents minutes; pH represents the negative logarithm of the molar concentration of hydrogen ions; AlMe3 represents trimethylaluminum; TFA represents trifluoroacetic acid; DMSO represents dimethyl sulfoxide.

[0081] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0082] (i) inhibiting a disease or disease state, i.e. arresting its development;

[0083] (ii) ameliorating a disease or condition, even if causing regression of the disease or condition.

[0084] The term "prevention" means administering the compounds or formulations described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0085] The term "therapeutically effective amount" means an amount of the compound of the present application that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of the compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure. DETAILED DESCRIPTION

[0086] The present application is described in detail below by way of example, but it is not intended to limit the present application in any adverse way. The present application has been described in detail herein, and its specific embodiment modes are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications can be made to the present application without departing from the spirit and scope of the present application. All reagents used in the present application are commercially available and can be used without further purification.

[0087] Examples 1 and 2

[0088]

[0089] Synthesis route:

[0090]

[0091] Step 1: Synthesis of compound 001_2

[0092] At room temperature, compound 001_1 (100 g, 380.21 mmol) was added to N,N-dimethylformamide (1 L), followed by 1,1,1,2,2-pentafluoro-4-iodobutane (520.83 g, 1.90 mol) and potassium carbonate (131.37 g, 950.53 mmol), and the reaction system was stirred at 80°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated by chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–15 / 1, volume ratio) to obtain compound 001_2.

[0093] Step 2: Synthesis of compound 001_3

[0094] At room temperature and nitrogen, compound 001_2 (30 g, 73.34 mmol) was added to methanol (100 mL) and N,N-dimethylformamide (300 mL), and cyclopenta-2,4-dien-1-yl (diphenyl)phosphine dichloromethane dichloropalladium ferrocene (3.76 g, 5.13 mmol) and triethylamine (29.68 g, 293.35 mmol, 40.83 mL) were added. The reaction mixture was stirred at 80 ° C for 12 hours under a nitric oxide environment (15 Psi). After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated by chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-10 / 1, volume ratio) to obtain compound 001_3.

[0095] Step 3: Synthesis of the hydrochloride salt of compound 001_4

[0096] At room temperature and nitrogen, ammonium chloride (28.22 g, 527.54 mmol) was dispersed in toluene (360 mL), trimethylaluminum toluene solution (2M, 253.22 mL) was added, and compound 001_3 (36 g, 105.51 mmol) was added after heating to 80°C, and stirred at 80°C for 30 minutes, then heated to 110°C for reaction for 1.5 hours, cooled to 25°C, methanol (48.68 g, 1.52 mol, 61.48 mL) was added dropwise, and the temperature was kept below 40°C, and then hydrochloric acid (3M, 675.25 mL) was added, and the temperature was kept below 40°C, and the temperature was heated to 80°C and stirred for 10 minutes, and then cooled to 0°C and stirred for 30 minutes. After the reaction was completed, the reaction solution was filtered, and the filter cake was collected. The filter cake was rinsed with water (200 mL) and concentrated under reduced pressure to remove the solvent. The hydrochloride of compound 001_4 was obtained. 1 H NMR (400MHz, DMSO-d6) δppm 9.49 (br d, J = 11.2Hz, 4H) 8.87 (s, 1H) 8.53 (dd, J = 8.8, 2.4Hz, 1H) 4.94 (t, J = 6.8Hz, 2H) 2.97-3.18 (m, 2H).

[0097] Step 4: Synthesis of Compound 001_6

[0098] At room temperature and under nitrogen protection, compound 001_5 (5 g, 56.71 mmol) was dissolved in dry toluene (20 mL), and bromoacetonitrile (7.48 g, 62.38 mmol) was added. The reaction system was stirred at 25°C for 12 hours. The reaction system gradually changed from clear to white solid precipitated. After the reaction was completed, the suspension was filtered, the filter cake was washed with toluene (50 mL), the solid was collected, and it was dried under reduced pressure to obtain compound 001_6.

[0099] Step 5: Synthesis of Compound 001_8

[0100] At room temperature, compound 001_7 (2.7 g, 18.73 mmol) was dissolved in dichloromethane (50 mL), cooled to 0°C, and N,N-diisopropylethylamine (7.26 g, 56.20 mmol), tri-n-propyl cyclophosphoric anhydride (50% ethyl acetate solution) (17.88 g, 28.10 mmol) and compound 001_6 (4.29 g, 20.61 mmol) were added. The reaction system was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was poured into a saturated sodium bicarbonate aqueous solution (100 mL) and extracted with ethyl acetate (50 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 1–0 / 1, volume ratio) to obtain compound 001_8.

[0101] Step 6: Synthesis of Compound 001_9

[0102] At room temperature and under nitrogen protection, compound 001_8 (8.0 g, 31.58 mmol) was dissolved in methanol (500 mL) and water (50 mL), potassium monopersulfate (58.25 g, 94.74 mmol) was added, and the reaction system was stirred at 25 ° C for 12 hours. After the reaction, the reaction solution was poured into a saturated sodium sulfite aqueous solution (50 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–4 / 1, volume ratio). Compound 001_9 was obtained.

[0103] Step 7: Synthesis of Compound 001_10

[0104] At room temperature and under nitrogen protection, compound 001_9 (5 g, 26.86 mmol) was dissolved in anhydrous methanol (50 mL), and malononitrile (2.13 g, 32.23 mmol) and ammonium acetate (4.14 g, 53.72 mmol) were added thereto. The reaction system was heated to 60 ° C and stirred for 4 hours under nitrogen protection. The reaction solution was poured into a saturated aqueous ammonium chloride solution (70 mL) and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–5 / 1, volume ratio) to obtain compound 001_10.

[0105] Step 8: Synthesis of Compound 001_11

[0106] Under nitrogen protection, compound 001_10 (1.1 g, 4.70 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0°C, and a toluene solution of methylmagnesium bromide (3M, 3.13 mL) was added dropwise. After the addition was complete, the mixture was stirred for 15 minutes. After the reaction was completed, the mixture was poured into a saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–5 / 1, volume ratio) to obtain compound 001_11.

[0107] Step 9: Synthesis of compounds 001_12 and 001_13

[0108] At room temperature and under nitrogen protection, compound 001_4 (1g, 2.76mmol, hydrochloride) was dissolved in tert-butyl alcohol (20mL), compound 001_11 (1g, 4.00mmol) and potassium bicarbonate (692.06mg, 6.91mmol) were added thereto, and the reaction system was heated to 85°C and stirred for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and poured into water (70mL), and extracted with ethyl acetate (50mL×3). The organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–1 / 1, volume ratio). A mixture of 001_12 and 001_13 was obtained.

[0109] Step 10: Synthesis of Compound 001_14

[0110] At room temperature and under nitrogen protection, a mixture of 001_12 and 001_13 (500 mg, 920.10 μmol) was dissolved in toluene (5 mL), and a toluene solution of trimethylaluminum (2M, 1.38 mL) was added to the reaction system. The reaction system was heated to 75°C and stirred for 5 hours. After the reaction was completed, the reaction system was cooled to room temperature, and dilute hydrochloric acid (1N, 10 mL) was added to the reaction system to quench the reaction. Ethyl acetate (20 mL) was added to dilute, the liquids were separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (20 mL×3), 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. The residue was first separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–1 / 1, volume ratio), and then separated by preparative HPLC (column type: Phenomenex luna C18 (80mm*30mm ID, 3μm); mobile phase: A: ACN, B: [H2O (containing 0.04% HCl)], gradient: B%: 30%-70%, 8min) to obtain compound 001_14. MS–ESI m / z: 512.0 [M+H] + .1 H NMR(400MHz, DMSO_d6)δ:11.52(s,1H),11.29(s,1H),8.81–8.68(m,2H),4.91(t,J=6.7Hz,2H),3. 00(tt,J=6.6,19.1Hz,2H),1.60–1.48(m,1H),1.44(s,3H),1.18–1.08(m,1H),0.81–0.64(m,2H).

[0111] Step 11: Synthesis of compounds 001 and 002

[0112] Compound 001_14 was separated by chiral column (column type: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 μm); mobile phase: [EtOH (containing 0.1% NH 3 H 2 O)] %: 35%-35%, 7 min) to obtain Compound 001 and 002.

[0113] SFC analysis method: column type: Chiralpak AD (50*4.6mm ID, 3μm); mobile phase: A: CO2, B: [EtOH (containing 0.1% IPAm)], gradient: B%: 5%-50%, 3min.

