Biphenyl derivatives and their applications

Abstract

A biphenyl derivative, its preparation method and its use in preparing drugs for treating related diseases, specifically relating to a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.

Description

[0001] This application claims priority to:

[0002] CN202110066211.5, application date January 18, 2021. Technical Field

[0003] The present invention relates to a biphenyl derivative, a preparation method thereof and application thereof in the preparation and treatment of related diseases, and particularly to a compound represented by formula (I) and a pharmaceutically acceptable salt thereof. Background Art

[0004] Programmed cell death molecule 1 (PD-1), also known as CD279, is an important immunosuppressive molecule in the CD28 / CTLA-4 receptor family. It is a membrane protein containing 268 amino acid residues and is widely expressed on the surface of various immune cells, including T cells, macrophages, and B cells. Its ligands are PD-L1 and PD-L2. PD-L1 is a protein encoded by the CD274 gene and primarily expressed on the surface of tumor cells, dendritic cells, and macrophages. Upon binding of PD-1 and PD-L1, the PD-1 / PD-L1 signaling pathway is activated, thereby inhibiting T cell activation, causing T cell dysfunction and contributing to the immune escape of tumor cells. PD-L2, another ligand of PD-1, is primarily expressed on the surface of dendritic cells, macrophages, and B cells and is associated with inflammatory and autoimmune diseases.

[0005] PD-1 negatively regulates immune responses by binding to its ligand, PD-L1, and dephosphorylating multiple key molecules in the TCR signaling pathway. In a healthy body, activation of the PD-1 / PD-L1 signaling pathway prevents damage to surrounding tissues caused by excessive immune responses, thereby reducing the occurrence of autoimmune diseases. However, under the induction of the tumor microenvironment, the expression of both PD-1 and PD-L1 increases abnormally. Tumor cells can successfully evade recognition and attack by the body's immune system through the binding of these PD-L1 molecules to PD-1 on T cells. PD-(L)1 monoclonal antibodies can block this "tumor immune escape mechanism" and restore the patient's own immune system's anti-cancer function.

[0006] Currently, all commercially available drugs targeting the PD-1 / PD-L1 pathway are monoclonal antibodies (mAbs). In 2014, the U.S. Food and Drug Administration (FDA) approved the first two mAbs targeting the PD-1 molecule (pembrolizumab and nivolumab). In the following years, three additional mAbs targeting the PD-L1 molecule (atezolizumab, durvalumab, and avelumab) became available. These are all biomacromolecules, which have significant inherent drawbacks, such as susceptibility to protease degradation, poor in vivo stability, and the need for injection; difficult to control product quality and requiring high production technology; difficulty in large-scale preparation and purification, resulting in high production costs and the potential for immunogenicity. Small-molecule PD-1 / PD-L1 inhibitors are gaining increasing attention. Incyte's PD-L1 inhibitor INCB86550 (WO2018119263, WO2019191707) and Gilead's PD-L1 inhibitor GS-4224 (US20180305315, WO2019160882) have entered Phase II clinical trials, while BMS's benzylphenyl ether-based small-molecule PD-1 / PD-L1 inhibitor (WO2015034820, WO2015160641) is in preclinical research. Small-molecule drugs have the advantages of being able to cross cell membranes to act on intracellular targets, being easy to store and transport, having low production costs, being non-immunogenic, and generally being orally administered. Therefore, the research and development of small-molecule PD-1 / PD-L1 inhibitors holds broad application prospects. Summary of the Invention

[0007] The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0008]

[0009] in,

[0010] R1 and R2 are independently selected from H, F, Cl, Br, I, CN and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 halogens;

[0011] R3 is selected from H, CN, C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 Alkylamino, the C 1-3 Alkyl, C 1-3 Alkoxy and C 1-3 The alkylamino groups are each independently optionally substituted with 1, 2 or 3 halogen groups;

[0012] R4 and R5 are independently selected from H, C1-6 Alkyl, C 1-6 Alkylamino, C 3-6 Cycloalkyl and -C 1-3 Alkyl-(3-6 membered heterocycloalkyl), the C 1-6 Alkyl, C 1-6 Alkylamino, C 3-6 Cycloalkyl and -C 1-3 Alkyl-(3-6 membered heterocycloalkyl) is optionally substituted by 1, 2 or 3 R a Alternatively, R4 and R5 are linked to form a 3- to 8-membered heterocycloalkyl group, wherein the 3- to 8-membered heterocycloalkyl group is optionally substituted by 1, 2 or 3 R b replace;

[0013] R6 is selected from 1, 2 or 3 R c Substituted C 1-3 alkyl;

[0014] L is selected from the group consisting of 1, 2 or 3 R d Substituted -C 1-6 alkyl-;

[0015] X is selected from CH and N;

[0016] Y is selected from CH and N;

[0017] Z1 is selected from a single bond and CH2;

[0018] Z2 is selected from CH and N;

[0019] R a Selected from F, Cl, Br, I, OH, =O, NH2, C 1-3 Alkylamino, C 1-3 Alkoxy and C 1-3 Alkyl, the C 1-3 Alkylamino, C 1-3 Alkoxy and C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R groups, each independently;

[0020] R b Selected from CN, F, Cl, Br, I, OH, -C(=O)NH2, C 1-3 Alkylamino, C 1-3 Alkoxy and C 1-3 alkyl;

[0021] R c selected from the group consisting of F, Cl, Br, I, CN, OH, ═O, and NH 2 ;

[0022] R d selected from the group consisting of F, Cl, Br, I, CN, OH, ═O, and NH 2 ;

[0023] R is selected from F, Cl, Br, I, CN, OH, =O and NH2;

[0024] The 3- to 6-membered heterocycloalkyl group and the 3- to 8-membered heterocycloalkyl group each independently contain 1, 2 or 3 heteroatoms or heteroatom groups each independently selected from N, O, S and NH.

[0025] In some embodiments of the present invention, the above Z2 is selected from CH, and other variables are as defined in the present invention.

[0026] In some embodiments of the present invention, R1 and R2 are independently selected from H, F, Cl, Br, I, CN, CF3 and CH3, and other variables are as defined in the present invention.

[0027] In some embodiments of the present invention, the above R3 is selected from H, CN, CH3, -OCH3 and The CH3, -OCH3 and are each independently optionally substituted with 1, 2 or 3 halogens, and the other variables are as defined herein.

[0028] In some embodiments of the present invention, the above R3 is selected from H, CN, CH3, -OCH3, Other variables are as defined in the present invention.

[0029] In some embodiments of the present invention, R4 and R5 are independently selected from H, C 1-4 Alkyl, C 1-3 Alkylamino, cyclopropyl and The C 1-4 Alkyl, C 1-3 Alkylamino, cyclopropyl and Each independently optionally replaced by 1, 2 or 3 R a Substitution, other variables are as defined in the present invention.

[0030] In some embodiments of the present invention, the above R a is selected from the group consisting of F, Cl, Br, I, OH, =O, NH2, -NHCH3, -OCH3, -CH2OH and CH3, and the other variables are as defined herein.

[0031] In some embodiments of the present invention, R4 and R5 are independently selected from H, Other variables are as defined in the present invention.

[0032] In some embodiments of the present invention, the above R4 is selected from H, Other variables are as defined in the present invention.

[0033] In some embodiments of the present invention, the above R5 is selected from H, Other variables are as defined in the present invention.

[0034] In some embodiments of the present invention, the above R4 and R5 are connected to form pyrrolidinyl, 8-azabicyclo[3.2.1]octanyl, azetidinyl and 2-azaspiro[3.3]heptyl, and the pyrrolidinyl, 8-azabicyclo[3.2.1]octanyl, azetidinyl and 2-azaspiro[3.3]heptyl are independently optionally substituted by 1, 2 or 3 R b Substitution, other variables are as defined in the present invention.

[0035] In some embodiments of the present invention, the above R b is selected from CN, OH, -C(=O)NH2, -OCH3 and CH3, and other variables are as defined herein.

[0036] In some embodiments of the present invention, the above R4 and R5 are connected to form Other variables are as defined in the present invention.

[0037] In some embodiments of the present invention, the above R6 is selected from CH3, and other variables are as defined in the present invention.

[0038] In some embodiments of the present invention, the above L is selected from Other variables are as defined in the present invention.

[0039] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0040] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0041] In some embodiments of the present invention, the above compound is selected from

[0042]

[0043] wherein R1, R2, R3, R4, R5, R6, and Z1 are as defined in the present invention, and R7 and R8 are selected from H, F, Cl, Br, I, CN, OH, ═O, and NH2.

[0044] In some embodiments of the present invention, the above compound is selected from

[0045]

[0046] wherein R1, R2, R3, R6, Z1, Z2, X and Y are as defined in the present invention,

[0047] Ring A is selected from 3- to 8-membered heterocycloalkyl groups,

[0048] R9 and R 10 are independently selected from H, CN, F, Cl, Br, I, OH, -C(=O)NH2, C 1-3 Alkylamino, C 1-3 Alkoxy and C 1-3 alkyl.

[0049] The present invention also provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from

[0050]

[0051]

[0052]

[0053]

[0054] In some embodiments of the present invention, the above compound is selected from

[0055]

[0056] The present invention also provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a PD-1 / PD-L1 inhibitor.

[0057] In some embodiments of the present invention, the PD-1 / PD-L1 inhibitor is an anti-tumor drug.

[0058] Technical Effects

[0059] The compound of the present invention has a good inhibitory effect on the overactivation of the PD-1 / PD-L1 signaling pathway, thereby obtaining excellent activity in inhibiting tumor growth.

[0060] Definition and Description

[0061] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0062] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0063] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0064] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0065] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0066] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0067] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0068] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0069] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0070] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond and straight dashed bond

[0071] Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can readily interconvert into each other. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur via reorganization of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0072] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0073] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0074] 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. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0075] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0076] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0077] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0078] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0079] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0080] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0081] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A. When the substituent is listed without specifying which atom it is connected to the substituted group, the substituent can be bonded through any atom of the substituent. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0082] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0083] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0084] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of members of the ring, for example, a "5-7 membered ring" refers to a "ring" having 5-7 atoms arranged around it.

[0085] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6 and C5 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, and the like.

[0086] Unless otherwise specified, the term “C 1-4 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 Alkyl groups include C1-2 、C 1-3 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), and the like.

[0087] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0088] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, and the like.

[0089] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0090] Unless otherwise specified, the term “C 1-6 "Alkylamino" means an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an amino group. 1-6Alkylamino groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4, C3 and C2 alkylamino, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0091] Unless otherwise specified, the term “C 1-3 "Alkylamino" means an alkyl group containing 1 to 3 carbon atoms which is attached to the rest of the molecule via an amino group. 1-3 Alkylamino groups include C 1-2 , C3 and C2 alkylamino, etc. 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0092]

[0046] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0093] Unless otherwise specified, “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic ring system. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0094] Unless otherwise specified, the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). This includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the term "3-8 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The term "3-8 membered heterocycloalkyl" includes 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. Examples of 3-8 membered heterocycloalkyl groups include, but are not limited to, 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-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.

[0095] Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., C(=O), NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, fused and bridged rings. In addition, with respect to the "3-6 membered heterocycloalkyl", heteroatoms may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 3-6 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, 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-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

[0096] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0097] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0098] The solvent used in the present invention is commercially available.

[0099] Unless otherwise specified, the ratios of reagents used in silica gel column chromatography, silica gel chromatographic column chromatography and silica gel thin layer chromatography plates in the present invention are all by volume.

[0100] The present invention uses the following abbreviations: HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; DMSO stands for dimethyl sulfoxide; CD3OD stands for deuterated methanol; CDCl3 stands for deuterated chloroform; TBSO stands for tert-butyldimethylsilyloxy.

[0101] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names. DETAILED DESCRIPTION

[0102] The present invention is described in detail below by examples, but it is not intended to limit the present invention in any way. The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement modes well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0103] Intermediate A

[0104]

[0105] first step

[0106] Compound A-1 (10 g, 48.43 mmol) and compound A-2 (15.99 g, 62.96 mmol) were dissolved in dioxane (100 ml). 1,1′-bis(diphenylphosphino)ferrocenepalladium chloride (3.54 g, 4.84 mmol) and potassium acetate (11.88 g, 121.08 mmol) were added to the reaction solution. After the reaction mixture was purged with gas, it was stirred at 80°C under nitrogen for 15 hours. After the reaction was completed, the reaction mixture was filtered and concentrated to obtain the crude product Intermediate A. MS-ESI calculated value [M+H] + 254, measured value 254.

[0107] Intermediate B

[0108]

[0109] first step

[0110] Compound B-1 (20 g, 144.80 mmol) and ethyl pyruvate (84.07 g, 723.99 mmol) were mixed and stirred at 20°C for 15 minutes. Phosphorus oxychloride (222.02 g, 1.45 mol) was then added and stirred at 100°C for 1 hour. After the reaction was completed, the reaction solution was poured into ice water (1 L), the pH was adjusted to 7 with sodium carbonate, and the mixture was extracted with ethyl acetate (150 ml x 2). The organic phase was washed with saturated brine (100 ml x 2), the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1 to 3:1) to obtain compound B-2. MS-ESI calculated value [M+H] + 236.8 Actual measured value 236.8.

[0111] Step 2

[0112] Compound B-2 (16.8 g, 70.99 mmol) and sodium cyanoborohydride (13.387 g, 212.97 mmol) were dissolved in acetic acid (100 ml). The reaction mixture was reacted at 20°C under nitrogen for 1 hour. After the reaction was completed, the reaction mixture was poured into ice water, the pH was adjusted to 7 with sodium carbonate, and extracted with ethyl acetate (200 ml x 2). The organic phase was washed with saturated brine (100 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound B-3, which was used directly in the next step without further purification. MS-ESI calculated value [M+H] + 240.8, measured value 240.8.

[0113] Step 3

[0114] Compound B-3 (23 g, 95.56 mmol) was dissolved in dichloromethane (200 ml), and di-tert-butyl dicarbonate (31.28 g, 143.34 mmol) and triethylamine (29.01 g, 286.68 mmol) were added. The mixture was stirred at 25°C for 0.5 hours. After the reaction was completed, water (300 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane (200 ml x 2). The organic phase was washed with saturated brine (150 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1 to 5:1) to obtain compound B-4. MS-ESI calculated value [M+H] + 340.8, measured value 340.8.

