Preparation, application and application of benzo spiro indole compound

Abstract

The invention discloses preparation, application and application of a benzo spiro indole compound, and particularly discloses a compound as shown in a formula (I), an optical isomer or pharmaceutically acceptable salt of the compound, and application of the compound to treatment and / or prevention of complement factor B activity and expression quantity related diseases. # imgabs0 #

Description

Preparation, application and use of benzospiroindole compounds

[0001] The present invention claims the following priority:

[0002] Application number CN 202211516706.4, filing date November 29, 2022;

[0003] Application number CN 202311563895.5, application date November 21, 2023. Technical Field

[0004] The present invention belongs to the field of medicinal chemistry, and in particular, relates to the preparation, application and use of benzospiroindole compounds. Background Art

[0005] The complement system is a crucial component of the innate immune system, comprising a group of proteins that normally exist in an inactive state. These proteins are organized into 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 known as C3-convertase and C5-convertase. The classical pathway is a calcium / magnesium-dependent cascade that is typically activated by the formation of antigen-antibody complexes. It can also be activated in an antibody-independent manner by the binding of ligand-complexed C-reactive protein and by many pathogens, including Gram-positive bacteria. The alternative pathway is a magnesium-dependent cascade that is activated by the deposition and activation of C3 on certain sensitive surfaces, such as yeast and bacterial cell wall polysaccharides, and certain biopolymer materials.

[0006] Currently, there is little research on the treatment of diseases or disorders associated with increased complement activity, and more and more relevant research is needed.

[0007] Summary of the Invention

[0008] 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,

[0009] in,

[0010] X is selected from C(R5)2, O or N(R5);

[0011] R1 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Heteroalkyl and C 3-9 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl or C 3-9Cycloalkyl is optionally substituted with 1, 2 or 3 R;

[0012] R2 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, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;

[0013] L is selected from a single bond, O, S, NH, The NH, Optionally substituted with 1, 2 or 3 R;

[0014] R3 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, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;

[0015] R4 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, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;

[0016] Alternatively, R3 and R4 are connected together to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;

[0017] R5 is selected from H, F, Cl, CN, OH, C 1-6 Alkyl, C 1-6 Heteroalkyl and C 3-9 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl or C 3-9 Cycloalkyl is optionally substituted with 1, 2 or 3 R;

[0018] R6 is selected from H, OH, CN, F, Cl, Br, I, C1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, the C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl is optionally substituted with 1, 2 or 3 R;

[0019] 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;

[0020] The C 1-6 The heteroalkyl or 3-6 membered heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

[0021] The present invention also provides the following compound, its optical isomer or its pharmaceutically acceptable salt, whose structure is shown below:

[0022] in,

[0023] L, R1, R2, R3, R4, R5 and R6 are as defined above.

[0024] In some embodiments of the present invention, R1 is selected from H, OH, CN, F, Cl, Br, I, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino and C 3-6 Cycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino or C 3-6 The cycloalkyl group is optionally substituted with 1, 2 or 3 R groups, and the other variables are as defined herein.

[0025] In some embodiments of the present invention, R1 is selected from H, OH, CN, F, Cl, Br, I, CH3, Other variables are as defined in the present invention.

[0026] In some embodiments of the present invention, R2 is selected from H, OH, CN, F, Cl, Br, I, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C1-4 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R groups, and the other variables are as defined herein.

[0027] In some embodiments of the present invention, R2 is selected from H, OH, CN, F, Cl, Br, I, CH3, Other variables are as defined in the present invention.

[0028] In some embodiments of the present invention, R3 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 The alkylthio or 3-6 membered heterocycloalkyl group is optionally substituted with 1, 2 or 3 R groups, and the other variables are as defined herein.

[0029] In some embodiments of the present invention, R3 is selected from H, OH, CN, F, Cl, Br, I, CH3, Other variables are as defined in the present invention.

[0030] In some embodiments of the present invention, the structural unit Selected from H, OH, CN, F, Cl, Br, I, CH3, Other variables are as defined in the present invention.

[0031] In some embodiments of the present invention, R4 is selected from H, OH, CN, F, Cl, Br, I, C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino and 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3The alkylamino or 3-6 membered heterocycloalkyl group is optionally substituted with 1, 2 or 3 R groups, and the other variables are as defined herein.

[0032] In some embodiments of the present invention, R4 is selected from H, OH, CN, F, Cl, Br, I, CH3, The CH3, Optionally substituted with 1, 2 or 3 R.

[0033] In some embodiments of the present invention, R4 is selected from H, OH, CN, F, Cl, Br, I, CH3, Other variables are as defined in the present invention.

[0034] It is understood that in the present invention, R3 and R4 are connected together to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl refers to R3 and R4 connected together to form a C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl.

[0035] In some embodiments of the present invention, R3 and R4 are linked together to form described It is optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0036] In some embodiments of the present invention, R3 and R4 are linked together to form Other variables are as defined in the present invention.

[0037] In some embodiments of the present invention, R5 is selected from H, F, Cl, CN, OH, CH3, Other variables are as defined in the present invention.

[0038] The present invention also provides a compound of the following formula, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or an isotope thereof, which is selected from:

[0039] In yet another aspect of the present invention, the present invention further provides a pharmaceutical composition. In some embodiments of the present invention, the pharmaceutical composition protects the aforementioned compound, its optical isomers or pharmaceutically acceptable salts thereof.

[0040] In some embodiments of the present invention, the pharmaceutical composition further comprises a pharmaceutical excipient.

[0041] In another aspect of the present invention, the present invention also provides the use of the above-mentioned compound, its optical isomer or pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of drugs for treating and / or preventing diseases related to complement factor B activity and expression.

[0042] The object of the present invention is to provide a compound as a complement factor B inhibitor or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and their use in the preparation of drugs for treating diseases related to complement factor B activity and expression.

[0043] 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 kidney diseases or disorders with significant unmet needs, including IgA nephropathy (IgAN), C3 glomerulopathy (C3G), atypical hemolytic uremic 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.