[0114] 001 (retention time: 0.900min): MS–ESI m / z: 512.0 [M+H] + . 1 H NMR(400MHz, DMSO_d6)δ:11.52(s,1H),11.34–11.24(m,1H),8.82–8.68(m,2H),4.91(t,J=6.5Hz,2H),3 .09–2.91(m,2H),1.55(ddd,J=4.4,6.0,10.0Hz,1H),1.44(s,3H),1.20–1.08(m,1H),0.81–0.64(m,2H);

[0115] 002 (retention time: 1.017 min): MS–ESI m / z: 511.9 [M+H] + . 1H NMR(400MHz,DMSO_d6)δ:11.61–11.46(m,1H),11.28(s,1H),8.78–8.70(m,2H),4.91(t,J=6.7Hz,2H),3 .10–2.88(m,2H),1.55(ddd,J=4.0,6.4,10.0Hz,1H),1.44(s,3H),1.19–1.04(m,1H),0.82–0.66(m,2H).

[0116] Examples 3 and 4

[0117]

[0118] Synthesis route:

[0119]

[0120] Step 1: Synthesis of compound 003_1

[0121] At room temperature and under nitrogen protection, compound 001_10 (1.5 g, 6.40 mmol) was added to chloroform (10 mL) and ethanol (10 mL) to dissolve, and 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (2.43 g, 9.61 mmol) was added to the reaction system. The reaction solution was stirred at 25 ° C for 12 hours under nitrogen protection. After the reaction, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–1 / 1, volume ratio). Compound 003_1 was obtained.

[0122] Step 2: Synthesis of compound 003_2

[0123] At room temperature and under nitrogen protection, compound 001_4 (1.5 g, 4.15 mmol, hydrochloride) was dissolved in tert-butyl alcohol (30 mL), compound 003_1 (2 g, 8.47 mmol) and potassium bicarbonate (1.04 g, 10.37 mmol) were added thereto, and the reaction system was heated to 85°C and stirred for 12 hours. After the reaction solution was cooled to room temperature, it was poured into water (70 mL) and extracted with 2-methyltetrahydrofuran (30 mL×3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–1 / 1, volume ratio). Compound 003_2 was obtained.

[0124] Step 3: Synthesis of compound 003_3

[0125] At room temperature and under nitrogen protection, compound 003_2 (500 mg, 944.48 μmol) was added to anhydrous methanol (10 mL) to dissolve, bis(trifluoroacetic acid) iodobenzene (2.03 g, 4.72 mmol) was added, and stirred at 50°C for 6 hours. The reaction solution was poured into saturated sodium bicarbonate water (50 mL) and extracted with ethyl acetate (30 mL×3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–1 / 1, volume ratio). Compound 003_3 was obtained.

[0126] Step 4: Synthesis of compound 003_4

[0127] At room temperature and under nitrogen protection, compound 003_3 (150 mg, 268.13 μmol) was dissolved in anhydrous toluene (2 mL), trimethylaluminum toluene solution (2M, 429.02 μL) was added to the reaction system, and the reaction system was heated to 80°C and stirred for 6 hours. After the reaction was completed, the reaction system was cooled to room temperature, and dilute hydrochloric acid (1N, 10 mL) was slowly added to the reaction system to quench the reaction, and 2-methyltetrahydrofuran (50 mL×4) was used for extraction, and the organic phases were combined. The organic phase was washed with semi-saturated brine (10 mL×2), saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0-1 / 1, volume ratio) and preparative HPLC separation (column type: Phenomenexluna C18 (80mm*30mm ID, 3μm); mobile phase: A: ACN, B: [H2O (containing 0.04% HCl)], gradient: B%: 30%-55%, 8min) to obtain compound 003_4. MS-ESI m / z: 527.9 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ:11.77(s,1H),11.48(s,1H),8.85–8.65(m,2H),4.93(t,J=6.8Hz,2H),3.19 (s,3H),3.10–2.92(m,2H),1.63(ddd,J=4.2,6.8,9.6Hz,1H),1.43–1.34(m,1H),1.00–0.84(m,2H).

[0128] Step 5: Synthesis of compounds 003 and 004

[0129] Compound 003_4 (40 mg, 75.85 μmol) was separated by chiral column (column type: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 μm); mobile phase: A: CO2, B: [Neu-IPA], gradient: B%: 25%-25%, 10 min) to obtain compounds 003 and 004.

[0130] SFC analysis method: column type: Chiralcel OX-3 (50*4.6mm ID, 3μm); mobile phase: A: CO2, B: [0.1% IPAm IPA], gradient: B%: 5%-50%, 3min.

[0131] 003 (retention time: 0.997 min): MS–ESI m / z: 527.9 [M+H] + . 1 H NMR(400MHz, DMSO_d6)δ:11.77(s,1H),11.47(s,1H),8.82–8.70(m,2H),4.93(t,J=6.8Hz,2 H),3.19(s,3H),3.02–2.95(m,2H),1.66–1.59(m,1H),1.42–1.35(m,1H),1.00–0.84(m,2H);

[0132] 004 (retention time: 1.075 min): MS–ESI m / z: 528.2 [M+H] + . 1 H NMR(400MHz,DMSO_d6)δ:11.88–11.70(m,1H),11.46(br s,1H),8.83–8.69(m,2H),4.93(t,J=6.8Hz,2H),3.19(s,3H),3.10–2.92(m,2H),1.68–1.58(m,1H),1.43–1.34(m,1H),0.99–0.84(m,2H).

[0133] Example 5

[0134]

[0135] Synthesis route:

[0136]

[0137] Step 1: Synthesis of compound 005_2

[0138] At room temperature, potassium tert-butoxide tetrahydrofuran solution (1M, 276.95mL) was added to toluene (2L), followed by compound 005_1 (50g, 247.28mmol, 45.87mL), and finally iodomethane (228.14g, 1.61mol, 100.06mL) and octadecanoyl crown ether-6 (6.54g, 24.73mmol). After the addition was completed, the reaction solution was stirred at 25°C for 12 hours. The reaction solution was added to 500mL of 25% ammonia water to quench the reaction, and 1L of water was added. The mixture was extracted with ethyl acetate (1L×2), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0–1 / 1, volume ratio) to obtain compound 005_2.

[0139] MS–ESI m / z:216.9[M+H] + .

[0140] Step 2: Synthesis of compound 005_3

[0141] At room temperature, compound 005_2 (20 g, 92.49 mmol) and propanediol (24.44 g, 369.98 mmol) were added to ethanol (200 mL), and then pyridine (36.58 g, 462.47 mmol, 37.33 mL) was added. The reaction solution was stirred at 70°C for 12 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate (200 mL) was added to dissolve it, and the pH was adjusted to 5-6 with 3M hydrochloric acid aqueous solution, and the liquid was separated. The aqueous phase was extracted with ethyl acetate (100 mL×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 chromatography column (eluent: petroleum ether / ethyl acetate = 1 / 0-6 / 1, volume ratio). Compound 005_3 was obtained. 1 H NMR (400MHz, CDCl3) δ: 4.42 (q, J = 7.2Hz, 2H), 4.25 (q, J = 7.2Hz, 2H), 1.61-1.66 (m, 6H), 1.39-1.47 (m, 6H).

[0142] Step 3: Synthesis of compound 005_4

[0143] At room temperature, compound 005_3 (3.2 g, 12.11 mmol) was added to chloroform (16 mL) and ethanol (16 mL), followed by the addition of 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (4.60 g, 18.16 mmol), and the reaction solution was stirred at 50 ° C for 12 hours. The reaction solution was poured into water (30 mL), extracted with dichloromethane (30 mL × 3), 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 and purified by chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–95 / 5, volume ratio). Compound 005_4 was obtained. MS–NEG m / z: 265.2 [MH] -

[0144] Step 4: Synthesis of compounds 005_5 and 005_6

[0145] Compounds 001_4 (2.12 g, 5.87 mmol, hydrochloride) and 005_4 (2.50 g, 9.39 mmol) were added to tert-butyl alcohol (30 mL) at room temperature, followed by potassium carbonate (2.03 g, 14.67 mmol). The reaction mixture was stirred at 85°C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and diluted with water (30 mL), extracted with dimethyltetrahydrofuran (30 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. 30 mL of methyl tert-butyl ether was added to the residue and stirred at 20°C for 1 hour. Clear solids were generated. The reaction solution was filtered, and the filter cake was rinsed with methyl tert-butyl ether (10 mL) to obtain a mixture of 005_5 and 005_6. MS–ESI m / z: 546.1[M+H] + .

