TWI869080B - Benzospirocycloindole compound and preparation, and use thereof - Google Patents

Abstract

The present invention discloses the preparation and use of benzospirocycloindole compounds. Specifically, the present invention discloses the compound shown in formula (I), a optical isomer or pharmaceutically acceptable salt thereof, as well as its use for the treatment and/or prevention of activity and expression of complement factor B related diseases.

Description

Preparation and use of benzospiroindole compounds

This invention claims the following priority: Chinese application number CN 202211516706.4, application date November 29, 2022; Chinese application number CN 202311563895.5, application date November 21, 2023.

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

The complement system is a defining component of the innate immune system and includes a group of proteins that are normally present in an inactive state. These proteins are organized in three activation pathways: the classical pathway, the lectin pathway, and the alternative pathway. Molecules from microorganisms, antibodies, or cellular components can activate these pathways, leading to the formation of protease complexes called C3-convertase and C5-convertase. The classical pathway is a calcium/magnesium-dependent cascade that is usually activated by the formation of antigen-antibody complexes. It can also be activated by binding of C-reactive protein complexed with a ligand and by many pathogens, including Gram-positive bacteria, in an antibody-independent manner. The alternative pathway is a magnesium-dependent cascade that is activated by 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 the treatment of diseases or disorders associated with increased tonic activity, and more research is needed.

其中，X選自C(R₅)₂、O或N(R₅)；R₁選自H、OH、CN、F、Cl、Br、I、C_1-6烷基、C_1-6雜烷基和C_3-9環烷基，所述C_1-6烷基、C_1-6雜烷基或C_3-9環烷基任選被1、2或3個R取代；R₂選自H、OH、CN、F、Cl、Br、I、C_1-6烷基、C_1-6雜烷基、C_3-6環烷基和3-6員雜環烷基，所述C_1-6烷基、C_1-6雜烷基、C_3-6環烷基或3-6員雜環烷基任選被1、2或3個R取代；L選自單鍵、O、S、NH、

、

、

、

、

和

，所述NH、

、

、

、

、

或

任選被1、2或3個R取代；R₃選自H、OH、CN、F、Cl、Br、I、C_1-6烷基、C_3-6環烷基、C_1-6雜烷基和3-6員雜環烷基，所述C_1-6烷基、C_3-6環烷基、C_1-6雜烷基或3-6員雜環烷基任選被1、2或3個R取代； R₄選自H、OH、CN、F、Cl、Br、I、C_1-6烷基、C_3-6環烷基、C_1-6雜烷基和3-6員雜環烷基，所述C_1-6烷基、C_3-6環烷基、C_1-6雜烷基或3-6員雜環烷基任選被1、2或3個R取代；或者，R₃和R₄連接在一起，形成C_3-6環烷基或3-6員雜環烷基，所述C_3-6環烷基或3-6員雜環烷基任選被1、2或3個R取代；R₅選自H、F、Cl、CN、OH、C_1-6烷基、C_1-6雜烷基和C_3-9環烷基，所述C_1-6烷基、C_1-6雜烷基或C_3-9環烷基任選被1、2或3個R取代；R₆選自H、OH、CN、F、Cl、Br、I、C_1-6烷基、C_2-6烯基和C_2-6炔基，所述C_1-6烷基、C_2-6烯基或C_2-6炔基任選被1、2或3個R取代；R分別獨立地選自OH、CN、F、Cl、Br、I、C_1-6烷基、C_1-6雜烷基、C_3-6環烷基和3-6員雜環烷基；所述C_1-6雜烷基或3-6員雜環烷基包含1、2、3或4個獨立選自-O-、-NH-、-N=、-S-、-C(=O)-、-C(=O)O-、-S(=O)-、-S(=O)₂-和N的雜原子或雜原子團。 In one aspect of the present invention, the present invention provides a compound represented by formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof,

wherein X is selected from C(R ₅ ) ₂ , O or N(R ₅ ); 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, wherein the C _1-6 alkyl, C _1-6 heteroalkyl or C _3-9 cycloalkyl is optionally substituted by 1, 2 or 3 R; R ₂ is 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 heterocycloalkyl, wherein the C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl or _3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; L is selected from a single bond, O, S, NH,

,

,

,

,

and

, the NH,

,

,

,

,

or

_R is selected from H, OH, CN, F, Cl, Br, I, C _1-6 alkyl, C 3-6 cycloalkyl, C _1-6 heteroalkyl and 3-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heteroalkyl or _3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; _R is selected from H, OH, CN, F, Cl, Br, I, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heteroalkyl and 3-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heteroalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; or, _R and _R are linked together to form C _R is selected from H, OH, CN, F, Cl, Br, I, C _1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, and the C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl is optionally substituted by 1, 2 or 3 R; R is selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, and the C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl is optionally substituted by 1, 2 or 3 R; _R is selected from H, OH, CN, F, Cl, Br, I, C _1-6 alkyl, C 2-6 alkenyl and C _2-6 alkynyl, and the C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl is optionally substituted by 1, 2 or 3 R; R is independently selected from OH, CN, F, Cl, Br, I, C _1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl. _{C 1-6} heteroalkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl; the C _1-6 heteroalkyl or 3-6 membered heterocycloalkyl contains 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) ₂ - and N.

其中，L、R₁、R₂、R₃、R₄、R₅和R₆如上述所定義。 The present invention also provides a compound of the following formula, an optical isomer thereof or a pharmaceutically acceptable salt thereof, the structure of which is shown below:

wherein L, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as defined above.

In some embodiments of the present 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, and 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 with 1, 2 or 3 R, and other variables are as defined in the present invention.

、

、

、

、

、

、

、

和

，其它變數如本發明所定義。 In some embodiments of the present invention, R ₁ is selected from H, OH, CN, F, Cl, Br, I, CH ₃ ,

,

,

,

,

,

,

,

and

, other variables are as defined in the present invention.

In some embodiments of the present invention, _R2 is selected from H, OH, CN, F, Cl, Br, I, _C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, _{C1-4 alkylamino} , _C3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein the _C1-4 alkyl, _C1-4 alkoxy, _C1-4 alkylthio, _{C1-4 alkylamino} , _C3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.

、

、

、

、

、

、

、

和

，其它變數如本發明所定義。 In some embodiments of the present invention, R ₂ is selected from H, OH, CN, F, Cl, Br, I, CH ₃ ,

,

,

,

,

,

,

,

and

, other variables are as defined in the present invention.

In some embodiments of the present invention, _R3 is selected from H, OH, CN, F, Cl, Br, I, _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 alkoxy, _C1-6 alkylthio and 3-6 membered heterocycloalkyl, wherein the _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 alkoxy, _C1-6 alkylthio or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention.

、

、

、

、

、

、

、

、

、

、

和

，其它變數如本發明所定義。 In some embodiments of the present invention, R ₃ is selected from H, OH, CN, F, Cl, Br, I, CH ₃ ,

,

,

,

,

,

,

,

,

,

,

and

, other variables are as defined in the present invention.

選自H、OH、CN、F、Cl、Br、I、CH₃、

、

、

、

、

、

、

、

、

、

、

、

、

、

、

和

，其它變數如本發明所定義。 In some embodiments of the present invention, the structural unit

Selected from H, OH, CN, F, Cl, Br, I, CH ₃ ,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

and

, other variables are as defined in the present invention.

In some embodiments of the present invention, _R4 is selected from H, OH, CN, F, Cl, Br, I, _C1-3 alkyl, _C3-6 cycloalkyl, _C1-3 alkoxy, _C1-3 alkylthio, _C1-3 alkylamino and 3-6 membered heterocycloalkyl, wherein the _C1-3 alkyl, C3-6 cycloalkyl, _C1-3 alkoxy, _C1-3 alkylthio, _C1-3 alkylamino or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R, and other variables are as defined in the present invention _.

、

、

、

、

和

，所述CH₃、

、

、

、

、

或

任選被1、2或3個R取代。 In some embodiments of the present invention, R ₄ is selected from H, OH, CN, F, Cl, Br, I, CH ₃ ,

,

,

,

,

and

, the CH ₃ ,

,

,

,

,

or

Optionally replaced by 1, 2 or 3 Rs.

、

、

、

、

、

、

、

、

、

、

和

，其它變數如本發明所定義。 In some embodiments of the present invention, R ₄ is selected from H, OH, CN, F, Cl, Br, I, CH ₃ ,

,

,

,

,

,

,

,

,

,

,

and

, other variables are as defined in the present invention.

It can be understood that in the present invention, R ₃ and R ₄ are connected together to form a C _3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group, which means that R ₃ and R ₄ are connected together, together with L and the carbon atoms on the ring connected to R _4, form a C _3-6 cycloalkyl group or a 3-6 membered heterocycloalkyl group.

、

和

，所述

、

或

任選被1、2或3個R取代，其它變數如本發明所定義。 In some embodiments of the present invention, _R3 and _R4 are linked together to form

,

and

,

,

or

is optionally substituted with 1, 2 or 3 R, and the other variables are as defined in the present invention.

、

、

、

、

和

，其它變數如本發明所定義。 In some embodiments of the present invention, _R3 and _R4 are linked together to form

,

,

,

,

and

, other variables are as defined in the present invention.

