WO2023246870A1

WO2023246870A1 - Preparation, application and use of indole compound

Info

Publication number: WO2023246870A1
Application number: PCT/CN2023/101727
Authority: WO
Inventors: 别平彦; 周明伟; 彭建彪
Original assignee: 上海济煜医药科技有限公司
Priority date: 2022-06-23
Filing date: 2023-06-21
Publication date: 2023-12-28
Also published as: WO2023246870A9

Abstract

Disclosed in the present invention are a preparation, application and use of an indole compound, and particularly disclosed are a compound as shown in a formula (I), an optical isomer or pharmaceutically acceptable salt thereof, and using same for treating conditions and diseases associated with the alternative complement pathway activation.

Description

Preparation, application and uses of indole compounds

The present invention claims the following priority:

1) Application number CN202210782253.3, application date June 23, 2022;

2) Application number CN202211494575.4, application date is November 25, 2022.

Technical field

The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to the preparation, application and use of indole compounds.

Background technique

The complement system is a decisive component of the innate immune system and consists of a group of proteins that normally exist in an inactive state. These proteins are organized in three activation pathways: the classical pathway, the lectin pathway, and the alternative pathway. Molecules, antibodies or cellular components from microorganisms can activate these pathways, leading to the formation of protease complexes known as C3-convertase and C5-convertase. The classical pathway is a calcium/magnesium-dependent cascade that is typically activated by formation of antigen-antibody complexes. It is also activated by binding of C-reactive protein complexed with ligands and by many pathogens, including Gram-positive bacteria, in an antibody-independent manner. The alternative pathway is a magnesium-dependent cascade that is activated through the deposition and activation of C3 on certain sensitive surfaces (e.g., cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials).

There is currently little research on treating diseases or disorders associated with increased complement activity, and more and more research is needed.

Contents of the invention

In one aspect of the present invention, the present invention provides the compound represented by formula (I), its optical isomer or its pharmaceutically acceptable salt,

in,

R ₁ is selected from H, OH, CN, F, Cl, Br, I, C _1-6 alkyl, C _1-6 heteroalkyl and C _3-9 cycloalkyl, the C _1-6 alkyl, C _1-6 heteroalkyl or C _3-9 cycloalkyl is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br, I or C _1-6 alkyl;

R ₂ is selected from H, OH, CN, F, Cl, Br, I, C _1-6 alkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _3-9 cycloalkyl, phenyl and 5-9 membered heteroaryl, the C _1-6 alkyl, C _{1-6 heteroalkyl, C 2-6} _alkenyl , C _3-9 cycloalkyl, phenyl or 5-9 membered heteroaryl The group is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br, I or C _1-6 alkyl;

R ₃ is selected from phenyl, naphthyl and 5-9-membered heteroaryl, and the phenyl, naphthyl or 5-9-membered heteroaryl is optionally substituted by 1, 2 or 3 R _3A ;

R _3A are independently selected from C _1-6 alkyl, C(=O)OH, OH, CN, F, Cl, Br, I and

R ₄ is selected from H, OH, CN, F, Cl, Br, I, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, -C( =O)R ₉ , -C(=O)OR ₉ , -C(=O)N(H) _p (R ₉ ) _2-p and -NHC(=O)R ₉ , the C _1-6 alkane group, C _1-6 heteroalkyl group, -C(=O)R ₉ , -C(=O)OR ₉ , -C(=O)N(H) _p (R ₉ ) _2-p or -NHC( =O) R ₉ is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br or I;

Or R ₃ and R ₄ are connected together to form a benzo 5-6 membered heterocyclyl group, which is optionally replaced by 1, 2 or 3 -C(=O)OH, OH , CN, F, Cl, Br or I substitution;

R ₅ , R ₆ and R ₇ are each independently selected from H, C _1-6 alkyl, C _1-6 heteroalkyl, C _3-9 cycloalkyl, 3-9 membered heterocyclyl, -C _{1- 6alkyl} -C _3-9 cycloalkyl, -C _1-6 alkyl-3-9 membered heterocyclyl, -S(=O) ₂ R ₉ , -C(=O)R ₉ , -C( =O)OR ₉ , -C(=O)N(H) _p (R ₉ ) _2-p and -NHC(=O)R ₉ , the C _1-6 alkyl, C _1-6 heteroalkyl , C _3-9 cycloalkyl, 3-9 membered heterocyclyl, -C _1-6 alkyl-C _3-9 cycloalkyl, -C _1-6 alkyl-3-9 membered heterocyclyl, - S(＝O) ₂ R ₉ , -C(＝O)R ₉ , -C(＝O)OR ₉ , -C(＝O)N(H) _p (R ₉ ) _2-p or -NHC(＝ O) R ₉ is optionally replaced by 1, 2 or 3 R _5A ;

Or R ₅ and R ₇ are connected together to form a 5-6-membered heteroaryl or 5-6-membered heterocyclyl, and the 5-6-membered heteroaryl or 5-6-membered heterocyclyl is optionally replaced by 1, 2 or 3 R _7A substitutions;

Or R ₅ and R ₆ are connected together to form a 5-6-membered heteroaryl or 5-6-membered heterocyclyl, and the 5-6-membered heteroaryl or 5-6-membered heterocyclyl is optionally replaced by 1, 2 or 3 R _6A substitutions;

R _5A , R _6A , R _7A and R ₉ are each independently selected from H, OH, CN, F, Cl, Br, I, C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 ring Alkyl and 3-6 membered heterocyclyl, the C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally replaced by 1, 2 or 3 OH, CN, F, Cl, Br or I substitutions;

Represents a single bond or a double bond; (It should be noted here that the two places in the general compound of formula (I) It can be a double bond or a single bond at the same time, or one can be a single bond and the other a double bond)

when When it is a single bond, R ₆ and/or R ₇ are independently selected from H, OH, CN, F, Cl, Br, I, C _1-6 alkyl and C _1-6 heteroalkyl;

Or, when two When both are single bonds, R ₆ and R ₇ are connected together and form a 5-9-membered heterocyclic group with the skeleton where N(R ₅ ) is located. The 5-9-membered heterocyclic group is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br or I substitution;

when When it is a double bond, R ₆ and/or R ₇ are independently selected from O;

R ₈ is selected from H, OH, CN, F, Cl, Br, I, C _1-6 alkyl, C _1-6 heteroalkyl, phenyl and 5-6 membered heteroaryl, the C _1-6 Alkyl, C _1-6 heteroalkylphenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br, I or C _1-6 alkyl;

p is selected from 0, 1 or 2;

n is selected from 0, 1 or 2;

The C _1-6 heteroalkyl group, 3-9 membered heterocyclyl group, 5-9 membered heterocyclyl group, 5-6 membered heterocyclyl group, 5-9 membered heteroaryl group, and 5-6 membered heteroaryl group include 1, 2, 3 or 4 independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(=O) -, -S(=O) ₂ - and N heteroatoms or heteroatom groups.

In another aspect of the present invention, the present invention also proposes compounds represented by formulas (II-1)-(II-4), their optical isomers or their pharmaceutically acceptable salts, and their structures are as follows

in,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ are as defined before;

R _5X are independently selected from H, C _1-6 alkyl, C _1-6 heteroalkyl, C _3-9 cycloalkyl, 3-9 membered heterocyclyl, -C _1-6 alkyl-C _{3 -9} cycloalkyl, -C _1-6 alkyl, -3-9 membered heterocyclyl, -S(=O) ₂ R ₉ , -C(=O)R ₉ , -C(=O)OR ₉ , -C(=O)N(H) _p (R ₉ ) _2-p and -NHC(=O)R ₉ , the C _1-6 alkyl group, C _1-6 heteroalkyl group, C _3-9 ring Alkyl group, 3-9 membered heterocyclyl group, -C _1-6 alkyl-C _3-9 cycloalkyl group, -C _1-6 alkyl-3-9 membered heterocyclyl group, -S(=O) ₂ R ₉ , -C(=O)R ₉ , -C(=O)OR ₉ , -C(=O)N(H) _p (R ₉ ) _2-p or -NHC(=O)R ₉ optional Replaced by 1, 2 or 3 R _5A ;

R _5A is independently selected from H, OH, CN, F, Cl, Br, I, C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl and 3-6 membered heterocycle base, the C _1-6 alkyl group, C _1-6 heteroalkyl group, C _3-6 cycloalkyl group or 3-6 membered heterocyclic group is optionally replaced by 1, 2 or 3 OH, CN, F, Cl , Br or I substitution; R _10a , R _10b , R _10c , R _10d are independently selected from H, OH, CN, F, Cl, Br, I, C _1-6 alkyl, C _1-6 heteroalkyl and C _3-9 cycloalkyl, the C _1-6 alkyl, C _1-6 heteroalkyl or C _3-9 cycloalkyl is optionally replaced by 1, 2 or 3 OH, CN, F, Cl, Br, I or C _1-6 alkyl substitution;

m is selected from 0, 1, 2 or 3.

In another aspect of the present invention, the present invention also proposes compounds represented by formula (III-1) to formula (III-6), their optical isomers or their pharmaceutically acceptable salts, and their structures are as follows

in,

R ₄ is selected from H, OH, CN, F, Cl, Br, I, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, -C( =O)R ₉ , -C(=O)OR ₉ , -C(=O)N(H) _p (R ₉ ) _2-p and -NHC(=O)R ₉ , the C _1-6 alkane group, C _1-6 heteroalkyl group, -C(=O)R ₉ , -C(=O)OR ₉ , -C(=O)N(H) _p (R ₉ ) _2- _p or -NHC( =O) R ₉ is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br or I;

R _3A and R _3B are independently selected from H, C _1-6 alkyl, C(=O)OH, OH, CN, F, Cl, Br, I and

Or R _3B and R ₄ are connected together to form a 5-9 membered heterocyclyl group, which is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br or I;

R ₅ , R _5X , R ₆ and R ₇ are each independently selected from H, C _1-6 alkyl, C _1-6 heteroalkyl, C _3-9 cycloalkyl, 3-9 membered heterocyclyl, - C _1-6 alkyl-C _3-9 cycloalkyl, -C _1-6 alkyl-3-9 membered heterocyclyl, -S(=O) ₂ R ₉ , -C(=O)R ₉ , -C(=O)OR ₉ , -C(=O)N(H) _p (R ₉ ) _2-p and -NHC(=O)R ₉ , the C _1-6 alkyl group, C _1-6 Heteroalkyl, C _3-9 cycloalkyl, 3-9 membered heterocyclyl, -C _1-6 alkyl-C _3-9 cycloalkyl, -C _1-6 alkyl-3-9 membered heterocycle Base, -S(=O) ₂ R ₉ , -C(=O)R ₉ , -C(=O)OR ₉ , -C(=O)N(H) _p (R ₉ ) _2-p or - NHC(=O)R ₉ is optionally replaced by 1, 2 or 3 R _5A ;

Ring A is selected from 5-6-membered heterocyclyl and 5-6-membered heteroaryl, and the 5-6-membered heterocyclyl and 5-6-membered heteroaryl are optionally substituted by 1, 2 or 3 R _7A ;

Ring B is selected from 5-6-membered heterocyclyl and 5-6-membered heteroaryl, and the 5-6-membered heterocyclyl and 5-6-membered heteroaryl are optionally substituted by 1, 2 or 3 R _6A ;

R _10a , R _10b , R _10c , R _10d are each independently selected from H, OH, CN, F, Cl, Br, I, C _1-6 alkyl, C _1-6 heteroalkyl and C _3-9 ring Alkyl, the C _1-6 alkyl, C _1-6 heteroalkyl or C _3-9 cycloalkyl is optionally replaced by 1, 2 or 3 OH, CN, F, Cl, Br, I or C _{1 -6} alkyl substitution;

m is 0, 1 or 2;

In another aspect of the present invention, the present invention also provides compounds represented by formula (III-1-A)-formula (III-6-A), optical isomers thereof or pharmaceutically acceptable salts thereof, which The structure is as follows

The variables in the general formula are as defined in the present invention.

In some embodiments of the invention, R ₁ is selected from H, OH, CN, F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino and C _3-6 cycloalkyl, the C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino or C _3-6 Cycloalkyl is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br, I or C _1-4 alkyl, and the remaining variables are as defined in the present invention.

In some embodiments of the invention, _R1 is selected from methyl, and the remaining variables are as defined in the invention.

In some aspects of the invention, R ₂ is selected from H, OH, CN, F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _2-4 alkenyl, C _3-6 cycloalkyl, phenyl and 5-6 membered heteroaryl, the C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _2-4 alkenyl, C _3-6 cycloalkyl, phenyl or 5-6 membered heteroaryl are optionally replaced by 1, 2 or 3 OH, CN, F, Cl, Br, I or C _1-4 alkyl substitution, the remaining variables are as defined in the present invention.

In some embodiments of the invention, R ₂ is selected from methoxy, and the remaining variables are as defined in the invention.

In some embodiments of the invention, R ₃ is selected from phenyl and 5-6 membered heteroaryl, and the phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R _3A , and the remaining variables As defined herein.

In some aspects of the invention, R ₃ is selected from The remaining variables are as defined in the present invention.

In some embodiments of the invention, R ₄ is selected from H, OH, CN, F, Cl, Br, I, methyl, ethyl and CF ₃ , and the remaining variables are as defined in the invention.

In some aspects of the invention, R ₃ and R ₄ are joined together to form The remaining variables are as defined in the present invention.

In some aspects of the invention, R _3A is selected from H, C _1-3 alkyl, C(=O)OH, OH, CN, F, Cl, Br, I and

R ₄ is selected from H;

R _3B is selected from H;

Alternatively, R _3B and R ₄ are linked together to form a 5-6 membered heterocyclyl group optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br or I ; Alternatively, R _3B and R ₄ are connected together to form The remaining variables are as defined in the present invention. .

In some embodiments of the invention, R ₅ is selected from H, C _1-4 alkyl, -C _1-3 alkyl-C _3-6 cycloalkyl, C _3-6 cycloalkyl, -S(=O ) ₂ R ₉ and -C(=O)R ₉ , the C _1-4 alkyl, -C _1-3 alkyl, -C _3-6 cycloalkyl, C _3-6 cycloalkyl, -S( =O) ₂ R ₉ or -C(=O)R ₉ is optionally replaced by 1, 2 or 3 R _5A , The remaining variables are as defined in the present invention.

In some aspects of the invention, R _5A and R ₉ are independently selected from H, OH, CN, F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkoxy, C _{1- 4} alkylamino, C _1-4 alkylthio, C _3-6 cycloalkyl and 3-6 membered heterocyclyl, the C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl Amino, C _1-4 alkylthio, C _3-6 cycloalkyl or 3-6 membered heterocyclyl are optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br or I, and the remaining variables are as follows defined by the present invention.

In some aspects of the invention, R ₉ is independently selected from methyl, ethyl, CF ₃ , The remaining variables are as defined in the present invention.

In some aspects of the invention, R ₅ and R ₇ are joined together to form The remaining variables are as defined in the present invention.

In some aspects of the invention, Ring A is selected from described Optionally substituted by 1, 2 or 3 R _7A , the remaining variables are as defined in the invention.

In some embodiments of the invention, R _7A is independently selected from H, OH, CN, F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino , C _1-4 alkylthio group, C _3-6 cycloalkyl group and 3-6 membered heterocyclyl group, the C _1-4 alkyl group, C _1-4 alkoxy group, C _1-4 alkylamino group, C _1-4 alkylthio, C _3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br or I, and the remaining variables are as defined in the present invention. definition.

In some aspects of the invention, R _7A is independently selected from H, OH, CN, F, Cl, Br, I, methyl and CF ₃ , and the remaining variables are as defined in the invention.

In some aspects of the invention, Ring A is selected from The remaining variables are as defined in the present invention.

In some aspects of the invention, R ₅ and R ₆ are joined together to form The remaining variables are as defined in the present invention.

In some aspects of the invention, Ring B is selected from described Optionally substituted by 1, 2 or 3 R _6A , the remaining variables are as defined herein.

In some embodiments of the invention, R _6A is independently selected from H, OH, CN, F, Cl, Br, I, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino , C _1-4 alkylthio group, C _3-6 cycloalkyl group and 3-6 membered heterocyclyl group, the C _1-4 alkyl group, C _1-4 alkoxy group, C _1-4 alkylamino group, C _1-4 alkylthio, C _3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br or I, and the remaining variables are as defined in the present invention. definition.

In some aspects of the invention, R _6A is independently selected from H, OH, CN, F, Cl, Br, I, methyl and CF ₃ , and the remaining variables are as defined in the invention.

In some aspects of the invention, Ring B is selected from The remaining variables are as defined in the present invention.

In some embodiments of the invention, R ₅ is selected from H, methyl, ethyl, The remaining variables are as defined in the present invention.

In some embodiments of the invention, R _5X is selected from H, C _1-4 alkyl, -C _1-3 alkyl-C _3-6 cycloalkyl, C _3-6 cycloalkyl, -S(=O ) ₂ R ₉ and -C(=O)R ₉ , the C _1-4 alkyl, -C _1-3 alkyl, -C _3-6 cycloalkyl, C _3-6 cycloalkyl, -S( =O) ₂ R ₉ or -C(=O)R ₉ is optionally replaced by 1, 2 or 3 R _5A , and the remaining variables are as defined in the present invention.

In some aspects of the invention, R _5X is selected from H, methyl, ethyl, CF ₃ , The remaining variables are as defined in the present invention.

In another aspect of the present invention, the present invention also provides compounds of the following formula, their optical isomers or their pharmaceutically acceptable salts, which are selected from:

In another aspect of the present invention, the present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition contains the above-mentioned compound, its optical isomer and its pharmaceutically acceptable salt.

In some aspects of the present invention, the above-mentioned pharmaceutical composition further includes a pharmaceutically acceptable carrier or excipient.

In another aspect of the present invention, the present invention also proposes the use of the above-mentioned compounds, their optical isomers and pharmaceutically acceptable salts thereof or the above-mentioned pharmaceutical compositions in the preparation of drugs for the treatment of diseases related to the activity and expression of complement factor B. applications in.

In some solutions of the present invention, the diseases related to the activity and expression of complement factor B are selected from the group consisting of IgA nephropathy (IgAN), C3 glomerular disease (C3G), atypical hemolytic uremic syndrome (aHUS), membranous nephropathy ( MN), paroxysmal nocturnal hemoglobinuria (PNH), and other diseases related to the complement cascade, age-related macular degeneration (AMD), geographic atrophy (GA), hemodialysis complications, neuromyelitis (NMO), Liver disease, inflammatory bowel disease, myasthenia gravis (MG).

Definition and Description

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. Where a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.

As used herein, the phrase "at least one" when used in reference to a list of one or more elements shall be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including At least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that elements other than those specifically identified within the stated list of elements referred to by the phrase "at least one" may optionally be present, whether related or unrelated to those specifically identified elements.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases. When the compound of the present invention contains a relatively acidic functional group, it can be dissolved in a pure solution or a suitable inert solvent. Base addition salts are obtained by contacting the neutral form of such compounds with a sufficient amount of base in the preparation. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in 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, hydriodic acid, phosphorous acid, etc.; and organic acid salts, including acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, Similar acids such as suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also includes amino acids such as arginine etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.

The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.

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

A dash ("-") not between two letters or symbols indicates the attachment site of the substituent. For example, C _1-6 alkylcarbonyl—refers to a C _1-6 alkyl group attached to the rest of the molecule through a carbonyl group. However, when the attachment point of the substituent is obvious to one skilled in the art, for example, a halogen substituent, the "-" may be omitted.

When there is a dotted line on the valence bond of the group when, for example, , the dashed line indicates the point of attachment of the group to the rest of the molecule. When the single key has when, for example, , the dotted line represents a single bond or its absence, which also means represents a single key or double bond

The term "substituted" or "substituted by" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and variants of hydrogen, as long as the valence state of the specific atom is normal and the substituted compound is stable. The term "optionally substituted" or "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be based on what is chemically achievable. is arbitrary.