[0146] Step 5: Synthesis of Compound 005

[0147] At room temperature and under nitrogen protection, a mixture of 005_5 and 005_6 (2.36 g, 4.33 mmol) was added to toluene (25 mL), followed by a toluene solution of trimethylaluminum (2M, 6.92 mL), heated to 80°C and stirred for 12 hours. The reaction solution was cooled to room temperature, the pH was adjusted to 5-6 with 3M HCl, extracted with ethyl acetate (25 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Methyl tert-butyl ether (10 mL) was added to the residue, stirred at 25°C for 1 hour, filtered, and concentrated under reduced pressure to obtain compound 005. MS–ESI m / z: 500.2[M+H] + ; 1H NMR (400MHz, DMSO-d6) δ: 11.50 (s, 1H), 11.10-11.19 (m, 1H), 8.75 (dd, J = 2.58, 1.58Hz, 1H), 8.72 (dd ,J=8.7,2.8Hz,1H),4.90(t,J=6.8Hz,2H),4.0(s,1H),2.89-3.09(m,2H),1.48(s,3H),0.79(s,3H).

[0148] Examples 6, 7, 8 and 9

[0149]

[0150] Synthesis route:

[0151]

[0152] Step 1: Synthesis of compounds 006_1 and 008_1

[0153] At room temperature and under nitrogen protection, compound 005 (660 mg, 1.32 mmol) was added to tetrahydrofuran (6 mL) and acetonitrile (3 mL), followed by methanol (169.39 mg, 5.29 mmol), potassium monopersulfate (1.63 g, 2.64 mmol), potassium dihydrogen phosphate (359.73 mg, 2.64 mmol) and cuprous bromide (37.92 mg, 264.33 μmol), and the reaction solution was stirred at 80°C for 2 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (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 obtain a residue. The residue was separated by preparative HPLC (column type: Phenomenexluna C18 (80 mm*30 mm ID, 3 μm); mobile phase: A: ACN, B: [H2O (containing 0.04% HCl)], gradient: B%: 25%-50%, 8 min) to obtain compounds 006_1 and 008_1.

[0154] Compound 006_1: MS–ESI m / z: 530.0 [M+H] +1 H NMR(400MHz, DMSO-d6)δ:11.85(s,1H),11.33,(s,1H)8.77(dd,J=2.8,1.6Hz,1H),8.71(dd,J=8.4,2 .8Hz,1H),4.92(t,J=6.8Hz,2H),3.15(s,3H),3.00(tt,J=19.2,6.8Hz,2H),1.35(s,3H)0.79(s,3H);

[0155] Compound 008_1: MS–ESI m / z: 516.2 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ:11.49(s,1H),11.19(s,1H),8.76(dd,J=2.8,1.6Hz,1H),8.70(dd,J=8.8,2.8Hz,1H),6.63(br s,1H),4.86-4.98(m,2H),3.00(tt,J=19.2,6.4Hz,2H),1.38(s,3H),0.77(s,3H).

[0156] Step 2: Synthesis of compounds 006 and 007

[0157] Compound 006_1 (40 mg, 75.85 μmol) was separated by chiral column (column type: REGIS (S, S) WHELK-O1 (250 mm*25 mm, 10 μm); mobile phase: A: CO2, B: [IPA (containing 0.1% NH3H2O)], gradient: B%: 25%-25%, 7 min) to obtain compounds 006 and 007.

[0158] SFC analysis method: column type: Chiralcel (S, S)-Whelk-O1 (100*4.6mm, ID, 3.5μm); mobile phase: [IPA (containing 0.1% IPAm)]%: 10%-50%, 3min.

[0159] 006 (retention time: 1.518 min): MS–ESI m / z: 530.2 [M+H] + .1H NMR(400MHz,DMSO-d6)δ:11.33(br s,1H)11.70-12.03(m,1H)8.77(dd,J=2.4,1.6Hz,1H)8.71(dd,J=8.8,2.8Hz,1H),4.93 (t,J=6.72Hz,2H),3.16(s,3H),3.00(tt,J=19.2,7.2Hz,2H),1.35(s,3H),0.79(s,3H);

[0160] 007 (retention time: 1.644 min): MS–ESI m / z: 530.2 [M+H] +1H NMR (400 MHz, DMSO-d6) δ: 8.76-8.79 (m, 1H) 8.70 (br d, J = 8.8 Hz, 1H), 4.93 (t, J = 6.8 Hz, 2H), 3.15 (s, 3H), 2.93-3.09 (m, 2H), 1.35 (s, 3H), 0.79 (s, 3H). Step 3: Synthesis of compounds 008 and 009

[0161] Compound 008_1 (70 mg, 135.83 μmol) was separated by chiral column (column type: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 μm); mobile phase: A: CO2, B: [MeOH (containing 0.1% NH3H2O)]; gradient: B%: 30%-30%, 10 min) to obtain compounds 008 and 009.

[0162] SFC analysis method: column type: Chiralcel OD-3 (50mm*4.6mm ID, 3μm); mobile phase: A: CO2, B: [MeOH (containing 0.1% IPAm)]; gradient: B%: 5%-50%, 3min.

[0163] 008 (retention time: 1.008min): MS–ESI m / z: 516.2 [M+H] + .1H NMR (400MHz, DMSO-d6) δ: 11.48 (s, 1H), 11.19 (s, 1H), 8.77 (dd, J=2.8, 1.6Hz, 1H), 8.70 (dd, J= 8.4,2.8Hz,1H),6.62(s,1H),4.87-4.97(m,2H),2.93-3.09(m,2H),1.38(s,3H),0.77(s,3H);

[0164] 009 (retention time: 1.198 min): MS–ESI m / z: 516.2 [M+H] + .1H NMR(400MHz,DMSO-d6)δ:11.34-11.71(m,1H),11.09-11.30(m,1H),8.76(s,1H),8.70(dd,J=8.4,2.8Hz,1H),6.62(s,1H),4.92(br t,J=6.4Hz,2H),2.92-3.12(m,2H),1.38(s,3H),0.77(s,3H).

[0165] Examples 10, 11, 12 and 13

[0166]

[0167] Synthesis route:

[0168]

[0169] Step 1: Synthesis of compound 010_1

[0170] At room temperature, compound 005_1 (50 g, 247.28 mmol) was dissolved in toluene (500 mL), and malononitrile (16.34 g, 247.28 mmol), β-alanine (660.92 mg, 7.42 mmol) and acetic acid (14.85 g, 247.28 mmol) were added thereto, and the reaction system was heated to 130°C and stirred for 12 hours. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (500 mL) and separated. The aqueous phase was extracted with ethyl acetate (100 mL×3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–5 / 1, volume ratio). Compound 010_1 was obtained.

[0171] Step 2: Synthesis of compound 010_2

[0172] Compound 010_1 (7 g, 27.97 mmol) was dissolved in THF (15 mL), and nitrogen was replaced three times. The reaction system was cooled to 0°C, and a solution of methylmagnesium bromide in ether (3M, 13.99 mL) was slowly added dropwise. The reaction system was stirred at 0°C for 15 minutes. The reaction system was poured into a saturated ammonium chloride solution (100 mL), and ethyl acetate (50 mL × 3) was added for extraction, and the organic phases were combined. The organic phase was washed with semi-saturated brine (10 mL × 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–5 / 1, volume ratio). Compound 010_2 was obtained.

[0173] Step 3: Synthesis of a mixture of compounds 010_3 and 012_1

[0174] Dissolve 001_4 (3.5 g, 9.68 mmol, hydrochloride) in tert-butanol (50 mL), add compound 010_2 (4.4 g, 16.52 mmol) and potassium bicarbonate (2.42 g, 24.19 mmol), and heat the reaction system to 85 ° C and stir for 12 hours. Pour the reaction solution into water (100 mL) and extract with ethyl acetate (50 mL×3). The organic phase is washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue is separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–1 / 1, volume ratio). A mixture of compounds 010_3 and 012_1 is obtained. Step 4: Synthesis of compounds 010_4 and 010_6

[0175] The above mixture (800.00 mg, 1.47 mmol) was dissolved in toluene (10 mL), nitrogen was replaced three times, trimethylaluminum toluene solution (2M, 2.20 mL) was added to the reaction system, and the reaction system was heated to 75 ° C and stirred for 5 hours. After the reaction was completed, the reaction system was cooled to room temperature, dilute hydrochloric acid (1N 10 mL) was added to the reaction system to quench the reaction, ethyl acetate (50 mL) was added to dilute, the liquid was separated, the organic phase was collected, the aqueous phase was extracted with ethyl acetate (50 mL × 3), and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain a crude product. The obtained residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–2 / 1, volume ratio) and preparative HPLC separation (column type: Phenomenex lunaC18 (250mm*50mm ID, 10μm); mobile phase: A: ACN, B: [H2O (containing 0.04% HCl)], gradient: B%: 30%-60%, 10min) to obtain compounds 010_4 and 010_6.

