Pyrimidine tricyclic derivatives and their use in pharmacy

Abstract

The application discloses a pyrimidine tri-nuclear ring derivative and its pharmaceutical application, and particularly discloses a compound shown in formula (I), stereoisomers of the compound and pharmaceutically acceptable salts of the compound.

Description

[0001] This application is a divisional application of the Chinese Invention Patent Application with the application date of October 13, 2022, the application number of 202280067441.6, and the invention name of “Pyrimidine Triheterocyclic Derivatives and Their Pharmaceutical Applications”.

[0002] This application claims priority to

[0003] This application claims priority to 1) Chinese Patent Application No. 2021111941776 filed on October 13, 2021, 2) Chinese Patent Application No. 2021115653068 filed on December 20, 2021, and 3) Chinese Patent Application No. 2022111609592 filed on September 22, 2022, in the State Intellectual Property Office of China, the disclosures of which are incorporated herein in their entirety by reference. TECHNICAL FIELD

[0004] The present application relates to a pyrimidine triheterocyclic derivative and its pharmaceutical applications, in particular to a compound represented by formula (I), stereoisomers thereof and pharmaceutically acceptable salts thereof. BACKGROUND

[0005] Soluble guanylate cyclase (sGC) is widely present in the cytosol of mammalian cells and is a heterodimer composed of two subunits, alpha and beta. Soluble guanylate cyclase is a key signal transduction enzyme in the NO-sGC-cGMP signaling pathway. sGC, when activated in vivo, catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP is an important secondary messenger molecule that activates various effector molecules downstream, such as cGMP-dependent protein kinase G and cGMP-gated ion channels, and then triggers 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 vasodilation 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, arteriosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual dysfunction. In the past two years, studies have shown that abnormalities in the sGC-mediated signaling pathway 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 can act independently of NO, but require the presence of a Fe 2+The sGC stimulator directly activates the sGC-cGMP signaling pathway by mimicking the action of the heme prosthetic group of sGC. It also enhances the sensitivity of sGC to endogenous NO, thus synergizing with NO production. Therefore, the sGC stimulator is a heme-dependent, NO-independent sGC stimulator. Stimulation of sGC to produce more cGMP can regulate a variety of important physiological processes: promoting vasodilation of vascular smooth muscle, inhibiting platelet aggregation, etc. In addition, activation of sGC can also regulate other signaling pathways, such as TGF-β, to exert anti-fibrosis and anti-tumor effects. Therefore, the sGC stimulator can be used as a potential therapeutic agent for the treatment of cardiovascular diseases (heart failure, pulmonary arterial hypertension, angina pectoris, myocardial infarction) and fibrosis diseases (renal fibrosis, systemic sclerosis).

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

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

[0009]

[0010] wherein,

[0011] R1is selected from H, -OH, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylamino;

[0012] R2is selected from benzyl or C 1-8 alkyl, said benzyl or C 1-8 alkyl is optionally substituted with 1, 2, 3, 4 or 5 halogen atoms;

[0013] R3, R4are each independently selected from H or C 1-3 alkyl;

[0014] or R3and R4and the atoms to which they are both attached form a C 3-6 cycloalkyl;

[0015] provided that the compound is not selected from the following structures, a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0016]

[0017] In some embodiments of the present application, the above R1is selected from H, -OH, C 1-3 alkyl or C 1-3alkyl, said alkyl being optionally substituted with 1, 2, 3, 4, or 5 halogen atoms, and other variables are as defined in the application.

[0018] In some embodiments of the application, the above R1is selected from H, -OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, or isopropoxy, and other variables are as defined in the application.

[0019] In some embodiments of the application, the above R1is selected from H, -OH, methyl, or methoxy, and other variables are as defined in the application.

[0020] In some embodiments of the application, the above R2is selected from benzyl or C 1-6 alkyl, said alkyl being optionally substituted with 1, 2, 3, 4, or 5 halogen atoms, and other variables are as defined in the application. 1-6 alkyl, said alkyl being optionally substituted with 1, 2, 3, 4, or 5 halogen atoms, and other variables are as defined in the application.

[0021] In some embodiments of the application, the above R2is selected from benzyl or C 1-4 alkyl, said alkyl being optionally substituted with 1, 2, 3, 4, or 5 halogen atoms, and other variables are as defined in the application. 1-4 alkyl, said alkyl being optionally substituted with 1, 2, 3, 4, or 5 halogen atoms, and other variables are as defined in the application.

[0022] In some embodiments of the application, the above R2is selected from benzyl or C 1-4 alkyl, said alkyl being optionally substituted with 1, 2, 3, 4, or 5 halogen atoms, and other variables are as defined in the application. 1-4 alkyl, said alkyl being optionally substituted with 1, 2, 3, 4, or 5 halogen atoms, and other variables are as defined in the application.

[0023] In some embodiments of the application, the above R2is selected from benzyl or C 1-4 alkyl, said alkyl being optionally substituted with 1, 2, 3, 4, or 5 halogen atoms, and other variables are as defined in the application. 1-4 alkyl, said alkyl being optionally substituted with 1, 2, 3, 4, or 5 halogen atoms, and other variables are as defined in the application.

[0024] In some embodiments of the application, the above R2is selected from C 1-4 alkyl, said alkyl being optionally substituted with 1, 2, 3, 4, or 5 halogen atoms, and other variables are as defined in the application. 1-4 alkyl, said alkyl being optionally substituted with 1, 2, 3, 4, or 5 halogen atoms, and other variables are as defined in the application.

[0025] In some embodiments of the application, the above R2is selected from C 1-4 alkyl, said alkyl being optionally substituted with 1, 2, 3, 4, or 5 halogen atoms, and other variables are as defined in the application. 1-4 alkyl, said alkyl being optionally substituted with 1, 2, 3, 4, or 5 halogen atoms, and other variables are as defined in the application.

[0026] In some embodiments of the application, the above R2is selected from C 1-4 alkyl, said alkyl being optionally substituted with 1, 2, 3, 4, or 5 halogen atoms, and other variables are as defined in the application. 1-4 alkyl, said alkyl being optionally substituted with 1, 2, 3, 4, or 5 halogen atoms, and other variables are as defined in the application.

[0027] In some embodiments of the application, R2is selected from benzyl substituted with one fluoro, or n-butyl substituted with five fluoro, and the other variables are as defined herein.

[0028] In some embodiments of the application, R2is selected from and the other variables are as defined herein.

[0029] In some embodiments of the application, R3, R4are each independently selected from H, methyl, ethyl, n-propyl, or i-propyl, or R3and R4, together with the atom to which they are both attached, form a cyclopropane group, and the other variables are as defined herein.

[0030] In some embodiments of the application, R3, R4are each independently selected from H or methyl, or R3and R4, together with the atom to which they are both attached, form a cyclopropane group, and the other variables are as defined herein.

[0031] In some embodiments of the application, the structural unit is selected from and the other variables are as defined herein.

[0032] The application also provides some embodiments of the application that are combinations of any of the above variables.

[0033] The application also provides a compound, stereoisomer, or pharmaceutically acceptable salt thereof, selected from:

[0034]

[0035] The application also provides a compound, stereoisomer, or pharmaceutically acceptable salt thereof, selected from:

[0036]

[0037]

[0038] In another aspect, the application provides a pharmaceutical composition comprising a compound of the application, stereoisomer, or pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition of the application further comprises a pharmaceutically acceptable excipient.

[0039] In another aspect, the application provides the use of a compound, stereoisomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of a sGC agonist or stimulator related disease.

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

[0041] In another aspect, the present application provides the use of a compound of the present application, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating a sGC agonist or stimulator related disease.

[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 use in treating a sGC agonist or stimulator related disease.

[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 volume of distribution and half-life, have good cardiac distribution and no risk of entering the brain.