When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. Thus, for example, if a group is substituted by 1, 2 or 3 R', then said group may optionally be substituted by 1 or 2 or 3 R', and in each case R' All have independent options. Furthermore, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.

When one of the variables is selected from a single bond, it means that the two groups to which it is connected are directly connected, e.g. When L ₁ represents a single bond, it means that the structure is actually

When a listed substituent does not indicate through which atom it is connected to the substituted group, the substituent may be connected to the substituted group through its atom. Any atom is bonded. For example, a pyridyl group as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

When the listed linking groups do not specify the direction of connection, the direction of connection is arbitrary, for example, The middle connecting group L is -CH ₂ O-. At this time, -CH ₂ O- can be formed by connecting phenyl and cyclopentyl in the same direction as the reading order from left to right. It can also be composed by connecting phenyl and cyclopentyl in the opposite direction to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Unless otherwise specified, the number of atoms on a ring is usually defined as the number of ring members. For example, a "3-6 membered ring" refers to a "ring" with 3-6 atoms arranged around it.

Unless otherwise specified, the term "C _1-6 alkyl" is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C _1-6 alkyl group 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 can Is it monovalent (such as CH ₃ ), bivalent (-CH ₂ -) or polyvalent (such as ). Examples of C _1-6 alkyl groups include, but are not limited to, CH ₃ , wait.

Unless otherwise specified, the term "C _1-4 alkyl" is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C _1-4 alkyl group includes C _1-2 , C _1-3 , C _3-4 and C _2-3 alkyl groups, etc.; it can be monovalent (such as CH ₃ ), divalent (-CH ₂ - ) or multiple prices (such as times ). Examples of C _1-4 alkyl groups include, but are not limited to, CH ₃ , wait.

Unless otherwise specified, "C _2-6 alkenyl" is used to mean a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond. Can be located anywhere on the group. The C _2-6 alkenyl group includes C _2-4 , C _2-3 , C ₄ , C ₃ and C ₂ alkenyl groups, etc.; it can be monovalent, divalent or multivalent. Examples of C _2-6 alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene, hexadienyl, and the like.

Unless otherwise specified, "C _2-3 alkenyl" is used to mean a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, carbon-carbon double bond Can be located anywhere on the group. The C _2-3 alkenyl group includes C ₃ and C ₂ alkenyl groups; the C _2-3 alkenyl group can be monovalent, divalent or multivalent. Examples of C _2-3 alkenyl groups include, but are not limited to wait.

Unless otherwise specified, "C _2-6 alkynyl" is used to mean a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, carbon-carbon triple bond Can be located anywhere on the group. It can be monovalent, bivalent or polyvalent. The C _2-6 alkynyl group includes C _2-3 , C _2-4 , C _{2-5, C 3-4} _, C _3-5 , C _3-6 , C _4-5 , C _4-6 , C _5-6 , C ₆ , C ₅ , C ₄ , C ₃ and C ₂ alkynyl. Examples of C _2-6 alkynyl groups include, but are not limited to wait.

Unless otherwise specified, "C2-3 alkynyl" is used to mean a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may anywhere in the group. It can be monovalent, bivalent or polyvalent. The C _2-3 alkynyl group includes C ₃ and C ₂ alkynyl groups. Examples of C _2-3 alkynyl groups include, but are not limited to wait.

The term "oxo" refers to an oxygen atom that is double bonded to a carbon atom or another element, including to the nitrogen of the pyridine ring, to form pyridine N-oxide. For example, the term "oxo 5-6 membered heteroaryl" includes, but is not limited to

The term "heteroalkyl" by itself or in combination with another term refers to a stable linear or branched alkyl group or a combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatoms are selected from B, O, N, and S, where Nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) ₂ N(H)- and -S(=O)N( H)-. In some embodiments, the heteroalkyl group is C _1-6 heteroalkyl; in other embodiments, the heteroalkyl group is C _1-3 heteroalkyl. Heteroatoms or groups of heteroatoms can be located at any internal position of a heteroalkyl group, including where the alkyl group is attached to the rest of the molecule, but the term "alkoxy" is a conventional expression meaning attachment to the rest of the molecule through an oxygen atom of those alkyl groups. Examples of heteroalkyl groups include, but are not limited to, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ CH ₃ , -OCH ₂ (CH ₃ ) ₂ , -CH ₂ -CH ₂ -O-CH ₃ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ )(CH ₂ CH ₃ ), -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N( CH ₃ )-CH ₃ , -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH ₂ (CH ₃ ) ₂ , -CH ₂ -S-CH ₂ -CH ₃ , -CH ₂ - CH ₂ , -S(=O)-CH ₃ , -CH ₂ -CH ₂ -S(=O) ₂ -CH ₃ , and up to two heteroatoms may be consecutive, for example -CH ₂ -NH-OCH ₃ .

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 an oxygen atom. The C _1-6 alkoxy group includes C _1-4 , C1 _-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ and C ₃ alkoxy groups, etc. Examples of C _1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy oxygen group, s-butoxy group and t-butoxy group), pentyloxy group (including n-pentyloxy group, isopentyloxy group and neopentyloxy group), hexyloxy group, etc.

Unless otherwise specified, the term "C _1-3 alkoxy" means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom. The C _1-3 alkoxy group includes C _1-3 , C _1-2 , C _2-3 , C ₁ , C ₂ and C ₃ alkoxy groups, etc. Examples of C _1-3 alkoxy 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 attached to the remainder of the molecule through an amino group. The C _1-6 alkylamino group 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 group wait. Examples of C _1-6 alkylamino 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 _1-3 alkylamino group includes C _1-3 , C _1-2 , C _2-3 , C ₁ , C ₂ and C ₃ alkylamino groups, etc. Examples of C _1-3 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 "C _1-6 alkylthio" means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through a sulfur atom. The C _1-6 alkylthio group 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 alkane Sulfur group etc. Examples of C _1-6 alkylthio groups include, but are not limited to, -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH ₂ (CH ₃ ) ₂ , and the like.

Unless otherwise specified, the term "C _1-3 alkylthio" means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through a sulfur atom. The C _1-3 alkylthio group includes C _1-3 , C _1-2 , C _2-3 , C ₁ , C ₂ and C ₃ alkylthio groups, etc. Examples of C _1-3 alkylthio groups include, but are not limited to, -SCH ₃ , -SCH ₂ CH ₃ , -SCH ₂ CH ₂ CH ₃ , -SCH ₂ (CH ₃ ) ₂ , and the like.

Unless otherwise specified, "C _3-6 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C _3-6 cycloalkyl group includes C _3-5 , C _4-5 and C _5-6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent. Examples of C _3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

Unless otherwise specified, the term "3-9 membered heterocyclyl" by itself or in combination with other terms means a saturated or partially unsaturated cyclic group consisting of 3 to 9 ring atoms, of which 1, 2, 3 or 4 Two ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes single-ring and double-ring systems, where the double-ring system includes spiro rings, parallel rings and bridged rings. Furthermore, in the case of the "3-9 membered heterocyclyl", the heteroatom may occupy the attachment position of the heterocyclyl to the rest of the molecule. The 3-9-membered heterocyclic group includes 3-8-membered, 3-7-membered, 3-6-membered, 3-5-membered, 3-4-membered, 4-5-membered, 4-6-membered, 4-7-membered, 4-8 yuan, 4-9 yuan, 5-6 yuan, 5-7 yuan, 5-8 yuan, 5-9 yuan, 6-7 yuan, 6-8 yuan, 6-9 yuan, 7-8 yuan, 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered and 9-membered heterocyclic groups, etc. Examples of 3-9 membered heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl base, thietanyl, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydrofuranyl Hydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), methyl Phyllinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxalyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2 - Thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

Unless otherwise specified, the term "3-6 membered heterocyclyl" by itself or in combination with other terms means a saturated or partially unsaturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which Two ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes single-ring and double-ring systems, where the double-ring system includes spiro rings, parallel rings and bridged rings. Furthermore, in the case of the "3-6 membered heterocyclyl", the heteroatom may occupy the attachment position of the heterocyclyl to the rest of the molecule. The 3-6-membered heterocyclic groups include 4-6-membered, 5-6-membered, 4-membered, 5-membered and 6-membered heterocyclic groups, etc. Examples of 3-6 membered heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydrofuranyl Hydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), methyl Phyllinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxalyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2 - Thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

Unless otherwise specified, the term "5-6 membered heterocyclyl" by itself or in combination with other terms means a saturated or partially unsaturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which Two ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes single-ring and double-ring systems, where the double-ring system includes spiro rings, parallel rings and bridged rings. Furthermore, in the case of the "5-6 membered heterocyclyl", the heteroatom may occupy the attachment position of the heterocyclyl to the rest of the molecule. The 5-6 membered heterocyclyl group includes 5-membered and 6-membered heterocyclyl groups, etc. Examples of 5-6 membered heterocyclyl groups include, but are not limited to, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydrofuranyl Hydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), methyl Phyllinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxalyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2 - Thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

Unless otherwise specified, the terms "5-9 membered heteroaromatic ring" and "5-9 membered heteroaryl" can be used interchangeably in the present invention. The term "5-9 membered heteroaryl" means from 5 to 9 ring atoms. It consists of a monocyclic group with a conjugated π electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). A 5- to 9-membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-9 yuan heteroaryl group includes 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 5 yuan and 6 yuan heteroaryl. Examples of the 5-9-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl). azolyl group, etc.), imidazolyl group (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl) Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2 -pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.).

Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" may be used interchangeably in the present invention, and the term "5-6 membered heteroaryl" means 5 to 6 ring atoms. It consists of a monocyclic group with a conjugated π electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). A 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl include but are not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl). azolyl group, etc.), imidazolyl group (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl) Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-thienyl, etc.) -pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.).

Unless otherwise specified, C _n-n+m or C _n -C _n+m includes any specific case of n to n+m carbons, for example, C _1-12 includes 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 include any range from n to n+m, for example, C _1-12 includes 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 yuan to n The +m member indicates that the number of atoms in the ring is n to n+m. For example, a 3-12 membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, and a 9-membered ring. , 10-membered ring, 11-membered ring, and 12-membered ring, also including any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring ring, 5-7-membered ring, 5-10-membered ring, 6-7-membered ring, 6-8-membered ring, 6-9-membered ring and 6-10-membered ring, etc.

The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction, such as an affinity substitution reaction. For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate Ester, etc.; acyloxy group, such as acetoxy group, trifluoroacetoxy group, etc.

The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4′-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.

It will be understood by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and thus two or more stereoisomers exist. Accordingly, the compounds of the invention may exist in the form of individual stereoisomers (e.g. enantiomers, diastereomers) and mixtures in any proportions, e.g. racemates, and, where appropriate, Can exist in the form of its tautomers and geometric isomers.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of protection of the present invention.

The term "stereoisomer" as used herein refers to compounds that have the same chemical constitution but differ in the spatial arrangement of atoms or groups. Stereoisomers include enantiomers, diastereomers and conformational isomers.

The term "enantiomers" as used herein refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

The term "diastereomer" as used herein refers to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography such as HPLC.

Stereochemical definitions and conventions may be followed from S.P. Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons , Inc., New York, 1994. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign of a compound's rotation of plane-polarized light, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be called enantiomers, and mixtures of such isomers are often called enantiomeric mixtures. A 50:50 mixture of enantiomers, known as a racemic mixture or racemate, can occur in a chemical reaction or process without stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that are not optically active.

The racemic mixture can be used in its own form or separated into the individual isomers. By resolution, stereochemically pure compounds can be obtained or mixtures enriched in one or more isomers. Methods for separating isomers are well known (see Allinger N.L. and Eliel E.L., "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) and include physical methods such as chromatography using chiral adsorbents. Chiral forms of individual isomers can be prepared from chiral precursors. Alternatively, it can be prepared by combining individual enantiomers with chiral acids (e.g., 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.) Chemical separation of the mixture to obtain the individual isomers is accomplished by forming diastereomeric salts, fractionally crystallizing said salts, and then freeing one or both of the separated bases, optionally repeating this process, thereby One or both isomers are obtained substantially free of the other isomer, i.e. with an optical purity by weight of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% of the desired stereoisomer. Alternatively, as is well known to those skilled in the art, the racemate can be covalently linked to the chiral compound (auxiliary) to give the diastereomers.

The compounds of the present invention may exist in specific species. Unless otherwise stated, the term "tautomer" or "tautomeric form" means that at room temperature, isomers with different functional groups are in dynamic equilibrium and can quickly convert into each other. If tautomers are possible (eg in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enol isomerization. Amine isomerization. Valence tautomers include interconversions through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the tautomerization between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds can be labeled with radioactive isotopes such as tritium ( ^3H ), iodine-125 ( ^125I ) or C-14 ( ^14C ). For another example, deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

"Optional" or "optionally" means that the subsequently described event or condition may but need not occur, and that the description includes instances in which the stated event or condition occurs and instances in which it does not occur.

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

The solvent used in the present invention is commercially available.

Compounds are named according to conventional naming principles in the field or use For software naming, commercially available compounds adopt supplier catalog names.

The compounds disclosed in the present invention may have one or more chiral centers, and each chiral center independently has an R configuration or an S configuration. The chiral center of some compounds disclosed in the present invention is marked *R, *S, R*, or S*, which means that the absolute configuration of the chiral center of the compound has not been identified, but the compound has been chirally resolved and the chirality The center is a chiral center with a single configuration. The compound is an enantiomeric monomer with a single configuration, a diastereoisomer monomer with a single configuration, or a diastereomer with a single configuration of the chiral center. Mixture of isomers (for example: other chiral center configurations are not resolved). When the absolute configuration (R configuration, or S configuration) of the chiral center of the compound disclosed in the present invention has not been identified, this type of compound can be determined according to its corresponding chromatography column conditions (such as chromatography column model, chromatography column packing) , column size, mobile phase, etc.) to confirm the corresponding retention time (RT).

The invention is explained more specifically in the following examples. However, it should be understood that these examples are intended to illustrate the invention and do not limit the scope of the invention in any way. In the following examples, if the experimental methods do not indicate specific conditions, they usually follow the conventional conditions of this type of reaction, or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight. Unless stated otherwise, ratios of liquids are by volume.

Technical and scientific terms not specifically defined used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

Detailed ways

The present application is described in detail below through examples, but does not mean that there are any adverse limitations to the present application. The present application has been described in detail, and its specific embodiments have also been disclosed. For those skilled in the art, various changes and improvements can be made to the specific implementations of the present application without departing from the spirit and scope of the present application. will be obvious.

The raw materials used in the present invention are all commercially available unless otherwise specified.

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR was measured using a BrukerASCEND ^TM -400 nuclear magnetic instrument. The measurement solvents were deuterated sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD). The internal standard was tetramethylsilane. (TMS).

MS was measured using Agilent 6110, Agilent 1100, Agilent 6120, and Agilent 6125B liquid chromatography mass spectrometers.

HPLC measurement used Shimadzu HPLC-2010C high-pressure liquid chromatograph (XBRIDGE 2.1*50mm, 3.5μm column).

Chiral HPLC analysis was performed using THARSFC X5.

The thin layer chromatography silica gel plate uses Yantai Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.2mm. The specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm. .

Column chromatography generally uses Qingdao Ocean Silica Gel 200-300 mesh silica gel as the carrier.

High-performance liquid phase preparation uses Waters2767, Waters2545, and Innovation Hengtong LC3000 preparative chromatographs.

Chiral preparative column chromatography uses Shimadzu LC20-AP and THARSFC PREP80.

The pressurized hydrogenation reaction uses Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

Microwave reaction uses Biotage initiator+ type microwave reactor.

Unless otherwise specified in the experimental examples, the reactions were carried out under an argon atmosphere or a nitrogen atmosphere.

Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 liter.

The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 liter.

Unless otherwise specified in the experimental examples, the reaction temperature is room temperature, and the temperature range is 20°C-30°C.

Example 1: Synthesis of Compound 1

Step 1: Preparation of Compound 1-2

Compound 1-1 (5.00g, 19.1mmol), 2-chloropyrazine (2.62g, 22.9mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (1.40 g, 1.91 mmol) and potassium phosphate (12.2 g, 57.23 mmol) were dissolved in 1,4-dioxane/water (50/15 mL). The reaction system was stirred at 100°C for 12 hours. LCMS showed the reaction was complete. Add water (50 mL) to quench, and extract with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 1- 2 (3.20g, yield: 78.3%).

LC-MS(ESI)[M+H] ⁺ 214.6.

Step 2: Preparation of Compounds 1-3

Compound 1-2 (1.00 g, 4.67 mmol) was dissolved in methanol (10 mL). Palladium on carbon (552.84 mg, 0.47 mmol, 10 wt%) and one drop of concentrated hydrochloric acid were added. The reaction was stirred at room temperature for 4 hours under the protection of hydrogen gas. LCMS showed the reaction was complete. After filtration and concentration under reduced pressure, crude compound 1-3 (1.00g) was obtained. The crude product was used directly in the next reaction without further purification.

LC-MS(ESI)[M+H] ⁺ 220.8.

Step 3: Preparation of Compounds 1-4

Add 4A molecular sieve (1.00g) into a three-necked flask (50mL), and heat with a heat gun for 10 minutes to dry. After the system was cooled to room temperature, crude compound 1-3 (1.00g), 3-oxetanone (294mg, 4.09mmol), sodium borohydride acetate (1.92g, 9.08mmol) and 1,2-dichloroethyl were added. alkane (20 mL). The reaction solution was stirred at 40°C for 12 hours. LCMS showed the reaction was complete. The reaction system was filtered and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (water/acetonitrile = 6/4) to obtain compound 1-4 (1.00 g, two-step total yield: 77.5%).

LC-MS(ESI)[M+H] ⁺ 277.1

Step 4: Preparation of Compounds 1-5

Add 4A molecular sieve (1.00g) into a three-necked flask (50mL), and heat with a heat gun for 10 minutes to dry. After the system was cooled to room temperature, compound 1-4 (300 mg, 1.09 mmol), 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (377 mg, 1.30 mmol), sodium borohydride acetate (690 mg, 3.26 mmol) and 1,2-dichloroethane (20 mL). The reaction solution was stirred at 40°C for 12 hours. LCMS showed the reaction was complete. The reaction system was filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 1-5 (200 mg, yield: 33.5%).

LC-MS(ESI)[M+H] ⁺ 549.8.

Step 5: Preparation of Compound 1

Compound 1-5 (200 mg, 364 μmol) was dissolved in water/methanol/tetrahydrofuran (5 mL/5 mL/5 mL), and lithium hydroxide monohydrate (76.3 mg, 1.82 mmol) was added. The reaction solution was stirred at 40°C for 12 hours. LCMS showed the reaction was complete. The reaction system was filtered and concentrated under reduced pressure. The obtained crude product was purified by preparative-HPLC to obtain compound 1 (49.0 mg, yield: 30.9%).

LC-MS(ESI)[M+H] ⁺ 436.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.84 (d, J = 2.4Hz, 1H), 8.40 (s, 1H), 7.99-7.89 (m, 2H), 7.64 (d, J = 7.7Hz, 2H), 7.25 (t, J=2.8Hz, 1H), 6.66 (s, 1H), 6.42 (dd, J=3.1, 1.9Hz, 1H), 4.53-4.34 (m, 4H), 3.71 (s, 3H ), 3.58(d, J=11.8Hz, 1H), 3.41 (dd, J=10.3, 2.8Hz, 1H), 3.34 (q, J=6.3Hz, 1H), 3.24 (d, J=11.8Hz, 1H), 2.69-2.55 ( m, 3H), 2.42 (s, 3H), 2.23 (dd, J=12.6, 10.0Hz, 1H), 1.95-1.76 (m, 2H).