[0176] LCMS analysis method: column type: Luna 5μm C18 (2*50mm); mobile phase A: H2O+0.05% (v / v) TFA; mobile phase B: ACN+0.05% (v / v) TFA, gradient: B%: 10%-100%, 6min.

[0177] 010_4 (retention time: 2.789 min) MS–ESI m / z: 500.1 [M+H] +.1H NMR(400MHz, DMSO-d6)δ:11.55(s,1H),11.24(s,1H),8.75(dd,J=1.6,2.8Hz,1H),8.70(dd,J=2.8,8.4Hz,1H), 4.91(t,J=6.8Hz,2H),3.00(tt,J=6.4,19.2Hz,2H),2.80(q,J=7.2Hz,1H),1.41(s,3H),0.79(d,J=7.2Hz,3H);

[0178] 010_6 (retention time: 2.848 min) MS–ESI m / z: 500.0 [M+H] + .1H NMR (400MHz, DMSO-d6) δ: 11.42 (s, 1H), 11.09 (s, 1H), 8.82–8.65 (m, 2H), 4.91 (t, J = 6.6Hz, 2H), 3.09–2.89 (m, 3H), 1.25 (t, J = 3.4Hz, 6H).

[0179] Step 5: Synthesis of compounds 010 and 011

[0180] Compound 010_4 (retention time: 2.789 min) (720 mg, 1.27 mmol) was separated by chiral column (column type: DAICEL CHIRALPAK IE (250 mm*30 mm, 10 μm); mobile phase: A: CO2, B: [EtOH (containing 0.1% NH3H2O)]; gradient: B%: 38%-38%, 6 min) to obtain compounds 010 and 011.

[0181] SFC analysis method: column type: Chiralpak AD-3 (50mm*4.6mm ID, 3μm); mobile phase: A: CO2, B: [EtOH (containing 0.1% IPAm)]; gradient: B%: 5%-50%, 3min.

[0182] Compound 010 (retention time: 1.00 min): MS–ESI m / z: 500.0 [M+H] + .1H NMR(400MHz, DMSO_d6)δ:11.41(br s,1H),11.09(br s,1H),8.82–8.59(m,2H),4.90(t,J=6.8Hz,2H),3.13–2.87(m,3H),1.25(t,J=3.2Hz,6H);

[0183] Compound 011 (retention time: 1.311 min): MS–ESI m / z: 500.0 [M+H] + .1H NMR(400MHz, DMSO_d6)δ:11.42(s,1H),11.09(s,1H),8.75(dd,J=1.6,2.8Hz,1H),8.7 1(dd,J=2.8,8.6Hz,1H),4.91(t,J=6.8Hz,2H),3.13–2.91(m,3H),1.31–1.19(m,6H).

[0184] Step 6: Synthesis of compounds 012 and 013

[0185] Compound 010_6 (retention time: 2.848 min) (270 mg, 540.68 μmol) was separated by chiral column (column type: DAICEL CHIRALPAK IE (250 mm*30 mm, 10 μm); mobile phase: A: CO2, B: [EtOH (containing 0.1% NH3H2O)]; gradient: B%: 33%-33%, 7 min) to obtain compounds 012 and 013.

[0186] SFC analysis method: column type: Chiralpak IE-3 (50mm*4.6mm ID, 3μm); mobile phase: A: CO2, B: [EtOH (containing 0.1% IPAm)], gradient: B%: 5%-50%, 3min.

[0187] Compound 012 (retention time: 1.087 min): MS–ESI m / z: 499.9 [M+H] + .1H NMR(400MHz,DMSO_d6)δ:11.54(br s,1H),11.23(s,1H),8.75(dd,J=1.6,2.8Hz,1H),8.70(dd,J=2.8,8.8Hz,1H),4.91(t,J=6.8 Hz,2H),3.00(tt,J=6.4,19.1Hz,2H),2.85–2.76(m,1H),1.41(s,3H),0.80(d,J=7.2Hz,3H);

[0188] Compound 013 (retention time: 1.193 min): MS–ESI m / z: 499.9 [M+H] +.1H NMR(400MHz,DMSO_d6)δ:11.53(br s,1H),11.23(br s,1H),8.78–8.66(m,2H),4.91(t,J=6.8Hz,2H),2.99(tt,J=6.8,19.2Hz,2H),2.80(q,J=7.2Hz,1H),1.41(s,3H),0.80(d,J=7.2Hz,3H).

[0189] Examples 14 and 15

[0190]

[0191] Synthesis route:

[0192]

[0193] Step 1: Synthesis of compound 014_1

[0194] At room temperature and under nitrogen protection, compound 001_1 (300 g, 1.14 mol) was added to N,N-dimethylformamide (3 L), followed by o-fluorobenzyl chloride (164.91 g, 1.14 mol, 135.17 mL) and cesium carbonate (408.81 g, 1.25 mol), and the reaction solution was stirred at 80°C for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature and filtered to obtain a 3L N,N-dimethylformamide solution of compound 014_1 (423 g), which was used directly.

[0195] Step 2: Synthesis of compound 014_2

[0196] At room temperature and under nitrogen protection, compound 014_1 (70 g, 188.62 mmol) was added to 1L N,N-dimethylformamide solution, methanol (300 mL) was added, cyclopenta-2,4-dien-1-yl (diphenyl)phosphine dichloromethane dichloropalladium ferrocene (6.90 g, 9.43 mmol) and triethylamine (76.34 g, 754.47 mmol, 105.01 mL) were added, and stirred at 80°C for 12 hours under a carbon monoxide (15 psi) atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-15 / 1, volume ratio) to obtain compound 014_2.

[0197] Step 3: Synthesis of the hydrochloride salt of compound 014_3

[0198] At room temperature and under nitrogen protection, ammonium chloride (4.41 g, 82.44 mmol) was dispersed in toluene (50 mL), trimethylaluminum toluene solution (2M, 39.57 mL) was added, heated to 80°C, and then compound 014_2 (5 g, 16.49 mmol) was added to the reaction system, stirred at 80°C for 30 minutes, then heated to 110°C for 1.5 hours, cooled to 25°C, methanol (7.61 g, 237.42 mmol) was added dropwise, the temperature was kept below 40°C, and then hydrochloric acid (3M, 105.52 mL) was added, the temperature was kept below 40°C, heated to 80°C and stirred for 10 minutes, then cooled to 0°C and stirred for 30 minutes. After the reaction was completed, the filter cake was collected by filtration. The filter cake was rinsed with water (100 mL) to obtain the hydrochloride of compound 014_3.

[0199] Step 4: Synthesis of compounds 014_4 and 014_5

[0200] At room temperature and under nitrogen protection, compound 005_4 (6.58 g, 24.71 mmol) was added to tert-butyl alcohol (70 mL), and the hydrochloride of compound 014_3 (5 g, 15.45 mmol) and potassium carbonate (5.34 g, 38.61 mmol) were added in sequence, and the reaction solution was stirred at 85°C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (100 mL) was added, and it was extracted with dimethyltetrahydrofuran (100 mL×2), and the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a mixture of compound 014_4 and 014_5.

[0201] Step 5: Synthesis of compound 014_6

[0202] At room temperature and under nitrogen protection, a mixture of compounds 014_4 and 014_5 (7g, 13.79mmol) was dissolved in toluene (100mL). A toluene solution of trimethylaluminum (2M, 28.97mL) was slowly added dropwise and stirred at 80°C for 12 hours. The reaction solution was cooled to room temperature and slowly poured into water (100mL), 3M hydrochloric acid was added, the pH was adjusted to 5-6, dimethyltetrahydrofuran (100mL×3) was added for extraction, 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. Methyl tert-butyl ether (50mL) was added to the residue, stirred at 25°C for 1 hour and filtered to obtain compound 014_6.

