CN116981660A

CN116981660A - Fluoro vinyl biphenyl derivative and application thereof

Info

Publication number: CN116981660A
Application number: CN202280021337.3A
Authority: CN
Inventors: 陈曙辉
Original assignee: Medshine Discovery Inc
Current assignee: Medshine Discovery Inc
Priority date: 2021-03-22
Filing date: 2022-03-22
Publication date: 2023-10-31
Also published as: WO2022199578A1

Abstract

The fluoro vinyl biphenyl derivatives and pharmaceutically acceptable salts thereof, in particular to application of a compound shown in a formula (II) and pharmaceutically acceptable salts thereof in preparing medicaments for treating related diseases.

Description

Fluoro vinyl biphenyl derivative and application thereof

The present application claims the following priorities:

CN202110305025.2, application date 2021, month 03, 22;

CN202111601553.9, application date 2021, 12, 24.

Technical Field

The application relates to a biphenyl derivative of fluorovinyl and application thereof, in particular to a compound shown in a formula (II) and pharmaceutically acceptable salts thereof.

Background

Programmed cell death molecule 1 (PD-1) is also called CD279, is an important immunosuppressive molecule in the CD28/CTLA-4 receptor family, is a membrane protein containing 268 amino acid residues, is widely expressed on the surfaces of various immune cells such as T cells, macrophages and B cells, and the ligands of the programmed cell death molecule are PD-L1 and PD-L2.PD-L1 is a protein encoded by the CD274 gene and expressed predominantly on the surface of tumor cells, dendritic cells and macrophages. Another ligand of PD-1, PD-L2, is expressed predominantly on the surfaces of dendritic cells, macrophages and B cells, and is associated with inflammatory and autoimmune diseases.

Under normal conditions, the immune system of the human body has an immune monitoring function. When malignant cells appear, the immune system can specifically recognize and clear these "non-self" cells to prevent tumor growth. However, in some cases, malignant cells prevent immune responses to tumors by up-regulating immunosuppressive or down-regulating immune activating molecules, thereby achieving immune escape and immortalization. PD-1/PD-L1 is the most studied axis of negative regulatory immune checkpoints in recent years and plays an important role in tumor immune escape. The interaction of PD-1 and PD-L1 induces phosphorylation of the intracellular immunoreceptor tyrosine repression motif (ITIM) and Immunoreceptor Tyrosine Switching Motif (ITSM), recruiting tyrosine acid phosphatase Src homology phosphatase 1 (SHP-1) and Src homology phosphatase 2 (SHP-2) in the intracellular domain of PD-1. These phosphatases can dephosphorize several key proteins in the T cell antigen receptor (TCR) signaling pathway and inhibit signaling pathway downstream of the TCR, thereby impeding the progression of the T cell cycle and expression of related proteins, ultimately inhibiting cytokine production and proliferation and differentiation of T cells, resulting in loss of immune function.

In immune checkpoints, PD-1/PD-L1 has been considered as an anticancer drug target for many years, and various monoclonal antibodies have been used for achieving encouraging effects in tumor treatment by targeting PD-1/PD-L1 signaling pathways. However, macromolecular antibody drugs cannot penetrate tumor tissue effectively and cannot accumulate sufficient concentrations in all areas of the tumor. The immunogenicity of antibody drugs induces the body to produce anti-drug antibodies, resulting in loss of potency. At the same time, disruption of immune system function leads to an imbalance in immune tolerance, which may clinically manifest as autoimmune side effects. In addition, monoclonal antibodies are difficult to prepare, expensive, inconvenient to store and transport, and limit the clinical application of PD-1/PD-L1 antibody medicaments. Small molecule inhibitors have significant advantages in solving these problems. The small molecule inhibitor is more suitable for oral administration, can avoid serious immune related adverse events by adjusting half-life, has the characteristics of convenient transportation and storage, good stability, high membrane permeability and the like, and is beneficial to clinical treatment in future. Research into small molecule inhibitors based on the PD-1/PD-L1 signaling pathway has gradually resuscitated over several decades. The small molecule inhibitors INCB86550 of Incyte (WO 2018119263, WO 2019191707) and GS-4224 of Gilead (US 20180305315, WO 2019160882) have entered clinical phase 1, and the small molecule inhibitors PD-1/PD-L1 of BMS benzyl phenyl ethers (WO 2015034820, WO 2015160641) are in preclinical research stages. Therefore, the research and development of the small molecule inhibitor of PD-1/PD-L1 has wide application prospect.

Disclosure of Invention

The present invention provides a compound of formula (III) or a pharmaceutically acceptable salt thereof,

wherein,

ring a is absent or selected from 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl;

when ring A is absent, the building blockIs that

Ring B is selected from 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl;

x is selected from CR ₇ And N;

y is selected from CR ₈ And N;

z is selected from C, CH and N;

e is selected from N and CR ₅ ；

L is selected from-CH ₂ -and-CH ₂ -NH-CH ₂ -；

R ₁ And R is ₂ Are independently selected from H, F, cl, br, I, CN and CH ₃ ；

R ₃ Selected from H and C _1-3 An alkoxy group;

R ₄ selected from C _1-3 Alkyl and 3-8 membered heterocycloalkyl, said C _1-3 Alkyl and 3-8 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3R _a Substitution;

R ₅ selected from H, CN, -OCH ₃ 、-OCHF ₂ Cyclopropyl and-C _1-3 alkyl-NH-C _1-3 alkyl-OH;

R ₆ are each independently selected from-C _1-6 alkyl-OH, -C _1-6 alkyl-COOH, -C _1-6 alkyl-C (=o) NH ₂ 、-C _1-3 alkyl-NH-C _1-3 alkyl-OH, -C _1-3 Alkyl-3-6 membered heterocycloalkyl-COOH, -C _1-3 Alkyl-3-6 membered heterocycloalkyl-OH, -C _1-3 alkyl-NH-C _1-3 Alkyl-3-6 membered heterocycloalkyl, C _1-6 Alkoxy, -C _1-3 Alkyl-5-6 membered heteroaryl-C _1-3 Alkyl, -C _1-3 alkyl-C _3-6 cycloalkyl-COOH,-C _1-3 Alkyl-5-6 membered heteroaryl, -C _1-3 alkyl-C _3-6 cycloalkyl-OH, -C _1-3 alkyl-C _3-6 cycloalkyl-C _1-3 alkyl-OH and-C _1-3 Alkyl-5-6 membered heterocycloalkyl;

R ₇ and R is ₈ Selected from H and CF, respectively and independently ₃ ；

R _a Are independently selected from H, F, cl, br, I, CN, OH, COOH, = O, C _1-3 Alkyl, C _1-3 Alkoxy, -C _1-3 alkyl-OH, -C (=o) NH ₂ 、-O-C _1-3 alkyl-OH, -C _1-3 alkyl-O-C _1-3 Alkane and-O-C _1-3 alkyl-O-C _1-3 An alkane;

n is selected from 0, 1 and 2.

The present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof,

wherein,

when ring A is absent, the building blockIs that

X is selected from CR ₇ And N;

y is selected from CR ₈ And N;

z is selected from C, CH and N;

e is selected from N and CR ₅ ；

L is selected from-CH ₂ -and-CH ₂ -NH-CH ₂ -；

R ₃ Selected from H and C _1-3 An alkoxy group;

R ₆ are each independently selected from-C _1-6 alkyl-OH, -C _1-6 alkyl-COOH, -C _1-6 alkyl-C (=o) NH ₂ 、-C _1-3 alkyl-NH-C _1-3 alkyl-OH, -C _1-3 Alkyl-3-6 membered heterocycloalkyl-COOH, -C _1-3 Alkyl-3-6 membered heterocycloalkyl-OH, -C _1-3 alkyl-NH-C _1-3 Alkyl-3-6 membered heterocycloalkyl, C _1-6 Alkoxy, -C _1-3 Alkyl-5-6 membered heteroaryl-C _1-3 Alkyl, -C _1-3 alkyl-C _3-6 cycloalkyl-COOH, -C _1-3 Alkyl-5-6 membered heteroaryl, -C _1-3 alkyl-C _3-6 cycloalkyl-OH, -C _1-3 alkyl-C _3-6 cycloalkyl-C _1-3 alkyl-OH and-C _1-3 Alkyl-5-6 membered heterocycloalkyl;

R _a Are independently selected from H, F, cl, br, I, CN, OH, COOH, = O, C _1-3 Alkyl, C _1-3 Alkoxy, -C _1-3 Alkyl group-OH、-C(＝O)NH ₂ 、-O-C _1-3 alkyl-OH, -C _1-3 alkyl-O-C _1-3 Alkane and-O-C _1-3 alkyl-O-C _1-3 An alkane;

n is selected from 0, 1 and 2.

In some aspects of the invention, R is as defined above _a Are independently selected from H, OH, = O, CH ₃ 、-OCH ₃ 、-CH ₂ -OH、-C(＝O)NH ₂ 、COOH、 The other variables are as defined herein.

In some aspects of the invention, R is as defined above _a Are independently selected from H, OH, = O, CH ₃ 、-OCH ₃ 、-CH ₂ -OH and-C (=o) NH ₂ The other variables are as defined herein.

In some aspects of the invention, R is as defined above ₁ And R is ₂ Are each independently selected from H, cl, CN and CH ₃ The other variables are as defined herein.

In some aspects of the invention, R is as defined above ₁ Selected from Cl, R ₂ Selected from Cl and CH ₃ The other variables are as defined herein.

In some aspects of the invention, R is as defined above ₁ And R is ₂ All selected from Cl, the other variables being as defined herein.

In some aspects of the invention, R is as defined above ₃ Selected from H and-OCH ₃ The other variables are as defined herein.

In some aspects of the invention, R is as defined above ₄ Selected from CH ₃ 、-CH ₂ -CH ₃ Azetidinyl, pyrrolidinyl, 2-azaspiro [3.3 ]]Heptyl and 8-azabicyclo [3.2.1]Octyl radical, the CH ₃ 、-CH ₂ -CH ₃ Azetidinyl, pyrrolidinyl, 2-azaspiro [3.3 ]]Heptyl and 8-azabicyclo [3.2.1]Octyl is optionally substituted with 1, 2 or 3R _a Instead, the other variables are as defined herein.

In some aspects of the invention, R is as defined above ₄ Selected from the group consisting of The other variables are as defined herein.

In some aspects of the invention, R is as defined above ₆ Are respectively and independently selected from The other variables are as defined herein.

In some aspects of the invention, the structural units described aboveSelected from the group consisting of The other variables are as defined herein.

In some embodiments of the invention, the above-mentioned compounds are selected from

Wherein R is ₁ 、R ₂ 、R ₃ 、R ₆ And R is _a As defined herein.

The present invention also provides a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

In some embodiments of the invention, the above compound or a pharmaceutically acceptable salt thereof is selected from

The invention also provides application of the compound, pharmaceutically acceptable salt or isomer thereof in inhibiting PD-1/PD-L1 signal path conduction.

The invention also provides application of the compound, pharmaceutically acceptable salt or isomer thereof in antitumor drugs.

Still other embodiments of the present invention are derived from any combination of the variables described above.

Technical effects

The compound has good inhibition effect on the overactivation of PD-1/PD-L1 signal channels, and further obtains excellent activity of inhibiting tumor growth.

Definition and description

The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.

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

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting such compounds with a sufficient amount of base in pure 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, the acid addition salts may be obtained by contacting such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts including acids 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; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.

Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.

The term "effective amount" or "therapeutically effective amount" refers to an amount that is non-toxic but which achieves the desired effect, unless otherwise specified. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

The compounds of the 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 invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.

Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.

Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" is caused by the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely.

Unless otherwise indicated, the term "diastereoisomer" refers to stereoisomers of a molecule having two or more chiral centers and having a non-mirror relationship between the molecules.

Unless otherwise indicated, "(+)" means dextrorotation, "(-)" means levorotatory, "(±)" means racemization.

Unless otherwise indicated, with solid wedge bondsAnd a wedge-shaped dotted bondRepresenting the absolute configuration of a solid centre by straight solid keysAnd straight dotted line keyRepresenting the relative configuration of the three-dimensional center by wavy linesSolid key representing wedge shapeOr wedge-shaped dotted bondOr by wave linesRepresenting straight solid keysOr straight dotted line key

Unless otherwise indicated, when there is a double bond structure in a compound, such as a carbon-carbon double bond, a carbon-nitrogen double bond, and a nitrogen-nitrogen double bond, and each atom on the double bond is attached to two different substituents (a lone pair of electrons on the nitrogen atom is considered to be one substituent to which it is attached in a double bond containing a nitrogen atom), if there is a double bond in the compound, there is used an electron on the double bond and a substituent thereof The expression "Z" isomer, (E) isomer or a mixture of both isomers "of the compound.

Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to the fact that at room temperature, different functional group isomers are in dynamic equilibrium and are capable of rapid interconversion. If tautomers are possible (e.g., in solution), chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as proton tautomers) (prototropic tautomer) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence isomer (valance tautomer) includes the interconversion by recombination of some of the bond-forming electrons. A specific example of where keto-enol tautomerization is the interconversion between two tautomers of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one.

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

Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or enantiomers. For example, where one isomer or enantiomer is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomer excess (ee value) is 80%.

Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods well known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).

The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example ³ H) Iodine-125% ¹²⁵ I) Or C-14% ¹⁴ C) A. The invention relates to a method for producing a fibre-reinforced plastic composite For example, deuterium can be substituted for hydrogen to form a deuterated drug, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, so that the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life of the drug and the like compared with the non-deuterated drug. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

The term "optional" or "optionally" means 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.

The term "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, and may include deuterium and variants of hydrogen, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =o), it means that two hydrogen atoms are substituted.

The term "optionally substituted" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.

When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.

When the number of one linking group is 0, such as- (CRR) ₀ -represents that the linking group is a single bond, -C ₀ alkyl-A means that the structure is actually-A.

When the number of a substituent is 0, this indicates that the substituent is absent, such as-A- (R) ₀ Indicating that the structure is actually-a.

When a substituent is absent, it is meant that the substituent is absent, e.g., X in A-X is absent, meaning that the structure is actually A.

When one of the variables is selected from a single bond, the two groups to which it is attached are indicated as being directly linked, e.g., when L in A-L-Z represents a single bond, it is indicated that the structure is actually A-Z.

When the listed substituents do not indicate which atom is attached to the substituted group, such substituents may be bonded through any atom thereof, for example, a pyridyl group may be attached to the substituted group as a substituent through any carbon atom on the pyridine ring.

Where a bond of a substituent may be cross-linked to more than one atom of a ring, such substituent may be bonded to any atom of the ring, e.g. a building blockIt means that the substituent R may be substituted at any position on the cyclohexyl or cyclohexadiene.

When the exemplified linking group does not indicate its linking direction, its linking direction is arbitrary, for example,the linking group L is-M-W-, in which case-M-W-may be a group formed by linking the rings A and B in the same direction as the reading order from left to rightThe ring A and the ring B may be connected in a direction opposite to the reading order from left to rightCombinations of such linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, when a group has one or more bondable sites, any one or more of the sites of the group may be bonded to other groups by chemical bonds. When the connection mode of the chemical bond is not positioned and the H atoms exist in the connectable site, the number of the H atoms of the site can be correspondingly reduced to be changed into the corresponding valence group along with the number of the connected chemical bond when the chemical bond is connected. The chemical bond of the site and other groups can be a straight solid line bondStraight dotted line keyOr wave linesAnd (3) representing. For example-OCH ₃ The straight solid line bond in (a) represents the connection to other groups through the oxygen atom in the group;the straight dashed bonds in (a) represent the attachment to other groups through both ends of the nitrogen atom in the group;the wavy line means that the carbon atoms at positions 1 and 2 in the phenyl group are attached to other groups;it means that any of the ligatable sites on the piperidinyl group may be attached to other groups by 1 chemical bond, including at leastThese 4 connection modes, even though H atom is drawn on-N-, areStill includeThe group of this linkage is only when 1 chemical bond is linked, the H at this site will be correspondingly reduced by 1 to the corresponding monovalent piperidinyl group.

Unless otherwise specified, the number of atoms on a ring is generally defined as the number of ring elements, e.g., "5-7 membered ring" refers to a "ring" of 5-7 atoms arranged around a ring.

Unless otherwise specified, the term "C _1-6 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C is _1-6 Alkyl includes C _1-5 、C _1-4 、C _1-3 、C _1-2 、C _2-6 、C _2-4 、C ₆ And C ₅ Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) _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.

Unless otherwise specified, the term "C _1-5 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 5 carbon atoms. The C is _1-5 Alkyl includes C _1-4 、C _1-3 、C _1-2 、C _2-5 、C _2-4 And C ₅ Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) _1-5 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), and the like.

Unless otherwise specified, the term "C _1-4 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C is _1-4 Alkyl includes C _1-2 、C _1-3 And C _2-3 Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) _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.

Unless otherwise specified, the term "C _1-3 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C is _1-3 Alkyl includes C _1-2 And C _2-3 Alkyl groups, etc.; it may be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., methine). C (C) _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.

Unless otherwise specified, the term "C _1-6 Alkoxy "means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through one oxygen atom. The C is _1-6 Alkoxy includes C _1-4 、C _1-3 、C _1-2 、C _2-6 、C _2-4 、C ₆ 、C ₅ 、C ₄ And C ₃ Alkoxy groups, and the like. C (C) _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), hexoxy, and the like.

Unless otherwise specified, the term "C _1-4 Alkoxy "means those alkyl groups containing 1 to 4 carbon atoms that are attached to the remainder of the molecule through one oxygen atom. The C is _1-4 Alkoxy includes C _1-3 、C _1-2 、C _2-4 、C ₄ And C ₃ Alkoxy groups, and the like. C (C) _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), hexoxy, and the like.

Unless otherwise specified, the term "C _1-3 Alkoxy "means those containing 1 to 3 carbon atoms attached to the remainder of the molecule through one oxygen atomIs a group of alkyl groups of (a). The C is _1-3 Alkoxy includes C _1-2 、C _2-3 、C ₃ And C ₂ Alkoxy groups, and the like. C (C) _1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

Unless otherwise specified, the term "C _1-6 Alkylamino "means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through an amino group. The C is _1-6 Alkylamino includes C _1-4 、C _1-3 、C _1-2 、C _2-6 、C _2-4 、C ₆ 、C ₅ 、C ₄ 、C ₃ And C ₂ Alkylamino, and the like. C (C) _1-6 Examples of alkylamino groups include, but are not limited to, -NHCH ₃ 、-N(CH ₃ ) ₂ 、-NHCH ₂ CH ₃ 、-N(CH ₃ )CH ₂ CH ₃ 、-N(CH ₂ CH ₃ )(CH ₂ CH ₃ )、-NHCH ₂ CH ₂ CH ₃ 、-NHCH ₂ (CH ₃ ) ₂ 、-NHCH ₂ CH ₂ CH ₂ CH ₃ Etc.

Unless otherwise specified, the term "C _1-4 Alkylamino "means those alkyl groups containing 1 to 4 carbon atoms attached to the remainder of the molecule through an amino group. The C is _1-4 Alkylamino includes C _1-3 、C _1-2 、C _2-4 、C ₄ 、C ₃ And C ₂ Alkylamino, and the like. C (C) _1-4 Examples of alkylamino groups include, but are not limited to, -NHCH ₃ 、-N(CH ₃ ) ₂ 、-NHCH ₂ CH ₃ 、-N(CH ₃ )CH ₂ CH ₃ 、-N(CH ₂ CH ₃ )(CH ₂ CH ₃ )、-NHCH ₂ CH ₂ CH ₃ 、-NHCH ₂ (CH ₃ ) ₂ 、-NHCH ₂ CH ₂ CH ₂ CH ₃ Etc.

Unless otherwise specified, the term "C _1-3 Alkylamino "means those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group. The C is _1-3 Alkylamino includes C _1-2 、C ₃ And C ₂ Alkylamino, and the like. C (C) _1-3 Examples of alkylamino groups include, but are not limited to, -NHCH ₃ 、-N(CH ₃ ) ₂ 、-NHCH ₂ CH ₃ 、-N(CH ₃ )CH ₂ CH ₃ 、-NHCH ₂ CH ₂ CH ₃ 、-NHCH ₂ (CH ₃ ) ₂ Etc.

Unless otherwise specified, the term "halo" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

Unless otherwise specified, "C _3-8 Cycloalkyl "means a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, which includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings. The C is _3-8 Cycloalkyl includes C _3-6 、C _3-5 、C _4-8 、C _4-6 、C _4-5 、C _5-8 Or C _5-6 Cycloalkyl groups, and the like; it may be monovalent, divalent or multivalent. C (C) _3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [ 2.2.2.2 ]]Bicyclooctane, and the like.

Unless otherwise specified, "C _3-6 Cycloalkyl "means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, said C _3-6 Cycloalkyl includes C _3-5 、C _4-5 And C _5-6 Cycloalkyl groups, and the like; it may be monovalent, divalent or multivalent. C (C) _3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

Unless otherwise specified, "C _3-8 Cycloalkenyl "means a partially unsaturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms containing at least one carbon-carbon double bond, which includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings, any ring of which system is non-aromatic. The C is _3-8 Cycloalkenyl includes C _3-6 、C _3-5 、C _4-10 、C _4-8 、C _4-6 、C _4-5 、C _5-8 Or C _5-6 Cycloalkenyl groups, and the like; it may be monovalent, divalent or multivalent. C (C) _3-8 Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

Unless otherwise specified, "C _3-6 Cycloalkenyl "means a partially unsaturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms containing at least one carbon-carbon double bond, which includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings, any ring of which system is non-aromatic. The C is _3-6 Cycloalkenyl includes C _4-6 、C _4-5 Or C _5-6 Cycloalkenyl groups, and the like; it may be monovalent, divalent or multivalent. C (C) _3-6 Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

Unless otherwise specified, the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms, denotes a saturated cyclic group consisting of 3 to 8 ring atoms, respectively, 1,2, 3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atoms are optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms may optionally be oxidized (i.e. C (=o), NO and S (O) p, p being 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings. In addition, with respect to the "3-8 membered heterocycloalkyl" group, the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the remainder of the molecule. The 3-8 membered heterocycloalkyl group includes 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered, 6 membered heterocycloalkyl group and the like. 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, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, or dioxacycloheptyl, etc.

Unless otherwise specified, the term "3-6 membered heterocycloalkyl" alone or in combination with other terms, respectively, denotes 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, the remainder being carbon atoms, wherein the nitrogen atoms are optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms may optionally be oxidized (i.e. C (=o), NO and S (O) p, p being 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings. In addition, with respect to the "3-6 membered heterocycloalkyl" group, the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the remainder of the molecule. The 3-6 membered heterocycloalkyl group includes 4-6 membered, 5-6 membered, 4 membered, 5 membered, 6 membered heterocycloalkyl group and the like. 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, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, etc.

Unless otherwise specified, the term "5-10 membered heterocycloalkyl" alone or in combination with other terms, respectively, denotes a saturated cyclic group consisting of 5 to 10 ring atoms, 1,2, 3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atoms are optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms may optionally be oxidized (i.e. C (=o), NO and S (O) p, p being 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, fused and bridged rings. In addition, with respect to the "5-10 membered heterocycloalkyl" group, the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the remainder of the molecule. The 5-to 10-membered heterocycloalkyl group includes 5-to 8-membered, 5-to 6-membered, 5-to 7-membered, 5-to 9-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered heterocycloalkyl group and the like. Examples of 5-10 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, or dioxacycloheptyl, etc.

Unless otherwise specified, the term "5-6 membered heterocycloalkyl" alone or in combination with other terms, respectively, denotes a saturated cyclic group consisting of 5 to 6 ring atoms, 1,2, 3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atoms are optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms may optionally be oxidized (i.e. C (=o), NO and S (O) p, p being 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings. In addition, in the case of the "5-6 membered heterocycloalkyl" group, the heteroatom may occupy the position of attachment of the heterocycloalkyl group to the remainder of the molecule. The 5-6 membered heterocycloalkyl group includes 5-and 6-membered heterocycloalkyl groups. Examples of 5-6 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl 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, etc.