Example 2: Synthesis of Compounds 2a and 2b

Step 1: Preparation of compound 2-2

Compound 2-1 (5.00g, 19.5mmol) and N-methylethylenediamine (1.44g, 19.5mmol) were dissolved in toluene (50mL). The reaction system liquid was stirred at 110°C for 12 hours. LCMS showed the reaction was complete. Add water (100 mL) to quench, and extract with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 2- 2 (2.30g, yield: 44.3%).

LC-MS(ESI)[M+H] ⁺ 266.6.

Step 2: Preparation of Compound 2-3

Compound 2-2 (2.00g, 7.49mmol) was dissolved in N-methylpyrrolidone (20mL), and then copper cyanide (1.34g, 15.0mmol) was added. The reaction solution was stirred in the microwave at 170°C for 4 hours. LCMS showed the reaction was complete. Add water (50 mL) to quench, and extract with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 2- 3 (1.20g, yield: 75.2%).

LC-MS(ESI)[M+H] ⁺ 213.6.

Step 3: Preparation of Compound 2-4

At room temperature, intermediate 2-3 (800 mg, 3.75 mmol) was dissolved in a mixed solvent (water/isopropyl alcohol = 21/7 mL), and then barium hydroxide octahydrate (5.91 g, 18.7 mmol) was added. The reaction mixture was stirred at 100°C for 16 hours. LCMS showed the reaction was complete. Adjust pH=5-6 with half-saturated potassium hydrogen sulfate aqueous solution. Extract with ethyl acetate (50mL×3). The combined organic phases were washed with water (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude compound 2-4 (800 mg). The crude product was used directly in the next reaction without further purification.

LC-MS(ESI)[M+H]+231.0.

Step 4: Preparation of Compounds 2-5

Oxalyl chloride (1.10 g, 8.69 mmol) was added dropwise to methanol (10 mL) at 0°C, and stirred for 15 minutes. A solution of compound 2-4 (500 mg, 2.17 mmol) in methanol (10 mL) was then added. After the addition was completed, the reaction mixture was stirred at 40°C for 2 hours. LCMS showed the reaction was complete. Add water (50 mL) to quench, extract with dichloromethane (100 mL Ether/ethyl acetate = 4/1) was isolated and purified to obtain compound 2-5 (300 mg, two-step total yield 52.4%). LC-MS(ESI)[M+H] ⁺ 244.6.

Step 5: Preparation of Compound 2-6

Compound 2-5 (200 mg, 0.820 mmol) was dissolved in methanol (10 mL), and then palladium on carbon (194 mg, 0.160 mmol, 10 wt%) was added. The reaction solution was stirred at room temperature for 4 hours under the protection of hydrogen gas. LCMS showed the reaction was complete. The reaction system was filtered and concentrated under reduced pressure to obtain crude compound 2-6 (200 mg). The crude product was used directly in the next reaction without further purification.

LC-MS(ESI)[M+H] ⁺ 249.0.

Step 6: Preparation of Compounds 2-7

Add 4A molecular sieve (1.00g) into a three-necked flask (50mL), and heat with a heat gun for 10 minutes to dry. After the system was cooled to room temperature, crude compound 2-6 (200 mg) and 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (466 mg, 1.61 mmol) were added. , sodium borohydride acetate (682.90 mg, 3.22 mmol) and 1,2-dichloroethane (20 mL). The reaction solution was stirred at 40°C for 12 hours. LCMS showed the reaction was complete. The reaction system was filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain compound 2-7 (50.0 mg, two-step total yield: 11.7%).

LC-MS(ESI)[M+H] ⁺ 522.2.

Step 7: Preparation of Compound 2

Compound 2-7 (50.0 mg, 95.9 μmol) was dissolved in a water/methanol/tetrahydrofuran mixed solvent (5 mL/5 mL/5 mL) at room temperature, and then lithium hydroxide monohydrate (20.1 mg, 479 μmol) was added. The reaction solution was stirred at 40°C for 12 hours. LCMS showed the reaction was complete. The reaction system was filtered and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to obtain compound 2 (10.0 mg, yield: 25.6%).

LC-MS(ESI)[M+H] ⁺ 408.2.

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.86 (d, J = 2.4Hz, 1H), 7.89 (d, J = 8.1Hz, 2H), 7.45 (d, J = 7.9Hz, 2H), 7.22 (t, J=2.8Hz, 1H), 6.68 (s, 1H), 6.19 (dd, J=3.1, 1.9Hz, 1H), 4.01 (s, 1H), 3.71 (s, 3H), 3.53 (s, 2H), 3.32 (td, J=10.8, 10.0, 4.1Hz, 1H), 3.16 (dt, J=11.9, 3.5Hz, 1H), 2.82 (s, 3H), 2.80 (d, J=4.5Hz, 1H ), 2.47(d, J=2.6Hz, 1H), 2.42(s, 3H).

Step 8: Preparation of Compounds 2a and 2b

Compound 2 (22.0 mg) was passed through SFC (column AD (250*25mm, 10μm)); mobile phase [A: carbon dioxide, B: methanol (containing 0.1% 7.0mol/L ammonia)]; B%: 0% ~ 50% to obtain compound 2a (retention time 3.236 minutes) and Compound 2b (retention time 1.028 minutes). Retention times were determined using the following analytical method: Column: IB, 250*25mm, 10μm, mobile phase [A: carbon dioxide, B: methanol (containing 0.1% 7.0mol/L ammonia)], 50% B, flow rate: 70mL/min, column temperature: 35°C. Compound 2a (7.09 mg, recovery rate 32.2%) and compound 2b (7.69 mg, recovery rate 35.0%) were separated by SFC.

Compound 2a, LC-MS (ESI) [M+H] ⁺ 408.2. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 10.85 (s, 1H), 7.94 (d, J = 8.2Hz, 2H), 7.56 (d, J=8.1Hz, 2H), 7.23 (t, J=2.7Hz, 1H), 6.68 (s, 1H), 6.25-6.17 (m, 1H), 4.08 (d, J=13.5Hz, 1H) , 3.70 (s, 3H), 3.54 (s, 2H), 3.34 (s, 1H), 3.17 (d, J = 11.9Hz, 1H), 2.82 (d, J = 7.1Hz, 4H), 2.47 (s, 1H), 2.42(s, 3H).

Compound 2b, LC-MS (ESI) [M+H] ⁺ 408.2. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 10.85 (s, 1H), 7.94 (d, J = 8.2Hz, 2H), 7.56 (d, J=8.1Hz, 2H), 7.23 (t, J=2.7Hz, 1H), 6.68 (s, 1H), 6.25-6.17 (m, 1H), 4.08 (d, J=13.5Hz, 1H) , 3.70 (s, 3H), 3.54 (s, 2H), 3.34 (s, 1H), 3.17 (d, J = 11.9Hz, 1H), 2.82 (d, J = 7.1Hz, 4H), 2.47 (s, 1H), 2.42(s, 3H).

Example 3: Synthesis of Compound 3

Step 1: Preparation of compound 3-2

At room temperature, compound 3-1 (450 mg, 2.69 mmol), methyl p-formate, phenylboronic acid (532 mg, 2.95 mmol) and cesium carbonate (2.62 g, 8.06 mmol) were dissolved in a mixed solvent (ethylene glycol dimethyl ether/water =10/2mL). The catalyst [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (98.2 mg, 0.130 mmol) was added to replace the argon gas. The reaction mixture was stirred at 90°C for 4 hours. LCMS showed the reaction was complete. Cool to room temperature, dilute with water (20 mL), and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (50 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 5/1). Compound 3-2 (416 mg, product rate: 57.9%).

LC-MS(ESI)[M+H] ⁺ 268.3.

Step 2: Preparation of compound 3-3

Compound 3-2 (200 mg, 0.750 mmol) was dissolved in a mixed solvent (isopropyl alcohol/tetrahydrofuran=10/10 mL) at room temperature. Palladium on carbon (182 mg, 0.150 mmol, 10 wt%) was added to replace hydrogen. The reaction mixture was stirred at room temperature for 12 hours. LCMS showed the reaction was complete. The reaction system was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by reversed-phase column chromatography [acetonitrile/water (containing 0.03% ammonia water) = 1/1] to obtain compound 3-3 (147 mg, yield: 72.3%).

LC-MS(ESI)[M+H] ⁺ 272.3.

Step 3: Preparation of Compound 3-4

Compound 3-3 (147 mg, 0.540 mmol) was dissolved in dichloroethane (5 mL) at room temperature, and 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid was added. Butyl ester (312.48 mg, 1.08 mmol) and type 3A molecular sieve (200 mg). After stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (344.61 mg, 1.63 mmol) was added. After the addition was completed, the reaction mixture was stirred at room temperature for 48 hours. LCMS showed the reaction was complete. Add water (10 mL) to dilute, filter, and rinse the filter cake with dichloromethane (10 mL). The filtrate was extracted with dichloromethane (40 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by reversed-phase column chromatography [acetonitrile/water (0.03% formic acid) = 2/1] to obtain target compound 3-4 (171 mg, Yield: 58.0%).

LC-MS(ESI)[M+H] ⁺ 545.4.

Step 4: Preparation of Compound 3

Compound 3-4 (170 mg, 0.310 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=2/2/1 mL) at room temperature. Lithium hydroxide monohydrate (65.5 mg, 1.56 mmol) was then added. After the addition was completed, the reaction mixture was stirred at 50°C for 12 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 3 (49.1 mg, yield: 36.6%).

LC-MS(ESI)[M+H] ⁺ 431.3.

¹ H NMR (400MHz, CD ₃ OD) δ7.98 (d, J=8.1Hz, 2H), 7.36 (d, J=8.1Hz, 2H), 7.15 (d, J=3.1Hz, 1H), 6.71 ( d, J=6.7Hz, 2H), 6.26 (d, J=3.1Hz, 1H), 4.73 (s, 1H), 4.03-3.97 (m, 1H), 3.93-3.84 (m, 2H), 3.82-3.75 (m, 4H), 3.20-3.12 (m, 1H), 2.79-2.71 (m, 1H), 2.47 (s, 3H), 2.09 (s, 3H).

Example 4: Synthesis of Compound 4

Step 1: Preparation of compound 4-2

Compound 4-1 (1.00g, 7.72mmol), 3-bromo-1,1,1-trifluoroacetone (5.92g, 31.0mmol) and 3A molecular sieve (400mg) were mixed with ethylene glycol dimethyl ether (12mL) in, replacing argon. The reaction system was stirred at 90°C for 4 hours. LCMS showed the reaction was complete and cooled to room temperature. Dilute with water (50 mL) and extract with ethyl acetate (100 mL × 3). The combined organic phases were washed successively with water (80 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 2/1). Compound 4-2 (644 mg, yield: 37.7%) was obtained.

LC-MS(ESI)[M+H] ⁺ 222.2.

Step 2: Preparation of compound 4-3

At room temperature, compound 4-2 (380 mg, 1.72 mmol), methyl p-formate phenylboronic acid (340 mg, 1.89 mmol) and cesium carbonate (1.68 g, 5.16 mmol) were dissolved in a mixed solvent (ethylene glycol dimethyl ether/water =10/2mL). Then the catalyst [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (62.9 mg, 86.0 μmol), replacing argon. The reaction system was stirred at 90°C for 4 hours, and LCMS showed that the reaction was complete. Cool to room temperature, dilute with water (20 mL), and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (50 mL) and saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 2/1). Compound 4-3 (298 mg, yield: 54.0%) was obtained.

LC-MS(ESI)[M+H] ⁺ 322.2.

Step 3: Preparation of compound 4-4

Compound 4-3 (298 mg, 0.930 mmol) was dissolved in a mixed solvent (isopropyl alcohol/tetrahydrofuran=6/6 mL) at room temperature. Palladium on carbon (226 mg, 0.186 mmol, 10 wt%) was then added to replace hydrogen. The reaction system was stirred at room temperature for 12 hours. LCMS showed the reaction was complete. The reaction system was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 4-4 (264 mg, yield: 87.3%). LC-MS(ESI)[M+H] ⁺ 326.2.

Step 4: Preparation of Compounds 4-5

To a solution of intermediate 4-4 (264 mg, 0.810 mmol) in dichloroethane (10 mL) was added tert-butyl 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylate Ester (469 mg, 1.62 mmol), type 3A molecular sieve (400 mg). After the reaction system was stirred at room temperature for 30 minutes, sodium triacetoxyborohydride (517 mg, 2.44 mmol) was added in an ice bath. The reaction mixture was stirred at room temperature for 24 hours. LCMS showed the reaction was complete. Add water (20 mL) to dilute, filter, and rinse the filter cake with dichloromethane (20 mL). Extract with dichloromethane (50 mL×3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue is separated and purified by column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 4-5 (83.0 mg). , yield: 17.1%).

LC-MS(ESI)[M+H] ⁺ 599.3.

Step 5: Preparation of Compound 4

Compound 4-5 (40.0 mg, 66.8 μmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=2/2/1 mL) at room temperature, and lithium hydroxide monohydrate (14 mg, 0.330 mmol) was added. After the addition was complete, the reaction mixture was stirred at 60°C for 12 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 4 (2.26 mg, yield: 6.76%).

LC-MS(ESI)[M+H] ⁺ 485.3.

¹ H NMR (400MHz, CD ₃ OD) δ8.00 (d, J=8.1Hz, 2H), 7.53 (s, 1H), 7.39 (d, J=8.1Hz, 2H), 7.18 (d, J=3.1 Hz, 1H), 6.71 (s, 1H), 6.30 (d, J=3.0Hz, 1H), 4.84 (s, 1H), 4.16 (dd, J=8.6, 3.8Hz, 1H), 4.06-3.96 (m , 1H), 3.95-3.80(m, 2H), 3.76(s, 3H), 3.25-3.17(m, 1H), 2.89-2.79(m, 1H), 2.48(s, 3H).

Example 5: Synthesis of Compound 5

Step 1: Preparation of compound 5-2

To a solution of compound 5-1 (5.00 g, 33.8 mmol) in dioxane (17 mL) was added 1-amino2-propanol (5.09 g, 67.6 mmol). The reaction system was stirred and refluxed for 16 hours. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 2/1) to obtain compound 5-2 (6.30 g, yield: 99.0%).

LC-MS(ESI)[M+H] ⁺ 188.1.

Step 2: Preparation of compound 5-3

At room temperature, add ultra-dry dichloromethane (40 mL) into a three-necked flask and protect with nitrogen. After the system temperature dropped to -78°C, oxalyl chloride (4.61g, 36.4mmol) was added dropwise, and then anhydrous dimethyl sulfoxide (16.8g, 87.6mmol) in ultra-dry dichloromethane (20mL) was added. Stir at -78°C for 30 minutes. A solution of compound 5-2 (6.80 g, 36.4 mmol) in ultra-dry dichloromethane (10 mL) was added to the reaction system. Stir at -78°C for 45 minutes. A solution of triethylamine (18.4g, 182mmol) in ultradry dichloromethane (20mL) was added to the reaction system. It was naturally raised to room temperature, and the reaction was stirred for 3 hours. LCMS showed the reaction was complete. Add water (50 mL) to quench, and extract with dichloromethane (100 mL × 3). The combined organic phases were washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated and purified by reversed-phase column chromatography [acetonitrile/water (containing 0.03% ammonia) = 3/1] to obtain the compound. 5-3 (3.22g, yield: 47.9%).

LC-MS(ESI)[M+H] ⁺ 186.1.

Step 3: Preparation of compound 5-4

A solution of compound 5-3 (900 mg, 4.83 mmol) in toluene (15 mL) was cooled to 0°C, and then trifluoroacetic acid (3.87 g, 33.9 mmol) was added. The system was stirred for 30 minutes, and then trifluoroacetic anhydride (7.11g, 33.9mmol) was added dropwise. Transfer to room temperature and react for 16 hours. LCMS showed the reaction was complete. Adjust the pH to weak alkaline with saturated sodium bicarbonate solution in an ice bath. Extract with ethyl acetate (100mL×3). The combined organic phases were washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was compound 5-4 (548 mg, yield: 67.9%). LC-MS(ESI)[M+H] ⁺ 168.1.

Step 4: Preparation of Compound 5-5

At room temperature, compound 5-4 (548 mg, 3.28 mmol), methyl p-formate phenylboronic acid (649 mg, 3.61 mmol) and cesium carbonate (3.47 g, 9.84 mmol) were dissolved in a mixed solvent (ethylene glycol dimethyl ether/water =10/2mL). Then the catalyst [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (120 mg, 0.164 mmol) was added to replace the argon gas. The reaction mixture was stirred at 90°C for 4 hours. LCMS showed the reaction was complete. Cool to room temperature, add water (30 mL) to dilute, and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (50 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1). Compound 5-5 (620 mg, yield: 70.64%) was obtained.

LC-MS(ESI)[M+H] ⁺ 268.1.

Step 5: Preparation of Compounds 5-6

To a solution of compound 5-5 (220 mg, 82.4 mmol) in anhydrous methanol (10 mL), palladium on carbon (70.0 mg, 57.6 μmol, 10 wt%) was added to replace hydrogen gas. Stir at room temperature for 4 hours. LCMS showed the reaction was complete. Filter, and the filtrate is concentrated under reduced pressure. The resulting residue is separated and purified by column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 5-6 (136 mg, yield: 60.9%).

LC-MS(ESI)[M+H] ⁺ 272.3.

Step 6: Preparation of Compounds 5-7

To a solution of compound 5-6 (136 mg, 0.500 mmol) in dichloroethane (10 mL) was added 4-formyl-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (289mg, 1.00mmol) and type 3A molecular sieve (300mg). After stirring at room temperature for 30 minutes, sodium triacetoxyborohydride (319 mg, 1.50 mmol) was added in an ice bath, and the reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. The system was diluted with water (20 mL), filtered, and the filter cake was rinsed with dichloromethane (20 mL). The filtrate was extracted with dichloromethane (20 mL×2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (dichloromethane/ethanol=9/1) to obtain compound 5-7 (103 mg, yield: 37.8%). LC-MS(ESI)[M+H] ⁺ 545.1.

Step 7: Preparation of Compound 5

Compound 5-7 (51.0 mg, 93.6 μmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=2/2/1 mL). Lithium hydroxide monohydrate (19.6 mg, 0.470 mmol) was then added. The reaction mixture was stirred at 60°C for 12 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 5 (3.31 mg, yield: 8.18%,).

LC-MS(ESI)[M+H] ⁺ 431.3.

¹ H NMR (400MHz, CD3OD) δ8.02 (d, J=8.1Hz, 2H), 7.44 (d, J=8.0Hz, 2H), 7.19 (d, J=3.0Hz, 1H), 6.80 (s, 1H), 6.72(s, 1H), 6.29(d, J=3.0Hz, 1H), 4.82(s, 1H), 4.06-3.99(m, 1H), 3.92-3.80(m, 3H), 3.77(s , 3H), 3.29-3.23(m, 1H), 2.91-2.81(m, 1H), 2.49(s, 3H), 2.23(s, 3H).

Example 6: Synthesis of Compound 6

Step 1: Preparation of compound 6-2

At room temperature, compound 6-1 (1.00 g, 6.51 mmol) was dissolved in a mixed solvent (ethylene glycol dimethyl ether/water = 30/6 mL). Then, methyl phenylboronic acid (2.34g, 13.0mmol), cesium carbonate (4.24g, 13.0mmol), and 1,1-bis(diphenylphosphine)diphenylironium dichloride (476mg, 651μmol) were added. Nitrogen protection, reaction at 90°C for 5 hours. LCMS showed the reaction was complete. Dilute with water (100 mL) and extract with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 3/7) to obtain compound 6-2 ( 1.10g, yield: 66.7%).

LC-MS(ESI)[M+H] ⁺ 254.0

Step 2: Preparation of compound 6-3

Compound 6-2 (400 mg, 1.58 mmol) was dissolved in methanol (20 mL), palladium on carbon (50.0 mg, 41.1 μmol, 10 wt%) was added, and the mixture was protected by hydrogen. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. The reaction system was filtered and concentrated under reduced pressure to obtain crude compound 6-3 (370 mg). The crude product was used directly in the next reaction without further purification.