[0203] Step 5: Synthesis of compound 014_7

[0204] Compound 014_6 (4.24 g, 9.19 mmol) was dissolved in methanol (80 mL) at room temperature and under nitrogen protection, and iodobenzene (7.90 g, 18.38 mmol) was added and stirred at 50°C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was obtained, which was concentrated under reduced pressure to obtain a residue. The residue was separated by preparative HPLC (column type: Welch Xtimate C18 (250 mm*70 mm ID, 10 μm); mobile phase: A: ACN, B: [H2O (containing 0.04% HCl)], gradient: B%: 35%-70%, 20 min) to obtain compound 014_7. MS–ESI m / z: 492.0 [M+H] +1 H NMR(400MHz,DMSO-d6)δ11.81(br s,1H),11.26–11.39(m,1H),8.77(d,J=1.00Hz,1H),8.71(dd,J=8.8,2.8Hz,1H),7.35–7.43(m,1H),7.2 7–7.32(m,1H),7.20–7.26(m,1H),7.14–.20(m,1H),5.86(s,2H),3.14(s,3H),1.34(s,3H),0.77(s,3H).

[0205] Step 6: Synthesis of compounds 014 and 015

[0206] Compound 014_7 (200 mg, 406.96 μmol) was separated by chiral column (column type: REGIS (s, s) WHELK-O1 (250 mm*30 mm, 5 μm); mobile phase: [0.1% NH3H2O ​​MeOH]%: 32%-32%, 16.5 min) to obtain compounds 014 and 015.

[0207] SFC analysis method: column type: Chiralpak IE-3 (50mm*4.6mm ID, 3μm); mobile phase: A: CO2, B: [EtOH (containing 0.1% IPAm)], gradient: B%: 5%-50%, 3min.

[0208] 014 (retention time: 2.612 min) MS–ESI m / z: 492.0 [M+H] +1H NMR (400MHz, DMSO-d6) δ11.73–11.96(m,1H),11.31(s,1H),8.77(dd,J=2.8,1.6Hz,1H),8.71(dd,J=8.8,2.8Hz,1H),7.35– 7.42(m,1H),7.27–7.32(m,1H),7.20–7.26(m,1H),7.14–7.20(m,1H),5.86(s,2H),3.14(s,3H),1.34(s,3H),0.77(s,3H);

[0209] 015 (retention time: 2.749 min) MS–ESI m / z: 492.0 [M+H] +1 H NMR (400MHz, DMSO-d6) δ11.75–11.89(m,1H),11.28–11.36(m,1H),8.77(d,J=2.63Hz,1H),8.71(dd,J=8.66,2.76Hz,1H),7.3 5–7.42(m,1H),7.27–7.32(m,1H),7.20–7.26(m,1H),7.14–7.20(m,1H),5.86(s,2H),3.14(s,3H),1.34(s,3H),0.77(s,3H).

[0210] Example 16

[0211]

[0212] Synthesis route:

[0213]

[0214] Step 1: Synthesis of compound 016

[0215] At room temperature and under nitrogen protection, compound 014_6 (500 mg, 1.08 mmol) was dissolved in THF (5 mL) and H2O (5 mL), potassium monopersulfate (1.33 g, 2.17 mmol), potassium dihydrogen phosphate (294.94 mg, 2.17 mmol) and cuprous bromide (31.09 mg, 216.72 μmol) were added, and the reaction solution was stirred at 80°C for 2 hours. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL×2) were added to the reaction solution for separation, 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 preparative HPLC (Waters Xbridge Prep OBD C18 (150mm*40mm ID, 10μm); mobile phase: A: ACN, B: [H2O (containing 10mmol NH4HCO3+0.05% NH3.H2O)], gradient: B%: 40%-60%, 8min) to give compound 016. MS–ESI m / z: 478.2 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ11.38–11.54(m,1H)11.17(br s,1H)8.76(s,1H)8.70(dd,J=8.4,2.8Hz,1H)7.33–7.43(m,1H)7.20–7.31(m,2 H)7.15–7.20(m,1H)6.61(s,1H)5.85(d,J=3.2Hz,2H)1.37(s,3H)0.75(s,3H).

[0216] Examples 17, 18, 19 and 20

[0217]

[0218] Synthesis route:

[0219]

[0220] Step 1: Synthesis of compounds 017_1 and 017_2

[0221] At room temperature and under nitrogen protection, the hydrochloride of intermediate 014_3 (2.76 g) was added to tert-butyl alcohol (40 mL), followed by the addition of intermediate 010_2 (2.72 g, 10.21 mmol) and potassium bicarbonate (2.13 g, 21.28 mmol), and the reaction solution was stirred at 80 ° C for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (100 mL) and dimethyltetrahydrofuran (100 mL × 2) were added for separation, and the organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–4 / 1, volume ratio) to obtain intermediate 017_1 and intermediate 017_2.

[0222] Step 2: Synthesis of compounds 017_3 and 017_4

[0223] At room temperature and under nitrogen protection, the intermediate 017_1 (500.00 mg, 985.24 μmol) was dissolved in toluene (5 mL), AlMe3 (2M, 1.48 mL) was added to the reaction system, and the reaction system was heated to 75 ° C and stirred for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature. The reaction solution was poured into water (50 mL), diluted hydrochloric acid (1N) was added to adjust the pH to 3-4, 2-methyltetrahydrofuran (50 mL) was added to separate the liquids, and the organic phase was collected. The aqueous phase was extracted with 2-methyltetrahydrofuran (20 mL×3), 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 to obtain a crude product. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–3 / 1, volume ratio) and preparative HPLC (column type: Phenomenex lunaC18 (80mm*40mm ID, 3μm); mobile phase: A: ACN, B: [H2O (containing 0.04% HCl)], gradient: B%: 33%-49%, 7min) to obtain compound 017_3.

[0224] At room temperature and under nitrogen protection, the intermediate 017_2 (700.00 mg, 1.38 mmol) was dissolved in toluene (10 mL), the nitrogen was replaced three times, AlMe3 (2M, 2.07 mL) was added to the reaction system, and the reaction system was heated to 75 ° C and stirred for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature. The reaction system was poured into water (100 mL), diluted hydrochloric acid (1N) was added to adjust the pH to 3-4, 2-methyltetrahydrofuran (50 mL) was added to dilute, the liquid was separated, and the organic phase was collected. The aqueous phase was extracted with 2-methyltetrahydrofuran (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain a crude product. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-3 / 1, volume ratio), preparative HPLC (mobile phase: acetonitrile / water; hydrochloric acid system: 0.04% HCl), and preparative HPLC (column type: Phenomenex luna C18 (75mm*30mm ID, 3μm); mobile phase: A: ACN, B: [H2O (containing 10mmol NH4HCO3+0.05% NH3.H2O)], gradient: B%: 35%-55%, 8min) to obtain compound 017_4.

[0225] HPLC analysis method: column type: Kinetex 5μm C18 (2.1*50mm); mobile phase A: H2O+0.04% (v / v) TFA; mobile phase B: ACN+0.02% (v / v) TFA, gradient: B%: 10%-80%, 6min.

[0226] 017_3 (retention time: 3.482 min) MS–ESI m / z: 462.2 [M+H] + .1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),11.22(s,1H),8.81–8.62(m,2H),7.42–7.33(m,1H), 7.30–7.14(m,3H),5.85(s,2H),2.78(q,J=7.2Hz,1H),1.39(s,3H),0.78(d,J=7.4Hz,3H).

[0227] 017_4 (retention time: 3.574 min) MS–ESI m / z: 462.2 [M+H] +.1H NMR (400MHz, DMSO-d6) δ11.14–10.77(m,2H),8.76–8.73(m,1H),8.72–8.67(m,1H),7.41–7.34( m,1H),7.28–7.20(m,2H),7.19–7.13(m,1H),5.84(s,2H),3.09–2.99(m,1H),1.28–1.19(m,6H).

[0228] Step 3: Synthesis of compounds 017 and 018

[0229] Compound 017_3 (30 mg, 65.02 μmol) was separated by chiral column (column type: DAICEL CHIRALPAK IE (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O ​​MeOH; 20%-45%, 18 min) to obtain compounds 017 and 018.

[0230] SFC analysis method: column type: Chiralpak AS-3 (50mm*4.6mm ID, 3μm); mobile phase: A: CO2, B: [MeOH (containing 0.1% IPAm)]; gradient: B%: 5%-50%, 3min.