[0046] Definitions and descriptions

[0047] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as undefined or unclear unless specifically defined, but should be interpreted in accordance with the ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0048] The term "pharmaceutically acceptable" as used herein, pertains 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 problem or complication, commensurate with a reasonable benefit / risk ratio.

[0049] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application, which is prepared from a compound of the present application having a particular substituent with a relatively nontoxic acid or base. When a compound of the present application contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of the base in a pure solution or in a suitable inert solvent. When a compound of the present application contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of the acid in a pure solution or in a suitable inert solvent. Certain specific compounds of the present application contain both basic and acidic functionalities and, as such, can be converted into either base or acid addition salts.

[0050] The pharmaceutically acceptable salts of the present application can be synthesized from the parent compound that contains an acid or a base moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two.

[0051] The term "isomers" is meant to include geometric isomers, cis / trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers, and tautomers, unless otherwise indicated.

[0052] The compounds of the present application can exist in particular 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, as well as the racemic mixtures and other mixtures of the enantiomers or diastereomers, and all such isomers are intended to be within the scope of the present application. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as, their mixtures are intended to be within the scope of the present application.

[0053] The term "enantiomers" or "optical isomers" means stereoisomers that are mirror images of one another unless otherwise indicated.

[0054] The term "cis-trans isomers" or "geometric isomers" means stereoisomers that differ in the orientation of substituents around a carbon-carbon single bond or a ring atom, as a result of which they are not superimposable.

[0055] The term "diastereomers" means stereoisomers that have two or more chiral centers and are not mirror images of one another.

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

[0057] Unless otherwise indicated, the absolute configuration of a stereogenic center is indicated by a wedged and dashed wedge bond and the relative configuration of a stereogenic center is indicated by a straight or dashed bond and a wavy line indicates a wedged or dashed wedge bond or a wavy line indicates a straight or dashed bond

[0058] The terms "enantiomerically enriched," "enantiomeric excess," "enantiomeric excess" or "enantiomeric excess" refer to the difference between the relative percentages of two enantiomers, unless otherwise indicated. For example, where one enantiomer is present in an amount of 90% and the other enantiomer is present in an amount of 10%, the enantiomeric excess (ee value) is 80%.

[0059] The terms "enantiomerically enriched," "enantiomeric excess," "enantiomeric excess" or "enantiomeric excess" refer to the difference between the relative percentages of two enantiomers, unless otherwise indicated. For example, where one enantiomer is present in an amount of 90% and the other enantiomer is present in an amount of 10%, the 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 application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide the pure desired enantiomeric isomer. Alternatively, when a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group) is present in the molecule, a diastereomeric salt form of the compound with an appropriate optically active acid or base can be formed, and the desired enantiomer recovered by conventional meansafforded the pure enantiomer. In addition, separation of enantiomers and diastereomers is typically accomplished by chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (e.g., formation of a carbamate from an amine).

[0061] The compounds of the application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). For example, deuterium can be substituted for hydrogen to form deuterated drugs, which have advantages over non-deuterated drugs, such as reduced toxicity, increased stability, increased efficacy, increased biological half-life, etc. All isotopic variations of the compounds of the application, whether radioactive or not, are encompassed within the scope of the present application.

[0062] The term "optionally" or "optional" means that the subsequently described event or circumstance may or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0063] The term "substituted" means that any one or more hydrogen atoms on the designated atom is replaced with a substituent, which can include deuterium and variations of hydrogen, provided that the valence of the designated atom is not thereby normal and that the substituted compound is stable. When the substituent is oxygen (i.e., =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that the moiety can or can not be substituted and that the types and number of substituents, if present, are optional on a chemically feasible basis.

[0064] When any variable (e.g., R) occurs more than one time in a compound; each definition is independent. Thus, for example, if a group is substituted with 0-2 R groups, then the group is optionally substituted with up to two R groups, and at each occurrence R is selected independently. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

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

[0066] When the number of occurrences of a substituent is zero, it means that the substituent is absent, such as -A-(R)0 means that the structure is actually -A.

[0067] When a substituent is null, it means that the substituent is absent, such as X is null in A-X 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 to which it is attached are directly connected, such as L represents a single bond in A-L-Z means that the structure is actually A-Z.

[0069] When a substituent can be attached via more than one atom to a ring, then the substituent can be attached via any of the available atoms, for example, the structural element means that the substituent R can be attached to the ring at any of the available positions. When a listed substituent is not designated as being attached to a substituted group via a particular atom, then the substituent can be attached via any of the available atoms, for example, a pyridyl group as a substituent can be attached to a substituted group via any of the carbon atoms of the pyridyl ring.

[0070] When the recited linking group does not indicate its direction of attachment, its direction of attachment is arbitrary, e.g. When the linking group L is -M-W-, then -M-W- can attach ring A and ring B to form the compound of formula (I) either in the same direction as the reading order from left to right or in the opposite direction as the reading order from left to right Combinations of the recited linking groups, substituents, and / or variations thereof are only permitted if such combinations result in stable compounds.

[0071] Unless otherwise specified, when a group has one or more attachment sites, any one or more of the sites of the group can be attached to other groups by a chemical bond. When the attachment of the chemical bond is not defined and there is an H atom at the site, the number of H atoms at the site is reduced by one for each chemical bond that is attached to the site, resulting in a group of the corresponding valence. The chemical bond that attaches the site to other groups can be represented by a straight solid line a straight dashed line or a wavy line. For example, the straight solid line in -OCH3represents attachment to other groups through the oxygen atom in the group; the straight dashed line in -NH2represents attachment to other groups through both ends of the nitrogen atom in the group; and the wavy line in -Ph represents attachment to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; represents that any of the attachment sites on the piperidinyl group can be attached to other groups by one chemical bond, including at least This includes This includes

[0072] Unless otherwise specified, the term "alkyl" is used to denote straight chain or branched chain, saturated carbon hydride groups. In some embodiments, the alkyl group is a C 1-8 alkyl group; in other embodiments, the alkyl group is a C 1-4 alkyl group; in other embodiments, the alkyl group is a C 1-3 ​​Alkyl. It can be mono-substituted (e.g., -CH2F) or poly-substituted (e.g., -CF3), and it can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, and t-butyl), pentyl (including n-pentyl, isopentyl, and neopentyl), hexyl, and the like.

[0073] Unless otherwise specified, the term "C 1-4 Alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of from 1 to 4 carbon atoms. The C 1-4 alkyl group includes C 1-2 , C 1-3 , and C 2-3 alkyl groups and the like; it can be monovalent, divalent, or polyvalent. Examples of C 1-4 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 denote a straight or branched chain saturated hydrocarbon group consisting of from 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 , and C 2-3 alkyl groups and the like; it can be monovalent, divalent, or polyvalent. Examples of C 1-3 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" denotes -NH-C 1-3 alkyl.

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

[0077] Unless otherwise specified, the term "halogen" or "halo" by itself or as part of another substituent is meant to include fluorine, chlorine, bromine, or iodine atoms.

[0078] The compounds of the present application can be prepared by a variety of synthetic processes known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the embodiments set forth below with other chemical synthetic processes known to those skilled in the art, and equivalents thereof known to those skilled in the art, preferred embodiments including, but not limited to, the examples of the present application.

[0079] The compounds of the present application can be confirmed by conventional methods known to those skilled in the art, and if the present application relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional techniques known in the art. For example, single crystal X-ray diffraction (SXRD), the diffraction intensity data of the single crystal grown is collected by a Bruker D8 venture diffractometer, the light source is Cu Ka radiation, the scanning mode is φ / ω scanning, after collecting the relevant data, the crystal structure is further analyzed by direct method (Shelxs97), and the absolute configuration can be confirmed.