LC-MS(ESI)[M+H] ⁺ 258.0.

Step 3: Preparation of compound 6-4

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (120 mg, 0.410 mmol) and compound 6-3 crude product (70.0 mg) were activated. A mixed system of 4A molecular sieve (1.00g) and anhydrous 1,2-dichloroethane (5mL) was stirred at room temperature for 1 hour. Then sodium acetate borohydride (576 mg, 2.72 mmol) was added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 6-4 (30.0 mg, two-step total yield: 18.9%).

LC-MS(ESI)[M+H] ⁺ 531.2.

Step 4: Preparation of Compound 6

Compound 6-4 (30.0 mg, 57.0 μmol) was dissolved in a mixed solvent (water/methanol = 2/2 mL), and then lithium hydroxide monohydrate (13.5 mg, 570 μmol) was added. Reaction at 70 degrees for 2 hours. After cooling to room temperature, it was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by Prep-HPLC to obtain compound 6 (2.58 mg, yield 11.0%).

LC-MS(ESI)[MH] ^- 415.0

¹ H NMR (400MHz, DMSO-d ₆ ) δ = 10.84 (s, 1H), 7.82-7.80 (m, 2H), 7.27-7.22 (m, 3H), 7.01 (d, J = 4.0Hz, 1H), 6.77(s, 1H), 6.70(s, 1H), 6.27-6.26(m, 1H), 5.46(s, 1H), 4.01-3.97(m, 1H), 3.84-3.78(m, 1H), 3.72- 3.65(m, 5H), 3.02-2.98(m, 1H), 2.67-2.59(m, 1H), 2.49(s, 3H).

Example 7: Synthesis of Compound 7

Step 1: Preparation of compound 7-1

To a solution of compound 1-3 (200 mg, 0.910 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (251 mg, 1.82 mmol) at room temperature. Ethyl iodide (170 mg, 1.09 mmol) was slowly added dropwise in an ice-water bath. After the dripping was completed, the mixture was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. Add water (20 mL) to quench, and extract with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (dichloromethane/methanol = 4/1) to obtain compound 7-1 (66.0 mg, yield: 29.3%).

LC-MS(ESI)[M+H] ⁺ 249.1.

Step 2: Preparation of compound 7-2

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (138 mg, 0.480 mmol), compound 7-1 (66.0 mg, 0.270 mmol) , a mixed system of activated 3A molecular sieve (200 mg) and anhydrous 1,2-dichloroethane (10 mL) was stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride (85.0 mg, 0.400 mmol) was added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 7-2 (100 mg, yield: 72.1%).

LC-MS(ESI)[M+H] ⁺ 522.2.

Step 3: Preparation of Compound 7

Compound 7-2 (100 mg, 0.190 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=4/2/2 mL), and then lithium hydroxide monohydrate (40.0 mg, 0.960 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 7 (13.9 mg, yield: 17.8%).

LC-MS(ESI)[M+H] ⁺ 408.2

¹ H NMR (400MHz, CD ₃ OD) δ=8.09 (d, J=8.4Hz, 2H), 7.66 (d, J=7.6Hz, 2H), 7.24 (d, J=3.1Hz, 1H), 6.72 ( s, 1H), 6.41 (d, J=3.1Hz, 1H), 3.97-3.88 (m, 1H), 3.78 (s, 4H), 3.58-3.47 (m, 1H), 3.27-3.18 (m, 2H) , 3.13-3.07(m, 1H), 2.87-2.58(m, 5H), 2.48(s, 3H), 1.20(t, J=7.2Hz, 3H).

Example 8: Synthesis of Compound 8

Step 1: Preparation of compound 8-1

To a solution of compound 1-3 (200 mg, 0.910 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (251 mg, 1.82 mmol) at room temperature. A solution of isopropane iodide (240 mg, 1.32 mmol) in N, N-dimethylformamide (5 mL) was slowly added dropwise in an ice-water bath. After the dripping was completed, the mixture was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. Add water (30 mL) to quench, and extract with ethyl acetate (30 mL × 3). The combined organic phases were washed with water (30 mL Compound 8-1 (60.0 mg, yield: 25.1%) was purified.

LC-MS(ESI)[M+H] ⁺ 263.1.

Step 2: Preparation of compound 8-2

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (132 mg, 0.480 mmol), compound 8-1 (60.0 mg, 0.240 mmol) , a mixed system of activated 3A molecular sieve (100 mg) and anhydrous 1,2-dichloroethane (3 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (144 mg, 0.720 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain compound 8-2 (60.0 mg, yield: 49.5%).

LC-MS(ESI)[M+H] ⁺ 536.2.

Step 3: Preparation of Compound 8

Dissolve compound 8-2 (100 mg, 0.120 mmol) in a mixed solvent (methanol/tetrahydrofuran/water=4/2/2 mL), and then add hydrogen oxide monohydrate Lithium chloride (24.0 mg, 0.600 mmol). Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 8 (22.0 mg, yield: 46.7%).

LC-MS(ESI)[M+H] ⁺ 422.2

¹ H NMR (400MHz, CD ₃ OD) δ=8.03 (d, J=8.4Hz, 2H), 7.61 (s, 2H), 7.19 (d, J=3.1Hz, 1H), 6.69 (s, 1H), 6.44 (d, J=3.1Hz, 1H), 3.83 (d, J=11.9Hz, 1H), 3.78 (s, 3H), 3.49 (d, J=8.9Hz, 1H), 3.31-3.28 (m, 1H ), 2.97-2.91(m, 1H), 2.90-2.81(m, 2H), 2.74-2.63(m, 1H), 2.46(s, 3H), 2.45-2.34(m, 3H), 1.07(d, J =6.5Hz, 6H).

Example 9: Synthesis of Compound 9

Step 1: Preparation of compound 9-1

To a solution of compound 1-3 (500 mg, 2.27 mmol) and 1-ethoxy-1-trimethylsiloxycyclopropane (792 mg, 4.54 mmol) in anhydrous methanol (20 mL) at room temperature, acetic acid (1.36 g , 22.7mmol), 3A molecular sieve (3.00g) and sodium cyanoborohydride (642mg, 10.2mmol). Stir at 40 degrees for 16 hours. LCMS showed the reaction was complete. Filter, add water (50 mL) to the filtrate to quench, and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed with water (50 mL Compound 9-1 (360 mg, yield: 60.9%) was purified.

LC-MS(ESI)[MH] ⁺ 275.2.

Step 2: Preparation of compound 9-2

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (1.20g, 4.15mmol), compound 9-1 (360mg, 1.38mmol) , a mixed system of activated 3A molecular sieve (500 mg) and anhydrous 1,2-dichloroethane (15 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (879 mg, 4.15 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain compound 9-2 (215 mg, yield: 29.1%).

LC-MS(ESI)[M+H] ⁺ 534.0.

Step 3: Preparation of Compound 9

Compound 9-2 (215 mg, 0.400 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=5/5/2 mL), and then lithium hydroxide monohydrate (84.5 mg, 2.01 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 9 (113 mg, yield: 66.8%).

LC-MS(ESI)[M+H] ⁺ 420.3

¹ H NMR (400MHz, CD ₃ OD) δ=8.13 (d, J=8.0Hz, 2H), 7.65 (d, J=7.1Hz, 2H), 7.26 (d, J=3.1Hz, 1H), 6.73 ( s, 1H), 6.38 (d, J=3.1Hz, 1H), 4.05 (d, J=12.0Hz, 1H), 3.87 (s, 1H), 3.78 (s, 3H), 3.66 (d, J=12.2 Hz, 1H), 3.19-2.95 (m, 3H), 2.76 (d, J=11.4Hz, 1H), 2.62 (dt, J=25.2, 12.1Hz, 2H), 2.49 (s, 3H), 1.97 (s , 1H), 1.77 (d, J=4.2Hz, 1H), 0.49 (dd, J=7.8, 5.2Hz, 4H).

Example 10: Synthesis of Compound 10

Step 1: Preparation of Compound 10-1

Under argon protection, a mixed system of compound 1-3 (500 mg, 2.27 mmol), cyclobutanone (127 mg, 1.82 mmol), activated 3A molecular sieve (2.00 g) and methanol (10 mL) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (428 mg, 6.81 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain compound 10-1 (370 mg, yield: 59.4%).

LC-MS(ESI)[M+H] ⁺ 275.1.

Step 2: Preparation of compound 10-2

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (719 mg, 2.49 mmol), compound 10-1 (340 mg, 1.24 mmol), A mixed system of activated 3A molecular sieve (500 mg) and anhydrous 1,2-dichloroethane (15 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (788 mg, 3.72 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain compound 10-2 (312 mg, yield: 46.0%).

LC-MS(ESI)[M+H] ⁺ 548.1.

Step 3: Preparation of Compound 10

Compound 10-2 (300 mg, 0.540 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=5/5/2 mL), and then lithium hydroxide monohydrate (115 mg, 2.74 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 10 (113 mg, yield: 47.6%).

LC-MS(ESI)[M+H] ⁺ 434.2

¹ H NMR (400MHz, CD ₃ OD) δ=8.02 (d, J=8.3Hz, 2H), 7.59 (d, J=6.4Hz, 2H), 7.19 (d, J=3.1Hz, 1H), 6.68 ( s, 1H), 6.44 (d, J=3.1Hz, 1H), 3.82 (d, J=11.9Hz, 1H), 3.77 (s, 3H), 3.49-3.42 (m, 1H), 3.29 (s, 1H ), 2.89 (d, J = 12.1Hz, 1H), 2.77 (d, J = 8.3Hz, 3H), 2.46 (s, 3H), 2.40 (dd, J = 12.0, 9.9Hz, 1H), 2.03 (dd , J=21.8, 10.5Hz, 4H), 1.96-1.84 (m, 4H), 1.70 (dd, J=14.1, 8.0Hz, 2H).

Example 11: Synthesis of Compound 11

Step 1: Preparation of compound 11-1

Under argon protection, a mixed system of compound 1-3 (500 mg, 2.27 mmol), cyclopropylcarboxaldehyde (127 mg, 1.82 mmol), activated 3A molecular sieve (2.00 g) and methanol (10 mL) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (428 mg, 6.81 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain compound 11-1 (330 mg, yield: 53.0%).

LC-MS(ESI)[M+H] ⁺ 275.2.

Step 2: Preparation of compound 11-2

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (696 mg, 2.40 mmol), compound 11-1 (330 mg, 1.20 mmol), The mixed system of activated 3A molecular sieve (1.00g) and anhydrous 1,2-dichloroethane (5mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (765 mg, 3.61 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain compound 11-2 (215 mg, yield: 32.6%).

LC-MS(ESI)[M+H] ⁺ 548.1.

Step 3: Preparation of Compound 11

Compound 11-2 (90.0 mg, 0.160 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water = 5/5/2 mL), and then hydroxide monohydrate was added Lithium chloride (34.4 mg, 0.820 mmol). Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 11 (11.3 mg, yield: 15.9%).

LC-MS(ESI)[M+H] ⁺ 434.7

¹ H NMR (400MHz, CD ₃ OD) δ=8.04 (d, J=8.3Hz, 2H), 7.61 (d, J=6.5Hz, 2H), 7.20 (d, J=3.1Hz, 1H), 6.70 ( s, 1H), 6.45 (d, J=3.1Hz, 1H), 3.88-3.80 (m, 1H), 3.79 (s, 3H), 3.51 (d, J=8.1Hz, 1H), 3.30 (s, 1H) ), 3.07-2.86 (m, 3H), 2.49 (d, J=9.3Hz, 4H), 2.25 (dd, J=23.1, 8.5Hz, 4H), 1.25 (s, 1H), 0.89 (s, 1H) , 0.51 (d, J=7.6Hz, 2H), 0.12 (dd, J=8.1, 4.1Hz, 2H).

Example 12: Synthesis of Compound 12

Step 1: Preparation of compound 12-1

Under argon protection, a mixed system of compound 1-3 (500 mg, 2.27 mmol), cyclobutylcarboxaldehyde (153 mg, 1.82 mmol), activated 3A molecular sieve (1.00 g) and methanol (10 mL) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (428 mg, 6.81 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain compound 12-1 (330 mg, yield: 50.4%).

LC-MS(ESI)[M+H] ⁺ 289.1.

Step 2: Preparation of compound 12-2

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (549 mg, 1.87 mmol), compound 12-1 (270 mg, 0.940 mmol), A mixed system of activated 3A molecular sieve (500 mg) and anhydrous 1,2-dichloroethane (15 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (595 mg, 2.81 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 4/1) to obtain compound 12-2 (310 mg, yield: 58.9%).

LC-MS(ESI)[M+H] ⁺ 562.2.

Step 3: Preparation of Compound 12

Compound 12-2 (300 mg, 0.540 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=5/5/2 mL), and then lithium hydroxide monohydrate (112 mg, 2.67 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 12 (123 mg, yield: 51.5%).

LC-MS(ESI)[M+H] ⁺ 448.2

¹ H NMR (400MHz, CD ₃ OD) δ=8.03 (d, J=8.2Hz, 2H), 7.60 (s, 2H), 7.20 (d, J=3.0Hz, 1H), 6.70 (s, 1H), 6.45 (d, J=3.1Hz, 1H), 3.88-3.80 (m, 1H), 3.79 (s, 3H), 3.47 (d, J=10.7Hz, 1H), 3.29 (d, J=11.9Hz, 2H ), 2.86 (d, J=12.1Hz, 1H), 2.77 (t, J=11.4Hz, 2H), 2.57 (dd, J=15.0, 7.6Hz, 1H), 2.48 (s, 3H), 2.46-2.37 (m, 3H), 2.21 (dd, J=23.8, 12.2Hz, 2H), 2.13-2.00 (m, 2H), 1.99-1.64 (m, 5H).

Example 13: Synthesis of Compound 13

Step 1: Preparation of compound 13-1

To a solution of compound 1-3 (500 mg, 2.27 mmol) in N,N-dimethylformamide (5 mL) at room temperature, tetrabutylammonium iodide (84.0 mg, 0.230 mmol) and potassium carbonate (470 mg, 3.40 mmol) and 3-(bromomethyl)-1,1-difluorocyclobutane (336 mg, 1.82 mmol). Stir at room temperature for 16 hours. LCMS showed the reaction was complete. Add water (30 mL) to quench, and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (dichloromethane/methanol=10/1) to obtain Compound 13-1 (190 mg, yield: 25.8%).

LC-MS(ESI)[M+H] ⁺ 325.2.

Step 2: Preparation of compound 13-2

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (508 mg, 1.76 mmol), compound 13-1 (190 mg, 0.590 mmol), A mixed system of activated 4A molecular sieve (100 mg) and anhydrous 1,2-dichloroethane (10 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (372 mg, 1.76 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 13-2 (180 mg, yield: 51.4%).

LC-MS(ESI)[M+H] ⁺ 598.3.

Step 3: Preparation of Compound 13

Compound 13-2 (180 mg, 0.300 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=5/5/2 mL), and then lithium hydroxide monohydrate (63.0 mg, 1.51 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 13 (56.3 mg, yield: 38.7%).

LC-MS(ESI)[M+H] ⁺ 484.4

¹ H NMR (400MHz, DMSO-d ₆ ) δ = 13.33-12.35 (m, 1H), 10.82 (s, 1H), 7.97 (d, J = 7.8Hz, 2H), 7.69 (s, 2H), 7.25 ( s, 1H), 6.66 (s, 1H), 6.43 (s, 1H), 3.70 (s, 3H), 3.56 (d, J = 11.9Hz, 1H), 3.39 (d, J = 11.1Hz, 1H), 3.22 (d, J=12.0Hz, 1H), 2.75-2.56 (m, 5H), 2.42 (s, 3H), 2.35 (dd, J=19.6, 10.1Hz, 2H), 2.30-2.09 (m, 4H) , 1.99 (dt, J=32.8, 10.4Hz, 2H).

Example 14: Synthesis of Compound 14

Step 1: Preparation of compound 14-1

Under argon protection, combine compound 1-3 (500mg, 2.27mmol), tert-butyldimethylsiloxyacetaldehyde (320mg, 1.82mmol), activated 3A molecular sieve (5.00g) and methanol (30mL). The mixed system was stirred at room temperature for 1 hour. Sodium cyanoborohydride (428 mg, 6.81 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 14-1 (420 mg, yield: 48.9%).

LC-MS(ESI)[M+H] ⁺ 379.3.

Step 2: Preparation of compound 14-2

To a solution of compound 14-1 (374 mg, 0.990 mmol) in anhydrous dichloromethane (5 mL) at room temperature, a solution of hydrogen chloride in 1,4-dioxane (2.00 mol/L, 4.00 mL, 8.00 mmol) was added. . The reaction system was stirred at room temperature for 4 hours. LCMS showed the reaction was complete. The reaction solution was adjusted to pH 8-9 with ammonia water (1.00 mol/L), concentrated under reduced pressure, and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with water (20 mL × 3) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 14-2 (234 mg, yield: 89.7%). LC-MS(ESI)[M+H] ⁺ 265.1.

Step 3: Preparation of compound 14-3

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (531 mg, 1.84 mmol), compound 14-2 (234 mg, 0.920 mmol), A mixed system of activated 4A molecular sieve (500 mg) and anhydrous 1,2-dichloroethane (10 mL) was stirred at room temperature for 1 hour. back Sodium triacetoxyborohydride (583 mg, 2.75 mmol) was added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 14-3 (189 mg, yield: 80.3%).

LC-MS(ESI)[M+H] ⁺ 538.3.

Step 4: Preparation of Compound 14

Compound 14-3 (189 mg, 0.350 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=2/2/1 mL), and then lithium hydroxide monohydrate (88.9 mg, 2.12 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 14 (45.0 mg, yield: 30.1%).

LC-MS(ESI)[M+H] ⁺ 424.2

¹ H NMR (400MHz, CD ₃ OD) δ=8.02 (d, J=8.3Hz, 2H), 7.59 (d, J=6.0Hz, 2H), 7.18 (d, J=3.1Hz, 1H), 6.68 ( s, 1H), 6.43 (d, J=3.1Hz, 1H), 3.81 (d, J=11.9Hz, 1H), 3.77 (s, 3H), 3.65 (t, J=6.0Hz, 2H), 3.48 ( dd, J=10.5, 2.6Hz, 1H), 3.28 (d, J=11.9Hz, 1H), 2.91-2.80 (m, 3H), 2.51 (t, J=6.0Hz, 2H), 2.48-2.39 (m , 4H), 2.33-2.22(m, 2H).

Example 15: Synthesis of Compound 15

Step 1: Preparation of compound 15-1

To a solution of compound 1-3 (500 mg, 2.27 mmol) in N,N-dimethylformamide (5 mL) at room temperature, tetrabutylammonium iodide (84.0 mg, 0.230 mmol) and potassium carbonate (630 mg, 4.54mmol) and 2-bromoethyl methyl ether (580mg, 3.40mmol). Stir at room temperature for 16 hours. LCMS showed the reaction was complete. Add water (50 mL) to quench, and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed with water (50 mL Compound 15-1 (150 mg, yield: 23.7%) was obtained by isolation and purification.

LC-MS(ESI)[M+H] ⁺ 279.2.

Step 2: Preparation of compound 15-2

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (249 mg, 0.86 mmol), compound 15-1 (120 mg, 0.430 mmol), A mixed system of activated 3A molecular sieve (100 mg) and anhydrous 1,2-dichloroethane (3 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (274 mg, 1.32 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 15-2 (120 mg, yield: 50.6%).

LC-MS(ESI)[M+H] ⁺ 552.2.

Step 3: Preparation of Compound 15

Compound 15-2 (100 mg, 0.180 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=2/2/1 mL), and then lithium hydroxide monohydrate (40.0 mg, 0.900 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 15 (42.0 mg, yield: 50.1%).