[0231] Compound 017 (retention time: 1.138 min): MS–ESI m / z: 462.2 [M+H] + .1H NMR(400MHz,DMSO_d6)δ11.65–11.40(m,1H),11.23(br s,1H),8.81–8.61(m,2H),7.43–7.34(m,1H),7.31–7.14(m,3H),5.85(s,2H),2.79(d,J=7.4Hz,1H),1.40(s,3H),0.78(d,J=7.4Hz,3H);

[0232] Compound 018 (retention time: 1.422 min): MS–ESI m / z: 462.2 [M+H] + .1H NMR(400MHz,DMSO_d6)δ11.71–11.01(m,2H),8.83–8.64(m,2H),7.42–7.35(m,1H),7.3 1–7.13(m,3H),5.85(s,2H),2.78(q,J=7.3Hz,1H),1.39(s,3H),0.78(d,J=7.4Hz,3H).

[0233] Step 4: Synthesis of compounds 019 and 020

[0234] Compound 017_4 (150 mg, 325.08 μmol) was separated by chiral column (column type: DAICEL CHIRALPAK IE (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH 3 H 2 O EtOH]; gradient: B%: 50%, 12 min) to obtain compounds 019 and 020.

[0235] SFC analysis method: column type: (S,S)-WHELK-O1 (50mm*4.6mm ID, 3.5μm); mobile phase: A: CO2, B: [EtOH (containing 0.1% IPAm)], gradient: B%: 5%-50%, 3min.

[0236] Compound 019 (retention time: 1.669 min): MS–ESI m / z: 462.31 [M+H] + .1H NMR(400MHz,DMSO_d6)δ:11.38(br s,1H),11.07(s,1H),8.77–8.66(m,2H),7.41–7.32(m,1H),7.29–7.13(m,3H),5.84(s,2H),3.04(q,J=7.1Hz,1H),1.27–1.20(m,6H);

[0237] Compound 020 (retention time: 1.808 min): MS–ESI m / z: 462.34 [M+H] + .1H NMR(400MHz,DMSO_d6)δ:11.38(br s,1H),11.08(br s,1H),8.76–8.65(m,2H),7.37(q,J=7.1Hz,1H),7.28–7.12(m,3H),5.84(s,2H),3.04(q,J=6.9Hz,1H),1.29–1.17(m,6H).

[0238] Examples 21 and 22

[0239]

[0240] Synthesis route:

[0241]

[0242] Step 1: Synthesis of compound 021_1

[0243] At room temperature and under nitrogen protection, compound 001_11 (9.04 g, 36.14 mmol) was added to tert-butyl alcohol (100 mL), followed by the addition of the hydrochloride of compound 014_3 (5 g) and potassium carbonate (3.87 g, 38.61 mmol), and the reaction solution was stirred at 80°C for 12 hours. After the reaction was completed, water (500 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was added with methyl tert-butyl ether (70 mL) and pulped at room temperature, filtered, and the filter cake was collected. The filter cake was concentrated under reduced pressure to obtain compound 021_1.

[0244] Step 2: Synthesis of compound 021_2

[0245] At room temperature and under nitrogen protection, compound 021_1 (4.5 g, 8.90 mmol) was dissolved in anhydrous toluene (130 mL), trimethylaluminum toluene solution (2 M, 13.35 mL) was slowly added dropwise, and the reaction system was stirred at 75°C for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature and slowly poured into water (100 mL), 3 M hydrochloric acid was added to adjust the pH to 3-4, dimethyltetrahydrofuran (100 mL×3) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was separated by preparative HPLC (column type: Phenomenex C18 (250 mm*70 mm ID, 10 μm); mobile phase: A: ACN, B: [H2O (containing 0.04% HCl)], gradient: B%: 40%-70%, 20 min) to obtain compound 021_2. 1 H NMR(400MHz, DMSO-d6)δ:11.50(s,1H),11.28(s,1H),8.78–8.68(m,2H),7.44–7.34(m,1H),7.30–7.19(m, 2H),7.20–7.12(m,1H),5.85(s,2H),1.58–1.49(m,1H),1.44(s,3H),1.18–1.08(m,1H),0.82–0.62(m,2H).

[0246] Step 3: Synthesis of compounds 021 and 022

[0247] Compound 021_2 (200 mg, 422.45 μmol) was separated by chiral column (column type: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH 3 H 2 O EtOH]%: 40%-40%, 8 min) to obtain compounds 021 and 022.

[0248] SFC analysis method: column type: Chiralpak AD-3 (50mm*4.6mm ID, 3μm); mobile phase: A: CO2, B: [EtOH (containing 0.1% IPAm)], gradient: B%: 5%-50%, 3min.

[0249] 021 (retention time: 1.253 min) MS–ESI m / z: 474.2.0 [M+H] +1 H NMR(400MHz,DMSO-d6)δ11.50(s,1H),11.28(s,1H),8.78(s,2H),7.43–7.32(m,1H),7.30–7.20(m,2H) ,7.19–7.13(m,1H),5.85(s,2H),1.58–1.50(m,1H),1.43(s,3H),1.15–1.10(m,1H)0.77–0.67(m,2H);

[0250] 022 (retention time: 1.367 min) MS–ESI m / z: 474.2.0 [M+H] +1 H NMR (400MHz, DMSO-d6) δ11.54–11.46(m,1H),11.28(s,1H),8.78–8.70(m,2H),7.44–7.34(m,1H),7.30–7.20(m,2H), 7.20–7.14(m,1H),5.86(s,2H),1.60–1.50(m,1H),1.44(s,3H),1.13(ddd,J=9.2,7.2,4.0Hz,1H)0.80–0.66(m,2H).

[0251] Embodiment 23

[0252]

[0253] Synthesis route:

[0254]

[0255] Step 1: Synthesis of compound 023_1

[0256] At room temperature and under nitrogen protection, the hydrochloride of compound 014_3 (10 g, 30.89 mmol) was added to tert-butyl alcohol (150 mL), followed by compound 003_1 (14.59 g, 61.78 mmol) and potassium carbonate (7.73 g, 77.23 mmol), and the reaction solution was stirred at 80°C for 12 hours. After the reaction was completed, water (500 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was added with methyl tert-butyl ether (50 mL) for pulping, filtered, and the filter cake was collected. The filter cake was concentrated under reduced pressure to obtain compound 023_1.

[0257] Step 2: Synthesis of compound 023_2

[0258] At room temperature and under nitrogen protection, the mixture of compound 023_1 (5 g, 10.17 mmol) was added to anhydrous methanol (100 mL), followed by the addition of bis(trifluoroacetic acid) iodobenzene (10.94 g, 25.43 mmol), and the reaction solution was stirred at 50°C for 12 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure and diluted with ethyl acetate (100 mL), washed with saturated sodium sulfite (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was separated by preparative HPLC (column type: Phenomenex luna C18 (250 mm*100 mm ID, 15 μm); mobile phase: A: ACN, B: [H2O (containing 0.1% TFA)], gradient: B%: 35%-65%, 20 min) to obtain compound 023_2.

[0259] Step 3: Synthesis of compound 023

[0260] At room temperature and under nitrogen protection, compound 023_2 (0.8 g, 1.53 mmol) was dissolved in anhydrous toluene (15 mL), and trimethylaluminum toluene solution (2M, 2.45 mL) was slowly added dropwise. After the addition was completed, the reaction solution was stirred at 100°C for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature and slowly poured into water (20 mL). 3M hydrochloric acid was added to adjust the pH to 3-4, and dimethyltetrahydrofuran (20 mL×3) was added for extraction, and the organic phases were combined. The organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–3 / 1, volume ratio) and preparative HPLC (column type: Phenomenex luna C18 (80 mm*40 mm ID, 3 μm); mobile phase: A: ACN, B: [H2O (containing 0.04% HCl)], gradient: B%: 45%-65%, 7 min)) to obtain compound 023. MS–ESI m / z: 490.0 [M+H] + .1H NMR(400MHz,DMSO-d6)δ:11.75(br s,1H),11.46(s,1H),8.82–8.68(m,2H),7.44–7.34(m,1H),7.32–7.14(m,3H),5.80 –5.94(m,2H),3.17(s,3H),1.58–1.68(m,1H),1.32–1.44(m,1H),0.82–0.98(m,2H).

[0261] Examples 24 and 25

[0262]

[0263] Synthesis route:

[0264]

[0265] Step 1: Synthesis of compound 024_1

[0266] At room temperature and under nitrogen protection, compound 010_1 (10 g, 39.96 mmol) was added to chloroform (40 mL) and ethanol (40 mL), followed by 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (15.18 g, 59.94 mmol), and the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The obtained residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–4 / 1, volume ratio) to obtain compound 024_1.

