Piperazine derivatives and their uses

Abstract

The present invention provides piperazine derivatives and uses thereof, specifically compounds of formula (III) or pharma- ceutically acceptable salts thereof: JPEG2024514978000081.jpg61127

Description

[Technical field]

[0001] This application claims priority to CN202110461572X, filed on April 27, 2021, CN2021108530383, filed on July 27, 2021, CN202111223627X, filed on October 20, 2021, and CN202111521983X, filed on December 13, 2021.

[0002] The present invention relates to the technical field of medicine, in particular to piperazine derivatives and their uses, particularly to the compound represented by formula (III) and its pharma- ceutically acceptable salts: [Background technology]

[0003] Melanocortin receptors belong to the subfamily of G-protein-coupled receptors (GPCRs), and currently five receptor subtypes of the melanocortin family, namely MC1R, MC2R, MC3R, MC4R, and MC5R, have been cloned and characterized and are distributed in various tissues. These are receptors for endogenous agonists such as MSH, and when activated, they can initiate the downstream cAMP signaling pathway, which can mediate a wide range of physiological functions. Among them, the melanocortin 1 receptor (MC1R) is mainly expressed in melanocytes, monocytes, and mast cells, and mediates hair and skin pigmentation and blocks inflammation. MC2R is expressed in adipocytes and adrenal cells, and mediates steroid production in the adrenal gland. MC3R is present in the brain, hypothalamus, heart, intestine, and placenta, and is related to energy homeostasis and inflammation in the body. MC5R is present in a wide range of tissues and is thought to act in the exocrine system. MC4R is specifically expressed in the brain and controls feeding behavior, energy homeostasis in the body, and erectile function. MC4R-deficient mice and humans exhibit severe obesity phenotypes, and synthetic MC4R agonists have been reported to have many biological effects. Initially, a series of synthetic peptides and peptide analogs were developed based on endogenous agonists such as MSH. NDP-MSH is a nonselective agonist that simultaneously acts on MC1R, MC3R, MC4R, and MC5R, and has been reported to reduce food intake and weight gain in rat models. Cycloheptapeptide MT-II is another nonselective specific agonist whose therapeutic use in the treatment of erectile dysfunction has been demonstrated in clinical trials. Bumenotide (BMT), a cyclic 7-amino acid melanocortin peptide, has agonistic effects on MC1R, MC3R, and MC4R, and was approved by the FDA in June 2019 for the treatment of sexual desire disorder in premenopausal women. Setmelanotide is a polypeptide-selective MC4R agonist that was approved by the FDA in July 2020 for the treatment of genetic obesity caused by POMC, PCSK1, or LEPR deficiency. These studies have opened a new chapter for MC4R-targeted drugs.However, all of these studies have focused on polypeptide molecules, which have drawbacks such as poor target selectivity and the inability to be taken orally, so research into small molecule selective MCR agonists in this field is of great significance. Summary of the Invention

[0004] The present invention provides a compound represented by the following formula (III), or a pharma- ceutically acceptable salt thereof, selected from the following: JPEG0007675849000001.jpg61127 (However, Each R1 is independently a halogen, C 1~3 Alkyl, C 1~3 Alkoxy, -C(=O)NR a R b , and -CHC(=O)NR a R b C is selected from 1~3 Alkyl and C 1~3 The alkoxy is optionally substituted with 1, 2 or 3 halogens; Each R2 is independently C 1~3 Alkyl and C 3~6 cycloalkyl; Each R3 is independently halogen, C 1~3 Alkyl and C 1~3 alkoxy; R4 is C 1~4 Alkyl, Phenyl, C 3~6 cycloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, 1~4 Alkyl, Phenyl, C 3~6 Cycloalkyl, 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl each independently optionally contain 1, 2, or 3 R c is replaced by R a and R b are each independently H and C 1~3 alkyl, Each R c are each independently halogen, -CN and C 1~3alkyl, m, n, and t are each independently selected from 0, 1, and 2; T1 is selected from N and CH; The "hetero" in the "4- to 8-membered heterocycloalkyl" or "5- to 6-membered heteroaryl" each independently represents 1, 2, 3, or 4 heteroatoms or heteroatom groups selected from O, NH, S, and N.

[0005] In some embodiments of the present invention, the above R a and R b are each independently selected from H, and -CH3, and other variables are as defined herein.

[0006] In some embodiments of the present invention, each R1 above is independently selected from F, Cl, -CF3, -C(=O)NHCH3, and -CH2C(=O)NHCH3, and all other variables are as defined herein.

[0007] JPEG0007675849000002.jpg72170

[0008] In some aspects of the invention, each R2 above is independently selected from -CH3 and cyclopropyl, and all other variables are as defined herein.

[0009] In some aspects of the invention, each R3 above is independently selected from F, Cl, and Br, and the other variables are as defined herein.

[0010] In some embodiments of the invention, each of the R c are each independently selected from -CN, and -CH3, and the other variables are as defined herein.

[0011] In some forms of the invention, R4 above is selected from t-butyl, phenyl, pyridyl, pyridazinyl, tetrahydropyranyl, cyclobutyl, cyclohexyl, tetrahydrofuranyl, and oxabicyclooctyl, each of which is independently optionally selected from 1, 2, or 3 R c and other variables are as defined herein.

[0012] JPEG0007675849000003.jpg54170

[0013] The present invention provides a compound represented by the following formula (III) or a pharma- ceutically acceptable salt thereof, selected from the following: JPEG0007675849000004.jpg65127 (However, Each R1 is independently a halogen, C 1~3 Alkyl, C 1~3 Alkoxy, -C(=O)NR a R b , and -CHC(=O)NR a R b C is selected from 1~3 Alkyl and C 1~3 each alkoxy is independently optionally substituted with 1, 2 or 3 halogen; Each R2 is independently C 1~3 Alkyl and C 3~6 cycloalkyl; Each R3 is independently halogen, C 1~3 Alkyl and C 1~3 alkoxy; R4 is C 1~4 alkyl, phenyl, 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, 1~4 Alkyl, phenyl, 5- to 6-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each independently optionally selected from 1, 2, or 3 R c is replaced by R a and R b are each independently H and C 1~3 alkyl, Each R c are each independently selected from halogen and CN; m, n, and t are each independently selected from 0, 1, and 2; T1 is selected from N and CH; The "hetero" in the "5- to 6-membered heterocycloalkyl" or "5- to 6-membered heteroaryl" refers to 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from O, NH, S, and N.

[0014] In some embodiments of the present invention, the above R a and R b are each independently selected from H, and -CH3, and other variables are as defined herein.

[0015] In some embodiments of the present invention, each R1 above is independently selected from F, Cl, -CF3, -C(=O)NHCH3, and -CH2C(=O)NHCH3, and all other variables are as defined herein.

[0016] JPEG0007675849000005.jpg70170

[0017] In some aspects of the invention, each R2 above is independently selected from -CH3 and cyclopropyl, and all other variables are as defined herein.

[0018] In some aspects of the invention, each R3 above is independently selected from F, Cl, and Br, and the other variables are as defined herein.

[0019] In some forms of the invention, R4 above is selected from t-butyl, phenyl, pyridyl, pyridazinyl, and tetrahydropyranyl, each of which is independently optionally selected from 1, 2, or 3 R c and other variables are as defined herein.

[0020] JPEG0007675849000006.jpg34170

[0021] The present invention provides a compound represented by the following formula (II) or a pharma- ceutically acceptable salt thereof, selected from the following: JPEG0007675849000007.jpg64127 (However, Each R1 is independently a halogen, C 1~3 Alkyl, C 1~3 Alkoxy, -C(=O)NR a R b , and -CHC(=O)NR a R b is selected from Each R2 is independently C 1~3 alkyl, Each R3 is independently halogen, C 1~3 Alkyl and C 1~3 alkoxy; R a and R b are each independently H and C 1~3 alkyl, m, n, and t are each independently selected from 0, 1, and 2; T1 is selected from CH and N.

[0022] In some embodiments of the present invention, the above R a and R b are each independently selected from H, and -CH3, and other variables are as defined herein.

[0023] In some aspects of the invention, each R1 above is independently selected from F, Cl, -C(=O)NHCH3, and -CH2C(=O)NHCH3, and all other variables are as defined herein.

[0024] JPEG0007675849000008.jpg52170

[0025] In some aspects of the invention, each R2 above is independently selected from -CH3, and the other variables are as defined herein.

[0026] In some aspects of the invention, each R3 above is independently selected from F and Cl, and the other variables are as defined herein.

[0027] The present invention provides a compound represented by the formula below, or a pharma- ceutically acceptable salt thereof, selected from the following: JPEG0007675849000009.jpg65127 (However, Each R1 is independently a halogen, C 1~3 Alkyl, C 1~3 Alkoxy, -C(=O)NR a R b , and -CHC(=O)NR a R b is selected from Each R2 is independently C 1~3 alkyl, Each R3 is independently halogen, C 1~3 Alkyl and C 1~3 alkoxy; R a and R b are each independently H and C 1~3 alkyl, m, n, and t are each independently selected from 0, 1, and 2.

[0028] In some embodiments of the present invention, the above R a and R bare each independently selected from H, and -CH3, and other variables are as defined herein.

[0029] In some aspects of the invention, each R1 above is independently selected from F, Cl, -C(=O)NHCH3, and -CH2C(=O)NHCH3, and all other variables are as defined herein.

[0030] JPEG0007675849000010.jpg49170

[0031] In some aspects of the invention, each R2 above is independently selected from -CH3, and the other variables are as defined herein.

[0032] In some aspects of the invention, each R3 above is independently selected from F and Cl, and the other variables are as defined herein.

[0033] In some aspects of the invention, the compound or a pharma- ceutically acceptable salt thereof is selected from compounds of the formula: JPEG0007675849000011.jpg81170 (wherein R1, R2, R3, m, n, and t are as defined in the present invention.)

[0034] In some aspects of the invention, the compound or a pharma- ceutically acceptable salt thereof is selected from compounds of the formula: JPEG0007675849000012.jpg42169 (wherein R1, R3, R4, m, and t are as defined in the present invention.)

[0035] The present invention also includes any combination of the above variables.

[0036] The present invention also provides the following compound, or a pharma- ceutically acceptable salt thereof, selected from compounds represented by the following formula: JPEG0007675849000013.jpg62170JPEG0007675849000014.jpg208170JPEG0007675849000015.jpg71170

[0037] The present invention also provides the following compound, or a pharma- ceutically acceptable salt thereof, selected from compounds represented by the following formula: JPEG0007675849000016.jpg161170JPEG0007675849000017.jpg238170JPEG0007675849000018.jpg222170

[0038] The present invention also provides the following compound, or a pharma- ceutically acceptable salt thereof, selected from compounds represented by the following formula: JPEG0007675849000019.jpg214170

[0039] The present invention also provides the use of the above compound, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating an MC4R agonist-related disorder.

[0040] In some forms of the invention, the MC4R agonist-related disorder is selected from male erectile dysfunction and female sexual desire disorders.

[0041] Technical effects As an MC4R receptor agonist, the compound of the present invention has selective agonistic effect on the human MC4R receptor, exhibits good activity in in vitro tests, exhibits good pharmacokinetic properties in rats, and can pass through the blood-brain barrier to reach brain tissue with a high brain / blood ratio, thereby achieving a high drug concentration. Thus, the compound of the present invention is useful for the development of therapeutic agents for diseases related to the MC4R signal pathway, such as sexual dysfunction.

[0042] Definitions and Explanations Unless otherwise specified, the following terms and phrases as used herein are intended to have the following meanings: Certain terms and phrases should not be regarded as indefinite or uncertain, but should be understood in their general sense, unless specifically defined. When trade names are used herein, they are intended to refer to the corresponding commercial product or its active ingredients. As used herein, the term "pharmacologically acceptable" means those compounds, materials, compositions and / or dosage forms which are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without undue toxicity, irritation, anaphylaxis, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0043] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention made from a compound found in the present invention having a particular substituent and a relatively harmless acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting a sufficient amount of base with the neutral form of such a compound in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, magnesium salts or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting a sufficient amount of acid with the neutral form of such a compound in a pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, as well as salts of amino acids (such as arginine), and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain basic and acidic functional groups, and can therefore be converted into either base or acid addition salts.

[0044] The pharma- ceutically acceptable salts of the present invention can be synthesized from parent compounds that contain an acid or base group by conventional chemical methods. Generally, methods for preparing such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometrically appropriate base or acid in water or an organic solvent, or in a mixture of both.

[0045] As used herein and as is well known in the art, "treatment" or "treating" is a method for obtaining beneficial or desired results (including clinical results). Beneficial or desired clinical results include, but are not limited to, a reduction in tumor progression, a reduction in tumor size, a slowing of tumor growth rate, a reduction in the invasive and metastatic potential of a tumor, alleviation or amelioration of one or more symptoms or conditions, a reduction in the extent of disease, a stable (i.e., not worsening) state of disease, prevention of disease spread, a delay or mitigation of disease progression, an improvement or palliation of the disease state, and remission (partial or total), whether detectable or undetectable. "Treatment" or "treating" can also mean a prolongation of survival beyond that expected in the absence of treatment.

[0046] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof with pharma- ceutical acceptable auxiliary substances. The purpose of a pharmaceutical composition is to facilitate the administration of a compound of the present application to an organism.

[0047] The therapeutic dosage of the compounds of the present application will be determined, for example, by the particular therapeutic application, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the present application in a pharmaceutical composition may not be fixed, depending on a variety of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.

[0048] The term "treatment" means the administration of a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with a disease, and includes the following: (i) Inhibiting the disease or disease state, i.e., inhibiting its onset. (ii) Alleviating the disease or disease state, i.e., eliminating the disease or disease state.

[0049] The term "therapeutically effective amount" refers to the amount of a compound described herein used to (i) treat a particular disease, condition, or disorder, (ii) alleviate, ameliorate, or eliminate one or more symptoms of a particular disease, condition, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the method of administration, and the age of the mammal being treated, but can be routinely determined by one of ordinary skill in the art based on his or her knowledge and the contents of this disclosure.

[0050] Unless otherwise required in this application, throughout the entire specification and the claims that follow, the term "comprise" and its English variations, such as "comprises" and "comprising," are to be interpreted in their open and inclusive sense as meaning "including but not limited to."

[0051] Throughout the specification, references to "one embodiment" or "an embodiment" or "in another embodiment" or "in some embodiments" are meant to include the particular referenced elements, structures, or features associated with that embodiment in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" or "in another embodiment" or "in some embodiments" in different places throughout the specification do not necessarily all refer to the same embodiments. Furthermore, particular elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0052] Unless otherwise specified, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers, and tautomers.

[0053] The compounds of the present invention may have specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Substituents such as alkyl may also have additional asymmetric carbon atoms. All of these isomers and mixtures thereof are within the scope of the present invention.

[0054] Unless otherwise specified, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.

[0055] Unless otherwise specified, the terms "cis-trans isomers" or "geometric isomers" refer to isomers that arise from the inability to freely rotate about double bonds or single bonds of ring-forming carbon atoms.

[0056] Unless otherwise specified, the term "diastereomer" refers to stereoisomers whose molecules have two or more centers of chirality and in which the molecules are not in a mirror-image relationship.