LC-MS(ESI)[M+H] ⁺ 438.1

¹ H NMR (400MHz, CD ₃ OD) δ=8.03 (d, J=8.4Hz, 2H), 7.60 (d, J=6.8Hz, 2H), 7.20 (d, J=3.1Hz, 1H), 6.69 ( s, 1H), 6.42 (d, J=3.1Hz, 1H), 3.85 (d, J=12.0Hz, 1H), 3.77 (s, 3H), 3.59 (d, J=9.4Hz, 1H), 3.52 ( t, J=5.5Hz, 2H), 3.36 (d, J=12.0Hz, 1H), 3.31 (s, 3H), 2.91 (dd, J=19.1, 9.3Hz, 3H), 2.67-2.59 (m, 2H ), 2.53 (t, J=11.3Hz, 1H), 2.46 (s, 3H), 2.40-2.29 (m, 2H).

Example 16: Synthesis of Compounds 16a and 16b

Step 1: Preparation of Compound 16-1

At room temperature, compound 1-1 (95.0g, 0.530mol), 2,3-dichloropyrazine (86.5g, 0.580mol), cesium carbonate (516g, 1.58mol) and 1,1′-bisdiphenyl Phosphoferrocene palladium dichloride (3.86g, 5.28mmol) was mixed in glycol dimethyl ether/water (1000/200mL). The nitrogen gas was replaced, and the reaction system was stirred at 90°C for 4 hours. LCMS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the filtrate was extracted with ethyl acetate (1000 mL × 3). The combined organic phases were washed with saturated brine (1000 mL That is compound 16-1 (74.1g, yield: 56.6%).

LC-MS(ESI)[M+H] ⁺ 249.3.

Step 2: Preparation of compound 16-2

Compound 16-1 (74.1g, 0.300mol) was dissolved in concentrated hydrochloric acid (12.0mol/L, 1.00L, 12.0mol) at room temperature. The nitrogen gas was replaced, and the reaction system was stirred at 100°C for 48 hours. LCMS showed the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain crude compound 16-2 (75.0 g), which was directly used in the next reaction without purification.

LC-MS(ESI)[M+H] ⁺ 217.2.

Step 3: Preparation of compound 16-3

To a solution of crude compound 16-2 (75.0 g) in methanol (1.00 L) at room temperature, concentrated sulfuric acid (18.4 mol/L, 15.0 mL, 276 mmol) was added. Nitrogen was replaced, and the reaction system was stirred at 80°C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The resulting residue was slurried with a mixed solvent of petroleum ether/ethyl acetate (20/20 mL) and filtered with suction. The filter cake was compound 16-3 (62.0 g, two-step total yield: 90.4%).

LC-MS(ESI)[M+H] ⁺ 231.2.

Step 4: Preparation of compound 16-4

To a solution of compound 16-3 (30.0g, 0.130mol) in methanol (1.00L) at room temperature, concentrated ammonia (13.3mol/L, 15.0mL, 200mmol) and di-tert-butyl dicarbonate (85.3g, 0.391 mol) and palladium on carbon (3.00 g, 2.82 mmol, 10 wt%). The hydrogen gas was replaced, and the reaction system was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. Suction filtration through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 16-4 (9.68g, yield: 22.2%).

LC-MS(ESI)[M+H] ⁺ 279.1.

Step 5: Preparation of Compound 16-5

To a solution of compound 16-4 (200 mg, 0.600 mmol) in N-methylpyrrolidone (15 mL) at room temperature, cesium carbonate (974 mg, 2.99 mmol) and ethyl iodide (933 mg, 5.98 mmol) were added. Nitrogen was replaced, and the reaction system was stirred at 80°C for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, add water (30 mL) to quench, and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (dichloromethane/methanol=20/1) to obtain Compound 16-5 (100 mg, yield: 46.1%).

LC-MS(ESI)[M+H] ⁺ 307.1.

Step 6: Preparation of Compound 16-6

To a solution of compound 16-5 (100 mg, 0.280 mmol) in dichloromethane (5 mL) at room temperature, a solution of hydrogen chloride in 1,4-dioxane (4.00 mol/L, 1.00 mL, 4.00 mmol) was added. The reaction system was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the resulting residue was purified by a reverse-phase column (acetonitrile/water=1/4) to obtain compound 16-6 (46.0 mg, yield: 63.6%).

LC-MS(ESI)[M+H] ⁺ 263.1.

Step 7: Preparation of Compound 16-7

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (152 mg, 0.53 mmol), compound 16-6 (46.0 mg, 0.180 mmol) , a mixed system of activated 4A molecular sieve (100 mg) and anhydrous 1,2-dichloroethane (5 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (112 mg, 0.530 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 16-7 (50 mg, yield: 53.2%).

LC-MS(ESI)[M+H] ⁺ 535.2.

Step 8: Preparation of Compound 16

Compound 16-7 (50.0 mg, 93.0 μmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=5/5/2 mL), and then lithium hydroxide monohydrate (19.6 mg, 0.470 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain compound 16 (23.0 mg, yield: 58.7%).

LC-MS(ESI)[M+H] ⁺ 422.1

¹ H NMR (400MHz, CD ₃ OD) δ=8.02 (d, J=8.9Hz, 2H), 7.55 (d, J=8.2Hz, 2H), 7.17 (d, J=3.1Hz, 1H), 6.70 ( s, 1H), 6.22 (d, J = 3.1Hz, 1H), 4.12 (s, 1H), 3.77 (s, 3H), 3.76-3.71 (m, 1H), 3.63 (d, J = 11.9Hz, 1H ), 3.45-3.37(m, 1H), 3.27-3.21(m, 1H), 3.06-2.98(m, 1H), 2.78-2.71(m, 1H), 2.61-2.52(m, 1H), 2.47(s , 3H), 0.84-0.70 (m, 3H), 0.59-0.52 (m, 1H).

Step 9: Preparation of Compounds 16a and 16b

Compound 16 (20.0 mg, 47.0 μmol) was purified by preparative SFC (column (250*25mm, 10μm)); mobile phase [A: carbon dioxide, B: methanol (containing 0.1% diethylamine)]; B%: 50% to obtain 16a (retention time 1.076 minutes) and 16b (retention time 0.822 minutes) . Retention times were determined using the following analytical method: Column: 100*3.0mm 3.0μm, mobile phase [A: carbon dioxide, B: methanol (containing 0.1% diethylamine)], 40% B, flow rate: 1.5mL/min, column temperature: 35°C.

Target substance 16a (4.50 mg, recovery rate: 22.5%), LC-MS (ESI) [M+H] ⁺ 422.1, ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.05 (d, J = 8.1 Hz, 2H ), 7.60 (d, J = 8.0Hz, 2H), 7.18 (d, J = 3.1Hz, 1H), 6.70 (s, 1H), 6.25 (d, J = 3.1Hz, 1H), 4.15 (s, 1H) ), 3.76 (d, J=14.4Hz, 4H), 3.66 (d, J=11.9Hz, 1H), 3.55-3.48 (m, 1H), 3.46-3.36 (m, 3H), 3.05 (dd, J= 8.8, 3.6Hz, 1H), 2.65-2.56 (m, 1H), 2.47 (s, 3H), 1.14 (t, J=7.1Hz, 3H).

Target substance 16b (3.91 mg, yield: 19.6%), LC-MS (ESI) [M+H] ⁺ 422.1, ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.05 (d, J = 8.1 Hz, 2H ), 7.60 (d, J = 8.0Hz, 2H), 7.18 (d, J = 3.1Hz, 1H), 6.70 (s, 1H), 6.25 (d, J = 3.1Hz, 1H), 4.15 (s, 1H) ), 3.76 (d, J=14.4Hz, 4H), 3.66 (d, J=11.9Hz, 1H), 3.55-3.48 (m, 1H), 3.46-3.36 (m, 3H), 3.05 (dd, J= 8.8, 3.6Hz, 1H), 2.65-2.56 (m, 1H), 2.47 (s, 3H), 1.14 (t, J=7.1Hz, 3H).

Example 17: Synthesis of Compound 17

Step 1: Preparation of Compound 17-1

To a solution of compound 16-3 (1.00 g, 4.34 mmol) in N-methylpyrrolidone (20 mL) at room temperature, potassium carbonate (1.20 g, 8.69 mmol) and isopropane iodide (1.48 g, 8.69 mmol) were added. Nitrogen was replaced, and the reaction system was stirred at 50°C for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, add water (40 mL) to quench, and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 3/1). Compound 17-1 (180 mg, yield: 15.2%) was obtained.

LC-MS(ESI)[M+H] ⁺ 273.1.

Step 2: Preparation of compound 17-2

At room temperature, a mixture of compound 17-1 (160 mg, 0.590 mmol) and palladium on carbon (50 mg, 0.0470 μmol, 10 wt%) in methanol (20 mL) was replaced with hydrogen. The reaction system was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. . The mixture was suction-filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (dichloromethane/methanol=20/1) to obtain compound 17-2 (145 mg, yield: 89.2%).

LC-MS(ESI)[M+H] ⁺ 277.1.

Step 3: Preparation of compound 17-3

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (304 mg, 1.05 mmol), compound 17-2 (145 mg, 0.530 mmol), A mixed system of activated 3A molecular sieve (200 mg) and anhydrous 1,2-dichloroethane (15 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (334 mg, 1.58 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 3/1) to obtain compound 17-3 (155 mg, yield: 54.0%).

LC-MS(ESI)[M+H] ⁺ 550.2.

Step 3: Preparation of Compound 17

Compound 17-3 (155 mg, 0.280 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=5/5/2 mL), and then lithium hydroxide monohydrate (59.2 mg, 1.41 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 17 (40.0 mg, yield: 32.8%).

LC-MS(ESI)[M+H] ⁺ 436.0

¹ H NMR (400MHz, CD ₃ OD) δ=8.01 (d, J=8.1Hz, 2H), 7.53 (d, J=8.0Hz, 2H), 7.15 (d, J=3.1Hz, 1H), 6.69 ( s, 1H), 6.20 (d, J=3.1Hz, 1H), 4.61 (dq, J=13.8, 6.9Hz, 1H), 4.09 (s, 1H), 3.78-3.70 (m, 4H), 3.62 (d , J=12.0Hz, 1H), 3.31-3.18 (m, 2H), 3.05 (d, J=12.3Hz, 1H), 2.54-2.42 (m, 4H), 1.13 (dd, J=6.2, 1.6Hz, 6H).

Example 18: Synthesis of Compound 18

Step 1: Preparation of Compound 18-1

Compound 16-4 (300 mg, 0.900 mmol), cyclopropylboronic acid (155 mg, 1.80 mmol), copper acetate (163 mg, 0.900 mmol), cesium carbonate (585 mg, 1.79 mmol) and pyridine (142 mg, 1.79 mmol) were added to the solution at room temperature. ) mixture was added toluene (20 mL). Replace the oxygen and stir at 100 degrees for 16 hours. Cool to room temperature and concentrate under reduced pressure. The resulting residue is purified by column chromatography (petroleum ether/ethyl acetate = 5/1) to obtain compound 18-1. (140 mg, yield: 41.7%).

LC-MS(ESI)[M+H-56] ⁺ 319.1.

Step 2: Preparation of compound 18-2

To a solution of compound 18-1 (140 mg, 0.370 mmol) in dichloromethane (5 mL) at room temperature, a solution of hydrogen chloride in 1,4-dioxane (4.00 mol/L, 1.00 mL, 4.00 mmol) was added. The reaction system was stirred at room temperature for 2 hours. Concentrate under reduced pressure and add water (20 mL). Adjust the pH to 8-9 with ammonia water (1.00mmol/L), and extract with ethyl acetate (50mL×3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 18-2 (103 mg, yield: 100%).

LC-MS(ESI)[M+H] ⁺ 275.1.

Step 3: Preparation of compound 18-3

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (158 mg, 0.550 mmol) and compound 18-2 (75.0 mg, 0.270 mmol) were added. , a mixed system of activated 4A molecular sieve (300 mg) and anhydrous 1,2-dichloroethane (10 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (174 mg, 0.820 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 18-3 (120 mg, yield: 80.3%).

LC-MS(ESI)[M+H] ⁺ 548.2.

Step 4: Preparation of Compound 18

Compound 18-3 (120 mg, 0.220 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=5/5/2 mL), and then lithium hydroxide monohydrate (46.0 mg, 1.10 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 18 (42.3 mg, yield: 44.5%).

LC-MS(ESI)[M+H] ⁺ 434.1

Example 19: Synthesis of Compound 19

Step 1: Preparation of compound 19-2

To a solution of compound 19-1 (5.00 g, 69.3 mmol) in pyridine (25 mL) at room temperature, p-toluenesulfonyl chloride (19.8 g, 104 mmol) was added. The nitrogen gas was replaced, and the reaction system was stirred at room temperature for 48 hours. Concentrate under reduced pressure, add water (100 mL) to quench, and extract with ethyl acetate (100 mL × 3). The combined organic phases were washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 4/1). Compound 19-2 (2.60g, yield: 16.6%) was obtained.

LC-MS(ESI)[M+H] ⁺ 227.1.

Step 2: Preparation of compound 19-3

To a solution of compound 19-2 (609 mg, 2.69 mmol) in N-methylpyrrolidone (15 mL), compound 16-4 (300 mg, 0.900 mmol), cesium carbonate (876 mg, 2.69 mmol) and potassium iodide (14.9 mg, 0.0900mmol). Nitrogen was replaced, and the reaction system was stirred at 80 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, dilute with water (30 mL), and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (dichloromethane/methanol=20/1) to obtain Compound 19-3 (140 mg, yield: 40.0%).

LC-MS(ESI)[M+H] ⁺ 333.1.

Step 3: Preparation of compound 19-4

To a solution of compound 19-3 (140 mg, 0.360 mmol) in dichloromethane (5 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4.00 mol/L, 1.00 mL, 4.00 mmol) at room temperature. The reaction system was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the resulting residue was purified by a reverse-phase column (acetonitrile/water=1/4) to obtain compound 19-4 (30.0 mg, yield: 28.9%).

LC-MS(ESI)[M+H] ⁺ 289.0.

Step 4: Preparation of compound 19-5

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (90.3 mg, 0.310 mmol) and compound 19-4 (30.0 mg, 0.104 mmol) were added. ), a mixed system of activated 3A molecular sieve (100 mg) and anhydrous 1,2-dichloroethane (5 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (65.7 mg, 0.310 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 19-5 (28.0 mg, yield: 47.9%).

LC-MS(ESI)[M+H] ⁺ 562.2.

Step 5: Preparation of Compound 19

Compound 19-5 (28.0 mg, 50.0 μmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=2/2/1 mL), and then lithium hydroxide monohydrate (10.5 mg, 0.250 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 19 (9.18 mg, yield: 41.0%).

LC-MS(ESI)[M+H] ⁺ 448.1

¹ H NMR (400MHz, CD ₃ OD) δ=8.01 (d, J=8.2Hz, 2H), 7.51 (d, J=8.2Hz, 2H), 7.16 (d, J=3.1Hz, 1H), 6.70 ( s, 1H), 6.24 (t, J=4.5Hz, 1H), 5.87-5.74 (m, 1H), 5.17-5.03 (m, 2H), 4.11 (s, 1H), 3.79 (s, 3H), 3.75 (d, J=12.0Hz, 1H), 3.65 (d, J=11.9Hz, 1H), 3.62-3.48 (m, 2H), 3.39-3.35 (m, 1H), 3.31-3.24 (m, 1H), 3.05-2.98(m, 1H), 2.61-2.53(m, 1H), 2.48(s, 3H), 2.40-2.30(m, 2H).

Example 20: Synthesis of Compound 20

Step 1: Preparation of Compound 20-1

To a solution of compound 16-4 (300 mg, 0.900 mmol) in N-methylpyrrolidone (15 mL) at room temperature, cesium carbonate (877 mg, 2.69 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate were added acid ester (624 mg, 2.69 mmol). Nitrogen was replaced, and the reaction system was stirred at 80 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, dilute with water (30 mL), and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 3/1). Compound 20-1 (200 mg, yield: 53.5%) was obtained.

LC-MS(ESI)[M+H] ⁺ 361.0.

Step 2: Preparation of compound 20-2

To a solution of compound 20-1 (200 mg, 0.480 mmol) in dichloromethane (10 mL) at room temperature, a solution of hydrogen chloride in 1,4-dioxane (4.00 mol/L, 2.00 mL, 8.00 mmol) was added. The reaction system was stirred at room temperature for 1 hour. Concentrate under reduced pressure and add water (20 mL). Adjust the pH to 8-9 with ammonia water (1.00mmol/L), and extract with ethyl acetate (50mL×3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 20-2 (140 mg, yield: 92.1%).

LC-MS(ESI)[M+H] ⁺ 317.1.

Step 3: Preparation of Compound 20-3

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (329 mg, 1.14 mmol), compound 20-2 (120 mg, 0.380 mmol), A mixed system of activated 4A molecular sieve (200 mg) and anhydrous 1,2-dichloroethane (10 mL) was stirred at room temperature for 1 hour. back Sodium triacetoxyborohydride (241 mg, 1.14 mmol) was added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 20-3 (100 mg, yield: 44.6%).

LC-MS(ESI)[M+H] ⁺ 612.2.

Step 4: Preparation of Compound 20

Compound 20-3 (100 mg, 0.170 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=5/5/2 mL), and then lithium hydroxide monohydrate (71.0 mg, 1.70 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 20 (28.6 mg, yield: 35.5%).

LC-MS(ESI)[M+H] ⁺ 476.1

¹ H NMR (400MHz, CD ₃ OD) δ=8.02 (d, J=8.1Hz, 2H), 7.51 (d, J=8.2Hz, 2H), 7.18 (d, J=3.1Hz, 1H), 6.72 ( s, 1H), 6.26 (d, J=3.1Hz, 1H), 4.35 (dq, J=15.1, 9.5Hz, 1H), 4.23 (s, 1H), 4.04-3.93 (m, 1H), 3.78 (d , J=9.6Hz, 4H), 3.70 (d, J=12.0Hz, 1H), 3.63 (dd, J=15.5, 5.9Hz, 1H), 3.45 (dt, J=11.6, 3.4Hz, 1H), 3.05 (dt, J=12.6, 3.8Hz, 1H), 2.69-2.60 (m, 1H), 2.49 (s, 3H).

Example 21: Synthesis of Compound 21

Step 1: Preparation of compound 21-1

To a solution of compound 16-4 (300 mg, 0.900 mmol) in N-methylpyrrolidone (3 mL) at room temperature, cesium carbonate (1.46 g, 4.49 mmol) and bromomethylcyclopropane (605 mg, 4.49 mmol) were added. Nitrogen was replaced, and the reaction system was stirred at 80 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, dilute with water (30 mL), and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by reversed-phase column chromatography (acetonitrile/water = 1/1) to obtain Compound 21-1 (100 mg, yield: 28.6%).

LC-MS(ESI)[M+H] ⁺ 389.0.

Step 2: Preparation of compound 21-2

To a solution of compound 21-1 (100 mg, 0.260 mmol) in dichloromethane (5 mL) at room temperature, a solution of hydrogen chloride in 1,4-dioxane (4.00 mol/L, 1.00 mL, 4.00 mmol) was added. The reaction system was stirred at room temperature for 1 hour. Concentrate under reduced pressure and add water (20 mL). Adjust the pH to 8-9 with ammonia water (1.00mmol/L), and extract with ethyl acetate (50mL×3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 21-2 (72.2 mg, yield: 100%).

LC-MS(ESI)[M+H] ⁺ 289.1.

Step 3: Preparation of compound 21-3

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (217mg, 0.750mmol), compound 21-2 (72.2mg, 0.250mmol) , a mixed system of activated 3A molecular sieve (200 mg) and anhydrous 1,2-dichloroethane (10 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (159 mg, 0.750 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 21-3 (32.0 mg, yield: 22.8%).