[0115] Step 4

[0116] Compound B-4 (500 mg, 1.38 mmol) was dissolved in methanol (10 ml), and sodium methoxide (744.99 mg, 13.79 mmol) was added to the reaction solution, followed by stirring at 70°C for 10 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous solution of ammonium chloride (10 ml) and extracted with 30 ml of ethyl acetate (10 ml x 3). The combined organic phases were washed with 30 ml of saturated brine (10 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound B-5. MS-ESI calculated value [M+H] + 308, measured value 308.

[0117] Step 5

[0118] Compound B-5 (400 mg, 1.30 mmol) was dissolved in N, N-dimethylformamide (5 ml), and then iodoethane (1.01 g, 6.49 mmol) and potassium carbonate (359.59 mg, 2.59 mmol) were added to the reaction solution and stirred at 60°C for 10 hours. After the reaction was completed, water (10 ml) was added to dilute the mixture and extracted with 40 ml of ethyl acetate (20 ml × 2). The combined organic phase was washed with 40 ml of saturated brine (20 ml × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether ∶ Ethyl acetate = 10:1 to 3:1) to give compound B-6. MS-ESI calculated value [M+H] + 337, measured value 337. 1 H NMR (400MHz, CDCl3) δ=7.53 (s, 1H), 4.80 (s, 2H), 4.51 (q, 2H), 3.97 (s, 3H), 3.68 (t, 2H), 2.79 (br t, 2H), 1.67 (br s, 9H), 1.43-1.48 (m, 3H).

[0119] Step 6

[0120] Compound B-6 (300 mg, 891.84 μmol) was dissolved in ethyl acetate (3 mL), and then a solution of hydrogen chloride in ethyl acetate (4 mol / L, 1.11 mL) was added dropwise, and the mixture was stirred at 20° C. for 0.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the hydrochloride of compound B-7.

[0121] MS-ESI calculated value [M+H] + 236, measured value 236.

[0122] Step 7

[0123] Compound B-7 (250 mg, 916.67 μmol, hydrochloride) and compound B-8 (319.5 mg, 1.83 mmol) were dissolved in dichloromethane (3 ml), followed by the addition of N,N-diisopropylethylamine (118.47 mg, 916.67 μmol) and sodium triethoxyborohydride (582.84 mg, 2.75 mmol). The mixture was reacted at 20°C for 2 hours. After completion of the reaction, the reaction solution was filtered and concentrated under reduced pressure. The residue was separated by silica gel thin layer chromatography (petroleum ether: ethyl acetate = 3:1) to obtain Intermediate B. MS-ESI calculated value [M+H] + 395, measured value 395.

[0124] Intermediate D

[0125]

[0126] first step

[0127] Intermediate A (600 mg, 2.37 mmol) and compound D-1 (511.84 mg, 1.89 mmol) were dissolved in dioxane (10 ml), and then 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (173.16 mg, 236.66 μmol) and potassium carbonate (981.22 mg, 7.10 mmol) were added. The air in the solution was replaced with nitrogen three times, and the reaction solution was stirred at 80°C under nitrogen protection for 12 hours. After the reaction was completed, it was diluted with 20 ml of water and extracted with 60 ml of ethyl acetate (20 ml × 3). The organic phase was washed with 40 ml of saturated brine (20 ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (petroleum ether ∶ The product was separated by ethyl acetate (5:1) to give compound D-2. MS-ESI calculated value [M+H]+: 317, found value: 317.

[0128] Step 2

[0129] Compound D-2 (8 g, 25.24 mmol) and compound A-2 (7.05 g, 27.76 mmol) were dissolved in dioxane (100 ml), followed by the addition of 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (1.85 g, 2.52 mmol) and potassium acetate (7.43 g, 75.72 mmol). The air in the solution was purged with nitrogen three times, and the reaction solution was stirred at 90°C under nitrogen for 4 hours. After completion of the reaction, the reaction solution was filtered and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1 to 10:1) to obtain Intermediate D. MS-ESI calculated [M+H] value: 364, found: 364. 1 H NMR (400MHz, CDCl3) δ=7.68 (dd, J=4.3, 4.9Hz, 1H), 7.33-7.28 (m, 2H), 7.11 (t, J=7 .8Hz, 1H), 6.83 (dd, J=1.5, 8.0Hz, 1H), 6.64 (dd, J=1.4, 7.5Hz, 1H), 1.39 (s, 12H).

[0130] Intermediate C

[0131]

[0132] first step

[0133] Compound C-1 (10 g, 49.01 mmol) was added to acetonitrile (100 ml) and water (150 ml). Aqueous hydroiodic acid (100 ml, 55% by mass) was added, and the mixture was stirred at 0°C for 0.5 hours. Sodium nitrite (50.73 g, 735.21 mmol) was dissolved in water (100 ml) and added dropwise to the reaction mixture at 0°C. After the addition was complete, the mixture was stirred at 20°C for 1 hour and then at 50°C for 16 hours. After the reaction was complete, the mixture was cooled to 20°C and added dropwise to aqueous sodium hydroxide solution (600 ml, 20% by mass) while maintaining the temperature at 0°C. The mixture was extracted with ethyl acetate (500 ml x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1) to obtain compound C-2. 1 H NMR (400MHz, CDCl3) δ = 8.08 (s, 1H), 4.05 (s, 3H).

[0134] Step 2

[0135] Compound C-2 (9.2 g, 29.22 mmol) was dissolved in tetrahydrofuran (100 ml) and added dropwise to isopropylmagnesium chloride lithium chloride complex (1.3 mol / L, 40.45 ml) at -60°C and stirred for 30 minutes. N,N-dimethylformamide (6.41 g, 87.65 mmol) was then added at -40°C and stirred for 1 hour. After the reaction was completed, saturated aqueous ammonium chloride solution (100 ml) was carefully added dropwise to the reaction mixture, followed by extraction with ethyl acetate (50 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound C-3. MS-ESI calculated value [M+H] + 217 and 219, measured values ​​217 and 219.

[0136] Step 3

[0137] Compound C-3 (1.5 g, 6.91 mmol) was dissolved in methanol (15 ml), and then sodium borohydride (784.47 mg, 20.74 mmol) was added at 0°C and stirred at 25°C for 2 hours. After the reaction was completed, the reaction was quenched with 20 ml of saturated aqueous ammonium chloride solution. After most of the methanol was concentrated under reduced pressure, water (20 ml) was added for dilution, and then extracted with ethyl acetate (90 ml). The organic phase was washed with saturated brine (60 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether ∶ Ethyl acetate = 30 ∶ 1 to 10:1) to obtain compound C-4. 1 H NMR (400MHz, DMSO-d6) δ = 8.34 (s, 1H), 5.24 (t, J = 6.0Hz, 1H), 4.52 (d, J = 6.0Hz, 2H), 3.94 (s, 3H)

[0138] Step 4

[0139] Compound C-4 (1.4 g, 6.39 mmol) and intermediate D (2.33 g, 6.39 mmol) were dissolved in dioxane (15 ml) and water (2 ml), and then [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium (467.68 mg, 639.17 μmol) and potassium carbonate (2.65 g, 19.17 mmol) were added. The air in the solution was replaced with nitrogen three times, and the reaction solution was stirred at 65°C for 4 hours under nitrogen protection. After the reaction was completed, it was diluted with water (40 ml) and extracted with ethyl acetate (150 ml). The organic phase was washed with saturated brine (60 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether ∶ Ethyl acetate = 30 ∶ 1 to 3 ∶ 1) Compound C-5 was isolated and obtained.

[0140] Step 5

[0141] Compound C-5 (171.63 mg, 456.18 μmol) and intermediate B (200 mg, 506.87 μmol) were dissolved in tetrahydrofuran (4 ml), and a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1 mol / L, 1.77 ml) was added under nitrogen protection at zero degrees. The reaction solution was reacted at zero degrees for 1 hour. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (20 ml) and extracted with ethyl acetate (20 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel thin layer chromatography (petroleum ether ∶ Ethyl acetate = 1 ∶ 2) Purification and separation to obtain compound C-6. MS-ESI calculated value [M+H] + 724, measured value 724.

[0142] Step 6

[0143] Compound C-6 (130 mg, 186.27 μmol) was dissolved in 1,1-dichloroethane (2 ml), and manganese dioxide (161.94 mg, 1.86 mmol) was added. The reaction solution was heated to 90°C under nitrogen for 2 hours. After completion of the reaction, the mixture was filtered and concentrated to obtain Intermediate C. MS-ESI calculated value [M+H] + 722, measured value 722.

[0144] Intermediate L

[0145]

[0146] first step

[0147] Compound L-1 (6 g, 27.65 mmol) was used to replace compound K-1 (5.30 g, 48.38 mmol) in the same manner as intermediate K. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain compound L-2. MS-ESI calculated value [M+H] + 288 and 290, measured values ​​288 and 290.

[0148] Step 2

[0149] Compound L-2 (5 g, 17.35 mmol) was used to replace compound K-2 (9 g, 32.83 mmol) in the same manner as intermediate K. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain intermediate L. MS-ESI calculated value [M+H] + 402 and 404, measured values ​​402 and 404.

[0150] Intermediate E

[0151]

[0152] first step

[0153] Intermediate L (100 mg, 248.51 μmol) and Intermediate D (99.52 mg, 273.36 μmol) were dissolved in dioxane (5 mL) and water (0.5 mL). [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (18.18 mg, 24.85 μmol) and potassium carbonate (103.04 mg, 745.53 μmol) were then added. The air in the solution was purged with nitrogen three times, and the reaction mixture was stirred at 65°C under nitrogen for 4 hours. After completion of the reaction, the mixture was diluted with 20 mL of water and extracted with 120 mL of ethyl acetate (40 mL x 3). The organic phase was washed with 60 mL of saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel thin layer chromatography (petroleum ether:ethyl acetate = 3:1) to obtain Intermediate E. MS-ESI calculated value [M+H] + 559, measured value 559. 1 H NMR (400MHz, CD3OD) δ=8.31 ​​(s, 1H), 7.53 (dd, J=1.7, 7.7Hz, 1H), 7.40 (t, J=7.6Hz, 1H), 7.26 (dd, J=1.7, 7.5Hz, 1H), 7.03 (t, J=7.8Hz, 1H), 6.81 (dd, J=1. 5, 8.2Hz, 1H), 6.52 (dd, J=1.5, 7.5Hz, 1H), 4.49 (s, 2H), 3.97 (s, 3H), 3.83 (s , 2H), 3.48-3.43(m, 2H), 1.47(s, 3H), 1.11(s, 1H), 0.80(s, 9H), 0.00(s, 6H).

[0154] Intermediate F

[0155]

[0156] first step

[0157] Compound B-2 (1 g, 4.23 mmol) was dissolved in tetrahydrofuran (10 ml) and water (2 ml). Sodium hydroxide (845.05 mg, 21.13 mmol) was then added to the reaction mixture and stirred at 70°C for 10 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a crude product of compound F-1. MS-ESI calculated value [M+H] + 191, measured value 191.

[0158] Step 2

[0159] Compound F-1 (0.9 g, 4.73 mmol) was dissolved in ethanol (10 ml), and concentrated sulfuric acid (2.32 g, 23.66 mmol) was added to the reaction solution, and stirred at 70°C for 2 hours. After the reaction was completed, the filtrate was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether). ∶ Ethyl acetate = 20:1 to 1:1) was purified to give compound F-2. MS-ESI calculated value [M+H] + 219, measured value 219.

[0160] Step 3

[0161] Compound F-2 (130 mg, 583.85 μmol) and compound F-3 (267.04 mg, 1.75 mmol) were dissolved in N,N-dimethylformamide (2 ml) and stirred at 80°C for 0.5 hours. After the reaction was complete, the residue was filtered and concentrated under reduced pressure, and purified by silica gel thin layer chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound F-4. MS-ESI calculated value [M+H] + 268, measured value 268.

[0162] Step 4

[0163] Compound F-4 (90 mg, 325.48 μmol) was dissolved in glacial acetic acid (2 mL), and sodium cyanoborohydride (40.91 mg, 650.97 μmol) was added to the reaction mixture, and stirred at 20°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain crude compound F-5. MS-ESI calculated value [M+H] + 272, measured value 272.

[0164] Step 5

[0165] Compound F-5 (80 mg, 293.85 μmol) was dissolved in dichloromethane (2 ml), followed by the addition of compound B-8 (102.44 mg, 587.70 μmol) and sodium triethoxyborohydride (186.84 mg, 881.55 μmol). The reaction mixture was allowed to react at 20°C for 1 hour. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure. The residue was separated by silica gel thin layer chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound F-6. MS-ESI calculated value [M+H] + 431, measured value 431.

[0166] Step 6

[0167] Compound F-6 (1.2 g, 2.79 mmol) and compound C-5 (838.88 mg, 2.23 mmol) were dissolved in tetrahydrofuran (15 ml). A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1 mol / L, 9.75 ml) was then added to the reaction mixture at 0°C and stirred at 25°C for 1 hour. After completion of the reaction, the reaction mixture was poured into a saturated aqueous ammonium chloride solution (50 ml) at 0°C, diluted with water (30 ml), and extracted with ethyl acetate (50 ml x 3). The combined organic phases were washed with saturated brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to obtain Intermediate F. MS-ESI calculated value [M+H] + 760, measured value 760.

[0168] Intermediate G

[0169]

[0170] first step

[0171] Compound B-4 (1 g, 2.76 mmol) was dissolved in N,N-dimethylacetamide (10 ml). Zinc cyanide (649.76 mg, 5.52 mmol) and methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (500.06 mg, 551.64 μmol) were added to the reaction solution. The mixture was stirred at 120°C for 10 hours under nitrogen. After completion of the reaction, the mixture was diluted with water (10 ml) and extracted with 30 ml of ethyl acetate (10 ml x 3). The combined organic phases were washed with 30 ml of saturated brine (10 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was separated by HPLC (Phenomenex luna C18 column, 250 x 50 mm x 10 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 25%-55%, 30 min) to obtain compound G-1. MS-ESI calculated value [M+H] + 332, measured value 332. 1 H NMR (400MHz, DMSO-d6) δppm 8.23 ​​(s, 1H), 4.64 (br s, 2H), 3.66-3.72 (m, 2H), 3.02 (br s, 2H), 1.44 (s, 9H).