、

、

和

，其它變數如本發明所定義。 In some embodiments of the present invention, R ₅ is selected from H, F, Cl, CN, OH, CH ₃ ,

,

,

and

, other variables are as defined in the present invention.

The present invention also provides a compound of the following formula, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or an isotope thereof, which is selected from:

In another aspect of the present invention, the present invention also provides a drug composition. In some embodiments of the present invention, the above-mentioned drug composition protects the aforementioned compound, its optical isomer or its pharmaceutically acceptable salt.

In some embodiments of the present invention, the above-mentioned pharmaceutical composition further comprises pharmaceutical excipients.

In another aspect of the present invention, the present invention also provides the use of the above-mentioned compound, its optical isomer or its pharmaceutically acceptable salt or the above-mentioned drug composition in the preparation of drugs for treating and/or preventing diseases related to the activity and expression of complement factor B.

The purpose of the present invention is to provide a compound as a complement factor B inhibitor or its stereoisomers, deuterated compounds, solvent compounds, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods, as well as its use in the preparation of drugs for treating diseases related to complement factor B activity and expression.

The compounds of the present invention can be used to treat and/or prevent diseases mediated by complement factor B (Factor B), involvement of the complement system, or some renal diseases or disorders with significant unmet needs, including IgA nephropathy (IgAN), C3 glomerular disease (C3G), atypical uremic hemolytic syndrome (aHUS), membranous nephropathy (MN), paroxysmal nocturnal hemoglobinuria (PNH), etc., as well as other diseases related to the complement cascade, including age-related macular degeneration (AMD), geographic atrophy (GA), hemodialysis complications, neuromyelitis (NMO), liver diseases, inflammatory bowel disease, myasthenia gravis (MG) and other diseases.

Definition and description

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

As used in the present invention, the phrase "at least one" used when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include 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 the specifically identified elements in the list of elements referred to by the phrase "at least one" may optionally exist, whether related to or not to those specifically identified elements.

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

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

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

可以選自

、

、

和

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

You can choose from

,

,

and

wait.

A hyphen ("-") not between two letters or symbols indicates the point of attachment of a substituent. For example, _{C1-6alkylcarbonyl-} refers to a _C1-6alkyl group attached to the rest of the molecule via a carbonyl group. However, when the point of attachment of the substituent is obvious to one skilled in the art, for example, a halogen substituent, the "-" may be omitted.

」時，例如在「

」中，該虛線表示該基團與分子其它部分的連接點。當單鍵上帶有「

」時，例如在「

」中，該虛線代表單鍵或者不存在，也意味著「

」代表了單鍵「

」或者雙鍵「

」。 When the group bond has a dotted line

", for example, in "

”, the dashed line indicates the point of attachment of the group to the rest of the molecule.

", for example, in "

", the dotted line represents a single key or does not exist, which also means "

" represents a single key "

" or double-click "

".

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 hydrogen variants, 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 by..." means that it may be substituted or not substituted. Unless otherwise specified, the type and number of substituents can be any on a chemically feasible basis.

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 with 1, 2, or 3 R's, the group may optionally be substituted with 1 or 2 or 3 R's, and each instance of R' has independent options. Furthermore, combinations of substituents and/or their variants are permitted only if such combinations result in stable compounds.

中L₁代表單鍵時表示該結構實際上是

。 When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected, such as

When L ₁ represents a single bond, it means that the structure is actually

.

When the listed substituents do not specify which atom they are connected to the substituted group through, the substituent can be bonded through any atom of it. For example, pyridyl as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

中連接基團L為-CH₂O-，此時-CH₂O-既可以按與從左往右的讀取順序相同的方向連接苯基和環戊基構成

，也可以按照與從左往右的讀取順序相反的方向連接苯基和環戊基構成

。所述連接基團、取代基和/或其變體的組合只有在這樣的組合會產生穩定的化合物的情況下才是被允許的。 When a linker group is listed without specifying its direction of attachment, the direction of attachment is arbitrary, e.g.

The connecting group L is -CH ₂ O-. In this case, -CH ₂ O- can be connected to the phenyl group and the cyclopentyl group in the same direction as the reading order from left to right.

, or by connecting phenyl and cyclopentyl groups in the opposite direction of the reading order from left to right.

Combinations of linking groups, substituents and/or variants thereof are permitted only if such combinations result in stable compounds.

Unless otherwise specified, the number of atoms on a ring refers to the number of atoms that make up the ring itself in a compound (such as a monocyclic compound, a cyclic compound, a spirocyclic compound, a bridged compound, a cross-linked compound, a carbocyclic compound, or a heterocyclic compound) that is formed by bonding atoms. The number of atoms on a ring is usually defined as the number of members in the ring. For example, "3-6 membered ring" refers to a "ring" with 3-6 atoms arranged around it. When a ring is substituted with a substituent, the atoms contained in the substituent are not included in the ring atoms. Unless otherwise specified, benzene is a 6-membered ring, naphthalene is a 10-membered ring, and thiophene is a 5-membered ring.

Unless otherwise specified, the term "alkyl" refers to a saturated alkyl group containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof, which may represent a straight chain and/or branched alkyl group, which may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Unless otherwise specifically stated in the specification, the alkyl group may be optionally substituted.

)。C_1-6烷基的實例包括但不限於CH₃、

、

、

等。 Unless otherwise specified, the term "C _1-6 alkyl" is used to refer to a straight or branched 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 be monovalent (such as CH ₃ ), divalent (-CH ₂ -) or polyvalent (such as divalent

). Examples of _{C 1-6} alkyl include but are not limited to CH ₃ ,

,

,

wait.

)。C_1-4烷基的實例包括但不限於CH₃、

、

、

、

、

等。 Unless otherwise specified, the term "C _1-4 alkyl" is used to refer to a straight or branched 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 polyvalent (such as divalent

). Examples of _{C 1-4} alkyl include but are not limited to CH ₃ ,

,

,

,

,

wait.

Unless otherwise specified, the term "alkenyl" refers to a alkyl group having at least one unsaturated site, i.e., a carbon-carbon ^sp2 double bond, which may represent a straight chain and/or a branched chain alkenyl group, wherein a branched chain refers to one or more alkyl groups such as methyl, ethyl or propyl groups connected to a straight chain alkenyl chain. It may be monovalent, divalent or polyvalent. Unless otherwise specifically stated in the specification, an alkenyl group may be optionally substituted.

Unless otherwise specified, " _C2-6 alkenyl" is used to represent a linear or branched carbon hydrogen group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond can be located at any position of the group. The _C2-6 alkenyl includes _C2-4 , _C2-3 , _C4 , _C3 and _C2 alkenyl, etc.; it can be monovalent, divalent or polyvalent. Examples of _C2-6 alkenyl include but are not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, ethenylene, propenylene, sec-butenylene, etc.

、

、

、

、

等。 Unless otherwise specified, "C _2-3 alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. The C _2-3 alkenyl group includes C ₃ and C ₂ alkenyl groups; the C _2-3 alkenyl group may be monovalent, divalent or polyvalent. Examples of C _2-3 alkenyl groups include but are not limited to

,

,

,

,

wait.

Unless otherwise specified, the term "alkynyl" refers to a alkyl group containing at least one unsaturated site, i.e., a carbon-carbon sp triple bond, which may represent a straight chain and/or a branched chain alkynyl group, wherein a branched chain refers to one or more alkyl groups such as methyl, ethyl or propyl groups attached to a straight chain alkynyl chain. It may be monovalent, divalent or polyvalent. Unless otherwise specified in the specification, an alkynyl group may be optionally substituted.

、

、

、

等。 Unless otherwise specified, "C _2-6 alkynyl" is used to represent a linear or branched carbon hydrogen group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent 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 groups. Examples of C _2-6 alkynyl groups include but are not limited to

,

,

,

wait.

、

、

、

等。 Unless otherwise specified, "C _2-3 alkynyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent 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.

。 Unless otherwise specified, the term "penoxy" refers to an oxygen atom doubly bonded to a carbon atom or another member, including to the nitrogen of the pyridine ring to form a pyridine N-oxide. For example, the term "penoxy 5-6 membered heteroaryl" includes but is not limited to

.

Unless otherwise specified, the term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group, wherein the "alkyl" in the "alkyl radical" is as defined above in the present invention. In some embodiments, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom 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 a C _1-6 heteroalkyl group; in other embodiments, the heteroalkyl group is a C _1-3 heteroalkyl group. The heteroatom or heteroatom group may be located at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule. 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, etc.; up to two heteroatoms thereof may be consecutive, for example -CH ₂ -NH-OCH _3. Unless otherwise specifically stated in the specification, a heteroalkyl group may be optionally substituted.

Unless otherwise specified, the term "alkoxy" refers to an alkyl group connected to the rest of the molecule via an oxygen atom, wherein "alkyl" in "alkyl group" has the same meaning as defined above in the present invention. Unless otherwise specifically stated in the specification, an alkoxy group may be optionally substituted.

Unless otherwise specified, the term "C _1-6 alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule via an oxygen atom. The C _1-6 alkoxy group includes C _1-4 , C _1-3 , C _1-2 , C _2-6 , C _2-4 , C ₆ , C ₅ , C ₄ and C ₃ alkoxy groups, etc. Examples of C _1-6 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n -propoxy and isopropoxy), butoxy (including n -butoxy, isobutoxy, s -butoxy and t -butoxy), pentoxy (including n-pentoxy, isopentyl and neopentyl), hexyloxy, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentyleneoxy, etc.