LC-MS(ESI)[M+H] ⁺ 562.1.

Step 4: Preparation of Compound 21

Compound 21-3 (32.0 mg, 0.0600 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=5/5/2 mL), and then lithium hydroxide monohydrate (12.6 mg, 0.300 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 21 (5.60 mg, yield: 20.9%).

LC-MS(ESI)[M+H] ⁺ 448.2

¹ H NMR (400MHz, CD ₃ OD) δ=7.80 (d, J=8.2Hz, 2H), 7.36 (d, J=8.2Hz, 2H), 6.94 (d, J=3.1Hz, 1H), 6.46 ( s, 1H), 6.01 (d, J = 3.1Hz, 1H), 3.93 (s, 1H), 3.57-3.51 (m, 4H), 3.44 (d, J = 11.9Hz, 1H), 3.40-3.32 (m , 1H), 3.19-3.11(m, 3H), 2.97-2.91(m, 1H), 2.85-2.79(m, 1H), 2.43-2.35(m, 1H), 2.24(s, 3H), 0.33-0.25 (m, 2H), 0.07--0.03(m, 2H).

Example 22: Synthesis of Compound 22

Step 1: Preparation of compound 22-1

To a solution of compound 16-4 (200 mg, 0.600 mmol) in N-methylpyrrolidone (3 mL) at room temperature, cesium carbonate (974 mg, 2.99 mmol) and bromomethylcyclobutane (446 mg, 2.99 mmol) were added. Nitrogen was replaced, and the reaction system was stirred at 80 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, dilute with water (30 mL), and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by reversed-phase column chromatography (acetonitrile/water = 1/1) to obtain Compound 22-1 (130 mg, yield: 53.8%).

LC-MS(ESI)[M+H] ⁺ 403.1.

Step 2: Preparation of compound 22-2

To a solution of compound 22-1 (130 mg, 0.320 mmol) in dichloromethane (5 mL) at room temperature, a solution of hydrogen chloride in 1,4-dioxane (4.00 mol/L, 1.00 mL, 4.00 mmol) was added. The reaction system was stirred at room temperature for 1 hour. Concentrate under reduced pressure and add water (20 mL). Adjust the pH to 8-9 with ammonia water (1.00mmol/L), and extract with ethyl acetate (50mL×3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 22-2 (52.0 mg, yield: 53.3%).

LC-MS(ESI)[M+H] ⁺ 303.1.

Step 3: Preparation of compound 22-3

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (149 mg, 0.510 mmol), compound 22-2 (52.0 mg, 0.170 mmol) , a mixed system of activated 3A molecular sieve (200 mg) and anhydrous 1,2-dichloroethane (10 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (108 mg, 0.510 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 22-3 (27.0 mg, yield: 27.6%).

LC-MS(ESI)[M+H] ⁺ 562.1.

Step 4: Preparation of Compound 22

Compound 22-3 (27.0 mg, 47.0 μmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=5/5/2 mL), and then lithium hydroxide monohydrate (9.80 mg, 0.230 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 22 (3.30 mg, yield: 15.2%).

LC-MS(ESI)[M+H] ⁺ 462.2

¹ H NMR (400MHz, CD ₃ OD) δ=8.04 (d, J=8.2Hz, 2H), 7.59 (d, J=8.2Hz, 2H), 7.18 (d, J=3.1Hz, 1H), 6.69 ( s, 1H), 6.23 (d, J=3.1Hz, 1H), 4.15 (s, 1H), 3.80-3.71 (m, 4H), 3.69-3.58 (m, 2H), 3.53-3.44 (m, 1H) , 3.29-3.22(m, 2H), 3.05-2.98(m, 1H), 2.72-2.54(m, 2H), 2.47(s, 3H), 2.10-2.00(m, 2H), 1.96-1.69(m, 4H).

Example 23: Synthesis of Compound 23

Step 1: Preparation of compound 23-1

To a solution of compound 16-4 (500 mg, 2.17 mmol) in N-methylpyrrolidone (10 mL) at room temperature, potassium carbonate (600 mg, 4.34 mmol), potassium iodide (36.0 mg, 0.220 mmol) and 3-(bromomethyl) were added. (804 mg, 4.34 mmol). Nitrogen was replaced, and the reaction system was stirred at 80 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, dilute with water (30 mL), and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1). Compound 23-1 (1.28g, yield: 87.0%) was obtained.

LC-MS(ESI)[M+H] ⁺ 335.2.

Step 2: Preparation of compound 23-2

To a solution of compound 23-1 (631 mg, 1.89 mmol) in dichloromethane (10 mL) at room temperature, a solution of hydrogen chloride in 1,4-dioxane (4.00 mol/L, 2.00 mL, 8.00 mmol) was added. The reaction system was stirred at room temperature for 1 hour. Concentrate under reduced pressure and add water (20 mL). Adjust the pH to 8-9 with ammonia water (1.00mmol/L), and extract with ethyl acetate (50mL×3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 23-2 (253 mg, yield: 40.0%).

LC-MS(ESI)[M+H] ⁺ 339.2.

Step 3: Preparation of compound 23-3

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (433 mg, 1.50 mmol), compound 23-2 (253 mg, 0.750 mmol), A mixed system of activated 3A molecular sieve (200 mg) and anhydrous 1,2-dichloroethane (15 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (476 mg, 2.24 mml) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 23-3 (260 mg, yield: 57.0%).

LC-MS(ESI)[M+H] ⁺ 612.4.

Step 4: Preparation of compound 23

Compound 23-3 (260 mg, 0.430 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=5/5/2 mL), and then lithium hydroxide monohydrate (89.0 mg, 2.13 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 23 (43.0 mg, yield: 20.0%).

LC-MS(ESI)[M+H] ⁺ 498.2

¹ H NMR (400MHz, CD ₃ OD) δ=8.06 (d, J=8.2Hz, 2H), 7.61 (d, J=8.2Hz, 2H), 7.20 (d, J=3.1Hz, 1H), 6.71 ( s, 1H), 6.25 (d, J=3.1Hz, 1H), 4.19 (s, 1H), 3.82-3.75 (m, 4H), 3.72-3.65 (m, 2H), 3.58-3.50 (m, 1H) , 3.47-3.40(m, 1H), 3.33-3.28(m, 1H), 3.09-3.03(m, 1H), 2.70-2.59(m, 3H), 2.55-2.47(m, 4H), 2.43-2.22( m, 2H).

Example 24: Synthesis of Compound 24

Step 1: Preparation of Compound 24-1

To a solution of compound 16-4 (300 mg, 0.900 mmol) in N-methylpyrrolidone (10 mL) at room temperature, cesium carbonate (879 mg, 2.70 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (1080 mg, 4.50 mmol). Nitrogen was replaced, and the reaction system was stirred at 80 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, dilute with water (30 mL), and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1). Compound 24-1 (336 mg, yield: 75.7%) was obtained.

LC-MS(ESI)[M+H] ⁺ 493.3.

Step 2: Preparation of compound 24-2

To a solution of compound 24-1 (336 mg, 0.680 mmol) in dichloromethane (4 mL) at room temperature, a solution of hydrogen chloride in 1,4-dioxane (4.00 mol/L, 1.00 mL, 4.00 mmol) was added. The reaction system was stirred at room temperature for 1 hour. Concentrate under reduced pressure and add water (20 mL). Adjust the pH to 8-9 with ammonia water (1.00mmol/L), and extract with ethyl acetate (50mL×3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 24-2 (198 mg, yield: 100%).

LC-MS(ESI)[M+H] ⁺ 279.3.

Step 3: Preparation of Compound 24-3

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (355 mg, 1.23 mmol), compound 24-2 (198 mg, 0.680 mmol), A mixed system of activated 3A molecular sieve (200 mg) and anhydrous 1,2-dichloroethane (15 mL) was stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride (430 mg, 2.04 mmol) was added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by reversed-phase column chromatography (acetonitrile/water=1/1) to obtain compound 24-3 (90.0 mg, yield: 24.0%).

LC-MS(ESI)[M+H] ⁺ 552.4.

Step 4: Preparation of Compound 24

Compound 24-3 (90.0 mg, 0.160 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=5/5/2 mL), and then lithium hydroxide monohydrate (15.5 mg, 0.370 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 24 (38.0 mg, yield: 54.3%).

LC-MS(ESI)[M+H] ⁺ 438.2

¹ H NMR (400MHz, CD ₃ OD) δ=8.03 (d, J=8.1Hz, 2H), 7.54 (d, J=8.1Hz, 2H), 7.17 (d, J=3.0Hz, 1H), 6.72 ( s, 1H), 6.25 (d, J=3.1Hz, 1H), 4.16 (s, 1H), 3.80 (s, 3H), 3.78-3.57 (m, 6H), 3.46-3.38 (m, 2H), 3.07 -3.00(m,1H),2.68-2.58(m,1H),2.49(s,3H).

Example 25: Synthesis of Compound 25

Step 1: Preparation of compound 25-1

To a solution of compound 16-4 (300 mg, 0.900 mmol) in N-methylpyrrolidone (3 mL) at room temperature, cesium carbonate (1.46 g, 4.49 mmol) and 2-bromoethyl methyl ether (624 mg, 4.49 mmol) were added. ). Nitrogen was replaced, and the reaction system was stirred at 80 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, dilute with water (30 mL), and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by reversed-phase column chromatography (acetonitrile/water = 1/1) to obtain Compound 25-1 (150 mg, yield: 42.5%).

LC-MS(ESI)[M+H] ⁺ 393.1.

Step 2: Preparation of compound 25-2

To a solution of compound 25-1 (150 mg, 0.380 mmol) in dichloromethane (5 mL) at room temperature, a solution of hydrogen chloride in 1,4-dioxane (4.00 mol/L, 1.00 mL, 4.00 mmol) was added. The reaction system was stirred at room temperature for 1 hour. Concentrate under reduced pressure and add water (20 mL). Adjust the pH to 8-9 with ammonia water (1.00mmol/L), and extract with ethyl acetate (50mL×3). The combined organic phases were washed with saturated brine (20 mL), anhydrous sulfur The solution was dried over sodium chloride, filtered, and concentrated under reduced pressure to obtain compound 25-2 (81.0 mg, yield: 72.5%).

LC-MS(ESI)[M+H] ⁺ 293.1.

Step 3: Preparation of compound 25-3

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (240 mg, 0.830 mmol), compound 25-2 (81.0 mg, 0.280 mmol) , a mixed system of activated 3A molecular sieve (200 mg) and anhydrous 1,2-dichloroethane (10 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (176 mg, 0.830 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 25-3 (110 mg, yield: 70.2%).

LC-MS(ESI)[M+H] ⁺ 566.2.

Step 4: Preparation of Compound 25

Compound 25-3 (110 mg, 0.190 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=5/5/2 mL), and then lithium hydroxide monohydrate (40.8 mg, 0.970 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 25 (38.0 mg, yield: 43.4%).

LC-MS(ESI)[M+H] ⁺ 452.1

¹ H NMR (400MHz, CD ₃ OD) δ=8.03 (d, J=8.1Hz, 2H), 7.56 (d, J=8.2Hz, 2H), 7.17 (d, J=3.1Hz, 1H), 6.70 ( s, 1H), 6.24 (d, J = 3.1Hz, 1H), 4.16 (s, 1H), 3.77 (d, J = 11.2Hz, 4H), 3.72-3.63 (m, 2H), 3.61-3.51 (m , 3H), 3.48-3.38(m, 2H), 3.35(s, 3H), 3.01(dt, J=12.3, 3.7Hz, 1H), 2.66-2.56(m, 1H), 2.48(s, 3H).

Example 26: Synthesis of Compound 26

Step 1: Preparation of compound 26-1

To a solution of compound 16-4 (500 mg, 1.500 mmol) in N-methylpyrrolidone (15 mL) at room temperature, cesium carbonate (1.47 g, 4.50 mmol) and n-propane iodide (1.50 g, 8.97 mmol) were added. Nitrogen was replaced, and the reaction system was stirred at 80 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, dilute with water (30 mL), and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (dichloromethane/methanol=20/1) to obtain Compound 26-1 (230 mg, yield: 40.7%).

LC-MS(ESI)[M+H] ⁺ 321.1.

Step 2: Preparation of compound 26-2

To a solution of compound 26-1 (230 mg, 0.610 mmol) in dichloromethane (10 mL) at room temperature, a solution of hydrogen chloride in 1,4-dioxane (4.00 mol/L, 2.00 mL, 8.00 mmol) was added. The reaction system was stirred at room temperature for 1 hour. Concentrate under reduced pressure and add water (20 mL). Adjust the pH to 8-9 with ammonia water (1.00mmol/L), and extract with ethyl acetate (50mL×3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 26-2 (169 mg, yield: 100%).

LC-MS(ESI)[M+H] ⁺ 277.1.

Step 3: Preparation of compound 26-3

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (530 mg, 1.83 mmol), compound 26-2 (169 mg, 0.610 mmol), A mixed system of activated 3A molecular sieve (200 mg) and anhydrous 1,2-dichloroethane (15 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (388 mg, 1.83 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 26-3 (150 mg, yield: 44.7%).

LC-MS(ESI)[M+H] ⁺ 550.2.

Step 4: Preparation of Compound 26

Compound 26-3 (150 mg, 0.270 mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=5/5/2 mL), and then lithium hydroxide monohydrate (57.3 mg, 1.36 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 26 (70.0 mg, yield: 59.5%).

LC-MS(ESI)[M+H] ⁺ 436.6

¹ H NMR (400MHz, CD ₃ OD) δ=8.03 (d, J=8.2Hz, 2H), 7.54 (d, J=8.2Hz, 2H), 7.18 (d, J=3.1Hz, 1H), 6.71 ( s, 1H), 6.25 (d, J = 3.1Hz, 1H), 4.14 (s, 1H), 3.81-3.74 (m, 4H), 3.67 (d, J = 11.9Hz, 1H), 3.55-3.41 (m , 2H), 3.31-3.23(m, 2H), 3.08-3.01(m, 1H), 2.66-2.55(m, 1H), 2.49(s, 3H), 1.69-1.56(m, 2H), 0.93(t , J=7.4Hz, 3H).

Example 27: Synthesis of Compounds 27a and 27b

Step 1: Preparation of compound 27-2

A solution of compound 27-1 (50.0 g, 218 mmol) in ultradry tetrahydrofuran (200 mL) was cooled to -78°C at room temperature. A solution of lithium hexamethyldisilazide in tetrahydrofuran (1.00 mol/L, 262 mL, 262 mmol) was added. The reaction system was stirred at -78°C for 0.5 hours. Then, methyl iodide (31.0 g, 218 mmol) was added dropwise. After the dripping was completed, the reaction system was slowly raised to room temperature, and then stirred for 16 hours. LCMS showed the reaction was complete. Add saturated aqueous ammonium chloride solution (100 mL) to quench the reaction, and extract with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain compound 27-2 ( 34.9g, yield: 69.0%).

LC-MS(ESI)[M+H] ⁺ 244.1.

Step 2: Preparation of compound 27-3

To a solution of compound 27-2 (34.9g, 144mmol) in carbon tetrachloride (250mL) at room temperature, N-bromosuccinimide (30.7g, 172mmol) and azobisisobutyronitrile (2.40g , 14.4mmol). Nitrogen was replaced, and the reaction system was stirred at 80°C for 16 hours. LCMS showed the reaction was complete. Concentrate under reduced pressure, dilute with water (200 mL), and extract with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to obtain compound 27-3 ( 22.0g, yield: 47.8%).

¹ H NMR (400MHz, CDCl ₃ ) δ = 7.50-7.46 (m, 2H), 7.44-7.42 (m, 2H), 3.79 (s, 3H), 2.27 (s, 3H).

Step 3: Preparation of compound 27-4

To a solution of compound 27-3 (22.0 g, 68.3 mmol) in ethanol (170 mL) at room temperature, diethylamine (12.3 g, 205 mmol) was added. Nitrogen was replaced, and the reaction system was stirred at 60°C for 16 hours. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (dichloromethane/methanol=10/1) to obtain compound 27-4 (9.00 g, yield: 48.9%).

LC-MS(ESI)[M+H] ⁺ 271.0.

Step 4: Preparation of Compound 27-5

To compound 27-4 (18.5 g, 68.7 mmol), a solution of borane in tetrahydrofuran (1.00 mmol/L, 344 mL, 344 mmol) was added at room temperature. Nitrogen was replaced, and the reaction system was stirred at 85°C for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, add methanol (50 mL) to quench the reaction, and concentrate under reduced pressure. Methanol (200 mL) and hydrochloric acid aqueous solution (1.00 mol/L, 344 ml, 344 mmol) were added, and the system was stirred at 80°C for 0.5 hours. Cool to room temperature, slowly add sodium hydroxide (16.5g, 413mmol) to adjust the pH to alkaline, and this solution is used directly for the next reaction.

LC-MS(ESI)[M+H] ⁺ 257.1.

Step 5: Preparation of compound 27-6

At room temperature, di-tert-butyl dicarbonate (18.0 g, 82.5 mmol) was added to the above solution. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. Extract with ethyl acetate (300mL×3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (dichloromethane/methanol = 10/1) to obtain compound 27-6 (20.3 g, two-step total yield: 83.2%).

LC-MS(ESI)[M+H] ⁺ 357.1.

Step 6: Preparation of Compound 27-7

To a solution of compound 27-6 (300 mg, 0.840 mmol) in methanol (10 mL) at room temperature, triethylamine (168 mg, 1.68 mmol) and [1,1′-bis(diphenylphosphine)ferrocene] were added Palladium dichloride dichloromethane complex (12.0 mg, 0.0180 mmol). Carbon monoxide was substituted, and the reaction system was stirred at 90°C for 5 hours. LCMS showed the reaction was complete. Cool to room temperature, dilute with water (60 mL), and extract with ethyl acetate (60 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/2) to obtain compound 27- 7 (200 mg, two-step total yield: 71.4%).

LC-MS(ESI)[M+H] ⁺ 335.2.

Step 7: Preparation of Compound 27-8

To a solution of compound 27-7 (200 mg, 0.600 mmol) in dichloromethane (5 mL) at room temperature, a solution of hydrogen chloride in 1,4-dioxane (4.00 mol/L, 2.00 mL, 8.00 mmol) was added. The reaction system was stirred at room temperature for 3 hours. LCMS showed the reaction was complete. The product was concentrated under reduced pressure to obtain compound 27-8 (130 mg, yield: 92.8%).

LC-MS(ESI)[M+H] ⁺ 235.2.

Step 8: Preparation of compound 27-9

Under an ice-water bath, to a solution of compound 27-8 (130 mg, 0.400 mmol) and triethylamine (80.0 mg, 0.800 mmol) in N, N-dimethylformamide (3 mL), methyl iodide (110 mg, 0.400 mmol) in N,N-dimethylformamide (1 mL). The nitrogen gas was replaced, and the reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. Dilute with water (30 mL) and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (dichloromethane/methanol=10/1) to obtain Compound 27-9 (50.0 mg, yield: 36.2%).

LC-MS(ESI)[M+H] ⁺ 249.4.

Step 9: Preparation of Compound 27-10

Under argon protection, 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (116 mg, 0.400 mmol), compound 27-9 (50.0 mg, 0.200 mmol) , a mixed system of activated 3A molecular sieve (100 mg) and anhydrous 1,2-dichloroethane (15 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (109 mg, 0.500 mmol) was then added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. It was filtered and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 31) to obtain compound 27-10 (6.0 mg, yield: 5.75%).

LC-MS(ESI)[M+H] ⁺ 522.4.

Step 10: Preparation of Compound 27

Compound 27-10 (6.0 mg, 11.5 μmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=2/2/1 mL), and then lithium hydroxide monohydrate (2.4 mg, 58.0 μmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain compound 27 (0.91 mg, yield: 19.4%).