[0172] Step 2

[0173] Compound G-1 (150 mg, 452.67 μmol) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (1 mL) and stirred at 20°C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of compound G-2. MS-ESI calculated value [M+H] + 232, measured value 232.

[0174] Step 3

[0175] Compound G-2 (100 mg, 432.43 μmol, trifluoroacetate) and compound B-8 (150.76 mg, 864.86 μmol) were dissolved in methanol (5 mL), followed by the addition of N,N-diisopropylethylamine (55.89 mg, 432.43 μmol) and sodium cyanoborohydride (67.94 mg, 1.08 mmol). The reaction mixture was allowed to react at 20°C for 1 hour. After completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride (30 mL) and extracted with 60 mL of ethyl acetate (30 mL x 2). The combined organic phases were washed with 60 mL of saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Intermediate G. MS-ESI calculated value [M+H] + 389, measured value 389.

[0176] Intermediate K

[0177]

[0178] first step

[0179] Compound C-3 (7 g, 32.26 mmol) and compound K-1 (5.30 g, 48.38 mmol) were dissolved in methanol (100 ml), N, N-diisopropylethylamine (8.34 g, 64.51 mmol) was added and stirred at 25°C for 0.5 hours, followed by the addition of sodium cyanoborohydride (2.43 g, 38.71 mmol) and stirring at 25°C for 0.5 hours. After the reaction was completed, water (200 ml) was carefully added to the reaction, followed by extraction with ethyl acetate (100 ml x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Compound K-2 was obtained. MS-ESI calculated value [M+H] + 274 and 276, measured values ​​274 and 276.

[0180] Step 2

[0181] Compound K-2 (9 g, 32.83 mmol) was dissolved in dichloromethane (100 ml), and tert-butyldimethylsilyl chloride (12.37 g, 82.08 mmol) and imidazole (7.82 g, 114.92 mmol) were added. The mixture was stirred at 25°C for 16 hours. After the reaction was completed, water (100 ml) and dichloromethane (100 ml) were added to the reaction mixture and stirred for 15 minutes. The organic phase was separated and dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain Intermediate K. MS-ESI calculated value [M+H] + 388 and 390, measured values ​​388 and 390.

[0182] Intermediate I

[0183]

[0184] Intermediate K (7.4 g, 19.05 mmol) and Intermediate D (6.94 g, 19.05 mmol) were dissolved in dioxane (150 ml) and water (15 ml), followed by the addition of [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (1.39 g, 1.91 mmol) and potassium carbonate (7.90 g, 57.16 mmol). The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at 65°C under nitrogen for 4 hours. After completion of the reaction, the mixture was diluted with 100 ml of water and extracted with ethyl acetate (100 ml x 2). The organic phase was washed with saturated brine (100 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel chromatography (petroleum ether:ethyl acetate = 50:1 to 5:1) to obtain Intermediate I. MS-ESI calculated value [M+H] + 545, measured value 545. 1 HNMR (400MHz, CDCl3) δ=8.43 (s, 1H), 7.56 (dd, J=1.8, 7.7Hz, 1H), 7.38 (t, J=7.6Hz, 1H), 7.28 (dd, J=1.8, 7.5Hz, 1H), 7.15-7.04 (m, 1H), 6.79 (dd, J=1.5, 8.1Hz, 1H), 6.66 (dd, J=1.5, 7.5Hz, 1H), 4.47 (t, J=6.2Hz, 1H), 4.15 (br s, 2H), 3.99 (s, 3H), 3.81-3.76 (m, 2H), 3.07-2.95 (m, 2H), 0.90-0.81 (m, 10H), 0.01 (br s, 6H).

[0185] Intermediate J

[0186]

[0187] first step

[0188] Compound B-4 (1 g, 2.93 mmol) was dissolved in dioxane (20 ml), and compound A-2 (968.66 mg, 3.81 mmol), potassium acetate (719.94 mg, 7.34 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex (239.62 mg, 293.43 μmol) were added. The reaction mixture was heated to 90°C under nitrogen for 14 hours. After completion of the reaction, the mixture was filtered, and the filtrate was diluted with ethyl acetate (60 ml) and washed with saturated brine (60 ml). The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain compound J-1. 1 H NMR (400MHz, CDCl3) δ = 8.07 (s, 1H), 4.61 (s, 2H), 4.37-4.33 (m, 2H), 3.65-3. 55(m, 2H), 3.10-3.06(m, 2H), 1.44(s, 9H), 1.35-1.31(m, 3H), 1.17(s, 12H).

[0189] Step 2

[0190] Compound J-1 (300 mg, 693.94 μmol) was dissolved in tetrahydrofuran (3 ml) and water (1.5 ml), and sodium perborate tetrahydrate (427.08 mg, 2.78 mmol) was added. The reaction mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the pH of the reaction mixture was adjusted to 6 with 1 mol / L dilute hydrochloric acid, extracted with ethyl acetate (20 ml), and the organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was separated by silica gel thin layer chromatography (ethyl acetate) to obtain intermediate J. MS-ESI calculated value [M+H] + 323, measured value 323.

[0191] Example 1

[0192]

[0193] first step

[0194] Compound D-1 (2 g, 7.40 mmol) was dissolved in tetrahydrofuran (20 ml), and n-butyl lithium in n-hexane solution (3.26 ml, 2.5 mol / L) was added under nitrogen protection at -78 degrees Celsius. After half an hour of reaction, trimethyl borate (1.54 g, 14.80 mmol) was added, and the reaction solution was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was quenched with dilute hydrochloric acid (1 mol / L, 40 ml) and extracted with ethyl acetate (40 ml). The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether∶ Ethyl acetate = 10:1) to separate and obtain compound 1-1. 1 H NMR (400MHz, DMSO-D6) δ = 8.42-8.46 (m, 2H), 7.70-7.73 (m, 1H), 7.36-7.39 (m, 1H), 7.22-7.24 (m, 1H).

[0195] Step 2

[0196] Compound 1-1 (800 mg, 3.40 mmol) was dissolved in dioxane (8 ml) and water (0.8 ml). Compound 1-2 (324.13 mg, 1.89 mmol), potassium carbonate (522.16 mg, 3.78 mmol), and tetrakis(triphenylphosphine)palladium (152.81 mg, 132.24 μmol) were added under nitrogen. The reaction solution was heated to 95°C under nitrogen for 3 hours. After completion of the reaction, the mixture was filtered, and the filtrate was diluted with ethyl acetate (50 ml) and washed with saturated brine (50 ml). The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 30:1) to obtain compound 1-3. MS-ESI calculated value [M+H] + 326, measured value 326.

[0197] Step 3

[0198] Compound 1-4 (337.58 mg, 2.24 mmol) was dissolved in dichloromethane (6 ml) and ethanol (6 ml), and N, N-diisopropylethylamine (482.81 mg, 3.74 mmol) and compound 1-3 (610 mg, 1.87 mmol) were added. After stirring for half an hour, sodium cyanoborohydride (1.19 g, 5.60 mmol) was added, and the reaction solution was reacted at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane (50 ml) and washed with saturated brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1-5. MS-ESI calculated value [M+H] + 424, measured value 424.

[0199] Step 4

[0200] Compound 1-5 (550 mg, 1.29 mmol) was dissolved in dichloromethane (11 ml), and di-tert-butyl dicarbonate (423.94 mg, 1.94 mmol) and triethylamine (327.59 mg, 3.24 mmol) were added. The reaction solution was allowed to react at room temperature for 0.5 hours. After completion of the reaction, the reaction solution was diluted with water (80 ml), extracted with dichloromethane (80 ml x 2), and the organic phase was washed with saturated brine (50 ml). Drying over anhydrous sodium sulfate, filtration, and concentration afforded compound 1-6. MS-ESI calculated value [M+H] + 526, measured value 526. 1 H NMR (400MHz, CD3OD) δ = 7.60 (dd, J = 7.88, 1.50Hz, 1H) 7.39 (br d, J=1.63Hz, 2H) 7.23-7.31 (m, 1H) 7.07-7.18 (m, 2H) 4.34-4.48 (m, 2H) 3.90-3.94 (m, 3H) 3.83 (br s, 1H) 3.24-3.31 (m, 2H) 2.04-2.35 (m, 4H) 1.52 (s, 9H).

[0201] Step 5

[0202] Compound 1-6 (413 mg, 786.92 μmol) was dissolved in a solution of dioxane (8 mL) and water (0.8 mL). Intermediate A (299.26 mg, 1.18 mmol), potassium carbonate (326.27 mg, 2.36 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (57.58 mg, 78.69 μmol) were added. After nitrogen was replaced three times, the reaction mixture was incubated at 85°C for 4 hours. After completion of the reaction, the reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (40 mL x 2). The organic phase was washed with saturated brine (10 mL). The crude product was dried over anhydrous sodium sulfate, filtered, and concentrated to afford compounds 1-7. The crude product was separated by HPLC (column: Phenomenex luna C18, 150 × 40 mm × 15 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 50%-80%, 10 min). MS-ESI calculated values ​​[M+H] + 571, measured value 571.

[0203] Step 6

[0204] Compound 1-7 (80 mg, 139.98 μmol) and intermediate B (60.76 mg, 153.98 μmol) were dissolved in tetrahydrofuran (4 ml). Under nitrogen protection at zero degrees Celsius, a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1 mol / L, 419.95 μl) was added. The reaction mixture was reacted at zero degrees Celsius for 1 hour. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (30 ml) and extracted with ethyl acetate (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified and isolated by silica gel thin layer chromatography (dichloromethane:methanol = 10:1) to obtain compound 1-8. MS-ESI calculated value [M+H] + 919, measured value 919.

[0205] Step 7

[0206] Compound 1-8 (101 mg, 109.78 μmol) was dissolved in dichloromethane (2 mL), and a solution of hydrogen chloride in ethyl acetate (4 mol / L, 2 mL) was added. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated. The crude product was separated by HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 15%-35%, 10 min) to obtain the formate salt of compound 1. MS-ESI calculated value [M+H] + 705, measured value 705. 1 H NMR (400MHz, CD3OD) δ=8.61 (d, J=8.4, 1H), 8.32-8.45 (m, 2H), 7.83-7.88 (m, 1H), 7.7 7(s, 1H), 7.65-7.70(m, 1H), 7.46-7.57(m, 2H), 7.38-7.43(m, 1H), 7.31-7.36(m, 1H), 7.13-7.21(m, 1H), 4.14-4.21(m, 2H), 4.04-4.12(m, 8H), 3.97-4.02(m, 1H), 3.84-3.9 0(m, 2H), 3.14-3.22(m, 2H), 2.94-3.09(m, 6H), 2.33-2.46(m, 3H), 1.83-1.97(m, 1H).

[0207] Example 2

[0208]

[0209] first step

[0210] Compound 2-1 (17.90 mg, 205.47 μmol) was dissolved in dichloromethane (3 ml), and N,N-diisopropylethylamine (35.41 mg, 273.96 μmol) and intermediate C (99 mg, 136.98 μmol) were added. After stirring for half an hour, sodium cyanoborohydride (87.10 mg, 410.94 μmol) was added. The reaction solution was reacted at room temperature for 12 hours. After the reaction was completed, the mixture was diluted with water (20 ml) and extracted with dichloromethane (25 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel thin layer chromatography (dichloromethane) ∶ Methanol = 12:1) to separate and obtain compound 2-2. MS-ESI calculated value [M+H] + 793, measured value 793.

[0211] Step 2

[0212] Compound 2-2 (62 mg, 78.10 μmol) was dissolved in dichloromethane (3 mL), and a solution of hydrogen chloride in ethyl acetate (4 mol / L, 1.5 mL) was added. The mixture was stirred at 25°C for 0.5 h. After completion of the reaction, the mixture was concentrated. The crude product was separated by HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 10%-40%, 8 min) to afford compound 2. MS-ESI calculated value [M+H] + 679, measured value 679. 1 H NMR (400MHz, CD3OD) δ = 8.62 (dd, J = 8.25, 1.50Hz, 1H), 8.50 (s, 1H), 7.71-7.76 (m, 2H), 7.58 (t, J = 7.63Hz, 1H), 7.44-7.52 (m , 2H), 7.18 (dd, J=7.63, 1.50Hz, 1H), 4.47-4.54 (m, 1H), 4.31 (s, 2H), 4.11 (s, 3H), 4.04 (s, 3H), 3.79-3.88 (m, 4H), 3.37 (br s, 1H), 3.30 (br d, J=5.38Hz, 1H), 3.14-3.25 (m, 1H), 3.10 (br d, J=11.01Hz, 1H), 2.85-2.95 (m, 4H), 2.76-2.83 (m, 2H), 2.20-2.31 (m, 1H), 1.89-2.00 (m, 1H).

[0213] Example 3

[0214]

[0215]

[0216] first step

[0217] Compound 3-1 (24.61 mg, 207.55 μmol) was dissolved in dichloromethane (3 ml), and N,N-diisopropylethylamine (35.76 mg, 276.73 μmol) and intermediate C (100 mg, 138.36 μmol) were added. After stirring for half an hour, sodium cyanoborohydride (87.97 mg, 415.09 μmol) was added. The reaction solution was reacted at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water (20 ml) and extracted with dichloromethane (25 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel thin layer chromatography (dichloromethane). ∶ Methanol = 13:1) to separate and obtain compound 3-2. MS-ESI calculated value [M+H] + 788, measured value 788.