[0080] The solvents used in the present application are commercially available. 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 nuclear magnetic resonance hydrogen spectrum; MS represents mass spectrum; min represents minutes; pH represents negative logarithm of hydrogen ion molar concentration; AlMe3 represents trimethylaluminum; TFA represents trifluoroacetic acid; DMSO represents dimethyl sulfoxide.

[0081] The term "treatment" means the administration of a 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 the disease or condition, i.e., arresting its development;

[0083] (ii) relieving the disease or condition, i.e., causing the disease or condition to regress.

[0084] The term "prevention" means the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes: preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the disease or condition but has not yet been diagnosed as having it.

[0085] The term "therapeutically effective amount" means an amount of a compound of the present application that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of the present application that will constitute a "therapeutically effective amount" will depend on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can readily be determined by one of ordinary skill in the art, according to his own knowledge and experience and according to the teachings contained in the disclosure. DETAILED DESCRIPTION

[0086] The present application is described in detail below by way of Examples, but it is not meant to be limited by any of the Examples. The present application has been described in detail by specifically exemplifying the embodiments thereof, and it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the present application. All reagents used in the present application are commercially available and used without further purification.

[0087] Examples 1 and 2

[0088]

[0089] Synthetic route:

[0090]

[0091] Step 1: Synthesis of compound 001_2

[0092] Compound 001_1 (100 g, 380.21 mmol) was added to N,N-dimethylformamide (1 L) at room temperature, followed by the addition of 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 column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 15 / 1, by volume) to obtain compound 001_2.

[0093] Step 2: Synthesis of compound 001_3

[0094] Compound 001_2 (30 g, 73.34 mmol) was added into methanol (100 mL) and N,N- dimethylformamide (300 mL) under room temperature and nitrogen atmosphere, and then (diphenyl- phosphino)ferrocenepalladium dichloride (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 under nitrogen atmosphere (15 Psi) for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-10 / 1, volume ratio) to obtain compound 001_3.

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

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

[0097] Step 4: Synthesis of compound 001_6

[0098] Compound 001_5 (5 g, 56.71 mmol) was dissolved in dry toluene (20 mL) under room temperature and nitrogen atmosphere, and then 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 precipitation. After the reaction was completed, the suspension was filtered, and the filter cake was washed with toluene (50 mL), and the solid was collected and dried under reduced pressure. Compound 001_6 was obtained.

[0099] Step 5: Synthesis of compound 001_8

[0100] Compound 001_7 (2.7 g, 18.73 mmol) was dissolved in dichloromethane (50 mL) at room temperature, and then N,N-diisopropylethylamine (7.26 g, 56.20 mmol), tri-n-propyl phosphite (50% ethyl acetate solution) (17.88 g, 28.10 mmol) and compound 001_6 (4.29 g, 20.61 mmol) were added after cooling to 0 °C. The reaction system was stirred at 25 °C for 12 hours. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium bicarbonate solution (100 mL), and extracted with ethyl acetate (50 mL x 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] Compound 001_8 (8.0 g, 31.58 mmol) was dissolved in methanol (500 mL) and water (50 mL) at room temperature under nitrogen protection, and potassium monopersulfate (58.25 g, 94.74 mmol) was added. The reaction system was stirred at 25 °C for 12 hours. After the reaction was completed, the reaction solution was poured into saturated aqueous sodium sulfite solution (50 mL), and extracted with ethyl acetate (20 mL x 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 / 0 - 4 / 1, volume ratio) to obtain compound 001_9.

[0103] Step 7: Synthesis of compound 001_10

[0104] Compound 001_9 (5 g, 26.86 mmol) was dissolved in anhydrous methanol (50 mL) at room temperature under nitrogen protection, and malononitrile (2.13 g, 32.23 mmol) and ammonium acetate (4.14 g, 53.72 mmol) were added. The reaction system was heated to 60 °C under nitrogen protection and stirred for 4 hours. The reaction solution was poured into saturated aqueous ammonium chloride solution (70 mL), and extracted with ethyl acetate (20 mL x 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 / 0 - 5 / 1, volume ratio) to obtain compound 001_10.

[0105] Step 8: Synthesis of compound 001_11

[0106] Compound 001_10 (1.1 g, 4.70 mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen protection, and the solution was cooled to 0 °C. Methyl magnesium bromide in toluene (3 M, 3.13 mL) was added dropwise. After the addition was completed, the mixture was stirred for 15 min. After the reaction was completed, the mixture was poured into saturated aqueous ammonium chloride solution (50 mL), and extracted with ethyl acetate (20 mL x 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 give compound 001_11.

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

[0108] Compound 001_4 (1 g, 2.76 mmol, hydrochloride) was dissolved in tert-butanol (20 mL) under nitrogen protection at room temperature, and compound 001_11 (1 g, 4.00 mmol) and potassium bicarbonate (692.06 mg, 6.91 mmol) were added. The reaction system was heated to 85 °C and stirred for 12 h. After the reaction was completed, the reaction solution was cooled to room temperature and poured into water (70 mL), and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL), 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) to give a mixture of 001_12 and 001_13.

[0109] Step 10: Synthesis of compound 001_14

[0110] The mixture of 001_12 and 001_13 (500 mg, 920.10 µmol) was dissolved in toluene (5 mL) under nitrogen protection at room temperature, and trimethylaluminum in toluene (2 M, 1.38 mL) was added. The reaction system was heated to 75 °C and stirred for 5 h. After the reaction was completed, the reaction system was cooled to room temperature, and diluted with ethyl acetate (20 mL). The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1, volume ratio), and then separated by preparative HPLC (column: Phenomenex luna C18 (80 mm*30 mm I.D., 3 µm); mobile phase: A: ACN, B: [H2O (containing 0.04% HCl)], gradient: B%: 30%-70%, 8 min) to give compound 001_14. MS–ESI m / z: 512.0 [M+H] + .1 H NMR (400 MHz, DMSO-d6) d: 11.52 (s, 1H), 11.29 (s, 1H), 8.81 - 8.68 (m, 2H), 4.91 (t, J = 6.7 Hz, 2H), 3.00 (tt, J = 6.6, 19.1 Hz, 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 (250mm*30mm, 10pm); mobile phase: [EtOH (containing 0.1% NH3H20)]%: 35%-35%, 7min). Compound 001 and 002 were obtained.

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

[0114] 001 (ret. time: 0.900 min): MS - ESI m / z: 512.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d: 11.52 (s, 1H), 11.34 - 11.24 (m, 1H), 8.82 - 8.68 (m, 2H), 4.91 (t, J = 6.5 Hz, 2H), 3.09 - 2.91 (m, 2H), 1.55 (ddd, J = 4.4, 6.0, 10.0 Hz, 1H), 1.44 (s, 3H), 1.20 - 1.08 (m, 1H), 0.81 - 0.64 (m, 2H);

[0115] 002 (ret. 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] Compound 001_10 (1.5 g, 6.40 mmol) was dissolved in chloroform (10 mL) and ethanol (10 mL) at room temperature and under nitrogen protection. Diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate (2.43 g, 9.61 mmol) was added to the reaction system. The reaction mixture was stirred at 25 °C for 12 hours under nitrogen protection. After the reaction was completed, the reaction mixture 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, and then filtered and concentrated. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0–1 / 1, v / v) to obtain compound 003_1.

[0122] Step 2: Synthesis of compound 003_2

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

[0124] Step 3: Synthesis of compound 003_3

[0125] Compound 003_2 (500 mg, 944.48 µmol) was dissolved in anhydrous methanol (10 mL) under room temperature and nitrogen protection, and bis(trifluoroacetic acid)iodobenzene (2.03 g, 4.72 mmol) was added. The reaction was stirred at 50 °C for 6 h. The reaction was poured into saturated aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate (30 mL x 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 / 0-1 / 1, volume ratio). Compound 003_3 was obtained.