Unless otherwise specified, the term "5-8 membered heterocycloalkenyl" alone or in combination with other terms, respectively, denotes a partially unsaturated cyclic group consisting of 5 to 8 ring atoms containing at least one carbon-carbon double bond, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atoms are optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms may optionally be oxidized (i.e. C (=o), NO and S (O) p, p being 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, fused and bridged rings, and any ring of such systems is non-aromatic. In addition, with respect to the "5-8 membered heterocycloalkenyl", the heteroatom may occupy the position of attachment of the heterocycloalkenyl to the remainder of the molecule. The 5-8 membered heterocycloalkenyl group includes 5-7 membered, 5-6 membered, 4-5 membered, 4 membered, 5 membered, 6 membered heterocycloalkenyl group and the like. Examples of 5-8 membered heterocycloalkenyl groups include, but are not limited to

Unless otherwise specified, the term "5-6 membered heterocycloalkenyl" alone or in combination with other terms, respectively, denotes a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atoms are optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms may optionally be oxidized (i.e. C (=o), NO and S (O) p, p being 1 or 2). It includes monocyclic and bicyclic ring systems, wherein Bicyclic ring systems include spiro, fused and bridged rings, any of which are non-aromatic. In addition, with respect to the "5-6 membered heterocycloalkenyl", the heteroatom may occupy the position of attachment of the heterocycloalkenyl to the remainder of the molecule. The 5-6 membered heterocycloalkenyl group includes 5-and 6-membered heterocycloalkenyl groups and the like. Examples of 5-6 membered heterocycloalkenyl groups include, but are not limited to

Unless otherwise specified, the term "C" in the present invention _6-10 Aromatic rings "and" C _6-10 Aryl "may be used interchangeably, the term" C _6-10 Aromatic ring "or" C _6-10 Aryl "means a cyclic hydrocarbon group consisting of 6 to 10 carbon atoms with a conjugated pi electron system, which may be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. It may be monovalent, divalent or multivalent, C _6-10 Aryl groups include C _6-9 、C ₉ 、C ₁₀ And C ₆ Aryl, and the like. C (C) _6-10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl, 2-naphthyl, and the like).

The terms "5-10 membered heteroaryl ring" and "5-10 membered heteroaryl" are used interchangeably herein unless otherwise specified, the term "5-10 membered heteroaryl" being a cyclic group consisting of 5 to 10 ring atoms with a conjugated pi electron system, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atoms are optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms are optionally oxidized (i.e., C (=o), NO and S (O) p, p being 1 or 2). It may be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. The 5-10 membered heteroaryl group may be attached to the remainder of the molecule through a heteroatom or carbon atom. The 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered, 6 membered heteroaryl, and the like. Examples of the 5-to 10-membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl and the like), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl and the like), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl and the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl and the like), triazolyl (1H-1, 2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl and the like), tetrazolyl, isoxazolyl (3-isoxazolyl) 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furanyl (including 2-furanyl, 3-furanyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), benzimidazolyl, benzoxazolyl, indolyl (including 5-indolyl, etc.), and the like, isoquinolinyl (including 1-isoquinolinyl, 5-isoquinolinyl, and the like), quinoxalinyl (including 2-quinoxalinyl, 5-quinoxalinyl, and the like), or quinolinyl (including 3-quinolinyl, 6-quinolinyl, and the like).

Unless otherwise specified, C _n-n+m Or C _n -C _n+m Comprising any one of the specific cases of n to n+m carbons, e.g. C _1-12 Comprises C ₁ 、C ₂ 、C ₃ 、C ₄ 、C ₅ 、C ₆ 、C ₇ 、C ₈ 、C ₉ 、C ₁₀ 、C ₁₁ And C ₁₂ Also included is any one of the ranges n to n+m, e.g. C _1-12 Comprises C _1-3 、C _1-6 、C _1-9 、C _3-6 、C _3-9 、C _3-12 、C _6-9 、C _6-12 And C _9-12 Etc.; similarly, n-to n+m-membered means that the number of atoms on the ring is n to n+m, for example, 3-to 12-membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, 10-membered ringsRings, 11-membered rings, and 12-membered rings, also including any of the ranges from n to n+m, e.g., 3-12 membered rings include 3-6 membered rings, 3-9 membered rings, 5-6 membered rings, 5-7 membered rings, 6-8 membered rings, 6-10 membered rings, and the like.

The term "leaving group" refers to a functional group or atom that may be substituted with another functional group or atom by a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromophenylsulfonate, p-toluenesulfonate and the like; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.

The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "mercapto protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: a formyl group; acyl groups such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl groups such as t-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), 1-bis- (4' -methoxyphenyl) methyl; silyl groups such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing side reactions of a hydroxy group. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and t-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl groups such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like.

The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.

The compounds of the present invention may be structured by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, the absolute configuration may be confirmed by conventional means in the art. For example, single crystal X-ray diffraction (SXRD), the grown single crystal is collected from diffraction intensity data using a Bruker D8 vent diffractometer, and the light source is cukα radiation, scanning:after scanning and collecting the related data, the absolute configuration can be confirmed by further analyzing the crystal structure by a direct method (Shellxs 97).

The compounds of the present invention may be structured by conventional methods well known to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, the absolute configuration may be confirmed by conventional means in the art. For example, single crystal X-ray diffraction (SXRD), the grown single crystal is collected from diffraction intensity data using a Bruker D8 vent diffractometer, and the light source is cukα radiation, scanning: the absolute configuration can be confirmed by further analyzing the crystal structure by a direct method (Shellxs 97) after the related data are collected by phi/omega scanning.

The solvent used in the present invention is commercially available.

The ratio of the reagents used in the silica gel column chromatography, the silica gel chromatographic column chromatography and the silica gel thin layer chromatography plate in the invention is the volume ratio unless otherwise specified.

The invention adopts the following abbreviations: HATU represents O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate; DMSO represents dimethylsulfoxide; CD (compact disc) ₃ OD represents deuterated methanol; CDCl ₃ Represents deuterated chloroform; TBSO represents tert-butyldimethylsilyloxy.

Compounds are either prepared according to the general nomenclature of the art or are usedSoftware naming, commercial compounds are referred to by vendor catalog names.

Detailed Description

The present invention is described in detail below by way of examples, but is not meant to be limiting in any way. The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention. Various changes and modifications to the specific embodiments of the invention will be apparent to those skilled in the art without departing from the spirit and scope of the invention.

Intermediate synthesis

Intermediate A

First step

Compound a-1 (10 g, 49.01 mmol) was added to acetonitrile (100 ml) and water (150 ml), aqueous hydroiodic acid (100 ml, mass fraction 55%) was added, and stirred at zero degrees celsius for 0.5 hours. Sodium nitrite (50.73 g, 735.21 mmol) was dissolved in water (100 ml) and added dropwise to the reaction solution at zero degrees celsius. After the addition, stirring was carried out at 20℃for 1 hour, and then stirring was continued at 50℃for 16 hours. After the reaction was completed, the mixture was cooled to 20℃and added to an aqueous sodium hydroxide solution (600 ml Rising, mass fraction 20%) while maintaining the temperature at zero degrees celsius. The mixture was extracted with ethyl acetate (500 ml×2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a column of silica gel (petroleum ether: ethyl acetate=100:1, volume ratio) to give compound a-2. ¹ H NMR(400MHz,CDCl ₃ )δppm 8.08(s,1H),4.05(s,3H)。

Second step

Compound a-2 (9.2 g, 29.22 mmol) was dissolved in tetrahydrofuran (100 ml), and isopropyl magnesium chloride lithium chloride complex (1.3 mol/l, 40.45 ml) was added dropwise at-60 ℃ and stirred for 30 minutes, then N, N-dimethylformamide (6.41 g, 87.65 mmol, 6.74 ml) was added at-40 ℃ and stirred for 1 hour. After the completion of the reaction, a saturated aqueous ammonium chloride solution (100 ml) was carefully added dropwise to the reaction mass, followed by extraction with ethyl acetate (50 ml. Times.2), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound A-3.MS-ESI calculated [ M+H ]] ⁺ 217 and 219, measured values 217 and 219.

Third step

Compound a-3 (7 g, 32.26 mmol) and compound a-4 (6 g, 27.65 mmol, hydrochloride) were dissolved in methanol (100 ml), diisopropylethylamine (8.34 g, 64.51 mmol) was added and stirred at 25 ℃ for 0.5 hours, then sodium cyanoborohydride (2.43 g, 38.71 mmol) was added and stirred at 25 ℃ for 0.5 hours. After the completion of the reaction, water (200 ml) was carefully added to the reaction mass, followed by extraction with ethyl acetate (100 ml. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound A-5.MS-ESI calculated [ M+H ] ] ⁺ 288 and 290, found 288 and 290.

Fourth step

Compound a-5 (5 g, 17.35 mmol) was dissolved in dichloromethane (100 ml) and t-butyldimethylchlorosilane (6.54 g, 43.38 mmol) and imidazole (4.13 g, 60.73 mmol) were added and the mixture stirred at 25 degrees celsius for 16 hours. After the reaction was completed, water (100 ml) and methylene chloride (100 ml) were added to the reaction mixture and stirred for 15 minutes, and an organic phase was separatedDried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a column of silica gel (petroleum ether: ethyl acetate=10:1 to 3:1) to give intermediate a. MS-ESI calculated [ M+H ]] ⁺ 402 and 404, measured values 402 and 404.

Intermediate B

First step

Compound B-1 (5.00 g, 22.6 mmol), pinacol borate (6.88 g, 27.1 mmol), potassium acetate (6.65 g, 67.7 mmol) was dissolved in dioxane (60 ml), and a 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride dichloromethane mixture (2.77 g, 3.39 mmol) was added to the reaction solution and reacted under nitrogen at 80 degrees celsius for 12 hours. After the reaction was completed, filtration was performed, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (petroleum ether: ethyl acetate=100:1 to 30:1, volume ratio) to obtain intermediate B-2. ¹ HNMR(400MHz,CDCl ₃ )δppm 7.63-7.59(m,1H),7.57-7.53(m,1H),7.32-7.28(m,1H),4.79(s,2H),1.71-1.65(m,1H),1.39(s,12H).

Second step

Intermediate B-2 (3.80 g, 14.2 mmol), B-3 (4.97 g, 18.4 mmol) was dissolved in dioxane (50 ml), water (10 ml), and then potassium carbonate (5.87 g, 42.5 mmol), 1-bis (diphenylphosphorus) ferrocene palladium chloride dichloromethane mixture (1.73 g, 2.12 mmol) was added to the reaction solution and reacted under nitrogen at 80 degrees celsius for 6 hours. After the reaction was completed, filtration was performed, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (petroleum ether: ethyl acetate=100:1 to 50:1, volume ratio) to obtain intermediate B-4. ¹ HNMR(400MHz,CDCl ₃ )δppm 7.70(dd,J＝5.9,3.58Hz,1H),7.63-7.57(m,1H),7.43-7.35(m,1H),7.27-7.15(m,3H),4.92-4.84(m,2H).

Third step

Intermediate B-4 (800 mg, 2.41 mmol), duplex pinacol borate (918 mg, 3.61 mmol), potassium acetate (709 mg, 7.23 mmol) was dissolved in dioxane (15 ml), and 1, 1-bis (diphenylphosphine) ferrocene palladium chloride dichloromethane mixture (197 mg, 241 μmol) was added to the reaction solution and reacted under nitrogen protection at 80 degrees celsius for 4 hours. After the completion of the reaction, the residue obtained by concentrating the filtrate under reduced pressure was filtered to obtain intermediate B-5.

Fourth step

Compound B-5 (1.1 g, 2.9 mmol, 1 eq.) and compound a (933.57 mg, 2.32 mmol, 0.8 eq.) were dissolved in dioxane (15 ml), water (1.5 ml), then potassium carbonate (1.20 g, 8.70 mmol, 3 eq.) and a 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride dichloromethane mixture (236.82 g, 290 μmol, 0.1 eq.) were added to the reaction solution and reacted under nitrogen at 65 ℃ for 4 hours. After completion of the reaction, a saturated aqueous solution (15 ml) of sodium sulfite was added, extraction (15 ml×3) was performed with methylene chloride, the organic phase was washed with a saturated aqueous solution (20 ml×3) of sodium sulfite, saturated brine (20 ml×3), the organic phase was dried over anhydrous sodium sulfate, filtration was performed, and the residue concentrated under reduced pressure was purified by silica gel column chromatography (petroleum ether: ethyl acetate=15:1 to 5:1) to give compound B-6.MS-ESI calculated [ M+H ] ] ⁺ 574, the actual measurement 574. ¹ H NMR(400MHz,CDCl ₃ )δppm 8.50-8.44(m,1H),7.66-7.57(m,2H),7.45(t,J＝7.6Hz,1H),7.41-7.36(m,1H),7.32(dd,J＝1.6,7.6Hz,1H),7.28(br d,J＝1.5Hz,1H),4.87(s,2H),4.03(s,3H),3.92(s,2H),3.63(br d,J＝6.0Hz,2H),3.25-3.13(m,2H),1.60(s,3H),1.28-1.22(m,9H),0.89(s,9H),0.07(s,6H).

Fifth step

Compound B-6 (200 mg, 348.06 micromolar, 1 eq) was dissolved in dichloromethane (2 ml), then dess-martin periodate (369.07 mg, 870.15 micromolar, 2.5 eq) was added to the reaction solution at 0 degrees celsius and reacted at 20 degrees celsius for 2 hours. After the reaction is completed, sulfurous acid is addedSaturated aqueous sodium (10 ml), dichloromethane extraction (10 ml×2), washing the organic phase with saturated brine (10 ml×2), drying the organic phase over anhydrous sodium sulfate, filtering, concentrating. The crude product was purified by thin layer chromatography on silica gel (petroleum ether: ethyl acetate=2:1, volume ratio) to give compound B. MS-ESI calculated [ M+H ]] ⁺ 572, measured value 572.

Intermediate C and intermediate D

First step

Compound C-1 (20 g, 144.80 mmol) and ethyl pyruvate (84.07 g, 723.99 mmol) were mixed and stirred at 20 degrees celsius for 15 minutes. Phosphorus oxychloride (222.02 g, 1.45 mol) was then added and stirred at 100 degrees celsius for 1 hour. After completion of the reaction, the reaction solution was poured into ice water (1 liter), pH was adjusted to 7 with sodium carbonate, extracted with ethyl acetate (150 ml×2), the organic phase was washed with saturated brine (100 ml×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, volume ratio) to give compound C-2.MS-ESI calculated [ M+H ] ] ⁺ 236.8 found 236.8.

Second step

Compound C-2 (16.8 g, 70.99 mmol) and sodium cyanoborohydride (13.387 g, 212.97 mmol) were dissolved in acetic acid (100 ml), and the reaction solution was reacted at 20℃for 1 hour under nitrogen protection. After the completion of the reaction, the reaction mixture was poured into ice water, pH was adjusted to 7 with sodium carbonate, extracted with ethyl acetate (200 ml. Times.2), the organic phase was washed with saturated brine (100 ml. Times.2), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give Compound C-3 which was used directly in the next step without requiringFurther purifying. MS-ESI calculated [ M+H ]] ⁺ 240.8, found 240.8.

Third step

Compound C-3 (23 g, 95.56 mmol) was dissolved in dichloromethane (200 ml), di-tert-butyl dicarbonate (31.28 g, 143.34 mmol), triethylamine (29.01 g, 286.68 mmol) was added and the reaction stirred at 25 ℃ for 0.5 h. After completion of the reaction, water (300 ml) was added to the reaction solution, extracted with methylene chloride (200 ml×2), the organic phase was washed with saturated brine (150 ml×2), the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=15:1 to 5:1) to give compound C-4.MS-ESI calculated [ M+H ] ] ⁺ 340.8, found 340.8.

Fourth step

Compound C-4 (500 mg, 1.38 mmol, 1 eq.) was dissolved in methanol (10 ml), followed by adding sodium methoxide (744.99 mg, 13.79 mmol, 10 eq.) to the reaction solution and stirring at 70 degrees celsius for 10 hours. The reaction solution was poured into a saturated aqueous ammonium chloride (10 ml), extracted with 30 ml (10 ml. Times.3) of ethyl acetate, and the combined organic phases were washed with 30 ml (10 ml. Times.3) of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound C-5.MS-ESI calculated [ M+H ]] ⁺ 308, measured value 308.

Fifth step

Compound C-5 (400 mg, 1.30 mmol, 1 eq.) was dissolved in N, N-dimethylformamide (5 ml), then ethyl iodide (1.01 g, 6.49 mmol, 5 eq.) and potassium carbonate (359.59 mg, 2.59 mmol, 2 eq.) were added to the reaction solution and stirred at 60 ℃ for 10 hours ] ⁺ 337, found 337. ¹ H NMR(400MHz,CDCl ₃ )δppm 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)

Sixth step

Compound C-6 (2.7 g, 8.03 mmol, 1 eq.) was dissolved in methanol (30 ml), tetrahydrofuran (10 ml), followed by the addition of calcium chloride (3.56 g, 32.11 mmol, 4 eq.) to the reaction solution at 0 degrees celsius, and the slow addition of sodium borohydride (1.21 g, 32.11 mmol, 4 eq.) in portions, for 10 hours at 25 degrees celsius. After completion of the reaction, a saturated aqueous ammonium chloride solution (50 ml) was added, extraction was performed with ethyl acetate (50 ml. Times.2), and the organic phase was washed with saturated brine (50 ml. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound C-7.MS-ESI calculated [ M+H ]] ⁺ 294, found 294.

Seventh step

Compound C-7 (200 mg, 679.47 μmol, 1 eq) was dissolved in dichloromethane (2 ml), then triethylamine (103.13 mg, 1.02 mmol, 141.86 μl, 1.5 eq) was added to the reaction solution at 0 degrees celsius, and methylsulfonyl chloride (93.40 g, 815.37 μmol, 63.11 μl, 1.2 eq) was reacted at 20 degrees celsius for 1 hour. After completion of the reaction, an aqueous sodium hydrogencarbonate solution (10 ml) was added, extraction was performed with methylene chloride (5 ml. Times.2), and the organic phase was washed with saturated brine (5 ml. Times.2), dried over anhydrous sodium sulfate, filtered and concentrated to give compound C-8.MS-ESI calculated [ M+H ] ] ⁺ 372, found 372.

Eighth step

Compound C-8 (240 mg, 644.41 micromolar, 1 eq.) and C-9 (107.78 mg, 644.41 micromolar, 1 eq.) were dissolved in acetonitrile (5 ml), then N, N-diisopropylethylamine (124.93 mg, 966.61 micromolar, 168.37 μl, 1.5 eq.) was added to the reaction solution and reacted at 20 degrees celsius for 10 hours. After completion of the reaction, a saturated aqueous sodium sulfite solution (10 ml) was added, extraction was performed with methylene chloride (25 ml×2), and the organic phase was washed with saturated brine (25 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by thin layer chromatography on silica gel (petroleum ether: ethyl acetate=2:1, volume ratio) to give compound C-10.MS-ESI calculated [ M+H ]] ⁺ 444, found 444.

Ninth step

Ammonium phosphomolybdate hydrate (355.32 mg, 189.37 μmol, 0.4 eq) and hydrogen peroxide (536.77 mg, 4.73 mmol, 454.89 μl, 30% purity, 10 eq) were reacted at 20 degrees celsius for 0.5 hours, then ethanol (4 ml) solution of compound C-10, dichloromethane (2 ml) was added to the reaction solution, and then reacted at 20 degrees celsius for 2 hours. After completion of the reaction, a saturated aqueous sodium sulfite solution ((10 ml), extraction with dichloromethane (25 ml. Times.2) and washing of the organic phase with saturated brine (25 ml. Times.2) were added, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated ] ⁺ 476, found 476.

Tenth step

Compound C-11 (200 mg, 420.54. Mu. Mol, 1 eq.) was dissolved in tetrahydrofuran (4 ml), lithium diisopropylamide (2 mol per liter, 420.54. Mu.l, 2 eq.) was added under nitrogen at 0℃and after half an hour of reaction, N-fluorobis-benzenesulfonamide (172.40 mg, 546.70. Mu. Mol, 1.3 eq.) was added and the reaction solution was stirred at 20℃for 1 hour. After completion of the reaction, the mixture was quenched with saturated aqueous ammonium chloride (10 ml), extracted with ethyl acetate (20 ml. Times.2), and the organic phase was washed with saturated brine (10 ml. Times.2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by thin layer chromatography on silica gel (petroleum ether: ethyl acetate=2:1) to give compound C-12.MS-ESI calculated [ M+H ]] ⁺ 494, found 494.

Eleventh step

Compound C-12 (490 mg, 992.77 μmol, 1.2 eq), compound B (473.718 mg, 827.30 μmol, 1 eq) and hexamethylphosphoric triamide (222.38 mg, 1.24 mmol, 1.5 eq) were dissolved in tetrahydrofuran (10 ml), lithium bis (trimethylsilyl) amide (1 mol per liter, 1.24 ml, 1.5 eq) was added under a nitrogen blanket at 0 degrees, and stirring was continued for 1 hour at 0 degrees. After completion of the reaction, the mixture was quenched with saturated ammonium chloride solution (30 ml), extracted with ethyl acetate (30 ml. Times.2), and the organic phase was washed with saturated brine (30 ml. Times.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 luna C: 150 x 40 mm x 15 μm; mobile phase: mobile phase a: 0.1% volume fraction aqueous trifluoroacetic acid; mobile phase B: acetonitrile; B%:47% -77%,11 min) to give compound C (retention time 1.151 min) and compound D (retention time 1.128 min).

Compound C: MS-ESI calculated [ M+H ]] ⁺ 850, found 850. ¹ H NMR(400MHz,CD ₃ OD)δppm 8.42(s,1H),8.02(dd,1H),7.67(dd,1H),7.37-7.56(m,4H),7.29(dd,1H),7.19(s,1H),4.60(s,2H),4.05(s,3H),3.98(s,3H),3.90(s,2H),3.64-3.71(m,2H),3.49-3.52(m,1H),3.27(br d,2H),2.75(br t,2H),1.49(s,9H),0.89(s,9H),0.08(s,6H).

Compound D: MS-ESI calculated [ M+H ]] ⁺ 850, found 850. ¹ H NMR(400MHz,CD ₃ OD)δppm 8.24-8.35(m,1H),7.58(dd,1H),7.44(t,1H),7.30(dd,1H),7.13-7.21(m,3H),6.62-6.74(m,2H),4.35(s,2H),3.96(s,3H),3.82(s,2H),3.62(s,3H),3.55(br s,2H),3.41-3.47(m,2H),3.19(br d,2H),2.56-2.63(m,2H),1.47(s,3H),1.38(s,9H),0.80(s,9H),0.00(s,6H).

Compound E

First step

Compound E-1 (1.99 g, 7.34 mmol, 3 eq) and triphenylphosphine (1.92 g, 7.34 mmol, 3 eq) were dissolved in tetrahydrofuran (50 ml) and reacted under nitrogen protection at 20 degrees celsius for 15 minutes, then compound B (1.4 g, 2.45 mmol, 1 eq) and diethyl zinc (1 mol per liter, 7.34 ml, 3 eq) were added to the reaction solution and reacted under nitrogen protection at 20 degrees celsius for 2 hours. After completion of the reaction, the reaction was quenched by addition of methanol (10 ml), and the residue concentrated under reduced pressure was purified by silica gel column chromatography (petroleum ether: ethyl acetate=40:1 to 3:1) to give a esterified productCompound E-2.MS-ESI calculated [ M+H ]] ⁺ 668, measured 668.

Second step

Compound E-2 (500 mg, 749.05 μmol, 1 eq) and compound E-3 (402.34 mg, 1.12 mmol, 1.5 eq) were dissolved in dioxane (10 ml), nitrogen displaced 3 times, and then stirred under nitrogen for 4 hours at 65 degrees celsius, potassium acetate (220.54 mg, 2.25 mmol, 3 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (109.62 mg, 149.81 μmol, 0.2 eq). After the reaction is finished, the reaction solution is filtered and concentrated to obtain a crude compound E-4.MS-ESI calculated [ M+H ] ] ⁺ 766, found 766.

Third step

Compound E-4 (100 mg, 130.44 micromolar, 1 eq) and compound E-5 (33.57 mg, 195.66 micromolar, 1.5 eq) were dissolved in dioxane (2 ml), water (0.2 ml), nitrogen displaced 3 times, then stirred under nitrogen atmosphere at 70 degrees celsius for 4 hours, potassium phosphate (83.07 mg, 391.32 micromolar, 3 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (19.09 mg, 26.09 micromolar, 0.2 eq). After the reaction is finished, the reaction solution is filtered and concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: phenomenex luna C: 150 x 40 mm x 15 microns; mobile phase: mobile phase A: formic acid aqueous solution with volume fraction of 0.225%, mobile phase B: acetonitrile; B%:37% -67%,10 minutes) to obtain compound E. MS-ESI calculated [ M+H ]] ⁺ 723, found 723.