[0057] Unless otherwise specified, "(+)" denotes dextrorotatory, "(-)" denotes levorotatory, and "(±)" denotes racemic.

[0058] JPEG0007675849000020.jpg40170

[0059] JPEG0007675849000021.jpg69170

[0060] The compounds of the present invention may exist in specific. Unless otherwise specified, the term "tautomer" or "tautomeric form" means that at room temperature, different functional group isomers are in dynamic equilibrium and rapidly convert into each other. When tautomers are possible (such as in solution), chemical equilibrium of tautomers can be achieved. For example, prototropic tautomers (also called prototropic tautomers) include interconversions by proton transfer, such as ketone-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions involving rearrangement of some bond electrons. A specific example of ketone-enol tautomerization is the interconversion between the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0061] Unless otherwise specified, the terms "enriched in one isomer," "isomer-enriched," "enriched in one enantiomer," or "enantiomer-enriched" mean less than 100% of one of these isomers or enantiomers, and more than 60%, more than 70%, more than 80%, more than 90%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or more than 99.9% of that isomer or enantiomer.

[0062] Unless otherwise specified, the term "isomer excess" or "enantiomeric excess" refers to the relative percentage difference between two isomers or two enantiomers. For example, if one isomer or enantiomer is present at 90% and the other isomer or enantiomer is present at 10%, then the isomer or enantiomer excess (ee value) is 80%.

[0063] Optically active (R)- and (S)-isomers, as well as D- and L-isomers, can be prepared by chiral synthesis or chiral reagents, or other conventional techniques. To obtain one enantiomer of the compound of the present invention, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary is cleaved to provide the pure desired enantiomer. In addition, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), the salt of the diastereomeric salt can be formed with an appropriate optically active acid or base, and the diastereomers can be separated by conventional methods and then recovered to obtain the pure enantiomers. Furthermore, separation of enantiomers and diastereomers is generally achieved by using chromatography using chiral stationary phases, optionally combined with chemical derivatization methods (e.g., formation of carbamates from amines).

[0064] The compounds of the present invention may contain unnatural ratios of atomic isotopes at one or more of the atoms that constitute such compounds. For example, tritium ( 3 H), iodine-125( 125 I) or C-14( 14 The compounds may be labeled with radioisotopes such as C). Also, for example, deuterium may be substituted for hydrogen to form deuterated drugs, where the bond between deuterium and carbon is more robust than the bond between normal hydrogen and carbon, and compared to non-deuterated drugs, deuterated drugs have the advantages of reduced toxicity and side effects, improved drug stability, enhanced therapeutic efficacy, and increased biological half-life of the drug. All isotopic variations of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention.

[0065] "Optional" or "optionally" means that the subsequently described event or condition may, but does not necessarily, occur, and the description includes cases where the event or condition occurs and cases where it does not occur.

[0066] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced with a substituent, which may include deuterium and hydrogen variants, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e. =O), it means that two hydrogen atoms are replaced. Oxygen replacement does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of the substituents may be any as long as it is chemically achievable.

[0067] When any variable (e.g., R) occurs more than one time in a composition or structure of a compound, each definition is independent. Thus, for example, if a group is substituted with 0-2 R, said group may also be optionally substituted with up to 2 R, with each occurrence of R having an independent option. Further, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0068] When the number of linking groups is 0, for example, -(CRR)0- indicates that this linking group is a single bond.

[0069] When one variable is selected from a single bond, it indicates that the two groups connected thereby are directly linked, e.g., when L represents a single bond in ALZ, it indicates that the structure is substantially AZ.

[0070] JPEG0007675849000022.jpg76170

[0071] JPEG0007675849000023.jpg71170JPEG0007675849000024.jpg72170

[0072] Unless otherwise specified, C n~n+m Or C n ~C n+m contains any one of n to n+m carbons, e.g., C 1~12are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 Also includes any of the ranges of n to n+m, for example, C 1~12 is C 1~3 , C 1~6 , C 1~9 , C 3~6 , C 3~9 , C 3~12 , C 6~9 , C 6~12 , and C 9~12 Similarly, n-membered to n+m-membered means that the number of atoms on the ring is n to n+m, and for example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any of the ranges of n to n+m, and for example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring, etc.

[0073] Unless otherwise specified, "C 1~4 The term "alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms. 1~4 Alkyl is C 1~2 , C 1~3 and C 2~3 alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1~4 Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl, isopropyl), butyl (including n-butyl, isobutyl, s-butyl, t-butyl), and the like.

[0074] Unless otherwise specified, "C 1~3 The term "alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 3 carbon atoms. 1~3 is C 1~2 and C 2~3 alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine).1~3 Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl, isopropyl), and the like.

[0075] Unless otherwise specified, "C 1~3 The term "alkoxy" refers to an alkyl group having 1 to 3 carbon atoms linked to the remainder of the molecule through an oxygen atom. 1~3 Alkoxy is C 1~2 , C 2~3 , C3 and C2 alkoxy, etc. 1~3 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy, isopropoxy), and the like.

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

[0077] Unless otherwise specified, the term "4 to 8 membered heterocycloalkyl", by itself or in combination with other terms, refers to a saturated cyclic group of 4 to 8 ring atoms, each of which one, two, three or four ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, wherein the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur atoms may be optionally oxidized (i.e., NO and S(O)). p(wherein p is 1 or 2). Monocyclic and bicyclic ring systems are included, where bicyclic ring systems include spiro rings, fused rings, and bridged rings. Additionally, for this "4-8 membered heterocycloalkyl", a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule. The 4-8 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyl, etc. Examples of 4-8 membered heterocycloalkyl include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidyl, 2-piperidyl, and 3-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, or dioxeptanyl.

[0078] Unless otherwise specified, the term "5- to 6-membered heterocycloalkyl", by itself or in combination with other terms, refers to a saturated cyclic group consisting of 5 to 6 ring atoms, each of which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur atoms may be optionally oxidized (i.e., NO and S(O)). p, p is 1 or 2). Monocyclic and bicyclic ring systems are included, where bicyclic ring systems include spiro rings, fused rings, and bridged rings. Additionally, for this "5- to 6-membered heterocycloalkyl", a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule. The 5- to 6-membered heterocycloalkyl includes 5- and 6-membered heterocycloalkyl. Examples of 5-6 membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, etc.

[0079] Unless otherwise specified, the terms "5- to 6-membered heteroaromatic ring" and "5- to 6-membered heteroaryl" of the present invention can be used interchangeably, and the term "5- to 6-membered heteroaryl" refers to a monocyclic ring consisting of 5 to 6 ring atoms and having a conjugated π-electron system, in which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur atoms may be optionally oxidized (i.e., NO and S(O)). p, p is 1 or 2). The 5-6 membered heteroaryl may be linked to the remainder of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5-6 membered heteroaryl include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), triazolyl (including 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1, Examples of the aryl group include, but are not limited to, 2,4-triazolyl, tetrazolyl, isoxazolyl (such as 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl), thiazolyl (such as 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl), furyl (including 2-furyl and 3-furyl, and the like), thienyl (including 2-thienyl and 3-thienyl, and the like), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, and the like), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, and the like).

[0080] Unless otherwise stated, the terms "halo" or "halogen," by themselves or as part of another substituent, represent a fluorine, chlorine, bromine, or iodine atom.

[0081] The compounds of the present invention can be prepared by a variety of synthetic methods familiar to those skilled in the art, including the specific embodiments listed below, embodiments formed in combination with other chemical synthetic methods, and equivalent alternatives familiar to those skilled in the art, and preferred embodiments include, but are not limited to, those of the present invention.

[0082] The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art, and when the present invention relates to the absolute configuration of the compound, the absolute configuration can be verified by conventional means of those skilled in the art. For example, in single crystal X-ray diffraction (SXRD), the cultivated single crystal is collected by Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuKα radiation, the scanning method is φ / ω scanning, and after collecting relevant data, the crystal structure is further analyzed by direct method (Shelxs97), so that the absolute configuration can be verified.

[0083] The solvents used in the present invention are commercially available.

[0084] Compounds are named according to conventional naming principles in the art or using ChemDraw® software; commercially available compounds are named from the supplier catalog.

[0085] The present invention employs the following abbreviations: EDTA stands for ethylenediaminetetraacetic acid; cAMP stands for cyclic adenosine monophosphate; TMS stands for trimethylsilyl; DCM stands for dichloromethane; THF stands for tetrahydrofuran; TFA stands for trifluoroacetic acid; TEA stands for triethylamine; NaBH(OAc)3 stands for sodium borohydride acetate; Me stands for methyl. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0086] The present invention will be described in detail below with reference to examples, but is not intended to be an adverse restriction of the present invention. The present invention has been described in detail in this specification, and specific examples thereof have been disclosed. It is obvious to those skilled in the art that various modifications and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0087] Reference Example 1 JPEG0007675849000025.jpg87170Step 1: Synthesis of intermediates 1-3 A DMSO (200 mL) solution of t-butylamine (33.41 g, 456.79 mmol, 2.24 eq) and intermediate 1-2 (25 g, 203.8 mmol, 1 eq) was added to a dry flask and stirred at 90° C. for 12 hours. When the reaction solution became cloudy and condensed water stopped dripping, the reaction was terminated. The reaction solution was left to stand and separated, the upper layer was collected and washed with water (100 mL), the organic phase was left to stand and separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 1-3. 1 H NMR (400MHz, CD3OD)δ: 1.97(s, 2H), 1.09(s, 9H), 0.07(s, 9H). Step 2: Synthesis of intermediate 1 A 37% aqueous formaldehyde solution (16.52 g, 203.52 mmol, 1.41 eq) and intermediate 1-3 (23 g, 114.34 mmol, 1 eq) were added to a dry flask, and potassium carbonate (11.97 g, 86.61 mmol, 0.6 eq) and methanol (13.87 g, 433.03 mmol, 3 eq) were added at 0°C. The temperature was gradually raised to room temperature, and the mixture was stirred for another hour. The aqueous phase was removed, potassium carbonate (5.98 g, 43.3 mmol, 0.3 eq) was added, and the reaction was stirred at 20°C for 12 hours. The reaction solution was filtered, 50 mL water was added to the filtrate, and the mixture was stirred for 0.5 hours, then left to stand for liquid separation. The organic phase was dried and then concentrated under reduced pressure to obtain intermediate 1. 1 H NMR(400MHz, CD3OD)δ:4.18(s, 2H), 3.35(s, 3H), 2.28(s, 2H), 1.12(s, 9H), 0.05(s, 9H).

[0088] Reference Example 2 JPEG0007675849000026.jpg146170Step 1: Synthesis of intermediate 2-3 A solution of intermediate 2-1 (50 g, 271.53 mmol, 1 eq) in dichloromethane (500 mL) was added to a dry flask, and then oxalyl chloride (75.82 g, 597.37 mmol, 52.29 mL, 2.2 eq) and DMF (0.99 g, 13.58 mmol, 1.04 mL, 0.05 eq) were added at 0° C., and the reaction was stirred for 1 hour at 15° C. The reaction solution was concentrated under reduced pressure, and then dichloromethane (600 mL) was added to dissolve the solution, and lithium chloride (57.55 g, 1.36 mol, 5 eq) and triethylamine (137.36 g, 1.36 mol, 188.94 mL, 5 eq) were added at 0° C., and finally a solution of intermediate 2-2 (48.11 g, 271.49 mmol, 1 eq) in dichloromethane was added, and the reaction was stirred for 12 hours at 20° C. The reaction mixture was adjusted to pH 7 with 5% to 10% aqueous citric acid solution, allowed to stand and separated, and then the aqueous phase was extracted with dichloromethane (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was added to methyl t-butyl ether (100 mL), homogenized for 1 hour, and then filtered to obtain intermediate 2-3. 1 H NMR(400MHz, CDCl3)δ:8.08-7.95(m, 2H), 7.76-7.70(m, 1H), 7.41-7.28(m, 5H), 7.00-6.89(m, 2H), 4.88-4.82(m, 1H), 4.33-4.25(m, 2H), 3.44-3.30(m, 1H), 2.92-2.87(m, 1H). Step 2: Synthesis of intermediate 2-4 Intermediate 2-3 (40 g, 116.51 mmol, 1 eq) and intermediate 1 (47.39 g, 139.81 mmol, 1.2 eq) were dissolved in dichloromethane (400 mL), trifluoroacetic acid (13.28 g, 116.51 mmol, 8.63 mL, 1 eq) was slowly added dropwise while stirring, and the reaction was stirred at 15 ° C. for 1 hour. After the reaction was completed, 200 mL of saturated sodium bicarbonate solution was added, and the mixture was allowed to stand and separated. The aqueous phase was then added to dichloromethane (200 mL × 2) for extraction, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was added to methyl t-butyl ether (100 mL) and homogenized to obtain intermediate 2-4. 1H NMR(400MHz, CDCl3)δ =7.49-7.43(m, 1H), 7.29-7.23(m, 3H), 7.11-7.09(m, 2H), 6.89-6.85(m, 1H), 6.82-6.79(m, 1H), 4.73-4.67(m, 1H), 4.34-4.28(m, 1H), 4.23-4.12(m, 3H), 3.39-3.35(m, 1H), 3.24-3.20(m, 2H), 2.87-2.81(m, 2H), 2.76-2.71(m, 1H), 1.12(s, 9H). Step 3: Synthesis of intermediate 2 Intermediate 2-4 (23 g, 51.98 mmol, 1 eq) was dissolved in tetrahydrofuran (160 mL) and lithium hydroxide monohydrate (5.45 g, 129.94 mmol, 2.5 eq) and water (80 mL) were added. The reaction was stirred at 15°C for 12 hours. The reaction solution was directly concentrated under reduced pressure, then water (50 mL) and ethyl acetate (30 mL x 3) were added and extracted. The aqueous phase was adjusted to pH ~2 with 2N hydrochloric acid, then directly concentrated under reduced pressure, the residue was added to dichloromethane (50 mL), dissolved and filtered, and the organic phase was concentrated under reduced pressure to obtain intermediate 2. 1 H NMR(400MHz, DMSO)δ =12.48(s, 1H), 7.82(s, 1H), 7.28-7.23(m, 1H), 7.16-7.12(m, 1H), 3.98-3.64(m, 3H), 3.50-3.40(m, 2H), 3.23-3.17(m, 1H), 1.36(s, 9H).