[0126] Step 4: Synthesis of compound 003_4

[0127] Compound 003_3 (150 mg, 268.13 µmol) was dissolved in anhydrous toluene (2 mL) under room temperature and nitrogen protection, and trimethylaluminum toluene solution (2 M, 429.02 µL) was added. The reaction was warmed to 80 °C and stirred for 6 h. After the reaction was completed, the reaction was cooled to room temperature, and dilute hydrochloric acid (1 N, 10 mL) was slowly added to quench the reaction. The reaction was extracted with 2-methyltetrahydrofuran (50 mL x 4), and the organic phase was combined. The organic phase was washed with half-saturated brine (10 mL x 2), saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated and purified by column chromatography (eluent: petroleum ether / 2-methyltetrahydrofuran = 1 / 0-1 / 1, volume ratio) and preparative HPLC (column: Phenomenex luna C18 (80 mm*30 mm I.D., 3 µm); mobile phase: A: ACN, B: [H2O (containing 0.04% HC1)], gradient: B%: 30%-55%, 8 min) to obtain compound 003_4. MS–ESI m / z: 527.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 11.77 (s, 1H), 11.48 (s, 1H), 8.85-8.65 (m, 2H), 4.93 (t, J = 6.8 Hz, 2H), 3.19 (s, 3H), 3.10-2.92 (m, 2H), 1.63 (ddd, J = 4.2, 6.8, 9.6 Hz, 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 pmol) was separated by chiral column (column type: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 pm); mobile phase: A: CO2, B: [Neu-IPA], gradient: B%: 25%-25%, 10 min). Compound 003 and 004 were obtained.

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

[0131] 003 (ret. time: 0.997 min): MS - ESI m / z: 527.9 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) d: 11.77 (s, 1H), 11.47 (s, 1H), 8.82 - 8.70 (m, 2H), 4.93 (t, J = 6.8 Hz, 2H), 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 (ret. time: 1.075 min): MS - ESI m / z: 528.2 [M+H] + . 1 H NMR (400 MHz, DMSO_d6) d: 11.88 - 11.70 (m, 1H), 11.46 (br s, 1H), 8.83 - 8.69 (m, 2H), 4.93 (t, J = 6.8 Hz, 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] Potassium tert-butoxide tetrahydrofuran solution (1 M, 276.95 mL) was added to toluene (2 L) at room temperature, then compound 005_1 (50 g, 247.28 mmol, 45.87 mL) was added, finally iodomethane (228.14 g, 1.61 mol, 100.06 mL) and crown ether-6 (6.54 g, 24.73 mmol) were added. The reaction was stirred at 25 °C for 12 h. The reaction was quenched by adding to 500 mL of 25% ammonia water, and 1 L of water was added. The organic phase was extracted with ethyl acetate (1 L x 2), and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column 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] Compound 005_2 (20 g, 92.49 mmol) and malononitrile (24.44 g, 369.98 mmol) were added to ethanol (200 mL) at room temperature, then pyridine (36.58 g, 462.47 mmol, 37.33 mL) was added. The reaction was stirred at 70 °C for 12 h. The reaction was concentrated under reduced pressure, then dissolved in ethyl acetate (200 mL), and the pH was adjusted to 5-6 with 3 M aqueous hydrochloric acid solution, and the liquid was separated. The aqueous phase was extracted with ethyl acetate (100 mL x 2), and the organic phase was combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was separated by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-6 / 1, volume ratio). Compound 005_3 was obtained. 1 H NMR (400 MHz, CDCl3) δ: 4.42 (q, J = 7.2 Hz, 2H), 4.25 (q, J = 7.2 Hz, 2H), 1.61-1.66 (m, 6H), 1.39-1.47 (m, 6H).

[0142] Step 3: Synthesis of compound 005_4

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

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

[0145] Compound 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 the addition of potassium carbonate (2.03 g, 14.67 mmol). The reaction mixture was stirred at 85 °C for 12 h. After the reaction was completed, the reaction was cooled to room temperature, diluted with water (30 mL), extracted with dimethyltetrahydrofuran (30 mL x 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. To the residue was added 30 mL of methyl tert-butyl ether, and stirring was performed at 20 °C for 1 h, during which time a solid was produced. The reaction 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] A mixture of 005_5 and 005_6 (2.36 g, 4.33 mmol) was added to toluene (25 mL) at room temperature under nitrogen protection, followed by the addition of a toluene solution (2 M, 6.92 mL) of trimethylaluminum, and the reaction was warmed to 80 °C and stirred for 12 h. The reaction was cooled to room temperature, adjusted to pH 5-6 with 3 M HCl, extracted with ethyl acetate (25 mL x 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. To the residue was added methyl tert-butyl ether (10 mL), and stirring was performed at 25 °C for 1 h. The reaction was filtered and concentrated under reduced pressure to obtain compound 005. MS - ESI m / z: 500.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ: 11.50 (s, 1H), 11.10-11.19 (m, 1H), 8.75 (dd, J = 2.58, 1.58 Hz, 1H), 8.72 (dd, J = 8.7, 2.8 Hz, 1H), 4.90 (t, J = 6.8 Hz, 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] Synthetic route:

[0151]

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

[0153] Compound 005 (660 mg, 1.32 mmol) was added into tetrahydrofuran (6 mL) and acetonitrile (3 mL) at room temperature under nitrogen protection, followed by the addition of methanol (169.39 mg, 5.29 mmol), 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 was stirred at 80 °C for 2 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, which was extracted with ethyl acetate (10 mL x 2), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was separated by preparative HPLC (column type: Phenomenex luna C18 (80 mm*30 mm I.D., 3 μm); mobile phase: A: ACN, B: [H2O (containing 0.04% HC1)], gradient: B%: 25%-50%, 8 min). Compound 006_1 and 008_1 were obtained.

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

[0155] Compound 008_1: MS - ESI m / z: 516.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ: 11.49 (s, 1H), 11.19 (s, 1H), 8.76 (dd, J = 2.8, 1.6 Hz, 1H), 8.70 (dd, J = 8.8, 2.8 Hz, 1H), 6.63 (br s, 1H), 4.86 - 4.98 (m, 2H), 3.00 (tt, J = 19.2, 6.4 Hz, 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 pmol) was separated by chiral column (column type: REGIS (S, S) WHELK-O1 (250 mm * 25 mm, 10 pm); mobile phase: A: CO2, B: [IPA (containing 0.1% NH3H2O)], gradient: B%: 25%-25%, 7 min). Compound 006 and 007 were obtained.

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

[0159] 006 (retention time: 1.518 min): MS - ESI m / z: 530.2 [M+H] + .1H NMR (400 MHz, DMSO-d6) δ: 11.33 (br s, 1H) 11.70 - 12.03 (m, 1H) 8.77 (dd, J = 2.4, 1.6 Hz, 1H) 8.71 (dd, J = 8.8, 2.8 Hz, 1H), 4.93 (t, J = 6.72 Hz, 2H), 3.16 (s, 3H), 3.00 (tt, J = 19.2, 7.2 Hz, 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 pmol) was separated by chiral column (column type: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 pm); mobile phase: A: CO2, B: [MeOH (with 0.1% NH3H2O)]; gradient: B%: 30%-30%, 10 min). Compound 008 and 009 were obtained.