¹ H NMR(400MHz,CD ₃ OD)δ＝10.49-8.59(m,1H),8.45-8.42(m,1H),7.71-7.67(m,1H),7.57-7.53(m,1H),7.44-7.39(m,1H),7.35-7.15(m,4H),6.98-6.79(m,2H),4.22(br s,2H),4.09-4.06(m,3H),3.90-3.84(m,3H),3.69(d,J＝1.8Hz,2H),3.65(br s,2H),1.61(s,3H),0.92(s,9H),0.13(s,6H)。

Compound F

First step

Compound a-3 (5 g, 23.04 mmol, 1 eq.) and F-1 (3.42 g, 27.65 mmol, 1.2 eq.) were dissolved in dichloromethane (60 ml), then di-N, N-diisopropylethylamine (8.93 g, 69.12 mmol, 12.04 ml, 3 eq.) was added dropwise to the reaction solution and reacted at 25 degrees celsius for 30 minutes. Sodium borohydride acetate (7.32 g, 34.56 mmol, 1.5 eq.) was added to the reaction. The reaction was continued at 25 degrees celsius for 1 hour.

After the completion of the reaction, the mixture was concentrated under reduced pressure, water (60 ml) was added, ethyl acetate was extracted (100 ml. Times.3), the combined organic phases were washed with saturated aqueous saline (100 ml. Times.2), the organic phases were dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by silica gel column chromatography (methanol: dichloromethane=0 to 1:4). Compound F-2 is obtained. MS-ESI calculated [ M+H ]] ⁺ 288, found 288.

Second step

Compound F-2 was dissolved in dichloromethane (60 ml), and t-butyldimethylchlorosilane (5.86 g, 38.87 mmol, 4.76 ml, 3.5 eq.) and imidazole (3.78 g, 55.53 mmol, 5 eq.) were added. The reaction was carried out at 25℃for 10 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure, water (60 ml) was added, ethyl acetate was extracted (100 ml. Times.3), the combined organic phases were washed with saturated aqueous saline (100 ml. Times.2), the organic phases were dried over anhydrous sodium sulfate, filtered, and the crude product concentrated under reduced pressure was purified by silica gel column chromatography (methanol: dichloromethane=0 to 1:10) to give compound F-3.MS-ESI calculated [ M+H ]] ⁺ 402, measured 402.

Third step

Compound F-3 (2.1 g, 5.22 mmol, 1 eq.) and compound B-5 (2.97 g, 7.83 mmol, 1.5 eq.) potassium carbonate (1.44 g, 10.44 mmol, 2 eq.) dichloro [1,1' -bis (diphenylphosphine) ferrocene ]Palladium (381.86 mg, 521.87. Mu. Mol, 0.1 equivalent) was dispersed in a mixed solvent of dioxane (20 ml), water (5 ml), and nitrogen was replaced 3 times. The reaction was continued at 65 degrees celsius for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, water (30 ml) was added, ethyl acetate was extracted (60 ml. Times.3), and the combined organic phases were washed with saturated aqueous saline (50 ml. Times.2),the organic phase was dried over anhydrous sodium sulfate, filtered, and the crude concentrated under reduced pressure was purified by column chromatography on silica gel (methanol: dichloromethane=0 to 1:10) to give compound F-4.MS-ESI calculated [ M+H ]] ⁺ 574, the actual measurement 574.

Fourth step

Compound F-4 (1.7 g, 2.96 mg, 1 eq) was dissolved in dichloromethane (20 ml), and dess-martin reagent (2.51 g, 5.92 mmol, 2 eq) was added to the system. The reaction was continued at 25 degrees celsius for 2 hours. After the reaction was completed, a saturated sodium sulfite solution (20 ml) was added, and saturated sodium bicarbonate (30 ml) was quenched. Extraction with dichloromethane (30 ml×3), washing the combined organic phases with saturated aqueous saline (30 ml×2), drying the organic phases with anhydrous sodium sulfate, filtering, purifying the crude product concentrated under reduced pressure by column chromatography on silica gel (methanol: dichloromethane=0-1:10) to give the compound F-5.Ms-ESI calculated [ m+h ] ⁺ 572, measured value 572.

Fifth step

Compound F-5 (150 mg, 261.96 μmol, 1 eq.) and compound C-12 (168.08 mg, 340.55 μmol, 1.3 eq.) were added to tetrahydrofuran (3 ml), and the reaction mixture was reacted at 20 degrees celsius under nitrogen for 2 hours. After the reaction was completed, the mixture was filtered, quenched with saturated ammonium chloride solution (5 ml), extracted with ethyl acetate (5 ml. Times.2), the combined organic phases were washed with saturated brine solution (5 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product which was separated by high performance liquid chromatography (column: phenomenex luna C: 250 x 50 mm. Times.15 μm; mobile phase: mobile phase A: aqueous formic acid; mobile phase B: acetonitrile; B%:57% -87%,10 minutes) to give compound F. MS-ESI calculated [ M+H ]] ⁺ 850, found 850.1H NMR (400 MHz, CD) ₃ OD)δ＝8.45(s,1H),8.04–8.02(m,1H),7.68–7.67(m,1H),7.55–7.54(m,1H),7.46–7.43(m,3H),7.30–7.25(m,1H),7.20(s,1H),4.60(s,3H),4.30(s,2H),4.08(s,3H),4.04–3.97(m,5H),3.76–3.68(m,5H),2.95–2.85(m,1H),2.76–2.74(m,2H),1.49(s,9H),0.96(s,9H),0.13(s,6H).

Compound G

First step

Compound B-4 (200 mg, 602.37 μmol, 1 eq.) was dissolved in 1, 2-dichloroethane (5 ml), manganese dioxide (523.68 mg, 6.02 mmol, 10 eq.) was added to the reaction solution and stirred at 90 degrees celsius for 12 hours. After the reaction, the reaction solution was filtered and concentrated to give Compound G-1. ¹ H NMR(400MHz,CDCl ₃ )δ＝10.49(s,1H),7.95-7.91(m,1H),7.68-7.63(m,1H),7.42(m,2H),7.15(m,2H)。

Second step

Compound G-1 (200 mg, 606.05 μmol, 1 eq) and compound C-12 (239.30 mg, 484.84 μmol, 0.8 eq) were dissolved in tetrahydrofuran (10 ml), and 1.0 mol of lithium bis (trimethylsilyl) amide per liter of tetrahydrofuran solution (1.82 ml, 3 eq) was added dropwise to the reaction solution at 0 degrees celsius, followed by stirring at 0 degrees celsius for 1 hour. After the reaction, adding saturated ammonium chloride solution (10 ml), extracting with ethyl acetate (10 ml×2), washing the organic phase with saturated saline (10 ml×2), drying with anhydrous sodium sulfate, filtering, separating the concentrated residue by high performance liquid chromatography (chromatographic column: phenomenex luna C18:150:40 mm×15 μm; mobile phase: mobile phase A: formic acid aqueous solution; mobile phase B: acetonitrile; B%:80% -100%,10 min), and purifying to obtain compound G-2.MS-ESI calculated [ M+H ]] ⁺ 609, found 609. ¹ H NMR(400MHz,CDCl ₃ )δ＝8.03-7.97(m,1H),7.72-7.66(m,1H),7.60-7.46(m,1H),7.41-7.35(m,1H),7.26-7.19(m,2H),7.19-7.15(m,1H),7.05-7.00(m,1H),4.67(s,2H),3.95(s,3H),3.68(br t,J＝5.6Hz,2H),2.76(br t,J＝5.4Hz,2H),1.50(s,9H)。

Third step

Compound G-2 (1.5G, 2.47 mmol, 1 eq.) was dissolved in dichloromethane (25 mmol)Liter), an ethyl acetate solution of hydrogen chloride (4 mol/liter, 15 ml, 24.33 eq.) was added and stirred at 25 degrees celsius for 0.25 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure, diluted with methylene chloride (20 ml), adjusted to pH 8 with saturated sodium hydrogencarbonate solution, extracted with methylene chloride (20 ml. Times.2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound G-3.MS-ESI calculated [ M+H ] ] ⁺ 509, found 509.

Fourth step

Compound G-3 (1.2G, 2.36 mmol, 1 eq.) is dissolved in dichloromethane (20 ml), compound G-4 (907.60 mg, 7.08 mmol, 3 eq.) is added, after stirring for 0.5 hours sodium triacetoxyborohydride (2.00G, 9.44 mmol, 4 eq.) is added and stirring is carried out at 25 ℃ for 1 hour. After the completion of the reaction, water (30 ml) was added to quench, methylene chloride (30 ml) was diluted, the pH was adjusted to 8 with saturated sodium hydrogen carbonate solution, methylene chloride (30 ml. Times.2) was extracted, the organic phase was washed with saturated brine (30 ml. Times.2), dried over anhydrous sodium sulfate, filtered, and the concentrated residue was added to methanol (40 ml) and stirred for 30 minutes, followed by filtration to give compound G. MS-ESI calculated [ M+H ]] ⁺ 621, measured 621. ¹ H NMR(400MHz,CDCl ₃ )δ＝8.04-7.95(m,1H),7.73-7.65(m,1H),7.51-7.33(m,2H),7.26-7.12(m,3H),7.04-6.96(m,1H),3.97-3.90(m,3H),3.79-3.73(m,2H),3.71-3.62(m,3H),2.88-2.84(m,2H),2.83-2.70(m,4H),1.36-1.22(m,2H),0.95-0.87(m,2H)。

Example 1

First step

Compound C (50 mg, 58.76. Mu. Mol, 1 eq.) was dissolved in dichloromethane (2 ml) and hydrogen chloride was addedEthyl acetate solution (4 moles per liter, 73.45 microliters, 5 equivalents), stirred at 20 degrees celsius for 0.1 hour. After the reaction, the reaction solution was concentrated to obtain hydrochloride of Compound 1-1. MS-ESI calculated [ M+H ]] ⁺ 636, found 636.

Second step

Compound 1-1 (hydrochloride, 50 mg, 74.29 micromolar, 1 eq) and compound 1-2 (25.90 mg, 148.59 micromolar, 28.31 μl, 2 eq) were dissolved in methanol (1 ml) and N, N-diisopropylethylamine (9.60 mg, 74.29 micromolar, 12.94 μl, 1 eq) and sodium cyanoborohydride (11.67 mg, 185.73 micromolar, 2.5 eq) were added and reacted at 20 degrees celsius for 2 hours. After the reaction, the reaction mixture was concentrated by filtration, and the crude product was purified by silica gel thin layer chromatography (dichloromethane: methanol=10:1, volume ratio) to give compounds 1 to 3.MS-ESI calculated [ M+H ] ] ⁺ 794, found 794.

Third step

Compounds 1-3 (35 mg, 44.03. Mu. Mol, 1 eq.) were dissolved in methanol (0.1 ml) and an ethyl acetate solution of hydrogen chloride (4 mol per liter, 55.04. Mu.l, 5 eq.) was added and stirred at 20℃for 0.5 hours. After the reaction is finished, the reaction solution is filtered and concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: shim-pack C18 is 150 x 25 x 10 microns; mobile phase: mobile phase A: formic acid aqueous solution with volume fraction of 0.225%, mobile phase B: acetonitrile; B%:12% -42%,10 minutes) to obtain formate of the compound 1. MS-ESI calculated [ M+H ]] ⁺ 680, measured 680. ¹ H NMR(400MHz,CD ₃ OD)δppm 8.49(s,2H),8.06(dd,1H),7.71(dd,1H),7.43-7.60(m,4H),7.31(dd,1H),7.24(s,1H),4.52(s,2H),4.09-4.16(m,5H),4.02(s,3H),3.90-3.99(m,4H),3.78-3.89(m,2H),2.98-3.09(m,2H),2.70-2.97(m,4H),1.57(s,3H)

Example 2

First step

The compound is 1 to 1%Hydrochloride, 280 mg, 416.05 μmol, 1 eq) and compound 2-1 (123.21 mg, 832.09 μmol, 92.64 μmol, 50% purity, 2 eq) were dissolved in methanol (2 ml) and N, N-diisopropylethylamine (53.77 mg, 416.05 μmol, 72.47 μmol, 1 eq) and sodium cyanoborohydride (65.36 mg, 1.04 mmol, 2.5 eq) were added and reacted at 20 degrees celsius for 2 hours. After the reaction is finished, the reaction solution is concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: phenomenex luna C: 150 x 40 mm x 15 microns; mobile phase: mobile phase A: formic acid aqueous solution with volume fraction of 0.225%, mobile phase B: acetonitrile; B%:15% -45%,10 minutes) to obtain formate of the compound 2. MS-ESI calculated [ M+H ] ] ⁺ 694, found 694. ¹ H NMR(400MHz,CD ₃ OD)δppm 8.47(s,1H),8.43(s,1H),8.03(dd,1H),7.68(dd,1H),7.41-7.59(m,4H),7.26-7.32(m,2H),4.51(s,2H),4.38(s,2H),4.08-4.14(m,5H),4.02(s,3H),3.95(br d,2H),3.73(s,2H),3.51(br t,2H),3.03(br t,2H),1.55(s,3H)

Example 3

First step

Compound 2 (formate salt, 51.02 mg, 67.51 μmol, 98% purity, 1 eq) was dissolved in N, N-dimethylformamide (2 ml), then ammonium chloride (18.06 mg, 337.56 μmol, 5 eq), N-diisopropylethylamine (17.45 mg, 135.03 μmol, 23.52 μl, 2 eq) and O- (7-azabenzotriazol-1-yl) -N, N-tetramethylurea hexafluorophosphine salt (51.34 mg, 135.03 μmol, 2 eq) were added and reacted at 20 degrees celsius for 2 hours. After the reaction is finished, the reaction solution is concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: phenomenex luna C: 150 x 40 mm x 15 μm; mobile phase: mobile phase A: formic acid aqueous solution with volume fraction of 0.225%, mobile phase B: acetonitrile; B%:12% -42%,10 minutes) to obtain formate of the compound 3. MS-ESI calculated [ M+H ]] ⁺ 693, found 693. ¹ H NMR(400MHz,CD ₃ OD)δppm 8.49(s,1H),8.28-8.38(m,1H),8.03(dd,1H),7.69(dd,1H),7.40-7.58(m,4H),7.29(dd,1H),7.19(s,1H),4.65(s,2H),4.26(br d,2H),4.08-4.16(m,5H),3.99(s,3H),3.79(s,2H),3.26(s,2H),2.78-2.94(m,4H),1.57(s,3H)

Example 4

First step

Compound D (65 mg, 76.39 μmol, 1 eq) was dissolved in dichloromethane (2 ml) and a solution of hydrogen chloride in ethyl acetate (4 mol per liter, 95.49 μmol, 5 eq) was added and stirred at 20 degrees celsius for 0.1 hour. After the reaction, the reaction solution was concentrated to obtain hydrochloride of Compound 4-1. MS-ESI calculated [ M+H ] ] ⁺ 636, found 636.

Second step

Compound 4-1 (hydrochloride, 70 mg, 88.92 micromolar, 1 eq) and compound 1-2 (31 mg, 177.83 micromolar, 33.88 μl, 2 eq) were dissolved in methanol (1 ml) and N, N-diisopropylethylamine (11.49 mg, 88.92 micromolar, 15.49 μl, 1 eq) and sodium cyanoborohydride (13.97 mg, 222.29 micromolar, 2.5 eq) were added and reacted at 20 degrees celsius for 2 hours. After the reaction, the reaction mixture was concentrated by filtration, and the crude product was purified by silica gel thin layer chromatography (dichloromethane: methanol=10:1, volume ratio) to give compound 4-2.MS-ESI calculated [ M+H ]] ⁺ 794, found 794.

Third step

Compound 4-2 (30 mg, 37.74 μmol, 1 eq) was dissolved in methanol (0.5 ml), and an ethyl acetate solution of hydrogen chloride (4 mol per liter, 47.18 μmol, 5 eq) was added and stirred at 20 degrees celsius for 0.5 hours. After the reaction is finished, the reaction solution is concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: shim-pack C18 is 150 x 25 x 10 microns; mobile phase: mobile phase A: formic acid aqueous solution with volume fraction of 0.225%, mobile phase B: acetonitrile; B%:10% -40%,10 minutes) to obtain formate of the compound 4. MS-ESI calculationValue [ M+H ]] ⁺ 680, measured 680. ¹ H NMR(400MHz,CD ₃ OD)δppm 8.47(s,2H),7.69(dd,1H),7.56(t,1H),7.41(dd,1H),7.22-7.31(m,3H),6.69-6.91(m,2H),4.64(s,2H),4.26(br d,2H),4.06-4.15(m,5H),3.85-3.92(m,2H),3.80-3.85(m,2H),3.73(s,3H),3.12(br t,2H),2.96(br t,2H),2.85(br t,2H),1.58(s,3H)

Example 5

First step

Compound 4-1 (hydrochloride, 70 mg, 104.01 micromolar, 1 eq) and compound 2-1 (30.80 mg, 208.02 micromolar, 23.16 μl, 50% purity, 2 eq) were dissolved in methanol (1 ml) and N, N-diisopropylethylamine (13.44 mg, 104.01 micromolar, 18.12 μl, 1 eq) and sodium cyanoborohydride (16.34 mg, 260.03 micromolar, 2.5 eq) were added and reacted at 20 degrees celsius for 2 hours. After the reaction is finished, the reaction solution is concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: phenomenex luna C: 150 x 25 mm x 10 microns; mobile phase: mobile phase A: formic acid aqueous solution with volume fraction of 0.225%, mobile phase B: acetonitrile; B%:11% -44%,11 minutes) to obtain formate of the compound 5. MS-ESI calculated [ M+H ]] ⁺ 694, found 694. ¹ H NMR(400MHz,CD ₃ OD)δppm 8.46(s,1H),8.44(s,1H),7.68(dd,1H),7.55(t,1H),7.41(dd,1H),7.25-7.32(m,3H),6.91(s,1H),6.73-6.84(m,1H),4.55(s,2H),4.16(br d,2H),4.10(s,5H),3.96-4.02(m,2H),3.79(s,3H),3.61(s,2H),3.38(br t,2H),2.94(br t,2H),1.56(s,3H)。

Example 6

First step

Compound 6-1 (4 g, 16.43 mmol, 1 eq.) and compound 6-2 (2.53 g, 16.43 mmol, 1 eq.) are dissolved in tert-butanol (40 ml) and water (40 ml) with tetra-triphenylphosphine palladium (1.9 g, 1.64 mmol, 0.1 eq.). The reaction solution was reacted at 90℃for 2 hours under nitrogen protection. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with saturated brine (50 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate=20:1) to give compound 6-3.MS-ESI calculated [ M+H ] ] ⁺ 191, found 191. ¹ H NMR(400MHz,CDCl ₃ )δ＝9.14–9.13(m,1H),8.31-8.29(m,1H),8.01-8.00(m,1H),7.54–7.52(m,1H),6.88-6.80(m,1H),6.07–6.02(m,1H),5.61–5.57(m,1H).

Second step

Compound 6-3 (2 g, 10.49 mmol, 1 eq) and compound 6-4 (2.05 g, 11.02 mmol, 1.05 eq) were dissolved in isopropanol (40 ml), purged with nitrogen, and methanesulfonic acid (1.06 g, 11.06 mmol, 1.05 eq) was added. The reaction solution was reacted at 90℃for 3 hours under nitrogen protection. After the reaction, adding water (100 ml) for quenching, adjusting pH to 8 with sodium bicarbonate solid, filtering, concentrating the filtrate to obtain a crude product, and separating and purifying by high performance chromatography (chromatographic column: welch Ultimate XB-CN 250 x 70 x 10 microns; mobile phase: mobile phase A:0.1% ammonia ethanol solution; mobile phase B: n-hexane; B%:1% -30%,12 minutes) to obtain the compound 6-5.MS-ESI calculated [ M+H ]] ⁺ 340, measured 340. ¹ H NMR(400MHz,CDCl ₃ )δ＝8.99(s,1H),8.85-8.84(m,1H),8.27–8.22(m,1H),8.01-8.00(m,1H),7.89–7.88(m,1H),7.31–7.29(m,1H),7.19–7.07(m,1H),6.94–6.92(m,1H),6.82–6.77(m,1H),6.01–5.96(m,1H),5.53–5.50(m,1H),2.48(s,3H).

Third step

Compound 6-5 (2.9 g, 8.52 mmol, 1 eq.) was dissolved in dioxane (65 ml) and water (20 ml), cooled to zero degrees, and a solution of osmium tetroxide (108.35 mg, 426.20 μmol, 0.05 eq.) in dioxane (20 ml), sodium periodate (9.12 g, 42.62 mmol, 5 eq.) was added. The reaction solution was reacted at 20℃for 1 hour under nitrogen protection. After the reaction, an aqueous sodium bicarbonate solution was added to adjust ph=8, an aqueous sodium sulfite solution (80 ml) was added, and the mixture was stirred at 20 ℃ for half an hour, followed by extraction with ethyl acetate (100 ml×2). The organic phase was washed with saturated brine (100 ml. Times.2), dried over anhydrous sodium sulfate, filtered and concentrated to give Compound 6-6.MS-ESI calculated [ M+H ] ] ⁺ 342, the actual measurement 342.

Fourth step

Compound 6-6 (2.6 g, 7.60 mmol, 1 eq.) and compound 6-7 (1.32 g, 15.20 mmol, 2 eq.) were dissolved in dichloromethane (30 ml) and acetic acid (684.42 mg, 11.40 mmol, 1.5 eq.) and sodium borohydride acetate (4.03 g, 19.00 mmol, 2.5 eq.) were added. The reaction solution was reacted at 20℃for 1 hour. After the reaction was completed, ph=8 was adjusted with sodium bicarbonate solid, diluted with water (20 ml) and extracted with dichloromethane (70 ml). The organic phase was washed with saturated brine (100 ml×2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to give crude product which was purified by silica gel column chromatography (ethyl acetate: methanol=50:1) to give compounds 6-8.MS-ESI calculated [ M+H ]] ⁺ 415, measured 415.

Fifth step

Compound 6-8 (50 mg, 120.97. Mu. Mol, 1 eq.) was dissolved in dioxane (2 ml), and dipyridyl borate (61.44 mg, 241.95. Mu. Mol, 2 eq.) was added to potassium acetate (35.62 mg, 362.92. Mu. Mol, 3 eq.) (2-dicyclohexylphosphine-2, 4, 6-triisopropyl-1, 1-biphenyl) [2- (2-amino-1, 1-biphenyl)]Palladium mesylate (20.48 mg, 24.19 μmol, 0.2 eq). The reaction solution was reacted at 90℃for 3 hours under nitrogen protection. After the completion of the reaction, the reaction mixture was filtered, and the filtrate was diluted with water (20 ml) and extracted with ethyl acetate (20 ml×3). The organic phases were combined and washed with saturated brine (20 ml. Times.2), dried over anhydrous sodium sulfate Drying, filtering and concentrating to obtain the compound 6-9.MS-ESI calculated [ M+H ]] ⁺ 461, found 461.

Sixth step

Compound C-12 (1.2 g, 2.43 mmol) was dissolved in dichloromethane (12 ml), trifluoroacetic acid (6.16 g, 4 ml) was added, and the reaction solution was reacted at room temperature at 25℃for 0.5 hours. After the reaction, concentrating. To obtain the trifluoroacetate salt of the crude compound 6-10.

MS-ESI calculated [ M+H ]] ⁺ 394, found 394.

Seventh step

Compound 6-10 (1.23 g, 2.42 mmol, trifluoroacetic acid) was dissolved in methanol (12 ml), N-diisopropylethylamine (313.25 mg, 2.42 μmol) and compound 1-2 (1.06 g, 6.06 mmol) were added, and after stirring for half an hour, sodium cyanoborohydride (456.94 mg, 7.27 mmol) was added, and the reaction solution was reacted at room temperature for 2 hours. After the reaction was completed, it was diluted with water (50 ml) and extracted with methylene chloride (50×3 ml). The organic phase was washed with saturated brine (50×2 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated by chromatography on silica gel (petroleum ether: ethyl acetate=8:1) to give compounds 6-11.MS-ESI calculated [ M+H ]] ⁺ 552, found 552. ¹ H NMR(400MHz,CDCl ₃ )δ＝8.19-8.24(m,1H)7.97(d,J＝7.70Hz,1H)7.52-7.64(m,2H)6.91-6.96(m,1H)6.42-6.60(m,1H)3.78(s,5H)3.50-3.68(m,2H)2.56-2.88(m,6H)1.41-1.63(m,1H)0.83(s,9H)-0.02-0.02(m,6H).