[0044] Definition and Description

[0045] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0046] As used herein, the phrase "at least one" 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 elements specifically identified in the list of elements to which the phrase "at least one" refers may optionally be present, whether related or unrelated to those specifically identified elements.

[0047] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0048] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat 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 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, bisulfate, hydroiodic acid, phosphorous acid, and the like; 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; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0049] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0050] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds. For example, Can be selected from wait.

[0051] A hyphen ("-") that is not between two letters or symbols indicates the site of attachment of a substituent. For example, C 1-6 Alkylcarbonyl - refers to a C-alkyl group attached to the rest of the molecule through a carbonyl group. 1-6 However, when the attachment point of the substituent is obvious to those skilled in the art, for example, a halogen substituent, the "-" may be omitted.

[0052] When the group valence bond is marked with a dotted line When, for example, In the example, the dashed line represents the point of attachment of the group to the rest of the molecule. When, for example, In the example, the dotted line represents a single bond or its absence, which also means Represents a single bond or double bond

[0053] The term "substituted" or "substituted with" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. The term "optionally substituted" or "optionally substituted with" means that the atom may or may not be substituted. Unless otherwise specified, the type and number of substituents may be any based on chemical practicability.

[0054] 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 1, 2, or 3 R's, the group may optionally be substituted with 1, 2, or 3 R's, with each occurrence of R' being an independent choice. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0055] 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 L1 represents a single bond, it means that the structure is actually

[0056] When the substituents listed do not specify through which atom they are connected to the substituted group, such substituents can be bonded through any atom thereof. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0057] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -CH2O-, in which case -CH2O- can connect phenyl and cyclopentyl in the same direction as reading from left to right to form It is also possible to connect phenyl and cyclopentyl groups in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0058] Unless otherwise specified, the number of ring atoms refers to the number of atoms that make up the ring itself in a compound (such as a monocyclic compound, a paracyclic compound, a spirocyclic compound, a bridged ring compound, a cross-linked compound, a carbocyclic compound, or a heterocyclic compound) formed by atoms bonded together to form a ring. The number of ring atoms is usually defined as the number of ring members. For example, a "3-6 membered ring" refers to a "ring" with 3-6 atoms arranged around it. 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.

[0059] Unless otherwise specified, the term "alkyl" refers to a saturated hydrocarbon group containing primary (normal) carbon atoms, secondary carbon atoms, tertiary carbon atoms, quaternary carbon atoms, or a combination thereof, which can represent a straight chain and / or branched alkyl group, which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Unless otherwise specified in the specification, the alkyl group may be optionally substituted.

[0060] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6 and C5 alkyl, etc.; which can be monovalent (such as CH3), divalent (-CH2-) or polyvalent (such as ). C 1-6 Examples of alkyl groups include, but are not limited to, CH3, wait.

[0061] Unless otherwise specified, the term “C 1-4 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 Alkyl groups include C 1-2 、C 1-3 、C 3-4 and C 2-3 Alkyl, etc.; it can be monovalent (such as CH3), divalent (-CH2-) or polyvalent (such as ). C 1-4 Examples of alkyl groups include, but are not limited to, CH3, wait.

[0062] Unless otherwise specified, the term "alkenyl" refers to a group containing a carbon-carbon sp 2A double-bonded hydrocarbon group may represent a straight and / or branched alkenyl group, wherein a branched group refers to one or more alkyl groups such as methyl, ethyl or propyl groups attached to a straight alkenyl chain. It may be monovalent, divalent or polyvalent. Unless otherwise specifically stated in the specification, an alkenyl group may be optionally substituted.

[0063] Unless otherwise specified, “C 2-6 "Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-6 Alkenyl groups include C 2-4 、C 2-3 , C4, C3 and C2 alkenyl, etc.; which may be monovalent, divalent or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylenyl, hexadienyl, ethenylene, propenylene, sec-butenylene, and the like.

[0064] 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. 2-3 Alkenyl includes C3 and C2 alkenyl; the C 2-3 Alkenyl groups can be monovalent, divalent, or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to wait.

[0065] Unless otherwise specified, the term "alkynyl" refers to a hydrocarbon group containing at least one unsaturated site, i.e., a carbon-carbon sp triple bond. It can represent a straight and / or branched alkynyl group, where a branched chain refers to one or more alkyl groups, such as methyl, ethyl, or propyl, attached to a straight alkynyl chain. It can be monovalent, divalent, or polyvalent. Unless otherwise specified in the specification, an alkynyl group may be optionally substituted.

[0066] Unless otherwise specified, “C 2-6 "Alkynyl" is used to represent a linear or branched hydrocarbon 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 groups include 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, C6, C5, C4, C3 and C2 alkynyl. 2-6 Examples of alkynyl groups include, but are not limited to wait.

[0067] Unless otherwise specified, “C 2-3 "Alkynyl" is used to represent 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 groups include C3 and C2 alkynyl groups. 2-3 Examples of alkynyl groups include, but are not limited to wait.

[0068] Unless otherwise specified, the term "oxo" refers to an oxygen atom doubly bonded to a carbon atom or another element, including a nitrogen atom of a pyridine ring, to form a pyridine N-oxide. For example, the term "oxo 5-6 membered heteroaryl" includes but is not limited to

[0069] Unless otherwise specified, the term "heteroalkyl" by itself or in combination with another term means 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 defined as 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 group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-. In some embodiments, the heteroalkyl group is C 1-6 In other embodiments, the heteroalkyl group is C 1-3Heteroalkyl. 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, -OCHCH, -OCHCHCH, -OCH(CH), -CH-CH-O-CH, -NHCH, -N(CH), -NHCHCH, -N(CH)(CHCH), -CH-CH-NH-CH, -CH-CH-N(CH)-CH, -SCH, -SCHCH, -SCHCHCH, -SCH(CH), -CH-S-CH-CH, -CH-CH, -S(=O)-CH, -CH-CH-S(=O)-CH, etc.; up to two heteroatoms thereof may be consecutive, for example, -CH-NH-OCH. Unless stated otherwise specifically in the specification, a heteroalkyl group may be optionally substituted.