[0089] Reference Example 3 JPEG0007675849000027.jpg69170JPEG0007675849000028.jpg75170Step 1: Synthesis of intermediate 3-2 Compound 3-1 (2.0 g, 8.81 mmol, 1 eq) and dichloromethane (2 mL) were added to a reaction flask, and oxalyl chloride (2.46 g, 19.38 mmol, 1.70 mL, 2.2 eq) and DMF (32.19 mg, 440.42 μmol, 33.88 μL, 0.05 eq) were added at 0° C., and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude acid chloride product, which was dissolved in 22 mL of dry dichloromethane. LiCl (1.90 g, 44.81 mmol, 917.56 μL, 5 eq) and triethylamine (4.53 g, 44.81 mmol, 6.24 mL, 5 eq) were added to the above solution, and then a dichloromethane (10 mL) solution of intermediate 2-2 (1.59 g, 8.96 mmol, 1 eq) was added dropwise, and the reaction solution was stirred at 25 ° C for 1 hour. The reaction solution was adjusted to pH ~ 7 with 5% ~ 10% citric acid aqueous solution, and after standing and separating, the aqueous phase was added to dichloromethane (200 ml × 2) for extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was slurried with tertiary methyl ether at room temperature (100 mL), followed by filtration to obtain intermediate 3-2. 1 H NMR (400 MHz, CDCl3) δ 7.83-7.92 (m, 2H), 7.47-7.51 (m, 4H), 7.31-7.331 (m, 2H), 7.21-7.24 (m, 3H), 4.76-4.80 (m, 1H), 4.18-4.21 (m, 1H), 3.35 (dd, 1H, J =2.8, 13.2 Hz), 3.08-3.10 (m, 1H), 2.83 (dd, 1H, J =9.6, 13.2 Hz). Step 2: Synthesis of intermediate 3-3 Intermediate 3-2 (1.0 g, 2.59 mmol, 1 eq), intermediate 1 (2.63 g, 7.77 mmol, 3.0 eq) and dichloromethane (10 mL) were added to a reaction flask, and trifluoroacetic acid (295.21 mg, 2.59 mmol, 191.69 μL, 1 eq) was slowly added dropwise at 25 ° C., and the reaction solution was stirred at 25 ° C. for 1 hour. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (30 mL), stirred for 10 minutes, and then allowed to stand to separate the layers. The aqueous phase was extracted with dichloromethane (30 mL × 3), and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative HPLC (column: Waters Xbridge BEH C18 250 * 50 mm * 10 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 45%-85%, 10 min), intermediate 3-3 was obtained. 1 H NMR (400 MHz, CDCl3) δ 7.39-7.41 (m, 2H), 7.17-7.23 (m, 5H), 6.94-6.97 (m, 2H), 4.61-4.65 (m, 1H),4.08-4.10 (m, 1H), 3.84-3.86 (m, 1H), 3.34-3.36 (m, 1H), 3.05-3.33 (m, 2H), 2.71-2.81 (m, 3H),2.51-2.69 (m, 2H). Step 3: Synthesis of intermediate 3 Intermediate 3-3 (0.8 g, 1.65 mmol, 1 eq) and tetrahydrofuran (8 mL) were added to a reaction flask, followed by lithium hydroxide monohydrate (207.46 mg, 4.94 mmol, 3.0 eq) and water (4 mL) at 0° C., and the reaction solution was stirred at 25° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and then extracted with water (50 mL) and ethyl acetate (30 mL×3). The organic phase was discarded, and the aqueous phase was adjusted to pH 2 with 2N hydrochloric acid, then concentrated under reduced pressure, and the residue was added to dichloromethane (50 mL), dissolved and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 3, which was used in the next step without further purification. MS m / z(ESI): 326.0 [M+H] + .

[0090] Reference Example 4 JPEG0007675849000029.jpg143170Step 1: Synthesis of intermediate 4-2 Add intermediate 4-1 (5g, 27.38mmol) and DCM (50mL) to a dry flask, add oxalyl chloride (7.65g, 60.24mmol) and DMF (200.13mg, 2.74mmol) in sequence at 0℃, slowly warm to 20℃, stir for 1 hour, and concentrate the reaction solution under reduced pressure to obtain a crude acid chloride product. Dissolve in 55mL of dichloromethane to obtain a solution, which was cooled to 0℃, add LiCl (5.80g, 136.78mmol, 2.80mL, 5eq), triethylamine (13.84g, 136.78mmol, 19.04mL, 5eq) and intermediate 2-2 (4.85g, 27.36mmol, 1eq) in sequence, warm to about 20℃, and stir for 12 hours. The pH was adjusted to 7 with 5% to 10% aqueous citric acid, and the mixture was allowed to stand for separation. The aqueous phase was extracted with dichloromethane (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Intermediate 4-2 was obtained by high-performance silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 4:1). MS m / z (ESI): 342.1 [M+H] + . Step 2: Synthesis of intermediate 4-3 A solution of intermediate 4-2 (2 g, 5.85 mmol) and intermediate 1 (2.38 g, 7.02 mmol) in DCM (20 mL) was added to a dry flask, and triethylamine (333.60 mg, 2.93 mmol) and 500 mg of trifluoroacetic acid were slowly added using a syringe at 0 °C, and the reaction was stirred at 15 °C for 12 hours. 20 mL of saturated sodium bicarbonate solution was injected into the reaction solution to adjust the pH to 7, and the mixture was allowed to stand and separated. The aqueous phase was extracted by adding 10 mL x 2 of dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Intermediate 4-3 was obtained by separation and purification using high-performance silica gel column chromatography (dichloromethane:methanol = 1:0-10:1). 1H NMR(400 MHz, CDCl3)δ ppm 7.12 - 7.25(m, 7 H), 6.93(dd, J =1.2, 6.8 Hz, 2 H), 4.62(m, 1 H), 4.05 - 4.21(m, 3 H), 3.85(q, J =8.0 Hz, 1 H), 3.33(t, J =9.2 Hz, 1 H), 3.18(t, J =8.0 Hz, 1 H), 3.04(dd, J =3.20, 13.60 Hz, 1 H), 2.80(br t, J =7.60 Hz, 1 H), 2.73(t, J =8.80 Hz, 1 H), 2.66(dd, J =8.8, 13.20 Hz, 1 H), 1.05(s, 9 H). MS m / z(ESI): 441.3 [M+H] + . Step 3: Synthesis of intermediate 4 A solution of intermediate 4-3 (300 mg, 680.33 μmol) in THF (2.4 mL) was added to a dry flask, LiOH.H2O (71.37 mg, 1.70 mmol) and H2O (1.2 mL) were added in sequence, and the mixture was stirred at 15°C for 3 hours. The reaction solution was concentrated under reduced pressure, 5 mL of water was added, and the pH was adjusted to 2 with 2N hydrochloric acid. Ethyl acetate (10 mL x 3) was added for extraction, and the organic phase was dried and directly concentrated under reduced pressure to obtain intermediate 4. MS m / z (ESI): 282.1 [M+H] + .

[0091] Reference Example 4 JPEG0007675849000030.jpg73170JPEG0007675849000031.jpg115170Step 1: Synthesis of intermediate 5-1 Compound 11-1 (1.6 g, 2.15 mmol, 52% purity, 1 eq), tetrahydropyran-4-one (431.15 mg, 4.31 mmol, 395.55 μL, 2 eq), dichloromethane (16 mL) and acetic acid (0.5 mL) were added to a dry flask, reacted at 20 ° C, stirred for 2 hours, then NaBH (OAc) 3 (684.54 mg, 3.23 mmol, 1.5 eq) was added and kept at 20 ° C., stirring was continued for 16 hours, 10 mL of saturated aqueous sodium bicarbonate was slowly added to pH ~ 7, extracted with dichloromethane (10 mL × 3), and the organic phase was combined, dried and concentrated under reduced pressure, separated and purified by silica gel column chromatography (DCM: MeOH = 1: 0 ~ 19: 1) to obtain intermediate 5-1. MS m / z (ESI): 471.2 [M + H] + . Step 2: Synthesis of intermediate 5 Add intermediate 5-1 (1.58 g, 1.98 mmol, 59% purity, 1 eq) and THF (15 mL) to a dry flask, add lithium hydroxide monohydrate (207.83 mg, 4.95 mmol, 2.5 eq) and water (5 mL), stir the reaction at 20 °C for 12 hours, concentrate under reduced pressure to remove THF, add ethyl acetate (10 mL x 3) to extract, discard the organic phase, adjust the aqueous phase to pH ~5 with 2N hydrochloric acid, then concentrate under reduced pressure to dryness, add the residue to 5 mL of dichloromethane for extraction, filter, and concentrate the filtrate under reduced pressure to give intermediate 5. MS m / z (ESI): 312.2 [M+H] + .

[0092] Example 1 JPEG0007675849000032.jpg123170Step 1: Synthesis of Compounds 1-3 A toluene (20 mL) solution of compound 1-1 (1.00 g, 4.67 mmol, 1 eq) and compound 1-2 (737.25 mg, 4.67 mmol, 444.13 μL, 1 eq) was added to a dry flask, sodium t-butoxide (672.66 mg, 7.00 mmol, 1.5 eq) and tri-t-butylphosphine palladium (238.47 mg, 466.62 μmol, 0.1 eq) were added, and the mixture was stirred at 100 ° C for 12 hours. The reaction solution was added to water (50 mL), and ethyl acetate (30 mL × 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and filtered, and the residue was separated and purified by column chromatography (gradient elution: petroleum ether: ethyl acetate (v / v) = 100: 0 to 80: 20). Compound 1-3 was obtained. 1 H NMR(400MHz, CDCl3)δ:8.21(dd, J=4.8, 1.2 Hz, 1H), 7.50-7.45(m, 1H), 6.61-6.59(m, 1H), 6.55(d, J=8.8 Hz, 1H), 4.51-4.32(m, 2H), 4.11-3.87(m, 2H), 3.22-3.03(m, 2H), 1.51(s, 9H), 1.22(d, J=6.8 Hz, 6H). Step 2: Synthesis of trifluoroacetate salts of compounds 1-4 Compound 1-3 (0.30 g, 1.03 mmol, 1 eq) and dichloromethane (5 mL) were added to a dry flask, followed by trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 13.12 eq) and stirred at 15° C. for 2 hours. The reaction was concentrated under reduced pressure to give the trifluoroacetate salt of compound 1-4, which was used in the next step without further purification. MS m / z (ESI): 192.3 [M+1] + . 1 H NMR(400MHz, CDCl3)δ:9.19-9.05(m, 1H), 8.02(s, 1H), 7.21-7.02(m, 2H), 4.48(s, 2H), 3.47(s, 4H), 1.50-1.26(m, 6H). Step 3: Synthesis of Compound 1 Compound 1-4 (300 mg, 1.06 mmol, 1 eq) and intermediate 2 (251.27 mg, 823.05 μmol, 0.78 eq) were dissolved in dichloromethane (10 mL) and triethylamine (214.30 mg, 2.12 mmol, 294.77 μL, 2 eq) and tri-n-propylphosphoric anhydride (673.84 mg, 1.06 mmol, 629.76 μL, 50% in ethyl acetate, 1 eq) were added at 0° C. The reaction was stirred at 15° C. for 1 h. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was separated and purified by preparative HPLC (column: Phenomenex Gemini-NX C18 250*50mm*10μm; mobile phase: [water ((0.05% ammonia water + 10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 50%-70%, 10min). Compound 1 was obtained. MS m / z(ESI): 457.2 [M+1] + . 1 H NMR(400MHz, DMSO)δ:8.14~8.09(m, 1H), 7.61-7.48(m, 2H), 7.19-7.01(m, 2H), 6.68-6.56(m, 2H), 4.45-4.27(m, 3H), 4.03-3.83(m, 2H), 3.53-3.17(m, 4H), 3.10-3.01(m, 1H), 2.89-2.78(m, 2H), 1.06(m, 9H), 1.04-1.01(m, 3H), 0.88-0.78(m, 3H).

[0093] Example 2 JPEG0007675849000033.jpg125170Step 1: Synthesis of compound 2-3 A toluene (10 mL) solution of compound 1-1 (0.50 g, 2.33 mmol, 1 eq) and compound 2-1 (492.72 mg, 2.80 mmol, 266.48 μL, 1.2 eq) was added to a dry flask, sodium t-butoxide (336.32 mg, 3.50 mmol, 1.5 eq) and tri-t-butylphosphine palladium (119.24 mg, 233.31 μmol, 0.1 eq) were added, and the mixture was stirred at 100 ° C for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (gradient elution: petroleum ether: ethyl acetate (v / v) = 100: 0 to 80: 20). Compound 2-2 was obtained. 1 H NMR(400MHz, CDCl3)δ =8.09(d, J=2.8 Hz, 1H), 7.29-7.24(m, 1H), 6.54-6.51(m, 1H), 4.23(s, 2H), 4.08-3.78(m, 2H), 3.18(s, 2H), 1.51(s, 9H), 1.16(d, J=6.8Hz, 6H). Step 2: Synthesis of the hydrochloride salt of compound 2-3 Compound 2-2 (0.40 g, 1.29 mmol, 1 eq) and ethyl acetate (4 mL) were added to a dry flask, and hydrochloric acid / ethyl acetate (4 M, 4 mL, 12.38 eq) was added and stirred at 15° C. for 1 h. The reaction was concentrated under reduced pressure to give the hydrochloride salt of compound 2-3, which was used in the next step without purification. MS m / z (ESI): 210.3 [M+H] + . Step 3: Synthesis of compound 2 Compound 2-3 hydrochloride (400 mg, 1.91 mmol, 1 eq) and intermediate 2 (541.55 mg, 1.91 mmol, 1 eq) were dissolved in dichloromethane (10 mL), and triethylamine (386.84 mg, 3.82 mmol, 532.11 μL, 2 eq) and tri-n-propyl phosphate anhydride (1.22 g, 1.91 mmol, 1.14 mL, 50% ethyl acetate solution, 1 eq) were added. The reaction was stirred at 15 °C for 1 h. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated and purified by preparative HPLC (column: Phenomenex Gemini-NX 80 * 40 mm * 3 μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile %: 35% ~ 65%, 8 min) to give compound 2. MS m / z (ESI): 475.2 [M + H] + . 1 H NMR(400MHz, DMSO)δ =8.12-8.08(m, 1H), 7.61-7.45(m, 2H), 7.16-7.00(m, 2H), 6.72-6.65(m, 1H), 4.34-4.21(m, 3H), 4.03-3.84(m, 2H), 3.52-3.43(m, 1H), 3.30-3.19(m, 2H), 3.07-3.02(m, 1H), 2.87-2.79(m, 3H), 1.06(s, 9H), 1.04-0.98(m, 2H)0.86(d, J=6.8 Hz, 2H), 0.77(d, J=6.8 Hz, 2H).