Eighth step

Compound 6-11 (250 mg, 453.09 μmol) and compound 6-12 (99.44 mg, 453.09 μmol) were dissolved in tetrahydrofuran solution (3 ml), hexamethylphosphoric triamide (121.79 mg, 679.63 μmol) was added, and lithium bis (trimethylsilylamide) (1 mol per liter, 679.63 μmol) was slowly added dropwise under nitrogen protection and reacted at 20 ℃ for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (30 ml), diluted with ethyl acetate (30 ml) and extracted with water 30 ml (15 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. High performance liquid chromatography of the crude product (chromatographic column: phenomenex Gemini-NX C18, 75X 30 mm X3. Mu.m, mobile phase: mobile phase A: 0.225% formic acid aqueous solution by volume fraction; mobile phase B: acetonitrile; B%:35% -65%,7 minutes) to obtain compound 6-13.MS-ESI calculated [ M+H ]] ⁺ 557, found 557. ¹ H NMR(400MHz,CDCl ₃ )δ＝7.78-7.83(m,1H)7.50-7.55(m,1H)7.25-7.37(m,1H)7.14(t,J＝7.95Hz,1H)7.04(s,1H)3.80-3.88(m,5H)3.70-3.78(m,2H)2.77-2.87(m,2H)2.70(br t,J＝5.56Hz,4H)0.83(s,9H)0.00(s,6H).

Ninth step

Compound 6-13 (50 mg, 89.93 μmol) was dissolved in dioxane solution (3 ml) and water (0.58 ml), compound 6-9 (34.50 mg, 74.94 μmol) and sodium carbonate (15.89 mg, 149.89 μmol) were added, and finally tetrakis (triphenylphosphine) palladium (8.66 mg, 7.49 μmol) was added, and reacted at 100 ℃ for 4 hours under nitrogen, after the reaction was completed, diluted with water (20 ml) and extracted with ethyl acetate (20×3 ml). The organic phase was washed with saturated brine (20×2 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by thin layer chromatography on silica gel (dichloromethane: methanol=10:1) to give compounds 6-14.

MS-ESI calculated [ M+H ]] ⁺ 809, found 809.

Tenth step

Compounds 6 to 14 (50 mg, 61.77. Mu. Mol) were dissolved in dichloromethane (3 ml), trifluoroacetic acid (7.04 mg, 4.57. Mu.l) was added, and the reaction mixture was reacted at room temperature at 25℃for 16 hours, and after completion of the reaction, concentrated. The crude product is separated by high performance liquid chromatography (chromatographic column: phenomenex Gemini-NX C18X 30 mm X3 μm, mobile phase: mobile phase A: formic acid aqueous solution with volume fraction of 0.225%, mobile phase B: acetonitrile, B%:5% -35%,7 min) to obtain formate of compound 6. MS-ESI calculated [ M+H ] ] ⁺ 695, found 695. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.94-8.98(m,1H)8.37-8.45(m,1H)8.26-8.30(m,1H)8.14-8.18(m,1H)7.97-8.05(m,2H)7.43-7.63(m,2H)7.37(t,J＝7.83Hz,1H)7.32(d,J＝7.46Hz,1H)7.25-7.28(m,1H)7.11-7.15(m,1H)7.01-7.05(m,1H)4.12-4.18(m,2H)4.03(s,3H)3.91(t,J＝5.50Hz,2H)3.55-3.67(m,1H)2.95-3.36(m,10H)2.22-2.34(m,1H)2.12-2.18(m,3H)1.89-1.97(m,1H)1.29-1.35(m,1H)1.12-1.25(m,1H).

Example 7

First step

Compound 7-1 (2 g, 11.52 mmol, 1 eq.) was dissolved in dichloromethane (20 ml) and methanesulfonyl chloride (2.91 g, 25.40 mmol, 2.2 eq.) was added to the reaction solution at 25 degrees celsius, and N, N-diisopropylethylamine (2.98 g, 23.04 mmol, 2 eq.) was reacted for 2 hours at 25 degrees celsius. After the completion of the reaction, a saturated aqueous sodium hydrogencarbonate solution (30 ml) was added, extraction was performed with methylene chloride (150 ml), the organic phase was washed with a saturated sodium chloride solution (30×2 ml), and dried over anhydrous sodium sulfate to obtain crude compound 7-2.MS-ESI calculated [ M+H ]] ⁺ 252, found 252.

Second step

Compound 7-2 (3.6 g, 14.30 mmol, 1 eq) and N, N-diisopropylethylamine (2.77 g, 21.46 mmol, 1.5 eq) were dissolved in acetonitrile (40 ml), compound 7-3 (3.76 g, 21.46 mmol, 1.5 eq) was added to the reaction solution, the reaction was carried out at 30 degrees celsius for 12 hours with nitrogen substitution, after the reaction was completed, concentrated, water (10 ml) was added, ethyl acetate (30 x 3 ml) was extracted, the organic phase was washed with saturated sodium chloride solution (20 x 2 ml), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude compound 7-4.MS-ESI calculated [ M+H ] ] ⁺ 331, measured 331.

Third step

Compound 7-4 (5 g, 15.11 mmol, 1 eq.) was dissolved in dichloromethane (50 ml) and reversedDi-tert-butyl dicarbonate (4.95 g, 22.66 mmol, 1.5 eq.) and N, N-diisopropylethylamine (2.93 g, 22.66 mmol, 1.5 eq.) were added to the reaction solution, the reaction mixture was stirred at 30℃for 12 hours, after completion of the reaction, concentrated, and water (10 ml) and ethyl acetate (50X 3 ml) were added. The combined organic phases were dried over saturated sodium chloride solution (30×2 ml) washed with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:0 to 10:1) to give compound 7-5.MS-ESI calculated [ M+H ]] ⁺ 432, found 432.

Fourth step

Compound 7-5 (2.88 g, 6.68 mmol, 1 eq.) was dissolved in dioxane (20 ml), H2O (10 ml), compound 6-2 (1.54 g, 10.02 mmol, 1 eq.) sodium carbonate (2.12 g, 20.04 mmol, 3 eq.) and tetrakis triphenylphosphine palladium (386.04 mg, 334.08 μmol, 0.05 eq.) were added to the reaction solution, the reaction mixture was stirred at 30 degrees celsius for 2 hours with nitrogen substitution, after completion of the reaction, concentrated in ethyl acetate (50 x3 ml), extracted with water (10 ml), the organic phase was washed with saturated brine (30 x2 ml), dried over anhydrous sodium sulfate, and chromatographed over silica gel column (petroleum ether: ethyl acetate=1:0 to 10:1) to give compound 7-6.MS-ESI calculated [ M+H ] ] ⁺ 423, measured 423.

Fifth step

Compound 7-6 (2 g, 4.73 mmol, 1 eq.) was dissolved in dichloromethane (30 ml), ozone was added to the reaction solution at-78 ℃ until the reaction solution turned blue, then sodium borohydride (820 mg, 21.68 mmol, 4.58 eq.) was added to the reaction solution, the reaction mixture was stirred at 25 ℃ for 2 hours with nitrogen substitution, after completion of the reaction, ethyl acetate (50 x3 ml) was added by concentration, water (20 ml) was extracted, the organic phase was washed with saturated brine (30 x2 ml), dried over anhydrous sodium sulfate, and concentrated by silica gel column chromatography (petroleum ether: ethyl acetate=1:0 to 10:1) to give compound 7-7.MS-ESI calculated [ M+H ]] ⁺ 427, found 427.

Sixth step

Compounds 7-7 (350 mg, 820.40. Mu. Mol, 1 eq.) were dissolved in dichloromethaneTo the reaction solution (10 ml) was added methanesulfonyl chloride (260 mg, 2.27 mmol, 2.77 eq.) at 25 degrees celsius, and N, N-diisopropylethylamine (212.06 mg, 1.64 mmol, 2 eq.) and reacted at 25 degrees celsius for 2 hours. After the completion of the reaction, a saturated aqueous sodium hydrogencarbonate solution (10 ml) was added, extraction was performed with methylene chloride (20×3 ml), the organic phase was washed with a saturated aqueous sodium chloride solution (10×2 ml), and dried over anhydrous sodium sulfate to give crude compound 7-8.MS-ESI calculated [ M+H ] ] ⁺ 505, found 505.

Seventh step

Compound 7-8 (400 mg, 792.53 μmol, 1 eq.) was dissolved in acetonitrile (5 ml), compound C-9 (132.55 mg, 792.53 μmol, 1 eq.) and N, N-diisopropylethylamine (204.85 mg, 1.59 mmol, 2 eq.) were added to the reaction solution and reacted at 25 degrees celsius for 12 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 ml) was added, extraction was performed with dichloromethane (20×3 ml), the organic phase was washed with saturated sodium chloride solution (10×2 ml), dried over anhydrous sodium sulfate and spin-dried, and then subjected to silica gel column chromatography (petroleum ether: ethyl acetate=1:0 to 50:1) to obtain compound 7-9.MS-ESI calculated [ M+H ]] ⁺ 576, the actual value 576.

Eighth step

Compound 7-9 (340 mg, 590.42 μmol, 1 eq.) was dissolved in dichloromethane (5 ml), ethanol (10 ml), hydrogen peroxide (800 mg, 7.06 mmol, purity: 30%,11.95 eq.) was added to the reaction solution, and phosphomolybdic acid amine tetrahydrate (443.14 mg, 236.17 mmol, 0.4 eq.) was reacted at 25 ℃ for 12.5 hours. After the completion of the reaction, a saturated aqueous sodium sulfite solution (20 ml) was added, extraction was performed with methylene chloride (30×3 ml), the organic phase was washed with a saturated sodium chloride solution (20×2 ml), and dried over anhydrous sodium sulfate to give crude compound 7-10.MS-ESI calculated [ M+H ] ] ⁺ 494, found 494.

Ninth step

Compounds 7 to 10 (359.27 mg, 727.86. Mu. Mol, 1 eq.) were dissolved in dichloromethane (10 ml) and imidazole (99.10 mg, 1.46 mmol, 2 eq.) was added to the reaction solution, tert-butylDimethylchlorosilane (329.11 mg, 2.18 mmol, 3 eq.) was reacted at 25 degrees celsius for 2 hours. After the completion of the reaction, an aqueous solution (10 ml) was added, extraction was performed with methylene chloride (20×3 ml), the organic phase was washed with a saturated sodium chloride solution (10×2 ml), dried over anhydrous sodium sulfate and spin-dried, and crude compound 7-11 was obtained by silica gel column chromatography (petroleum ether: ethyl acetate=1:0 to 5:1). MS-ESI calculated [ M+H ]] ⁺ 608, measured 608.

Tenth step

Compounds 7-11 (529.12 mg, 870.47. Mu. Mol, 1 eq.) were dissolved in tetrahydrofuran (10 ml), lithium hexamethyldisilazide (1 mol/l, 1.31 ml, 1.5 eq.) was added to the reaction solution at zero degrees Celsius, and N-fluorobiphenyl sulfonamide (411.74 mg, 1.31 mmol, 1.5 eq.) was added at 20 degrees Celsius and reacted for 1 hour at 20 degrees Celsius. After the completion of the reaction, an aqueous solution (10 ml) was added, extraction was performed with ethyl acetate (30×3 ml), the organic phase was washed with a saturated sodium chloride solution (20×2 ml), dried over anhydrous sodium sulfate and spin-dried, and crude compound 7-12 was obtained by silica gel column chromatography (petroleum ether: ethyl acetate=1:0 to 5:1). MS-ESI calculated [ M+H ] ] ⁺ 626, found 626.

Eleventh step

Compounds 7 to 12 (190 mg, 303.59. Mu. Mol, 1 eq.) were dissolved in tetrahydrofuran (10 ml), compound B (173.83 mg, 303.59. Mu. Mol, 1 eq.) was added to the reaction solution, lithium hexamethyl-silica amide (1 mol/l, 455.38. Mu.l, 1.5 eq.), hexamethylphosphoric triamide (81.60 mg, 455.38. Mu. Mol, 80. Mu.l, 1.5 eq.) and nitrogen substitution were reacted at 25℃for 2 hours. After the completion of the reaction, an aqueous solution (10 ml) was added, extraction was performed with methylene chloride (30×3 ml), the organic phase was dried over saturated brine (20×2 ml) and dried over anhydrous sodium sulfate, and the compound 7-13 was obtained by silica gel column chromatography (petroleum ether: ethyl acetate=1:0 to 0:1). MS-ESI calculated [ M+H ]] ⁺ 984, found 984.

Twelfth step

Compounds 7 to 13 (300 mg, 305.13. Mu. Mol, 1 eq.) were dissolved in methanol (10 ml), and an ethyl acetate solution of hydrogen chloride (4 mol) was added to the reaction solutionPer liter, 381.41 microliters, 5 equivalents), the reaction mixture was stirred for 2 hours at 25 degrees celsius with nitrogen substitution, after completion of the reaction, concentrated under reduced pressure, purified by high performance liquid chromatography (column: phenomenex Gemini-NX C18 75 x 30 mm x3 microns; mobile phase: mobile phase a: 0.225% formic acid aqueous solution by volume fraction; mobile phase B: acetonitrile; 13% -33% of B% and 10 minutes) to obtain formate of the compound 7. MS-ESI calculated [ M+H ] ] ⁺ 655, measured 655. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.54(s,1H),8.45(s,1H),8.06(d,J＝8.00Hz,1H),7.70(M,1H)7.53-7.67(m,2H),7.41-7.52(m,2H),7.39(s,1H),7.31(d,J＝7.38Hz,1H),6.88(s,1H),4.22(s,2H),4.10(s,3H),3.96-4.04(m,5H),3.83(m,2H),3.76(t,J＝5.44Hz,2H),3.62(m,2H),2.90(t,J＝5.32Hz,2H),1.53(s,3H)。

Example 8

First step

Compound E (60 mg, 82.90 micromolar, 1 eq) and compound 8-1 (21.42 mg, 16.81 micromolar, 2 eq) were dissolved in dichloromethane (1 ml) and sodium borohydride acetate (43.93 mg, 207.26 micromolar, 2.5 eq) was added and reacted for 2 hours at 15 degrees celsius. After the reaction is finished, the reaction solution is filtered and concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: 3_Phenomenex Luna C18 75*30 mm 3 microns; mobile phase: mobile phase A: 0.05% hydrogen chloride aqueous solution by volume fraction; mobile phase B: acetonitrile; B%:33% -53%,7 minutes) to obtain the compound 8-2.MS-ESI calculated [ M+H ]] ⁺ 836, measured 836.

Second step

Compound 8-2 (10 mg, 11.95. Mu. Mol, 1 eq.) was dissolved in dichloromethane (1 ml) and ethyl acetate as hydrogen chloride was addedThe ester solution (4 moles per liter, 59.74 microliters, 20 equivalents) was stirred at 20 degrees celsius for 0.1 hour. After the reaction is finished, the reaction solution is filtered and concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: phenomenex luna C: 150 x 25 mm x 10 microns; mobile phase: mobile phase A: formic acid aqueous solution with volume fraction of 0.2%, mobile phase B: acetonitrile; B%:22% -52%,12 minutes) to obtain compound 8.MS-ESI calculated [ M+H ] ] ⁺ 722, actual measurement 722. ¹ H NMR(400MHz,DMSO-d ₆ )δppm 8.35(s,1H),8.20(s,1H),7.67(dd,1H),7.56(t,1H),7.26-7.43(m,4H),6.74-6.97(m,2H),3.93(s,3H),3.86(s,2H),3.68(s,3H),3.41(br d,4H),3.23(br d,2H),2.65-2.68(m,2H),2.30-2.34(m,1H),1.90-2.00(m,2H),1.62-1.71(m,2H),1.39-1.51(m,2H),1.34(s,3H).

Example 9

First step

Compound E (50 mg, 69.09 micromolar, 1 eq) and compound 9-1 (8.44 mg, 138.17 micromolar, 8.36 μl, 2 eq) were dissolved in dichloromethane (1 ml) and sodium borohydride acetate (36.61 mg, 172.72 micromolar, 2.5 eq) was added and reacted for 2 hours at 15 degrees celsius. After the reaction, the reaction solution is filtered and concentrated to obtain a crude compound 9-2.MS-ESI calculated [ M+H ]] ⁺ 768, found 768.

Second step

Compound 9-2 (20 mg, 26.01 μmol, 1 eq) was dissolved in dichloromethane (1 ml) and an ethyl acetate solution of hydrogen chloride (4 mol per liter, 130.07 μmol, 20 eq) was added and stirred at 15 degrees celsius for 0.5 hours. After the reaction is finished, the reaction solution is filtered and concentrated, and the crude product is subjected to high performance liquid chromatography (chromatographic column: phenomenex Gemini-NX C18 is 75 mm by 3 microns;mobile phase: mobile phase a: ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; 25% -55% of B percent and 8 minutes) to obtain the formate of the compound 9. MS-ESI calculated [ M+H ]] ⁺ 654, found 654. ¹ H NMR(400MHz,CD ₃ OD)δppm 8.38(s,1H),8.32(s,1H),7.67(dd,1H),7.53(t,1H),7.38(dd,1H),7.20-7.30(m,3H),6.79-6.91(m,2H),4.04(s,3H),3.92(s,2H),3.79(s,2H),3.70(s,3H),3.64(t,2H),3.53(d,2H),3.28(s,2H),2.69(t,2H),1.49(s,3H).

Example 10

First step

Compound E (50 mg, 69.09 micromolar, 1 eq) and compound 10-1 (15.91 mg, 138.18 micromolar, 2 eq) were dissolved in dichloromethane (2 ml) and N, N-diisopropylethylamine (6.99 mg, 69.09 micromolar, 9.76 μl, 1 eq) and sodium borohydride acetate (43.93 mg, 207.27 micromolar, 3 eq) were added and reacted at 30 degrees celsius for 16 hours. After the reaction is finished, the reaction solution is filtered and concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: unisil 3-100C18Ultra 150*50 mm 3 microns; mobile phase: mobile phase A: formic acid aqueous solution with volume fraction of 0.225%, mobile phase B: acetonitrile; B%:25% -55%,10 minutes) to obtain compound 10-2.MS-ESI calculated [ M+H ] ] ⁺ 822, measured 822.

Second step

Compound 10-2 (20 mg, 24.31 μmol, 1 eq.) was dissolved in dichloromethane (2 ml) and a dioxane solution of hydrogen chloride (4 mol per liter, 1 ml) was added and stirred at 25 degrees celsius for 16 hours. After the reaction is finished, the reaction solution is filtered and concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: unisil 3-100C18Ultra 150*50 mm 3 microns; mobile phase: mobile phase A: formic acid aqueous solution with volume fraction of 0.225%, mobile phase B: acetonitrile; B%:10% -40%,10 minutes) to obtain compound 10.MS-ESI calculated [ M+H ]] ⁺ 708, found 708. ¹ H NMR(400MHz,CD ₃ OD)δppm 8.52(s,1H),8.38(d,J＝4.40Hz,2H),7.66(dd,J＝7.64,1.41Hz,1H)7.52(t,J＝7.64Hz,1H)7.32-7.40(m,3H),7.27-7.31(m,1H),6.96(d,J＝11.49Hz,1H),6.78-6.90(m,1H),4.27(s,2H),4.03-4.13(m,5H),3.91(br d,J＝9.78Hz,2H),3.67-3.78(m,5H),3.11-3.23(m,2H),2.92-3.10(m,3H),2.02-2.24(m,2H),1.53(s,3H)。

Example 11

First step

Compound E (50 mg, 69.09 μmol, 1 eq) and compound 11-1 (15.91 mg, 138.18 μmol, 2 eq) were dissolved in dichloromethane (2 ml) and sodium borohydride acetate (43.93 mg, 207.27 μmol, 3 eq) was added and reacted at 30 degrees celsius for 16 hours. After the reaction, the reaction mixture was concentrated by filtration, and the crude product was purified by silica gel thin layer chromatography (dichloromethane: methanol=10:1) to give compound 11-2.MS-ESI calculated [ M+H ]] ⁺ 822, measured 822.

Second step

Compound 11-2 (40 mg, 48.61 μmol, 1 eq.) was dissolved in dichloromethane (2 ml) and a dioxane solution of hydrogen chloride (4 mol per liter, 1 ml) was added and stirred at 25 degrees celsius for 16 hours. After the reaction is finished, the reaction solution is filtered and concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: unisil 3-100C18Ultra 150*50 mm 3 microns; mobile phase: mobile phase A: formic acid aqueous solution with volume fraction of 0.225%, mobile phase B: acetonitrile; B%:10% -40%,10 minutes) to obtain formate of the compound 11. MS-ESI calculated [ M+H ] ] ⁺ 708, found 708. ¹ H NMR(400MHz,CD ₃ OD)δppm 8.52(br s,1H),8.41(d,J＝5.75Hz,2H),7.67(dd,J＝7.64,1.53Hz,1H),7.53(t,J＝7.64Hz,1H),7.39(dd,J＝7.58,1.59Hz,1H),7.24-7.32(m,3H),7.03(d,J＝4.03Hz,1H),6.81-6.93(m,1H),4.25-4.45(m,2H),4.14(br d,J＝5.14Hz,2H),4.06(s,3H),3.83(d,J＝2.45Hz,4H),3.75(br t,J＝7.76Hz,2H),3.54(br t,J＝8.07Hz,3H),3.12(td,J＝5.23,1.41Hz,1H),2.34-2.52(m,1H),2.01-2.18(m,2H),1.82-1.94(m,1H),1.51(s,3H)。

Example 12

First step

Compound E (50 mg, 69.09 micromolar, 1 eq) and compound 12-1 (20.81 mg, 138.18 micromolar, 2 eq) were dissolved in dichloromethane (2 ml) and N, N-diisopropylethylamine (6.99 mg, 69.09 micromolar, 9.76 μl, 1 eq) and sodium borohydride acetate (43.93 mg, 207.27 micromolar, 3 eq) were added and reacted at 30 degrees celsius for 16 hours. After the reaction, the reaction mixture was concentrated by filtration, and the crude product was purified by silica gel thin layer chromatography (dichloromethane: methanol=10:1) to give compound 12-2.MS-ESI calculated [ M+H ]] ⁺ 821, measured 821.

Second step

Compound 12-2 (45 mg, 54.75 μmol, 1 eq.) was dissolved in dioxane (2 ml), and a dioxane solution of hydrogen chloride (4 mol per liter, 1 ml) was added and stirred at 25 degrees celsius for 0.2 hours. After the reaction is finished, the reaction solution is filtered and concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: unisil 3-100C18Ultra 150*50 mm 3 microns; mobile phase: mobile phase A: formic acid aqueous solution with volume fraction of 0.225%, mobile phase B: acetonitrile; B%:8% -38%,10 minutes) to obtain formate of compound 12. MS-ESI calculated [ M+H ]] ⁺ 707, the actual measurement 707. ¹ H NMR(400MHz,CD ₃ OD)δppm 8.46(s,1H),8.44(br s,1H),8.34(s,1H),7.68(dd,J＝7.65,1.63Hz,1H),7.55(t,J＝7.65Hz,1H),7.40(dd,J＝7.59,1.69Hz,1H),7.21-7.32(m,3H),6.95(s,1H),6.84(d,J＝19.70Hz,1H),4.56(s,2H),4.17(d,J＝10.79Hz,2H),4.10(s,3H),4.00(br d,J＝10.79Hz,2H),3.79-3.91(m,3H),3.74(s,3H),2.64-2.84(m,2H),2.20-2.36(m,3H),1.69-1.90(m,1H),1.56(s,3H)。

Example 13

First step

Compound E (50 mg, 69.09 micromolar, 1 eq) and compound 13-1 (17.08 mg, 138.18 micromolar, 2 eq) were dissolved in dichloromethane (2 ml) and N, N-diisopropylethylamine (8.93 mg, 69.09 micromolar, 12.03 μl, 1 eq) and sodium borohydride acetate (43.93 mg, 207.27 micromolar, 3 eq) were added and reacted at 30 degrees celsius for 16 hours. After the reaction, the reaction mixture was concentrated by filtration, and the crude product was purified by silica gel thin layer chromatography (dichloromethane: methanol=10:1) to give compound 13-2.MS-ESI calculated [ M+H ]] ⁺ 794, found 794.

Second step

Compound 13-2 (45 mg, 56.61 μmol, 1 eq.) was dissolved in dichloromethane (2 ml), and a dioxane solution of hydrogen chloride (4 mol per liter, 1 ml) was added and stirred at 25 degrees celsius for 16 hours. After the reaction is finished, the reaction solution is filtered and concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: unisil 3-100C18Ultra 150*50 mm 3 microns; mobile phase: mobile phase A: formic acid aqueous solution with volume fraction of 0.225%, mobile phase B: acetonitrile; B%:10% -40%,10 minutes) to obtain formate of the compound 13. MS-ESI calculated [ M+H ]] ⁺ 680, measured 680. ¹ H NMR(400MHz,CD ₃ OD)δppm 8.50(br s,1H),8.43(s,1H)8.38(s,1H),7.68(dd,J＝7.78,1.63Hz,1H),7.54(t,J＝7.72Hz,1H),7.40(dd,J＝7.59,1.57Hz,1H),7.24-7.34(m,3H),6.98(s,1H),6.85 (d,J＝19.70Hz,1H),4.31-4.46(m,3H),4.08(s,3H),3.91-4.01(m,4H),3.71-3.83(m,5H),3.01-3.13(m,2H),2.73-2.94(m,2H),2.17(dd,J＝13.93,7.03Hz,1H),1.77-1.90(m,1H),1.54(s,3H).