[0070] Unless otherwise specified, the term "alkoxy" refers to an alkyl group attached to the rest of the molecule via an oxygen atom, wherein "alkyl" in "alkyl group" is as defined above in the present invention. Unless otherwise specified in the specification, an alkoxy group may be optionally substituted.

[0071] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentyleneoxy, and the like.

[0072] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-3 、C 1-2 、C 2-3 , C1, C2 and C3 alkoxy, etc. 1-3Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), methyleneoxy, ethyleneoxy, propyleneoxy, and the like.

[0073] Unless otherwise specified, the term "amino" may be a monovalent Two-price or multi-price

[0074] Unless otherwise specified, the term "alkylamino" refers to an alkyl group attached to the rest of the molecule via an amino group as defined above, wherein "alkyl" in "alkyl group" has the same meaning as described above in the present invention. Unless otherwise specified in the specification, an alkylamino group may be optionally substituted.

[0075] Unless otherwise specified, the term “C 1-6 "Alkylamino" means an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an amino group. 1-6 Alkylamino groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4, C3 and C2 alkylamino, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0076] Unless otherwise specified, the term “C 1-3 "Alkylamino" means an alkyl group containing 1 to 3 carbon atoms which is attached to the rest of the molecule via an amino group. 1-3 Alkylamino groups include C 1-3 、C 1-2 、C 2-3 , C1, C2 and C3 alkylamino, etc. 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0077] Unless otherwise specified, the term "alkylthio" refers to an alkyl group attached to the rest of the molecule via a sulfur atom, wherein "alkyl" in "alkyl group" has the same meaning as described above in the present invention. Unless otherwise specified in the specification, an alkylthio group may be optionally substituted.

[0078] Unless otherwise specified, the term “C 1-6 "Alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-6 Alkylthio includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4, C3 and C2 alkylthio, etc. 1-6 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0079] Unless otherwise specified, the term “C 1-3 "Alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-3 Alkylthio includes C 1-3 、C 1-2 、C 2-3 , C1, C2 and C3 alkylthio, etc. 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0080] Unless otherwise specified, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic saturated hydrocarbon group composed of carbon and hydrogen atoms, which may include cyclic, spirocyclic and / or bridged ring systems. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyls include, but are not limited to, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. "C 4-6 "Cycloalkyl" means a cycloalkyl group having 4 to 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.

[0081] Unless otherwise specified, “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic ring system. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0082] Unless otherwise specified, the term "heterocycloalkyl" refers to a non-aromatic saturated cyclic group that exists as a monocyclic, fused, 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), the nitrogen heteroatom is optionally quaternized, and in other embodiments, each occurrence of the heteroatom group 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 positioned 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 stated otherwise specifically in the specification, the heterocycloalkyl group may be optionally substituted.

[0083] Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which 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). This includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "3-6 membered heterocycloalkyl", the heteroatom or heteroatom group may be located at any interior position of the heterocycloalkyl, including the position at which 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 heterocycloalkyls, etc.

[0084] Unless otherwise specified, the term "3-9 membered heterocyclyl" by itself or in combination with other terms means a saturated or partially unsaturated cyclic group consisting of 3 to 9 ring atoms, 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 ring systems, wherein bicyclic ring systems include spirocyclic, cyclic and bridged rings. In addition, with respect to the "3-9 membered heterocyclic group", heteroatoms can occupy the connection position of the heterocyclic group to the rest of the molecule. The 3-9 membered heterocyclic group includes 3-8, 3-7, 3-6, 3-5, 3-4, 4-5, 4-6, 4-7, 4-8, 4-9, 5-6, 5-7, 5-8, 5-9, 6-7, 6-8, 6-9, 7-8, 3, 4, 5, 6, 7, 8 and 9 membered heterocyclic groups. Examples of 3-9 membered heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

[0085] Unless otherwise specified, the term "3-6 membered heterocyclyl" by itself or in combination with other terms means a saturated or partially unsaturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which 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 ring systems, wherein the bicyclic ring system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "3-6 membered heterocyclic group", a heteroatom may occupy the position where the heterocyclic group is connected 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, azetidinyl, oxetanyl, thietanyl, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

[0086] Unless otherwise specified, the term "5-6 membered heterocyclyl" by itself or in combination with other terms means a saturated or partially unsaturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which 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 ring systems, wherein the bicyclic ring system includes spirocyclic, fused and bridged rings. In addition, with respect to the "5-6 membered heterocyclic group", a heteroatom may occupy the position where the heterocyclic group is connected 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, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

[0087] Unless otherwise specified, the terms "5-9 membered heteroaromatic ring" and "5-9 membered heteroaryl" are used interchangeably in the present invention. The term "5-9 membered heteroaryl" refers to a monocyclic group with a conjugated π electron system consisting of 5 to 9 ring atoms, 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 are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). 5-9 yuan of heteroaryl can be connected to the rest of the molecule by heteroatom or carbon atom. The 5-9 yuan of heteroaryl includes 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-9 yuan, 6-8 yuan, 6-7 yuan, 5 yuan and 6 yuan of heteroaryl. The example of the 5-9 yuan of heteroaryl includes but is not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl 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.).

[0088] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably in the present invention. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π electron system consisting of 5 to 6 ring atoms, 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 are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). 5-6 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl 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.).

[0089] 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, examples of which include but are not limited to wait.

[0090] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1- 3. C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12 etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, 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.

[0091] As used herein, the term "substituted" 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 bond to a non-hydrogen atom, including but not limited to halogen atoms (e.g., F, Cl, Br, I), oxygen-containing groups (e.g., hydroxyl, alkoxy, ester groups), sulfur-containing groups (e.g., thiol, thioalkyl, sulfone, sulfonyl, sulfoxide groups), nitrogen-containing groups (e.g., amine, amide, alkylamino, dialkylamine, arylamine, aryl-alkyl-amine, diarylamine, N-oxide groups, imide, enamine groups), silicon-containing groups (e.g., trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl), and other heteroatoms in various other groups.