[0094] Example 3 JPEG0007675849000034.jpg49170JPEG0007675849000035.jpg102170Step 1: Synthesis of Compounds 3-2 and 3-3 Compound 1-1 (1.74 g, 8.11 mmol, 1.2 eq), compound 3-1 (1.5 g, 6.76 mmol, 777.20 μL, 1 eq) and dioxane (15 mL) were added to a 15 mL sealed tube, and then KHMDS (1 M, 8.11 mL, 1.2 eq) was added at 25 ° C under nitrogen protection, and the reaction solution was heated to 100 ° C and stirred for 16 hours. The reaction solution was cooled and poured into 100 mL of saturated ammonium chloride aqueous solution, extracted with dichloromethane (150 mL × 3), and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The product was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:0 to 1:1) to obtain compounds 3-2 and 3-3. MS m / z (ESI): 309 [M + H] + . Compound 3-2: 1 H NMR(400 MHz, CDCl3)δ ppm 7.06 - 7.15(m, 2 H), 6.95 - 7.05(m, 2 H), 4.01(td, J=4.7, 2.3 Hz, 2 H), 2.89(ddd, J=9.5, 6.2, 3.2 Hz, 2 H), 2.69(br s, 2 H), 1.50(s, 9 H), 0.72(d, J=6.3 Hz, 6 H); Compound 3-3: 1 H NMR(400 MHz, CDCl3)δ ppm 7.28 - 7.35(m, 1 H), 7.00 - 7.20(m, 0.5 H), 6.77 - 6.93(m, 2.5 H), 3.81(br, 0.3H+1.7H=2 H), 3.24(br s, 1.7 H), 3.11(br dd, J=12.8, 7.9 Hz, 1.7 H), 2.88 - 3.01(m, 0.3 H), 2.75(br s, 0.3 H), 1.56(s, 9 H), 0.93(d, J=6.4 Hz, 5 H), 0.78(d, J=6.1Hz, 1H). Step 2: Synthesis of the hydrochloride salt of compound 3-4 Compound 3-2 (300 mg, 972.79 μmol, 1 eq) and dichloromethane (5 mL) were added to a reaction flask, and hydrogen chloride / ethyl acetate solution (4 M, 12.16 mL) was added at 0° C., and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure to give the hydrochloride salt of compound 3-4, which was used in the next step without further purification. MS m / z (ESI): 209 [M+H] + . Step 3: Synthesis of compound 3 Intermediate 2 (150 mg, 529.45 μmol, 1 eq), hydrochloride salt of compound 3-4 (275.68 mg) and dichloromethane (5 mL) were added to a reaction flask, followed by triethylamine (267.88 mg, 2.65 mmol, 368.47 μL, 5 eq) and tri-n-propyl phosphate anhydride (505.38 mg, 794.18 μmol, 472.32 μL, 50% ethyl acetate solution, 1.5 eq), and the reaction solution was stirred at 25 ° C. for 16 hours. 50 mL of water and 150 mL of dichloromethane were added to the reaction solution, and the solution was allowed to stand to separate the layers. The aqueous phase was extracted with dichloromethane (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (column: Phenomenex luna C18 250*50mm*10μm; mobile phase: [water (HCl)-acetonitrile]; acetonitrile%: 10%-40%, 10min) to obtain the hydrochloride salt of compound 3. MS m / z(ESI): 474.4 [M+H] + ; 1 H NMR(400 MHz, DMSO-d6)δ ppm 7.67-8.13(m, 3 H), 7.16-7.45(m, 4 H), 4.55-4.58(m, 1 H), 4.00-4.07(m, 6 H), 3.61-3.67(m, 2 H), 3.25-3.30(m, 3 H), 1.39(d, J =10 Hz, 9 H), 0.92-0.97(m, 6 H).

[0095] Example 4 JPEG0007675849000036.jpg78170Step 1: Synthesis of the hydrochloride salt of compound 4-1 Compound 3-3 (300 mg, 972.79 μmol, 1 eq) and dichloromethane (5 mL) were added to a reaction flask, and hydrogen chloride / ethyl acetate solution (4 M, 12.16 mL) was added at 0° C., and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure to give the hydrochloride salt of compound 4-1. This was used in the next step without further purification. MS m / z (ESI): 209 [M+H] + . Step 2: Synthesis of compound 4 Intermediate 2 (150 mg, 529.45 μmol, 1 eq), compound 4-1 hydrochloride (250 mg) and dichloromethane (5 mL) were added to a reaction flask, followed by triethylamine (267.88 mg, 2.65 mmol, 368.47 μL, 5 eq) and tri-n-propyl phosphate anhydride (505.38 mg, 794.18 μmol, 472.32 μL, 50% ethyl acetate solution, 1.5 eq), and the reaction solution was stirred at 25° C. for 16 hours. 50 mL of water and 150 mL of dichloromethane were added to the reaction solution, and the solution was allowed to stand to separate the layers. The aqueous phase was extracted with dichloromethane (10 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (column: Phenomenex luna C18 250*50mm*10μm; mobile phase: [water (HCl)-acetonitrile]; acetonitrile%: 10%-40%, 10min) to obtain the hydrochloride salt of compound 4. MS m / z(ESI): 474.4 [M+H] + ; 1 H NMR(400 MHz, DMSO-d6)δ ppm 7.68-7.86(m, 2 H), 7.08-7.34(m, 5 H), 3.97-4.05(m, 6 H), 3.48-3.52(m, 3 H), 3.28-3.49(m, 3 H), 1.39(d, J =5.2 Hz, 9 H), 0.81-0.95(m, 6 H).

[0096] Example 5 JPEG0007675849000037.jpg119170Step 1: Synthesis of compound 5-2 Compound 1-1 (500 mg, 2.33 mmol, 1 eq), compound 5-1 (1.27 g, 4.67 mmol, 686.08 μL, 2 eq), sodium t-butoxide (448.43 mg, 4.67 mmol, 2 eq) and toluene (5 mL) were added to a reaction flask, and bis(tri-t-butylphosphine)palladium (238.47 mg, 466.63 μmol, 0.2 eq) was added under a nitrogen atmosphere, and the reaction solution was stirred at 100 ° C. for 16 hours. After the reaction was completed, the reaction solution was filtered, 10 mL of water and dichloromethane (10 mL) were added to the filtrate, and the separated aqueous phase was extracted with dichloromethane (10 mL × 2), and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 1:0 to 10:1) to give compound 5-2. 1 H NMR(400 MHz, CDCl3)δ ppm 7.53(d, J =8.80 Hz, 2 H), 7.00(br d, J =8.40 Hz, 2 H), 3.42 - 3.59(m, 6 H), 1.51(s, 9 H), 1.01(d, J =6.40 Hz, 6 H). Step 2: Synthesis of the hydrochloride salt of compound 5-3 Compound 5-2 (300 mg, 837.06 μmol, 1 eq) and dichloromethane (2 mL) were added to a reaction flask, followed by hydrogen chloride in ethyl acetate (4 M, 33.66 mL, 160.86 eq), and the reaction was stirred at 25° C. for 1 h. When the raw material was consumed, the reaction was concentrated under reduced pressure to give the crude hydrochloride product of compound 5-3, which was used in the next step without purification. MS m / z(ESI): 259 [M+H] + . Step 3: Synthesis of compound 5 To a reaction flask was added intermediate 2 (192.24 mg, 542.85 μmol, 1 eq), the hydrochloride salt of compound 5-3 (240 mg, 814.27 μmol, 1.5 eq) and dichloromethane (10 mL), followed by triethylamine (274.65 mg, 2.71 mmol, 5 eq) and tri-n-propylphosphoric acid anhydride (518.17 mg, 814.27 μmol, 50% in ethyl acetate, 1.5 eq) and the reaction was stirred at 25° C. for 1 hour. After the reaction was completed, 20mL of water and 20mL of dichloromethane were added to the reaction solution, and the mixture was allowed to stand to separate the layers. The aqueous phase was then extracted with dichloromethane (50mL x 3), and the organic phases were combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (column: Waters Xbridge BEH C18 250*50mm*10μm; mobile phase: [water (10 mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 55%-75%, 10min) to obtain compound 5. 1 H NMR(400 MHz, CDCl3)δ ppm 7.38 - 7.57(m, 3 H), 6.98(br dd, J =12, 8.8 Hz, 2 H), 6.70 - 6.91(m, 2 H), 3.33 - 4.06(m, 6 H), 2.81 - 3.32(m, 6 MS m / z(ESI): 524 [M+H] + .

[0097] Example 6 JPEG0007675849000038.jpg50170JPEG0007675849000039.jpg73170Step 1: Synthesis of compound 6-1 Bromobenzene (1.10g, 7.00mmol, 738.15μL, 1.5eq), compound 1-1 (1.0g, 4.67mmol, 1eq), potassium t-butoxide (785.40mg, 7.00mmol, 1.5eq) and dimethylsulfoxide (10mL) were added to a microwave tube and stirred at 120℃ for 0.5 hours. After completion, the reaction solution was filtered, 50mL of water and ethyl acetate (10mL) were added to the filtrate, extracted and separated, the aqueous phase was extracted with ethyl acetate (10mL×3), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product, and separated by silica gel column chromatography (gradient elution: petroleum ether: ethyl acetate = 1:0 to 10:1) to obtain compound 6-1. 1 H NMR(400 MHz, CDCl3)δ ppm 7.28 - 7.33(m, 2 H), 7.09 - 7.18(m, 3 H), 3.80 - 4.06(m, 2 H), 2.99 - 3.16(m, 2 H), 2.72 - 2.92(m, 2 H), 1.50(s, 9H), 0.78(d, J=6.4Hz, 6H). Step 2: Synthesis of the hydrochloride salt of compound 6-2 Compound 6-1 (120 mg, 413.22 μmol, 1 eq) and dichloromethane (5 mL) were added to a reaction flask, followed by hydrogen chloride in ethyl acetate (4 M, 16.62 mL, 160.86 eq) and the reaction was stirred at 25° C. for 1 h. The reaction was concentrated under reduced pressure to give the crude hydrochloride salt of compound 6-2, which was used in the next step without further purification. MS m / z (ESI): 191.2 [M+H] + . Step 3: Synthesis of the hydrochloride salt of compound 6 Compound 6-2 hydrochloride (94 mg, 494.00 μmol, 1 eq), intermediate 2 (139.96 mg, 494.00 μmol, 1 eq) and dichloromethane (2 mL) were added to a reaction flask, followed by triethylamine (249.94 mg, 2.47 mmol, 5 eq) and a 50% concentration tri-n-propylphosphoric acid anhydride ethyl acetate solution (471.54 mg, 741.00 μmol, 1.5 eq), and the reaction solution was stirred at 25° C. for 1 hour. 20 mL of water and 20 mL of dichloromethane were added to the reaction solution, and the solution was allowed to stand to separate the layers. The aqueous phase was extracted with dichloromethane (20 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (column: Phenomenex luna C18 250*50mm*10μm; mobile phase: [water (HCl)-acetonitrile]; acetonitrile%: 10%~40%, 10min) to obtain the hydrochloride salt of compound 6. 1 H NMR(CDCl3, 400 MHz)δ 7.30-7.39(m, 1H), 7.21(br d, 2H, J =7.6 Hz), 7.08(br d, 1H, J =6.4 Hz), 6.9-7.0(m, 2H), 6.6-6.9(m, 2H), 4.2-4.5(m, 1H), 3.8-4.0(m, 1H), 3.5-3.7(m, 1H), 3.10-3.35(m, 1H), 3.0-3.2(m, 2H), 2.3-3.0(m, 6H), 1.06(br s, 9H), 0.4-0.7(m, 6H).MS m / z(ESI): 456.4 [M+H] + .

[0098] Example 7 JPEG0007675849000040.jpg128170Step 1: Synthesis of compound 7-2 Add intermediate 2-3 (2.0g, 5.83mmol, 1eq), compound 7-1 (1.66g, 6.99mmol, 1.2eq) and DCM (20mL) to a reaction flask, slowly add TFA (132.84mg, 1.17mmol, 86.26μL, 0.2eq) at 25℃, and after the addition, stir the reaction solution at 25℃ for 1 hour. After the reaction, pour the reaction solution into a saturated aqueous sodium bicarbonate solution (20mL), stir for 10 minutes, and then leave to separate the layers. Extract the aqueous phase with dichloromethane (100mL×3), combine the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=5:1) to obtain compound 7-2. 1 H NMR(400 MHz, CDCl3)δ 7.25-7.28(m, 5H), 7.19-7.20(m, 4H), 7.07-7.19(m, 2H), 6.70-6.78(m, 2H),4.60-4.61(m, 1H), 407-4.18(m, 4H), 3.56-3.68(m, 2H), 3.04-3.17(m, 3H), 2.67-2.71(m, 3H). Step 2: Synthesis of compound 7-3 Compound 7-2 (1.3 g, 2.73 mmol, 1 eq) and THF (13 mL) were added to a reaction flask, followed by lithium hydroxide monohydrate (343.42 mg, 8.18 mmol, 3.0 eq) and H2O (6 mL) at 0° C., and the reaction was stirred at 25° C. for 4 hours. The reaction was concentrated under reduced pressure to dryness, extracted with water (50 mL) and ethyl acetate (30 mL×3), the aqueous phase was adjusted to pH=2 with 2N hydrochloric acid, concentrated under reduced pressure, the residue was added to dichloromethane (50 mL), dissolved and filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 7-3, which was used in the next step without further purification. 1 H NMR(400 MHz, CDCl3)δ ppm 7.57(br d, J =7.2 Hz, 2 H), 7.38-7.47(m, 4 H), 6.73 - 6.84(m, 2 H), 4.39(s, 2 H), 4.10 - 4.34(m, 1H), 3.67- 3.74(m, 3H), 3.26 -3.54(m, 2H). Step 3: Synthesis of compound 7-4 Compound 3-4 hydrochloride (131.11 mg, 535.72 μmol, 1.0 eq), compound 7-3 (170 mg, 535.72 μmol, 1.0 eq) and DCM (5 mL) were added to the reaction flask, followed by triethylamine (271.05 mg, 2.68 mmol, 372.83 μL, 5 eq) and a 50% concentration tri-n-propyl phosphate anhydride ethyl acetate solution (511.37 mg, 803.58 μmol, 1.5 eq), and the reaction solution was stirred at 25 ° C. for 1 hour. 10 mL of water and 20 mL of dichloromethane were added to the reaction solution, and the solution was allowed to stand to separate the layers. The aqueous phase was extracted with dichloromethane (20 mL × 3), and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 0 to 1: 1) to obtain compound 7-4. 1 H NMR(CDCl3, 400 MHz)δ 7.4-7.5(m, 1H), 7.3(m, 2H), 7.20-7.26(m, 2H), 7.2(m, 1H), 6.9-7.0(m, 4H), 6.7-6.8(m, 1H), 6.6-6.7(m, 1H), 4.48(tdd, J =2.4, 7.2, 10 Hz, 1H), 3.9-4.0(m, 1H), 3.6-3.8(m, 2H), 3.4-3.5(m, 1H), 3.2-3.4(m, 1H), 3.0-3.2(m, 1H), 2.8-3.0(m, 3H), 2.4-2.7(m, 4H), 0.40-0.66(m, 6H). Step 4: Synthesis of the hydrochloride salt of compound 7-5 Wet Pd / C (0.3 g, 10% palladium content) and anhydrous methanol (20 mL) were added to the reaction flask, followed by compound 7-4 (170 mg, 334.92 μmol, 1 eq) and concentrated hydrochloric acid (0.5 mL), and the mixture was stirred at 40° C. under 40 psi H2 atmosphere for 3 h. The reaction was filtered through diatomaceous earth, the filter cake was washed with methanol (30 mL×2), and the filtrate was concentrated under reduced pressure to give the crude hydrochloride product of compound 7-5, which was used in the next step without purification. MS m / z(ESI): 418.2 [M+H] + . Step 5: Synthesis of compound 7 Compound 7-5 hydrochloride (152 mg, 334.86 μmol, 1 eq), tetrahydropyran-4-one (67.05 mg, 669.71 μmol, 61.51 μL, 2 eq), triethylamine (67.77 mg, 669.71 μmol, 93.22 μL, 2 eq), DCM (10 mL) and AcOH (0.1 mL) were added to the reaction flask, and the reaction solution was stirred at 25 ° C for 2 hours, after which NaBH (OAc) 3 (106.45 mg, 502.28 μmol, 1.5 eq) was added and the reaction solution was further stirred at 25 ° C for 16 hours. 5 mL of saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative HPLC (column: Waters Xbridge BEH C18 250*50mm*10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 45%-75%, 10min) to obtain compound 7. 1 H NMR(400 MHz, CDCl3)δ ppm 7.38 - 7.55(m, 1 H), 6.93 - 7.11(m, 4 H), 6.71 - 6.92(m, 2 H), 4.49 - 4.63(m, 1 H), 3.89 - 4.06(m, 3 H), 3.49 - 3.65(m, 1 H), 3.29 - 3.47(m, 3 H), 3.10 - 3.24(m, 1 H), 2.68 - 3.08(m, 5.5 H), 2.30 - 2.58(m, 2.5 H), 1.82(br d, J=11.0 Hz, 2 H), 1.62(br t, J=11.5 Hz, 2 H), 0.44 - 0.77(m, 6 H). MS m / z(ESI): 502.3 [M+H] + .