Example 14

First step

Compound E-4 (500 mg, 652.19 micromolar, 1 eq) and compound 14-1 (214.28 mg, 978.29 micromolar, 1.5 eq) potassium phosphate (415.31 mg, 1.96 mmol, 3 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (95.44 mg, 130.44 micromolar, 0.2 eq) were dissolved in dioxane (10 ml), water (1 ml), nitrogen displaced 3 times, and then stirred under nitrogen atmosphere at 70 degrees celsius for 4 hours. After the reaction is finished, the reaction solution is filtered and concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: phenomenex Synergi C: 150 x 25 mm x 10 micrometers; mobile phase: mobile phase A: formic acid aqueous solution with volume fraction of 0.1%, mobile phase B: acetonitrile; B%:51% -81%,10 minutes) to obtain the compound 14-2.MS-ESI calculated [ M+H ]] ⁺ 726, measured 726. ¹ H NMR(400MHz,CD ₃ OD)δppm 8.45(s,1H),8.29(s,1H),7.67(dd,1H),7.54(t,1H),7.34-7.41(m,3H),7.19-7.32(m,1H),6.70-6.90(m,1H),4.65(s,2H),4.36-4.45(m,2H),4.08(s,3H),4.01-4.06(m,2H),3.85(br dd,2H),3.48(s,3H),1.63(s,3H),0.93(s,9H),0.14(s,6H).

Second step

Compound 14-2 (30 mg, 41.28 μmol, 1 eq.) was dissolved in 1, 2-dichloroethane (3 ml), followed by manganese dioxide (35.89 mg, 412.8 μmol, 10 eq.) and the reaction was allowed to react at 80 ℃ for 2 hours. After the completion of the reaction, the reaction solution was filtered and concentrated to give crude compound 14-3.MS-ESI calculated [ M+H ]] ⁺ 724, found 724.

Third step

Compound 14-3 (30 mg, 41.40 micromolar, 1 eq) was dissolved in dichloromethane (3 ml), then 9-1 (5.06 mg 82.79 micromolar, 2 eq) was added to the reaction solution, and sodium borohydride acetate (26.32 mg, 124.19 micromolar, 3 eq) was reacted at 25 degrees celsius for 16 hours. After the reaction, the reaction mixture was concentrated by filtration, and the crude product was purified by silica gel thin layer chromatography (petroleum ether: ethyl acetate: ethanol=4:3:1) to give compound 14-4.MS-ESI calculated [ M+H ] ] ⁺ 769, found 769.

Fourth step

Compound 14-4(16 mg, 20.78. Mu. Mol, 1 eq.) in dichloromethane (1 ml) was added hydrogen chloride in dioxane (4 mol per liter, 1 ml) and stirred at 25℃for 0.2 h. After the reaction is finished, the reaction solution is filtered and concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: phenomenex Synergi C: 150 x 25 mm x 10 micrometers; mobile phase: mobile phase A: formic acid aqueous solution with volume fraction of 0.225%, mobile phase B: acetonitrile; B%:8% -38%,10 minutes) to obtain formate of the compound 14. MS-ESI calculated [ M+H ]] ⁺ 655, measured 655. ¹ H NMR(400MHz,CD ₃ OD)δppm 8.46(br s,1H),8.44(s,1H),8.38(s,1H),7.68(dd,J＝7.70,1.59Hz,1H),7.55(t,J＝7.64Hz,1H),7.32-7.45(m,3H),7.23-7.32(m,1H),6.81-6.92(m,1H),4.49(s,2H),4.31(s,2H),4.09(s,5H),3.92(br d,J＝10.51Hz,2H),3.78-3.87(m,2H),3.52(s,3H),3.11-3.26(m,2H),1.55(s,3H).

Example 15

First step

Compound 15-1 (2 g, 9.92 mmol, 1 eq.) was dissolved in tetrahydrofuran (15 ml), methanol (3 ml), lithium borohydride (648.30 mg, 29.76 mmol, 3 eq.) was added to the reaction solution at 25 degrees celsius, and the reaction was allowed to proceed for 12 hours at 25 degrees celsius with nitrogen substitution. After the completion of the reaction, a saturated aqueous ammonium chloride solution (30 ml), water (30 ml), dichloromethane extraction (30 ml) and extraction were added, and the organic phase was washed with a saturated aqueous sodium chloride solution (15 ml. Times.2), dried over anhydrous sodium sulfate and spun-dried to obtain a crude compound 15-2.MS-ESI calculated [ M+H ] ] ⁺ 174, found 174.

Second step

Compound 15-2 (1 g, 5.76 mmol, 1 eq.) and N, N-diisopropylethylamine (1.12 g, 8.64 mmol, 1.5 eq.) were dissolved in dichloromethane (15 ml), methanesulfonyl chloride (989.79 mg, 8.64 mmol, 1.5 eq.) was added to the reaction mixture, and the mixture was reacted at 25℃for 12 hours with nitrogen substitutionAfter that, a saturated solution of sodium hydrogencarbonate (30 ml) was added to the reaction solution, water (30 ml) was added, dichloromethane (30 ml) was extracted, and the organic phase was washed with a saturated sodium chloride solution (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude compound 15-3.MS-ESI calculated [ M+H ]] ⁺ 252, found 252.

Third step

Compound 15-3 (1.4 g, 5.56 mmol, 1 eq) was dissolved in acetonitrile (60 ml), compound 15-4 (2.05 g, 11.68 mmol, 2.1 eq), N-diisopropylethylamine (1.08 g, 8.34 mmol, 1.5 eq) was added to the reaction solution, the reaction mixture was stirred under nitrogen for 12 hours at 25 degrees celsius, after completion of the reaction, concentrated, water (10 ml) was added, and dichloromethane was extracted (10 ml). The combined organic phases were dried over saturated sodium chloride solution (10 ml) washed with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography on silica gel (petroleum ether: ethyl acetate=0:1 to dichloromethane: methanol=5:1) to give compound 15-5.MS-ESI calculated [ M+H ] ] ⁺ 331, measured 331.

Fourth step

Compound 15-5 (1 g, 3.02 mmol, 1 eq.) was dissolved in dichloromethane (20 ml), di-tert-butyl dicarbonate (989.26 mg, 4.53 mmol, 1.5 eq.) was added to the reaction solution, the reaction mixture was stirred for 12 hours at 25 degrees celsius under nitrogen protection, after the reaction was completed, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate=20:1 to 20:1) to obtain compound 15-6.MS-ESI calculated [ M+H ]] ⁺ 431, measured value 431.

Fifth step

Compound 15-6 (84.34 mg, 195.66. Mu. Mol, 1 eq.) was dissolved in dioxane (3 ml), H2O (1 ml), compound E-4 (150 mg, 195.66. Mu. Mol, 1 eq.) was added to the reaction solution, potassium phosphate (124.59 mg, 586.97. Mu. Mol, 3 eq.), 1-bis (diphenylphosphorus) ferrocene palladium chloride (28.63 mg, 39.13. Mu. Mol, 0.2 eq.) was added, the reaction mixture was stirred for 6 hours at 70℃with nitrogen substitution, and after the reaction was completed, the mixture was concentratedDichloromethane (30 ml) was added dropwise, water (30 ml) was extracted, the organic phase was dried over anhydrous sodium sulfate, and concentrated on a silica gel thin layer chromatography plate (dichloromethane: methanol=20:1) to give compounds 15-7.MS-ESI calculated [ M+H ] ] ⁺ 984, found 984.

Sixth step

Compound 15-7 (40 mg, 40.68 μmol, 1 eq) was dissolved in ethyl acetate (10 ml), ethyl acetate solution of hydrogen chloride (4 mol/l, 101.71 μmol, 10 eq) was added to the reaction solution, the reaction mixture was stirred for 6 hours at 25 ℃ with nitrogen substitution, after completion of the reaction, concentrated under reduced pressure, and subjected to high performance liquid chromatography (column: phenomenex Gemini-NX C18 x 30 mm x 3 μm; mobile phase: mobile phase a: 0.225% formic acid aqueous solution by volume; mobile phase B: acetonitrile; B%:12% -42%,7 minutes) to obtain formate of compound 15. MS-ESI calculated [ M+H ]] ⁺ 655, measured 655. ¹ HNMR(400MHz,CD ₃ OD)δ＝8.48(s,1H),7.70(m,1H),7.57(s,1H),7.46(s,1H),7.32(s,3H),7.08(s,1H),6.80-6.94(m,2H),4.69(s,2H),4.27-4.35(m,4H),4.08-4.18(m,5H),3.75-3.87(m,5H),3.12(m,2H),1.59(s,3H)。

Example 16

First step

Compound F (1.1 g, 1.29 mmol) was dissolved in dichloromethane (10 ml), and an ethyl acetate solution of hydrogen chloride (4 mol/l, 10 ml) was added thereto, followed by stirring at room temperature for 0.5 hours. After the reaction, the reaction solution was concentrated. The hydrochloride salt of compound 16-1 was obtained.

MS-ESI calculated [ M+H ]] ⁺ 636, found 636.

Second step

Compound 16-1 (hydrochloride, 60 mg, 89.15. Mu. Mol) was dissolved in methylene chloride (4 ml), N-diisopropylethylamine (23.04 mg, 178.31. Mu. Mol) was added, after stirring at room temperature for 0.5 hours, compound 16-2 (19.63 mg, 178.31. Mu. Mol) was added, and after stirring at room temperature for 0.5 hours, sodium triacetoxyborohydride (56.69 mg, 267.61. Mu. Mol) was added, and the reaction was carried out at room temperature for 12 hours. After the reaction, the reaction solution is diluted with dichloromethane (10 ml), filtered and concentrated to obtain crude product, which is separated by high performance liquid chromatography (chromatographic column: phenomenex luna C: 150 x 25 mm x 10 μm; mobile phase: mobile phase A: formic acid aqueous solution; mobile phase B: acetonitrile; B%:9% -39%,10 min) to obtain formate of compound 16. MS-ESI calculated [ m+h ] +730, found 730.1H NMR (400 mhz, METHANOL-d 4) delta = 2.36-2.42 (m, 3H), 2.79-2.83 (m, 2H), 2.84-2.89 (m, 2H), 3.01-3.09 (m, 1H), 3.68-3.72 (m, 2H), 3.72-3.79 (m, 4H), 3.96-4.00 (m, 3H), 4.00-4.15 (m, 5H), 4.17-4.34 (m, 2H), 4.56 (br s, 2H), 6.98-7.05 (m, 1H), 7.16-7.22 (m, 1H), 7.25-7.33 (m, 1H), 7.38-7.50 (m, 3H), 7.52-7.60 (m, 1H), 7.66-7.72 (m, 1H), 7.99-4.34 (m, 2H), 4.56 (br s, 2H), 7.25-7.33 (m, 1H), 8.43-8.53 (m, 2H).

Example 17

First step

Compound 16-1 (hydrochloride, 60 mg, 89.15 μmol) was dissolved in ethanol (3 ml), compound 17-1 (32.14 mg, 445.76 μmol) and potassium carbonate (36.97 mg, 267.46 μmol) were added, and the reaction solution was placed in a lock tube and heated to 110 degrees celsius for reaction for 0.5 hours with microwaves. After the reaction is finished, the reaction solution is filtered, and the crude product obtained by concentration is separated by high performance liquid chromatography (chromatographic column: phenomenex luna C: 150 x 25 mm x 10 micrometers; mobile phase: mobile phase A: formic acid aqueous solution; mobile phase B: acetonitrile; B%:7% -37%,10 minutes) to obtain formate of the compound 17. MS-ESI calculated [ m+h ] +708, found 708.1H NMR (400 mhz, METHANOL-d 4) delta = 1.20-1.28 (m, 6H), 2.46-2.59 (m, 2H), 2.75-2.83 (m, 3H), 2.89-2.95 (m, 2H), 3.44 (brt, J = 7.40hz, 2H), 3.65-3.70 (m, 2H), 3.71-3.76 (m, 2H), 3.80-3.85 (m, 2H), 3.95-3.99 (m, 3H), 4.01-4.04 (m, 2H), 4.06 (s, 2H), 4.05-4.07 (m, 1H), 7.13-7.19 (m, 1H), 7.24-7.31 (m, 1H), 7.38-7.49 (m, 3H), 7.52-7.56 (m, 1H), 7.65-7.70 (m, 8.8.8-8.8 (m, 8.8H), 8.8-8.8 (m, 8.8H).

Example 18

First step

Compound 16-1 (70.00 mg, 104.01 μmol, 1 eq) and compound 18-1 (29.38 mg, 156.02 μmol, 1.5 eq) were dissolved in dichloromethane (2 ml), then N, N-diisopropylethylamine (13.44 mg, 104.01 μmol, 1 eq), sodium triacetoxyborohydride (66.13 mg, 312.03 μmol, 3 eq) were added to the reaction solution and reacted at 25 degrees celsius for 2 hours. After completion of the reaction, water (5 ml) was added, extraction was performed with methylene chloride (10 ml×3), the organic phase was washed with saturated brine (10 ml×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the crude product was purified by silica gel thin layer chromatography (methylene chloride: methanol=10:1) to give compound 18-2.MS-ESI calculated [ M+H ] ] ⁺ 808, found 808.

Second step

Compound 18-2 (80.00 mg, 98.90 μmol, 1 eq.) was dissolved in ethyl acetate (2 ml), followed by addition of an ethyl acetate solution of hydrogen chloride (24.73 μl, 98.90 μmol, 1 eq.) to the reaction solution at 25 degrees celsius, and reaction at 25 degrees celsius for 0.5 hours. After completion of the reaction, water (6 ml) was added, dichloromethane extraction (10 ml×3), and the organic phase was washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is separated by high performance liquid chromatography (chromatographic column: 3_Phenomenex Luna C18 150*25 mm. Times.5 μm; mobile phase: mobile phase A: aqueous ammonia bicarbonate solution; mobile phase B: acetonitrile; B%:46% -76%,9 min) to obtain formate of compound 18. MS-ESI calculated [ M+H ]] ⁺ 694, found 694. ¹ HNMR(400MHz,CD ₃ OD)δ＝8.43-8.40(m,1H)8.06(d,J＝1.50Hz,1H)8.07-8.02(m,1H)7.72-7.66(m,1H)7.44-7.41(m,1H)7.58-7.41(m,1H)7.31(dd,J＝7.57,1.56Hz,1H)7.21(s,1H)4.09-4.05(m,3H)4.00(s,3H)3.91-3.86(m,2H)3.74(s,2H)3.70-3.66(m,4H)3.61(t,J＝7.88Hz,2H)3.31-3.26(m,1H)2.84(s,4H)2.76-2.68(m,3H)2.05(s,6H)1.92-1.3(m,2H)1.33-1.28(m,1H).

Example 19

First step

Compound 16-1 (hydrochloride, 200 mg, 297.18 micromoles) was dissolved in methylene chloride (4 ml), N-diisopropylethylamine (76.82 mg, 594.35 micromoles) was added, and after stirring at room temperature for 0.5 hours, compound G-4 (19.63 mg, 178.31 micromoles) was added, and after stirring at room temperature for 1 hour, sodium triacetoxyborohydride (188.95 mg, 891.53 micromoles) was added, and the reaction was carried out at room temperature for 0.5 hours. After the completion of the reaction, the reaction mixture was quenched with water (10 ml), diluted with dichloromethane (5 ml), extracted with dichloromethane (10 ml×2), the combined organic phases were washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentration was purified by silica gel thin layer chromatography (dichloromethane: methanol=10:1) to obtain compound 19-1.MS-ESI calculated [ M+H ] ] ⁺ 747, found 747.

Second step

Compound 19-1 (25 mg, 33.39 micromolar) was dissolved in methanol (2 ml) and water (0.2 ml), lithium hydroxide (1.2 mg, 50.09 micromolar) was added, and reacted at room temperature for 13 hours. After the reaction, the reaction solution is quenched with acetic acid (0.1 ml), filtered and concentrated to obtain a crude product, and the crude product is separated by high performance liquid chromatography (chromatographic column: waters Xbridge 150 x 25 mm x 5 μm; mobile phase: mobile phase a: ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; B%:33% -63%,10 min) to obtain a compound 19.MS-ESI calculated [ m+h ] +734, found 734.1H NMR (400 mhz, METHANOL-d 4) delta = 0.77-0.83 (m, 2H), 1.26-1.31 (m, 2H), 2.67-2.86 (m, 1H), 2.92-3.03 (m, 2H), 3.16-3.22 (m, 2H), 3.35-3.42 (m, 4H), 3.64-3.73 (m, 4H), 3.95-4.00 (m, 2H), 4.00-4.04 (m, 3H), 4.04-4.08 (m, 3H), 4.15-4.35 (m, 2H), 7.24-7.28 (m, 1H), 7.28-7.32 (m, 1H), 7.39-7.43 (m, 1H), 7.44-7.57 (m, 3H), 7.65-7.70 (m, 1H), 8.01-8.06 (m, 8.38-8.42H).

Example 20

First step

Compound 16-1 (hydrochloride, 100 mg, 148.59 micromolar) was dissolved in dichloromethane (4 ml), N-diisopropylethylamine (38.41 mg, 297.18 micromolar) was added, and after stirring at room temperature for 0.5 hours, compound 20-1 (28.85 mg, 297.18 micromolar) was added, and after stirring at room temperature for 0.5 hours, sodium triacetoxyborohydride (94.48 mg, 445.76 micromolar) was added, and the reaction was carried out at room temperature for 0.5 hours. After the reaction is finished, the reaction solution is filtered, and the crude product obtained by concentration is separated by high performance liquid chromatography (chromatographic column: unisil 3-100C18Ultra 150*50 mm 3 microns; mobile phase: mobile phase A: formic acid aqueous solution; mobile phase B: acetonitrile; B%:6% -36%,10 minutes) to obtain formate of the compound 20. MS-ESI calculated m+h+717, found 717.1H NMR (400 mhz, METHANOL-d 4) delta = 2.76-2.87 (m, 4H), 2.96-3.06 (m, 1H), 3.67-3.71 (m, 2H), 3.72-3.76 (m, 2H), 3.92-3.96 (m, 2H), 3.96-4.02 (m, 5H), 4.08-4.13 (m, 3H), 4.16-4.23 (m, 2H), 4.45-4.51 (m, 2H), 7.15-7.21 (m, 1H), 7.26-7.31 (m, 1H), 7.38-7.50 (m, 3H), 7.51-7.58 (m, 1H), 7.65-7.71 (m, 1H), 7.80-7.86 (m, 1H), 7.99-8.05 (m, 1H), 8.44-8.8.48 (m, 8.50 (m, 1H), 8.55-8.50 (m, 1H).

Example 21

First step

Compound 16-1 (hydrochloride, 80 mg, 118.87 micromoles) was dissolved in methylene chloride (4 ml), N-diisopropylethylamine (30.73 mg, 237.74 micromoles) was added, and after stirring at room temperature for 0.5 hours, compound 21-1 (17.61 mg, 237.74 micromoles) was added, and after stirring at room temperature for 1 hour, sodium triacetoxyborohydride (75.58 mg, 356.61 micromoles) was added, and the reaction was carried out at room temperature for 0.5 hours. After the reaction, the reaction solution was quenched with water (10 ml), diluted with dichloromethane (5 ml), extracted with dichloromethane (10 ml×2), the combined organic phases were washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the concentrated crude product was separated by high performance liquid chromatography (column: phenomenex Luna C: 150×25 mm×10 μm; mobile phase: aqueous formic acid; mobile phase: acetonitrile; B%:11% -41%,10 min) to give formate of compound 21. MS-ESI calculated [ M+H ] +694, found 694.1H NMR (400 mhz, METHANOL-d 4) delta = 1.18-1.33 (m, 3H), 2.87-2.94 (m, 2H), 2.99-3.27 (m, 4H), 3.69-3.95 (m, 4H), 3.98-4.03 (m, 3H), 4.04-4.20 (m, 7H), 4.29-4.38 (m, 2H), 4.60-4.64 (m, 2H), 7.20-7.27 (m, 1H), 7.29-7.34 (m, 1H), 7.44-7.60 (m, 4H), 7.69-7.74 (m, 1H), 8.02-8.09 (m, H), 8.48-8.51 (m, 2H).

Example 22

First step

Compound 19-1 (90 mg, 120.21 micromolar) was dissolved in tetrahydrofuran (5 ml) and lithium aluminum hydride (9.13 mg, 120.21 micromolar) was added at 0 degrees celsius and reacted at room temperature for 1 hour. After the reaction, the reaction solution was quenched with water (10 ml), diluted with tetrahydrofuran (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was separated by high performance liquid chromatography (column Phenomenex luna C: 150 x 25 mm x 10 μm; mobile phase: mobile phase a: aqueous formic acid; mobile phase B: acetonitrile; B%:9% -39%,10 min) to give formate of compound 22. MS-ESI calculated [ M+H ] +720, found 720.1H NMR (400 mhz, METHANOL-d 4) delta = 0.44-0.50 (m, 2H), 0.55-0.60 (m, 2H), 2.60-2.65 (m, 2H), 2.77-2.83 (m, 3H), 2.84-2.89 (m, 2H), 3.47-3.51 (m, 2H), 3.52-3.55 (m, 2H), 3.68 (d, J = 6.11hz, 2H), 3.73-3.79 (m, 4H), 3.97-4.00 (m, 3H), 4.04-4.08 (m, 5H), 7.17-7.21 (m, 1H), 7.27-7.31 (m, 1H), 7.39-7.50 (m, 3H), 7.52-7.56 (m, 1H), 7.65-7.70 (m, 1H), 7.99-8.7.7.7 (m, 8H), 8.45 (m, 8.46-8.46H).

Example 23

First step

Compound 16-1 (100.00 mg, 148.59 μmol, 1 eq) and compound 23-1 (132.26 mg, 742.94 μmol, 5 eq) were dissolved in N, N-dimethylformamide (2 ml), then N, N-diisopropylethylamine (96.02 mg, 742.94 μmol, 5 eq), cesium carbonate (48.41 mg, 148.59 μmol, 1 eq) were added to the reaction solution and reacted at 25 degrees celsius for 2 hours. After the reaction is finished, the reaction solution is filtered and concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: 3_Phenomenex Luna C18 75*30 mm 3 microns; mobile phase: mobile phase A: hydrochloric acid aqueous solution; mobile phase B: acetonitrile; B%:25% -45%,7 minutes) to obtain the hydrochloride of the compound 23. MS-ESI calculated [ M+H ] ] ⁺ 733, found 733. ¹ HNMR(400MHz,CD ₃ OD)δ＝8.51-8.45(m,1H)8.07-8.01(m,1H)7.72-7.68(m,1H)7.63-7.42(m,5H)7.36-7.30(m,2H)4.70(d,J＝9.17Hz,3H)4.50(s,2H)4.44-4.34(m,2H)4.32-4.25(m,1H)4.12-4.10(m,3H)4.07-4.04(m,3H)3.80-3.50(m,11H)3.26-3.19(m,4H)3.19-3.12(m,2H)3.07–2.97(m,1H)2.54-2.28(m,3H)2.00-1.90(m,1H)1.3-1.30(m,1H).

Example 24

First step

Compound 16-1 (100.00 mg, 148.59 μmol, 1 eq.) and compound 24-1 (28.34 mg, 222.88 μmol, 1.5 eq.) were dissolved in dichloromethane (2 ml), then N, N-diisopropylethylamine (19.20 mg, 148.59 μmol, 1 eq.) and sodium triacetoxyborohydride (94.48 mg, 445.76 μmol, 3 eq.) were added to the reaction solution to react at 25 degrees celsius2 hours. After the completion of the reaction, water (2 ml) was added, dichloromethane extraction (5 ml. Times.3) was performed, the organic phase was washed with saturated brine (10 ml. Times.3), dried over anhydrous sodium sulfate, filtered, and separated by high performance liquid chromatography (column: 3_Phenomenex Luna C18 150*50 mm. Times.3 μm; mobile phase: mobile phase A: oxalic acid aqueous solution; mobile phase B: acetonitrile; B%:20% -25%,10 min) to obtain compound 24.MS-ESI calculated [ M+H ]] ⁺ 747, found 747. ¹ HNMR(400MHz,CD ₃ OD)δ＝8.45-8.40(m,1H)8.05-7.99(m,1H)7.71-7.65(m,1H)7.56-7.51(m,1H)7.50-7.45(m,1H)7.44-7.37(m,3H)7.31-7.26(m,1H)7.20-7.15(m,1H)4.11-4.05(m,5H)4.03-4.01(m,2H)4.00–3.97(m,3H)3.83-3.76(m,4H)3.71-3.67(m,2H)3.55-3.47(m,2H)3.35-3.30(m,4H)2.89-2.78(m,5H)2.49-2.44(m,3H).