[0267] Step 2: Synthesis of compound 024_2

[0268] At room temperature and under nitrogen protection, the hydrochloride salt of intermediate 001_4 (8.5 g) was dissolved in tert-butyl alcohol (150 mL), and intermediate 024_1 (9.49 g, 37.60 mmol) and potassium bicarbonate (5.88 g, 58.75 mmol) were added. The reaction solution was stirred at 90°C for 12 hours. After the reaction was completed, the reaction solution was added to water (500 mL), and solids precipitated. The mixed solution was filtered, and the filter cake was washed with tert-methyl ether (20 mL). The filter cake was collected and dried under reduced pressure. A mixture of compound 024_2 and compound 024_3 was obtained.

[0269] Step 3: Synthesis of compound 024_4

[0270] At room temperature and under nitrogen protection, compound 024_2 and compound 024_3 (5 g, 9.41 mmol) were dispersed in anhydrous methanol (100 mL) and bis(trifluoroacetoxy)iodobenzene (12.14 g, 28.23 mmol) was added. The reaction solution was stirred in a 50°C oil bath for 2 hours. After the reaction was completed, the temperature was cooled to room temperature and the solvent was concentrated to obtain an oily residue. Isopropyl ether (100 mL) was added to the residue, and a white solid was precipitated after stirring at room temperature for 30 minutes. The filtrate was filtered and concentrated under reduced pressure to obtain a crude product. The residue was purified by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0–1 / 1, volume ratio) to obtain intermediate 024_4.

[0271] Step 4: Synthesis of compound 024_5

[0272] At room temperature and under nitrogen protection, compound 024_4 (0.3 g, 534.34 μmol) was dissolved in anhydrous toluene (6 mL) and trimethylaluminum toluene solution (2M, 854.95 μL) was added. The reaction system was stirred at 50 ° C for 12 hours, and then heated to 90 ° C and stirred for 12 hours. After the reaction, it was cooled to room temperature. The reaction solution was poured into water (100 mL), diluted hydrochloric acid (1N) was added to pH 3-4, and ethyl acetate (50 mL×3) was used for extraction. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The residue was separated by preparative HPLC (column type: Phenomenex C18 (75 mm*30 mm ID, 3 μm); mobile phase: A: ACN, B: [H2O (containing 10 mmol NH4HCO3)], gradient: B%: 35%-55%, 8 min) to obtain compound 024_5. MS–ESI m / z:516.2[M+H] +.1H NMR(400MHz,DMSO_d6)δ11.95–11.71(m,1H),11.38(br s,1H),8.82–8.66(m,2H),4.93(t,J=6.6Hz,2H),3.19(s,3H),3.01(tt,J=6.8,19.1Hz,2H),2.89(q,J=7.6Hz,1H),0.82(d,J=7.5Hz,3H).

[0273] Step 5: Synthesis of compounds 024 and 025

[0274] Compound 024_5 (100 mg, 153.29 μmol) was separated by chiral column (column type: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH 3 H 2 O EtOH]%: 10%-10%, 12 min) to obtain compounds 024 and 025.

[0275] SFC analysis method: column type: Chiralpak AS-3 (150mm*4.6mm ID, 3μm); mobile phase: A: CO2, B: [EtOH (containing 0.1% IPAm)], gradient: B%: 10%-50%, 3min.

[0276] 024 (retention time: 1.496 min) MS–ESI m / z: 515.9 [M+H] +1 H NMR(400MHz,DMSO-d6)δ11.85(br s,1H),11.38(br s,1H),8.77(dd,J=1.6,2.8Hz,1H),8.71(dd,J=2.8,8.6Hz,1H),4.93(t,J=6.6H z,2H),3.19(s,3H),3.09–2.94(m,2H),2.90(q,J=7.6Hz,1H),0.95–0.74(m,3H);

[0277] 025 (retention time: 1.789 min) MS–ESI m / z: 516.2 [M+H] +1 H NMR (400MHz, DMSO-d6) δ12.09–11.16(m,2H),8.88–8.61(m,2H),4.93(t,J=6.8Hz,2H), 3.19 (s, 3H), 3.01 (tt, J = 6.6, 19.2Hz, 2H), 2.90 (q, J = 7.6Hz, 1H), 0.82 (d, J = 7.6Hz, 3H).

[0278] Examples 26 and 27

[0279]

[0280] Synthesis route:

[0281]

[0282] Step 1: Synthesis of compound 026_1

[0283] At room temperature and under nitrogen protection, compound 024_1 (2.99 g, 11.86 mmol) was dissolved in tert-butyl alcohol (150 mL), and the hydrochloride of compound 014_3 (2.4 g, 7.41 mmol) and potassium bicarbonate (1.86 g, 18.53 mmol) were added, and stirred at 85°C for 12 hours. After the reaction was completed, 2-methyltetrahydrofuran (100 mL) and water (100 mL) were added to the reaction solution, and the liquid was separated. The aqueous phase was extracted with 2-methyltetrahydrofuran (100 mL×3), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a mixture of intermediates 026_1 and 026_2.

[0284] Step 2: Synthesis of compound 026_3

[0285] At room temperature and under nitrogen protection, a mixture of compound 026_1 and compound 026_2 (1 g, 2.03 mmol) was dispersed in anhydrous methanol (20 mL) and bis(trifluoroacetoxy)iodobenzene (1.74 g, 4.05 mmol) was added. The reaction solution was stirred in a 50°C oil bath for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and concentrated to remove the solvent to obtain an oily residue. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–7 / 3, volume ratio) to obtain compound 026_3.

[0286] Step 3: Synthesis of compound 026_4

[0287] At room temperature and under nitrogen protection, compound 026_3 (350 mg, 668.59 μmol) was dissolved in anhydrous toluene (10 mL) and trimethylaluminum toluene solution (2M, 1.34 mL) was added. The reaction system was stirred at 75°C for 5 hours. After the reaction was completed, it was cooled to room temperature. The reaction solution was poured into water (50 mL), 1N dilute hydrochloric acid was added to pH 3-4, and ethyl acetate (50 mL×3) was used for extraction. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The residue was separated by preparative HPLC (column type: Waters Xbridge BEH C18 (100 mm*30 mm ID, 10 μm); mobile phase: A: ACN, B: [H2O (containing 10 mmol NH4HCO3)], gradient: B%: 30%-60%, 8 min)) to obtain compound 026_4.

[0288] Step 4: Synthesis of compounds 026 and 027

[0289] Compound 026_4 (50 mg, 104.73 μmol) was separated by chiral column (column type: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH 3 H 2 O IPA] %: 45%-45%, 9 min) to obtain compounds 026 and 027.

[0290] SFC analysis method: column type: Chiralpak IC-3 (50mm*4.6mm ID, 3μm); mobile phase: A: CO2, B: [IPA (containing 0.1% IPAm)], gradient: B%: 5%-50%, 3min.

[0291] 026 (retention time: 1.369 min) MS–ESI m / z: 478.2 [M+H] +1 H NMR(400MHz,DMSO-d6)δ11.82(br s,1H),11.37(br s,1H),8.77(dd,J=1.6,2.4Hz,1H),8.71(dd,J=2.8,8.8Hz,1H),7.41-7.36(m,1H),7.3 1-7.16(m,3H),5.86(s,2H),3.17(s,3H),2.88(q,J=7.6Hz,1H),0.80(d,J=7.6Hz,3H);

[0292] 027 (retention time: 1.499 min) MS–ESI m / z: 478.2 [M+H] +1H NMR(400MHz,DMSO-d6)δ11.82(br s,1H),11.37(br s,1H),8.78-8.69(m,2H),7.41-7.37(m,1H),7.31-7.16(m,3H),5.86(s,2H),3.17(s,3H),2.88(q,J=7.6Hz,1H),0.80(d,J=7.6Hz,3H).

[0293] Biological Testing

[0294] Experimental Example 1: In vitro activity test

[0295] 1. cGMP expression test based on lnCap cells

[0296] 1. Experimental Procedure

[0297] 1) Solution preparation

[0298] · 10% BSA (bovine serum albumin)

[0299] 10 g of BSA was dissolved in 100 mL of double distilled water (ddH2O) to obtain 10% BSA.

[0300] · 5mMDETA(diethylenetriamine)-NO

[0301] Weigh 10 mg of DETA-NO and dissolve it in 12.2 mL of double distilled water (ddH2O) to obtain 5 mM DETA-NO, which is then divided and stored in a -20°C refrigerator.