[0099] Example 8 JPEG0007675849000041.jpg88170Step 1: Synthesis of the hydrochloride salt of compound 8 Compound 3-4 hydrochloride (90.02 mg, 367.84 μmol), intermediate 3 (200 mg, 367.84 μmol) and dichloromethane (5 mL) were added to the reaction flask, then TEA (186.11 mg, 1.84 mmol) and tri-n-propyl phosphate anhydride 50% ethyl acetate solution (351.12 mg, 551.76 μmol) were added, and the reaction solution was stirred at 25 ° C for 1 hour. After the reaction was completed, 10 mL of water was added to the reaction solution, extracted with dichloromethane (3 × 10 mL), and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (column: Phenomenex Luna 80 * 30 mm * 3 μm; mobile phase: [water (HCl)-acetonitrile]; acetonitrile %: 1% ~ 35%, 8 min) to obtain the hydrochloride salt of compound 8. 1 H NMR(DMSO-d6, 400 MHz)δ 10.8-12.0(m, 1H), 7.65(d, 2H, J =8.4 Hz), 7.50-7.56(m, 3H), 7.35-7.47(m, 3H), 4.41-4.55(m, 1H), 3.51-3.90(m, 11H), 1.38(s, 9H), 0.56-0.84(m, 6H). MS m / z(ESI): 516.2 [M+H] + .

[0100] Example 9 JPEG0007675849000042.jpg79170Step 1: Synthesis of compound 9 A dry flask was charged with intermediate 4 (150 mg, 399.25 μmol), hydrochloride salt of compound 3-4 (97.71 mg, 399.25 μmol) and dichloromethane (5 mL) solution, then triethylamine (121.20 mg, 1.20 mmol) and ethyl acetate solution of tri-n-propyl phosphate anhydride (381.10 mg, 598.88 μmol, 50%) were added and stirred at 25 ° C for 12 hours. The reaction solution was extracted three times with 5 mL of water and 5 mL of dichloromethane, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the crude product was separated by preparative HPLC (column: Phenomenex C18 75 * 30 mm * 3 μm; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile %: 30% to 80%, 8 min) to obtain compound 9. 1 H NMR(400 MHz, CD3OD)δ ppm 7.36 - 7.44(m, 3 H), 7.31(s, 1 H), 6.90 - 7.16(m, 4 H), 4.36 - 4.48(m, 1 H), 3.63 - 3.72(m, 1 H), 3.40 - 3.58(m, 2 H), 3.08 - 3.27(m, 2 H), 2.62 - 3.05(m, 3 H), 2.40 - 2.57(m, 2 H), 1.52 - 1.65(m, 1 H), 1.18(s, 9 H), 0.71(d, J =6.0 Hz, 1H), 0.62 - 0.69(m, 3H), 0.46(d, J =6.4 Hz, 2H). MS m / z(ESI): 472.3 [M+H] + .

[0101] Example 10 JPEG0007675849000043.jpg50170JPEG0007675849000044.jpg64170Step 1: Synthesis of compound 10-2 Compound 10-1 (2.0 g, 17.46 mmol, 1.56 mL, 1 eq), cyclopropyl borate (1.50 g, 17.46 mmol, 1 eq) and toluene-H2O (22 mL, 10:1) were added to a reaction flask, followed by the addition of Cs2CO3 (17.07 g, 52.39 mmol, 3 eq), and then Pd(dppf)Cl2 (1.28 g, 1.75 mmol, 0.1 eq) was added under a N2 atmosphere and stirred at 110 ° C for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, 20 mL of water and 20 mL of ethyl acetate were added, and the mixture was allowed to stand to separate the layers. The aqueous phase was extracted with ethyl acetate (3 × 10 mL), and the organic phase was combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a crude product. The crude product was subjected to high-performance silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 10:1) to obtain compound 10-2. MS m / z(ESI): 121.1 [M+H] + . Step 2: Synthesis of compound 10-3 PtO2 (75.60 mg, 332.91 μmol, 0.05 eq) and acetic acid (44 mL) were added to the reaction flask, followed by compound 10-2 (0.8 g, 6.66 mmol, 1 eq), and the reaction was stirred at 25 °C under H2 (15 PSI) for 16 h. After completion of the reaction, the reaction was filtered through diatomaceous earth, the filter cake was washed with methanol (30 mL x 2), and the filtrate was concentrated under reduced pressure to obtain the crude acetate product of compound 10-3, which was used in the next step without purification. MS m / z (ESI): 127.1 [M+H] + . Step 3: Synthesis of compound 10-4 The acetate crude product of compound 10-3 (1.64 g, 8.81 mmol, 1 eq), 1,4-dioxane (50 mL), and H2O (25 mL) were added to a reaction flask, and then sodium bicarbonate (4.44 g, 52.83 mmol, 2.05 mL, 6 eq) and benzyl chloroformate (751.05 mg, 4.40 mmol, 625.88 μL, 0.5 eq) were added at 0 ° C., and the reaction solution was stirred at 25 ° C. for 1 hour. Ethyl acetate (10 mL) was added to the reaction solution, and the mixture was allowed to stand to separate the layers, and the aqueous phase was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by high-performance silica gel column chromatography (petroleum ether: ethyl acetate = 1:0 to 1:1) to obtain compound 10-4. 1 HNMR(CDCl3, 400 MHz)δ 7.31-7.50(m, 6H), 5.10-5.18(m, 2H), 4.01-4.05(m, 2H), 2.91-2.97(m, 2H), 2.67-2.78(m, 2H), 1.77(br s, 1H), 0.71-0.75(m, 1H), 0.49-0.51(m, 2H), 0.18-0.30(m, 2H). Step 4: Synthesis of compound 10-6 Compound 10-4 (500 mg, 1.92 mmol, 1 eq), compound 10-5 (852.75 mg, 3.84 mmol, 441.84 μL, 2 eq), sodium t-butoxide (369.15 mg, 3.84 mmol, 2 eq) and toluene (5 mL) were added to a reaction flask, and bis(tri-t-butylphosphine)palladium (196.31 mg, 384.13 μmol, 0.2 eq) was added under a nitrogen atmosphere, and the reaction solution was stirred at 100° C. for 16 hours. The reaction mixture was concentrated under reduced pressure, and 20 mL of dichloromethane and 20 mL of water were added. The mixture was allowed to stand to separate the layers. The aqueous phase was extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain compound 10-6. 1HNMR(CDCl3, 400 MHz)δ 7.33-7.39(m, 5H), 6.95(br d, J =6.8Hz, 4H), 5.13-5.23(m, 2H), 3.40-3.91(m, 4H), 3.00-3.30(m, 2H), 2.51-2.54(m, 1H), 0.89-0.90(m, 1H), 0.21-0.50(m, 1H), 0.18-0.20(m, 1H), - 0.08-0.1(m, 1H), - 0.28-0.26(m, 1H). Step 5: Synthesis of compound 10-7 Pd / C (0.3 g, 10% palladium content) and ethyl acetate (20 mL) were added to the reaction flask, followed by compound 10-6 (0.15 g, 423.23 μmol, 1 eq), and the reaction was stirred at 25° C. for 4 h under H2 (15 psi). The reaction was filtered through diatomaceous earth, the filter cake was washed with methanol (100 mL×2), and the filtrate was concentrated under reduced pressure to give compound 10-7 crude, which was used in the next step without purification. MS m / z(ESI): 221.1 [M+H] + . Step 6: Synthesis of compound 10 Compound 10-7 (81 mg, 367.71 μmol, 1.0 eq), intermediate 2 (130.22 mg, 367.71 μmol, 1 eq) and dichloromethane (3 mL) were added to a reaction flask, followed by triethylamine (186.04 mg, 1.84 mmol, 5 eq) and a 50% solution of tripropylphosphonic anhydride in ethyl acetate (350.99 mg, 551.56 μmol, 1.5 eq), and the reaction solution was stirred at 25° C. for 1 hour. After the reaction was completed, 20 mL of water and 20 mL of dichloromethane were added, and the mixture was allowed to stand to separate the layers. The aqueous phase was extracted with dichloromethane (20 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 55%-75%, 8min) to obtain compound 10. 1H NMR(CDCl3, 400 MHz)δ 7.4-7.5(m, 1H), 6.9-7.0(m, 2H), 6.7-6.9(m, 4H), 3.8-4.1(m, 2H), 3.4-3.7(m, 4H), 3.1-3.3(m, 3H), 2.8-3.0(m, 3H), 2.2-2.5(m, 1H), 1.1-1.2(m, 9H), 0.6-0.9(m, 1H), -0.2-0.4(m, 3H), -0.4 - -0.2(m, 1H). MS m / z(ESI): 486.3 [M+H] + .

[0102] Example 11 JPEG0007675849000045.jpg124170Step 1: Synthesis of compound 11-1 Palladium carbon catalyst (1.0 g, 10% palladium content) and methanol (30 mL) were added to the reaction flask, followed by compound 7-2 (1.0 g, 2.10 mmol, 1 eq) and 2 mol / L hydrochloric acid (0.5 mL), and stirred at 40° C. for 16 hours under the action of H2 (40 PSI). The reaction solution was filtered through diatomaceous earth, the filter cake was washed with methanol (200 mL×2), and the filtrate was concentrated under reduced pressure to give compound 11-1. MS m / z(ESI): 387.1 [M+H] + . Step 2: Synthesis of compound 11-2 Compound 11-1 (500mg, 1.29mmol, 1eq), 3-chloropyridazine hydrochloride (976.95mg, 6.47mmol, 5eq) and DMSO (5mL) were added to the reaction flask, then N,N-diisopropylethylamine (1.00g, 7.76mmol, 1.35mL, 6eq) and cesium fluoride (196.56mg, 1.29mmol, 1eq) were added, and the reaction solution was stirred at 100°C for 16 hours. After the reaction was completed, 150mL of water was added, and the mixture was extracted with ethyl acetate (50mL x 3), and the organic phase was combined and washed with 100mL of water. The organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 0:1) to obtain compound 11-2. 1H NMR(CDCl3, 400 MHz)δ 8.51-8.52(m, 1H), 7.14-7.41(m, 5H), 7.00-7.01(m, 2H), 6.80-6.82(m, 2H), 6.57-6.59(m, 1H), 4.62-4.66(m, 2H), 4.04-4.27(m, 5H), 3.63-3.80(m, 2H), 3.06-3.10(m, 1H), 2.64-2.69(m, 1H). MS m / z(ESI): 465.2 [M+H] + . Step 3: Synthesis of compound 11-3 Compound 11-2 (110 mg, 236.83 μmol, 1 eq) and tetrahydrofuran (4 mL) were added to the reaction flask, followed by lithium hydroxide monohydrate (29.81 mg, 710.50 μmol, 3.0 eq) and H2O (2 mL) at 0°C, and the reaction solution was stirred at 25°C for 4 hours. The reaction solution was concentrated under reduced pressure, and then water (10 mL) was added, and ethyl acetate (10 mL x 3) was added for extraction. The aqueous phase was adjusted to pH ~5 with 2N hydrochloric acid, and then directly concentrated under reduced pressure to obtain compound 11-3. It was used in the next step without further purification. MS m / z (ESI): 306.1 [M+H] + . Step 4: Synthesis of compound 11 Compound 3-4 (100 mg, 480.14 μmol, 1 eq), compound 11-3 (146.58 mg, 480.14 μmol, 1.0 eq) and DCM (2 mL) were added to a reaction flask, followed by triethylamine (242.92 mg, 2.40 mmol, 334.15 μL, 5 eq) and a 50% solution of tripropyl phosphate anhydride in ethyl acetate (458.31 mg, 720.20 μmol, 1.5 eq), and the reaction solution was stirred at 25° C. for 2 hours. 20 mL of water and 20 mL of dichloromethane were added to the reaction solution, and the solution was allowed to stand to separate the layers. The aqueous phase was extracted with dichloromethane (20 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 35%-65%, 8min) to obtain compound 11. 1 H NMR(CDCl3, 400 MHz)δ 8.59-8.61(m, 1H), 7.21-7.26(m, 2H), 7.00-7.02(m, 1H), 6.95-6.98(m, 5H), 6.68-6.69(m, 1H), 4.54-4.57(m, 1H), 4.05-4.13(m, 3H), 3.69-3.90(m, 4H), 2.90-2.98(m, 2H), 2.17-2.7(m, 1H), 2.42-2.60(m, 1H), 0.65-0.77(m, 6H). MS m / z(ESI): 496.3 [M+H] + .