[0092] As used herein, the term "substituted" 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 (e.g., double bond or triple bond) of a heteroatom, such as the oxygen in carbonyl, carboxyl, and ester groups, and the nitrogen in imines, oximes, hydrazones, and nitriles. For example, "substituted" means that one or more hydrogen atoms in any of the above groups are replaced by -NR g R h 、-NR g C(=O)R h 、-NR g C(=O)NR g R h 、-NR g C(=O)OR h 、-NR g SO2R h 、-OC(=O)NR g R h 、-OR g 、-SR g 、-SOR g 、SO2R g 、-OSO2R g 、-SO2OR g , =NSO2R g With -SO2NR g R h Substituted. "Substituted" may also mean that one or more hydrogen atoms in any of the above groups are replaced by -C(=O)R g 、-C(=O)OR g 、-C(=O)NR g R h 、-CH2SO2R g 、-CH2SO2NRg R h The R g With R h Identical or different, independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxyl, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic radical, N-heterocyclic radical, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, heteroaryl-alkyl." substituted " can also represent that one or more hydrogen atoms in any of the above-mentioned groups are replaced by amino, cyano, hydroxyl, imino, nitro, oxo, thio, halogen, alkyl, alkenyl, alkynyl, alkoxyl, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic radical, N-heterocyclic radical, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, heteroaryl-alkyl. In addition, each of the above-mentioned substituents can also be optionally replaced by one or more of the above-mentioned substituents.

[0093] 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 (e.g., an affine substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chloro, bromo, iodo; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, etc.; acyloxy groups such as acetoxy and trifluoroacetoxy, etc.

[0094] The term "protecting group" includes, but is not limited to, an "amino protecting group," a "hydroxy protecting group," or a "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., 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-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions at the hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., 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), and the like.

[0095] It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and therefore exist as two or more stereoisomers. Therefore, the compounds of the present invention may exist as single stereoisomers (e.g., enantiomers, diastereomers) and mixtures thereof in any proportion, such as racemates, and, where appropriate, as tautomers and geometric isomers.

[0096] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, are contemplated by the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0097] As used herein, the term "stereoisomers" refers to compounds that have identical chemical constitution but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, and conformers, among others.

[0098] As used herein, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0099] As used herein, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, or biological activities. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography, such as HPLC.

[0100] Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign of the compound's rotation of plane polarized light, where (-) or l indicate that the compound is left-handed. Compounds with a prefix of (+) or d are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers can also be referred to as enantiomers, and mixtures of such isomers are commonly referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur in chemical reactions or methods without stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that do not have optical activity.

[0101] The racemic mixture can be used as is or resolved into its individual isomers. Resolution can 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 chromatography using chiral adsorbents. Individual isomers can be prepared in chiral form from chiral precursors. Alternatively, the individual isomers can be chemically separated from the mixture by forming diastereomeric salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salts, then liberating one or both of the resolved bases, and optionally repeating this process to obtain one or both isomers 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 racemates can be covalently linked to chiral compounds (auxiliaries) to obtain diastereomers.

[0102] 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 readily interconvert into each other. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0103] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0104] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0105] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0106] The solvent used in the present invention is commercially available.

[0107] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names.

[0108] 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, and the compound is a single-configuration enantiomer monomer, or a single-configuration diastereoisomer monomer, or a diastereoisomer mixture 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 compound disclosed in the present invention has not been identified, such compounds can be identified based on their corresponding retention time (R configuration) under corresponding chromatographic column conditions (for example, chromatographic column model, chromatographic column filling material, chromatographic column size, mobile phase, etc.). T ) to confirm.

[0109] The present invention is explained in more detail in the following examples. However, it should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention in any way. The experimental methods in the following examples, unless otherwise specified, generally follow conventional conditions for such reactions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight. Unless otherwise stated, liquid ratios are by volume.

[0110] Technical and scientific terms used herein without specific definition have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. BRIEF DESCRIPTION OF THE DRAWINGS

[0111] FIG1 is a bar graph showing the results of a pharmacodynamic experiment of a compound according to an example of the present invention in LPS-induced AP activation mice. DETAILED DESCRIPTION

[0112] The present application is described in detail below by way of examples, but this does not necessarily mean that there are any adverse limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0113] Unless otherwise specified, the raw materials used in the present invention are commercially available.

[0114] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker ASCEND TM-400 NMR spectrometer, the determination solvents were deuterated sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0115] MS was determined using Agilent 6110, Agilent 1100, Agilent 6120, and Agilent 6125B liquid chromatography-mass spectrometers.

[0116] HPLC analysis was performed using a Shimadzu HPLC-2010C high pressure liquid chromatograph (XBRIDGE 2.1*50 mm, 3.5 μm column).

[0117] Chiral HPLC analysis was performed using THARSFC X5.

[0118] The thin layer chromatography silica gel plate used was Yantai Qingdao GF254 silica gel plate. The specifications of the silica gel plate used in thin layer chromatography (TLC) were 0.15mm-0.2mm, and the specifications used for thin layer chromatography separation and purification products were 0.4mm-0.5mm.

[0119] Column chromatography generally uses Qingdao Marine Silica Gel 200-300 mesh silica gel as the carrier.

[0120] High performance liquid phase preparation used Waters2767, Waters2545, and Chuangxin Hengtong LC3000 preparative chromatographs.

[0121] Chiral preparative column chromatography used Shimadzu LC20-AP and THARSFC PREP80.

[0122] The pressurized hydrogenation reaction used a Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0123] A Biotage initiator+ microwave reactor was used for the microwave reaction.

[0124] Unless otherwise specified in the experimental examples, all reactions were carried out under an argon or nitrogen atmosphere.

[0125] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 liter.

[0126] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1 liter.

[0127] Unless otherwise specified in the experimental examples, the reaction temperature was room temperature, which ranged from 20°C to 30°C.

[0128] Example 1: Synthesis of Compound 1

[0129] Step 1: Preparation of compound 1-2

[0130] The starting 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°C under a Dean-Stark trap for 5 hours 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 was used directly in the next reaction. The crude yield was 100%. MS (ESI) m / z [M+H] + =304.2.