Unless otherwise specified, the term "C _1-3 alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms connected to the rest of the molecule via 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 groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), methyleneoxy, ethyleneoxy, propyleneoxy, etc.

或者多價

。 Unless otherwise specified, the term "amine" may refer to either a monovalent NH ₂ or a divalent

Or multiple price

.

Unless otherwise specified, the term "alkylamino" refers to an alkyl group connected to the rest of the molecule via an amine group as defined above, wherein the "alkyl" in the "alkyl group" is as defined above in the present invention. Unless otherwise specifically stated in the specification, the alkylamino group may be optionally substituted.

Unless otherwise specified, the term "C _1-6 alkylamino" refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule via an amine 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 groups, etc. Examples of C _1-6 alkylamino groups include, but are not limited to, -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCH ₂ CH ₃ , -N(CH ₃ ) CH ₂ CH ₃ , -N(CH ₂ CH ₃ )(CH ₂ CH ₃ ), -NHCH ₂ CH ₂ CH ₃ , -NHCH ₂ (CH ₃ ) ₂ , -NHCH ₂ CH ₂ CH ₂ CH ₃ , etc.

Unless otherwise specified, the term "C _1-3 alkylamino" refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule via an amine 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 "alkylthio" refers to an alkyl group connected to the rest of the molecule via a sulfur atom, wherein "alkyl" in "alkyl group" has the same meaning as defined above in the present invention. Unless otherwise specifically stated in the specification, an alkylthio group may be optionally substituted.

Unless otherwise specified, the term "C _1-6 alkylthio" refers to an alkyl group containing 1 to 6 carbon atoms attached to the rest of the molecule via 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 alkylthio groups, 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" refers to an alkyl group containing 1 to 3 carbon atoms attached to the rest of the molecule via 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 , etc.

Unless otherwise specified, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic saturated alkyl group consisting of carbon and hydrogen atoms, which may include cyclocyclic, spirocyclic and/or bridged ring systems. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. "C _4-6 cycloalkyl" means a cycloalkyl group having 4-6 ring carbon atoms. Similarly, "C _3-4 cycloalkyl" means a cycloalkyl group having 3-4 ring carbon atoms. Unless stated otherwise specifically in the specification, a cycloalkyl group may be optionally substituted.

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

Unless otherwise specified, the term "heterocycloalkyl" refers to a non-aromatic saturated cyclic group in the form of a monocyclic, cyclic, spirocyclic and/or bridged ring, wherein at least one of the ring atoms is a heteroatom or heteroatom group, and the rest are carbon atoms; in some embodiments, each occurrence of the heteroatom is independently selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2), and the nitrogen heteroatom is optionally quaternized; in other embodiments, each occurrence of the heteroatom is independently selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) ₂ -, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) _2N (H)-, and -S(=O)N(H)-. The heteroatom or heteroatom group may be located at any interior position of the heterocycloalkyl group, including the position at which the heterocycloalkyl group is attached to the rest of the molecule. In some embodiments, the heterocycloalkyl group is a 3-20 membered heterocycloalkyl group; in some embodiments, the heterocycloalkyl group is a 3-10 membered heterocycloalkyl group; in other embodiments, the heterocycloalkyl group is a 3-6 membered heterocycloalkyl group. Unless otherwise specifically stated in the specification, the heterocycloalkyl group may be optionally substituted.

Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from B, O, S and N or heteroatoms as described above, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, paracyclic and bridged rings. In addition, with respect to the "3-6 membered heterocycloalkyl", the heteroatom or heteroatom group may be located at any internal position of the heterocycloalkyl, including the position where the heterocycloalkyl is connected to the rest of the molecule. The 3-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc.

、

、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基(包括四氫噻吩-2-基和四氫噻吩-3-基等)、四氫呋喃基(包括四氫呋喃-2-基等)、四氫吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、嗎啉基(包括3-嗎啉基和4-嗎啉基等)、二噁烷基、二噻烷基、異噁唑烷基、異噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氫噠嗪基、高哌嗪基或高哌啶基等。 Unless otherwise specified, the term "3-9 membered heterocyclic group" by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 3 to 9 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spiro, paracyclic and bridged rings. In addition, with respect to the "3-9 membered heterocyclic group", the heteroatom may occupy the position of attachment of the heterocyclic group to the rest of the molecule. The 3-9 membered heterocyclic group includes 3-8 members, 3-7 members, 3-6 members, 3-5 members, 3-4 members, 4-5 members, 4-6 members, 4-7 members, 4-8 members, 4-9 members, 5-6 members, 5-7 members, 5-8 members, 5-9 members, 6-7 members, 6-8 members, 6-9 members, 7-8 members, 3 members, 4 members, 5 members, 6 members, 7 members, 8 members and 9 members. Examples of 3-9 membered heterocyclic groups include, but are not limited to, nitrogen heterocyclobutyl, oxygen heterocyclobutyl, thioheterocyclobutyl, 1,3-dioxolane,

,

, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydroxazinyl, homopiperazinyl or homopiperidinyl, etc.

、

、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基(包括四氫噻吩-2-基和四氫噻吩-3-基等)、四氫呋喃基(包括四氫呋喃-2-基等)、四氫吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、嗎啉基(包括3-嗎啉基和4-嗎啉基等)、二噁烷基、二噻烷基、異噁唑烷基、異噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氫噠嗪基、高哌嗪基或高哌啶基等。 Unless otherwise specified, the term "3-6 membered heterocyclic group" by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spiro, bis-cyclic and bridged rings. In addition, with respect to the "3-6 membered heterocyclic group", the heteroatom may occupy the position of attachment of the heterocyclic group to the rest of the molecule. The 3-6 membered heterocyclic group includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocyclic groups. Examples of 3-6 membered heterocyclic groups include, but are not limited to, nitrogen heterocyclobutyl, oxygen heterocyclobutyl, thio heterocyclobutyl, 1,3-dioxolane,

,

, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydroxazinyl, homopiperazinyl or homopiperidinyl, etc.

、吡咯烷基、吡唑烷基、咪唑烷基、四氫噻吩基(包括四氫噻吩-2-基和四氫噻吩-3-基等)、四氫呋喃基(包括四氫呋喃-2-基等)、四氫吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、嗎啉基(包括3-嗎啉基和4-嗎啉基等)、二噁烷基、二噻烷基、異噁 唑烷基、異噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氫噠嗪基、高哌嗪基或高哌啶基等。 Unless otherwise specified, the term "5-6 membered heterocyclic group" by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) _p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spiro, bis-cyclic and bridged rings. In addition, with respect to the "5-6 membered heterocyclic group", the heteroatom may occupy the position of attachment of the heterocyclic group to the rest of the molecule. The 5-6 membered heterocyclic group includes 5-membered and 6-membered heterocyclic groups. Examples of 5-6 membered heterocyclic groups include but are not limited to 1,3-dioxolane,

, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydroxazinyl, homopiperazinyl or homopiperidinyl, etc.

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

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

中的R可與

連接，形成一個6員環，其實施例包括但不限於

、

、

等。 Unless otherwise specified, when a substituent connected to ring A can be connected to ring A to form a ring, it means that the substituent can be connected to any position of ring A to form a new ring together with ring A, including a cyclic, spirocyclic or bridged ring; wherein ring A can be selected from the cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc. as described above. For example, when

The R in

connected to form a 6-membered ring, embodiments include but are not limited to

,

,

wait.

Unless otherwise specified, Cn _-n+m or _Cn - _Cn+m includes any specific case of n to n+m carbon atoms, for example, _C1-12 includes _C1 , _C2 , C3, _C4 , _C5 , _C6 , _C7 , _C8 , _C9 , _C10 , _C11 , and _C12 , and also includes any range from n to n+m, for example, _C1-12 includes _C1-3 , _{C1-6, C1-9 , C3-6} , _C3-9 , _C3-12 , _C6-9 , _C6-12 , _and C13. _Similarly , n-membered to n+m-membered means that the number of atoms on 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, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 5-10-membered ring, a 6-7-membered ring, a 6-8-membered ring, a 6-9-membered ring, and a 6-10-membered ring, etc.

The term "substituted" as used in the present invention means that in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl), at least one hydrogen atom is replaced by a non-hydrogen atom, and the non-hydrogen atom includes but is not limited to a halogen atom (such as F, Cl, Br, I), an oxygen-containing group (such as a hydroxyl group, an alkoxy group, an ester group), a Sulfur atom groups (such as thiol groups, alkylthio groups, sulfonyl groups, sulfonyl groups, sulfonyl groups), nitrogen atom groups (such as amine groups, amide groups, alkylamine groups, dialkylamine groups, arylamine groups, aryl-alkyl-amine groups, diarylamine groups, N-oxide groups, amide groups, enamine groups), silicon atom groups (such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, triarylsilyl groups) and other impurity atoms in various other groups.