[0302] · Washing Buffer (50 mL)

[0303]

[0304] ● Assay Buffer (50 mL)

[0305]

[0306] ● Detection Buffer

[0307] a) Add 50 μL cGMP-D2 (D2-labeled cyclic GMP) into 1 mL lysis buffer and mix well.

[0308] b) 50 μL of anti-cGMP cryptate (Eu 3+ The cryptate-labeled anti-cGMP antibody was added into 1 mL of lysis buffer and mixed evenly.

[0309] 2) Compound dilution

[0310] (1) Dilute the compound to 5 mM with DMSO. Transfer 10 μL of the compound to a shallow well plate for Echo.

[0311] (2) Use Echo to perform gradient dilution of the compounds. Dilute each compound into 10 concentration gradients and add 50 nL to a 384-well microplate.

[0312] 3) Preparation of LNCap cells

[0313] (1) LNCap culture medium: RPMI1640 + 10% fetal bovine serum + 1% double antibody.

[0314] (2) Preheat the phosphate buffer, trypsin, and culture medium used in the cell culture process in a 37°C water bath.

[0315] (3) Take out the cells (passage 14) from the 37°C 5% CO2 incubator and remove the old culture medium in the culture bottle with a pipette.

[0316] (4) Pipette 5 mL of phosphate buffer into the culture flask to rinse the cells, and then discard the liquid.

[0317] (5) Pipette 3 mL of pancreatic enzyme into the culture bottle, shake it and discard the liquid, then place the culture bottle in the incubator.

[0318] (6) After about 2 minutes, remove the culture flask and observe that all cells have separated. Then, pipette 9 mL of culture medium into the culture flask and pipette it several times to transfer the cell suspension to a 50 mL centrifuge tube.

[0319] (7) Pipette 0.7 mL of cell suspension into a counting cup and count on a ViCell XR. Centrifuge the remaining cells at 1000 rpm for 5 min and discard the supernatant.

[0320] (8) Add 10 mL of washing buffer to wash the cells, centrifuge at 1000 rpm for 5 min, and remove the supernatant.

[0321] (9) Add assay buffer and adjust the cell concentration to 1.25×10 6 / mL. 8μL / well was added to the microplate.

[0322] 4) DETA-NO preparation and addition

[0323] (1) Take 10 μL of 5 mM DETA-NO and add it to 1240 μL and 1657 μL assay buffer, respectively, to obtain 40 μM and 30 μM DETA-NO.

[0324] (2) Use Bravo to transfer 2 μL / well of DETA-NO to a 384-well microplate.

[0325] (3) Centrifuge at 1500 rpm for 5 min. Incubate the microplate at 37°C for 30 min.

[0326] 5) Prepare cGMP standard curve

[0327] (1) Dilute the 1 mM cGMP stock solution to 10 μM with assay buffer, and then perform 4-fold serial dilutions to 11 concentration gradients.

[0328] (2) Add 10 μL / well of the diluted cGMP to the microplate.

[0329] 6) Add detection reagent and read the plate

[0330] (1) Use Bravo to transfer 5 μL / well of cGMP-D2 to a 384-well microplate. Centrifuge at 1500 rpm for 1 min.

[0331] (2) Use Bravo to transfer 5 μL / well of anti-cGMP cryptate to a 384-well microplate. Centrifuge at 1500 rpm for 1 min.

[0332] (3) Incubate at room temperature for 1 h.

[0333] (4) Use Envision to read 665 / 615.

[0334] 7) Data analysis

[0335] (1) cGMP standard curve: A standard curve was prepared using Graphpad prism based on the cGMP concentration and the 665 / 615 ratio.

[0336] (2) Conversion of HTRF (homogeneous time-resolved fluorescence) ratio (665 / 615) into cGMP concentration: In Graphpadprism, copy the HTRF ratio (665 / 615) into the ratio column of the cGMP standard curve, run the analysis “Loginhibitor vs response-variable slope”, select “interpolate”, and convert the HTRF ratio (665 / 615) into cGMP concentration.

[0337] (3) Compound activation curve: The curve was drawn based on the converted cGMP concentration and the compound concentration using the “Log agonist vs response-variable slope” analysis method in Graphpad prism.

[0338] The MEC values ​​of the sGC stimulating activity of the compounds of the present application are shown in Table 1:

[0339] Table 1 MEC values ​​of the sGC stimulating activity of the compounds of the present application

[0340]

[0341]

[0342] MEC: Minimum effective concentration that stimulates cGMP production (three times greater than basal value) in lnCap cells.

[0343] Conclusion: The compounds of the present application can effectively stimulate sGC and significantly increase cGMP levels.

[0344] Experimental Example 2: In vivo pharmacokinetic properties study

[0345] Objective: The purpose of this study was to determine the pharmacokinetic parameters of the compound in male SD rats.

[0346] Experimental Materials:

[0347] Sprague Dawley rats (male, 200-300 g, 7-9 weeks old, Shanghai Slake)

[0348] Experimental methods:

[0349] This project used 4 male SD rats. One group of 2 SD rats received intravenous administration, with a dose of 0.3 mg / kg and a concentration of 0.15 mg / mL. Another group of 2 SD rats received oral administration, with a dose of 1 mg / kg and a concentration of 0.2 mg / mL. Plasma samples were collected at 0.083 (only intravenous group), 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration, and then the collected samples were analyzed by LC-MS / MS and data were collected. The collected analytical data were used to calculate relevant pharmacokinetic parameters using Phoenix WinNonlin6.3 software.

[0350] The experimental results are shown in Table 2.

[0351] Table 2 In vivo pharmacokinetic experimental results

[0352]

[0353] Conclusion: The compounds of the present application have good apparent distribution volume and half-life.

[0354] Experimental Example 3: Tissue Distribution Test: Tissue Distribution Study in Animals

[0355] Purpose: To test the distribution ratio of the compound in plasma, heart, cerebrospinal fluid and brain tissue under oral administration.

[0356] Experimental Materials:

[0357] Sprague Dawley rats (male, 200-300 g, 7-9 weeks old, Shanghai Slake)

[0358] Experimental methods:

[0359] This project used 6 male SD rats for oral administration, with a dose of 1 mg / kg and a concentration of 0.2 mg / mL; cerebrospinal fluid, brain, heart tissue and plasma samples were collected 2, 6 and 12 hours after administration, and then the collected samples were analyzed by LC-MS / MS and data were collected. The collected analysis data were used to calculate the relevant pharmacokinetic parameters using Phoenix WinNonlin 6.3 software.

[0360] The experimental results are shown in Table 3.

[0361] Table 3 In vivo tissue distribution results

[0362]

[0363] ND:Below detection limit.

[0364] Conclusion: The compounds of the present application have no risk of entering the brain and have good cardiac distribution.

Claims

1. A compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, R1 is selected from H, -OH, C 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Alkylamino; R2 is selected from benzyl or C 1-8 Alkyl, benzyl or C 1-8 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 halogen atoms; R3 and R4 are each independently selected from H or C 1-3 alkyl; Or R3 and R4 and the atoms they are connected to form C 3-6 Cycloalkyl; Provided that the compound is not selected from the following structures, stereoisomers thereof or pharmaceutically acceptable salts thereof:

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from H, -OH, C 1-3 Alkyl or C 1-3 Alkoxy; optionally, R1 is selected from H, -OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy or isopropoxy; optionally, R1 is selected from H, -OH, methyl or methoxy.

3. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R2 is selected from benzyl or C 1-6 Alkyl, benzyl or C 1-6 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 halogen atoms; optionally, R2 is selected from benzyl or C 1-4 Alkyl, benzyl or C 1-4 The alkyl group is optionally substituted by 1, 2, 3, 4 or 5 halogen atoms; optionally, R2 is selected from benzyl or C 1-4 Alkyl, benzyl or C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 F, Cl or Br atoms; optionally, R2 is selected from benzyl or C 1-4 Alkyl, benzyl or C 1-4 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 F atoms; optionally, R2 is selected from 4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R3 and R4 are each independently selected from H, methyl, ethyl, n-propyl or isopropyl, or R3 and R4 and the atoms to which they are commonly connected form a cyclopropane group; optionally, R3 and R4 are each independently selected from H or methyl, or R3 and R4 and the atoms to which they are commonly connected form a cyclopropane group.

5. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 6. The compound of the following formula, its stereoisomer or its pharmaceutically acceptable salt:

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

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

9. Use of the compound according to any one of claims 1 to 7, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8 in the preparation of a drug for treating diseases associated with sGC agonists or stimulants.

10. The use according to claim 9, wherein The sGC agonist or stimulator-related disease is selected from heart failure or hypertension.

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