[0131] Step 2: Preparation of compound 1-3

[0132] Under nitrogen, 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 refluxed under a Dean-Stark trap for 1 hour to remove moisture. A toluene solution (30 mL) of compound 1-2 (7.97 g, 26.27 mmol) was then added dropwise. After complete addition, the reaction mixture was stirred at 140°C for 30 minutes until completion. After cooling, the reaction was quenched with saturated aqueous sodium carbonate solution and extracted with ethyl acetate (20 mL x 2). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the crude product. The crude product was purified on a silica gel column (eluent: dichloromethane:methanol = 10:1) to afford compound 1-3 (3.40 g) in a yield of 42.6%. MS (ESI) m / z [M+H] + =304.2.

[0133] Step 3: Preparation of Compound 1-4

[0134] 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 stirred at room temperature for 1 hour until the reaction was complete. The reaction solution was concentrated in vacuo, and the resulting oil was dissolved in ethyl acetate and washed with saturated aqueous sodium carbonate. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a crude product of compound 1-4 (500 mg), which was used directly in the next reaction. The crude product yield was 97.5%. MS (ESI) m / z [M+H] + =260.2.

[0135] Step 4: Preparation of Compound 1-5

[0136] Compound 1-4 (3.5 g, 13.50 mmol) was dissolved in a mixture of Boc2O (5.83 g, 27.00 mmol) and TEA (1.88 g, 18.58 mmol, 2.59 mL). The reaction mixture was heated to 55°C and stirred for 1 hour until the reaction of the raw materials was complete. After the reaction mixture was cooled to room temperature, it was directly separated and purified on 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%.

[0137] 1 HNMR(400MHz, Methanol-d4)δ7.85–7.72(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.

[0138] Step 5: Preparation of Compound 1-6

[0139] Compound 1-5 (370 mg, 1.03 mmol) was dissolved in EtOH (5 mL) and cooled to -10°C. NaBH4 (38.95 mg, 1.03 mmol) was slowly added portionwise. The reaction mixture was then warmed to room temperature and stirred for 1 hour until the reaction was complete. The reaction mixture was concentrated in vacuo and quenched with saturated brine. The product was extracted with ethyl acetate (5 mL x 2). The organic phase was washed with saturated ammonium chloride, separated, and dried over anhydrous sodium sulfate. After vacuum concentration and drying, compound 1-6 (368.0 mg) was obtained, which was used directly in the next reaction with a yield of 99%.

[0140] 1 H NMR(400MHz,DMSO-d6)δ7.83-7.72(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.

[0141] Step 6: Preparation of Compound 1-7

[0142] Under nitrogen, compound 1-6 (900 mg, 2.49 mmol) was dissolved in DMF (10 mL). NaH (597.57 mg, 14.94 mmol, 60% purity) was slowly added at room temperature. The mixture was stirred for 5 minutes, and then 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. The reaction was then quenched by the addition of aqueous ammonium chloride. The product was extracted with ethyl acetate (10 mL x 2). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to obtain compound 1-7 (640 mg) in a yield of 66%. MS (ESI) m / z [M+H] + =390.2.

[0143] Step 7: Preparation of Compound 1-8

[0144] Compound 1-7 (900 mg, 2.31 mmol) was dissolved in DCM (9 mL) at room temperature, and 2,6-lutidine (742.81 mg, 6.93 mmol) and TMSOTf (769.48 mg, 3.47 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour until the reaction was complete. Saturated aqueous sodium carbonate 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 was used directly in the next reaction with a yield of 100%. MS (ESI) m / z [M+H] + =290.2.

[0145] Step 8: Preparation of Compound 1-9

[0146] Tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (785.32 mg, 2.70 mmol) was dissolved in DCM (8 mL). PPh3Br2 (1.48 g, 3.50 mmol) in dichloromethane (5 mL) was added at 0°C under nitrogen. The reaction mixture was stirred at 0°C for 1 hour. Compound 1-8 (600 mg, 2.07 mmol) and DIEA (905.78 mg, 7.01 mmol) in dichloromethane (4 mL) were then added. The reaction mixture was stirred at room temperature for another 2 hours until the reaction was complete. The reaction mixture was quenched with water and the product was extracted with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to yield the crude product. The crude product was purified on a silica gel column (eluent: petroleum ether:ethyl acetate = 5:1) to afford 945 mg of compound 1-9 in an 81% yield. MS (ESI) m / z [M+H] + =563.4.

[0147] Step 9: Preparation of Compound 1-10

[0148] Compound 1-9 (1.1 g, 1.95 mmol) was dissolved in a mixture of MeOH (3 mL) / THF (3 mL) / water (3 mL). NaOH (781.89 mg, 19.55 mmol) was added with stirring. The reaction mixture was then heated to 60°C and stirred for 2 hours until the reaction was complete. After cooling to room temperature, the reaction mixture was adjusted to pH 6.0 with aqueous citric acid solution. The product was then extracted with ethyl acetate (10 mL x 3). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain compound 1-10 (873.6 mg). The crude yield was 100%. MS (ESI) m / z [M+H] + =449.2.

[0149] Step 10: Preparation of Compound 1-11

[0150] Compound 1-10 (873.6 mg) was isolated and purified by HPLC (Separation conditions: Column: Agilent 10Prep-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 (as the second peak), with a yield of 55%. MS (ESI) m / z [M+H] + =449.2.

[0151] Step 11: Preparation of Compound 1

[0152] The racemic compound 1-11 (36 mg) was chirally separated and purified by SFC (SFC preparation method: instrument: MG II preparative SFC (SFC-13), column model: ChiralPak IC, 250×30 mm ID, 10 μm, mobile phase: A-CO2, B-ethanol (0.1% NH3·H2O), gradient: B 50%, flow rate: 80 mL / min, back pressure: 100 bar, column temperature: 38°C, wavelength: 220 nm, cycle: ~12 min) to give 14.7 mg of chiral compound 1 (as the first peak) (analytical method: instrument: Waters UPC2analytical SFC (SFC-H), column model: ChiralPak IC, 100×4.6 mm ID, 3 μm, mobile phase: A-CO2, B-ethanol (0.05% DEA), gradient: B 50%, flow rate: 2.5 mL / min, back pressure: 100 bar, column temperature: 35° C., wavelength: 220 nm), and the yield was 41%.