The term "substituted" as used in the present invention also means that one or more hydrogen atoms in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl) are replaced by a higher-order bond (such as a double bond or a triple bond) of a hetero atom, such as oxygen in carbonyl, carboxyl and ester groups, and nitrogen in imine, oxime, hydrazone and nitrile. For example, "substituted" means that one or more hydrogen atoms in any of the above groups are _replaced by _{-NRgRh , -NRgC} (=O _{) Rh} , -NRgC(=O) _NRgRh , _-NRgC (=O)ORh, _{-NRgSO2Rh , -OC} (=O)NRgRh _{, -ORg} , _-SRg , _{-SORg , SO2Rg} , _{-OSO2Rg , -SO2ORg} , _{= NSO2Rg and -SO2NRgRh .} " _Substituted " may also mean that one or more hydrogen atoms in any of the _above groups are replaced by -C(= _O ) _Rg , _-C ( _{= O ) ORg} , -C(= _{O ) NRgRh} , _{-CH2SO2Rg , -CH2SO2NRgRh} . The _Rg and _Rh are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, heterocyclic, N-heterocyclic, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, heteroaryl-alkyl. "Substituted" may also mean that one or more hydrogen atoms in any of the above groups are replaced by amino, nitrile, hydroxyl, imino, nitro, pendoxy, thio, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, halogenated alkyl, halogenated alkenyl, halogenated alkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl-alkyl, heteroaryl, N-heteroaryl, heteroaryl-alkyl. In addition, each of the above substituents may be optionally substituted by one or more of the above substituents.

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 trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, etc.; acyloxy groups, such as acetyloxy, trifluoroacetyloxy, etc.

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

It should be understood by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and thus have two or more stereoisomers. Therefore, the compounds of the present invention may exist in the form of single stereoisomers (e.g., mirror isomers, non-mirror isomers) and mixtures thereof in any proportion, such as racemates, and, where appropriate, in the form of tautomeric isomers 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 (+)-mirror isomers, ( R )- and ( S )-mirror isomers, non-mirror isomers, ( D )-isomers, ( L )-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in mirror isomers or non-mirror isomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present invention.

The term "stereoisomer" used herein refers to compounds that have the same chemical composition but differ in the spatial arrangement of atoms or groups. Stereoisomers include mirror isomers, non-mirror isomers, and conformational isomers, etc.

As used herein, the term "mirror isomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.

As used herein, the term "non-mirror image isomer" refers to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Non-mirror image isomers have different physical properties, such as melting points, boiling points, spectral properties or biological activities. Mixtures of non-mirror image isomers can be separated by high-resolution analytical methods such as electrophoresis and column analysis such as HPLC.

Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. In 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 centers. The prefixes d and l or (+) and (-) are used to indicate the sign with which the compound rotates 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 referred to as mirror image isomers, and mixtures of such isomers are often referred to as mixtures of mirror image isomers. A 50:50 mixture of mirror image isomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two mirror image isomers that are not optically active.

The racemic mixture may be used as such or resolved into the individual isomers. Resolution may yield a stereochemically pure compound or a mixture enriched in one or more isomers. Methods for separating isomers are well known and include physical methods such as column chromatography using chiral adsorbents. Individual isomers may be prepared in chiral form from chiral precursors. Alternatively, the individual isomers can be chemically separated from the mixture by forming non-mirror image isomer salts with chiral acids (e.g., individual mirror image isomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, apple acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salts, and then isolating one or both of the resolved bases, optionally repeating this process, to obtain one or two isomers that are substantially free of the other isomer, i.e., the desired stereoisomer having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight. Alternatively, as is well known to those skilled in the art, the racemate may be covalently linked to a chiral compound (auxiliary) to obtain a non-mirror isomer.

Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can rapidly interconvert. If tautomerism is possible (such as in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerizations and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism 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 atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium ( ^3H ), iodine-125 ( ^125I ) or C-14 ( ^14C ). For another example, deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic efficacy, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur.

The compounds of the present invention can be prepared by a variety of synthetic methods known to those of ordinary skill in the art to which the present invention belongs, including the specific implementation methods listed below, implementation methods formed by combining them with other chemical synthesis methods, and equivalent substitution methods known to those of ordinary skill in the art to which the present invention belongs. Preferred implementation methods include but are not limited to the embodiments of the present invention.

The solvent used in the present invention can be obtained commercially.

Compounds are named according to conventional naming principles in this field or using ChemDraw® software, and commercially available compounds use the supplier's catalog name.

The compounds disclosed in the present invention may have one or more chiral centers, each of which independently has an R configuration or an S configuration. The chiral centers of some compounds disclosed in the present invention are marked with *R, *S, R*, or S*, indicating that the absolute configuration of the chiral center of the compound has not been identified, but the compound has been chirally resolved and the chiral center is a chiral center of a single configuration, the compound is a single configuration mirror image isomer monomer, or a single configuration non-mirror image isomer monomer, or a mixture of non-mirror image isomers with a single configuration of the chiral center (for example: the configuration of other chiral centers has not been resolved). When the absolute configuration (R configuration or S configuration) of the chiral center of the compounds disclosed in the present invention has not been identified, the compounds can be identified according to their corresponding retention time ( _RT ) under corresponding column chromatography conditions (e.g. column chromatography column model, column chromatography column packing, column chromatography column size, mobile phase, etc.).

The present invention is explained more specifically in the following examples. However, it should be understood that these examples are for the purpose of illustrating the present invention and are not intended to limit the scope of the present invention in any way. The experimental methods in the following examples, if no specific conditions are specified, are generally carried out according to the conventional conditions of such reactions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and weight parts. Unless otherwise specified, the ratio of liquids is volume ratio.

Technical and scientific terms used herein without specific definition have the meanings commonly understood by technicians in the field to which the present invention belongs.

Figure 1 is a bar graph showing the results of the efficacy test of the compounds according to the embodiments of the present invention in LPS-induced AP-activated mice.

The present application is described in detail below by way of an embodiment, but this does not mean that there are any adverse restrictions on the present application. This article has described the present application in detail, and its specific embodiments are also disclosed. For those with ordinary knowledge in the relevant technical field, it will be obvious to make various changes and improvements to the specific embodiments of the present application without departing from the spirit and scope of the present application.

Unless otherwise specified, the raw materials used in this invention are commercially available.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR measurements were performed using a Bruker ASCEND ^TM -400 NMR spectrometer, with deuterated sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

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

HPLC determination was performed using Shimadzu HPLC-2010C high pressure liquid phase column chromatograph (XBRIDGE 2.1*50mm, 3.5μm column chromatography column).

Chiral HPLC analysis was performed using THARSFC X5.

The thin layer chromatography silica plate uses the Yantai Qingdao GF254 silica plate. The silica plate used in thin layer column chromatography (TLC) uses a specification of 0.15mm-0.2mm, and 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 as the carrier.

High performance liquid phase preparation uses Waters2767, Waters2545, and Chuangxin Hengtong LC3000 preparative column chromatographs.

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

The pressurized hydrogenation reaction uses the 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 in an argon or 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.

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℃-30℃.

Example 1: Synthesis of Compound 1

Step 1: Preparation of compound 1-2

The raw material compound 1-1 ( 5.00 g, 26.29 mmol) and 2-(2-methyl-1,3-dioxolan-2-yl)ethane-1-amine (3.79 g, 28.92 mmol) were dissolved in toluene (60.0 mL), and molecular sieves (4.99 g) were added at room temperature. The reaction system was stirred and refluxed at 140 degrees Celsius for 5 hours under a dean-stark water separator until the reaction was complete. After cooling to room temperature, dichloromethane (50 mL) was added and filtered. The filtrate was concentrated to dryness in vacuo to obtain compound 1-2 (7.97 g) which can be directly used in the next reaction. The yield of the crude product is 100%. MS (ESI) m/z [M+H] ⁺ = 304.2.

Step 2: Preparation of Compound 1-3

Under nitrogen protection, p-toluenesulfonic acid (9.04 g, 52.55 mmol) was dissolved in toluene (40 mL) and heated to 140 °C. The reaction system was stirred and heated under reflux under a dean-stark water separator for 1 hour to remove water from the system, and then a toluene solution (30 mL) of compound 1-2 (7.97 g, 26.27 mmol) was added dropwise. After the addition was completed, the reaction solution was stirred at 140 °C for 30 minutes until the reaction was complete. After cooling, a saturated aqueous sodium carbonate solution was added to quench the reaction, and ethyl acetate (20 mL×2) was added for extraction. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product. The crude product was purified by silica gel column (eluent: dichloromethane: methanol = 10:1) to obtain 1-3 (3.40 g) with a yield of 42.6%. MS (ESI) m/z [M+H] ⁺ = 304.2.

Step 3: Preparation of Compound 1-4

Compound 1-3 (600 mg, 1.98 mmol) was dissolved in dichloromethane (2 mL), TFA (2 mL) and TfOH (0.2 mL) were added at room temperature, and the mixture was stirred at room temperature for 1 hour until the reaction was complete. The reaction solution was concentrated in vacuo, and the obtained oil was dissolved in ethyl acetate and washed with a saturated sodium carbonate aqueous solution. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude compound 1-4 (500 mg), which can be directly used in the next step. The crude yield is 97.5%. MS (ESI) m/z [M+H] ⁺ = 260.2.

Step 4: Preparation of Compound 1-5

Compound 1-4 (3.5 g, 13.50 mmol) was dissolved in a mixture of Boc ₂ O (5.83 g, 27.00 mmol) and TEA (1.88 g, 18.58 mmol, 2.59 mL). The reaction solution was heated to 55°C and stirred for 1 hour until the raw materials reacted completely. The reaction solution was cooled to room temperature and directly separated and purified using a silica gel column (eluent: petroleum ether: ethyl acetate = 4:1) to obtain 3.3 g of compound 1-5 with a yield of 68%.