[0103] Example 12 JPEG0007675849000046.jpg51170JPEG0007675849000047.jpg126170 Step 1: Synthesis of compound 12-1 Compound 7-3 (1.2 g, 3.78 mmol, 1 eq), toluene (9 mL) and methanol (1 mL) were added to a reaction flask, trimethylsilyldiazomethane (2 M, 5.67 mL, 3 eq) was added dropwise to the solution, and the reaction was stirred at 25° C. for 1 hour. Glacial acetic acid was added dropwise to the reaction until it became colorless, and the reaction was directly concentrated under reduced pressure, followed by addition of water (20 mL), followed by extraction with dichloromethane (10 mL×3). The organic phase was collected and concentrated under reduced pressure to obtain the crude acetate product of compound 12-1, which was used in the next step without further purification. MS m / z(ESI): 332.1 [M+H] + . Step 2: Synthesis of compound 12-2 Acetate salt of compound 12-1 (0.61 g, 1.56 mmol, 1 eq) and palladium carbon catalyst (1 g, 10% palladium content) were added to a reaction flask, followed by methanol (10 mL) and ethyl acetate (10 mL), and the mixture was stirred at 40° C. under an H2 (40 psi) atmosphere for 4 hours. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with methanol (200 mL×2), and the filtrate was concentrated under reduced pressure to obtain crude compound 12-2. MS m / z(ESI): 242.0 [M+H] + . Step 3: Synthesis of compound 12-3 Compound 12-2 (80 mg, 265.53 μmol, 1 eq), 2-fluoro-5-cyanopyridine hydrochloride (126.40 mg, 1.04 mmol, 5 eq) were added to a reaction flask, followed by toluene (1 mL) and N,N-diisopropylethylamine (1 mL), and the mixture was stirred at 80° C. for 1 hour in a microwave. The reaction solution was concentrated under reduced pressure, and then water (20 mL) was added, followed by extraction with dichloromethane (10 mL×3). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by a silica gel column (petroleum ether:ethyl acetate=10:0 to 2:1) to obtain compound 12-3. MS m / z(ESI): 344.1 [M+H] + . Step 4: Synthesis of compound 12-4 Compound 12-3 (113 mg, 329.13 μmol, 1 eq) and tetrahydrofuran (3 mL) were added to a reaction flask, followed by lithium hydroxide monohydrate (41.43 mg, 987.40 μmol, 3.0 eq) and H2O (1.5 mL) at 0°C, and the reaction was stirred at 25°C for 4 hours. 10 mL of water and dichloromethane (10 mL x 3) were added for extraction, the organic phase was discarded, and the aqueous phase was adjusted to pH = 2 with 2M dilute hydrochloric acid and concentrated under reduced pressure. The obtained solid was extracted with a mixed solvent of dichloromethane:methanol = 10:1 (10 mL x 3), filtered, and the filtrate was collected and evaporated to dryness under reduced pressure to obtain crude compound 12-4, which was used in the next step without further purification. 1 H NMR(400 MHz, DMSO-d6)δ 8.52 - 8.48(m, 1H), 7.85(dd, J =2.1, 9.0 Hz, 1H), 7.57 - 7.50(m, 1H), 7.28 - 7.21(m, 1H), 7.13 - 7.07(m, 1H), 6.64(br d, J =9.1 Hz, 1H), 4.07 - 3.61(m, 6H). MS m / z(ESI): 330.1 [M+H] + . Step 5: Synthesis of compound 12 Compound 12-4 (80 mg, 242.94 μmol, 1 eq), compound 3-4 (83.94 mg, 291.53 μmol, 1.2 eq) and dichloromethane (1 mL) were added to the reaction flask, and then triethylamine (122.92 mg, 1.21 mmol, 169.07 μL, 5 eq) and 50% ethyl acetate solution of tri-n-propyl phosphate anhydride (231.90 mg, 364.41 μmol, 1.5 eq) were added, and the mixture was stirred at 25 ° C for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 μm; mobile phase: [water (10 mM ammonium bicarbonate) -acetonitrile]; acetonitrile%: 50% ~ 80%, 8 min) to obtain compound 12. 1H NMR(400 MHz, DMSO-d6)δ 8.54 - 8.48(m, 1H), 7.90 - 7.84(m, 1H), 7.67 - 7.45(m, 1H), 7.40 - 7.21(m, 1H), 7.20 - 7.06(m, 4H), 7.04 - 6.97(m, 1H), 6.70 - 6.61(m, 1H), 4.31 - 4.14(m, 1H), 4.12 - 3.92(m, 4H), 3.89 - 3.78(m, 1H), 3.67 - 3.43(m, 2H), 3.04 - 2.82(m, 2H), 2.64 - 2.55(m, 2H), 0.68 - 0.50(m, 6H). MS m / z(ESI): 520.3 [M+H] + .

[0104] Example 13 JPEG0007675849000048.jpg50170JPEG0007675849000049.jpg74170Step 1: Synthesis of compound 13-1 Dichloromethane (20 mL) was added to the reaction flask, and compound 11-1 (600 mg, 1.55 mmol, 1 eq), phenylboronic acid (378.67 mg, 3.11 mmol, 2 eq), Cu(OAc)2 (564.08 mg, 3.11 mmol, 2 eq) and triethylamine (1.26 g, 12.42 mmol, 1.73 mL, 8 eq) were added in sequence, and the reaction solution was stirred at 25 ° C for 6 hours. It was filtered, extracted with dichloromethane (20 mL × 3), and the organic phase was combined and dried over anhydrous sodium sulfate, and then concentrated to obtain a crude product. It was purified by high-performance silica gel column chromatography (petroleum ether: ethyl acetate = 1: 0 to 10: 1) to obtain compound 13-1. MS m / z (ESI): 463.2 [M + H] + . Step 2: Synthesis of compound 13-2 Tetrahydrofuran (1 mL) and H2O (0.5 mL) were added to a reaction flask, compound 13-1 (93 mg, 201.09 μmol, 1 eq) was added, lithium hydroxide monohydrate (25.31 mg, 603.26 μmol, 3 eq) was added, and then the mixture was stirred at 25°C for 2 hr. The reaction solution was concentrated under reduced pressure, 6 mL of water was added, and ethyl acetate (6 mL x 3) was added for extraction. The organic phase was discarded, and the aqueous phase was adjusted to pH ~5 with 2 mol / L hydrochloric acid, and then concentrated to dryness. The hydrochloride salt of compound 13-2 was obtained and used in the next step without further purification. MS m / z (ESI): 304.2 [M+H] + . Step 3: Synthesis of compound 13 Dichloromethane (5 mL) was added to the reaction flask, followed by the hydrochloride salt of compound 13-2 (53 mg, 174.74 μmol), compound 3-4 (53.46 mg, 205.33 μmol, 1.18 eq), triethylamine (88.41 mg, 873.71 μmol, 121.61 μL, 5 eq) and a 50% solution of tri-n-propyl phosphate anhydride in ethyl acetate (166.80 mg, 262.11 μmol, 1.5 eq) and the reaction was stirred for 16 hours at 25° C. Extraction was performed by adding 10 mL of water and 10 mL of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was separated and purified by HPLC (column: Phenomenex C18 80*40mm*3μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 40%-70%, 8min) to obtain compound 13. 1 H NMR(400 MHz, CDCl3)δ 7.38 - 7.24(m, 3H), 7.08 - 6.75(m, 7H), 6.62 - 6.59(m, 2H), 4.58 - 4.51(m, 1H), 4.25 - 4.09(m, 1H), 3.81 - 3.61(m, 6H), 3.05 - 2.81(m, 2H), 2.62 - 2.15(m, 2H), 0.81 - 0.61(m, 6H). MS m / z(ESI): 494.3 [M+H] + .

[0105] Example 14 JPEG0007675849000050.jpg132170Step 1: Synthesis of compound 14-1 Compound 1-1 (0.5 g, 2.33 mmol, 1 eq), 4-bromo-1,2-difluorobenzene (540.32 mg, 2.80 mmol, 1.2 eq) and tetrahydrofuran (10 mL) were added to a reaction flask, and at 0° C., under a nitrogen atmosphere, KHMDS solution (1 M, 2.80 mL, 1.2 eq) was slowly added, and the reaction solution was slowly heated to 25° C. and stirred for 4 hours. The reaction solution was evaporated to dryness under reduced pressure, and extracted by adding 30 mL of water and dichloromethane (20 mL×3). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1-20: 1) to obtain compound 14-1. MS m / z (ESI): 327.2 [M+H] + . Step 2: Synthesis of compound 14-2 Compound 14-1 (750 mg, 2.30 mmol, 1 eq) and dichloromethane (3 mL) were added to a reaction flask, followed by a solution of hydrogen chloride in ethyl acetate (4 M, 11.49 mL, 20 eq) at 0° C., and the reaction was stirred for 4 hours at 25° C. The reaction was concentrated under reduced pressure to give the hydrochloride salt of compound 14-2, which was used in the next step without further purification. 1 HNMR(400 MHz, DMSO-d6)δ 9.71 - 9.21(m, 1H), 7.52 - 7.36(m, 1H), 7.34 - 7.16(m, 1H), 7.14 - 6.94(m, 1H), 3.49 - 2.65(m, 6H), 0.89 - 0.53(m, 6H). MS m / z(ESI):227.1 [M+H] + . Step 3: Synthesis of compound 14 Compound 14-2 hydrochloride (150 mg, 448.09 μmol, 1 eq), intermediate 5 (220.73 mg, 537.71 μmol, 1.2 eq), triethylamine (226.71 mg, 2.24 mmol, 311.84 μL, 5 eq), 50% ethyl acetate solution of tripropyl phosphate anhydride (427.72 mg, 672.13 μmol, 1.5 eq) and dichloromethane (4 mL) were added to the reaction flask, and then the mixture was stirred at 25 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 * 40 mm * 10 μm; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile %: 40% ~ 75%, 8 min) to obtain compound 14. 1 HNMR(400 MHz, DMSO-d6)δ 7.64 - 7.51(m, 1H), 7.37 - 7.26(m, 1H), 7.23 - 7.02(m, 3H), 6.83(br d, J =4.5 Hz, 1H), 4.06 - 3.97(m, 1H), 3.95 - 3.79(m, 3H), 3.69 - 3.61(m, 1H), 3.54 - 3.39(m, 1H), 3.32 - 3.25(m, 2H), 3.23 - 3.04(m, 3H), 3.03 - 2.89(m, 2H), 2.83 - 2.58(m, 3H), 2.34 - 2.27(m, 1H), 1.77(br s, 2H), 1.47 - 1.32(m, 2H), 0.72(dd, J =4.6, 5.6 Hz, 3H), 0.64(dd, J =6.1, 12.6 Hz, 3H). MS m / z(ESI):520.3 [M+H] + .

[0106] Example 15 JPEG0007675849000051.jpg128170Step 1: Synthesis of compound 15-1 Compound 1-1, p-chlorobromobenzene (1.34 g, 5.60 mmol, 1.2 eq), sodium t-butoxide (896.86 mg, 9.33 mmol, 2 eq) and toluene (10 mL) were added to a dry flask, and bis(tri-t-butylphosphine)palladium (476.94 mg, 933.26 μmol, 0.2 eq) was added under a nitrogen atmosphere, and the mixture was stirred at 110 ° C for 20 hours. After cooling to room temperature, it was filtered through diatomaceous earth, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by high-performance silica gel column chromatography (petroleum ether: ethyl acetate = 1: 0 to 9: 1) to obtain compound 15-1. MS m / z (ESI): 325.2 [M + H] + . Step 2: Synthesis of compound 15-2 Compound 15-1 (255 mg, 400.35 μmol) and dichloromethane (5 mL) were added to a dry flask and dissolved by stirring. The mixture was cooled to 0° C., and a solution of hydrogen chloride in ethyl acetate (4 M, 5 mL) was added and reacted for 1 hour with stirring at 20° C. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of compound 15-2. MS m / z (ESI): 225.1 [M+H] + . Step 3: Synthesis of compound 15 Add intermediate 5 (166.62mg, 497.72μmol), compound 15-2 hydrochloride (200mg, 497.72μmol, 1eq), dichloromethane (2mL) to a dry flask, and finally add triethylamine (151.09mg, 1.49mmol, 3eq) and 50% ethyl acetate solution of tripropyl phosphate anhydride (475.10mg, 746.58μmol, 1.5eq), stir at 20℃ and react for 12 hours, add 10mL water, extract the aqueous phase with dichloromethane three times (5mL×3), combine the organic phase, dry and concentrate under reduced pressure to obtain the crude product, which is then analyzed by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10μm; organic phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 40%~60%, 8 min) to obtain compound 15. 1H NMR(400 MHz, CDCl3)δ ppm 7.43 - 7.53(m, 1 H), 7.28(s, 1 H), 6.98(dd, J =16.0, 8.4 Hz, 2 H), 6.75 - 6.91(m, 2 H), 4.39 - 4.49(m, 1 H), 3.91 - 4.01(m, 3 H), 2.80 - 3.59(m, 12 H), 2.44 - 2.73(m, 3 H), 1.83(br d, J=11.6 Hz, 2 H), 1.26 - 1.29(m, 1 H), 0.72 - 0.77(m, 3 H), 0.53 - 0.68(m, 3 H). MS m / z(ESI): 518.3 [M+H] + .

[0107] Example 16 JPEG0007675849000052.jpg49170JPEG0007675849000053.jpg121170Step 1: Synthesis of compound 16-1 Add intermediate 4-2 (1.6g, 4.68mmol, 1eq), N-methoxymethyl-N-(trimethylsilylmethyl)benzylamine (1.67g, 7.02mmol, 1.5eq) and dichloromethane (16mL) to a reaction flask, slowly add trifluoroacetic acid (266.88mg, 2.34mmol, 173.30μL, 0.5eq) at 25℃, and after the dropwise addition, stir the reaction solution at 25℃ for 16 hours. The reaction solution was poured into a saturated aqueous sodium bicarbonate solution (20mL), stirred for 10 minutes, and then allowed to stand to separate the layers. The aqueous phase was extracted with dichloromethane (100mL×3), and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by flash column chromatography (petroleum ether:ethyl acetate=1:0-5:1) to obtain compound 16-1. 1H NMR(400 MHz, CDCl3)δ 7.29 - 7.32(m, 5H), 7.21 - 7.27(m, 7H), 7.04 - 7.25(m, 2H), 4.64-4.66(m, 1H), 4.01 - 4.22(m, 4H), 3.60 - 3.73(m, 2H), 3.12 - 3.20(m, 3H), 2.66 - 2.75(m, 3H). MS m / z(ESI): 475.2 [M+H] + . Step 2: Synthesis of compound 16-2 Palladium on carbon catalyst (0.3 g, 10% palladium content) and ethyl acetate (15 mL) were added to the reaction flask, followed by compound 16-1 (500 mg, 1.05 mmol, 1 eq), zinc bromide (237.06 mg, 1.05 mmol, 52.68 μL, 1 eq), and the reaction was stirred at 40° C. under H2 (15 Psi) atmosphere for 16 h. The reaction was filtered through diatomaceous earth, the filter cake was washed with methanol (200 mL×2), and the filtrate was concentrated under reduced pressure to give crude compound 16-2, which was used in the next step without purification. MS m / z(ESI): 385.1 [M+H] + . Step 3: Synthesis of compound 16-3 Compound 16-2 (0.4 g, 1.04 mmol, 1 eq), tetrahydropyran-4-one (208.11 mg, 2.08 mmol, 190.93 μL, 2 eq), triethylamine (210.34 mg, 2.08 mmol, 289.33 μL, 2 eq), dichloromethane (10 mL) and acetic acid (0.1 mL) were added to the reaction flask, and the reaction was stirred at 25° C. for 2 hours, after which NaBH(OAc)3 (330.42 mg, 1.56 mmol, 1.5 eq) was added and the reaction was stirred at 25° C. for another 16 hours. 10 mL of saturated aqueous sodium bicarbonate was added to the reaction, and the mixture was extracted with dichloromethane (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to flash column chromatography separation (dichloromethane:methanol=1:0 to 10:1) to give compound 16-3. 1H NMR(400 MHz, CDCl3)δ 7.20-7.31(m, 7H), 7.02-7.05(m, 2H), 4.70-4.72(m, 1H), 4.14-4.24(m, 3H), 3.97-4.01(m, 3H), 3.30-3.41(m, 2H), 3.23-3.25(m, 3H), 2.80-2.89(m, 1H), 2.69-2.78(m, 2H), 2.38-2.44(m, 1H), 1.78-1.81(m, 2H), 1.61-1.75(m, 2H). MS m / z(ESI): 469.2 [M+H] + . Step 4: Synthesis of compound 16-4 Compound 16-3 (96 mg, 204.70 μmol, 1 eq) and tetrahydrofuran (4 mL) were added to the reaction flask, followed by lithium hydroxide monohydrate (25.77 mg, 614.11 μmol, 3.0 eq) and water (2 mL) at 0° C. The reaction solution was stirred at 25° C. for 16 hours, and the reaction solution was directly concentrated under reduced pressure, followed by addition of water (10 mL), followed by addition of ethyl acetate (10 mL×3) for extraction, and the aqueous phase was adjusted to pH ∼2 with 2N hydrochloric acid, followed by direct concentration under reduced pressure to obtain crude compound 16-4, which was used in the next step without further purification. MS m / z(ESI): 310.1 [M+H] + . Step 5: Synthesis of compound 16 Compound 16-4 (63 mg, 203.37 μmol, 1.0 eq), the hydrochloride salt of compound 3-4 (68.62 mg, 244.04 μmol, 1.2 eq) and dichloromethane (5 mL) were added to a reaction flask, followed by triethylamine (102.89 mg, 1.02 mmol, 141.53 μL, 5 eq) and a 50% solution of tripropylphosphoric anhydride in ethyl acetate (194.12 mg, 305.05 μmol, 1.5 eq) and the reaction was stirred at 25° C. for 1 h. Add 20mL of water and 20mL of dichloromethane, leave to stand and separate the layers, then extract the aqueous phase with dichloromethane (100mL×3), combine the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product, which is separated and purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 40%~75%, 8min) to obtain compound 16. 1 H NMR(400 MHz, DMSO-d6)δ 7.20 - 7.28(m, 4H), 6.88 -6.92(m, 4H), 4.44 - 4.50(m, 1H), 3.93(br s, 2H), 3.59- 3.80(m, 1H), 3.32 - 3.50(m, 3H), 3.00-3.28(m, 2H), 2.50 - 2.85(m, 5H), 2.35 - 2.41(m, 2H), 1.92-2.19(m, 1H), 1.65-1.82(m, 2H), 1.52-1.60(m, 1H), 1.45-1.48(m, 1H), 0.56- 0.65(m, 4H), 0.39(d, J =6.0 Hz, 2H). MS m / z(ESI): 500.3 [M+H] + .