[0218] Step 2

[0219] Compound 3-2 (83 mg, 105.22 μmol) was dissolved in dichloromethane (3 mL), and a solution of hydrogen chloride in ethyl acetate (4 mol / L, 1.5 mL) was added. The mixture was stirred at 25°C for 0.5 h. After completion of the reaction, the mixture was concentrated. The crude product was separated by HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 20%-30%, 7 min) to afford compound 3. MS-ESI calculated value [M+H] + 692, measured value 692. 1 H NMR (400MHz, CD3OD) δ = 8.62 (dd, J = 8.32, 1.19Hz, 1H), 8.43-8.47 (m, 1H), 7. 70-7.76 (m, 2H), 7.57 (t, J=7.63Hz, 1H), 7.43-7.52 (m, 2H), 7.17 (dd, J=7.63 , 1.25Hz, 1H), 4.25-4.31(m, 2H), 4.02-4.14(m, 8H), 3.88-3.97(m, 4H), 3.83 (t, J=5.82Hz, 2H), 3.50-3.60 (m, 1H), 2.94-3.00 (m, 2H), 2.81-2.92 (m, 4H).

[0220] Example 4

[0221]

[0222]

[0223] first step

[0224] Intermediate C (80 mg, 110.69 μmol) and compound 4-1 (28.16 mg, 221.38 μmol) were dissolved in dichloromethane (2 ml), and sodium triethoxyborohydride (58.65 mg, 276.73 μmol) was added. The mixture was reacted at 20°C for 2 hours. After completion of the reaction, the reaction solution was filtered and concentrated, and the crude product was purified by silica gel thin layer chromatography (dichloromethane:methanol = 10:1) to obtain compound 4-2. MS-ESI calculated value [M+H] + 833, measured value 833.

[0225] Step 2

[0226] Compound 4-2 (30 mg, 35.97 μmol) was dissolved in ethyl acetate (1 mL), and a solution of hydrogen chloride in ethyl acetate (4 mol / L, 44.97 μL) was added. The mixture was stirred at 25°C for 0.5 h. After completion of the reaction, the reaction solution was filtered and concentrated, and the crude product was separated by HPLC (column: Shim-pack C18 150*25 mm*10 μm; mobile phase: mobile phase A: 0.225% formic acid aqueous solution; mobile phase B: acetonitrile; B%: 11%-41%, 10 min) to obtain the formate salt of compound 4. MS-ESI calculated value [M+H] + 719, measured value 719. 1 H NMR (400MHz, CD3OD) δppm 8.61(dd, 1H), 8.57(s, 1H), 8.38-8.48(m, 2H), 7.70-7.77(m, 2H), 7.59(t, 1H), 7.44-7.52(m, 2H), 7.17(dd, 1H), 4.48(s, 2H), 4.09-4.19(m, 6H), 4.04(s, 3H), 3.94(s, 2H), 3.83(t, 2H), 2.99-3.08(m, 2H), 2.89(q, 4H), 2.64(br d, 2H), 2.45 (br d, 2H), 2.28-2.40 (m, 2H), 2.09 (br d, 2H).

[0227] Example 5

[0228]

[0229] first step

[0230] Compound 5-1 (25.65 mg, 207.55 μmol) was dissolved in dichloromethane (3 ml), and N,N-diisopropylethylamine (35.76 mg, 276.73 μmol) and intermediate C (100 mg, 138.36 μmol) were added. After stirring for half an hour, sodium cyanoborohydride (87.97 mg, 415.09 μmol) was added. The reaction solution was reacted at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water (20 ml) and extracted with dichloromethane (25 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel thin layer chromatography (dichloromethane) ∶ Methanol = 13:1) to separate and obtain compound 5-2. MS-ESI calculated value [M+H] + 793, measured value 793.

[0231] Step 2

[0232] Compound 5-2 (62 mg, 78.10 μmol) was dissolved in dichloromethane (3 mL), and a solution of hydrogen chloride in ethyl acetate (4 mol / L, 1.5 mL) was added. The mixture was stirred at 25°C for 0.5 h. After completion of the reaction, the mixture was concentrated. The crude product was separated by HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 18%-28%, 7 min) to afford compound 5. MS-ESI calculated value [M+H] + 679, measured value 679. 1 H NMR (400MHz, CD3OD) δ=8.62 (dd, J=8.28, 1.25Hz, 1H), 8.44-8.47 (m, 1H), 7.70 -7.77(m, 2H), 7.54-7.60(m, 1H), 7.43-7.53(m, 2H), 7.18(dd, J=7.59, 1.19Hz, 1H), 4.27-4.33(m, 2H), 3.97-4.14(m, 8H), 3.85(t, J=5.65Hz, 2H), 3.66(s, 2H ), 3.04-3.11(m, 2H), 2.89-2.96(m, 4H), 0.88-0.94(m, 2H), 0.72-0.78(m, 2H).

[0233] Example 6

[0234]

[0235] first step

[0236] Intermediate C (110 mg, 152.20 μmol) was dissolved in dichloromethane (3 ml), and compound 6-1 (17.15 mg, 228.30 μmol) and sodium triethoxyborohydride (96.77 mg, 456.60 μmol) were added. The reaction mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the reaction mixture was quenched with water (10 ml), diluted with dichloromethane (5 ml), and extracted with dichloromethane (10 ml x 3). The organic phase was washed with saturated brine (20 ml x 2), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel thin layer chromatography (dichloromethane: methanol = 8:1) to obtain compound 6-2 (80 mg, crude product). MS-ESI calculated value [M+H] + 781, measured value 781.

[0237] Step 2

[0238] Compound 6-2 (80 mg, 102.32 μmol) was dissolved in dichloromethane (2 mL), and a solution of hydrogen chloride in ethyl acetate (4 mol / L, 1 mL) was added. The mixture was stirred at room temperature for 0.25 h. After completion of the reaction, the mixture was concentrated. The crude product was separated by HPLC (column: Xtimate C18 150 x 25 mm x 10 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 7%-37%, 10 min) to obtain the formate salt of compound 6. MS-ESI calculated value [M+H] + 667, measured value 667. 1 H NMR (400MHz, CD3OD) δ = 8.62 (dd, J = 1.5, 8.3Hz, 1H), 8.55 (s, 1H), 8.52-8.49 (m, 1H), 7.7 6-7.71 (m, 2H), 7.59 (t, J=7.6Hz, 1H), 7.53-7.45 (m, 2H), 7.18 (dd, J=1.5, 7.6Hz, 1H), 4. 34-4.25 (m, 2H), 4.13 (s, 3H), 4.05 (s, 3H), 3.86-3.79 (m, 4H), 3.74 (t, J=5.9Hz, 2H), 3. 16 (t, J=7.2Hz, 2H), 2.93-2.85 (m, 4H), 2.79 (t, J=5.9Hz, 2H), 1.95 (quin, J=6.6Hz, 2H).

[0239] Example 7

[0240]

[0241] first step

[0242] Intermediate C (100 mg, 138.36 μmol) was dissolved in dichloromethane (3 mL), and compound 7-1 (25.64 mg, 345.91 μmol) and sodium triethoxyborohydride (87.98 mg, 415.09 μmol) were added. The reaction mixture was allowed to react at room temperature for 1 hour, followed by the addition of intermediate 7-1 (10.26 mg, 138.36 μmol) and sodium triethoxyborohydride (29.33 mg, 138.36 μmol). The reaction mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction mixture was quenched with water (10 mL), diluted with dichloromethane (5 mL), and extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated brine (20 mL x 2), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel thin layer chromatography (dichloromethane:methanol = 10:1) to obtain compound 7-2. MS-ESI calculated value [M+H] + 780, measured value 780.

[0243] Step 2

[0244] Compound 7-2 (35 mg, 44.82 μmol) was dissolved in dichloromethane (2 mL), and a solution of hydrogen chloride in ethyl acetate (4 mol / L, 1 mL) was added. The mixture was stirred at room temperature for 0.25 h. After completion of the reaction, the mixture was concentrated. The crude product was separated by HPLC (column: Xtimate C18 150 x 25 mm x 10 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 15%-35%, 10 min) to obtain the formate salt of compound 7. MS-ESI calculated value [M+H] + 666, measured value 666. 1 H NMR (400MHz, CD3OD) δ = 8.60 (brd, J = 8.4Hz, 1H), 8.55 (s, 1H), 8.46-8.40 (m, 1H), 7.75-7.67 ( m, 2H), 7.56 (brt, J=7.5Hz, 1H), 7.51-7.41 (m, 2H), 7.18-7.13 (m, 1H), 4.08 (s, 3H), 4.03 (br d, J=3.8Hz, 5H), 3.80 (br d, J=7.2Hz, 4H), 3.04 (br d, J=5.5Hz, 2H), 2.97 (br d, J=5.6Hz, 2H), 2.91-2.84 (m, 4H), 2.76 (br t, J=5.7Hz, 2H), 2.67(s, 3H).

[0245] Example 8

[0246]

[0247] first step

[0248] Compound 8-1 (28.21 mg, 228.30 μmol) was dissolved in dichloromethane (3 ml), and N,N-diisopropylethylamine (39.34 mg, 304.40 μmol) and intermediate C (110 mg, 152.20 μmol) were added. After stirring for half an hour, sodium cyanoborohydride (96.77 mg, 456.60 μmol) was added. The reaction solution was reacted at room temperature for 12 hours. After the reaction was completed, the mixture was diluted with water (20 ml) and extracted with dichloromethane (25 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel thin layer chromatography (dichloromethane). ∶ Methanol = 10:1) to separate and obtain compound 8-2. MS-ESI calculated value [M+H] + 793, measured value 793.

[0249] Step 2

[0250] Compound 8-2 (68 mg, 85.66 μmol) was dissolved in dichloromethane (3 mL), and a solution of hydrogen chloride in ethyl acetate (4 mol / L, 1.5 mL) was added. The mixture was stirred at 25°C for 0.5 h. After completion of the reaction, the mixture was concentrated. The crude product was separated by HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 10%-40%, 7 min) to obtain the formate salt of compound 8. MS-ESI calculated value [M+H] + 679, measured value 679. 1 H NMR (400MHz, CD3OD) δ = 8.58-8.65 (m, 1H), 8.49 (s, 1H) 8.43 (br s, 1H), 7.70-7.78 (m, 2H), 7.59 (t, J=7.63Hz, 1H), 7.45-7.53 (m, 2H), 7.18 (dd, J=7.63, 1.38Hz, 1H), 4.52 (s, 2H), 4.30-4.41 (m, 3 H), 4.12 (s, 3H), 4.06 (s, 3H), 3.94-4.01 (m, 4H), 3.81-3.87 (m, 2H), 3.35-3.37 (m, 3H), 3.02-3.07 (m, 2H), 2.91 (q, J=5.38Hz, 4H).

[0251] Example 9

[0252]

[0253]

[0254] first step

[0255] Compound 3-1 (25.84 mg, 217.92 μmol) was dissolved in dichloromethane (3 ml), and N,N-diisopropylethylamine (37.55 mg, 290.56 μmol) and intermediate C (105 mg, 145.28 μmol) were added. After stirring for half an hour, sodium cyanoborohydride (92.37 mg, 435.85 μmol) was added. The reaction solution was reacted at room temperature for 1 hour. After the reaction was completed, the mixture was diluted with water (20 ml) and extracted with dichloromethane (25 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel thin layer chromatography (dichloromethane) ∶ Methanol = 14 ∶ 1) Compound 9-1 was isolated. MS-ESI calculated value [M+H] + 788, measured value 788.

[0256] Step 2

[0257] Compound 9-1 (51 mg, 64.65 μmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at 25°C for 16 hours. LC-MS analysis of the reaction solution revealed unreacted starting material. The reaction solution was heated to 30°C and stirred for 4 hours. After completion of the reaction, it was concentrated. The crude product was separated by HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 10%-40%, 7 minutes) to obtain compound 9. MS-ESI calculated value [M+H] + 674, measured value 674. 1 H NMR (400MHz, CD3OD) δ = 8.60-8.63 (m, 1H), 8.42 (s, 1H), 7.83 (s, 1H), 7.72 (dd, J = 7.69, 1.69Hz, 1H), 7.55-7.60 (m, 1H), 7.51 (t , J=7.94Hz, 1H), 7.45 (dd, J=7.57, 1.69Hz, 1H), 7.19 (dd, J=7.63, 1.63Hz, 1H), 4.30-4.39 (m, 2H), 4.07-4.10 (m, 6H), 3.94 (br t, J=5.38Hz, 4H), 3.81-3.90 (m, 2H), 3.69 (t, J=7.25Hz, 2H), 3.52-3.60 (m, 1H), 3.44 (br s, 2H), 3.25 (br d, J=4.50Hz, 2H), 3.06 (brt, J=5.88Hz, 2H).

[0258] Example 10

[0259]

[0260]

[0261] first step

[0262] Compound L-1 (1.72 g, 13.95 mmol) was dissolved in dichloromethane (20 ml). Compound 10-1 (2 g, 9.30 mmol) and N,N-diisopropylethylamine (3.61 g, 27.90 mmol) were added to the reaction solution, and the mixture was stirred at 25°C for 0.5 hours. Sodium triacetoxyborohydride (5.91 g, 27.90 mmol) was added to the reaction solution, and the mixture was stirred at 25°C for 2 hours. After the reaction was completed, water (100 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 ml x 3). The organic phase was washed with saturated brine (50 ml x 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel chromatography (dichloromethane:methanol = 10:1) to obtain compound 10-2. MS-ESI calculated value [M+H] + 288, measured value 288.

[0263] Step 2

[0264] Compound 10-2 (1.7 g, 5.94 mmol) was dissolved in dichloromethane (20 ml). Imidazole (1.21 g, 17.82 mmol), tert-butyldimethylsilyl chloride (1.79 g, 17.82 mmol), and N,N-dimethylaminopyridine (145.15 mg, 1.19 mmol) were added to the reaction mixture. The mixture was stirred at 45°C under nitrogen for 10 hours. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 10-3.

[0265] MS-ESI calculated value [M+H] + 402, measured value 402.

[0266] Step 3

[0267] Compound 10-3 (1.6 g, 4.00 mmol), intermediate D (1.45 g, 4.00 mmol), potassium carbonate (1.66 g, 11.99 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (292.37 mg, 399.58 μmol) were dissolved in dioxane (20 ml) and water (2 ml) and stirred at 75°C under nitrogen for 10 hours. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel chromatography (petroleum ether:ethyl acetate = 8:1 to 3:1) to obtain compound 10-4. MS-ESI calculated value [M+H] + 557, measured value 557.