Example 25

First step

Compound 16-1 (120 mg, 178.31 micromolar, 1 eq) was dissolved in dichloromethane (5 ml), followed by N, N-diisopropylethylamine (23.04 mg, 178.31 micromolar, 1 eq) added after stirring for 0.5 hours, 25-1 (46.41 mg, 356.61 micromolar, 2 eq) added after stirring for 1.5 hours at 25 degrees celsius, and sodium borohydride acetate (113.37 mg, 534.92 micromolar, 3 eq) added after stirring for 10 hours at 25 degrees celsius. After the completion of the reaction, water (20 ml) was added to the residue concentrated under reduced pressure, extraction was performed with ethyl acetate (20 ml×3), the organic phase was washed with saturated brine (20 ml×2), dried over anhydrous sodium sulfate, filtered, and the concentrated crude residue was purified by silica gel thin layer chromatography (dichloromethane: methanol=10:1) to give compound 25-2.MS-ESI calculated [ M+H ] ] ⁺ 752, measured 752.

Second step

Compound 25-2 (59 mg, 72.54 μmol, 1 eq.) was dissolved in methanol (2 ml) water (0.2 ml) followed by addition of lithium hydroxide @2.61 mg, 108.81 micromoles, 1.5 eq) was stirred at 25 degrees celsius for 1 hour. After the reaction, the reaction solution was filtered, and the residue after the concentration of the filtrate under reduced pressure was subjected to preparative high performance liquid chromatography (column: phenomenex Synergi C: 150X 25 mm. Times.5 μm; mobile phase: mobile phase A: aqueous formic acid solution-mobile phase B: acetonitrile: 14% -44%,10 minutes) to obtain compound 25.MS-ESI calculated [ M+H ]] ⁺ 736, measured 736. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.48-8.40(m,1H),8.07-8.00(m,1H),7.72-7.65(m,1H),7.57-7.40(m,4H),7.34-7.26(m,1H),7.20(s,1H),4.33-4.23(m,2H),4.11-4.06(m,3H),4.02-3.93(m,7H),3.79-3.67(m,4H),3.09-3.01(m,2H),2.94-2.79(m,5H),1.22(s,6H).

Example 26

First step

Compound 16-1 (30 mg, 47.13 μmol, 1 eq), 26-1 (13.79 mg, 70.69 μmol, 1.5 eq), potassium carbonate (19.54 mg, 141.39 μmol, 3 eq) was dissolved in acetonitrile (2 ml) and stirred under nitrogen for 12 hours at 50 ℃. After the reaction, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the concentrated residue was separated by preparative high performance liquid chromatography (column: waters Xbridge 150×25 mm×5 μm; mobile phase: mobile phase a: ammonium bicarbonate aqueous solution-mobile phase B: acetonitrile: 23% -53%,8 min) to give compound 26.MS-ESI calculated [ M+H ] ] ⁺ 750, found 750. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.49(s,1H),8.08-8.02(m,1H),7.68(s,1H),7.61-7.54(m,1H),7.52-7.40(m,3H),7.32-7.27(m,1H),7.20-7.15(m,1H),4.98-4.95(m,2H),4.58-4.54(m,4H),4.31-4.21(m,2H),4.12(s,3H),4.10-4.01(m,2H),4.00-3.97(m,3H),3.84-3.79(m,2H),3.73-3.69(m,2H),3.22(s,2H),3.11-2.94(m,1H),2.91-2.83(m,2H),2.82-2.73(m,2H).

Example 27

First step

Compound 16-1 (60 mg, 94.26 micromolar, 1 eq) was dissolved in dichloromethane (2 ml), N-diisopropylethylamine (60.91 mg, 471.30 micromolar, 5 eq) compound 27-1 (27.17 mg, 282.78 micromolar, 3 eq) and sodium triacetylborohydride (59.93 mg, 282.78 micromolar, 3 eq) were added to the reaction solution and stirred at 25 degrees celsius for 2 hours. After the reaction is finished, filtering, concentrating the filtrate under reduced pressure, and separating the crude product by high performance liquid chromatography (chromatographic column: waters Xbridge 150 x 25 mm x 5 μm; mobile phase: mobile phase A: ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; B%:45% -75%,10 min) to obtain compound 27.MS-ESI calculated [ M+H ]] ⁺ 716, actual measurement 716. ¹ HNMR(400MHz,CD ₃ OD)δ＝7.56(s,1H),7.55-7.54(m,1H),7.53(s,1H),7.51-7.50(m,1H),7.50-7.47(m,3H),7.43(s,1H),7.42(s,1H),7.41(s,1H),3.87-4.3.85(m,3H),3.72–3.70(m,3H),3.70(s,2H),3.68-3.67(m,2H),3.64-3.60(m,6H),3.62-3.56(m,2H),3.37–3.35(m,5H)。

Example 28

First step

Compound G-1 (450 mg, 1.36 mmol) and compound 6-11 (752.40 mg, 1.36 mmol) were dissolved in tetrahydrofuran solution (15 ml), hexamethylphosphoric triamide (366.54 mg, 2.05 mmol) was added, and lithium bis (trimethylsilylamide) (1 mol per liter, 2.05 ml) was slowly added dropwise under nitrogen protection to react for 2 hours at 20 ℃. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (40 ml), diluted with ethyl acetate (40 ml) and extracted with water 30 ml (15 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. High performance liquid chromatography (chromatographic column) : phenomenex luna C18, 150×40 mm×15 μm, mobile phase: mobile phase a: 0.225% formic acid aqueous solution by volume fraction; mobile phase B: acetonitrile; 43% -73% of B, 10 minutes) and separating to obtain the compound 28-1.MS-ESI calculated [ M+H ]] ⁺ 667, found 667. ¹ H NMR(400MHz,CDCl ₃ )δ＝8.00-8.05(m,1H)7.71(m,1H)7.43-7.58(m,1H)7.38(t,J＝7.78Hz,1H)7.15-7.27(m,3H)7.02(s,1H)3.95(s,3H)3.85-3.93(m,2H)3.77-3.85(m,2H)2.83-2.90(m,2H)2.73-2.82(m,4H)0.90-0.96(m,9H)0.08-0.12(m,6H).

Second step

Compound 28-1 (330 mg, 495.11 μmol) was dissolved in dioxane solution (3 ml), and duplex pinacol borate (188.59 mg, 742.66 μmol) and potassium acetate (145.77 mg, 1.49 μmol) were added, and finally 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (36.23 mg, 49.51 μmol) was added, followed by reaction at 110 ℃ for 5 hours under nitrogen, and after completion of the reaction, diluted with ethyl acetate (40×2 ml) and extracted with water (40 ml). The organic phase was washed with saturated brine (40 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 28-2 was obtained. MS-ESI calculated [ M+H ]] ⁺ 713.3, found 713.3.

Third step

Compound 28-2 (75 mg, 105.10 μmol) was dissolved in dioxane solution (5 ml) and water (1 ml), compound F-3 (42.29 mg, 105.10 μmol) and potassium carbonate (43.58 mg, 315.30 μmol) were added, and finally 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (7.69 mg, 10.51 μmol) was added, and reacted at 85 ℃ for 4 hours under nitrogen protection, after the reaction was completed, diluted with water (20 ml) and extracted with ethyl acetate (20×2 ml). The organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by thin layer chromatography on silica gel (petroleum ether (ethyl acetate: ethanol) =1:1, ethyl acetate: ethanol=3:1) to give compound 28-3.MS-ESI calculated [ M+H ] ] ⁺ 910.4, found 910.4.

Fourth step

Compound 28-3 (45 mg, 49.50)Micromolar) was dissolved in methanol (5 ml), ethyl hydrogen chloride acetate solution (4 moles per liter, 12.37 μl) was added, and the reaction solution was reacted at room temperature 25 degrees celsius for 0.5 hours. After the reaction, concentrating. The crude product is separated by high performance liquid chromatography (chromatographic column: phenomenex Gemini-NX C18X 30 mm X3 μm, mobile phase: mobile phase A: formic acid aqueous solution with volume fraction of 0.225%, mobile phase B: acetonitrile, B%:12% -42%,7 min) to obtain compound 28.MS-ESI calculated [ M+H ]] ⁺ 680.4, found 680.4. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.41-8.45(m,1H)8.02-8.07(m,1H)7.70(m,1H)7.41-7.59(m,4H)7.31(m,1H)7.21(s,1H)3.98-4.11(m,8H)3.67-3.85(m,8H)3.43-3.52(m,2H)2.75-2.91(m,7H).

Example 29

First step

Compound 29-1 (104.78 mg, 691.18 μmol, 1.5 eq) was dissolved in dichloromethane (4 ml), then potassium carbonate (95.53 mg, 691.18 μmol, 1.5 eq) was added to the reaction solution, the reaction solution was stirred at 0 ℃ for 0.5 hours, then compound a-3 (100 mg, 460.79 μmol, 1 eq) was added, and stirred at 0 ℃ for 0.5 hours, and sodium borohydride acetate (390.64 mg, 1.84 mmol, 4 eq) was added, and the reaction solution was reacted at 0 ℃ for 1 hour. After the completion of the reaction, the reaction solution was filtered and concentrated under reduced pressure. The crude product was separated by high performance liquid chromatography (column: waters Xbridge C18 x 50 mm x 10 microns; mobile phase: mobile phase a: ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; B%:1% -31%,10 min) to give compound 29-2.

Second step

Compound 29-2 (300 mg, 94)8.91 micromoles, 1 eq) in dichloromethane (4 ml) followed by adding a solution of trimethylsilyl diazomethane in n-hexane (2 moles/liter, 1.42 ml, 3 eq) to the reaction at 0 degrees celsius and stirring the reaction at 25 degrees celsius for 1 hour. After completion of the reaction, the reaction was quenched with water (20 ml) at 25 ℃, extracted with dichloromethane (15 ml×2), and the organic phase was washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by thin layer chromatography on silica gel (petroleum ether: ethyl acetate=2:3) to give compound 29-3.MS-ESI calculated [ M+H ]] ⁺ 330, the actual measurement 330. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.25-8.21(m,1H),4.03-4.00(m,3H),3.81-3.78(m,2H),3.77-3.71(m,5H),3.33(s,2H),1.58-1.49(m,3H)。

Third step

Compound 28-2 (100 mg, 140.14 micromolar, 1 eq) was dissolved in dioxane (6 ml) and water (1.5 ml), compound 29-3 (46.27 mg, 140.14 micromolar, 1 eq), potassium carbonate (58.10 mg, 420.41 micromolar, 3 eq), bis (triphenylphosphine) palladium dichloride (9.84 mg, 14.01 micromolar, 0.1 eq), replaced three times with nitrogen and stirred at 70 degrees celsius for 3 hours. After the reaction was completed, the reaction solution was filtered, concentrated, and the crude product was purified by silica gel thin layer chromatography (dichloromethane: methanol=10:1) to give compound 29-4.MS-ESI calculated [ M+H ] ] ⁺ 836, measured 836.

Fourth step step by step

Compound 29-4 (40 mg, 47.80 μmol, 1 eq) was dissolved in dichloromethane (2 ml), and an ethyl acetate solution of hydrogen chloride (4 mol/l, 2 ml, 167.38 eq) was added and stirred at 15 degrees celsius for 0.5 hours. After the reaction, the mixture was concentrated under reduced pressure to give hydrochloride of Compound 29-5. MS-ESI calculated [ M+H ]] ⁺ 722, actual measurement 722.

Fifth step

Compound 29-5 (40 mg, 59.28. Mu. Mol, 1 eq., hydrochloride) was dissolved in methanol (2 ml), tetrahydrofuran (1 ml) and water (0.3 ml), and lithium hydroxide (28.39 mg, 1.19 mmol, 20 eq.) was added to the reaction solution, followed byStirring was carried out at 60℃for 1 hour. After the reaction, the pH is regulated to 7 by acetic acid, the mixture is filtered, and the crude product obtained by concentrating the filtrate under reduced pressure is separated by high performance liquid chromatography (chromatographic column: waters Xbridge 150 x 25 mm x 5 μm; mobile phase: mobile phase A: ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; B%:32% -62%,8 minutes) to obtain the compound 29.MS-ESI calculated [ M+H ]] ⁺ 708, found 708. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.50-8.44(m,1H),8.06-7.99(m,1H),7.72-7.66(m,1H),7.57-7.42(m,4H),7.32-7.28(m,1H),7.27-7.23(m,1H),4.70-4.62(m,2H),4.53-4.44(m,2H),4.17-4.13(m,2H),4.12-4.05(m,5H),4.03-3.99(m,3H),3.93-3.86(m,2H),3.30-3.22(m,2H),3.14-3.07(m,2H),3.00-2.93(m,2H),1.72-1.46(m,3H)。

Example 30

First step

Compound 30-1 (118.36 mg, 691.18 μmol, 1.5 eq) was dissolved in dichloromethane (4 ml), and then compound a-3 (100 mg, 460.79 μmol, 1 eq) and sodium borohydride acetate (390.64 mg, 1.84 mmol, 4 eq) were added to the reaction solution and reacted at 0 degrees celsius for 1 hour. After completion of the reaction, the reaction was quenched with water (10 ml) at 25 degrees celsius, extracted with dichloromethane (20 ml×2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by thin layer chromatography on silica gel (petroleum ether: ethyl acetate=0:1) to give compound 30-2.MS-ESI calculated [ M+H ] ] ⁺ 372, found 372.

¹ H NMR(400MHz,CD ₃ OD)δ＝8.25(s,1H),4.01(s,3H),3.82(s,2H),3.09-2.95(m,2H),2.91-2.78(m,2H),2.73-2.64(m,1H),2.12-2.00(m,2H),1.45(s,9H)。

Second step

Compound 28-2 (100 mg, 140.14 micromolar, 1 eq) was dissolved in dioxane (6 ml) and water (1.5 ml), compound 30-2 (52.17 mg, 140.14 micromolar, 1 eq), potassium carbonate (58.10 mg, 420.41 micromolar, 3 eq), bis (triphenylphosphine) palladium dichloride (9.84 mg, 14.01 micromolar, 0.1 eq), replaced three times with nitrogen and stirred at 70 degrees celsius for 3 hours. After the reaction was completed, the reaction solution was filtered, concentrated, and the crude product was purified by silica gel thin layer chromatography (dichloromethane: methanol=10:1) to give compound 30-3.MS-ESI calculated [ M+H ]] ⁺ 878, found 878.

Third step

Compound 30-3 (60 mg, 68.26 μmol, 1 eq) was dissolved in dichloromethane (2 ml), a dioxane solution of hydrogen chloride (4 mol/l, 2 ml, 117.20 eq) was added and stirred at 15 degrees celsius for 0.5 hours. After the reaction is finished, the crude product obtained by decompression concentration is separated by high performance liquid chromatography (chromatographic column: unisil 3-100C18 150-50 mm-3 microns; mobile phase: mobile phase A: formic acid aqueous solution; mobile phase B: acetonitrile; B%:8% -38%,10 minutes) to obtain the compound 30.MS-ESI calculated [ M+H ]] ⁺ 708, found 708. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.56-8.49(m,1H),8.06-7.99(m,1H),7.74-7.67(m,1H),7.58-7.41(m, 4H),7.32-7.27(m,1H),7.23-7.15(m,1H),4.68-4.57(m,2H),4.16-4.06(m,3H),3.99(s,3H),3.93-3.89(m,2H),3.88-3.79(m,2H),3.74-3.48(m,4H),3.23-3.10(m,1H),3.05-2.96(m,2H),2.92-2.79(m,4H),2.47-2.19(m,2H)。

Example 31

First step

Compound a-3 (500 mg, 2.30 mmol, 1 eq.) and 31-1 (510.84 mg, 2.30 mmol, 1 eq.) were dissolved in dichloromethane (10 ml), N-diisopropylethylamine (595.52 mg, 461 mmol, 2 eq.) for 0.5 hours at 25 degrees celsius, sodium triacetoxyborohydride (1.46 g, 6.91 mmol, 3 eq.) was added to the reaction at 0 degrees celsius and stirred for 2 hours at 25 degrees celsius. After the completion of the reaction, water (20 ml) was added to quench, saturated aqueous sodium hydrogencarbonate (10 ml) was diluted, dichloromethane was extracted (15 ml×3), the organic phase was washed with saturated brine (30 ml×2), dried over anhydrous sodium sulfate, filtered, and the concentrated residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=50:1-10:1) to give compound 31-2.MS-ESI calculated [ M+H ]] ⁺ 388, found 388.

Second step

Compound 31-2 (57.92 mg, 149.95 μmol, 1 eq.) and compound 28-2 (107 mg, 149.95 μmol, 1 eq.) were dissolved in dioxane (6 ml), water (1.5 ml), then potassium carbonate (62.17 mg, 449.84 μmol, 3 eq.) and bis (triphenylphosphine) palladium (II) dichloride (10.52 mg, 14.99 μmol, 0.1 eq.) were added to the reaction solution and stirred under nitrogen for 2 hours at 70 ℃. After the completion of the reaction, water (10 ml) was added, extraction (10 ml×3) was performed with ethyl acetate, the organic phase was washed with saturated brine (20 ml×2), dried over anhydrous sodium sulfate, filtered, and the residue obtained by concentrating the filtrate under reduced pressure was purified by thin layer chromatography (dichloromethane: methanol=20:1) to give compound 31-3.MS-ESI calculated [ M+H ] ] ⁺ 892, found 892.

Third step

Compound 31-3 (30 mg, 33.59 μmol, 1 eq) was dissolved in methanol (1 ml), followed by addition of a dioxane solution of hydrogen chloride (4 mol/l, 1 ml) to the reaction solution, and stirring at 20 degrees celsius for 1 hour. After the reaction, the mixture was concentrated under reduced pressure to give Compound 31-4.MS-ESI calculated [ M+H ]] ⁺ 778, found 778.

Fourth step

Compound 31-4 (25 mg, 33.94 μmol, 1 eq) was dissolved in methanol (1 ml), water (0.2 ml), and lithium hydroxide monohydrate (14.24 mg, 339.37 μmol, 10 eq) was added to the reaction solution and stirred at 20 ℃ for 1 hour. After the reaction is completed, the mixture is concentrated under reduced pressureThe crude product is separated by high performance liquid chromatography (chromatographic column: phenomenex luna C: 150 x 25 mm x 10 μm; mobile phase: mobile phase a: formic acid aqueous solution; mobile phase B: acetonitrile; B%:10% -40%,10 min) to obtain compound 31.MS-ESI calculated [ M+H ]] ⁺ 722, actual measurement 722. ¹ HNMR(400MHz,CD ₃ OD)δ＝8.56-8.53(m,1H),8.09-8.03(m,1H),7.77-7.71(m,1H),7.62-7.43(m,4H),7.34-7.29(m,1H),7.24-7.19(m,1H),4.34-4.26(m,2H),4.12(s,3H),4.01(s,3H),3.89-3.82(m,4H),3.51-3.43(m,2H),3.05-2.93(m,4H),2.90-2.83(m,4H),2.50-2.35(m,1H),2.15-2.06(m,2H),2.04-1.94(m,2H)。

Example 32

First step

Compound 32-1 (590.76 mg, 3.45 mmol, 1.5 eq) was dissolved in dichloromethane (20 ml) under nitrogen protection, then potassium carbonate (1.91 g, 13.82 mmol, 3 eq) and sodium borohydride acetate (1.46 g, 6.90 mmol, 3 eq) were added to the reaction solution and reacted for 1 hour. After completion of the reaction, a small amount of ice water was poured into the mixture to adjust ph=8 with sodium carbonate, extracted with methylene chloride (30 ml×3), washed with saturated brine (30 ml×3), finally dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 32-2.MS-ESI calculated [ M+H ] ⁺ ] ⁺ 374, measured 374. ¹ H NMR(400MHz,CD ₃ Cl)δ＝8.25-8.14(m,1H),4.01-4.00(m,3H),3.39-3.12(m,2H),2.67-2.58(m,1H),2.18-2.08(m,1H),1.97-1.89(m,2H),1.84-1.75(m,1H),1.45-1.44(m,9H).

Second step

Compound 28-1 (100 mg, 150.03 μmol, 1 eq.) was dissolved in dioxane (6 ml), and dipyridyl borate (57.15 mg, 225.05 μmol, 1.5 eq.) was added, potassium acetate (44.17 mg, 450.10 μmol, 3 eq.) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (10.53 mg, 15.00 μmol, 0.1 eq.) were reacted under nitrogen for 2 hours at 110 ℃. After the reaction was completed, the reaction solution was cooled to room temperature, water (1.5 ml) was added, and compound 32-2 (55.82 mg, 149.95. Mu. Mol, 1 eq.) and potassium carbonate (62.17 mg, 449.84. Mu. Mol, 3 eq.) were reacted with 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (10.52 mg, 14.99. Mu. Mol, 0.1 eq.) at 75℃for 2 hours under nitrogen. After completion of the reaction, the reaction mixture was filtered, and the filtrate was diluted with ethyl acetate (20 ml) and washed with saturated brine (20 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel thin layer chromatography (dichloromethane: methanol=15:1) to give compound 32-3.MS-ESI calculated [ M+H ]] ⁺ 878, found 878.

Third step

Compound 32-3 (69 mg, 78.50 μmol, 1 eq) was dissolved in dichloromethane (4 ml), and a dioxane solution of hydrogen chloride (4 mol/l, 3.48 ml, 177.32 eq) was added and reacted at 25 degrees celsius for 1 hour. After the reaction, the crude product concentrated under reduced pressure is separated by high performance liquid chromatography (chromatographic column: unisil 3-100C18Ultra 150*50 mm 3 micron; mobile phase: mobile phase A: formic acid aqueous solution; mobile phase B: acetonitrile; B%:12% -42%,10 min) and (chromatographic column: waters Xbridge 150 x 25 mm 5 micron; mobile phase: mobile phase A: ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; B%:35% -65%,8 min) to obtain compound 32.MS-ESI calculated [ M+H ] ] ⁺ 708, found 708. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.58-8.53(m,1H),8.09-8.02(m,1H),7.77-7.70(m,1H),7.60-7.43(m,4H),7.35-7.29(m,1H),7.26-7.18(m,1H),4.74-4.61(m,2H),4.19-4.11(m,4H),4.04-3.98(m,3H),3.94-3.87(m,1H),3.86-3.76(m,4H),3.32-3.31(m,1H),2.92-2.76(m,6H),2.57-2.45(m,1H),2.26-2.02(m,3H).

Example 33

First step

Compound G (100 mg, 161.20 micromolar, 1 eq) was dissolved in dioxane (6 ml), and duplex pinacol borate (61.40 mg, 241.80 micromolar, 1.5 eq), potassium acetate (47.46 mg, 483.61 micromolar, 3 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (11.80 mg, 16.12 micromolar, 0.1 eq) was added, replaced three times with nitrogen and stirred at 110 degrees celsius for 3 hours. After the reaction, the reaction mixture was filtered and concentrated to give Compound 33-1.MS-ESI calculated [ M+H ]] ⁺ 667, found 667.

Second step

Compound 33-1 (107 mg, 160.30 μmol, 1 eq) was dissolved in dioxane (6 ml) and water (0.5 ml), compound a (46.20 mg, 160.32 μmol, 1 eq), potassium carbonate (66.47 mg, 480.97 μmol, 3 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (11.73 mg, 16.03 μmol, 0.1 eq) was added, replaced three times with nitrogen, and stirred at 70 degrees celsius for 3 hours. After the reaction, the reaction mixture was filtered, concentrated, and the crude product was purified by silica gel thin layer chromatography (dichloromethane: methanol=20:1) to give compound 33-2.MS-ESI calculated [ M+H ]] ⁺ 748, the actual measurement 748.