LC-MS(ESI)[M+H] ⁺ 408.2

¹ H NMR (400MHz, CD ₃ OD) δ = 8.03 (s, 2H), 7.85 (s, 2H), 7.21 (s, 1H), 6.69 (s, 1H), 6.54-6.35 (m, 1H), 4.59 (s, 1H), 3.74 (s, 3H), 2.88-2.80 (m, 1H), 2.74-2.64 (m, 1H), 2.46 (s, 3H), 2.29 (s, 3H), 2.19 (t, J =7.4Hz, 2H), 2.06-2.01(m, 3H), 1.81-1.75(m, 1H), 1.64-1.58(m, 2H).

Step 11: Preparation of Compounds 27a and 27b

Compound 27 (217 mg, 0.533 mmol) was purified by preparative SFC (column (250*30mm, 10μm)); mobile phase [A: carbon dioxide, B: isopropyl alcohol (containing 0.1% ammonia)]; B%: 35% to obtain 27a (retention time 1.300 minutes) and 27b (retention time 1.850 minutes) . Retention times were determined using the following analytical method: Column: 100*4.6mm 3.0μm, mobile phase [A: carbon dioxide, B: isopropyl alcohol (containing 0.05% diethylamine)], 40% B, flow rate: 2.5mL/min, column temperature: 35°C.

Target substance 27a (41.0 mg, recovery rate: 18.9%), LC-MS (ESI) [M+H] ⁺ 408.2, ¹ H NMR (400MHz, CD ₃ OD) δ = 8.03 (s, 2H), 7.85 (s , 2H), 7.21(s, 1H), 6.69(s, 1H), 6.54-6.35(m, 1H), 4.59(s, 1H), 3.74(s, 3H), 2.88-2.80(m, 1H), 2.74-2.64(m, 1H), 2.46(s, 3H), 2.29(s, 3H), 2.19(t, J=7.4Hz, 2H), 2.06-2.01(m, 3H), 1.81-1.75(m, 1H), 1.64-1.58(m, 2H).

Target substance 27b (51.0 mg, yield: 23.5%), LC-MS (ESI) [M+H] ⁺ 408.2, ¹ H NMR (400MHz, CD ₃ OD) δ = 8.03 (s, 2H), 7.85 (s , 2H), 7.21(s, 1H), 6.69(s, 1H), 6.54-6.35(m, 1H), 4.59(s, 1H), 3.74(s, 3H), 2.88-2.80(m, 1H), 2.74-2.64(m, 1H), 2.46(s, 3H), 2.29(s, 3H), 2.19(t, J=7.4Hz, 2H), 2.06-2.01(m, 3H), 1.81-1.75(m, 1H), 1.64-1.58(m, 2H).

Example 28: Synthesis of Compounds 28a and 28b

Step 1: Preparation of Compound 28-1

Under an ice-water bath, to a mixture of compound 27-8 (667 mg, 2.83 mmol) and potassium carbonate (781 mg, 5.66 mmol) in N, N-dimethylformamide (10 mL), 2,2,2- was slowly added dropwise. A solution of trifluoroethyl trifluoromethanesulfonate (660 mg, 2.83 mmol) in N,N-dimethylformamide (3 mL). The nitrogen gas was replaced, and the reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. Dilute with water (50 mL) and extract with ethyl acetate (60 mL × 3). The combined organic phases were washed successively with water (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1). Compound 28-1 (300 mg, yield: 33.2%) was obtained.

LC-MS(ESI)[M+H] ⁺ 317.2.

Step 2: Preparation of compound 28-2

To a solution of compound 28-1 (80.0 mg, 0.240 mmol) in ultradry acetonitrile (5 mL) at room temperature, potassium carbonate (524 mg, 3.75 mmol) and 4-methylene chloride-5-methoxy-7- were added. Methyl-indole-1-carboxylic acid tert-butyl ester (240 mg, 0.780 mmol). Nitrogen was replaced, and the reaction system was stirred at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, dilute with water (30 mL), and extract with ethyl acetate (50 mL × 3). The combined organic phases were washed successively with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 4/1). Compound 28-2 (40.0 mg, yield: 26.8%) was obtained.

LC-MS(ESI)[M+H] ⁺ 590.8.

Step 3: Preparation of Compound 28

Compound 28-2 (40.0 mg, 70.0 μmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=2/2/1 mL), and then lithium hydroxide monohydrate (16.0 mg, 0.260 mmol) was added. Reaction at 60 degrees for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to neutral with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain compound 28 (6.95 mg, yield: 21.8%).

LC-MS(ESI)[M+H] ⁺ 476.3

¹ H NMR (400MHz, CD ₃ OD) δ=8.06 (d, J=8.5Hz, 2H), 7.88 (s, 2H), 7.22 (d, J=3.1Hz, 1H), 6.70 (s, 1H), 6.40(s, 1H), 3.86-3.54(m, 5H), 3.13-2.96(m, 3H), 2.96-2.75(m, 3H), 2.75-2.58(m, 2H), 2.48(s, 3H), 1.99-1.79(m,3H).

Step 4: Preparation of Compounds 28a and 28b

Compound 28 (275 mg, 0.579 mmol) was purified by preparative SFC (column (250*30mm, 10μm)); mobile phase [A: carbon dioxide, B: methanol (containing 0.1% ammonia)]; B%: 30% to obtain 28a (retention time 3.600 minutes) and 28b (retention time 4.072 minutes). Retention times were determined using the following analytical method: Column: 150*4.6mm 3.0μm, mobile phase [A: carbon dioxide, B: methanol (containing 0.05% diethylamine)], 40% B, flow rate: 2.5mL/min, column temperature: 35°C.

Target substance 28a (131 mg, recovery rate: 47.6%), LC-MS (ESI) [M+H] ⁺ 476.3, ¹ H NMR (400MHz, CD ₃ OD) δ = 8.06 (d, J = 8.5Hz, 2H) , 7.88 (s, 2H), 7.22 (d, J=3.1Hz, 1H), 6.70 (s, 1H), 6.40 (s, 1H), 3.86-3.54 (m, 5H), 3.13-2.96 (m, 3H ), 2.96-2.75(m, 3H), 2.75-2.58(m, 2H), 2.48(s, 3H), 1.99-1.79(m, 3H).

Target substance 28b (91.0 mg, yield: 33.1%), LC-MS (ESI) [M+H] ⁺ 476.3, ¹ H NMR (400 MHz, CD ₃ OD) δ = 8.06 (d, J = 8.5 Hz, 2H ), 7.88 (s, 2H), 7.22 (d, J = 3.1Hz, 1H), 6.70 (s, 1H), 6.40 (s, 1H), 3.86-3.54 (m, 5H), 3.13-2.96 (m, 3H), 2.96-2.75(m, 3H), 2.75-2.58(m, 2H), 2.48(s, 3H), 1.99-1.79(m, 3H).

Example 29: Synthesis of Compounds 29a and 29b

Step 1: Preparation of compound 29-1

Compound 1-3 (4.20g, 19.1mmol) and triethylamine (9.65g, 95.4mmol) were dissolved in acetone/N,N-dimethylformamide (60/60mL) mixed solvent at room temperature. Under an ice-water bath, a solution of methyl iodide (3.72g, 26.2mmol) in acetone (10mL) was added dropwise. After the dripping was completed, the system was stirred at room temperature for 5 hours. LCMS showed the reaction was complete. Dilute with water (120 mL) and extract with ethyl acetate (120 mL × 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (dichloromethane/methanol=4/1) to obtain compound 29-1 ( 2.57g, yield: 46.4%, yellow solid).

LC-MS(ESI)[M+H] ⁺ 235.1

Step 2: Preparation of compound 29-2

Under argon protection, compound 29-1 (2.57g, 11.0mmol), 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (5.71g, 19.7mmol) was added ), a mixed system of activated 4A molecular sieve (3.00g) and anhydrous 1,2-dichloroethane (80mL) was stirred at room temperature for 30 minutes. Then sodium acetate borohydride (6.97g, 32.9mmol) was added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. Filter and add water (80 mL) to the filtrate to quench the reaction. Extract with dichloromethane (80mL×3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 29-2. (2.70g, yield: 46.7%, yellow solid).

LC-MS(ESI)[M+H] ⁺ 508.2

Step 3: Preparation of Compounds 29-3a and 29-3b

Compound 29-2 (2.70g, 5.32mmol) was passed through SFC (column (250*25mm, 10μm)); mobile phase [A: carbon dioxide, B: methanol (containing 0.1% 7.0mol/L ammonia)]; B%: 0% ~ 35%. Purified compound 29-3a (1.01g, collected Yield: 37.4%, white solid, retention time 4.225 minutes) and 29-3b (1.01g, yield: 37.4%, white solid, retention time 4.778 minutes). Retention times were determined using the following analytical method: Column: 100*3.0mm 3.0μm, mobile phase [A: carbon dioxide, B: methanol (containing 0.1% diethylamine)], 40% B, flow rate: 1.5mL/min, column temperature: 35°C.

Step 4: Preparation of Compound 29a

Compound 29-3a (1.01g, 1.99mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=15/15/7.5mL). Lithium hydroxide monohydrate (417 mg, 9.95 mmol) was then added. The reaction mixture was stirred at 60°C for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to 9-10 with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 29a (730.96 mg, yield: 93.4%, white solid).

LC-MS(ESI)[M+H] ⁺ 394.1

¹ H NMR (400MHz, DMSO-d ₆ ) δ = 10.80 (s, 1H), 7.84 (s, 2H), 7.42 (s, 2H), 7.24 (t, J = 2.8Hz, 1H), 6.64 (s, 1H), 6.44(s, 1H), 3.71(s, 3H), 3.57(d, J＝11.6Hz, 1H), 3.28-3.24(m, 1H), 3.18(d, J＝11.7Hz, 1H), 2.64 (d, J=11.6Hz, 1H), 2.59 (d, J=9.3Hz, 2H), 2.41 (s, 3H), 2.21-2.13 (m, 1H), 2.11 (s, 3H), 2.01-1.84 (m,2H).

Step 5: Preparation of Compound 29b

Compound 29-3b (1.01g, 1.99mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=15/15/7.5mL). Lithium hydroxide monohydrate (417 mg, 9.95 mmol) was then added. The reaction mixture was stirred at 60°C for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to 9-10 with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 29b (582 mg, yield: 74.1%, white solid).

LC-MS(ESI)[M+H] ⁺ 394.1

Example 30: Synthesis of Compounds 30a and 30b

Step 1: Preparation of Compound 30-1

To a solution of compound 1-3 (5.00g, 22.7mmol) in N,N-dimethylformamide (100mL) at room temperature, potassium carbonate (6.28g, 45.4mmol) and 2,2,2-trifluorocarbon were added successively. Ethyl trifluoromethanesulfonate (6.32g, 27.2mmol). The system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. Dilute with water (200 mL) and extract with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (dichloromethane/methanol=4/1) to obtain compound 30-1 ( 3.74g, yield: 54.5%, yellow solid).

LC-MS(ESI)[M+H] ⁺ 303.3

Step 2: Preparation of Compound 30-2

Under argon protection, compound 30-1 (3.74g, 12.4mmol), 4-formyl-5-methoxy-7-methyl-indole-1-carboxylic acid tert-butyl ester (6.44g, 22.3mmol) was added ), a mixed system of activated 4A molecular sieve (3.20g) and anhydrous 1,2-dichloroethane (80mL) was stirred at room temperature for 30 minutes. Then sodium acetate borohydride (7.87g, 37.1mmol) was added. The reaction system was stirred at room temperature for 16 hours. LCMS showed the reaction was complete. Filter and add water (80 mL) to the filtrate to quench the reaction. Extract with dichloromethane (100mL×3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (petroleum ether/ethyl acetate = 1/1) to obtain compound 30-2. (4.67g, yield: 65.5%, red-yellow oily liquid).

LC-MS(ESI)[M+H] ⁺ 576.4

Step 3: Preparation of Compounds 30-3a and 30-3b

Compound 30-2 (4.67g, 8.11mmol) was passed through SFC (column (250*25mm, 10μm)); mobile phase [A: carbon dioxide, B: methanol (containing 0.1% 7.0mol/L ammonia)]; B%: 0% ~ 40%. Purified compound 30-3a (2.00g, collected Yield: 42.8%, white solid, retention time 2.995 minutes) and 30-3b (1.58g, yield: 33.8%, white solid, retention time 3.254 minutes). Retention times were determined using the following analytical method: Column: 100*3.0mm 3.0μm, mobile phase [A: carbon dioxide, B: methanol (containing 0.1% diethylamine)], 40% B, flow rate: 1.5mL/min, column temperature: 35°C.

Step 4: Preparation of Compound 30a

Compound 30-3a (2.00g, 3.47mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=30/30/15mL). Lithium hydroxide monohydrate (728 mg, 17.4 mmol) was then added. The reaction mixture was stirred at 60°C for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to 9-10 with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 30a (1.00 g, yield: 62.6%, white solid).

LC-MS(ESI)[M+H] ⁺ 462.2

¹ H NMR (400MHz, MeOD) δ=8.00 (d, J=8.4Hz, 2H), 7.57 (d, J=7.2Hz, 2H), 7.16 (d, J=3.1Hz, 1H), 6.66 (s, 1H), 6.41 (d, J=3.1Hz, 1H), 3.83-3.72 (m, 4H), 3.47 (dd, J=10.3, 2.6Hz, 1H), 3.27 (d, J=11.3Hz, 1H), 3.08-2.94(m, 2H), 2.89-2.72(m, 3H), 2.57-2.46(m, 2H), 2.45-2.36(m, 4H).

Step 5: Preparation of Compound 30b

Compound 30-3b (1.58g, 2.74mmol) was dissolved in a mixed solvent (methanol/tetrahydrofuran/water=30/30/15mL). Lithium hydroxide monohydrate (576 mg, 13.7 mmol) was then added. The reaction mixture was stirred at 60°C for 16 hours. LCMS showed the reaction was complete. Cool to room temperature, adjust the pH to 9-10 with dilute hydrochloric acid (1 mol/L), and concentrate under reduced pressure. The resulting residue is purified by Prep-HPLC to obtain target compound 30b (877 mg, yield: 69.3%, white solid).

LC-MS(ESI)[M+H] ⁺ 462.2

References for the preparation method of the control compound (Example 26c, WO2015009616A1)

Biological Examples

Experimental example 1: C3 proteolysis experiment

1. Prepare CVF:Bb complex: First prepare the reaction buffer (10mM MgCl ₂ , 0.05% w/v CHAPS, PBS pH 7.4), and use the reaction buffer to prepare a final concentration of 300nM FD (A409, Quidel), 1μM FB (A408 , Quidel), 1 μM CVF (A600, Quidel) mixed reaction system, incubated at 37°C for 3 hours. The digested products were divided into small portions and stored at -80°C for subsequent experiments.

2. C3 hydrolysis reaction: The compound was first diluted three times with DMSO in a gradient to a total of ten concentrations, then diluted 40 times with reaction buffer, and 1 μL was transferred to a 384-well plate (ProxiPlate-384plus, PE). Use reaction buffer to prepare 2.5nM CVF: Bb and 1uM C3 (A401, Quidel). Transfer 2 μL of CVF:Bb to the ProxiPlate 384 wells containing the compound and incubate at 37°C for 30 minutes. Add 2 μL of C3 to start the reaction and incubate at 37°C for 180 minutes. Pay attention to sealing the 384-well plate during the reaction. Add 5uL 2x protease inhibitor cocktail (5892970001, Roche) to each well to stop the reaction. After mixing, transfer 1.25μL reaction solution to a 384-well black plate (OptiPlate-384 F HB, PE), and add 23.8μL coating buffer (containing 100mM sodium carbonate pH9.0: C3041, Sigma and 1M NaCl: A610476-0001, BBI Life Science), centrifuge at 1000 rpm for 1 minute, and place at 4°C for overnight coating. The next day, discard the liquid in the 384-well plate coated the day before, pat dry on clean absorbent paper, and wash 3 times with PBST. Add 25 μL starting block T20 (37539, Thermofisher) to each well, incubate at room temperature for 15 minutes, discard the supernatant, and wash 3 times with PBST. Add 25 μL 25ul Anti-C3a neo-epitope antibody (C7850-13G, US Biological, dilution factor 100) to each well, incubate at room temperature for 1 hour, discard the supernatant, and wash 3 times with PBST. Add 25 μL Quantablu fluorogenicperoxidase substrate (15169, Thermofisher) and centrifuge at 1000 rpm for 30 seconds. Incubate at room temperature for 30 minutes, and read the fluorescence value with Envision (PE, Envision@2105). The excitation wavelength is 340nm and the emission wavelength is 460nm. Finally, GraphPad Prism 8 software was used to analyze the data, and the IC ₅₀ value was calculated by GraphPad Prism software using the dose-response-inhibition (four parameters) equation.

The experimental results are shown in Table 1.

Table 1. IC ₅₀ values for selected compounds in C3 proteolysis experiments

As can be seen from the experimental results in Table 1, the compound of the present invention has excellent in vitro activity and can inhibit the hydrolysis activity of CVF:Bb on C3.

Experimental example 2: TR-FRET experiment

Prepare a buffer solution with the following ingredients: 50mM Tris-HCl, pH 7.0, 50mM NaCl, 0.01% w/v Triton X-100. The compound to be tested was first diluted 3 times with DMSO, then 0.6uL was transferred to a 96-well plate with a pipette, 99.4μL buffer was added and pipetted to mix, and 2.5μL of the diluted compound was transferred to a 384-well plate (ProxiPlate-384plus, PE) . Use buffer to prepare 90 nM His-FB protein (ab276729, Abcam), and transfer 2.5 μL to a 384-well plate containing the compound. Then use buffer to prepare 300 nM Cy5 fluorescently labeled probe, and transfer 5 μL to a 384-well plate. Finally, add 5 μL of 15 nM LANCE Eu-anti-6xHis antibody (AD0110, Perkin Elmer) in buffer, centrifuge at 1000 rpm for 30 seconds, and incubate at room temperature for 2 hours in the dark. Use Envision to read the fluorescence value (Exc.Filter is UV2(TRF)320, Ems.Filter is APC665, 2nd ems.filter is LANCE Laser attenuated Europium filter, 50μs delay), and calculate the 665nm/615nm ratio. Finally, GraphPad Prism 8 software was used to analyze the data, and the IC ₅₀ value was calculated by GraphPad Prism software using the dose-response-inhibition (four parameters) equation.

The experimental results are shown in Table 2.

Table 2. IC ₅₀ values for selected compounds in TR-FRET experiments

As shown in the experimental results in Table 2, the compounds of the present invention can compete with fluorescent probes for binding to FB.

Experimental Example 3: Caco-2 permeability evaluation experiment

1. Cell culture

Culture conditions: DMEM contains 10% FBS, 1% GlutaMAX, 100 units/mL penicillin, 100 μg/mL streptomycin and 1% NEAA, grown in a humidified 37°C incubator with 5% CO ₂ . Caco-2 cells in the logarithmic growth phase were digested with 0.25% trypsin and dispersed evenly, and then inoculated into 96-Multiwell Insert Systems at a concentration of 2×10 ⁵ /mL. The upper layer volume was 70 μL and the lower layer volume was 30 mL. Replace with new culture medium every two to three days and use it for penetration test after 21 days of continuous culture.

2. Caco-2 cell permeability test

2.1. Experimental design

2.2. Preparation of working solution

This experiment used HBSS (pH 7.4±0.2) containing 10 mM HEPES as the transport buffer. The preparation methods of pre-incubation solution, administration solution and receiving solution are shown in the table below.