[0268] Step 4

[0269] Compound 10-4 (200.0 mg, 358.66 μmol) was dissolved in tetrahydrofuran (3 ml). Intermediate B (183.98 mg, 466.26 μmol) and lithium bis(trimethylsilyl)amide (1 mol / L n-hexane solution, 1.08 ml) were added to the reaction solution, and the mixture was stirred at 0°C for 1 hour under nitrogen. After the reaction was completed, saturated ammonium chloride (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel thin layer chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 10-5. MS-ESI calculated value [M+H] + 905, measured value 905.

[0270] Step 5

[0271] Compound 10-5 (110.0 mg, 121.39 μmol) was dissolved in dichloromethane (1 mL). A solution of hydrogen chloride in ethyl acetate (4 mol / L, 5.5 mL) was then added to the reaction mixture, which was stirred at 25°C for 0.5 h. After completion of the reaction, the mixture was concentrated, and the crude product was separated by HPLC (column: Waters Xbridge C18 150 x 25 mm x 5 μm; mobile phase: mobile phase A: 10 mM ammonium bicarbonate in water; mobile phase B: acetonitrile; B%: 54%-84%, 10 min) to yield compound 10. MS-ESI calculated value [M+H] + 677, measured value 677. 1H NMR (400MHz, CD3OD) δ=8.58 (dd, J=1.4, 8.3Hz, 1H), 7.70 (s, 1H), 7.49-7.41 (m, 3H), 7.33-7.27 (m, 2H), 7.13 (dd, J=1.5, 7.6H z, 1H), 7.05-6.97 (m, 2H), 4.01 (s, 3H), 3.86 (s, 3H), 3.82-3.73 (m, 6H), 3.40 (d, J=8.9Hz, 2H), 3.21 (d, J=8.6Hz, 2H), 2.86 (br dd, J=4.4, 10.8Hz, 4H), 2.76 (t, J=5.9Hz, 2H), 1.46 (s, 3H).

[0272] Example 11

[0273]

[0274] first step

[0275] Compound L-1 (858.07 mg, 6.94 μmol) was dissolved in dichloromethane (15 ml), and N, N-diisopropylethylamine (1.20 g, 9.26 μmol) and compound 11-1 (1 g, 4.63 mmol) were added. After stirring for half an hour, sodium cyanoborohydride (2.94 g, 13.89 mmol) was added. The reaction solution was reacted at 25°C for 14 hours. After the reaction was completed, it was diluted with dichloromethane (120 ml x 2) and washed with water (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (ethyl acetate ∶ Methanol = 30 ∶ 1) Compound 11-2 was isolated. MS-ESI calculated value [M+H] + 287, measured value 287.

[0276] Step 2

[0277] Compound 11-2 (1.1 g, 3.83 mmol) was dissolved in dichloromethane (20 ml), and N,N-dimethylaminopyridine (93.60 mg, 766.14 μmol) and imidazole (1.04 g, 15.32 mmol) were added. t-Butyldimethylsilyl chloride (1.73 g, 11.49 μmol) was added to the reaction solution at 0°C under nitrogen protection. The reaction solution was reacted at 45°C under nitrogen protection for 16 hours. LC-MS monitoring showed that the remaining starting material was formed. N,N-dimethylaminopyridine (93.60 mg, 766.14 μmol) and imidazole (1.04 g, 15.32 mmol) were further added. t-Butyldimethylsilyl chloride (1.73 g, 11.49 μmol) was added to the reaction solution at 0°C under nitrogen protection. The reaction solution was reacted at 45°C under nitrogen protection for 14 hours. After the reaction was completed, the mixture was diluted with water (100 ml) and extracted with dichloromethane (110 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by high-performance liquid chromatography (HPLC column: Kromasil Eternity XT 250 × 80 mm × 10 μm, mobile phase: mobile phase A: 0.05% ammonia solution by volume; mobile phase B: acetonitrile; B%: 35%-95%, 20 minutes) to obtain the crude product, which was then purified by silica gel thin layer chromatography (dichloromethane: methanol = 12:1) to obtain compound 11-3. MS-ESI calculated value [M+H] + 401, measured value 403.

[0278] Step 3

[0279] Compound 11-3 (90 mg, 224.21 μmol) was dissolved in dioxane (3 mL) and water (0.3 mL). Intermediate D (106.12 mg, 291.47 μmol), potassium carbonate (92.96 mg, 672.62 μmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (24.61 mg, 33.63 μmol) were added. The reaction mixture was stirred at 65°C under nitrogen for 8 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was diluted with water (40 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 11-4 was isolated by silica gel thin layer chromatography (dichloromethane:methanol = 12:1). MS-ESI calculated value [M+H] + 558, measured value 558.

[0280] Step 4

[0281] Compound 11-4 (70 mg, 125.31 μmol) and intermediate B (64.28 mg, 162.90 μmol) were dissolved in tetrahydrofuran (2 ml), and a tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1 mol / L, 375.93 μl) was added under nitrogen protection at zero temperature. The reaction solution was reacted at 25°C for 1 hour. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (20 ml) and extracted with ethyl acetate (25 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel thin layer chromatography (dichloromethane). ∶ Methanol = 12 ∶ 1) Purification and separation to obtain compound 11-5. MS-ESI calculated value [M+H] + 907, measured value 906.

[0282] Step 5

[0283] Compound 11-5 (50 mg, 55.12 μmol) was dissolved in dichloromethane (5 mL), and a solution of hydrogen chloride in ethyl acetate (4 mol / L, 1 mL) was added. The reaction mixture was allowed to react at 25°C for 0.5 h. After completion of the reaction, the mixture was concentrated. The crude product was separated by HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm, mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 10%-40%, 7 min) to obtain compound 11. MS-ESI calculated value [M+H] + 678, measured value 678. 1 H NMR (400MHz, CD3OD) δ=8.61 (dd, J=8.31, 1.47Hz, 1H), 8.18-8.24 (m, 1H), 7.72 (s, 1H), 7.40-7.56 (m, 5 H), 7.16 (dd, J=7.58, 1.47Hz, 1H), 4.12 (s, 2H), 4.04 (s, 3H), 3.96 (s, 3H), 3.78-3.84 (m, 4H), 3.70 (br d, J=9.54Hz, 2H), 3.53(br d, J=9.29Hz, 2H), 2.88(br dd, J=12.53, 4.71Hz, 4H), 2.78 (t, J=5.87Hz, 2H), 1.51 (s, 3H).

[0284] Example 12

[0285]

[0286]

[0287] first step

[0288] Intermediate C (80.0 mg, 111 μmol) and 12-1 (36.2 mg, 221 μmol) were dissolved in dichloromethane (2 ml). N,N-diisopropylethylamine (28.6 mg, 221 μmol) was added to the reaction solution, and the mixture was stirred at 20°C for 1 hour. Sodium triacetoxyborohydride (70.4 mg, 332 μmol) was added to the reaction solution, and the mixture was stirred at 20°C for 2 hours. After the reaction was completed, the concentrated residue was separated and purified by silica gel thin layer chromatography (dichloromethane:methanol = 10:1) to obtain compound 12-2. MS-ESI calculated value [M+H] + 833, measured value 833.

[0289] Step 2

[0290] Intermediate 12-2 (30.0 mg, 29.3 μmol) was dissolved in dichloromethane (2 mL). A solution of hydrogen chloride in ethyl acetate (4 mol / L, 500 μL) was then added to the reaction mixture, which was stirred at 20°C for 0.5 h. After completion of the reaction, the mixture was concentrated, and the crude product was separated by HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 10%-40%, 7 min) to afford compound 12. MS-ESI calculated value [M+H] + 719, measured value 719. 1 H NMR (400MHz, CD3OD) δ=8.63 (dd, J=1.5, 8.3Hz, 1H), 8.47 (s, 1H), 7.79-7.66 (m, 2H), 7.58 (t, J=7 .6Hz, 1H), 7.52-7.43(m, 2H), 7.22-7.15(m, 1H), 4.32(s, 2H), 4.10(s, 3H), 4.05(s, 3H), 3.99(br d, J=13.6Hz, 4H), 3.88-3.76 (m, 4H), 3.01-2.84 (m, 4H), 2.80 (t, J=5.9Hz, 2H), 2.45-2.20 (m, 4H), 1.29 (s, 3H).

[0291] Example 13

[0292]

[0293]

[0294] first step

[0295] Compound B-6 (300 mg, 892 μmol) and intermediate E (334 mg, 595 μmol) were dissolved in tetrahydrofuran (6 mL). Lithium bis(trimethylsilyl)amide (1 mol / L, 1.49 mL) was then added to the reaction mixture at 0°C and stirred at 15°C for 2 hours. After completion of the reaction, saturated aqueous ammonium chloride (20 mL) was added to the reaction mixture, and extraction with ethyl acetate (15 mL x 3) was performed. The organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and filtered. The concentrated residue was separated by silica gel thin layer chromatography (petroleum ether:ethyl acetate = 2:1) to obtain compound 13-1. MS-ESI calculated value [M+H] + 849, measured value 849.

[0296] Step 2

[0297] Compound 13-1 (200 mg, 235.32 μmol) was dissolved in dichloromethane (3 ml), and trifluoroacetic acid (924.00 mg, 8.10 mmol, 0.6 ml) was added. The reaction mixture was reacted at 15°C for 0.5 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain compound 13-2. MS-ESI calculated value [M+H] + 749, measured value 749.

[0298] Step 3

[0299] Compound 13-2 (100 mg, 133.37 μmol) and lithium perchlorate (28.38 mg, 266.74 μmol) were dissolved in ethanol (1.5 ml), followed by the addition of compound 13-3 (28.85 mg, 400.11 μmol). The reaction mixture was placed in a sealed tube and stirred at 80°C for 6 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was separated by silica gel thin layer chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 13-4. MS-ESI calculated value [M+H] + 821, measured value 821.

[0300] Step 4

[0301] Compound 13-4 (90 mg, 109.50 μmol) was dissolved in dichloromethane (1 mL), and a solution of hydrogen chloride in ethyl acetate (4 mol / L, 0.2 mL) was added. The reaction mixture was incubated at 25°C for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a residue, which was then separated by HPLC (column: Phenomenex luna C18 150 x 25 mm x 10 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 7%-37%, 10 min) to afford the formate salt of compound 13. MS-ESI calculated value [M+H] +707, measured value 707. 1 H NMR (400MHz, CD3OD) δ = 8.63 (dd, J = 1.4, 8.3Hz, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 7.7 8-7.68 (m, 2H), 7.59 (t, J=7.7Hz, 1H), 7.53-7.41 (m, 2H), 7.17 (dd, J=1.4, 7.7Hz, 1 H), 4.59 (s, 2H), 4.19 (d, J=10.9Hz, 2H), 4.13 (s, 3H), 4.08-3.99 (m, 5H), 3.94 (s, 2H), 3.07-2.94(m, 2H), 2.91-2.80(m, 2H), 2.61(s, 2H), 1.58(s, 3H), 1.26(s, 6H).

[0302] Example 14

[0303]

[0304] first step

[0305] Compound 14-1 (43.45 mg, 345.91 μmol) was dissolved in dichloromethane (3 ml), and N,N-diisopropylethylamine (53.65 mg, 415.09 μmol) and intermediate C (100 mg, 138.36 μmol) were added. After the reaction solution was stirred at room temperature for 0.5 hours, sodium triethoxyborohydride (87.98 mg, 415.09 μmol) was added. The reaction solution was reacted at room temperature for 1 hour. After the reaction was completed, the reaction solution was quenched with water (10 ml), diluted with dichloromethane (5 ml), extracted with dichloromethane (10 ml × 3), and the organic phase was washed with saturated brine (20 ml × 2), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel thin layer chromatography (dichloromethane ∶ Methanol = 10 ∶ 1) Compound 14-2 was isolated. MS-ESI calculated value [M+H] + 795, measured value 795.

[0306] Step 2

[0307] Compound 14-2 (90 mg, 113.08 μmol) was dissolved in dichloromethane (2 mL), and a solution of hydrogen chloride in ethyl acetate (4 mol / L, 1 mL) was added. The mixture was stirred at room temperature for 0.25 h. After completion of the reaction, the mixture was concentrated. The crude product was separated by HPLC (column: Xtimate C18 150 x 25 mm x 10 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 9%-39%, 10 min) to obtain compound 14. MS-ESI calculated value [M+H]+ 681, measured value 681. 1 H NMR (400MHz, CD3OD) δ = 8.62 (dd, J = 1.5, 8.3Hz, 1H), 8.55 (s, 1H), 8.52-8.49 (m, 1H), 7.7 6-7.71 (m, 2H), 7.59 (t, J=7.6Hz, 1H), 7.53-7.45 (m, 2H), 7.18 (dd, J=1.5, 7.6Hz, 1H), 4. 34-4.25 (m, 2H), 4.13 (s, 3H), 4.05 (s, 3H), 3.86-3.79 (m, 4H), 3.74 (t, J=5.9Hz, 2H), 3. 16 (t, J=7.2Hz, 2H), 2.93-2.85 (m, 4H), 2.79 (t, J=5.9Hz, 2H), 1.95 (quin, J=6.6Hz, 2H).

[0308] Example 15

[0309]

[0310]

[0311] first step

[0312] Intermediate F (150 mg, 197.18 μmol) was dissolved in 1,2-dichloroethane (2 ml), and manganese dioxide (171.42 mg, 1.97 mmol) was added. The reaction solution was heated to 90°C under nitrogen protection. After 2 hours, manganese dioxide (171.42 mg, 1.97 mmol) was added. The reaction solution was heated to 90°C under nitrogen protection for 2 hours. After the reaction was completed, the mixture was filtered and concentrated to obtain compound 15-1. MS-ESI calculated value [M+H] + 758, measured value 758.