[0108] Example 17 JPEG0007675849000054.jpg79170Step 1: Synthesis of compound 17 Compound 7-5 (300 mg), cyclobutanone (90.66 mg, 1.29 mmol, 96.65 μL), dichloromethane (10 mL) and acetic acid (0.3 mL) were added to a dry flask, and after stirring for 2 hours, NaBH(OAc)3 (205.61 mg, 970.14 μmol) was added, and the mixture was kept at 20 ° C. and stirred for 10 hours. Dichloromethane 10 mL and water 10 mL were added to the reaction solution, and the aqueous phase was extracted twice with dichloromethane (10 mL × 2), and the organic phase was combined and dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and separated and purified by preparative HPLC (column: Waters Xbridge BEH C18 100 * 30 mm * 10 μm; mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile %: 50% to 80%, 8 min) to obtain compound 17. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) =7.55 - 7.40 (m, 1H), 7.11-6.94 (m, 4H), 6.92 - 6.69 (m, 2H), 4.63 - 4.48 (m, 1H), 4.10 - 3.92 (m, 1H), 3.65 - 3.50 (m, 1H), 3.44 - 3.28 (m, 1H), 3.16 - 2.68 (m, 8H), 2.58-2.42 (m, 1H), 2.10 - 1.92 (m, 4H), 1.84 - 1.66 (m, 2H), 0.76 - 0.68 (m, 3H), 0.67 - 0.48 (m, 3H). MS m / z(ESI): 472.1 [M+H] + .

[0109] Example 18 JPEG0007675849000055.jpg50170JPEG0007675849000056.jpg34170Step 1: Synthesis of compound 18 Compound 7-5 100mg and cyclohexanone (42.32mg, 431.17μmol, 44.68μL) were dissolved in dichloromethane (10mL), acetic acid (0.3mL) was added and stirred for 2 hours, then NaBH(OAc)3 (68.54mg, 323.38μmol) was added, and the mixture was kept at 20℃ and stirred for 10 hours. Dichloromethane 10mL and water 10mL were added to the reaction solution, and the mixture was extracted and separated, and the aqueous phase was extracted twice with dichloromethane (10mL×2). The organic phase was combined and dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and separated and purified by preparative HPLC (column: Phenomenex C18 80*40mm*3μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 40%~75%, 8min), to obtain compound 18. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) =7.58 - 7.40 (m, 1H), 7.09 - 6.96 (m, 4H), 6.93 - 6.70 (m, 2H), 4.61 - 4.47 (m, 1H), 4.10 - 3.91 (m, 1H), 3.67 - 3.52 (m, 1H), 3.46 - 2.18 (m, 10H), 2.01 - 1.65 (m, 5H), 1.38 - 1.15 (m, 5H), 0.75 - 0.68 (m, 3H), 0.67 - 0.48 (m, 3H). MS m / z (ESI): 500.3 [M+H] + .

[0110] Example 19 JPEG0007675849000057.jpg77170Step 1: Synthesis of compound 19 Compound 7-5 300 mg, 8-oxo-bicyclo[3,2,1]octan-3-one (122.39 mg, 970.14 μmol, 1.23 mL) was dissolved in DCM (10 mL) and AcOH (0.3 mL), the reaction solution was stirred at 25 ° C for 1 hour, then NaBH(OAc)3 (205.61 mg, 970.14 μmol) was added, and the reaction solution was stirred at 25 ° C for 16 hours. Saturated sodium bicarbonate aqueous solution 20 mL was added to the reaction solution, extracted with dichloromethane (10 mL × 3), the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1 to 0: 1) to obtain compound 19. 1 H NMR (400 MHz, CD3OD) δ (ppm) =7.44-7.45(m, 1H), 6.97-7.05 (m, 4H), 6.79-6.89 (m, 2H), 4.48-4.58 (m, 1H), 4.31 (s, 2H), 3.78-4.00 (m, 1H), 3.36-3.46 (m, 2H), 3.08-3.20(m, 1H), 2.75-2.95 (m, 5H), 2.42-2.60 (m, 2H),1.70-2.42(m, 9H), 0.63 - 0.73 (m, 4H), 0.45-0.46 (m, 2H). MS m / z (ESI): 528.1 [M+H] + .

[0111] Example 20 JPEG0007675849000058.jpg83170 Step 1: Synthesis of Compound 20a and Compound 20b Compound 7-5 (500 mg) and 3-tetrahydrofuranone (139.20 mg, 1.62 mmol, 1.23 mL) were dissolved in DCM (10 mL) and AcOH (1 mL). The reaction solution was stirred at 25°C for 1 hour, and then NaBH(OAc)3 (342.69 mg, 1.62 mmol, 1.5 eq) was added and the reaction solution was stirred at 25°C for 16 hours. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative HPLC (column: C18 (250 * 50 mm * 10 μm); mobile phase: [water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile%: 45% ~ 65%, 10 min), and then purified by SFC (column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 μm); mobile phase: [supercritical CO2-methanol (containing 0.1% aqueous ammonia)]; methanol (containing 0.1% aqueous ammonia) %: 30% to 30%, 5 min) to obtain Compound 20a and Compound 20b. SFC analysis method: Column: Lux Cellulose-2, 50 × 4.6 mm ID, 3 μm; Mobile phase: [supercritical CO2-methanol (containing 0.1% isopropylamine)]; Methanol (containing 0.1% isopropylamine)%: 50%~50%, 3 min. Compound 20a (retention time=1.102 min, ee =99.7%): 1 H NMR (400 MHz, CDCl3) δ (ppm) =7.45- 7.52 (m, 1H), 6.97 - 7.04 (m, 4H), 6.74 - 6.86 (m, 2H), 4.51 - 4.56 (m, 1H), 4.67 - 3.96 (m, 5H), 3.01 - 3.59 (m, 4H), 2.76 - 2.99 (m, 5H), 2.30 - 2.55 (m, 2H), 1.86-2.20 (m, 2H), 0.62-0.72 (m, 4H), 0.47-0.49 (m, 2H). MS m / z (ESI): 488.2 [M+H] + . Compound 20b (retention time=1.236 min, ee =99.5%): 1 H NMR (400 MHz, CDCl3) δ (ppm) =7.49 - 7.51 (m, 1H), 6.97 - 7.04 (m, 4H), 6.74 - 6.86 (m, 2H), 4.51 - 4.56 (m, 1H), 4.67 - 3.96 (m, 5H), 3.01 - 3.59 (m, 4H), 2.76 - 2.99 (m, 5H), 2.30 - 2.55 (m, 2H), 1.86-2.20 (m, 2H), 0.62-0.72 (m, 4H), 0.47-0.48 (m, 2H). (ESI): 488.1 [M+H] + .

[0112] Example 21 JPEG0007675849000059.jpg84170 Step 1: Synthesis of Compound 21a and Compound 21b Compound 7-5 (500 mg) and 2,2-dimethyltetrahydropyran-4-one (207.24 mg, 1.62 mmol, 1.23 mL, 1.5 eq) were dissolved in DCM (10 mL) and AcOH (1 mL), and the reaction solution was stirred at 25° C. for 1 hour, after which NaBH(OAc)3 (342.69 mg, 1.62 mmol, 1.5 eq) was added and the reaction solution was stirred at 25° C. for 16 hours. 20 mL of saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative HPLC (column: C18 (250*50mm*10μm); mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 50%-70%, 10min), and then separated by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm, 10μm); mobile phase: [supercritical CO2-isopropyl alcohol (containing 0.1% aqueous ammonia)]; isopropyl alcohol (containing 0.1% aqueous ammonia)%: 25%-25%, 5min) to obtain compound 21a and compound 21b. SFC analysis method: Column: Lux Cellulose-2, 50×4.6 mm I.D., 3 μm; Mobile phase: [supercritical CO2 - methanol (containing 0.1% isopropylamine)]; Methanol (containing 0.1% isopropylamine) %: 50% - 50%, 3 min). Compound 21a (retention time = 1.027 min, ee = 100%): 1 H NMR (400 MHz, CDCl3) δ (ppm) = 7.48 - 7.51 (m, 1H), 6.98 - 7.04 (m, 4H), 6.77 - 6.87 (m, 2H), 4.53 - 4.57 (m, 1H), 3.16 - 4.15 (m, 6H), 2.76 - 2.93 (m, 8H), 1.76 - 1.79 (m, 2H), 1.41 - 1.59 (m, 2H), 1.22 - 1.25 (m, 6H), 0.62 - 0.72 (m, 4H), 0.49 - 0.50 (m, 2H). MS m / z (ESI): 530.2 [M + H] + 。 Compound 21b (retention time = 1.090 min, ee = 96%): 1 H NMR (400 MHz, CDCl3) δ (ppm) = 7.48 - 7.51 (m, 1H), 6.98 - 7.04 (m, 4H), 6.77 - 6.87 (m, 2H), 4.53 - 4.57 (m, 1H), 3.16 - 4.15 (m, 6H), 2.76 - 2.93 (m, 8H), 1.76 - 1.79 (m, 2H), 1.41 - 1.59 (m, 2H), 1.22 - 1.25 (m, 6H), 0.62 - 0.72 (m, 4H), 0.49 - 0.50 (m, 2H). MS m / z (ESI): 530.2 [M + H] + 。

[0113] Example 22 JPEG0007675849000060.jpg115170 Step 1: Synthesis of Compounds 22a - 22d Compound 7-5 (500 mg) and 2-methyltetrahydropyran-4-one (246.07 mg, 2.16 mmol, 88.01 μL, 2 eq) were dissolved in DCM (5 mL) and AcOH (0.5 mL), and the reaction solution was stirred at 25 ° C for 1 hour, after which NaBH(OAc) 3 (342.69 mg, 1.62 mmol, 1.5 eq) was added and the reaction solution was stirred at 25 ° C for 16 hours. 20 mL of saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 30%~65%, 8min) to obtain Peak1 (retention time=2.932min, column: Xbridge C18 5μm 2.1*50mm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 10%~80%, 4.5min) and Peak2 (retention time=3.172min, column: Xbridge C18 5μm 2.1*50mm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 10%~80%, 4.5min). Peak 1 was separated by chiral HPLC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 μm); mobile phase: [n-heptane-ethanol (containing 0.1% isopropylamine)]; ethanol (containing 0.1% isopropylamine) %: 20% to 20%, 10 min) to obtain Compound 22a and Compound 22b. SFC analysis method: Column: Chiralpak IC-3, 100 × 4.6 mm I.D., 3 μm; Mobile phase: [n-hexane-ethanol (containing 0.1% isopropylamine)]; Ethanol (containing 0.1% isopropylamine)%: 20% to 20%, 6.0 min). Peak 2 was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 μm); mobile phase: [supercritical CO2-isopropyl alcohol (containing 0.1% aqueous ammonia)]; isopropyl alcohol (containing 0.1% aqueous ammonia) %: 33% to 33%, 8 min) to obtain compound 22c and compound 22d. SFC analysis method: Column: Chiralpak IC-3, 100 × 4.6 mm ID, 3 μm; Mobile phase: [supercritical CO2-isopropyl alcohol (containing 0.1% isopropylamine)]; Isopropyl alcohol (containing 0.1% isopropylamine)%: 50%~50%, 4.0 min). Compound 22a (retention time=3.118min): 1 H NMR (400 MHz, DMSO-d6) δ (ppm) =7.65 - 7.50 (m, 1H), 7.26 - 7.02 (m, 6H), 4.32 - 4.12 (m, 1H), 4.02 - 3.81 (m, 2H), 3.81 - 3.66 (m, 1H), 3.57 - 3.43 (m, 1H), 3.25 - 3.04 (m, 1H), 3.02 - 2.78 (m, 3H), 2.78 - 2.58 (m, 4H), 2.46 - 2.26 (m, 2H), 1.93 - 1.70 (m, 2H), 1.39 - 1.13 (m, 2H), 1.13 - 1.06 (m, 3H), 1.06 - 0.97 (m, 1H), 0.70 - 0.46 (m, 6H). MS m / z (ESI): 516.2 [M+H] + . Compound 22b (retention time=4.100min): 11H NMR (400 MHz, DMSO-d6) δ (ppm) = 7.65 - 7.50 (m, 1H), 7.25 - 7.01 (m, 6H), 4.32 - 4.12 (m, 1H), 4.00 - 3.82 (m, 2H), 3.81 - 3.67 (m, 1H), 3.55 - 3.33 (m, 2H), 3.29 (br s, 1H), 3.23 - 3.03 (m, 1H), 3.02 - 2.78 (m, 3H), 2.77 - 2.61 (m, 3H), 2.46 - 2.25 (m, 2H), 1.92 - 1.69 (m, 2H), 1.36 - 1.21 (m, 1H), 1.16 - 0.97 (m, 4H), 0.71 - 0.45 (m, 6H). MS m / z (ESI): 516.2 [M+H] + 。 Compound 22c (Retention time = 1.861 min): 1 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 7.70 - 7.57 (m, 1H), 7.25 - 7.04 (m, 6H), 4.33 - 4.11 (m, 1H), 4.01 - 3.79 (m, 2H), 3.79 - 3.63 (m, 2H), 3.60 - 3.40 (m, 2H), 3.27 - 3.07 (m, 1H), 2.99 - 2.78 (m, 3H), 2.77 - 2.57 (m, 3H), 2.47 - 2.30 (m, 1H), 1.83 - 1.73 (m, 1H), 1.68 - 1.54 (m, 2H), 1.40 - 1.28 (m, 1H), 1.08 - 1.00 (m, 3H), 0.71 - 0.44 (m, 6H). MS m / z (ESI): 516.2 [M+H] + 。 Compound 22d (Retention time = 1.984 min): 1H NMR (400 MHz, DMSO-d6) δ (ppm) =7.70 - 7.57 (m, 1H), 7.26 - 6.97 (m, 6H), 4.31 - 4.13 (m, 1H), 4.02 - 3.84 (m, 1H), 3.84 - 3.64 (m, 3H), 3.62 - 3.40 (m, 2H), 3.28 - 3.07 (m, 1H), 2.99 - 2.79 (m, 3H), 2.78 - 2.54 (m, 4H), 2.46 - 2.30 (m, 1H), 1.78 - 1.55 (m, 3H), 1.39 - 1.26 (m, 1H), 1.08 - 0.99 (m, 3H), 0.69 - 0.45 (m, 6H) . MS m / z (ESI): 516.2 [M+H] + .