Third step

Compound 33-2 (65 mg, 86.82 μmol, 1 eq) was dissolved in methanol (2 ml), water (0.3 ml) and tetrahydrofuran (1 ml), lithium hydroxide (20.9 mg, 868.21 μmol, 10 eq) was added to the reaction solution, and stirred at 60 degrees celsius for 1 hour. After the reaction, the pH is regulated to 7 by acetic acid, the mixture is filtered, and the crude product obtained by concentrating the filtrate under reduced pressure is separated by high performance liquid chromatography (chromatographic column: waters Xbridge150 x 25 mm x 5 μm; mobile phase: mobile phase A: ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; B%:36% -66%,8 minutes) to obtain the compound 33.MS-ESI calculated [ M+H ]] ⁺ 734, found 734. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.52-8.47(m,1H),8.08-8.01(m,1H),7.73-7.67(m,1H),7.61-7.42(m,4H),7.35-7.27(m,2H),4.76-4.72(m,2H),4.55-4.50(m,2H),4.45-4.08(m,7H),4.07-4.02(m,3H),3.79-3.61(m,2H),3.54-3.48(m,2H),3.14-3.06(m,2H),1.63-1.53(m,3H),1.53-1.47(m,2H),1.16-1.08(m,2H)。

Example 34

First step

Compound 34-1 (1.12 g, 11.06 mmol, 1.2 eq.) was dissolved in methanol (20 ml), compound a-3 (2 g, 9.22 mmol, 1 eq.) and acetic acid (1.11 g, 18.43 mmol, 1.05 ml, 2 eq.) were added to the reaction solution, stirred for 0.5 hours, followed by addition of sodium cyanoborohydride (868.70 mg, 13.82 mmol, 1.5 eq.) and stirred for 1 hour at 0 ℃. After the reaction, water (50 ml) was added to quench, dichloromethane (50 ml. Times.3) was used to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, and the concentrated residue was separated by high performance liquid chromatography (column Kromasil Eternity XT X80 mm. 10 μm; mobile phase A: ammonia aqueous solution; mobile phase B: acetonitrile; B%:22% -52%,20 min) to obtain compound 34-2.MS-ESI calculated [ M+H ] ] ⁺ 302, measured 302. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.40-8.04(m,1H),4.03-3.95(m,3H),3.84-3.74(m,2H),2.98-2.62(m,4H),1.91-1.80(m,2H),1.34(s,3H)。

Second step

Compound 33-1 (160 mg, 239.74 micromolar, 1 eq) was dissolved in dioxane (9 ml) and water (0.9 ml), compound 34-2 (72.44 mg, 239.74 micromolar, 1 eq) carbonic acidPotassium (99.44 mg, 719.21. Mu. Mol, 3 eq.) 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (17.54 mg, 23.97. Mu. Mol, 0.1 eq.) was replaced three times with nitrogen and stirred at 70℃for 3 hours. After the reaction, the reaction mixture was filtered, concentrated, and the crude product was purified by silica gel thin layer chromatography (dichloromethane: methanol=20:1) to give compound 34-3.MS-ESI calculated [ M+H ]] ⁺ 764, found 764.

Third step

Compound 34-3 (100 mg, 131.11 μmol, 1 eq) was dissolved in methanol (2 ml), water (0.3 ml) and tetrahydrofuran (1 ml), lithium hydroxide (62.80 mg, 2.62 mmol, 20 eq) was added to the reaction solution, and stirred at 60 degrees celsius for 1 hour. After the reaction, regulating the pH to 7 by acetic acid, filtering, concentrating the filtrate under reduced pressure, and separating the crude product by high performance liquid chromatography (chromatographic column: phenomenex Synergi C, 150, 25 mm, 10 microns; mobile phase: mobile phase A: formic acid aqueous solution; mobile phase B: acetonitrile; B%: 13-43%, 10 minutes) to obtain the compound 34.MS-ESI calculated [ M+H ] ] ⁺ 748, the actual measurement 748. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.49-8.45(m,1H),8.06-8.00(m,1H),7.73-7.67(m,1H),7.60-7.40(m,4H),7.33-7.26(m,2H),4.39-4.32(m,2H),4.29-4.20(m,2H),4.11-4.06(m,3H),4.05-3.99(m,3H),3.56-3.46(m,2H),3.40-3.33(m,1H),3.27-3.22(m,2H),3.18-2.99(m,5H),2.05-1.96(m,2H),1.43-1.38(m,3H),1.33-1.29(m,2H),0.86-0.75(m,2H)。

Example 35

First step

Compound 35-1 (15 g, 86.60 mmol, 1 eq.) was combined with compound 35-2 (29 g, 121.24 mmol,1.4 eq.) in N, N dimethylformamide (50 ml) cesium carbonate (2.32 g, 129.90 mmol, 1.5 eq.) was added to the reaction solution and stirred under nitrogen for 12 hours at 70 ℃. After completion of the reaction, water (100 ml) was added, extraction was performed with ethyl acetate (100 ml×3), and the organic phase was washed with saturated brine (100 ml×3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=100:1 to 30:1) to give compound 35-3.MS-ESI calculated [ M+H ]] ⁺ 332。 ¹ HNMR(400MHz,CD ₃ OD)δ＝4.32-4.22(m,1H)4.17-4.03(m,2H)3.87-3.80(m,2H)3.78-3.69(m,2H)3.49-3.42(m,2H)1.49-1.36(m,9H)0.91-0.87(m,9H)0.10-0.05(m,6H).

Second step

Compound 35-3 (1 g, 3.02 mmol, 1 eq.) was dissolved in dichloromethane (15 ml) and zinc dibromide (1.36 g, 6.03 mmol, 2 eq.) was slowly added to the reaction and stirred at 25 degrees celsius for 12 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give Compound 35-4.

Third step

Compound 35-4 (0.7 g, 3.02 mmol, 1 eq.) a-3 (656.48 mg, 3.02 mmol, 1 eq.) was dissolved in dichloromethane (10 ml), sodium triacetoxyborohydride (961.67 mg, 4.54 mmol, 1.5 eq.) was added to the reaction solution after stirring at 25 ℃ for 0.5 hours, and stirring at 25 ℃ for 2 hours. After the reaction, adding saturated aqueous sodium bicarbonate (10 ml) to quench, extracting with dichloromethane (10 ml. Times.3), drying the organic phase with anhydrous sodium sulfate, filtering, separating the concentrated residue by high performance liquid chromatography (column: waters Xridge 150 x 25 mm. Times.5 μm; mobile phase: mobile phase A: aqueous ammonia solution; mobile phase B: acetonitrile; B%:64% -94%,9 min), and purifying to obtain compound 35-5.MS-ESI calculated [ M+H ] ] ⁺ 434, found 434. ¹ HNMR(400MHz,CDCl ₃ )δ＝8.29-8.17(m,1H),4.23(quin,J＝6.0Hz,1H),4.08-3.90(m,3H),3.80-3.65(m,6H),3.51-3.37(m,2H),3.10-3.04(m,2H),0.88(br s,9H),0.17-0.03(m,6H).

Fourth step

Compound 35-5 (69.98 mg, 161.82 μmol, 1 eq), 33-1 (108 mg, 161.82 μmol, 1 eq) was dissolved in dioxane (2 ml), water (0.2 ml), potassium carbonate (67.09 mg, 485.47 μmol, 3 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (11.84 mg, 16.18 μmol, 0.1 eq) was added to the reaction solution and stirred under nitrogen for 2 hours at 70 ℃. After the reaction was completed, filtration was performed, and the residue concentrated in the filtrate was purified by silica gel thin layer chromatography (dichloromethane: methanol=20:1) to give compound 35-6.MS-ESI calculated [ M+H ]] ⁺ 892, found 892.

Fifth step

Compound 35-6 (85 mg, 85.10 μmol, 1 eq) was dissolved in dichloromethane (1 ml), followed by addition of an ethyl acetate solution of hydrogen chloride (4 mol/l, 21.27 μmol, 1 eq) to the reaction solution and stirring at 25 degrees celsius for 0.5 hours. After the reaction, concentrating under reduced pressure to obtain a compound 35-7.MS-ESI calculated [ M+H ]] ⁺ 778, found 778.

Sixth step

Compound 35-7 (75 mg, 96.32 micromolar, 1 eq.) was dissolved in methanol (2 ml), water (0.2 ml), lithium hydroxide monohydrate (20.21 mg, 481.58 micromolar, 5 eq.) was added to the reaction solution and stirred at 25 degrees celsius for 12 hours. After the reaction is finished, filtering, concentrating the filtrate under reduced pressure, and separating the crude product by high performance liquid chromatography (chromatographic column: unisil 3-100C18Ultra 150*50 mm 3 μm; mobile phase: mobile phase A: formic acid water solution; mobile phase B: acetonitrile; B%:10% -40%,10 min) to obtain compound 35.MS-ESI calculated [ M+H ] ] ⁺ 764, found 764. ¹ HNMR(400MHz,CD ₃ OD)δ＝8.44-8.39(m,1H),8.07-8.00(m,1H),7.71-7.65(m,1H),7.59-7.39(m,4H),7.33-7.27(m,2H),4.40-4.34(m,2H),4.33-4.24(m,1H),4.11-4.05(m,5H),4.02(s,3H),3.98-3.91(m,2H),3.68-3.63(m,2H),3.55-3.46(m,6H),3.25(s,2H),3.06-2.99(m,2H),1.35-1.28(m,2H),0.84-0.80(m,2H).

Example 36

First step

Compound 36-1 (1.05 g, 6.91 mmol, 1.5 eq.) was dissolved in dichloromethane (20 ml), then potassium carbonate (1.91 g, 13.82 mmol, 3 eq.) was added to the reaction solution, the temperature was lowered by 0 degrees celsius, sodium borohydride acetate (2.93 g, 13.82 mmol, 3 eq.) was added, and then compound a-3 (1 g, 4.61 mmol, 1 eq.) was added to react for 1 hour. After completion of the reaction, ph=8 was adjusted with sodium carbonate, extracted with dichloromethane (30 ml×3), washed with saturated brine (30 ml×3), finally dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 36-2.MS-ESI calculated [ M+2H ]] ⁺ 318, found 318.

Second step

Compound 33-1 (160 mg, 239.74 μmol, 1 eq) was dissolved in dioxane (9 ml) and water (0.7 ml), compound 36-2 (75.80 mg, 239.74 μmol, 1 eq), potassium carbonate (99.40 mg, 719.22 μmol, 3 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (17.54 mg, 23.97 μmol, 0.1 eq) was added, replaced three times with nitrogen, and stirred at 70 degrees celsius for 3 hours. After the reaction was completed, the reaction solution was filtered, concentrated, and the crude product was purified by silica gel thin layer chromatography (dichloromethane: methanol=20:1) to give compound 36-3.MS-ESI calculated [ M+H ] ] ⁺ 776, found 776.

Third step

Compound 36-3 (65 mg, 83.69 μmol, 1 eq.) was dissolved in methanol (2 ml), water (0.3 ml) and tetrahydrofuran (1 ml), lithium hydroxide (40.08 mg, 1.67 mmol, 20 eq.) was added to the reaction solution, and stirred at 60 degrees celsius for 1 hour. After the reaction is finished, acetic acid is used for adjusting the pH value to 7, filtering is carried out, and the crude product obtained by decompression concentration of filtrate is subjected to high-efficiency liquid chromatographyThe spectrum (column Phenomenex Synergi C: 150 x 25 mm x 10 μm; mobile phase: mobile phase A: aqueous formic acid; mobile phase B: acetonitrile; B%:14% -44%,10 min) was separated to give compound 36.MS-ESI calculated [ M+H ]] ⁺ 762, measured value 762. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.47-8.41(m,1H),8.07-7.99(m,1H),7.72-7.65(m,1H),7.58-7.40(m,4H),7.33-7.23(m,2H),4.35- 4.17(m,4H),4.11-4.06(m,3H),4.02(br s,3H),4.00-3.75(m,4H),3.48-3.38(m,2H),3.26-3.15(m,2H),3.05-2.93(m,2H),2.87-2.74(m,1H),1.31-1.27(m,2H),1.17-1.09(m,6H),0.85-0.76(m,2H)。

Example 37

First step

Compound 37-1 (854.17 mg, 6.91 mmol, 790.90 μl, 1.5 eq) was dissolved in dichloromethane (20 ml), then potassium carbonate (1.91 g, 13.82 mmol, 3 eq) was added to the reaction solution, cooled to 0 degrees celsius, sodium borohydride (2.93 g, 13.82 mmol, 3 eq) was added, and then compound a-3 (1 g, 4.61 mmol, 1 eq) was added to react for 1 hour. After completion of the reaction, a small amount of ice water was poured into the mixture to adjust ph=8 with sodium carbonate, extracted with methylene chloride (30 ml×3), washed with saturated brine (30 ml×3), finally dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 37-2.MS-ESI calculated [ M+Na ] ⁺ ] ⁺ 310, measured 310.

Second step

Compound 33-1 (150 mg, 224.75 μmol, 1 eq) and compound 37-2 (64.76 mg, 293.39 μmol, 1.3 eq) potassium carbonate (93.19 mg, 674.26 μmol, 3 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (16.45 mg, 22.48 μmol, 0.1 eq) were dissolved in dioxane (9 ml), water (2.25 ml), nitrogen displaced 3 times, and then stirred under nitrogen atmosphere at 75 degrees celsius for 2 hours. Filtering and concentrating the reaction liquid after the reaction is finished, and coarselyThe product was purified by thin layer chromatography on silica gel (dichloromethane: methanol=15:1) to give compound 37-3.MS-ESI calculated [ M+H ]] ⁺ 748, the actual measurement 748.

Third step

Compound 37-3 (80 mg, 97.83 μmol, 1 eq.) was dissolved in methanol (2 ml), tetrahydrofuran (1 ml), water (0.3 ml), nitrogen displaced 3 times, then lithium hydroxide monohydrate (82.11 mg, 1.96 mmol, 20 eq.) was added and stirred at 35 degrees celsius for 10 hours. After the reaction is finished, the reaction solution is filtered and concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: waters Xbridge 150 x 25 mm x 10 microns; mobile phase: mobile phase A: ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; B%:36% -66%,8 minutes) to obtain the compound 37.MS-ESI calculated [ M+H ] ] ⁺ 734.2, found 734.2. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.56-8.54(m,1H),8.08-8.02(m,1H),7.75-7.70(m,1H),7.60-7.43(m,4H),7.33-7.30(m,2H),4.73(br s,2H),4.62(br s,1H),4.54(s,2H),4.13(s,3H),4.05(s,3H),3.94-3.37(m,8H),3.14-3.07(m,2H),2.49-2.11(m,2H),1.55-1.50(m,2H),1.17-1.12(m,2H)。

Example 38

First step

Compound 38-1 (699.11 mg, 6.91 mmol, 1.5 eq.) was dissolved in dichloromethane (20 ml), potassium carbonate (1.91 g, 13.82 mmol, 3 eq.) and sodium borohydride acetate (2.93 g, 13.82 mmol, 3 eq.) under nitrogen protection, and compound a-3 (1 g, 4.61 mmol, 1 eq.) was reacted for 1 hour. After completion of the reaction, a small amount of ice water was poured into the mixture to adjust ph=8 with sodium carbonate, extracted with methylene chloride (30 ml×3), washed with saturated brine (30 ml×3), finally dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 38-2.MS-ESI calculated [ M+H ] ⁺ ] ⁺ 302, measured 302.

Second step

Compound 33-1 (150 mg, 224.75 μmol, 1 eq) and compound 38-2 (67.91 mg, 224.75 μmol, 1.3 eq) potassium carbonate (93.19 mg, 674.26 μmol, 3 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (16.45 mg, 22.48 μmol, 0.1 eq) were dissolved in dioxane (9 ml), water (2.25 ml), nitrogen displaced 3 times, and then stirred under nitrogen atmosphere at 75 degrees celsius for 2 hours. After the reaction, the reaction mixture was concentrated by filtration, and the crude product was purified by silica gel thin layer chromatography (dichloromethane: methanol=15:1) to give compound 38-3.MS-ESI calculated [ M+H ] ] ⁺ 762, measured value 762.

Third step

Compound 38-3 (100 mg, 124.42 μmol, 1 eq.) was dissolved in methanol (2 ml), tetrahydrofuran (1 ml), water (0.3 ml), nitrogen replaced 3 times, then lithium hydroxide monohydrate (104.42 mg, 2.49 mmol, 20 eq.) was added and stirred at 35 degrees celsius for 10 hours. After the reaction is finished, the reaction solution is filtered and concentrated, and the crude product is separated by high performance liquid chromatography (chromatographic column: phenomenex Synergi C18150: 25 mm: 10 micrometers; mobile phase: mobile phase A: formic acid aqueous solution; mobile phase B: acetonitrile; B%:15% -45%,10 minutes) to obtain formate of the compound 38. MS-ESI calculated [ M+H ]] ⁺ 748, the actual measurement 748. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.51(s,1H),8.09-8.03(m,1H),7.76-7.70(m,1H),7.63-7.43(m,4H),7.36-7.29(m,2H),4.39(s,2H),4.32(s,2H),4.16-4.10(m,4H),4.05(s,3H),3.55(br t,J＝5.7Hz,2H),3.35(s,3H),3.32-3.16(m,6H),3.06(br t,J＝6.1Hz,2H),2.25-2.03(m,2H),1.35-1.31(m,2H),0.87-0.81(m,2H)。

Example 39

First step

Compound G (70 mg, 112.84. Mu. Mol, 1 eq.) was dissolved in dioxane (2 ml) and the geminal pinacol borate was added(37.25 mg, 146.69. Mu. Mol, 1.3 eq.) potassium acetate (33.22 mg, 338.53. Mu. Mol, 3 eq.) 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (8.26 mg, 11.28. Mu. Mol, 0.1 eq.) and the reaction solution reacted at 110℃for 3 hours under nitrogen. After the completion of the reaction, the reaction mixture was cooled to room temperature, water (0.4 ml), compound 39-1 (32.51 mg, 112.83. Mu. Mol, 1 eq.) was added, potassium carbonate (46.78 mg, 338.48. Mu. Mol, 3 eq.) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (8.26 mg, 11.28. Mu. Mol, 0.1 eq.) were reacted at 75℃for 3 hours under nitrogen. After completion of the reaction, the reaction mixture was filtered, and the filtrate was diluted with ethyl acetate (20 ml) and washed with saturated brine (20 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel thin layer chromatography (dichloromethane: methanol=15:1) to give compound 39-2.MS-ESI calculated [ M+H ] ] ⁺ 748, the actual measurement 748.

Second step

Compound 39-2 (80 mg, 106.86 μmol, 1 eq) was dissolved in methanol (2 ml), tetrahydrofuran (1 ml) and water (0.4 ml), lithium hydroxide monohydrate (44.84 mg, 1.07 mmol, 10 eq) was added, and the reaction solution was reacted at 30 degrees celsius for 12 hours. After the reaction, the reaction solution is filtered after the pH value is regulated to be 6 by acetic acid, and the crude filtrate is separated by high performance liquid chromatography (chromatographic column: unil 3-100C18Ultra150×50 mm×3 microns; mobile phase: mobile phase A: formic acid aqueous solution; mobile phase B: acetonitrile; B%:15% -45%,10 min) to obtain the compound 39.MS-ESI calculated [ M+H ]] ⁺ 708, found 708. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.45(s,1H),8.08-8.01(m,1H),7.73-7.67(m,1H),7.62-7.41(m,4H),7.35-7.28(m,2H),4.42-4.36(m,2H),4.24-4.17(m,3H),4.11-4.03(m,8H),3.34-3.33(m,4H),3.32(s,3H),3.29-3.26(m,2H),3.09-3.01(m,2H),1.39-1.30(m,2H),0.86-0.81(m,2H).

Example 40

First step

Compound 40-1 (951.12 mg, 6.91 mmol, 1.5 eq.) was dissolved in dichloromethane (20 ml), potassium carbonate (1.91 g, 13.82 mmol, 3 eq.) was added, sodium borohydride acetate (2.93 g, 13.82 mmol, 3 eq.) and compound a-3 (1 g, 4.61 mmol, 1 eq.) was reacted for 2 hours under nitrogen protection at 0 degrees celsius. After completion of the reaction, a small amount of ice water was poured into the mixture to adjust ph=8 with sodium carbonate, extracted with methylene chloride (30 ml×3), washed with saturated brine (30 ml×3), finally dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 40-2.MS-ESI calculated [ M+H ] ⁺ ] ⁺ 302, measured 302.

Second step

Compound G (120 mg, 193.44 micromolar, 1 eq) was dissolved in dioxane (6 ml), and duplex pinacol borate (63.86 mg, 251.48 micromolar, 1.3 eq), potassium acetate (56.96 mg, 580.33 micromolar, 3 eq), 1-bis (diphenylphosphorus) ferrocene palladium chloride (14.15 mg, 19.34 micromolar, 0.1 eq) was added and the reaction mixture reacted at 110 degrees celsius under nitrogen for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, water (1.5 ml) was added, and compound 40-2 (58.45 mg, 193.44. Mu. Mol, 1 eq.) was reacted with potassium carbonate (80.20 mg, 580.32. Mu. Mol, 3 eq.) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (14.15 mg, 19.34. Mu. Mol, 0.1 eq.) at 75℃for 3 hours under nitrogen. After completion of the reaction, the reaction mixture was filtered, and the filtrate was diluted with ethyl acetate (30 ml) and washed with saturated brine (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel thin layer chromatography (dichloromethane: methanol=15:1) to give compound 40-3.MS-ESI calculated [ M+H ]] ⁺ 762, measured value 762.

Third step

Compound 40-3 (86 mg, 112.76 μmol, 1 eq) was dissolved in methanol (2 ml), tetrahydrofuran (1 ml) and water (0.4 ml), lithium hydroxide monohydrate (47.31 mg, 1.13 mmol, 10 eq) was added, and the reaction solution was reacted at 60 degrees celsius for 1 hour. After the reaction, the reaction solution is filtered after the pH value is regulated to be 6 by acetic acid, and the crude filtrate is separated by high performance liquid chromatography (chromatographic column: unisil 3-100 C18 Ultra 150*50 mm 3 micron; mobile phase: mobile phase A: formic acid aqueous solution; mobile phase B: acetonitrile; B%:15% -45%,10 min) to obtain formate of the compound 40. MS-ESI calculated [ M+H ] ] ⁺ 708, found 708. ¹ H NMR(400MHz,CD ₃ OD)δ＝8.55(s,1H),8.46(s,1H),8.08-8.03(m,1H),7.73-7.68(m,1H),7.60-7.43(m,4H),7.35-7.28(m,2H),4.68-4.55(m,3H),4.45-4.31(m,4H),4.13-4.02(m,8H),3.89-3.79(m,2H),3.60-3.48(m,4H),3.47-3.42(m,3H),3.29-3.23(m,2H),3.08-2.99(m,3H),1.36-1.29(m,2H),0.86-0.79(m,2H).

Example 41

First step

Compound 41-1 (559.28 mg, 6.91 mmol, 1.5 eq.) was dissolved in dichloromethane (20 ml) and then potassium carbonate (1.91 g, 13.82 mmol, 3 eq.) was added to the reaction solution, sodium borohydride acetate (2.93 g, 13.82 mmol, 3 eq.) and compound a-3 (1 g, 4.61 mmol, 1 eq.) were added under nitrogen protection at 0 degrees celsius, and the reaction solution was allowed to react for 2 hours at zero degrees. After completion of the reaction, a small amount of ice water was poured into the mixture to adjust ph=8 with sodium carbonate, extracted with methylene chloride (30 ml×3), washed with saturated brine (30 ml×3), finally dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 41-2.MS-ESI calculated [ M+H ] ⁺ ] ⁺ 302, measured 302.

Second step

Compound G (120 mg, 193.44. Mu. Mol, 1 eq.) was dissolved in dioxane(6 ml) was added with bis-pinacolato borate (63.86 mg, 251.48. Mu. Mol, 1.3 eq.) and potassium acetate (56.96 mg, 580.33. Mu. Mol, 3 eq.) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (14.15 mg, 19.34. Mu. Mol, 0.1 eq.) and the reaction solution was reacted at 110℃for 3 hours under nitrogen. After the reaction was completed, the reaction solution was cooled to room temperature, water (1.5 ml) was added, and compound 41-2 (58.45 mg, 193.44. Mu. Mol, 1 eq.) was reacted with potassium carbonate (80.20 mg, 580.32. Mu. Mol, 3 eq.) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (14.15 mg, 19.34. Mu. Mol, 0.1 eq.) at 75℃for 3 hours under nitrogen. After completion of the reaction, the reaction mixture was filtered, and the filtrate was diluted with ethyl acetate (30 ml) and washed with saturated brine (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel thin layer chromatography (dichloromethane: methanol=15:1) to give compound 41-3.MS-ESI calculated [ M+H ] ] ⁺ 762, measured value 762.