2.3. Cell monolayer integrity test

Lucifer yellow transport assay was used to test the integrity of the Caco-2 cell layer. Randomly select 6 cell wells, add 70 μL of 100 μM Lucifer Yellow to the top, and add 260 μL of transport buffer to the bottom. The fluorescent yellow detection experiment and the transport experiment were performed simultaneously. After 120 minutes of incubation, take 20 μL of sample from the apical end and mix with 80 μL of transport buffer, and take 100 μL of sample from the basal end. Detect the relative fluorescence intensity of Lucifer Yellow in the sample at the 425/528nm (excitation/emission) spectrum.

2.4.Transfer test

Remove the culture medium from the culture plate and wash the cells three times with preheated HBSS with a pH of 7.4±0.2 (use 70 μL and 30 mL transport buffer at the top well and basal end respectively). Add blank or inhibitor-containing transport solution to the corresponding cell plate wells (70 and 260 μL for each apical and basal end well respectively), and place the cell plate under humidified conditions of 5% _CO2 and 37°C. Incubate for 30 minutes.

After the incubation, remove the transport solution from the culture plate, add the dosing solution and the receiving solution to the corresponding wells, and start the bidirectional transport experiment (top to basal end (AB) and basal end to apical end (BA)). . After loading, incubate the cell plate in humidified conditions of 5% _CO2 and 37 °C for 120 min.

The initial dosing solution is the T ₀ sample. Take 50 μL and mix it with an equal volume of acetonitrile. After 120 minutes of incubation, final samples were collected from the dosing and receiving ends and were also mixed with an equal volume of acetonitrile. Discard the remaining solution in the cell plate, wash the cell monolayer once with HBSS, then add 50 μL acetonitrile to each well, pipet up and down 5 times, and mix with an equal volume of transport solution. All samples were stored at -80°C pending analysis.

2.5.Sample testing

This experiment uses liquid chromatography tandem mass spectrometry (LC-MS/MS) method to determine the concentrations of test compounds, acyclovir, minoxidil and digoxin in Caco-2 transport experimental samples.

2.6.Data processing

V _Basolateral is the volume of the B-side solution, which is 260 μL; V _Apical is the volume of the A-side solution, which is 70 μL; _VR is the volume of the receiving end solution (A side is 70 μL, B side is 260 μL); Area is the cell monolayer Relative surface area (0.0804cm ² ); T is the incubation time (7200s); C ₀ is the initial concentration of the administration end (nM); V _D is the volume of the administration end (A side is 70 μL, B side is 260 μL); C _D and _CR are the final concentrations (nM) at the dosing end and receiving end respectively; C _lysate is the concentration in the cell lysate (nM); V _lysate is the volume of the cell lysate (50 μL)

2.7. Judgment and acceptance criteria

The experimental results are shown in Table 3.

Table 3. Caco-2 permeability data of compounds of the present application

Experimental Example 4: Plasma protein binding rate measurement experiment

The rapid equilibrium dialysis method was used to determine the binding rate of test compounds to human, monkey and mouse plasma proteins. And the stability of the test compound plasma samples incubated for 4 hours in a 37°C incubator containing 5% _CO2 was examined.

The test compound stock solution was diluted with blank plasma of different species respectively. The human and monkey species were prepared into plasma protein binding rate samples with concentrations of 30, 300 and 1500ng/mL, and the mouse species were prepared into plasma at 160, 1600 and 8000ng/mL. Protein binding rate sample. The control compounds warfarin and carbamazepine were prepared at a concentration of 500ng/mL.

After the plasma samples of each species are prepared, three samples of each concentration are taken and immediately stored at -20°C for testing to determine the total sample concentration C ₀ . Pipette 100 μL of plasma sample and 300 μL of PBS buffer and add them to the plasma sample side and PBS side of the dialysis device respectively. Each concentration is 3 samples, and shake at 37°C for 4 hours in a _CO2 incubator (rotation speed is about 250 rpm). Take out the plasma side sample and PBS side sample respectively for testing.

Use the following formula to calculate the plasma protein binding rate of the analyte at different concentration levels.

Free rate % = (PBS side concentration C _f /plasma side concentration C _p )*100%

Binding rate%=100%-free rate%

Stability RE%=(C _4h -C ₀ )/C ₀ *100%

2.1 Determination method

Concentrations of test compounds and positive compounds in plasma protein samples were quantitatively analyzed using LC-MS/MS.

The experimental results are shown in Table 4.

Table 4. Plasma protein binding and free rate data of the compounds of the present application

Claims

The compound represented by formula (I), its optical isomer or its pharmaceutically acceptable salt,

in,

R 1 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl and C 3-9 cycloalkyl, the C 1-6 alkyl, C 1-6 heteroalkyl or C 3-9 cycloalkyl is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br, I or C 1-6 alkyl;

R 2 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 3-9 cycloalkyl, phenyl and 5-9 membered heteroaryl, the C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl , C 3-9 cycloalkyl, phenyl or 5-9 membered heteroaryl The group is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br, I or C 1-6 alkyl;

R 3 is selected from phenyl, naphthyl and 5-9-membered heteroaryl, and the phenyl, naphthyl or 5-9-membered heteroaryl is optionally substituted by 1, 2 or 3 R 3A ;

R 3A are independently selected from C 1-6 alkyl, C(=O)OH, OH, CN, F, Cl, Br, I and

R 4 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, -C( =O)R 9 , -C(=O)OR 9 , -C(=O)N(H) p (R 9 ) 2-p and -NHC(=O)R 9 , the C 1-6 alkane group, C 1-6 heteroalkyl group, -C(=O)R 9 , -C(=O)OR 9 , -C(=O)N(H) p (R 9 ) 2-p or -NHC( =O) R 9 is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br or I;

Or R 3 and R 4 are connected together to form a benzo 5-6 membered heterocyclyl group, which is optionally replaced by 1, 2 or 3 -C(=O)OH, OH , CN, F, Cl, Br or I substitution;

R 5 , R 6 and R 7 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, 3-9 membered heterocyclyl, -C 1- 6alkyl -C 3-9 cycloalkyl, -C 1-6 alkyl-3-9 membered heterocyclyl, -S(=O) 2 R 9 , -C(=O)R 9 , -C( =O)OR 9 , -C(=O)N(H) p (R 9 ) 2-p and -NHC(=O)R 9 , the C 1-6 alkyl, C 1-6 heteroalkyl , C 3-9 cycloalkyl, 3-9 membered heterocyclyl, -C 1-6 alkyl-C 3-9 cycloalkyl, -C 1-6 alkyl-3-9 membered heterocyclyl, - S(＝O) 2 R 9 , -C(＝O)R 9 , -C(＝O)OR 9 , -C(＝O)N(H) p (R 9 ) 2-p or -NHC(＝ O) R 9 is optionally replaced by 1, 2 or 3 R 5A ;

Or R 5 and R 7 are connected together to form a 5-6-membered heteroaryl or 5-6-membered heterocyclyl, and the 5-6-membered heteroaryl or 5-6-membered heterocyclyl is optionally replaced by 1, 2 or 3 R 7A substitutions;

Or R 5 and R 6 are connected together to form a 5-6-membered heteroaryl or 5-6-membered heterocyclyl, and the 5-6-membered heteroaryl or 5-6-membered heterocyclyl is optionally replaced by 1, 2 or 3 R 6A substitutions;

R 5A , R 6A , R 7A and R 9 are each independently selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 ring Alkyl and 3-6 membered heterocyclyl, the C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally replaced by 1, 2 or 3 OH, CN, F, Cl, Br or I substitutions;

Represents a single or double bond;

when When it is a single bond, R 6 and/or R 7 are independently selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl and C 1-6 heteroalkyl;

Or, when two When both are single bonds, R 6 and R 7 are connected together and form a 5-9-membered heterocyclic group with the skeleton where N(R 5 ) is located. The 5-9-membered heterocyclic group is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br or I substitution;

when When it is a double bond, R 6 and/or R 7 are independently selected from O;

R 8 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl, phenyl and 5-6 membered heteroaryl, the C 1-6 Alkyl, C 1-6 heteroalkylphenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br, I or C 1-6 alkyl;

p is selected from 0, 1 or 2;

n is selected from 0, 1 or 2;

The C 1-6 heteroalkyl group, 3-9 membered heterocyclyl group, 5-9 membered heterocyclyl group, 5-6 membered heterocyclyl group, 5-9 membered heteroaryl group, and 5-6 membered heteroaryl group include 1, 2, 3 or 4 independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(=O) -, -S(=O) 2 - and N heteroatoms or heteroatom groups.
The compound according to claim 1, its optical isomer or its pharmaceutically acceptable salt, its structure is as follows

in,

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are as defined in claim 1;

R 5X are independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, 3-9 membered heterocyclyl, -C 1-6 alkyl-C 3 -9 cycloalkyl, -C 1-6 alkyl, -3-9 membered heterocyclyl, -S(=O) 2 R 9 , -C(=O)R 9 , -C(=O)OR 9 , -C(=O)N(H) p (R 9 ) 2-p and -NHC(=O)R 9 , the C 1-6 alkyl group, C 1-6 heteroalkyl group, C 3-9 ring Alkyl group, 3-9 membered heterocyclyl group, -C 1-6 alkyl-C 3-9 cycloalkyl group, -C 1-6 alkyl-3-9 membered heterocyclyl group, -S(=O) 2 R 9 , -C(=O)R 9 , -C(=O)OR 9 , -C(=O)N(H) p (R 9 ) 2-p or -NHC(=O)R 9 optional Replaced by 1, 2 or 3 R 5A ;

R 5A is independently selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and 3-6 membered heterocycle base, the C 1-6 alkyl group, C 1-6 heteroalkyl group, C 3-6 cycloalkyl group or 3-6 membered heterocyclic group is optionally replaced by 1, 2 or 3 OH, CN, F, Cl , Br or I substitution;

R 10a , R 10b , R 10c , R 10d are each independently selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl and C 3-9 ring Alkyl, the C 1-6 alkyl, C 1-6 heteroalkyl or C 3-9 cycloalkyl is optionally replaced by 1, 2 or 3 OH, CN, F, Cl, Br, I or C 1 -6 alkyl substitution;

m is selected from 0, 1, 2 or 3.
The compound according to claim 1, its optical isomer or its pharmaceutically acceptable salt, its structure is as follows

in,

R 1 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl and C 3-9 cycloalkyl, the C 1-6 alkyl, C 1-6 heteroalkyl or C 3-9 cycloalkyl is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br, I or C 1-6 alkyl;

R 2 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl, C 3-9 cycloalkyl, phenyl and 5-9 membered heteroaryl, the C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkenyl , C 3-9 cycloalkyl, phenyl or 5-9 membered heteroaryl The group is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br, I or C 1-6 alkyl;

R 4 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, -C( =O)R 9 , -C(=O)OR 9 , -C(=O)N(H) p (R 9 ) 2-p and -NHC(=O)R 9 , the C 1-6 alkane group, C 1-6 heteroalkyl group, -C(=O)R 9 , -C(=O)OR 9 , -C(=O)N(H) p (R 9 ) 2- p or -NHC( =O) R 9 is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br or I;

R 3A and R 3B are independently selected from H, C 1-6 alkyl, C(=O)OH, OH, CN, F, Cl, Br, I and

Or R 3B and R 4 are connected together to form a 5-9 membered heterocyclyl group, which is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br or I;

R 5 , R 5X , R 6 and R 7 are each independently selected from H, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-9 cycloalkyl, 3-9 membered heterocyclyl, - C 1-6 alkyl-C 3-9 cycloalkyl, -C 1-6 alkyl-3-9 membered heterocyclyl, -S(=O) 2 R 9 , -C(=O)R 9 , -C(=O)OR 9 , -C(=O)N(H) p (R 9 ) 2-p and -NHC(=O)R 9 , the C 1-6 alkyl group, C 1-6 Heteroalkyl, C 3-9 cycloalkyl, 3-9 membered heterocyclyl, -C 1-6 alkyl-C 3-9 cycloalkyl, -C 1-6 alkyl-3-9 membered heterocycle Base, -S(=O) 2 R 9 , -C(=O)R 9 , -C(=O)OR 9 , -C(=O)N(H) p (R 9 ) 2-p or - NHC(=O)R 9 is optionally replaced by 1, 2 or 3 R 5A ;

Ring A is selected from 5-6-membered heterocyclyl and 5-6-membered heteroaryl, and the 5-6-membered heterocyclyl and 5-6-membered heteroaryl are optionally substituted by 1, 2 or 3 R 7A ;

Ring B is selected from 5-6-membered heterocyclyl and 5-6-membered heteroaryl, and the 5-6-membered heterocyclyl and 5-6-membered heteroaryl are optionally substituted by 1, 2 or 3 R 6A ;

R 5A , R 6A , R 7A and R 9 are each independently selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 ring Alkyl and 3-6 membered heterocyclyl, the C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally replaced by 1, 2 or 3 OH, CN, F, Cl, Br or I substitutions;

R 10a , R 10b , R 10c , R 10d are each independently selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 1-6 heteroalkyl and C 3-9 ring Alkyl, the C 1-6 alkyl, C 1-6 heteroalkyl or C 3-9 cycloalkyl is optionally replaced by 1, 2 or 3 OH, CN, F, Cl, Br, I or C 1 -6 alkyl substitution;

m is 0, 1 or 2;

The C 1-6 heteroalkyl group, 3-9 membered heterocyclyl group, 5-9 membered heterocyclyl group, 5-6 membered heterocyclyl group, 5-9 membered heteroaryl group, and 5-6 membered heteroaryl group include 1, 2, 3 or 4 independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(=O) -, -S(=O) 2 - and N heteroatoms or heteroatom groups.
The compound according to claim 3, its optical isomer or its pharmaceutically acceptable salt, its structure is as follows
The compound according to any one of claims 1-4, its optical isomer or its pharmaceutically acceptable salt, wherein R 1 is selected from H, OH, CN, F, Cl, Br, I, C 1 -4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino and C 3-6 cycloalkyl, the C 1-4 alkyl, C 1-4 alkyl Oxygen, C 1-4 alkylthio, C 1-4 alkylamino or C 3-6 cycloalkyl is optionally replaced by 1, 2 or 3 OH, CN, F, Cl, Br, I or C 1-4 alkyl substitution;

Optionally, R 1 is selected from methyl;

Optionally, R 2 is selected from H, OH, CN, F, Cl, Br , I, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkyl Amino, C 2-4 alkenyl, C 3-6 cycloalkyl, phenyl and 5-6 membered heteroaryl, the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl Thio group, C 1-4 alkylamino, C 2-4 alkenyl, C 3-6 cycloalkyl, phenyl or 5-6 membered heteroaryl are optionally replaced by 1, 2 or 3 OH, CN, F, Cl, Br, I or C 1-4 alkyl substitution;

Optionally, R2 is selected from methoxy.
The compound according to claim 1 or 2, its optical isomer or its pharmaceutically acceptable salt, wherein R3 is selected from phenyl and 5-6 membered heteroaryl, the phenyl or 5-6 The heteroaryl group is optionally substituted by 1, 2 or 3 R 3A ;

Optionally, R 3 is selected from
The compound according to claim 1 or 2, its optical isomer or its pharmaceutically acceptable salt, wherein R 4 is selected from H, OH, CN, F, Cl, Br, I, methyl, ethyl and CF 3 .
The compound according to claim 1 or 2, its optical isomer or its pharmaceutically acceptable salt, wherein R 3 and R 4 are joined together to form
The compound according to claim 3 or 4, its optical isomer or its pharmaceutically acceptable salt, wherein R 3A is selected from H, C 1-3 alkyl, C(=O)OH, OH, CN , F, Cl, Br, I and

R 4 is selected from H;

R 3B is selected from H;

Alternatively, R 3B and R 4 are linked together to form a 5-6 membered heterocyclyl group optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br or I ;

Alternatively, R 3B and R 4 are joined together to form
The compound according to any one of claims 1-4, its optical isomer or its pharmaceutically acceptable salt, wherein R5 is selected from H, C 1-4 alkyl, -C 1-3 alkyl -C 3-6 cycloalkyl, C 3-6 cycloalkyl, -S(=O) 2 R 9 and -C(=O)R 9 , the C 1-4 alkyl, -C 1-3 Alkyl -C 3-6 cycloalkyl, C 3-6 cycloalkyl, -S(=O) 2 R 9 or -C(=O)R 9 is optionally substituted by 1, 2 or 3 R 5A ;

Optionally, R 5A and R 9 are independently selected from H, OH, CN, F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkylthio group, C 3-6 cycloalkyl group and 3-6 membered heterocyclyl group, the C 1-4 alkyl group, C 1-4 alkoxy group, C 1-4 alkylamino group, C 1 -4 alkylthio, C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br or I;

Optionally, R 9 are each independently selected from methyl, ethyl, CF 3 ,
The compound according to claim 1 or 2, its optical isomer or its pharmaceutically acceptable salt, wherein R 5 and R 7 are connected together to form
The compound according to claim 3 or 4, its optical isomer or its pharmaceutically acceptable salt, wherein ring A is selected from described optionally substituted by 1, 2 or 3 R 7A ;

Optionally, R 7A is independently selected from H, OH, CN, F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1- 4 alkylthio, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkyl Thio group, C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br or I;

Optionally, R 7A is each independently selected from H, OH, CN, F, Cl, Br, I, methyl, and CF 3 .

Optionally, Ring A is selected from
The compound according to claim 1 or 2, its optical isomer or its pharmaceutically acceptable salt, wherein R 5 and R 6 are connected together to form
The compound according to claim 3 or 4, its optical isomer or its pharmaceutically acceptable salt, wherein ring B is selected from described optionally substituted by 1, 2 or 3 R 6A ;

Optionally, R 6A is independently selected from H, OH, CN, F, Cl, Br, I, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1- 4 alkylthio, C 3-6 cycloalkyl and 3-6 membered heterocyclyl, the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, C 1-4 alkyl Thio group, C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted by 1, 2 or 3 OH, CN, F, Cl, Br or I;

Optionally, R6A is each independently selected from H, OH, CN, F, Cl, Br, I, methyl and CF3 ;

Optionally, Ring B is selected from
The compound according to any one of claims 1-4, its optical isomer or its pharmaceutically acceptable salt, wherein R5 is selected from H, methyl, ethyl, CF 3 ,
The compound according to any one of claims 2-4, its optical isomer or its pharmaceutically acceptable salt, wherein R 5X is selected from H, C 1-4 alkyl, -C 1-3 alkyl -C 3-6 cycloalkyl, C 3-6 cycloalkyl, -S(=O) 2 R 9 and -C(=O)R 9 , the C 1-4 alkyl, -C 1-3 Alkyl -C 3-6 cycloalkyl, C 3-6 cycloalkyl, -S(=O) 2 R 9 or -C(=O)R 9 is optionally substituted by 1, 2 or 3 R 5A ;

Optionally, R 5X is selected from H, methyl, ethyl, CF 3 ,
The compound of the following formula, its optical isomer or its pharmaceutically acceptable salt, which is selected from:
The compound according to claim 16, its optical isomer or its pharmaceutically acceptable salt, which is selected from:
A pharmaceutical composition, wherein the pharmaceutical composition contains the compound according to any one of claims 1 to 17, its optical isomers and pharmaceutically acceptable salts thereof.
The pharmaceutical composition according to claim 18, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.
The compound according to any one of claims 1 to 17, its optical isomer and its pharmaceutically acceptable salt or the pharmaceutical composition according to claim 18 or 19 is used in the preparation of therapeutic complement factor B activity and expression level. Applications in medicines for diseases.
The use according to claim 20, wherein the disease related to complement factor B activity and expression is selected from the group consisting of IgA nephropathy (IgAN), C3 glomerular disease (C3G), and atypical hemolytic uremic syndrome (aHUS). , membranous nephropathy (MN), paroxysmal nocturnal hemoglobinuria (PNH), and other diseases related to the complement cascade, age-related macular degeneration (AMD), geographic atrophy (GA), hemodialysis complications, neurospinal inflammatory bowel disease (NMO), liver disease, inflammatory bowel disease, myasthenia gravis (MG).