[0313] Step 2

[0314] Compound 2-1 (34.21 mg, 276.78 μmol) was dissolved in dichloromethane (3 mL), N,N-diisopropylethylamine (35.77 mg, 276.78 μmol), and compound 15-1 (140 mg, 184.52 μmol). After stirring at room temperature for 0.5 hours, sodium triethoxyborohydride (114.37 mg, 539.61 μmol) was added. The reaction mixture was allowed to react at room temperature for 1 hour. After completion of the reaction, the reaction mixture was quenched with water (10 mL), diluted with dichloromethane (5 mL), and extracted with dichloromethane (10 mL x 3). The organic phase was washed with saturated brine (20 mL x 2), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel thin layer chromatography (dichloromethane:methanol = 10:1) to obtain intermediate 15-2. MS-ESI calculated value [M+H] + 829, measured value 829.

[0315] Step 3

[0316] Compound 15-2 (75 mg, 90.38 μmol) in dichloromethane (2 mL) was added to a solution of hydrogen chloride in ethyl acetate (4 mol / L, 1 mL) and stirred at room temperature for 0.25 h. After completion of the reaction, the mixture was concentrated. The crude product was separated by HPLC (column: Xtimate C18 150 x 25 mm x 10 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 7%-37%, 10 min) to afford compound 15. MS-ESI calculated value [M+H] + 715, measured value 715. 1 H NMR (400MHz, CD3OD) δ=8.59 (dd, J=1.5, 8.3Hz, 1H), 8.46 (s, 1H), 7.82 (s, 1H), 7.74-7.68 (m, 1 H), 7.56 (t, J=7.6Hz, 1H), 7.51-7.42 (m, 2H), 7.29-7.22 (m, 1H), 7.20-7.14 (m, 1H), 7.34-6.95 (m, 1H), 4.49-4.36 (m, 1H), 4.11 (s, 2H), 4.08 (s, 3H), 3.91-3.85 (m, 2H), 3.83-3.76 (m, 2H), 3 .20-3.07(m, 2H), 3.01-2.84(m, 6H), 2.81-2.74(m, 2H), 2.28-2.12(m, 1H), 1.89-1.78(m, 1H).

[0317] Example 16

[0318]

[0319] first step

[0320] Compound 16-1 (500 mg, 2.85 mmol) was dissolved in N,N-dimethylformamide (6 mL). Potassium carbonate (472 mg, 3.42 mmol) and iodoethane (578 mg, 3.71 mmol) were added to the reaction solution, and the mixture was stirred at 50°C for 2 hours. After completion of the reaction, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (15 mL x 3). The organic phase was washed with aqueous sodium bicarbonate (20 mL x 3) and then with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 16-2. MS-ESI calculated value [M+H] + 204, measured value 204. 1 H NMR (400MHz, CDCl3) δ=8.51-8.35 (m, 1H), 7.09 (dd, J=5.7, 8.0Hz, 1H), 4.47 (q, J=7.2Hz, 2H), 1.42 (t, J=7.2Hz, 3H).

[0321] Step 2

[0322] Compound 16-2 (12.5 g, 61.40 mmol) was dissolved in N,N-dimethylformamide (80 ml). Cesium acetate (12.96 g, 67.54 mmol) was added to the reaction solution, and the atmosphere was purged with nitrogen three times. The mixture was then stirred at 80°C for 2 hours under a nitrogen atmosphere. TLC confirmed the remaining starting material. Cesium acetate (7.07 g, 36.84 mmol) was added to the reaction solution, and the atmosphere was purged with nitrogen three times. The mixture was then stirred at 80°C for 2 hours under a nitrogen atmosphere. The mixture was diluted with water (400 ml) and extracted with ethyl acetate (200 ml x 3). The organic phase was then washed with saturated brine (200 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified and isolated by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to afford compound 16-3. MS-ESI calculated value [M+H] + 202, measured value 202.

[0323] Step 3

[0324] Compound 16-3 (7 g, 34.72 mmol) and compound F-3 (10.59 g, 69.44 mmol) were dissolved in N,N-dimethylformamide (70 ml), followed by the addition of potassium carbonate (14.40 g, 104.16 mmol). The reaction mixture was stirred at 80°C for 2 hours. 90 ml of water was added to the reaction mixture for dilution, followed by extraction with ethyl acetate (60 ml x 3). The combined organic phases were washed with saturated brine (30 ml x 3) and dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified and isolated by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1 to 10:1) to obtain compound 16-4. MS-ESI calculated value [M+H] + 252, measured value 252. 1 H NMR (400MHz, CDCl3) δ = 8.62-8.33 (m, 1H), 7.19-7.03 (m, 1H), 6.95-6.40 (m, 1H), 4.65-4.28 (m, 2H), 1.50-1.26 (m, 3H).

[0325] Step 4

[0326] Compound 16-4 (1.6 g, 6.36 mmol) was dissolved in N,N-dimethylacetamide (16 ml), and zinc cyanide (1.49 g, 12.72 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl) palladium (II) (1.15 g, 1.27 mmol) were added. The reaction mixture was purged with nitrogen three times and stirred at 105°C under nitrogen for 12 hours. The mixture was filtered, water (50 ml) was added, and the mixture was extracted with ethyl acetate (40 ml x 3). The combined organic phases were washed with saturated brine (30 ml x 3) and dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified and isolated by silica gel column chromatography (petroleum ether:ethyl acetate = 50:1 to 10:1) to obtain compound 16-5. MS-ESI calculated value [M+H] + 243, measured value 243. 1 H NMR (400MHz, CDCl3) δ=8.75 (d, J=5.7Hz, 1H), 7.42 (td, J=1.3, 5.7Hz, 1H), 7.01-6.41 (m, 1H), 4.55 (q, J=7.2Hz, 2H), 1.48 (t, J=7.2Hz, 3H).

[0327] Step 5

[0328] Compound 16-5 (1.1 g, 4.54 mmol) was dissolved in methanol (40 mL). Raney nickel (389.14 mg, 454.21 μmol, 10% purity) was added under nitrogen. The reaction mixture was heated to 50°C under a hydrogen atmosphere (pressure 50 psi) for 12 hours. After completion of the reaction, the mixture was filtered and concentrated. The crude product was slurried with petroleum ether:ethyl acetate = 4:1 (25 mL), filtered, and the filter cake was dried to obtain compound 16-6. MS-ESI calculated value [M+H] + 201, measured value 201. 1 H NMR (400MHz, CDCl3-d) δ=8.72 (d, J=5.7Hz, 1H), 7.67-7.36 (m, 1H), 7.25 (s, 1H), 7.18 (d, J=5.7Hz, 1H), 6.67 (br s, 1H), 4.57 (s, 2H).

[0329] Step 6

[0330] Compound 16-6 (780 mg, 3.90 mmol) was dissolved in dichloromethane (10 ml), and di-tert-butyl dicarbonate (935.62 mg, 4.29 mmol) and 4-dimethylaminopyridine (71.42 mg, 584.58 μmol) were added. The reaction mixture was reacted at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product which was purified and isolated by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1 to 5:1) to obtain compound 16-7. MS-ESI calculated value [M+H] + 301, measured value 301.

[0331] Step 7

[0332] Compound 16-7 (900 mg, 3.00 mmol) was dissolved in tetrahydrofuran (10 ml). Diisobutylaluminum hydride (1 mol / L, 8.99 ml) was added at -5°C. The reaction mixture was allowed to react at 20°C for 2 hours. Sodium sulfate decahydrate (20 g) was added and stirred for 30 minutes to quench the reaction. The mixture was filtered and the filtrate was concentrated to give compound 16-8. MS-ESI calculated value [M+H] + 303, measured value 303.

[0333] Step 8

[0334] Compound 16-8 (800 mg, 2.65 mmol) was dissolved in acetic acid (8 ml), and sodium cyanoborohydride (166.32 mg, 2.65 mmol) was added. The reaction solution was reacted at 15°C for 1 hour. The reaction solution was slowly added dropwise to a saturated sodium bicarbonate aqueous solution (50 ml), stirred for 20 minutes, and then extracted with ethyl acetate (40 ml x 3). The combined organic phases were washed with saturated brine (30 ml x 2) and dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified and isolated by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1 to 5:1) to obtain compound 16-9. MS-ESI calculated value [M+H] + 287, measured value 287.

[0335] Step 9

[0336] Compound 16-9 (270 mg, 943.15 μmol) was dissolved in dichloromethane (3 mL), and m-chloroperbenzoic acid (406.90 mg, 1.89 mmol, 80% purity) was added. The mixture was stirred at 15°C for 4 hours. The reaction was quenched by the addition of 15 mL of saturated aqueous sodium sulfite at 0°C, and the pH was adjusted to 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL x 2) and dried over anhydrous sodium sulfate. The crude product was filtered and concentrated under reduced pressure. It was slurried with petroleum ether: methyl tert-butyl ether = 1:1 (10 mL), filtered, and the filter cake dried to yield compound 16-10. MS-ESI calculated value [M+H] + 303, measured value 303. 1 H NMR (400MHz, CDCl3) δ=8.14 (d, J=7.2Hz, 1H), 7.11 (br d, J=7.2Hz, 1H), 6.88-6.33 (m, 1H), 4.93-4.72 (m, 4H), 1.53 (s, 9H).

[0337] Step 10

[0338] Compound 16-10 (75 mg, 248.12 μmol) was dissolved in N,N-dimethylformamide (10 mL). Oxalyl chloride (725.02 mg, 5.71 mmol) was slowly added dropwise at 0°C. The mixture was heated to 30°C and stirred for 12 hours. The reaction mixture was added dropwise to 50 mL of saturated aqueous sodium bicarbonate solution at 0°C to quench the reaction. The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 2) and dried over anhydrous sodium sulfate. The crude product obtained by filtration and concentration under reduced pressure was purified by silica gel thin layer chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 16-11. MS-ESI calculated value [M+H] + 321, measured value 321.

[0339] Step 11

[0340] Compound 16-11 (30 mg, 93.54 μmol) was dissolved in methanol (5 mL) and N,N-dimethylformamide (1 mL). Triethylamine (28.40 mg, 280.62 μmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (6.84 mg, 9.35 μmol) were added. The reaction mixture was heated to 80°C under a carbon monoxide pressure (50 psi) for 12 hours. The mixture was filtered and concentrated, diluted with 10 mL of ethyl acetate and 20 mL of water, and then extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel thin layer chromatography (petroleum ether:ethyl acetate = 1:1) to yield compound 16-12. MS-ESI calculated value [M+H] + 345, measured value 345.

[0341] Step 12

[0342] Compound 16-12 (30 mg, 87.13 μmol) and intermediate E (43.88 mg, 78.42 μmol) were dissolved in tetrahydrofuran (2 ml). A solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1 mol / L, 304.96 μl) was added at 0°C under nitrogen. The reaction mixture was allowed to react at 15°C for 1 hour. Saturated ammonium chloride solution (20 ml) was added at 0°C to quench the reaction mixture, and the mixture was extracted with ethyl acetate (20 ml x 3). The combined organic phases were washed with saturated brine (15 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel thin layer chromatography (petroleum ether:ethyl acetate = 1:1) to yield compound 16-13. MS-ESI calculated value [M+H] + 871, measured value 871.

[0343] Step 13

[0344] Compound 16-13 (32 mg, 36.7 μmol) was dissolved in dichloromethane (2 mL), and a solution of hydrogen chloride in ethyl acetate (4 mol / L, 432.43 μL) was added. The mixture was stirred at 15°C for 6 hours. The reaction solution was concentrated to obtain the hydrochloride salt of compound 16-14. MS-ESI calculated value [M+H] + 657, measured value 657.

[0345] Step 14

[0346] Compound 16-14 (25 mg, 36.03 μmol) was dissolved in methanol (2 ml), and N, N-diisopropylethylamine (4.66 mg, 36.03 μmol) and compound B-8 (15.70 mg, 90.06 μmol) were added. After stirring at 15°C for 0.5 hours, sodium cyanoborohydride (6.79 mg) was added, and the reaction solution was reacted at 15°C for 1.5 hours. 10 ml of water was added to dilute the reaction solution, and the mixture was extracted with dichloromethane (10 ml × 3). The combined organic phase was washed with saturated brine (10 ml × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 16-15. MS-ESI calculated value [M+H] + 815, measured value 815.

[0347] Step 15

[0348] Compound 16-15 (29 mg, 35.55 μmol) was dissolved in ethyl acetate (1 mL). A solution of hydrogen chloride in ethyl acetate (0.5 mL, 4 mol / L) was added, and the reaction mixture was allowed to react at 15°C for 0.5 h. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then separated by HPLC (column: Phenomenex Synergi C18 150 x 25 mm x 10 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 8%-38%, 10 min) to afford compound 16. MS-ESI calculated value [M+H] + 701, measured value 701. 1 H NMR (400MHz, CD3OD) δ = 8.58 (dd, J = 1.5, 8.3Hz, 1H), 8.46 (s, 1H), 7.91 (s, 1H), 7.70 (dd, J=1.6, 7.7Hz, 1H), 7.56 (t, J=7.6Hz, 1H), 7.52-7.06 (m, 4H), 4.45 (br s, 2H), 4.16 (br d, J=10.9Hz, 4H), 4.09 (s, 3H), 4.06 (br d, J=8.5Hz, 2H), 3.93-3.83 (m, 2H), 3.77 (t, J=5.7Hz, 2H), 2.97 (t, J=5.7Hz, 2H), 1.54 (s, 3H).

[0349] Example 17

[0350]

[0351]

[0352] first step

[0353] Intermediate G (400.0 mg, 1.03 mmol) was dissolved in tetrahydrofuran (2.5 ml). Compound C-5 (347.68 mg, 924.11 μmol) and lithium bis(trimethylsilyl)amide (1 mol / L n-hexane solution, 3.08 ml) were added to the reaction mixture at 0°C and stirred at 20°C for 1 hour. After completion of the reaction, water (50 ml) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 ml x 3). The organic phase was washed with saturated brine (30 ml x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 1:1) to obtain compound 17-1. MS-ESI calculated value [M+H] + 719, measured value 719.