¹ HNMR (400MHz, Methanol- d ₄ ) δ 7.85-7.72 (m, 2H), 7.15 (d, J =8.0Hz,0H),4.25-4.12(m,1H),3.99-3.88(m,1H),3.80(s,3H),3.08-2.85(m,3H ),2.75-2.59(m,1H),2.58-2.41(m,3H),2.04-1.89(m,1H),0.97(s,9H); MS(ESI) m/z [M+H] ⁺ =360.2.

Step 5: Preparation of Compound 1-6

Compound 1-5 (370 mg, 1.03 mmol) was dissolved in EtOH (5 mL), cooled to -10 °C, and NaBH ₄ (38.95 mg, 1.03 mmol) was slowly added in batches, and then the reaction solution was heated to room temperature and stirred for 1 hour until the reaction was complete. The reaction solution was concentrated in vacuo, and saturated brine was added to quench the reaction, and the product was extracted with ethyl acetate (5 mL × 2). The organic phase was washed with saturated ammonium chloride aqueous solution, separated, and dried over anhydrous sodium sulfate, and then concentrated and dried under vacuum to obtain compound 1-6 ( 368.0 mg), which can be directly used in the next step reaction with a yield of 99%.

¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.83-7.72 (m, 2H), 7.157 (d, J=8.8Hz, 1H), 4.80 (d, J =3.2Hz,1H),4.05-3.93(m,1H),3.83(s,3H),3.70-3.62(m,1H),3.54-3.41(m,1H),2.98-2.83(m,2H), 2.79-2 .62(m,1H),2.37-2.18(m,2H),2.11-1.99(m,1H),1.82-1.69(m,2H),1.70-1.54(m,1H),0.95(s,9H) ;MS(ESI) m/z [M+H] ⁺ =362.2.

Step 6: Preparation of Compound 1-7

Under nitrogen protection, compound 1-6 ( 900 mg, 2.49 mmol) was dissolved in DMF (10 mL), and NaH (597.57 mg, 14.94 mmol, 60% purity) was slowly added at room temperature. After the mixture was stirred for 5 minutes, iodoethane (2.33 g, 14.94 mmol) was slowly added. The reaction solution was stirred at room temperature for 2 hours until the reaction was complete, and then an aqueous ammonium chloride solution was added to quench the reaction. The product was extracted with ethyl acetate (10 mL×2), and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product. The crude product was separated and purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1) to obtain compound 1-7 (640 mg) with a yield of 66%. MS (ESI) m/z [M+H] ⁺ =390.2.

Step 7: Preparation of Compound 1-8

Compound 1-7 (900 mg, 2.31 mmol) was dissolved in DCM (9 mL) at room temperature, 2,6-lutidine (742.81 mg, 6.93 mmol) and TMSOTf (769.48 mg, 3.47 mmol) were added, and the reaction solution was stirred at room temperature for 1 hour until the reaction was complete. A saturated sodium carbonate aqueous solution was added to quench the reaction, and the product was extracted with DCM (5 mL×2). The organic phase was separated, dried, and concentrated in vacuo to obtain 666 mg of compound 1-8, which can be directly used in the next step, with a yield of 100%. MS (ESI) m/z [M+H] ⁺ = 290.2.

Step 8: Preparation of Compound 1-9

Dissolve tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (785.32 mg, 2.70 mmol) in DCM (8 mL), add PPh ₃ Br ₂ (1.48 g, 3.50 mmol) in dichloromethane (5 mL) at 0°C under nitrogen protection, stir the reaction solution at 0°C for 1 hour, then add compound 1-8 ( 600 mg, 2.07 mmol) and DIEA (905.78 mg, 7.01 mmol) in dichloromethane (4 mL), and continue stirring the reaction solution at room temperature for 2 hours until the reaction is complete. Add water to the reaction solution to quench the reaction, extract the product with dichloromethane, separate the organic phase, dry it over anhydrous sodium sulfate, and concentrate it in vacuo to obtain a crude product. The crude product was purified and separated by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 945 mg of compound 1-9 with a yield of 81%. MS (ESI) m/z [M+H] ⁺ = 563.4.

Step 9: Preparation of Compound 1-10

Compound 1-9 ( 1.1 g, 1.95 mmol) was dissolved in a mixed solution of MeOH (3 mL)\THF (3 mL)\water (3 mL), and NaOH (781.89 mg, 19.55 mmol) was added under stirring. Then the reaction solution was heated to 60°C and stirred for 2 hours until the reaction was complete. After cooling to room temperature, the reaction solution was adjusted to pH = 6.0 with citric acid aqueous solution, and then the product was extracted with ethyl acetate (10 mL × 3). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated and dried under vacuum to obtain compound 1-10 ( 873.6 mg), with a crude yield of 100%. MS (ESI) m/z [M+H) ⁺ = 449.2.

Step 10: Preparation of Compound 1-11

Compound 1-10 (873.6 mg) was prepared, separated and purified by HPLC (separation conditions: column chromatography column: Agilent 10 Prep-C18 21.2×250 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 15%-35% in 12 min; flow rate 30 ml/min) to obtain 480 mg of compound 1-11 ( the second peak), with a yield of 55%. MS (ESI) m/z [M+H) ⁺ =449.2.

Step 11: Preparation of Compound 1

The racemate compound 1-11 (36 mg) was purified by chiral separation using SFC (SFC preparation method: instrument: MG II preparative SFC (SFC-13), column type: ChiralPak IC, 250×30 mm ID, 10 μm, mobile phase: A-CO ₂ , B-ethanol (0.1% NH ₃ .H ₂ O), gradient: B 50%, flow rate: 80 mL/min, back pressure: 100 bar, column temperature: 38°C, wavelength: 220 nm, cycle: ~12 min) to obtain 14.7 mg of chiral compound 1 (the first peak) (analytical method: instrument: Waters UPC2 analytical SFC (SFC-H), column type: ChiralPak IC, 100×4.6 mm ID, 3 μm, mobile phase: A-CO ₂ , B-ethanol (0.05% DEA), gradient: B 50%, flow rate: 2.5mL/min, back pressure: 100bar, column temperature: 35℃, wavelength: 220nm), the yield was 41%.

^1H NMR (400MHz, Methanol-d4)δ 7.98(d,J=8.0Hz,1H),7.88(s,1H),7.50(d,J=7.6Hz,1H),7.19(s,1H),6.63(s,1H),6.15 (s,1H),4.20-4.02(m,1H),3.96-3.86(m,1H),3.82-3.68(m,1H),3.57(s,3H),3.53-3.42( m,2H),3.33-3.26(m,1H),3.18-3.00(m,2H),3.01-2.89(m,1H),2.74-2.57(m,1H),2.39(s ,3H),2.36-2.35(m,1H),2.25-2.14(m,2H),2.00-1.83(m,2H),1.19-1.13(m,3H); MS(ESI) m/z [M+H] ⁺ =449.2.

Example 2: Synthesis of Compound 2

Step 1: Preparation of compound 2-1

Under nitrogen protection, compound 1-6 (1g, 2.49mmol) was dissolved in DMF (11mL), and NaH (597.71mg, 14.94mmol, 60% purity) was slowly added, and then stirred at room temperature for five minutes, and (iodomethyl)cyclopropane (0.96g, 4.98mmol) was added. After the reaction solution was heated to 60°C and stirred for 30 minutes, (iodomethyl)cyclopropane (0.96g, 4.98mmol) was added until the reaction of compound 1-6 was complete. The reaction solution was cooled to room temperature, and an aqueous solution of ammonium chloride was added to quench the reaction. The product was extracted with ethyl acetate (10mL×2), and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain a crude product. The crude product was separated and purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 853 mg of compound 2-1 with a yield of 82%. MS (ESI) m/z [M+H] ⁺ = 416.2.

Step 2: Preparation of compound 2-2

Compound 2-1 (1 g, 2.19 mmol) was dissolved in DCM (10 mL), 2,6-lutidine (705.59 mg, 6.58 mmol) and TMSOTf (974.57 mg, 4.39 mmol) were added at room temperature, and then stirred for 1 hour until the raw material reacted completely. A sodium carbonate aqueous solution was added to quench the reaction, and the product was extracted with DCM (5 mL×2). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated and dried under vacuum to obtain 690 mg of compound 2-2 , with a yield of 100%; MS (ESI) m/z [M+H] ⁺ =316.2.

Step 3: Preparation of compound 2-3

Under nitrogen protection, tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (800 mg, 2.74 mmol) was dissolved in DCM (8 mL), cooled to 0°C, and a dichloromethane solution (5 mL) of PPh ₃ Br ₂ (1.50 g, 3.57 mmol) was added. The reaction solution was stirred at 0°C for 1 hour, and then a dichloromethane solution (4 mL) of compound 2-2 (750 mg, 2.11 mmol) and DIEA (1.09 g, 8.44 mmol) was added. The reaction solution was heated to room temperature and stirred for 2 hours until the reaction was complete, and then water was added to quench the reaction. The product was extracted with dichloromethane, and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under vacuum to obtain a crude product. The crude product was separated and purified by silica gel column (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 0.95 g of compound 2-3 with a yield of 76.5%. MS (ESI) m/z [M+H] ⁺ = 589.4.