Third step

Compound 41-3 (82 mg, 107.51 mmol, 1 eq.) was dissolved in methanol (2 ml), tetrahydrofuran (1 ml) and water (0.4 ml), lithium hydroxide monohydrate (45.11 mg, 1.08 mmol, 10 eq.) was added and the reaction solution was reacted at 60 degrees celsius for 1 hour. After the reaction, the reaction solution is filtered after the pH value is regulated to be 6 by acetic acid, and the crude filtrate is separated by high performance liquid chromatography (chromatographic column: phenomenex Synergi C, 150, 25 mm, 10 microns; mobile phase: mobile phase A: formic acid aqueous solution; mobile phase B: acetonitrile; B%: 13-43%, 10 minutes) to obtain the compound 41.MS-ESI calculated [ M+H ]] ⁺ 748, the actual measurement 748.

¹ H NMR(400MHz,CD ₃ OD)δ＝8.51-8.46(m,1H),8.08-8.03(m,1H),7.75-7.69(m,1H),7.61-7.42(m,4H),7.36-7.28(m,2H),4.41-4.33(m,2H),4.22-4.16(m,2H),4.12-4.08(m,3H),4.05(s,3H),3.63-3.49(m,4H),3.28-3.19(m,3H),3.15-3.02(m,4H),2.90-2.81(m,1H),2.61-2.46(m,1H),2.17-2.05(m,1H),1.77-1.66(m,1H),1.36-1.30(m,2H),0.87-0.79(m,2H).

Example 42

First step

Compound 42-1 (2 g, 8.36 mmol, 1 eq.) was dissolved in tetrahydrofuran (2 ml), potassium tert-butoxide (1 mol, 25.07 ml, 3 eq.) was added to the reaction at 0 degrees celsius, followed by adding compound 42-2 (3.48 g, 25.07 mmol, 3 eq.) to the reaction, and stirring at 25 degrees celsius for 1 hour. After completion of the reaction, saturated aqueous ammonium chloride (100 ml) was added, diluted with ethyl acetate (50 ml), extracted with ethyl acetate (50 ml×3), and the organic phase was washed with saturated brine (80 ml×2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=100:1 to 40:1) to give compound 42-3.MS-ESI calculated [ M+H ] ] ⁺ 298, found 298. ¹ HNMR(400MHz,CDCl ₃ )δ＝7.45-7.29(m,4H),7.23-7.17(m,4H),7.14-7.02(m,2H),4.37-4.29(m,1H),4.18-4.06(m,1H),3.47-3.36(m,6H),3.33-3.22(m,3H),2.91-2.85(m,2H)。

Second step

Compound 42-3 (0.2 g, 672.52 μmol, 1 eq) was dissolved in 1,2 dichloroethane (4 ml), and 1-chloroethyl a-chloroformate (124.99 mg, 874.27 μmol, 1.3 eq) was slowly added to the reaction solution, stirred at 70 degrees celsius for 1.5 hours, then the reaction solution was cooled to 25 degrees celsius, methanol (4 ml) was added, and stirred at 70 degrees celsius for 1.5 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to give Compound 42-4. ¹ HNMR(400MHz,CDCl ₃ )δ＝4.56-4.43(m,1H),4.31-4.17(m,2H),4.14-4.01(m,2H),3.60(br d,J＝4.2Hz,2H),3.57-3.50(m,2H),3.39-3.35(m,3H)。

Third step

Compound 42-4(0.1 g, 596.54. Mu. Mol, 1 eq.) A-3 (129.46 mg, 596.54. Mu. Mol, 1 eq.) is dissolved in dichloromethane (4 ml), N-diisopropylethylamine (154.20 mg, 1.19. Mu. Mol, 2 eq.) is added to the reaction solution, stirred at 25℃for 0.5 hours, sodium triacetoxyborohydride (379.29 mg, 1.79. Mu. Mol, 3 eq.) is added to the reaction solution at 0℃and stirred at 25℃for 2 hours. After the completion of the reaction, saturated aqueous sodium bicarbonate (10 ml) was added, quenched with water (20 ml), extracted with dichloromethane (15 ml×3), the organic phase was washed with saturated brine (30 ml×2), dried over anhydrous sodium sulfate, filtered, and the concentrated residue was purified by silica gel thin layer chromatography (dichloromethane: methanol=20:1) to give compound 42-5.MS-ESI calculated [ M+H ] ] ⁺ 334, the actual measurement 334. ¹ HNMR(400MHz,CDCl ₃ )δ＝8.24-8.14(m,1H),4.27-4.22(m,1H),3.99(s,3H),3.81(s,2H),3.52(s,2H),3.52-3.50(s,4H),3.40-3.36(m,3H),3.21-3.16(m,2H)。

Fourth step

Compound 42-5 (79.64 mg, 239.74 μmol, 1 eq.) and compound 33-1 (160 mg, 239.74 μmol, 1 eq.) were dissolved in dioxane (6 ml), water (1 ml), and potassium carbonate (99.40 mg, 719.21 μmol, 3 eq.) and 1, 1-bis (diphenylphosphorus) ferrocene palladium chloride (17.54 mg, 23.97 μmol, 0.1 eq.) were added to the reaction mixture and stirred under nitrogen for 2 hours at 70 ℃. After the reaction was completed, filtration was performed, and the residue concentrated in the filtrate was purified by silica gel thin layer chromatography (dichloromethane: methanol=20:1) to give compound 42-6.MS-ESI calculated [ M+H ]] ⁺ 794, found 794.

Fifth step

Compound 42-6 (30 mg, 37.84 μmol, 1 eq.) was dissolved in methanol (2 ml), tetrahydrofuran (1 ml), water (0.3 ml), lithium hydroxide monohydrate (15.88 mg, 378.44 μmol, 10 eq.) was added to the reaction solution, and stirred at 65 degrees celsius for 10 hours. After the reaction, filtering, concentrating the filtrate under reduced pressure, and purifying with high performance liquid chromatography (chromatographic column: phenomenex Synergi C, 150 x 25 mm, 10 μm; mobile phase: mobile phase A: formic acid aqueous solution; flow)Mobile phase B: acetonitrile; b%:22% -40%,8 minutes) to obtain the formate of the compound 42. MS-ESI calculated [ M+H ] ] ⁺ 778, found 778. ¹ HNMR(400MHz,CD ₃ OD)δ＝8.42(s,1H),8.09-7.98(m,1H),7.71-7.64(m,1H),7.58-7.39(m,4H),7.33-7.25(m,2H),4.33(br s,2H),4.31-4.24(m,1H),4.15-4.08(m,2H),4.07(s,3H),4.03(s,3H),4.01-3.95(m,2H),3.60-3.56(m,2H),3.55-3.45(m,6H),3.36(s,3H),3.23(s,2H),3.02(br t,J＝6.1Hz,2H),1.30(br d,J＝2.8Hz,2H),0.84-0.79(m,2H).

Experimental example 1: PD-1/PD-L1 Homogeneous Time Resolved Fluorescence (HTRF) binding assay

Experimental principle:

small molecule compounds may compete for inhibition of PD-1 binding to PD-L1 by binding to PD-L1; when the PD-1 molecule as a donor is in close proximity to the PD-L1 molecule as an acceptor, the donor molecule transfers energy to the acceptor molecule, thereby causing the acceptor molecule to fluoresce; by detecting the fluorescence intensity, the ability of the small molecules to prevent the binding of PD-L1 to PD-1 can be tested. Homogeneous Time Resolved Fluorescence (HTRF) binding assays were used to examine the ability of the compounds of the invention to inhibit PD-1/PD-L1 binding to each other.

Experimental materials:

PD1/PD-L1TR-FRET detection kit is purchased from BPS Biosciences. Nivo Multi-labelling Analyzer (Perkinelmer).

The experimental method comprises the following steps:

the PD1-Eu, dye-labeled receptor (Dye-labeled receptor), PD-L1-biotin and the test compound are diluted with a buffer in the kit. The test compounds were diluted 5-fold with a row gun to 8 th concentration, i.e. from 40 degrees to 0.5nm, dmso concentration 4%, and a double-multiplex experiment was set up. Adding 5 a set of concentration gradients of inhibitor to the microplate,

Wherein 5. Mu.L of buffer containing 4% DMSO was added to the maximum (Max) signal well and the minimum (Min) signal well, 5. Mu.L of PD-L1-biotin (60 nM) was added, and the minimum (Min) signal well was incubated at 25℃for 20 minutes with only 5. Mu.L of buffer. . After the incubation was completed, 5. Mu.l of diluted PD1-Eu (10 nM) and 5. Mu.l of diluted Dye-labeled receptor (Dye-labeled receptor) were added to each well. The reaction system was left to react at 25℃for 90 minutes. After the reaction, the TR-FRET signal is read by a multi-label analyzer after the reaction is finished.

Data analysis:

raw data was converted to inhibition, IC, using the equation (sample-Min)/(Max-Min). Times.100% ₅₀ The values of (a) can be obtained by curve fitting with four parameters (log (inhibitor) vs. response-Variable slope mode in GraphPad Prism).

Experimental results: see table 1.

TABLE 1 IC for PD-1/PD-L1 binding of the inventive example compounds ₅₀ Value test results

Test compounds	IC ₅₀ (nM)
Compound 33	15.66
Compound 35	14.19
Compound 37	16.84
Formate of Compound 42	16.18

Conclusion of experiment: the compound provided by the invention has better capacity of inhibiting the mutual combination of PD-1/PD-L1.

Experimental example 2: detection of Compounds' influence on PD-L1 expression levels Using MDA-MR-231 cells

Experimental principle:

the use of a triple negative breast cancer cell line (MDA-MB-231) is an indirect method of assessing PD-L1 endocytosis. The PD-L1 molecules on the cell surface can be degraded through lysosome and proteasome pathways, and small molecule inhibitors are added to promote the induction of the endocytosis of the PD-L1. After 24 hours of incubation of the small molecules with MDA-MB-231 cells, detection of the cell surface PD-L1 content by flow cytometry (Fluorescence-activated Cell Sorting, FACS) may indirectly reflect the effect of the small molecules on the induction of PD-L1 endocytosis. Flow cytometry (FACS) was used to examine the effect of the compounds of the invention on the expression level of PD-L1 in MDA-MR-231 cells.

Experimental materials:

phosphate Buffer (DPBS), 1640 medium, green-streptomycin, fetal calf serum, nonessential amino acids, beta-mercaptoethanol (2-ME), human interferon gamma, LIVE/DEAD dye, dye (staining buffer), fixative (Fixation buffer), 0.25% pancreatin, EDTA, anti-human PD-L1, isotype control Anti-human PD-L1 (Anti-human PD-L1 Isotype).

1640 complete medium configuration: to 439.5 ml 1640 medium were added 50 ml fetal bovine serum, 5 ml non-essential amino acids, 5 ml green-streptomycin and 0.5 ml beta-liter mercaptoethanol and mixed well.

EDTA configuration at 10 mM: 1 ml of 0.5M EDTA was added to 49 ml of DPBS and mixed well.

The experimental steps are as follows:

1) MDA-MB-231 cell count and plating: the flask was removed, the medium removed and rinsed once with DPBS. After washing, 3 ml of 0.25% pancreatin was added to the flask and the flask was placed in an incubator at 37℃for 1.5min. The flask was removed and the reaction was stopped by adding 9 ml of 1640 complete medium, transferring the cells to a 50 ml centrifuge tube and centrifuging at 37℃for 5min at 1000 rpm. Appropriate volumes of culture medium were added to resuspend cells based on cell number and counted with a cytometer. The cell concentration was adjusted to 5X 10 with the medium ⁵ And each milliliter. And (3) paving: each of the 96-well platesA200. Mu.L volume of cell suspension was added to the wells so that the number of cells per well was 1X 10 ⁵ And each. Placed in an incubator for overnight incubation.

2) Drug incubation: a 100-fold compound dilution was prepared and the drug was diluted in a 5-fold gradient. mu.L of each 100-fold compound solution was added to each well cell. Incubate at 37℃for 24 hours. 3) PD-L1 cell staining and FACS detection: the plates were removed and the upper culture medium was discarded. 200 μL of 1-fold PBS was washed once. 100. Mu.L EDTA (final concentration 10 mM) was added and the mixture was treated at 37℃for 10min. 200. Mu.L of the staining solution was washed once after 5min at 1500 rpm. Dyeing: anti-human PD-L1 (2. Mu.L per well) and LIVE/DEAD dye (1:1000) were diluted in the dye, 50. Mu.L per well was added and stained at 4℃for 30min. 200. Mu.L of the staining solution was washed twice. Fixing: mu.L of the fixing solution was added to each well, and the mixture was fixed at 4℃for 15 minutes. 200. Mu.L of the staining solution was washed twice. 150. Mu.L of resuspended cells. FACS detection.

The experimental results are shown in Table 2.

TABLE 2 test results of the effect of the compounds of the invention on the expression level of PD-L1 in MDA-MR-231 cells

Test compounds	IC ₅₀ (nM)	Test compounds	IC ₅₀ (nM)
Formate of Compound 1	37.44	Compound 33	3.37
Formate of Compound 2	0.04	Compound 34	6.56
Formate of Compound 18	9.16	Compound 35	2.75
Compound 19	2.51	Compound 36	1.94
Formate of Compound 21	13.82	Compound 37	3.92
Compound 28	12.20	Compound 39	10.01
Compound 29	13.71	Compound 40 formate salt	4.17
Compound 30	8.93	Compound 41	3.07
Compound 31	17.06	Formate of Compound 42	7.37

Conclusion of experiment: the compound has obvious inhibiting effect on the expression level of PD-L1 of MDA-MR-231 cells.

Experimental example 3: NFAT activity assay

Experimental principle:

engineered T cell surface expression PD-1 molecules and T Cell Receptors (TCRs) can activate the NFAT signaling pathway of T cells after co-culture with engineered Antigen Presenting Cells (APCs). Expression of PD-L1 molecules on APC can effectively attenuate NFAT signaling pathways within T cells; the use of inhibitors against PD-L1 may be effective in blocking the PD-1/PD-L1 regulatory mechanism, thereby reversing the reduced NFAT signaling pathway. After pretreatment of small molecules and APC, co-culture with T cells, and then indirectly reflect the activation degree of NFAT pathway in T cells by detecting the expression level of luciferase.

Experimental materials:

PD1/PD-L1NFAT detection kit was purchased from BPS Biosciences. Birght-Glo reagent was purchased from Promega. Nivo Multi-labelling Analyzer (Perkinelmer).

The experimental method comprises the following steps:

paving the TCR activator/PD-L1 CHO cells with the growth confluence reaching 80% into plates according to 35000 cells per hole, and then placing the plates in a cell culture box at 37 ℃ for overnight; the test compounds were diluted 5-fold to the 8 th concentration, i.e. from 20. Mu.M to 0.25nM, with a DMSO concentration of 2% using a row gun, and a double multiplex well experiment was set up. The supernatant of TCR activator/PD-L1 CHO cells was discarded, 50. Mu.l of compound working solution was added to each well and incubated at 37℃for 30 minutes; after the incubation has ended, 50. Mu.L of the medium is added to each well at a density of 4 times 10 ⁵ Per ml of PD-1/NFAT Reporter-Jurkat cell suspension, incubated at 37℃for 5 hours. After the incubation was completed, 100. Mu.L Bright-Glo was added to each well, and after mixing, the chemiluminescent signal was read using a Nivo multi-standard analyzer.

Data analysis:

raw data was converted to inhibition, IC, using the equation (sample-Min)/(Max-Min). Times.100% ₅₀ The values of (a) can be obtained by curve fitting with four parameters (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 PD1/PD-L1 binding.

TABLE 3 results of test of inhibitory Activity of Compounds of the invention on PD1/PD-L1 binding

Conclusion of experiment: the compounds of the invention inhibit the interaction of PD-1/PD-L1 at the cellular level, thereby significantly activating the NFAT signaling pathway of T cells.

Experimental example 4: pharmacokinetic testing

The purpose of the experiment is as follows: study of the pharmacokinetics of Compounds in C57BL/6 mice in vivo

Experimental materials: c57BL/6 mouse (Male, 8 weeks old, weight 25g-30 g)

Experimental operation: the rodent drug-substitution profile of the compounds following Intravenous (IV) and oral (PO) administration was tested in standard protocols, with candidate compounds formulated as clear solutions at 1mg/mL in the experiments, and given to mice in a single intravenous and oral administration. Intravenous injection and oral vehicles are all 5% DMSO/5% 15-hydroxystearic acid polyethylene glycol ester (Solutol)/90% aqueous solution. Four male C57BL/6 mice were used for this project, two mice were given intravenous administration at a dose of 1mg/kg, and plasma samples of 0.0833,0.25,0.5,1,2,4,6,8, 24 hours after administration were collected, and the other two mice were given oral gavage administration at a dose of 10mg/kg, and plasma samples of 0.25,0.5,1,2,4,6,8, 24 hours after administration were collected. Collecting whole blood sample within 24 hr, centrifuging at 3000g for 15 min, separating supernatant to obtain plasma sample, adding acetonitrile solution containing internal standard to precipitate protein, mixing completely, centrifuging to obtain supernatant, introducing sample, quantitatively analyzing blood drug concentration by LC-MS/MS analysis method, and calculating drug generation parameters such as peak concentration (C) _max ) Clearance (CL), half-life (T _1/2 ) Tissue distribution (V _dss ) Area under the time curve (AUC _0-last ) Bioavailability (F), and the like.

The pharmacokinetic parameters of the compounds of the examples of the present invention in mice are shown in table 4 below.

TABLE 4 pharmacokinetic test results

Conclusion of experiment: the compounds of the present invention have good pharmacokinetic properties including good oral bioavailability, oral exposure, half-life, clearance, and the like.

Experimental example 5: pharmacodynamics evaluation study of the Compounds in C57BL/6-hPDL1 mouse colorectal cancer MC38-hPDL1 subcutaneous transplantation model Experimental purposes: the compounds were evaluated for their antitumor effect in mice colorectal cancer cells MC38-hPDL1 transplants humanized mice C57BL/6-hPDL 1.

Experiment design:

remarks: g: grouping; n: the animals are counted; p.o.: oral administration; BID: twice a day.

Experimental animals:

species of genus	A mouse
Strain of strain	C57BL/6-hPDL1
Level of	SPF stage
Week age	5.9～7.9
Sex (sex)	Female

The experimental method comprises the following steps:

1. tumor cell inoculation

Experimental cells: the MC38-hPDL1 cells of the colon cancer of the mice are revived, the revived times are Pn+7, the MC38-hPDL1 cells in the logarithmic phase are collected, the culture solution is removed, and the cells are inoculated after being washed twice by PBS (the survival rate of the MC38-hPDL1 cells before and after tumor loading is 97.4 percent and 96.5 percent respectively), and the inoculation amount is as follows: 1X 10 ⁶ 100. Mu.L/min, inoculation site: the right forelimb of the mouse.

2. Group administration

On day 7 post inoculation, the average tumor volume reached 89.02mm ³ At this time, mice were randomly divided into 5 groups of 8 mice each according to tumor volume. The day of grouping was defined as D0 and dosing was started on D0. The remaining mice were divided for subsequent supplemental experiments.

3. Pharmaceutical formulation

Dosing volume: adjustment according to mouse body weight (mouse administration volume=10. Mu.L/g×mouse body weight (g))

4. Experimental observation and data acquisition

Tumor size was observed on days D0, D2, D4, D7, D9, D11, D14, D16 after the start of dosing. The tumor volume calculation mode is as follows: tumor volume (mm) ³ ) =0.5× (tumor long diameter×tumor short diameter ² )。

5. End point of experiment

At the end of the experiment, the following indicators were analyzed: 1) Tumor volume change (TGItv); 2) Average body weight change; TGITV (relative tumor inhibition) calculation formula:

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

meanTVtn: average tumor volume of a given group when measured on day n

meanTVt0: average tumor volume of a given group when measured on day 0

meantmvn: mean tumor volume of solvent control group at day n

mean TVv0: mean tumor volume of the solvent control group at day 0 measurement

Experimental results: the evaluation of the tumor inhibition effect of the compound of the invention on the C57BL/6-hPDL1 mouse colorectal cancer MC38-hPDL1 subcutaneous transplantation model (calculated based on the tumor volume at 16 days after administration) is as follows:

The effect of the compounds of the invention on the average body weight of mice in the C57BL/6-hPDL1 mice colorectal cancer MC38-hPDL1 subcutaneous transplantation model is shown below:

group of	Average body weight (g) before administration (day 0)	Dosing balance weight (g) 16 th
Vehicle (blank)	18.9	19.9
Compounds of formula (I)33	19.0	19.6
Compound 35	19.1	19.9
Compound 37	19.2	19.6
Formate of Compound 42	19.1	19.7

Conclusion of experiment: the compound has excellent tumor inhibiting effect on a C57BL/6-hPDL1 mouse colorectal cancer MC38-hPDL1 subcutaneous transplantation model, and has the advantages of no obvious reduction of animal weight and good tolerance in the administration process.

Claims

A compound of formula (II) or a pharmaceutically acceptable salt thereof,

wherein,

ring a is absent or selected from 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl;

when ring A is absent, the building blockIs that

X is selected from CR ₇ And N;

y is selected from CR ₈ And N;

z is selected from C, CH and N;

e is selected from N and CR ₅ ；

L is selected from-CH ₂ -and-CH ₂ -NH-CH ₂ -；

R ₁ And R is ₂ Are independently selected from H, F, cl, br, I, CN and CH ₃ ；

R ₃ Selected from H and C _1-3 An alkoxy group;

R ₄ selected from C _1-3 Alkyl and 3-8 membered heterocycloalkyl, said C _1-3 Alkyl and 3-8 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3R _a Substitution;

R ₅ selected from H, CN, -OCH ₃ 、-OCHF ₂ Cyclopropyl and-C _1-3 alkyl-NH-C _1-3 alkyl-OH;

R ₆ are each independently selected from-C _1-6 alkyl-OH, -C _1-6 alkyl-COOH, -C _1-6 alkyl-C (=o) NH ₂ 、-C _1-3 alkyl-NH-C _1-3 alkyl-OH, -C _1-3 Alkyl-3-6 membered heterocycloalkyl-COOH, -C _1-3 Alkyl-3-6 membered heterocycloalkyl-OH, -C _1-3 alkyl-NH-C _1-3 Alkyl-3-6 membered heterocycloalkyl, C _1-6 Alkoxy, -C _1-3 Alkyl-5-6 membered heteroaryl-C _1-3 Alkyl, -C _1-3 alkyl-C _3-6 cycloalkyl-COOH, -C _1-3 Alkyl-5-6 membered heteroaryl, -C _1-3 alkyl-C _3-6 cycloalkyl-OH, -C _1-3 alkyl-C _3-6 cycloalkyl-C _1-3 alkyl-OH and-C _1-3 Alkyl-5-6 membered heterocyclesAn alkyl group;

R ₇ and R is ₈ Selected from H and CF, respectively and independently ₃ ；

R _a Are independently selected from H, F, cl, br, I, CN, OH, COOH, = O, C _1-3 Alkyl, C _1-3 Alkoxy, -C _1-3 alkyl-OH, -C (=o) NH ₂ 、-O-C _1-3 alkyl-OH, -C _1-3 alkyl-O-C _1-3 Alkane and-O-C _1-3 alkyl-O-C _1-3 An alkane;

n is selected from 0, 1 and 2.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R _a Are independently selected from H, OH, = O, CH ₃ 、-OCH ₃ 、-CH ₂ -OH、-C(＝O)NH ₂ 、COOH、
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ₁ And R is ₂ Are each independently selected from H, cl, CN and CH ₃ 。
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ₃ Selected from H and-OCH ₃ 。
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ₄ Selected from CH ₃ 、-CH ₂ -CH ₃ Azetidinyl, pyrrolidinyl, 2-azaspiro [3.3 ]]Heptyl and 8-azabicyclo [3.2.1]Octyl radical, the CH ₃ 、-CH ₂ -CH ₃ Azetidinyl, pyrrolidinyl, 2-azaspiro [3.3 ]]Heptyl and 8-azabicyclo [3.2.1]Octyl is optionally substituted with 1, 2 or 3R _a And (3) substitution.
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ₄ Selected from the group consisting of
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ₆ Are respectively and independently selected from
A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the structural unitSelected from the group consisting of
A compound according to claim 8, or a pharmaceutically acceptable salt thereofIn (a) structural unitSelected from the group consisting of
The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein the structural unitSelected from the group consisting of
A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of

Wherein R is ₁ 、R ₂ 、R ₃ 、R ₆ And R is _a As defined in any one of claims 1 to 7.
A compound or a pharmaceutically acceptable salt thereof selected from
A compound according to claim 12, or a pharmaceutically acceptable salt thereof, selected from