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

[0163] 008 (retention time: 1.008 min): MS - ESI m / z: 516.2 [M+H] + .1H NMR (400 MHz, DMSO-d6) δ: 11.48 (s, 1H), 11.19 (s, 1H), 8.77 (dd, J = 2.8, 1.6 Hz, 1H), 8.70 (dd, J = 8.4, 2.8 Hz, 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 (400 MHz, 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, 2.8 Hz, 1H), 6.62 (s, 1H), 4.92 (br t, J = 6.4 Hz, 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] Compound 005_1 (50 g, 247.28 mmol) was dissolved in toluene (500 mL) at room temperature, and malononitrile (16.34 g, 247.28 mmol), β-aminopropionic acid (660.92 mg, 7.42 mmol) and acetic acid (14.85 g, 247.28 mmol) were added thereto. The reaction system was warmed to 130 °C and stirred for 12 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate solution (500 mL), and the liquid was separated. The aqueous phase was extracted with ethyl acetate (100 mL x 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 the nitrogen was replaced three times. The reaction system was cooled to 0 °C, and methyl magnesium bromide in ether (3 M, 13.99 mL) was slowly added dropwise. The reaction system was stirred at 0 °C for 15 minutes. The reaction system was poured into saturated ammonium chloride solution (100 mL), and ethyl acetate (50 mL x 3) was added to extract, and the organic phases were combined. The organic phase was washed with half-saturated brine (10 mL x 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 / 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 salt) in tert-butanol (50 mL), add compound 010_2 (4.4 g, 16.52 mmol) and potassium bicarbonate (2.42 g, 24.19 mmol) to it, and stir the reaction system at 85 °C for 12 hours. Pour the reaction solution into water (100 mL), and extract with ethyl acetate (50 mL x 3). Wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate. Purify the obtained residue by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 1 / 1 by volume ratio). Obtain a mixture of compound 010_3 and 012_1. Step 4: Synthesis of compound 010_4 and 010_6

[0175] Dissolve the above mixture (800.00 mg, 1.47 mmol) in toluene (10 mL), replace nitrogen three times, add a toluene solution of trimethylaluminum (2 M, 2.20 mL) to the reaction system, and stir the reaction system at 75 °C for 5 hours. After the reaction is completed, cool the reaction system to room temperature, add dilute hydrochloric acid (1 N 10 mL) to quench the reaction, dilute with ethyl acetate (50 mL), separate the phases, collect the organic phase, extract the aqueous phase with ethyl acetate (50 mL x 3), and combine the organic phases. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to remove the solvent to obtain a crude product. Purify the obtained residue by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0 - 2 / 1 by volume ratio) and preparative HPLC (column type: Phenomenex luna C18 (250 mm*50 mm I.D., 10 μm); mobile phase: A: ACN, B: [H2O (containing 0.04% HCl)], gradient: B%: 30% - 60%, 10 min) to obtain compound 010_4 and 010_6.

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

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

[0178] 010_6 (Retention time: 2.848 min) MS - ESI m / z: 500.0 [M+H] + 1H NMR (400 MHz, DMSO-d6) d: 11.42 (s, 1H), 11.09 (s, 1H), 8.82 - 8.65 (m, 2H), 4.91 (t, J = 6.6 Hz, 2H), 3.09 - 2.89 (m, 3H), 1.25 (t, J = 3.4 Hz, 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 pm); Mobile phase: A: CO2, B: [EtOH (containing 0.1% NH3H2O)]; Gradient: B%: 38%-38%, 6 min). Compound 010 and 011 were obtained.

[0181] SFC analysis method: Column type: Chiralpak AD-3 (50 mm*4.6 mm I.D., 3 pm); Mobile phase: A: CO2, B: [EtOH (containing 0.1% IPAm)]; Gradient: B%: 5%-50%, 3 min.

[0182] Compound 010 (Retention time: 1.00 min): MS - ESI m / z: 500.0 [M+H] + 1H NMR (400 MHz, DMSO-d6) d: 11.41 (br s, 1H), 11.09 (br s, 1H), 8.82 - 8.59 (m, 2H), 4.90 (t, J = 6.8 Hz, 2H), 3.13 - 2.87 (m, 3H), 1.25 (t, J = 3.2 Hz, 6H);

[0183] Compound 011 (retention time: 1.311 min): MS - ESI m / z: 500.0 [M+H] + .1H NMR (400 MHz, DMSO-d6) d: 11.42 (s, 1H), 11.09 (s, 1H), 8.75 (dd, J = 1.6, 2.8 Hz, 1H), 8.71 (dd, J = 2.8, 8.6 Hz, 1H), 4.91 (t, J = 6.8 Hz, 2H), 3.13 - 2.91 (m, 3H), 1.31 - 1.19 (m, 6H).

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

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

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

[0187] Compound 012 (retention time: 1.087 min): MS - ESI m / z: 499.9 [M+H] + .1H NMR (400 MHz, DMSO-d6) d: 11.54 (br s, 1H), 11.23 (s, 1H), 8.75 (dd, J = 1.6, 2.8 Hz, 1H), 8.70 (dd, J = 2.8, 8.8 Hz, 1H), 4.91 (t, J = 6.8 Hz, 2H), 3.00 (tt, J = 6.4, 19.1 Hz, 2H), 2.85 - 2.76 (m, 1H), 1.41 (s, 3H), 0.80 (d, J = 7.2 Hz, 3H);

[0188] Compound 013 (retention time: 1.193 min): MS - ESI m / z: 499.9 [M+H] +1H NMR (400 MHz, DMSO-d6) d: 11.53 (br s, 1H), 11.23 (br s, 1H), 8.78 - 8.66 (m, 2H), 4.91 (t, J = 6.8 Hz, 2H), 2.99 (tt, J = 6.8, 19.2 Hz, 2H), 2.80 (q, J = 7.2 Hz, 1H), 1.41 (s, 3H), 0.80 (d, J = 7.2 Hz, 3H).

[0189] Examples 14 and 15

[0190]

[0191] Synthesis route:

[0192]

[0193] Step 1: Synthesis of compound 014_1

[0194] Compound 001_1 (300 g, 1.14 mol) was added to N,N-dimethylformamide (3 L) at room temperature under nitrogen protection, 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, filtered to obtain a 3 L N,N-dimethylformamide solution of compound 014_1 (423 g), which was used directly.

[0195] Step 2: Synthesis of compound 014_2

[0196] Compound 014_1 (70 g, 188.62 mmol) was added to a 1 L N,N-dimethylformamide solution at room temperature under nitrogen protection, followed by methanol (300 mL), 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), and stirred at 80 °C for 12 hours under the atmosphere of carbon monoxide (15 psi). 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, by volume) to obtain compound 014_2.

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

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

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

[0200] Compound 005_4 (6.58 g, 24.71 mmol) was added to tert-butyl alcohol (70 mL) under room temperature and nitrogen protection, and then the hydrochloride salt of compound 014_3 (5 g, 15.45 mmol) and potassium carbonate (5.34 g, 38.61 mmol) were added successively. The mixture was stirred at 85 °C for 12 h. The reaction was completed, and the mixture was cooled to room temperature. Water (100 mL) was added, and the mixture was extracted with dimethyltetrahydrofuran (100 mL x 2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a mixture of compounds 014_4 and 014_5.

[0201] Step 5: Synthesis of compound 014_6

[0202] The mixture of compounds 014_4 and 014_5 (7 g, 13.79 mmol) was dissolved in toluene (100 mL) under room temperature and nitrogen protection. Trimethylaluminum toluene solution (2 M, 28.97 mL) was added dropwise slowly, and the mixture was stirred at 80 °C for 12 h. The mixture was cooled to room temperature, and then was poured into water (100 mL). 3 M hydrochloric acid was added to adjust the pH to 5-6. The mixture was extracted with dimethyltetrahydrofuran (100 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was added to methyl tert-butyl ether (50 mL), stirred at 25 °C for 1 h, and then 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 added to methanol (80 mL) under room temperature and nitrogen protection, and bis(trifluoroacetic acid)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, diatomite was added to filter, to obtain a filtrate, 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 I.D., 10 μm); mobile phase: A: ACN, B: [H2O (containing 0.04% HC1)], gradient: B%: 35%-70%, 20 min) to obtain compound 014_7. MS–ESI m / z: 492.0 [M+H] +1 H NMR (400 MHz, DMSO-d6) δ 11.81 (br s, 1H), 11.26-11.39 (m, 1H), 8.77 (d, J = 1.00 Hz, 1H), 8.71 (dd, J = 8.8, 2.8 Hz, 1H), 7.35-7.43 (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).