[0114] Example 23 JPEG0007675849000061.jpg126170Step 1: Synthesis of compound 23-2 Compound 23-1 (20 g, 163.04 mmol, 22.75 mL), trimethylchloromethylsilane (532.69 g, 375.00 mmol, 43.81 mL) and DMSO (10 mL) were added to a reaction flask, and the reaction solution was slowly heated to 90° C. and stirred for 16 hours. After the reaction was completed, the heating device was removed, the reaction solution was cooled, and then the solution was allowed to stand for separation. The upper layer was collected, and 100 mL of ethyl acetate was added to the organic phase to dissolve it, and water (100 mL×2) was added to wash the organic phase. The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Compound 23-2 was obtained. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) =1.90 - 1.85 (m, 2H), 1.40 - 1.32 (m, 2H), 0.96 (s, 6H), 0.81 - 0.75 (m, 3H), 0.02 (s, 9H). Step 2: Synthesis of compound 23-3 A 37% aqueous formaldehyde solution (20.43 g, 251.77 mmol), methanol (8.07 g, 251.77 mmol, 10.19 mL) and potassium carbonate (34.80 g, 251.77 mmol) were added to a dry flask, the reaction system was cooled to 0 ° C, compound 23-2 (14.55 g, 83.92 mmol) was added, the temperature was gradually raised to room temperature, and further stirred at 25 ° C for 12 hours. It was filtered, and the filter cake was washed with a small amount of ethyl acetate. 20 mL of water was added to the filtrate, and it was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 23-3, which was used in the next step reaction without further purification (it contains unreacted compound 23-2 and does not affect the next step reaction). 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) =4.19 (s, 2H), 3.34 - 3.27 (m, 2H), 2.24 - 2.19 (m, 3H), 1.88 - 1.87 (m, 3H), 1.37 - 1.34 (m, 3H), 1.16 (t, J =7.0 Hz, 3H), 1.09 - 1.07 (m, 2H), 0.02 (s, 9H). Step 3: Synthesis of compound 23-4 A dry three-neck flask was prepared, and compound 23-3 (8.64 g, 13.11 mmol) and intermediate 2-3 (1.5 g, 4.37 mmol) were dissolved in dichloromethane (15 mL), and trifluoroacetic acid (1.49 g, 13.11 mmol, 970.44 μL) was slowly added dropwise, and the reaction was then stirred at 15 ° C for 1 hour. 50 mL of saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was allowed to stand and separated. After that, dichloromethane (50 mL × 2) was added to the aqueous phase for extraction, and the organic phases were combined and dried with anhydrous sodium sulfate. Gradient elution was then performed by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1 to 1: 1), and the obtained eluate was concentrated to dryness, methyl t-butyl ether (10 mL) was added, and the mixture was homogenized for 2 hours, filtered, and further homogenized with petroleum ether-ethyl acetate (1: 15) to obtain compound 23-4. 1H NMR (400 MHz, DMSO-d6, 298 K) δ (ppm) =7.58 - 7.46 (m, 1H), 7.28 - 7.17 (m, 2H), 7.17 - 7.08 (m, 3H), 6.99 - 6.93 (m, 2H), 4.72 - 4.63 (m, 1H), 4.36 - 4.30 (m, 1H), 4.21 - 4.11 (m, 2H), 4.02 - 3.94 (m, 1H), 3.21 - 3.14 (m, 1H), 3.07 (t, J =8.3 Hz, 1H), 2.93 - 2.84 (m, 2H), 2.76 - 2.65 (m, 2H), 1.42 - 1.33 (m, 2H), 1.01 - 0.91 (m, 6H), 0.82 (t, J =7.3 Hz, 3H). MS m / z (ESI): 457.2 [M+H] + . Step 4: Synthesis of compound 23-5 Compound 23-4 (0.71 g, 1.56 mmol) was dissolved in THF (7 mL), and a solution of LiOH·H2O in H2O (3 mL) (195.77 mg, 4.67 mmol) was added at 0°C, and the reaction solution was stirred at 25°C for 4 hours. The reaction solution was concentrated under reduced pressure until dry, and extracted with water (100 mL) and ethyl acetate (30 mL x 3). The organic phase was discarded, and the aqueous phase was adjusted to pH 2 with 2M dilute hydrochloric acid and concentrated under reduced pressure to obtain compound 23-5. 1 H NMR (400 MHz, DMSO-d6, 298 K) δ (ppm) =7.99 - 7.65 (m, 1H), 7.31 - 7.18 (m, 1H), 7.17 - 7.08 (m, 1H), 4.32 - 3.79 (m, 3H), 3.28 - 3.17 (m, 1H), 3.17 - 3.14 (m, 2H), 1.81 - 1.67 (m, 2H), 1.35 - 1.25 (m, 6H), 0.91 ( t, J =7.3 Hz, 3H). MS m / z (ESI): 298.0 [M+H] + . Step 5: Synthesis of compound 23 Compound 3-4 hydrochloride (322.21 mg), compound 23-5 (460 mg, 1.55 mmol) and triethylamine (782.73 mg, 7.74 mmol, 1.08 mL) were dissolved in dichloromethane (6 mL), and 50% ethyl acetate solution of propyl phosphate anhydride (1.38 mL, 2.32 mmol) was added dropwise and stirred at 25 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure and separated by preparative HPLC (column: Phenomenex C18 80 * 40 mm * 3 μm; mobile phase: water (10 mM ammonium bicarbonate) - acetonitrile]; acetonitrile %: 40% ~ 80%, 8 min) to obtain compound 23. 1 H NMR (400 MHz, DMSO-d6, 298 K) δ (ppm) =7.66 - 7.50 (m, 1H), 7.26 - 6.99 (m, 6H), 4.31 - 4.09 (m, 1H), 3.93 - 3.68 (m, 2H), 3.54 - 3.36 (m, 1H), 3.21 - 3.05 (m, 1H), 3.05 - 2.98 (m, 1H), 2.97 - 2.57 (m, 5H), 2.47 - 2.28 (m, 1H), 1.44 - 1.34 (m, 2H), 1.03 - 0.91 (m, 6H), 0.88 - 0.78 (m, 3H), 0.70 - 0.45 (m, 6H). MS m / z (ESI): 488.2 [M+H] + . Biological testing

[0115] Experimental Example 1: In vitro activity test of MCR receptors Experimental Objective: The agonistic effects of compounds on MCRs were evaluated by detecting changes in intracellular cAMP signals. Test materials: JPEG0007675849000062.jpg133170 Experimental steps and methods: Resuspend the cells in 1x PBS + 500 μM IBMX and add 10 μL of the cell suspension to a 384-well plate, resulting in a cell concentration of 1 × 10 per well. 4The wells were adjusted to 100 cells. The previously prepared test compound solutions were added, and the same amount of dimethyl sulfoxide was added to the blank control wells. The test plate was centrifuged at 300 rpm for 1 min and incubated at 37°C for 30 min. 5 μL of cAMP-d2 and 5 μL of cAMP-cry antibody detection reagent were added. The test plate was centrifuged at 300 rpm for 1 min and incubated at room temperature for 60 min. The test plate was read in the Envision multifunctional microplate reader and detected at wavelengths of 665 / 615 nm. The experimental results are shown in Table 2. JPEG0007675849000063.jpg133170Conclusion: The compounds of the present invention have selective agonistic activity against the human MC4R receptor.

[0116] Experimental Example 2: Measurement of pharmacokinetic parameters in rat plasma Four healthy 6-9 week old SD rats were selected and randomly divided into two groups of two. One group was administered the test compound in 5% DMSO + 95% (10% HP-β-CD aqueous solution) via intravenous injection, while the other group was administered the test compound in 50 mM citrate buffer, pH = 5 via intragastric administration. Plasma samples were collected from both the intravenous and intragastric administration groups at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after administration. WinNonlin TM Quantitative analysis of all biological samples was performed by LC-MS / MS using Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software, and relevant pharmacokinetic parameters were calculated by the noncompartmental linear-logarithmic trapezoidal method. AUC 0~last represents the area under the plasma concentration-time curve from time zero to the last detectable concentration. po represents oral administration, and iv represents intravenous administration. T 1 / 2 represents the half-life. CL represents the clearance rate. Vd represents the apparent volume of distribution. AUC 0~last represents the area under the curve. C max represents the peak concentration. T max represents the peak time. F% represents the oral bioavailability. Experimental Results The experimental results for the compounds of the present invention are shown in Table 3. JPEG0007675849000064.jpg66169Conclusion: The compounds of the present invention exhibit good pharmacokinetic properties in rats.

[0117] Experimental Example 3: Measurement of drug concentrations in rat brain tissue 3.1 Six healthy 6-9 week old SD rats were selected and administered the compound via intravenous injection. Two rats were randomly selected at 0.5, 2, and 4 hours after administration to collect plasma and brain tissue samples, and quantitative analysis of all biological samples was performed by LC-MS / MS. The experimental results for the compounds of the present invention are shown in Table 4. JPEG0007675849000065.jpg52170BQL: Below the detection limit, NA indicates not calculable. 3.2 Six healthy 6-9 week old SD rats were selected and the compound was administered orally (solvent: 50 mM citrate buffer solution, pH = 5). Two rats were randomly selected at 0.5 hours, 1 hour, and 4 hours after administration, and plasma and brain tissue samples were collected. Quantitative analysis of all biological samples was performed using LC-MS / MS. Experimental results for the compounds of the present invention are shown in Table 5. JPEG0007675849000066.jpg57170 Conclusion: The compound of the present invention can penetrate the blood-brain barrier and enter the brain tissue at a relatively high blood-brain ratio in rats, resulting in high drug concentration.

[0118] Experimental Example 4: In vitro MDCK-MDR1 permeability test MDR1-MDCKII cells (from the Netherlands Cancer Institute) were cultured in a 96-well plate (from Corning) at a cell density of 2.5 × 10 5The cells were inoculated at 1000 cells / ml and cultured for 4-7 days to form a copolymerized cell monolayer. Hank's balanced salt buffer (pH 7.40 ± 0.05) containing 10 mM 4-hydroxyethylpiperazineethanesulfonic acid was used as the transport buffer. Bidirectional transport of the test compounds at a concentration of 2 μM was tested, and the DMSO concentration of the incubation system was controlled to 1% or less. After adding the samples, the cell plates were incubated for 150 min under conditions of 37 ± 1 °C, 5% CO2, and saturated humidity. Quantitative analysis of all samples was performed by LC-MS / MS. Apparent permeability coefficient (P app , cm / s), ejection rate, and recovery rate were calculated using the following equations: Apparent permeability coefficient (P app , cm / s) was calculated using the following formula: P app =(dC r / d t )×V r / (A×C0) dC r / d t is the cumulative concentration of the compound at the receptor per unit time (μM / s), and V r is the volume of the solution on the receiving side (the volumes of the solutions on the top and base sides are 0.075 mL and 0.250 mL, respectively), and A is the relative surface area of ​​the cell monolayer (0.0804 cm 2 ) and C0 is the starting concentration of the test product (nM) on the administration side or the peak area ratio of the control product. The emission rate was calculated by the following formula: Emission rate=P app (BA) / P app (AB) The recovery rate was calculated by the following formula: % Recovery = 1 = 100 × [(V r ×C r )+(V d ×C d )] / (V d ×C0) C0 is the starting concentration of the test product (nM) or the peak area ratio of the control product at the administration side, and V d is the volume of the dispensed side (0.075 mL on the top side and 0.250 mL on the base side), and C d and Cr are the final concentrations (nM) of the test article or the peak area ratio of the control article at the administering and receiving sides, respectively. Experimental results for the compounds of the present invention are shown in Table 6. JPEG0007675849000067.jpg29170 Conclusion: The compounds of the present invention have good permeability and low efflux ratios.

Claims

1. A compound of formula (III) or a pharma- ceutically acceptable salt thereof: (however, Each R １ are each independently a halogen, C １～３ Alkyl, C １～３ Alkoxy, -C(=O)NR ａ R ｂ , and -CH ２ C(=O)NR ａ R ｂ and C is selected from １～３ Alkyl and C １～３ The alkoxy is optionally substituted with 1, 2 or 3 halogens; Each R ２ are each independently １～３ Alkyl and C ３～６ cycloalkyl; Each R ３ are each independently a halogen, -C １～３ Alkyl and C １～３ alkoxy; R ４ is selected from t-butyl, phenyl, pyridyl, pyridazinyl, tetrahydropyranyl, cyclobutyl, cyclohexyl, tetrahydrofuranyl, and oxabicyclooctyl, each of which is independently selected from one, two, or three R ｃ is replaced by R ａ and R ｂ are each independently H and C １～３ alkyl, Each R ｃ are each independently halogen, —CN and C １～３ alkyl, m, n, and t are each independently selected from 0, 1, or 2; T １ is selected from N or CH.

2. R ａ and R ｂ are each independently H and -CH ３ 2. The compound of claim 1, selected from:

3. Each R １ are each independently F, Cl, or -CF ３ , -C(=O)NHCH ３ , and -CH ２ C(=O)NHCH ３ 2. The compound of claim 1, selected from:

4.

5. Each R ２ are each independently -CH ３ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein said compound is selected from: cyclopropyl; and cyclopropyl.

6. Each R ３ or a pharma- ceutically acceptable salt thereof.

2. The compound of claim 1, wherein each of R, R and R is independently selected from F, Cl, and Br;

7. Each R ｃ are each independently -CN and -CH ３ 2. The compound of claim 1, selected from:

8.

9. The compound according to any one of claims 1 to 6 or 8, selected from the compounds represented by the following formulas: or a pharma- ceutically acceptable salt thereof. (However, R １ , R ２ , R ３ , m, n and t have the same meanings as in any one of claims 1 to 6 or 8.

10. The compound according to any one of claims 1 to 4 or 6 to 8, selected from the compounds represented by the following formulas, or a pharma- ceutically acceptable salt thereof: (However, R １ , R ３ , R ４ , m, and t have the same meanings as in any one of claims 1 to 4 or 6 to 8.)

11. A compound selected from the group consisting of compounds represented by the following formulas, or a pharma- ceutically acceptable salt thereof:

12. 12. The compound of claim 11, wherein the compound is selected from the group consisting of compounds of the formula: or a pharma- ceutically acceptable salt thereof.

13. 13. The compound of claim 12, wherein the compound is selected from the group consisting of compounds of the formula: or a pharma- ceutically acceptable salt thereof.

14. 13. Use of a compound according to claim 1 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating a disease associated with an MC4R agonist.

15. The use according to claim 14, wherein the MC4R agonist associated disease is selected from male erectile dysfunction and female sexual desire disorders.

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