Step 4: Preparation of compound 2-4

Compound 2-3 (1.0 g, 1.70 mmol) was dissolved in a mixed solution of MeOH (3 mL)/THF (3 mL)/water (3 mL), and NaOH (636 mg, 15.90 mmol) was added. The reaction solution was heated to 60°C and stirred for 4 hours. After cooling, the reaction solution was adjusted to pH = 6.0 with citric acid aqueous solution, and the product was extracted with ethyl acetate (10 mL × 3). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under vacuum to obtain 807.5 mg of compound 2-4 , with a yield of 100%. MS (ESI) m/z [M + H] ⁺ = 475.2.

Step 5: Preparation of Compound 2-5

Compound 2-4 (807.5 mg) was prepared, separated and purified by HPLC (separation conditions: column chromatography column: Agilent 10 Prep-C18 21.2×250 mm; column temperature: 25°C; mobile phase: water (0.1% FA)-acetonitrile; mobile phase acetonitrile ratio 20%-40% in 12 min; flow rate 30 ml/min) to obtain 408 mg of compound 2-5 (P2 peak), with a yield of 51%.

^1H NMR (400MHz, Methanol-d4)δ 8.10(d,J=8.0Hz,1H),8.00(s,1H),7.61(d,J=8.0Hz,1H),7.29(d,J=3.2Hz,1H),6.74(s,1H), 6 .27(s,1H),4.23(d,J=12.8Hz,1H),4.04(d,J=12.0Hz,1H),3.85(s,1H),3.67(s,3H),3.48-3.4 2(m,2H),3.18-3.01(m,3H),2.49(s,3H),2.47-2.23(m,2H),2.12-1.99(m,3H),1.65-1.54(m,1 H),1.16-1.05(m,1H),0.94-0.86(m,1H),0.56(d,J=6.8Hz,2H),0.27(d,J=4.4Hz,2H); MS(ESI) m/z [M+H] ⁺ =475.2.

Step 6: Preparation of Compound 2

The racemic compound 2-5 (530 mg) was purified by chiral separation using SFC (SFC preparation method: instrument: WATERS 150 preparative SFC (SFC-26), column type: ChiralPak IC, 250×30 mm ID, 10 μm, mobile phase: A-CO ₂ , B-ethanol (0.1% NH ₃ .H ₂ O), gradient: B 50%, flow rate: 130 mL/min, back pressure: 100 bar, column temperature: 38°C, wavelength: 220 nm, cycle: ~11 min) to obtain 238 mg of chiral compound 2 (analytical method: instrument: Waters UPC2 analytical SFC (SFC-H), column type: ChiralPak IC, 100×4.6 mm ID, 3 μm, mobile phase: A-CO ₂ , B-ethanol (0.05% DEA), gradient: B 50%, flow rate: 2.5mL/min, back pressure: 100bar, column temperature: 35℃, wavelength: 220nm), the yield was 45%.

^1H NMR(400MHz,Methanol-d4)δ 8.10(d,J=8.0Hz,1H),8.00(s,1H),7.61(d,J=8.0Hz,1H),7.29(d,J=3.2Hz,1H),6.74(s,1H), 6 .27(s,1H),4.23(d,J=12.8Hz,1H),4.04(d,J=12.0Hz,1H),3.85(s,1H),3.67(s,3H),3.48-3.4 2(m,2H),3.18-3.01(m,3H),2.49(s,3H),2.47-2.23(m,2H),2.12-1.99(m,3H),1.65-1.54(m,1 H),1.16-1.05(m,1H),0.94-0.86(m,1H),0.56(d,J=6.8Hz,2H),0.27(d,J=4.4Hz,2H); MS(ESI) m/z [M+H] ⁺ =475.2.

Example 3: Synthesis of Compound 3

Step 1: Preparation of compound 3-1

Under nitrogen protection, compound 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (73.0 mg, 0.25 mmol) was dissolved in dichloromethane (3 mL), and a dichloromethane solution (1 mL) of dibromotriphenylphosphine (137 mg, 0.32 mmol) was slowly added dropwise at 0°C. After the addition was completed, the mixture was stirred at 0°C for 1 hour, and then compound 1-3 was added. (41 mg, 0.14 mmol) and diisopropylethylamine (52.4 mg, 0.40 mmol) in dichloromethane (1 mL), the reaction solution was stirred at room temperature for 2 hours until the reaction was complete, water (2 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column (petroleum ether: ethyl acetate = 3:1) to obtain compound 3-1 ( 25 mg), with a yield of 32.0%. MS (ESI) m/z [M+H] ⁺ = 577.2.

Step 2: Preparation of compound 3

Under nitrogen protection, compound 3-1 ( 32.0 mg, 0.055 mmol) was dissolved in a mixed solvent of methanol (0.5 mL), tetrahydrofuran (0.5 mL), and water (0.5 mL), and sodium hydroxide (22.20 mg, 0.55 mmol) was added. The resulting mixture was heated to 60 ° C and stirred for 1 hour, then cooled to room temperature, adjusted to pH = 4.0 with saturated citric acid aqueous solution, extracted with ethyl acetate (2 mL × 3), and the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (column: Welch xtimate C18 21.2mm*250mm 10μm; column temperature: 25°C; mobile phase: water (0.1% ammonium bicarbonate)-acetonitrile; mobile phase acetonitrile ratio 25%-55% in 18min; flow rate 30ml/min) to obtain compound 3 (5.90mg) with a yield of 23%. MS (ESI) m/z[M+H] ⁺ =463.2.

¹ HNMR(400MHz, Methanol-d4)δ 7.99(d, J =8.0Hz,1H),7.89(s,1H),7.53(d, J =8.1Hz,1H),7.19(d, J =3.2Hz,1H),6.63(s,1H),6.24-6.13(m,1H),4.11-3.90(m,4H),3.85(t, J =6.3Hz,2H),3.57(s,3H) ,3.48(d, J =16.0Hz,2H),3.16-3.02(m,2H),2.88(d, J =10.2Hz,1H),2.71(d, J =15.2Hz,2H),2.39(s,3H),2.01(dd , J =14.3,3.0Hz,2H),1.88-1.75(m,1H).

Example 4: Synthesis of Compound 4

Step 1: Preparation of compound 4-2

Under nitrogen protection, compound 4-1 ( 102.58 mg, 0.5 mmol) was dissolved in dichloromethane (20.20 mL), and 2-methyl-1,3-dioxolane-2-ethylamine (65.59 mg, 0.5 mmol), magnesium sulfate (250.00 mg, 2.08 mmol) and p-toluenesulfonic acid (4.31 mg, 0.025 mmol) were added. The resulting reaction solution was heated and refluxed for 3 hours until the raw materials reacted completely, and then cooled to room temperature to obtain a reaction solution containing compound 4-2 , which was directly used in the next step reaction. The crude yield was 100%. MS (ESI) m/z [M+H] ⁺ = 319.2.

Step 2: Preparation of compound 4-3

Under nitrogen protection, a solution of boron trifluoride ether (221.88 mg, 0.75 mmol, 0.2 mL, 48% purity) was added to the reaction solution of compound 4-2 (159.6 mg, 0.5 mmol) in dichloromethane (20.20 mL), and the resulting mixture was heated and refluxed for 4 hours until the reaction was complete, cooled to room temperature, and a saturated aqueous NaHCO ₃ solution (8 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (20 mL×2), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 4-3 (90 mg) with a yield of 56.6%. MS (ESI) m/z[M+H] ⁺ =319.2.

Step 3: Preparation of compound 4-4

Under nitrogen protection, compound 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (73.0 mg, 0.25 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, dibromotriphenylphosphine (137.90 mg, 0.33 mmol) was added, and after stirring for 1.5 hours, compound 4-3 (80 mg, 0.25 mmol) and diisopropylethylamine (97.44 mg, 0.75 mmol) were added. After stirring at 0°C for 1 hour, the temperature was raised to room temperature and the stirring reaction was continued for 6 hours until the raw material reacted completely. Water (2 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL×2). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6:4) to obtain compound 4-4 (130 mg) with a yield of 87.4%. MS (ESI) m/z [M+H] ⁺ = 591.8.

Step 4: Preparation of compound 4

Under nitrogen protection, compound 4-4 (110 mg, 0.18 mmol) was dissolved in a mixed solvent of water (1 mL)/methanol (1 mL)/tetrahydrofuran (1 mL), sodium hydroxide (111.54 mg, 2.79 mmol) was added, the resulting reaction solution was heated to 60°C for 2 hours until the raw material reacted completely, the pH was adjusted to 4.0 with saturated citric acid aqueous solution, extracted with ethyl acetate (5 mL×3), the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to obtain compound 4 (45 mg) with a yield of 52%. MS (ESI) m/z[M+H] ⁺ =478.2.