[0153] 1 H NMR (400MHz, Methanol-d4) δ7.98(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.

[0154] Example 2: Synthesis of Compound 2

[0155] Step 1: Preparation of compound 2-1

[0156] Under nitrogen, compound 1-6 (1 g, 2.49 mmol) was dissolved in DMF (11 mL). NaH (597.71 mg, 14.94 mmol, 60% purity) was slowly added, and the mixture was stirred at room temperature for five minutes. (Iodomethyl)cyclopropane (0.96 g, 4.98 mmol) was then added. The reaction mixture was heated to 60°C and stirred for 30 minutes. (Iodomethyl)cyclopropane (0.96 g, 4.98 mmol) was then added until compound 1-6 was completely reacted. The reaction mixture was cooled to room temperature and quenched with aqueous ammonium chloride. The product was extracted with ethyl acetate (10 mL x 2). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to afford 853 mg of compound 2-1 in an 82% yield. MS (ESI) m / z [M+H] + =416.2.

[0157] Step 2: Preparation of compound 2-2

[0158] Compound 2-1 (1 g, 2.19 mmol) was dissolved in DCM (10 mL), and 2,6-lutidine (705.59 mg, 6.58 mmol) and TMSOTf (974.57 mg, 4.39 mmol) were added at room temperature. The mixture was stirred for 1 hour until the reaction of the starting materials was complete. Aqueous sodium carbonate solution was added to quench the reaction. The product was extracted with DCM (5 mL × 2). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain 690 mg of compound 2-2, with a yield of 100%; MS (ESI) m / z [M+H] + =316.2.

[0159] Step 3: Preparation of compound 2-3

[0160] Under nitrogen, tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (800 mg, 2.74 mmol) was dissolved in DCM (8 mL). The mixture was cooled to 0°C and a dichloromethane solution (5 mL) of PPh3Br2 (1.50 g, 3.57 mmol) was added. The reaction mixture was stirred at 0°C for 1 hour, followed by the addition of a dichloromethane solution (4 mL) of compound 2-2 (750 mg, 2.11 mmol) and DIEA (1.09 g, 8.44 mmol). The reaction mixture was warmed to room temperature and stirred for 2 hours until the reaction was complete. The reaction was then quenched with water and the product was extracted with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate = 5:1) to afford 0.95 g of compound 2-3 in a yield of 76.5%. MS (ESI) m / z [M+H]+ =589.4.

[0161] Step 4: Preparation of compound 2-4

[0162] Compound 2-3 (1.0 g, 1.70 mmol) was dissolved in a mixture of MeOH (3 mL) / THF (3 mL) / water (3 mL). NaOH (636 mg, 15.90 mmol) was added, and the reaction mixture was heated to 60°C and stirred for 4 hours. After cooling, the reaction mixture was adjusted to pH 6.0 with aqueous citric acid solution. 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.

[0163] Step 5: Preparation of compound 2-5

[0164] Compound 2-4 (807.5 mg) was prepared, separated and purified by HPLC (separation conditions: chromatographic column: Agilent 10Prep-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%.

[0165] 1 H NMR (400MHz, Methanol-d4) δ8.10(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), 3.48-3.42(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.

[0166] Step 6: Preparation of Compound 2

[0167] The racemic compound 2-5 (530 mg) was chirally separated and purified by SFC (SFC preparation method: instrument: WATERS 150preparative SFC (SFC-26), column model: ChiralPak IC, 250×30 mm ID, 10 μm, mobile phase: A-CO2, B-ethanol (0.1% NH3·H2O), gradient: B 50%, flow rate: 130 mL / min, back pressure: 100 bar, column temperature: 38°C, wavelength: 220 nm, cycle: ~11 min) to give 238 mg of chiral compound 2 (analytical method: instrument: Waters UPC2analytical SFC (SFC-H), column model: ChiralPak IC, 100×4.6 mm ID, 3 μm, mobile phase: A-CO2, B-ethanol (0.05% DEA), gradient: B 50%, flow rate: 2.5 mL / min, back pressure: 100 bar, column temperature: 35°C, wavelength: 220 nm), and the yield was 45%.

[0168] 1 H NMR (400MHz, Methanol-d4) δ8.10(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), 3.48-3.42(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.

[0169] Example 3: Synthesis of Compound 3

[0170] Step 1: Preparation of compound 3-1

[0171] Under nitrogen, tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (73.0 mg, 0.25 mmol) was dissolved in dichloromethane (3 mL). A solution of dibromotriphenylphosphine (137 mg, 0.32 mmol) in dichloromethane (1 mL) was slowly added dropwise at 0°C. After addition, stirring was continued at 0°C for 1 hour. Compound 1-3 (41 mg, 0.14 mmol) and a solution of diisopropylethylamine (52.4 mg, 0.40 mmol) in dichloromethane (1 mL) were then added. The reaction mixture 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 on a silica gel column (petroleum ether:ethyl acetate = 3:1) to obtain compound 3-1 (25 mg) in a yield of 32.0%. MS (ESI) m / z [M+H] + =577.2.

[0172] Step 2: Preparation of compound 3

[0173] Under nitrogen, compound 3-1 (32.0 mg, 0.055 mmol) was dissolved in a mixture of methanol (0.5 mL), tetrahydrofuran (0.5 mL), and water (0.5 mL). Sodium hydroxide (22.20 mg, 0.55 mmol) was then added. The resulting mixture was heated to 60°C, stirred for 1 hour, and then cooled to room temperature. The pH was adjusted to 4.0 with saturated aqueous citric acid and extracted with ethyl acetate (2 mL x 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 (column: Welch xtimate C18 21.2 mm x 250 mm 10 μm; column temperature: 25°C; mobile phase: water (0.1% ammonium bicarbonate)-acetonitrile; mobile phase acetonitrile ratio 25%-55% in 18 min; flow rate: 30 mL / min) to afford compound 3 (5.90 mg) in a 23% yield. MS (ESI) m / z [M+H] + =463.2.