[0354] Step 2

[0355] Compound 17-1 (200.0 mg, 277.88 μmol) was dissolved in dichloroethane (3 ml) and active manganese dioxide (241.59 mg, 2.78 μmol) was added. The mixture was stirred at 90°C for 2 hours. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain compound 17-2. MS-ESI calculated value [M+H] + 717, measured value 717.

[0356] Step 3

[0357] Compound 17-2 (70.0 mg, 97.53 μmol) was dissolved in dichloromethane (3 mL). Compound 12-1 (23.94 mg, 146.30 μmol) and N,N-diisopropylethylamine (37.82 mg, 292.60 μmol) were added to the reaction mixture, and the mixture was stirred at 25°C for 0.5 hours. Sodium triacetoxyborohydride (62.01 mg, 292.60 μmol) was added to the reaction mixture, and the mixture was stirred at 25°C for 10 hours. After completion of the reaction, water (5.0 mL) was added to the reaction mixture, and the mixture was extracted with 24 mL of dichloromethane (8 mL x 3). The organic phase was washed with saturated brine (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel thin layer chromatography (petroleum ether: ethyl acetate: ethanol = 4:3:1) to obtain compound 17-3. MS-ESI calculated value [M+H] + 828, measured value 828.

[0358] Step 4

[0359] Compound 17-3 (50.0 mg, 60.32 μmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at 25°C for 12 hours. After completion of the reaction, the mixture was concentrated, and the crude product was separated by HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 8%-38%, 10 min) to yield compound 17. MS-ESI calculated value [M+H] + 714, measured value 714. 1 HNMR (400MHz, CD3OD) δ=8.63 (dd, J=1.5, 8.3Hz, 1H), 8.47 (s, 1H), 7.79-7.66 (m, 2H), 7.58 (t, J=7.6Hz, 1H), 7.52-7.43 (m, 2H), 7.22 -7.15 (m, 1H), 4.32 (s, 2H), 4.10 (s, 3H), 4.05 (s, 3H), 3.99 (brd, J = 13.6Hz, 4H), 3.88-3.76 (m, 4H), 3.01-2.84 (m, 4H), 2.80 (t, J = 5.9 Hz, 2H), 2.45-2.20 (m, 4H), 1.29 (s, 3H).

[0360] Example 18

[0361]

[0362] first step

[0363] Compound 17-2 (60.0 mg, 83.60 μmol) was dissolved in dichloromethane (3 mL). Compound 2-1 (15.50 mg, 125.40 μmol) and N,N-diisopropylethylamine (32.41 mg, 250.80 μmol) were added to the reaction mixture, and the mixture was stirred at 25°C for 0.5 hours. Sodium triacetoxyborohydride (53.15 mg, 250.80 μmol) was added to the reaction mixture, and the mixture was stirred at 25°C for 2 hours. After the reaction was completed, water (5 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (8 mL x 3). The organic phase was washed with saturated brine (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by silica gel thin layer chromatography (petroleum ether: ethyl acetate: ethanol = 4:3:1) to obtain compound 18-1. MS-ESI calculated value [M+H] + 788, measured value 788.

[0364] Step 2

[0365] Compound 18-1 (21.0 mg, 26.62 μmol) was dissolved in trifluoroacetic acid (2 mL) and stirred at 25°C for 2 hours. After completion of the reaction, the mixture was concentrated, and the crude product was separated by HPLC (column: Unisil 3-100 C18 Ultra 150*50 mm*3 μm; mobile phase: mobile phase A: 0.225% formic acid in water; mobile phase B: acetonitrile; B%: 8%-38%, 10 min) to yield compound 18. MS-ESI calculated value [M+H] + 674, measured value 674. 1 H NMR (400MHz, CD3OD) δ=8.56 (dd, J=1.1, 8.3Hz, 1H), 8.51 (s, 1H), 8.34 (s, 1H), 7.73 (dd, J=1.4, 7.6Hz, 1H), 7.57 (t, J=7.6Hz, 1H), 7.53-7.42 (m, 2H), 7.19 (dd, J=1.4, 7.6Hz, 1H), 4.60-4.56 (m, 3H), 4.44 (br s, 2H), 4.10 (s, 3H), 3.95 (s, 2H), 3.79 (t, J=5.6Hz, 2H), 3.19 (br t, J=5.6Hz, 4H), 3.02-2.95 (m, 2H), 2.80 (t, J=5.7Hz, 2H), 2.34-2.19 (m, 1H), 2.35-2.15 (m, 1H), 2.09-1.92 (m, 1H)

[0366] Example 19

[0367]

[0368]

[0369] first step

[0370] Compound 6-1 (15.70 mg, 209.00 μmol) was dissolved in dichloromethane (3 mL), and compound 17-2 (100 mg, 139.33 μmol) and sodium triethoxyborohydride (88.59 mg, 417.99 μmol) were added. The reaction mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, the mixture was diluted with water (20 mL) and extracted with dichloromethane (25 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by silica gel thin layer chromatography (dichloromethane:methanol = 6:1) to obtain compound 19-1. MS-ESI calculated value [M+H] + 776, measured value 776.

[0371] Step 2

[0372] Compound 19-1 (70 mg, 90.11 μmol) was dissolved in dichloromethane (2 ml), trifluoroacetic acid (6 ml) was added, and the mixture was stirred at 20°C for 12 hours. LC-MS monitored the presence of starting material, and the reaction mixture was heated to 30°C and stirred for 3 hours. After completion of the reaction, the mixture was concentrated. The crude product was added to a solution of tetrahydrofuran (2 ml) and saturated aqueous sodium bicarbonate (2 ml), stirred at 20°C for 3 hours, diluted with water (20 ml), and extracted with dichloromethane (20 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by high-performance liquid chromatography (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: mobile phase A: 0.225% formic acid aqueous solution by volume; mobile phase B: acetonitrile; B%: 10%-40%, 7 minutes) to obtain compound 19. MS-ESI calculated value [M+H] + 662, measured value 662. 1 H NMR (400MHz, CD3OD) δ = 8.58 (d, J = 8.31Hz, 1H), 8.51 (s, 1H), 8.33-8.40 (m, 1H), 7.74 (dd , J=7.76, 0.92Hz, 1H), 7.56-7.60(m, 1H), 7.45-7.54(m, 2H), 7.18-7.24(m, 1H), 4.33(s , 2H), 4.12-4.14 (m, 3H), 3.96 (s, 2H), 3.81 (t, J=5.62Hz, 2H), 3.75 (t, J=5.81Hz, 2H), 3 .17-3.22(m, 4H), 2.98-3.04(m, 2H), 2.82(t, J=5.62Hz, 2H), 1.96(quin, J=6.48Hz, 2H).

[0373] Example 20

[0374]

[0375]

[0376] first step

[0377] Intermediate J (400 mg, 1.24 mmol) was dissolved in acetone (4 ml), and 2-iodopropane (1.05 mg, 6.20 mmol) and potassium carbonate (342.99 mg, 2.48 mmol) were added. The reaction mixture was reacted at 80°C for 4 hours. After completion of the reaction, the mixture was diluted with ethyl acetate (60 ml x 2) and extracted with water (60 ml). The organic phase was dried over sodium sulfate, filtered, and concentrated. The residue was separated by silica gel thin layer chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 20-1. MS-ESI calculated value [M+H] +365, measured value 365 1 H NMR (400MHz, CDCl3) δppm=7.48-7.50 (m, 1H), 4.71-4.84 (m, 3H), 4.50 (q, J=7 .15Hz, 2H), 3.62-3.71(m, 2H), 2.78(brt, J=5.71Hz, 2H), 1.40-1.50(m, 18H).

[0378] Step 2

[0379] Compound 20-1 (535 mg, 1.47 μmol) was dissolved in dichloromethane (6 mL), and a solution of hydrogen chloride in ethyl acetate (4 mol / L, 3.5 mL) was added. The reaction mixture was allowed to react at room temperature (25°C) for 1 hour. After completion of the reaction, the reaction mixture was concentrated to obtain crude compound 20-2. MS-ESI calculated value [M+H] + 265.2, measured value 265.2.

[0380] Step 3

[0381] Compound 20-2 (440 mg, 1.46 μmol) was dissolved in methanol (24 ml), and N,N-diisopropylethylamine (189.06 mg, 1.46 μmol) and compound B-8 (637.49 mg, 3.66 mmol) were added. After stirring for half an hour, sodium cyanoborohydride (275.79 mg, 4.39 mmol) was added. The reaction solution was reacted at 25°C for 16 hours. After completion of the reaction, the mixture was diluted with ethyl acetate (60 ml x 2) and washed with water (40 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel thin layer chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 20-3. MS-ESI calculated value [M+H] + 423.4, measured value 423.4. 1 H NMR (400MHz, CDCl3) δ = 7.38 (s, 1H), 4.58-4.74 (m, 1H), 4.39 (q, J = 7.05Hz, 2H), 3.64-3.93 (m, 4H), 2.50-2.94(m, 6H), 1.32-1.37(m, 4H), 1.30(d, J=6.00Hz, 6H), 0.83(s, 9H), 0.00(s, 6H).

[0382] Step 4

[0383] Compound 20-3 (120 mg, 283.93 μmol) and intermediate I (123.93 mg, 227.15 μmol) were dissolved in tetrahydrofuran (2 ml). Under nitrogen protection at zero degrees Celsius, a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1 mol / L, 851.80 μl) was added. The reaction mixture was allowed to react at zero degrees Celsius for 1 hour. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (20 ml) and extracted with ethyl acetate (20 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified and isolated by silica gel thin layer chromatography (dichloromethane:methanol = 10:1) to obtain compound 20-4. MS-ESI calculated value [M+H] + 922, measured value 921.

[0384] Step 5

[0385] Compound 20-4 (100 mg, 85.85 μmol) was dissolved in dichloromethane (5 mL), and a solution of hydrogen chloride in ethyl acetate (4 mol / L, 4 mL) was added. The reaction mixture was allowed to react at room temperature (25°C) for 0.5 h. After completion of the reaction, the mixture was concentrated. The crude product was separated by HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm, mobile phase: mobile phase A: 0.225% formic acid aqueous solution; mobile phase B: acetonitrile; B%: 12%-42%, 7 min) to obtain the formate salt of compound 20. MS-ESI calculated value [M+H] + 693, measured value 693. 1 H NMR (400MHz, CD3OD) δ = 8.61 (dd, J = 8.25, 1.41Hz, 1H), 8.44-8.52 (m, 2H), 7.70-7.74 ( m, 2H), 7.56-7.61 (m, 1H), 7.45-7.53 (m, 2H), 7.17 (dd, J=7.64, 1.41Hz, 1H), 4.94 (br s, 1H), 4.65-4.71 (m, 1H), 4.55 (s, 2H), 4.38-4.45 (m, 2H), 4.12 (s, 3H), 3.90-3.98 (m, 4H ), 3.84 (t, J=5.75Hz, 2H), 3.00-3.07 (m, 2H), 2.85-2.94 (m, 4H), 1.45 (d, J=5.99Hz, 6H).

[0386] Experimental Example 1: PD-1 / PD-L1 Homogenous Time-Resolved Fluorescence (HTRF) Combination Experimental Principle:

[0387] Small molecule compounds can competitively inhibit the binding of PD-1 to PD-L1 by binding to PD-L1. When the donor PD-1 molecule and the receptor PD-L1 molecule are in close proximity, the donor molecule transfers energy to the receptor molecule, causing the receptor molecule to emit fluorescence. By measuring the intensity of the fluorescence, the ability of the small molecule to prevent the binding of PD-L1 to PD-1 can be tested. A homogeneous time-resolved fluorescence (HTRF) binding assay is used to test the ability of the compounds of the present invention to inhibit the binding of PD-1 / PD-L1.

[0388] Experimental Materials:

[0389] The PD-1 / PD-L1 TR-FRET detection kit was purchased from BPS Biosciences. The Nivo multilabel analyzer was purchased from PerkinElmer.

[0390] Experimental methods:

[0391] Dilute PD1-Eu, the dye-labeled receptor, PD-L1-biotin, and the test compound using the buffer provided in the kit. Use a pipette to dilute the test compound five-fold to the eighth concentration, from 40 μM to 0.5 nM, using 4% DMSO. Set up a duplicate assay. Add a 5 μM concentration gradient of inhibitor to the microplate. Add 5 μL of buffer containing 4% DMSO and 5 μL of PD-L1-biotin (60 nM) to the wells with maximum and minimum signal, and only 5 μL of buffer to the well with minimum signal. Incubate at 25°C for 20 minutes. After incubation, add 5 μL of diluted PD1-Eu (10 nM) and 5 μL of diluted dye-labeled receptor to each well. Incubate the reaction system at 25°C for 90 minutes. After the reaction, the TR-FRET signal was read using a multi-label analyzer.

[0392] Data Analysis:

[0393] The raw data were converted into inhibition rate, IC, using the equation (sample-Min) / (Max-Min)×100%. 50 The value of can be obtained by four-parameter curve fitting (derived by log(inhibitor) vs. response--Variable slope mode in GraphPad Prism). Table 1 provides the inhibitory activity of the compounds of the examples of the present invention on PD1 / PD-L1 binding.

[0394] Table 1 IC values ​​of the compounds of the present invention for binding to PD-1 / PD-L150 Value test results

[0395] Test compound <![CDATA[IC 50 (nM)]]> Compound 2 1.49 Formate salt of compound 8 4.61 Compound 12 3.13 Compound 15 4.20

[0396] Experimental conclusion: The compounds of the present invention have a significant inhibitory effect on PD-1 / PD-L1 binding.

[0397] Experimental Example 2: Detecting the Effect of Compounds on PD-L1 Expression Levels Using MDA-MR-231 Cells

[0398] Experimental principle:

[0399] Using the triple-negative breast cancer cell line (MDA-MB-231) is an indirect method for assessing PD-L1 internalization. PD-L1 molecules on the cell surface can be degraded through the lysosomal and proteasomal pathways, and the addition of small molecule inhibitors can induce PD-L1 internalization. After incubating small molecules with MDA-MB-231 cells for 24 hours, the level of PD-L1 on the cell surface is measured using flow cytometry (FACS), which indirectly reflects the effect of small molecules on inducing PD-L1 internalization. Flow cytometry (FACS) was used to examine the effects of the compounds of the present invention on PD-L1 expression levels in MDA-MB-231 cells.