[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 (50 mm*4.6 mm I.D., 3 μm); mobile phase: A: CO2, B: [EtOH (containing 0.1% IPAm)], gradient: B%: 5%-50%, 3 min.

[0208] 014 (retention time: 2.612 min) MS–ESI m / z: 492.0 [M+H] +1H NMR (400 MHz, DMSO-d6) δ 11.73 - 11.96 (m, 1H), 11.31 (s, 1H), 8.77 (dd, J = 2.8, 1.6 Hz, 1H), 8.71 (dd, J = 8.8, 2.8 Hz, 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 (400 MHz, DMSO-d6) δ 11.75 - 11.89 (m, 1H), 11.28 - 11.36 (m, 1H), 8.77 (d, J = 2.63 Hz, 1H), 8.71 (dd, J = 8.66, 2.76 Hz, 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).

[0210] Example 16

[0211]

[0212] Synthesis route:

[0213]

[0214] Step 1: Synthesis of compound 016

[0215] Compound 016 was obtained by the procedure described in Example 1, using compound 014_6 (500 mg, 1.08 mmol) as starting material. MS - ESI m / z: 478.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 11.38 - 11.54 (m, 1H) 11.17 (br s, 1H) 8.76 (s, 1H) 8.70 (dd, J = 8.4, 2.8 Hz, 1H) 7.33 - 7.43 (m, 1H) 7.20 - 7.31 (m, 2H) 7.15 - 7.20 (m, 1H) 6.61 (s, 1H) 5.85 (d, J = 3.2 Hz, 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 compound 017_1 and 017_2

[0221] The intermediate 014_3 hydrochloride (2.76 g) was added to tert-butanol (40 mL) under room temperature and nitrogen protection, then the intermediate 010_2 (2.72 g, 10.21 mmol) and potassium bicarbonate (2.13 g, 21.28 mmol) were added successively, and the reaction was stirred at 80 °C for 12 hours. After the reaction was completed, the reaction was cooled to room temperature, water (100 mL) was added, and dimethyltetrahydrofuran (100 mL x 2) was separated, and the organic phase was 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 the intermediate 017_1 and the intermediate 017_2.

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

[0223] The intermediate 017_1 (500.00 mg, 985.24 µmol) was dissolved in toluene (5 mL) under room temperature and nitrogen protection, and AlMe3 (2M, 1.48 mL) was added to the reaction system, and the reaction system was warmed to 75 °C and stirred for 12 hours. After the reaction was completed, the reaction system was cooled to room temperature. The reaction was poured into water (50 mL), diluted hydrochloric acid (1N) was added to adjust pH to 3-4, 2-methyltetrahydrofuran (50 mL) was added to separate, and the organic phase was collected. The aqueous phase was extracted with 2-methyltetrahydrofuran (20 mL x 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 the 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 luna C18 (80 mm*40 mm I.D., 3 µm); mobile phase: A: ACN, B: [H2O (containing 0.04% HCl)], gradient: B%: 33%-49%, 7 min) to obtain the compound 017_3.

[0224] Intermediate 017_2 (700.00 mg, 1.38 mmol) was dissolved in toluene (10 mL) at room temperature under nitrogen protection, nitrogen was replaced for three times, AlMe3 (2 M, 2.07 mL) was added into the reaction system, the reaction system was warmed 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 with 2-methyltetrahydrofuran (50 mL), the pH was adjusted to 3-4 by adding dilute hydrochloric acid (1 N), and the organic phase was collected by liquid separation. The aqueous phase was extracted with 2-methyltetrahydrofuran (50 mL x 3), the organic phase was 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) and preparative HPLC separation (mobile phase: acetonitrile / water; hydrochloric acid system: 0.04% HCl) and preparative HPLC separation (column type: Phenomenex luna C18 (75 mm*30 mm I.D., 3 μm); mobile phase: A: ACN, B: [H2O (containing 10 mmol NH4HCO3+0.05% NH3.H2O)], gradient: B%: 35%-55%, 8 min) in sequence to obtain compound 017_4.

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

[0226] 017_3 (retention time: 3.482 min) MS - ESI m / z: 462.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 11.53 (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 = 7.2 Hz, 1H), 1.39 (s, 3H), 0.78 (d, J = 7.4 Hz, 3H).

[0227] 017_4 (retention time: 3.574 min) MS - ESI m / z: 462.2 [M+H] +1H NMR (400 MHz, DMSO-d6) δ 11.14 - 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). Compound 017 and 018 were obtained.

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

[0231] Compound 017 (retention time: 1.138 min): MS - ESI m / z: 462.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 11.65 - 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 = 7.4 Hz, 1H), 1.40 (s, 3H), 0.78 (d, J = 7.4 Hz, 3H);

[0232] Compound 018 (retention time: 1.422 min): MS - ESI m / z: 462.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 11.71 - 11.01 (m, 2H), 8.83 - 8.64 (m, 2H), 7.42 - 7.35 (m, 1H), 7.31 - 7.13 (m, 3H), 5.85 (s, 2H), 2.78 (q, J = 7.3 Hz, 1H), 1.39 (s, 3H), 0.78 (d, J = 7.4 Hz, 3H).

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

[0234] Compound 017_4 (150 mg, 325.08 pmol) was separated by chiral column (column type: DAICEL CHIRALPAK IE (250 mm*30 mm, 10 pm); mobile phase: [0.1% NH3H2O EtOH]; gradient: B%: 50%, 12 min) to give compounds 019 and 020.

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

[0236] Compound 019 (retention time: 1.669 min): MS - ESI m / z: 462.31 [M+H] + 1H NMR (400 MHz, DMSO_d6) d: 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 = 7.1 Hz, 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 (400 MHz, DMSO_d6) d: 11.38 (br s, 1H), 11.08 (br s, 1H), 8.76-8.65 (m, 2H), 7.37 (q, J = 7.1 Hz, 1H), 7.28-7.12 (m, 3H), 5.84 (s, 2H), 3.04 (q, J = 6.9 Hz, 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] Compound 001_11 (9.04 g, 36.14 mmol) was added into tert-butyl alcohol (100 mL) under room temperature and nitrogen protection, then hydrochloride of compound 014_3 (5 g) and potassium carbonate (3.87 g, 38.61 mmol) were added, and the reaction was stirred at 80 °C for 12 h. After the reaction was completed, water (500 mL) was added into the reaction solution, and the mixture was extracted with ethyl acetate (200 mL x 3), and the organic phases were combined. The combined organic phases were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was slurried in methyl tert-butyl ether (70 mL) at room temperature, filtered, and the filter cake was collected and concentrated under reduced pressure to obtain compound 021_1.

[0244] Step 2: Synthesis of compound 021_2

[0245] Compound 021_1 (4.5 g, 8.90 mmol) was dissolved in anhydrous toluene (130 mL) under room temperature and nitrogen protection, and trimethylaluminum toluene solution (2 M, 13.35 mL) was added dropwise slowly, and the reaction system was stirred at 75 °C for 12 h. After the reaction was completed, the reaction system was cooled to room temperature, and then slowly poured into water (100 mL), and 3M hydrochloric acid was added to adjust the pH to 3-4. Dimethyltetrahydrofuran (100 mL x 3) was added for extraction, and 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 I.D., 10 μm); mobile phase: A: ACN, B: [H2O (containing 0.04% HC1)], gradient: B%: 40%-70%, 20 min) to obtain compound 021_2. 1 H NMR (400 MHz, 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 a chiral column (column type: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O EtOH] %: 40%-40%, 8 min) to obtain compounds 021 and 022.

[0248] SFC analysis method: Column type: Chiralpak AD-3 (50mm*4.6mm I.D., 3pm); 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 (400 MHz, DMSO-d6) δ 11.50 (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 (400 MHz, DMSO-d6) δ 11.54 - 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, 4.0 Hz, 1H) 0.80 - 0.66 (m, 2H).