[0174] 1HNMR (400MHz, Methanol-d4) δ7.99(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).

[0175] Example 4: Synthesis of Compound 4

[0176] Step 1: Preparation of compound 4-2

[0177] Under nitrogen, 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 under reflux for 3 hours until the reaction was complete. The mixture was cooled to room temperature to obtain a reaction solution containing compound 4-2, which was used directly in the next step. The crude yield was 100%. MS (ESI) m / z [M+H] + =319.2.

[0178] Step 2: Preparation of compound 4-3

[0179] Under nitrogen, a solution of boron trifluoride in ether (221.88 mg, 0.75 mmol, 0.2 mL, 48% purity) was added to a dichloromethane (20.20 mL) solution of compound 4-2 obtained above (159.6 mg, 0.5 mmol). The resulting mixture was heated under reflux for 4 hours until the reaction was complete. After cooling to room temperature, the reaction was quenched by the addition of saturated aqueous NaHCO₃ (8 mL). 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) in a yield of 56.6%. MS (ESI) m / z [M+H] + =319.2.

[0180] Step 3: Preparation of compound 4-4

[0181] Under nitrogen, tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (73.0 mg, 0.25 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C, and dibromotriphenylphosphine (137.90 mg, 0.33 mmol) was added. After stirring for 1.5 hours, compound 4-3 (80 mg, 0.25 mmol) and diisopropylethylamine (97.44 mg, 0.75 mmol) were added. The mixture was stirred at 0°C for 1 hour, then warmed to room temperature and stirred for 6 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 chromatography (petroleum ether:ethyl acetate = 6:4) to obtain compound 4-4 (130 mg) in an 87.4% yield. MS (ESI) m / z [M+H] + =591.8.

[0182] Step 4: Preparation of compound 4

[0183] Under nitrogen, compound 4-4 (110 mg, 0.18 mmol) was dissolved in a mixture 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 and allowed to react for 2 hours until the reaction of the starting material was complete. The pH was adjusted to 4.0 with saturated aqueous citric acid solution and extracted with ethyl acetate (5 mL x 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) in a 52% yield. MS (ESI) m / z [M+H] + =478.2.

[0184] 1HNMR (400MHz, DMSO-d6) δ10.99–10.42(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),2.69–2.5 9(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).

[0185] Example 5: Synthesis of Compound 5

[0186] Step 1: Preparation of compound 5-2

[0187] Under nitrogen, compound 5-1 (615.5 mg, 3 mmol) was dissolved in DMF (10 mL). Sodium hydroxide (79.2 mg, 3.3 mmol) was added at 0°C. The mixture was allowed to react at room temperature for 30 minutes, followed by the addition of iodomethane (510.98 mg, 3.60 mmol). The resulting reaction solution was allowed to react at room temperature for 2 hours until complete. Water (5 mL) was added for quenching, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was 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 = 1:1) to afford compound 5-2 (510 mg) in a yield of 77.6%. MS (ESI) m / z [M+H] + =220.0.

[0188] 1 HNMR (400MHz, DMSO-d6) δ7.68 (qd, J=7.7, 0.9Hz, 2H), 7.56 (t, J=0.9Hz, 1H), 3.91 (s, 3H), 3.20 (s, 3H).

[0189] Step 2: Preparation of compound 5-3

[0190] 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 under reflux 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.

[0191] Step 2: Preparation of compound 5-4

[0192] Under nitrogen, a solution of boron trifluoride in ether (607.34 mg, 2.05 mmol, 0.54 ml, 48% purity) was added to a dichloromethane (20 mL) reaction solution of compound 5-3 obtained above (454.8 mg, 1.37 mmol). The resulting mixture was heated under reflux for 6 hours until the reaction was complete. After cooling to room temperature, the reaction was quenched by the addition of saturated aqueous NaHCO₃ (8 mL). The reaction solution was extracted with ethyl acetate (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 5-4 (300 mg) in a 66% yield. MS (ESI) m / z [M+H] + =333.0.

[0193] Step 3: Preparation of compound 5-5

[0194] Under nitrogen, tert-butyl 4-(hydroxymethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (114 mg, 0.39 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0°C. Dibromotriphenylphosphine (214.7 mg, 0.51 mmol) was added and stirred for 1.5 hours. Compound 5-4 (130.1 mg, 0.39 mmol) and diisopropylethylamine (151.7 mg, 1.17 mmol) were then added. The mixture was stirred at 0°C for 1 hour, then warmed to room temperature and stirred for 6 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 chromatography (petroleum ether:ethyl acetate = 7:3) to obtain compound 5-5 (125 mg) in a yield of 52.7%. MS (ESI) m / z [M+H] + =606.0.

[0195] Step 4: Preparation of compound 5

[0196] Under nitrogen, compound 5-5 (100 mg, 0.165 mmol) was dissolved in a mixture 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 reaction was complete. The pH was adjusted to 4.0 with saturated aqueous citric acid solution and extracted with ethyl acetate (5 mL x 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) in a 37% yield. MS (ESI) m / z [M+H] + =492.2.

[0197] 1 HNMR(400MHz,DMSO-d6)δ10.77(s,1H),7.94(d,J=7.9Hz,1H),7.75(dd,J=7.8,1.5Hz,1H), 7.52(d,J=1.5Hz,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).