¹ HNMR(400MHz,DMSO-d6)δ 10.99-10.42(m,2H),7.84(d, J =7.9Hz,1H),7.62(dd, J =7.8,1.6Hz,1H),7.39(d, J =1.5Hz,1H),7.22(t, J =2.8Hz,1H),6.87(dd, J =3.0,2.0Hz,1H),6.60(s,1H),3.90(d, J =5.6Hz,1H),3.84-3.74(m,3H),3.62 (s,3H),3.35(s,2H),2.86(t, J =11.4Hz,1H),2.69-2.59(m,1H),2.40(s,3H),2.08(d, J =13.4Hz,1H),1.74-1.61(m,2H),1.57(dt, J =12.5,6.1Hz,1H).

Example 5: Synthesis of Compound 5

Step 1: Preparation of compound 5-2

Under nitrogen protection, compound 5-1 (615.5 mg, 3 mmol) was dissolved in DMF (10 mL), sodium hydride (79.2 mg, 3.3 mmol) was added at 0°C, the temperature was raised to room temperature and reacted for 30 minutes, iodomethane (510.98 mg, 3.60 mmol) was added, the reaction solution was continued to react at room temperature for 2 hours until the reaction was complete, water (5 mL) was added to quench, and ethyl acetate (30 mL×2) was used for extraction, the organic phase was dried over anhydrous sodium sulfate, concentrated and dried under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 5-2 (510 mg), with a yield of 77.6%. MS (ESI) m/z[M+H] ⁺ =220.0.

¹ HNMR(400MHz, DMSO-d6)δ 7.68(qd,J=7.7,0.9Hz,2H),7.56(t,J=0.9Hz,1H),3.91(s,3H),3.20(s,3H).

Step 2: Preparation of compound 5-3

Under nitrogen protection, compound 5-2 ( 300 mg, 1.37 mmol) was dissolved in dichloromethane (20 mL), and 2-methyl-1,3-dioxolane-2-ethylamine (179.53 mg, 1.37 mmol), magnesium sulfate (684.33 mg, 5.70 mmol) and p-toluenesulfonic acid (11.78 mg, 0.068 mmol) were added. The resulting reaction solution was heated and refluxed for 3 hours until the raw materials reacted completely, and then cooled to room temperature to obtain a reaction solution containing compound 5-3 , which was directly used in the next reaction. The crude yield was 100%. MS (ESI) m/z [M+H] ⁺ = 333.0.

Step 2: Preparation of compound 5-4

Under nitrogen protection, a solution of boron trifluoride ether (607.34 mg, 2.05 mmol, 0.54 ml, 48% purity) was added to the dichloromethane (20 mL) reaction solution of the compound 5-3 obtained above (454.8 mg, 1.37 mmol), and the resulting mixture was heated and refluxed for 6 hours until the reaction was complete, cooled to room temperature, and a saturated NaHCO ₃ aqueous solution (8 mL) was added to quench the reaction. The reaction solution was extracted with ethyl acetate (20 mL×2), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 5-4 (300 mg) with a yield of 66%. MS (ESI) m/z[M+H] ⁺ =333.0.

Step 3: Preparation of compound 5-5

Under nitrogen protection, compound 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylic acid tert-butyl ester (114 mg, 0.39 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, dibromotriphenylphosphine (214.7 mg, 0.51 mmol) was added, and after stirring for 1.5 hours, compound 5-4 (130.1 mg, 0.39 mmol) and diisopropylethylamine (151.7 mg, 1.17 mmol) were added. After stirring at 0°C for 1 hour, the temperature was raised to room temperature and the stirring reaction was continued for 6 hours until the raw material reacted completely. Water (2 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (10 mL×2). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7:3) to obtain compound 5-5 (125 mg) with a yield of 52.7%. MS (ESI) m/z [M+H] ⁺ = 606.0.

Step 4: Preparation of compound 5

Under nitrogen protection, compound 5-5 (100 mg, 0.165 mmol) was dissolved in a mixed solvent of water (1.5 mL)/methanol (1.5 mL)/tetrahydrofuran (1.5 mL), sodium hydroxide (726.4 mg, 18.16 mmol) was added, the resulting reaction solution was heated to 60°C for 3 hours until the raw material reacted completely, the pH was adjusted to 4.0 with saturated citric acid aqueous solution, extracted with ethyl acetate (5 mL×3), the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC to obtain compound 5 (30 mg) with a yield of 37%. MS (ESI) m/z[M+H] ⁺ =492.2.

¹ HNMR(400MHz, DMSO-d6)δ 10.77(s,1H),7.94(d, J =7.9Hz,1H),7.75(dd, J =7.8,1.5Hz,1H),7.52(d, J =1.5 Hz,1H),7.23(t, J =2.8Hz,1H),6.84(dd, J =3.0,2.0Hz,1H),6.60(s,1H),3.95-3.85(m,1H),3.85-3.73(m,3H),3.62(s,3H),3.24(s,4H),3.04( d, J =11.8Hz,1H),2.87(t, J =11.3Hz,1H),2.73-2.64(m,1H),2.40(s,3H),2.09(d, J =13.5Hz,1H),1.78-1.52(m,3H).

Biological Examples

Experimental Example 1 : Human Factor B Protein Binding Test Experiment (TR-FRET Method)

Prepare a buffer solution with the following ingredients: 50mM Tris-HCl, pH7.0, 50mM NaCl, 0.01% w/v Triton X-100. The compound to be tested was first diluted 3-fold with DMSO, and then 0.6μL was transferred to a 96-well plate with a pipette, 99.4μL of buffer was added and pipetted to mix, and 2.5μL of the diluted compound was transferred to a 384-well plate (ProxiPlate-384 plus, PE). 90nM His-FB protein (ab276729, Abcam) was prepared with the buffer solution, and 2.5μL was transferred to the 384-well plate containing the compound. Then 300nM probe labeled with Cy5 fluorescence was prepared with the buffer solution, and 5μL was transferred to the 384-well plate. Finally, 5 μL of 15 nM LANCE Eu-anti-6xHis antibody (AD0110, Perkin Elmer) in buffer was added, centrifuged at 1000 rpm for 30 seconds, and incubated at room temperature for 2 hours in the dark. The fluorescence value was read using Envision (Exc.Filter is UV2 (TRF) 320, Ems.Filter is APC665, 2nd ems.filter is LANCE Laser attenuated Europium filter, 50 μs delay), and the 665nm/615nm ratio was calculated. Finally, the data were analyzed using GraphPad Prism 8 software, and the IC ₅₀ value was calculated using the dose-response-inhibition (four-parameter) equation by GraphPad Prism software.

Experimental results:

IC50值<1000nM；C代表：IC50值>1000nM。 The IC50 values of the test compounds for human complement factor B protein binding test (TR-FRET method) are shown in Table 1, where A represents: IC50 value <100nM; B represents: 100nM

IC50 value <1000nM; C represents: IC50 value >1000nM.

Conclusion: The compound of the present invention has significant binding activity to human promyelocytic factor B protein.

Experimental Example 2 : C3 protein hydrolysis experiment

1. Preparation of CVF:Bb complex: First, prepare reaction buffer (10mM MgCl ₂ , 0.05% w/v CHAPS, PBS pH 7.4), use reaction buffer to prepare a mixed reaction system with a final concentration of 300nM FD (A409, Quidel), 1μM FB (A408, Quidel), and 1μM CVF (A600, Quidel), and incubate at 37°C for 3 hours. Divide the digestion product into small portions and store at -80°C for subsequent experiments.

2. C3 hydrolysis reaction: The compound was first diluted three times with DMSO, with a total of ten concentrations, and then diluted 40 times with reaction buffer, and 1 μL was transferred to a 384-well plate (ProxiPlate-384 plus, PE). 2.5nM CVF:Bb and 1μM C3 (A401, Quidel) were prepared with reaction buffer. 2μL CVF:Bb was transferred to the ProxiPlate 384 plate well containing the compound and incubated at 37°C for 30 minutes. 2μL C3 was added to start the reaction and incubated at 37°C for 180 minutes. During the reaction, the 384-well plate was sealed. Add 5 μL 2x protease inhibitor cocktail (5892970001, Roche) to each well to stop the reaction. After mixing, transfer 1.25 μL of the reaction solution to a 384-well black plate (OptiPlate-384 F HB, PE), add 23.8 μL of coating buffer (containing 100 mM sodium carbonate pH 9.0: C3041, Sigma and 1 M 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 25μL starting block T20 (37539, Thermofisher) to each well, incubate at room temperature for 15 minutes, discard the supernatant, and wash three times with PBST. Add 25μL 25μL 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 three times with PBST. Add 25μL Quantablu fluorogenic peroxidase substrate (15169, Thermofisher) and centrifuge at 1000rpm for 30 seconds. Incubate at room temperature for 30 minutes, and read the fluorescence value with Envision (PE, Envision ^@ 2105), with an excitation wavelength of 340nm and an emission wavelength of 460nm. Finally, the data were analyzed using GraphPad Prism 8 software, and the _IC50 values were calculated using the dose-response-inhibition (four-parameter) equation by GraphPad Prism software.

Experimental results:

IC50值<1000nM；C代表：IC50值>1000nM，LNP023為參照化合物。 The IC50 values of the test compounds for C3 enzymatic hydrolysis are shown in Table 2, where A represents: IC50 value <100nM; B represents: 100nM

IC50 value <1000nM; C represents: IC50 value >1000nM, LNP023 is the reference compound.

Conclusion: The compound of the present invention has excellent in vitro activity and can significantly inhibit the hydrolysis activity of C3 enzyme.