[0400] Experimental Materials:

[0401] Phosphate-buffered saline (DPBS), 1640 culture medium, penicillin-streptomycin, fetal bovine serum, non-essential amino acids, β-mercaptoethanol (2-ME), human interferon-γ, LIVE / DEAD stain, staining buffer, fixation buffer, 0.25% trypsin, EDTA, anti-human PD-L1, and anti-human PD-L1 isotype control.

[0402] Preparation of 1640 complete medium: Add 50 ml of fetal bovine serum, 5 ml of nonessential amino acids, 5 ml of penicillin-streptomycin, and 0.5 ml of β-mercaptoethanol to 439.5 ml of 1640 medium and mix well.

[0403] 10mM EDTA preparation: Add 1 ml of 0.5M EDTA to 49 ml of DPBS and mix well.

[0404] Experimental steps:

[0405] 1) Counting and plating MDA-MB-231 cells: Remove the culture flask, remove the culture medium, and rinse once with DPBS. After rinsing, add 3 ml of 0.25% trypsin to the culture flask and place it in a 37°C incubator for 1.5 minutes. Remove the culture flask and add 9 ml of 1640 complete medium to terminate the reaction. Transfer the cells to a 50 ml centrifuge tube and centrifuge at 1000 rpm at 37°C for 5 minutes. Resuspend the cells in an appropriate volume of culture medium based on the cell number and count them using a cell counter. Adjust the cell concentration to 5 × 10 cells / mL using culture medium. 5 Plating: Add 200 μL of cell suspension to each well of a 96-well plate, so that the number of cells in each well is 1×10 5 Place in an incubator and culture overnight.

[0406] 2) Drug Incubation: Prepare 100X compound dilution buffer and serially dilute the drug in 5-fold increments. Add 2 μL of each 100X compound solution to each well. Incubate in a 37°C incubator for 24 hours. 3) PD-L1 Cell Staining and FACS Assay: Remove the culture plate and discard the supernatant. Wash once with 200 μL of 1X PBS. Add 100 μL of EDTA (final concentration 10 mM) and treat at 37°C for 10 minutes. Centrifuge at 1500 rpm for 5 minutes, then wash once with 200 μL of staining buffer. Staining: Dilute anti-human PD-L1 (2 μL per well) and LIVE / DEAD stain (1:1000) in staining buffer, add 50 μL to each well, and stain at 4°C for 30 minutes. Wash twice with 200 μL of staining buffer. Fixation: Add 100 μL of fixative to each well and fix at 4°C for 15 minutes. Wash twice with 200 μL of staining buffer. Resuspend the cells in 150 μL and perform FACS analysis. Table 2 provides the effects of the compounds of the present invention on the expression level of PD-L1 in MDA-MR-231 cells.

[0407] Table 2 Test results of the effects of the compounds of the present invention on the expression level of PD-L1 in MDA-MR-231 cells

[0408] Test compound <![CDATA[IC 50 (nM)]]> Formate salt of compound 1 3.41 Compound 2 3.52 Compound 3 4.07 Formate salt of compound 8 5.85 Compound 12 3.82 Compound 15 2.13

[0409] Experimental conclusion: The compound of the present invention has a significant inhibitory effect on the PD-L1 expression level of MDA-MR-231 cells.

[0410] Experimental Example 3: NFAT activity test

[0411] Experimental principle:

[0412] Engineered T cells express PD-1 molecules and T cell receptors (TCRs) on their surfaces. When co-cultured with engineered antigen-presenting cells (APCs), they can activate the NFAT signaling pathway in T cells. Expressing PD-L1 molecules on APCs can effectively attenuate the NFAT signaling pathway within T cells. PD-L1 inhibitors can effectively block the PD-1 / PD-L1 regulatory mechanism, thereby reversing the attenuated NFAT signaling pathway. After pre-treatment with small molecules and APCs, the cells are co-cultured with T cells, and luciferase expression is measured to indirectly reflect the degree of NFAT pathway activation within T cells.

[0413] Experimental Materials:

[0414] The PD-1 / PD-L1 NFAT detection kit was purchased from BPS Biosciences. Birght-Glo reagent was purchased from Promega. The Nivo multi-label analyzer was purchased from PerkinElmer.

[0415] Experimental methods:

[0416] TCR Activator / PD-L1 CHO cells with a confluence of 80% were plated at 35,000 cells per well and placed in a 37°C cell culture incubator overnight. The test compound was diluted 5-fold to the eighth concentration, from 20 μM to 0.25 nM, with a DMSO concentration of 2%, in duplicate wells. The supernatant of the TCR Activator / PD-L1 CHO cells was discarded, and 50 μL of the compound working solution was added to each well and incubated at 37°C for 30 minutes. After the incubation, 50 μL of a 4×10 5 100 μL of Bright-Glo was added to each well, mixed, and the chemiluminescent signal was read using a Nivo multilabel analyzer.

[0417] Data Analysis:

[0418] The raw data were converted into inhibition rate, IC, using the equation (sample-Min) / (Max-Min)×100%. 50 The value of can be obtained by four-parameter curve fitting (derived by log(inhibitor) vs. response--Variable slope mode in GraphPad Prism). Table 3 provides the inhibitory activity of the compounds of the examples of the present invention on PD-1 / PD-L1 binding.

[0419] Table 3 Test results of the inhibitory activity of the compounds of the present invention on PD-1 / PD-L1 binding

[0420]

[0421] Experimental conclusion: The compounds of the present invention can inhibit the interaction of PD-1 / PD-L1 at the cellular level, thereby significantly activating the NFAT signaling pathway of T cells.

[0422] Experimental Example 4: Pharmacokinetic Test

[0423] Experimental purpose: To study the pharmacokinetics of the compound in C57BL / 6 mice

[0424] Experimental materials: C57BL / 6 mice (male, 8 weeks old, weighing 25g-30g)

[0425] Experimental Procedure: The pharmacokinetic profile of the compound was tested in rodents following intravenous (IV) and oral (PO) administration using standard protocols. The candidate compound was formulated as a 1 mg / mL clear solution and administered to mice as a single intravenous and oral dose. Both the IV and oral vehicles were 5% DMSO / 5% 15-hydroxystearate polyethylene glycol (Solutol) in a 90% aqueous solution. Four male C57BL / 6 mice were used. Two mice received a 1 mg / kg IV dose, and plasma samples were collected at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose. Two mice received a 10 mg / kg oral gavage dose, and plasma samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-dose. Whole blood samples were collected within 24 hours and centrifuged at 3000 g for 15 minutes. The supernatant was separated to obtain plasma samples. An acetonitrile solution containing an internal standard was added to precipitate the protein. The samples were thoroughly mixed and centrifuged. The supernatant was sampled and the plasma concentration was quantitatively analyzed by LC-MS / MS analysis. Pharmacokinetic parameters such as peak concentration (C max ), clearance (CL), half-life (T 1 / 2 ), tissue distribution (V dss ), area under the drug-time curve (AUC 0-last ), bioavailability (F), etc.

[0426] The pharmacokinetic parameters of the compounds of the present invention in mice are shown in the following table.

[0427] Table 4 Pharmacokinetic test results

[0428]

[0429] Experimental conclusion: The compounds of the present invention have good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.

[0430] Experimental Example 5: Pharmacodynamic evaluation study of the compound in the C57BL / 6-hPDL1 mouse colorectal cancer MC38-hPDL1 subcutaneous transplantation model Experimental purpose: To evaluate the anti-tumor effect of the compound in humanized mice C57BL / 6-hPDL1 transplanted with mouse colorectal cancer cells MC38-hPDL1.

[0431] Table 5 Experimental design

[0432]

[0433] Note: G: group; N: number of animals; po: oral administration; BID: twice a day.

[0434] Table 6 Experimental animals

[0435] Species mice strain C57BL / 6-hPDL1 level SPF level Age 5.86～6.86 gender female

[0436] Experimental methods:

[0437] 1. Tumor Cell Inoculation

[0438] Experimental cells: Mouse colon cancer cells MC38-hPDL1 were revived at the Pn+6 generation. MC38-hPDL1 cells were collected in the logarithmic growth phase, the culture medium was removed, and the cells were washed twice with PBS before inoculation (the survival rates of MC38-hPDL1 cells before and after tumor loading were 97.4% and 95.0%, respectively). The inoculum size was 1×10 6 / 100μL / mouse, inoculation site: right forelimb of mouse.

[0439] 2. Grouped Dosing

[0440] On the 7th day after inoculation, the average tumor volume reached 85.23 mm 3 At 4 hr, mice were randomly divided into five groups of eight based on tumor volume. The day of grouping was defined as D0, and drug administration began on D0. The remaining mice were used for subsequent supplementary experiments.

[0441] 3. Drug preparation

[0442] Dosage volume: adjusted according to mouse weight (mouse administration volume = 10 μL / g × mouse weight (g))

[0443] 4. Experimental Observation and Data Collection

[0444] After the start of drug administration, the tumor size was observed on days 0, 2, 4, 6, 8, 11, 13, 15, 18, 20, 22, and 25. The tumor volume was calculated as follows: tumor volume (mm 3 ) = 0.5 × (long diameter of tumor × short diameter of tumor 2 ).

[0445] 5. Experimental Endpoint

[0446] At the end of the experiment, the following indicators were analyzed: 1) change in tumor volume (TGItv); 2) change in average body weight; TGITV (relative tumor inhibition rate) was calculated using the following formula:

[0447] TGItv(%)=[1-(meanTVtn-meanTVt0) / (meanTVvn-mean TVv0)]×100%

[0448] meanTVtn: average tumor volume of a certain drug-treated group measured on day n

[0449] meanTVt0: average tumor volume of a drug-treated group measured on day 0

[0450] meanTVvn: average tumor volume of the solvent control group measured on day n

[0451] Mean TVv0: Mean tumor volume of the solvent control group measured on day 0

[0452] Experimental results: The anti-tumor efficacy evaluation of the compounds of the present invention on the C57BL / 6-hPDL1 mouse colorectal cancer MC38-hPDL1 subcutaneous transplant model (calculated based on the tumor volume on the 25th day after administration) is shown in Table 7 below:

[0453] Table 7

[0454]

[0455] The effects of the compounds of the present invention on the average body weight of mice in the C57BL / 6-hPDL1 mouse colorectal cancer MC38-hPDL1 subcutaneous transplantation model are shown in Table 8 below:

[0456] Table 8

[0457] Group Average body weight before administration (day 0) (g) Average body weight on the 25th day of administration (g) Vehicle (blank group) 19.2 20.0 Formate salt of compound 8 19.0 19.9 Compound 12 19.2 19.3 Compound 15 19.5 20.0 Compound 2 19.0 18.8

[0458] Experimental conclusion: The compound of the present invention has an excellent tumor inhibitory effect on the C57BL / 6-hPDL1 mouse colorectal cancer MC38-hPDL1 subcutaneous transplantation model. No significant decrease in animal body weight was observed during administration, and the compound has good tolerance.

[0459] Experimental Example 6: Toxicology study of the compound in Beagle dogs after repeated oral administration for 28 days

[0460] Experimental purpose: To evaluate the compound in rats and Beagle dogs by oral gavage once a day at different doses for 4 consecutive weeks, followed by 4 weeks of recovery, to observe its toxic reactions and their reversibility or possible delayed toxic reactions, explore its toxic reaction situation, and determine the toxic target organs or target tissues.

[0461] Table 9: Experimental design

[0462] Group Dosage mg / kg Dosage volume ml / kg Theoretical concentration mg / ml Dosing frequency Vehicle control 0 0 0 Once a day Low dose 15 5 3 Once a day Medium dose 50 5 10 Once a day High dose 150 5 30 Once a day

[0463] Table 10: Experimental animals

[0464] Species dog strain Beagle dog level Ordinary Age 6 to 8 months old gender male and female

[0465] Experimental methods: The experiment was designed and carried out according to the existing guidelines and the results of the preliminary experiments.

[0466] Experimental Conclusions: The compound of this invention was well tolerated, with no significant weight loss observed during administration. Compared with the vehicle control group, the main observed effects were gastrointestinal disturbances, coughing, salivation, and elevated total bilirubin (TBIL). Target organs included the liver, lungs, thymus, spleen, mesenteric lymph nodes, submandibular lymph nodes, and ileum. All of these changes showed recovery or a trend toward recovery during the recovery period, demonstrating the compound's good safety profile.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula: in, R1 and R2 are independently selected from H, F, Cl, Br, I, CN and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 halogens; R3 is selected from C 1-3 Alkoxy, the C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 halogens; R6 is selected from 1, 2 or 3 R c Substituted C 1-3 alkyl; L is selected from the group consisting of 1, 2 or 3 R d Substituted -C 1-6 alkyl-; X is N; Y is selected from CH and N; Z1 is selected from a single bond and CH2; Z2 is CH; R c selected from the group consisting of F, Cl, Br, I, CN, OH, ═O, and NH 2 ; R d selected from the group consisting of F, Cl, Br, I, CN, OH, ═O, and NH 2 ; Selected from optionally independently 1 or 2 R b substituted pyrrolidinyl, 8-azabicyclo[3.2.1]octanyl, azetidinyl, and 2-azaspiro[3.3]heptanyl; R b is selected from the group consisting of CN, OH, -C(=O)NH2, -OCH3, and CH3; and the compound represented by formula (I-5) is not any of the following compounds:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each independently selected from H, F, Cl, Br, I, CN, CF3 and CH3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is selected from -OCH3 and The -OCH3 and Each independently is optionally substituted with 1, 2 or 3 halogens.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R3 is selected from -OCH3, 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Selected from 6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R6 is selected from CH3.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L is selected from and 8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Structural unit Selected from 9. A compound or a pharmaceutically acceptable salt thereof, wherein: Compounds selected from 10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein Compounds selected from 11. Use of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof in the preparation of a PD-1 / PD-L1 inhibitor; the PD-1 / PD-L1 inhibitor is an anti-tumor drug; and the tumor is mouse colorectal cancer MC38-hPDL1 or triple-negative breast cancer MDA-MB-231.

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