[0251] Example 23

[0252]

[0253] Synthesis route:

[0254]

[0255] Step 1: Synthesis of compound 023_1

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

[0257] Step 2: Synthesis of compound 023_2

[0258] The compound 023_1 mixture (5 g, 10.17 mmol) was added into anhydrous methanol (100 mL) under the protection of nitrogen at room temperature, then bis(trifluoroacetic acid)iodobenzene (10.94 g, 25.43 mmol) was added, 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, diluted with ethyl acetate (100 mL), washed with saturated sodium sulfite (50 mL x 3), and 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 I.D., 15 μm); mobile phase: A: ACN, B: [H2O (containing 0.1% TFA)], gradient: B%: 35%-65%, 20 min) to obtain the compound 023_2.

[0259] Step 3: Synthesis of compound 023

[0260] Compound 023_2 (0.8 g, 1.53 mmol) was dissolved in anhydrous toluene (15 mL) at room temperature under nitrogen protection, and a trimethylaluminum toluene solution (2 M, 2.45 mL) was added dropwise slowly. 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, slowly poured into water (20 mL), 3 M hydrochloric acid was added to adjust the pH to 3-4, dimethyltetrahydrofuran (20 mL x 3) was added for extraction, and the organic phase was combined. The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The 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 I.D., 3 μm); mobile phase: A: ACN, B: [H2O (containing 0.04% HC1)], gradient: B%: 45%-65%, 7 min) to obtain compound 023. MS-ESI m / z: 490.0 [M+H] + 1H NMR (400 MHz, 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] Synthetic route:

[0264]

[0265] Step 1: Synthesis of compound 024_1

[0266] Compound 010_1 (10 g, 39.96 mmol) was added to chloroform (40 mL) and ethanol (40 mL) at room temperature under nitrogen protection, followed by the addition of 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylate 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 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] The hydrochloride salt of intermediate 001_4 (8.5 g) was dissolved in tert-butanol (150 mL) under nitrogen protection at room temperature, and intermediate 024_1 (9.49 g, 37.60 mmol) and potassium bicarbonate (5.88 g, 58.75 mmol) were added. The reaction was stirred at 90 °C for 12 h. After the reaction was completed, the reaction was added to water (500 mL), and a solid was precipitated. The mixture was filtered, and the filter cake was washed with methyl tert-butyl 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] Compound 024_2 and compound 024_3 (5 g, 9.41 mmol) were dispersed in anhydrous methanol (100 mL) under nitrogen protection at room temperature, and bistrifluoroacetyloxyiodobenzene (12.14 g, 28.23 mmol) was added. The reaction was stirred in an oil bath at 50 °C for 2 h. After the reaction was completed, it was cooled to room temperature, and the solvent was removed by concentration 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 min. The solid was filtered, and the filtrate was 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, by volume) to obtain intermediate 024_4.

[0271] Step 4: Synthesis of compound 024_5

[0272] Compound 024_4 (0.3 g, 534.34 μmol) was dissolved in anhydrous toluene (6 mL) under nitrogen protection at room temperature, and a trimethylaluminum toluene solution (2 M, 854.95 μL) was added. The reaction was stirred at 50 °C for 12 h, and the temperature was increased to 90 °C for stirring for 12 h. After the reaction was completed, it was cooled to room temperature. The reaction was poured into water (100 mL), and dilute hydrochloric acid (1 N) was added to pH 3-4. Ethyl acetate (50 mL x 3) was added 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 I.D., 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 (400 MHz, DMSO-d6) δ 11.95 - 11.71 (m, 1H), 11.38 (br s, 1H), 8.82 - 8.66 (m, 2H), 4.93 (t, J = 6.6 Hz, 2H), 3.19 (s, 3H), 3.01 (tt, J = 6.8, 19.1 Hz, 2H), 2.89 (q, J = 7.6 Hz, 1H), 0.82 (d, J = 7.5 Hz, 3H).

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

[0274] Compound 024_5 (100 mg, 153.29 pmol) was separated by chiral column (column type: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 pm); mobile phase: [0.1% NH3H2O EtOH] %: 10%-10%, 12 min) to give compounds 024 and 025.

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

[0276] 024 (ret. time: 1.496 min) MS - ESI m / z: 515.9 [M+H] +1 1H NMR (400 MHz, DMSO-d6) δ 11.85 (br s, 1H), 11.38 (br s, 1H), 8.77 (dd, J = 1.6, 2.8 Hz, 1H), 8.71 (dd, J = 2.8, 8.6 Hz, 1H), 4.93 (t, J = 6.6 Hz, 2H), 3.19 (s, 3H), 3.09 - 2.94 (m, 2H), 2.90 (q, J = 7.6 Hz, 1H), 0.95 - 0.74 (m, 3H);

[0277] 025 (ret. time: 1.789 min) MS - ESI m / z: 516.2 [M+H] +1 1H NMR (400 MHz, DMSO-d6) δ 12.09 - 11.16 (m, 2H), 8.88 - 8.61 (m, 2H), 4.93 (t, J = 6.8 Hz, 2H), 3.19 (s, 3H), 3.01 (tt, J = 6.6, 19.2 Hz, 2H), 2.90 (q, J = 7.6 Hz, 1H), 0.82 (d, J = 7.6 Hz, 3H).

[0278] Examples 26 and 27

[0279]

[0280] Synthesis route:

[0281]

[0282] Step 1: Synthesis of compound 026_1

[0283] Compound 024_1 (2.99 g, 11.86 mmol) was dissolved in tert-butanol (150 mL) under room temperature and nitrogen protection, 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 x 3), and the organic phase was combined. The organic phase was washed with saturated brine (100 mL x 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] The mixture of compound 026_1 and compound 026_2 (1 g, 2.03 mmol) was dispersed in anhydrous methanol (20 mL) under room temperature and nitrogen protection, and bis-trifluoroacetoxyiodobenzene (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, it was cooled to room temperature, and the solvent was removed by concentration to obtain an oily residue. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 0-7 / 3, by volume) to obtain compound 026_3.

[0286] Step 3: Synthesis of compound 026_4

[0287] Compound 026_3 (350 mg, 668.59 pmol) was dissolved in anhydrous toluene (10 mL) under room temperature and nitrogen protection, and trimethylaluminum toluene solution (2 M, 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), 1 N dilute hydrochloric acid was added to pH 3-4, and ethyl acetate (50 mL x 3) was extracted. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The residue was separated by preparative HPLC (column type: Waters Xbridge BEH C18 (100 mm*30 mm I.D., 10 pm); mobile phase: A: ACN, B: [H2O (containing 10 mmol NH4HCO3)], gradient: B%: 30%-60%, 8 min) to give compound 026_4.

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

[0289] Compound 026_4 (50 mg, 104.73 pmol) was separated by chiral column (column type: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 pm); mobile phase: [0.1% NH3H2O IPA] %: 45%-45%, 9 min) to give compounds 026 and 027.

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

[0291] 026 (retention time: 1.369 min) MS - ESI m / z: 478.2 [M+H] +1 H NMR (400 MHz, DMSO-d6) d 11.82 (br s, 1H), 11.37 (br s, 1H), 8.77 (dd, J = 1.6, 2.4 Hz, 1H), 8.71 (dd, J = 2.8, 8.8 Hz, 1H), 7.41-7.36 (m, 1H), 7.31-7.16 (m, 3H), 5.86 (s, 2H), 3.17 (s, 3H), 2.88 (q, J = 7.6 Hz, 1H), 0.80 (d, J = 7.6 Hz, 3H);

[0292] 027 (retention time: 1.499 min) MS - ESI m / z: 478.2 [M+H] +1H NMR (400 MHz, DMSO-d6) δ 11.82 (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 = 7.6 Hz, 1H), 0.80 (d, J = 7.6 Hz, 3H).