Experimental Example 3: Drug efficacy in LPS-induced AP activation in mice

1. Experimental purpose

The plasma C3d/iC3b/C3c/activated C3 assay was used to evaluate the inhibitory effects of compounds on the activation of the complement alternative pathway (AP) in C57 mice induced by bacterial lipopolysaccharide.

2. Experimental materials

2.1 Experimental animals

SPF female C57BL/6J mice, weighing 16-19g, 7 weeks old, 44 in total; Source: purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.; Animal production license number: Production license SCXK (Shanghai) 2017-0011 or SCXK (Beijing) 2016-0006 or SCXK (Beijing) 2016-0011 or SCXK (Zhejiang) 2019-0001

The Zhangjiang Animal House of Charles River Pharmaceutical Technology (Shanghai) Co., Ltd. is located at 4F, Building 2, No. 1077, Zhangheng Road, Pudong New District, Shanghai. Animal husbandry environment: temperature 23±2℃, relative humidity 40-70%, lighting time 6AM/6PM switch lights; animals are fed with ordinary feed and sterilized drinking water freely. All animal experiments have been approved by the Animal Ethics Committee of Charles River Pharmaceutical Technology (Shanghai) Co., Ltd.

2.2 Test drugs and solvents

(1) Solvent formula: 0.5% MC + 0.5% Tween 80; (2) Test drug preparation method: Add the compound to the solvent, stir with ultrasound until a uniform solution/suspension is obtained, and prepare to the required concentration.

3. Experimental process

3.1 After the animals have adapted for 3-7 days, they will be grouped according to their weight as shown in Table 3.

(Solvent: 0.5% MC+0.5% Tween 80)

3.2 Salmonella typhimurium lipopolysaccharide (LPS) was dissolved in sterile PBS to prepare a 200μg/mL solution.

3.3 Animals in each group were first injected intraperitoneally with 0.1 mL PBS or LPS to establish the model according to the plan in Table 3, and then gavage with the solvent or the compound to be tested.

3.4 One hour after drug administration, animals in groups 1 to 5 were euthanized with CO ₂ or anesthetized with isoflurane and then blood was collected from the heart. EDTA-K2 was used as the anticoagulant.

3.5 Place the blood in wet ice, centrifuge at 4500g for 10 minutes at 4℃, collect the plasma, divide it into two tubes, 10-50μL/tube, store it in a -80℃ refrigerator, and use it to measure the C3d/iC3b/C3c/activated C3 content.

4. Statistical methods

The experimental data were expressed as mean ± standard error (Means ± SEM) and analyzed using Graphpad Prism 8.0 software and one-way ANOVA. p < 0.05 was considered statistically significant.

5. Experimental results

The experimental results are shown in Table 4 and Figure 1.

Experimental conclusion: The compound of the present invention has excellent in vivo activity in animals and has the effect of inhibiting the activation of the complement pathway (AP) in C57 mice induced by bacterial lipopolysaccharide (LPS).

The above is an explanation of the exemplary implementation of the present invention. It should be understood that the scope of protection of this application is not limited to the above exemplary implementation. Any modification, equal replacement, improvement, etc. made by a person with ordinary knowledge in the technical field to which the present invention belongs within the spirit and principles of the present invention shall be included in the scope of protection of this application.

Claims (19)

A compound represented by formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof,

wherein X is selected from C(R ₅ ) ₂ , O or N(R ₅ ); 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, wherein the C _1-6 alkyl, C _1-6 heteroalkyl or C _3-9 cycloalkyl is optionally substituted by 1, 2 or 3 R; R ₂ is 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 heterocycloalkyl, wherein the C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl or _3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; L is selected from a single bond, O, S, NH,

,

,

,

,

and

, the NH,

,

,

,

,

or

_R is selected from H, OH, CN, F, Cl, Br, I, C _1-6 alkyl, C 3-6 cycloalkyl, C _1-6 heteroalkyl and 3-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heteroalkyl or _3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; _R is selected from H, OH, CN, F, Cl, Br, I, C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heteroalkyl and 3-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, C _1-6 heteroalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R; or, _R and _R are linked together to form C R is selected from H, _OH , CN, F, Cl, Br, I and C _1-6 alkyl, and the C _1-6 alkyl is optionally substituted with 1, ₂ or ₃ R; _R is selected from H, OH, CN, F, Cl, Br, _I and C _1-6 alkyl, and the C _1-6 alkyl is optionally substituted with 1, 2 or 3 R; R is _{independently} selected from OH, CN, F, Cl, Br, I, C _1-6 alkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl; the C _1-6 alkyl, C _1-6 heteroalkyl or C 3-9 cycloalkyl is optionally substituted with 1, 2 or 3 R; The _1-6 membered heteroalkyl or 3-6 membered heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or heteroatoms independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) ₂ - and N. The compound as described in claim 1, its optical isomer or a pharmaceutically acceptable salt thereof has a structure as shown below:

wherein L, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ are as defined in claim 1. The compound as described in claim 1 or 2, its optical isomer or a pharmaceutically acceptable salt thereof, 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, and 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 R. The compound as claimed in claim 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein R ₁ is selected from H, OH, CN, F, Cl, Br, I, CH ₃ ,

,

,

,

,

,

,

,

and

. The compound as described in claim 1 or 2, its optical isomer or a pharmaceutically acceptable salt thereof, wherein _R2 is selected from H, OH, CN, F, Cl, Br, I, _C1-4 alkyl, _C1-4 alkoxy, _C1-4 alkylthio, C1-4 alkylamino, _C3-6 cycloalkyl and 3-6 membered heterocycloalkyl, and the _C1-4 alkyl, _C1-4 alkoxy, _C1-4 alkylthio, _{C1-4 alkylamino} , _C3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R. The compound as claimed in claim 5, its optical isomer or a pharmaceutically acceptable salt thereof, wherein R ₂ is selected from H, OH, CN, F, Cl, Br, I, CH ₃ ,

,

,

,

,

,

,

,

and

. The compound as described in claim 1 or 2, its optical isomer or a pharmaceutically acceptable salt thereof, wherein _R3 is selected from H, OH, CN, F, Cl, Br, I, _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 alkoxy, C1-6 alkylthio and 3-6 _membered heterocycloalkyl, and the _C1-6 alkyl, _C3-6 cycloalkyl, _C1-6 alkoxy, _C1-6 alkylthio or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R. The compound as claimed in claim 7, its optical isomer or a pharmaceutically acceptable salt thereof, wherein R ₃ is selected from H, OH, CN, F, Cl, Br, I, CH ₃ ,

,

,

,

,

,

,

,

,

,

,

and

. The compound as described in claim 8, its optical isomer or its pharmaceutically acceptable salt, wherein the structural unit

Selected from H, OH, CN, F, Cl, Br, I, CH ₃ ,

,

,

,

,

and

. The compound as described in claim 1 or 2, its optical isomer or a pharmaceutically acceptable salt thereof, wherein _R4 is selected from H, OH, CN, F, Cl, Br, I, _C1-3 alkyl, _C3-6 cycloalkyl, _C1-3 alkoxy, _C1-3 alkylthio, _C1-3 alkylamino and 3-6 membered heterocycloalkyl, and the _C1-3 alkyl, _C3-6 cycloalkyl, _{C1-3 alkoxy, C1-3 alkylthio} , _C1-3 alkylamino or 3-6 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R. The compound as claimed in claim 10, its optical isomer or a pharmaceutically acceptable salt thereof, wherein R ₄ is selected from H, OH, CN, F, Cl, Br, I, CH ₃ ,

,

,

,

,

and

, the CH ₃ ,

,

,

,

,

or

Optionally replaced by 1, 2 or 3 Rs. The compound as claimed in claim 11, its optical isomer or a pharmaceutically acceptable salt thereof, wherein R ₄ is selected from H, OH, CN, F, Cl, Br, I, CH ₃ ,

,

,

,

,

,

,

,

,

,

,

and

. The compound as claimed in claim 1 or 2, its optical isomer or a pharmaceutically acceptable salt thereof, wherein R ₃ and R ₄ are linked together to form

,

and

,

,

or

Optionally replaced by 1, 2 or 3 Rs. The compound as described in claim 13, its optical isomer or a pharmaceutically acceptable salt thereof, wherein R ₃ and R ₄ are linked together to form

,

,

,

,

and

. The compound as claimed in claim 1 or 2, its optical isomer or a pharmaceutically acceptable salt thereof, wherein R ₅ is selected from H, F, Cl, CN, OH, CH ₃ ,

,

,

and

. A compound of the following formula, an optical isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:

A pharmaceutical composition comprising a compound described in any one of claims 1 to 16, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Use of a compound as described in any one of claims 1 to 16, an optical isomer thereof or a pharmaceutically acceptable salt thereof, or a drug composition as described in claim 17 in the preparation of a drug for treating a disease related to the activity and expression of complement factor B. The use as described in claim 18, wherein the disease related to the activity and expression of complement factor B is selected from one or more of IgA nephropathy (IgAN), C3 glomerular disease (C3G), atypical hemolytic uremic syndrome (aHUS), membranous nephropathy (MN), paroxysmal nocturnal hemoglobinuria (PNH), age-related macular degeneration (AMD), geographic atrophy (GA), hemodialysis complications, neuromyelitis (NMO), liver disease, inflammatory bowel disease and myasthenia gravis (MG).