[0293] Biological testing

[0294] Example 1 : In vitro activity testing

[0295] I. cGMP expression testing based on lnCap cells

[0296] 1. Experimental procedure

[0297] 1) Solution preparation

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

[0299] Dissolve 10 g of BSA in 100 mL of double distilled water (ddH20) to obtain 10% BSA.

[0300] · 5 mM DETA (diethylenetriamine)-NO

[0301] Weigh 10 mg of DETA-NO and dissolve in 12.2 mL of double distilled water (ddH20) to obtain 5 mM DETA-NO, aliquot and freeze at -20 °C.

[0302] · Washing Buffer (50 mL)

[0303]

[0304] ● Assay Buffer (50 mL)

[0305]

[0306] ● Detection Buffer

[0307] a) Add 50 μL of cGMP-D2 (D2 labeled cyclic guanosine monophosphate) to 1 mL of lysis buffer and mix well.

[0308] b) Add 50 μL of anti-cGMP cryptate (Eu 3+ cryptate labeled anti-cyclic guanosine monophosphate antibody) to 1 mL of lysis buffer and mix well.

[0309] 2) Compound dilution

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

[0311] (2) Gradient dilution of compound with Echo, dilute each compound to 10 concentration gradients and add 50 nL to 384-well plate respectively.

[0312] 3) Preparation of LNCap cells

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

[0314] (2) Put the phosphate buffer, trypsin and medium used in the cell passage process into the 37°C water bath to preheat.

[0315] (3) Take the cells (14th generation) out of the 37°C 5% CO2 incubator, and use a pipette to remove the old culture solution in the culture bottle.

[0316] (4) Take 5 mL of phosphate buffer and add it to the culture bottle to rinse the cells, then discard the liquid.

[0317] (5) Take 3 mL of trypsin and add it to the culture bottle, shake it and discard the liquid, then put the culture bottle into the incubator.

[0318] (6) After about 2 minutes, take out the culture bottle, observe that the cells have been separated, take 9 mL of medium and add it to the culture bottle and blow it several times, then transfer the cell suspension to a 50 mL centrifuge tube.

[0319] (7) Take 0.7 mL of cell suspension and add it to the counting cup, and count it on the ViCell XR. The remaining cells are centrifuged at 1000 rpm for 5 min, and the supernatant is removed.

[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 x 10 6 / mL. 8 μL / well is added to the microplate.

[0322] 4) Preparation and addition of DETA-NO

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

[0324] (2) Transfer 2 μL / well of DETA-NO to 384-well plate using Bravo.

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

[0326] 5) Prepare cGMP standard curve

[0327] (1) Dilute 1 mM cGMP stock to 10 μM with assay buffer. Then dilute 4-fold to 11 concentrations.

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

[0329] 6) Add detection reagents and read plate

[0330] (1) Transfer 5 μL / well of cGMP-D2 to 384-well plate using Bravo. Centrifuge at 1500 rpm for 1 min.

[0331] (2) Transfer 5 μL / well of anti-cGMP cryptate to 384-well plate using Bravo. Centrifuge at 1500 rpm for 1 min.

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

[0333] (4) Read 665 / 615 using Envision.

[0334] 7) Data analysis

[0335] (1) cGMP standard curve: Make standard curve using Graphpad prism according to the ratio of 665 / 615 vs. cGMP concentration.

[0336] (2) Convert HTRF (homogeneous time-resolved fluorescence) ratio (665 / 615) to cGMP concentration: In Graphpad prism, copy the HTRF ratio (665 / 615) to the ratio column of the cGMP standard curve, run analysis "Log inhibitor vs response-variable slope", select "interpolate", and convert the HTRF ratio (665 / 615) to cGMP concentration.

[0337] (3) Compound activation curve: Make curve according to the converted cGMP concentration vs. compound concentration using "Log agonist vs response-variable slope" analysis method in Graphpad prism.

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

[0339] Table 1 MEC values of the compounds of the present application for sGC stimulatory activity

[0340]

[0341]

[0342] MEC: minimum effective concentration to stimulate cGMP production (more than three times the basal value) in lnCap cells.

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

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

[0345] Purpose of the experiment: The purpose of this study is 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 Slike)

[0348] Experimental method:

[0349] This project uses 4 male SD rats, one group of 2 SD rats for intravenous injection, the dose is 0.3 mg / kg, the concentration is 0.15 mg / mL; another group of 2 SD rats for oral administration, the dose is 1 mg / kg, the concentration is 0.2 mg / mL; collect plasma samples at 0.083 (only intravenous group), 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24 h after administration, then analyze the collected samples by LC-MS / MS and collect data. The collected analysis data is calculated by Phoenix WinNonlin 6.3 software to calculate the relevant pharmacokinetic parameters.

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

[0351] Table 2 In vivo pharmacokinetic experimental results

[0352]

[0353] Conclusion: The compound of the present application has a good apparent volume of distribution and half-life.

[0354] Experimental Example 3: Tissue distribution test: animal in vivo tissue distribution study

[0355] Experimental 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, 200-300g, 7-9 weeks old, Shanghai SLEEK)

[0358] Experimental method:

[0359] This project uses 6 male SD rats for oral administration, the administration dose is 1 mg / kg, and the administration concentration is 0.2 mg / mL; collect cerebrospinal fluid, brain, heart tissue and plasma samples at 2, 6, 12 h after administration, then analyze the collected samples by LC-MS / MS and collect data. The collected analysis data is used to calculate the relevant pharmacokinetic parameters by 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: lower than the detection limit.

[0364] Conclusion: The compound of the present application has no risk of entering the brain and has good heart distribution.

Claims

1. A compound represented by Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Formula (I) is: with the proviso that the compound is not selected from the group consisting of the following structures, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: R1is selected from H, -OH, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 alkylamino; R2is selected from benzyl or C 1-8 alkyl, said benzyl or C 1-8 alkyl is optionally substituted with 1, 2, 3, 4, or 5 halogen atoms; R3, R4are each independently selected from H or C 1-3 alkyl; or R3and R4, and the atom to which they are both attached form C 3-6 cycloalkyl; R1is selected from H, -OH, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propyloxy, or isopropyloxy. 。 2. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, R1is selected from H, -OH, C 1-3 alkyl or C 1-3 alkoxy.

3. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 2, wherein, R1is selected from H, -OH, methyl, or methoxy.

4. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 2, wherein, R3, R4are each independently selected from H, methyl, ethyl, n-propyl, or isopropyl, or R3and R4, together with the atom to which they are both attached, form a cyclopropane group.

5. The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R2is selected from benzyl or C 1-6 alkyl, said benzyl or C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 halogen atoms.

6. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 5, wherein, R2is selected from benzyl or C 1-4 alkyl, said benzyl or C 1-4 alkyl is optionally substituted with 1, 2, 3, 4, or 5 halogen atoms.

7. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 5, wherein, R2is selected from benzyl or C 1-4 alkyl, said benzyl or C 1-4 alkyl is optionally substituted with 1, 2, 3, 4 or 5 F, CI or Br atoms.

8. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 5, wherein, R2is selected from or .

9. The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R3, R4are each independently selected from H, or methyl, or R3and R4, together with the atom to which they are both attached, form a cyclopropane group.

10. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 9, wherein, 12. A compound represented by Formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

11. The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Structural unit selected from , or .

13. A compound represented by Formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 。 14. A pharmaceutical composition comprising a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-13, and a pharmaceutically acceptable excipient. 。 15. Use of a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1-13, or a pharmaceutical composition according to claim 14, in the manufacture of a medicament for the treatment of a disease associated with sGC agonists or stimulators. The disease associated with sGC agonists or stimulators is selected from heart failure, or hypertension.

16. Use according to claim 15, wherein, ​

Images