[0198] Biological Examples

[0199] Experimental Example 1: Human Complement Factor B Protein Binding Assay (TR-FRET Method)

[0200] Preparation buffer consists of 50 mM Tris-HCl, pH 7.0, 50 mM NaCl, and 0.01% w / v Triton X-100. Test compounds were first diluted 3-fold with DMSO. Then, 0.6 μL was pipetted into a 96-well plate. 99.4 μL of buffer was added and mixed thoroughly by pipetting. 2.5 μL of the diluted compound was transferred to a 384-well plate (ProxiPlate-384plus, PE). 90 nM His-FB protein (ab276729, Abcam) was prepared in buffer, and 2.5 μL was transferred to the 384-well plate containing the compound. 300 nM Cy5 fluorescently labeled probe was then prepared in buffer, and 5 μL was transferred to the 384-well plate. Finally, 5 μL of 15 nM LANCE Eu-anti-6xHis antibody (AD0110, Perkin Elmer) diluted in buffer was added. The plates were centrifuged at 1000 rpm for 30 seconds and incubated at room temperature for 2 hours in the dark. Fluorescence values ​​were read using Envision (Exc. Filter: UV2 (TRF) 320, Ems. Filter: APC665, 2nd ems. filter: LANCE Laser attenuated Europium filter, 50 μs delay), and the 665 nm / 615 nm ratio was calculated. Data were analyzed using GraphPad Prism 8 software, and the IC was calculated using the dose-response-inhibition (four-parameter) equation using GraphPad Prism software. 50 value.

[0201] Experimental results:

[0202] The IC50 values ​​of the test compounds for human complement factor B protein binding assay (TR-FRET method) are shown in Table 1, where A represents: IC50 value <100 nM; B represents: 100 nM ≤ IC50 value <1000 nM; C represents: IC50 value >1000 nM.

[0203] Table 1 Activity of compounds in human complement factor B protein binding assay (TR-FRET method)

[0204] Conclusion: The compounds of the present invention have significant binding activity to human complement Factor B protein.

[0205] Experimental Example 2: C3 protein hydrolysis experiment

[0206] 1. Prepare the CVF:Bb complex: First, prepare reaction buffer (10 mM MgCl2, 0.05% w / v CHAPS, PBS pH 7.4). Prepare a mixture of FD (A409, Quidel), FB (A408, Quidel), and CVF (A600, Quidel) to a final concentration of 300 nM in reaction buffer. Incubate at 37°C for 3 hours. Aliquot the digestion product and store at -80°C for subsequent experiments.

[0207] 2. C3 Hydrolysis Reaction: Compounds were first serially diluted three-fold in DMSO for a total of ten concentrations. Then, the mixture was diluted 40-fold in reaction buffer and 1 μL was transferred to a 384-well plate (ProxiPlate-384plus, PE). 2.5 nM CVF:Bb and 1 μM C3 (A401, Quidel) were prepared in reaction buffer. 2 μL of CVF:Bb was transferred to the ProxiPlate 384 well containing compound and incubated at 37°C for 30 minutes. The reaction was initiated by adding 2 μL of C3 and incubated at 37°C for 180 minutes. The 384-well plate was sealed during the reaction. The reaction was stopped by adding 5 μL of 2x protease inhibitor cocktail (5892970001, Roche) to each well. After mixing, 1.25 μL of the reaction solution was transferred to a 384-well black plate (OptiPlate-384F HB, PE). 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) was added. The plate was centrifuged at 1000 rpm for 1 minute and incubated at 4°C overnight for coating. The next day, the coated 384-well plate was discarded, patted dry on clean absorbent paper, and washed three times with PBST. 25 μL of starting block T20 (37539, Thermofisher) was added to each well and incubated at room temperature for 15 minutes. The supernatant was discarded and the plate was washed three times with PBST. Add 25 μL of 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 25 μL of Quantablu fluorogenic peroxidase substrate (15169, Thermofisher), centrifuge at 1000 rpm for 30 seconds. Incubate at room temperature for 30 minutes, and then use Envision (PE, Envision @2105) read the fluorescence value, the excitation wavelength was 340nm, and the emission wavelength was 460nm. Finally, the data were analyzed using GraphPad Prism8 software, and the IC was calculated using the dose-response-inhibition (four-parameter) equation using GraphPadPrism software. 50 value.

[0208] Experimental results:

[0209] The IC50 values ​​of the test compounds for C3 enzymatic hydrolysis experiments are shown in Table 2, where A represents: IC50 value <100 nM; B represents: 100 nM ≤ IC50 value <1000 nM; C represents: IC50 value >1000 nM, and LNP023 is the reference compound.

[0210] Table 2 Activity of compounds in C3 enzymatic hydrolysis assay

[0211] Conclusion: The compounds of the present invention have excellent in vitro activity and can significantly inhibit the hydrolytic activity of C3 enzyme.

[0212] Experimental Example 3: Drug Efficacy in LPS-Induced AP Activation Mice

[0213] 1. Experimental Purpose

[0214] The inhibitory effect of compounds on the alternative pathway (AP) activation of complement induced by bacterial lipopolysaccharide in C57 mice was evaluated by plasma C3d / iC3b / C3c / activated C3 assay.

[0215] 2. Experimental Materials

[0216] 2.1 Experimental Animals

[0217] 44 SPF female C57BL / 6J mice, weighing 16-19 g, 7 weeks old;

[0218] Source: Purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0219] 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

[0220] The Zhangjiang Animal Facility of Charles River Pharmaceuticals (Shanghai) Co., Ltd. is located at the 4th Floor, Building 2, 1077 Zhangheng Road, Pudong New Area, Shanghai. Animals were housed in a controlled environment with a temperature of 23 ± 2°C, a relative humidity of 40–70%, and lights on at 6 AM / 6 PM. Animals received free access to standard chow and sterile drinking water. All animal experiments were approved by the Animal Ethics Committee of Charles River Pharmaceuticals (Shanghai) Co., Ltd.

[0221] 2.2 Test drug and solvent

[0222] (1) Solvent formula: 0.5% MC + 0.5% Tween 80;

[0223] (2) Preparation of test drug: Add the compound to the solvent, stir ultrasonically to form a uniform solution / suspension, and prepare the required concentration.

[0224] 3. Experimental process

[0225] 3.1 After 3-7 days of animal adaptation, the animals were divided into groups according to the plan in Table 3 based on their body weight.

[0226] Table 3 Experimental groups

[0227] (Solvent: 0.5% MC+0.5% Tween 80)

[0228] 3.2 Salmonella enterica serovar Typhimurium lipopolysaccharide (LPS) was dissolved in sterile PBS to prepare a 200 μg / mL solution.

[0229] 3.3 According to the schedule in Table 3, the animals in each group were first injected intraperitoneally with 0.1 mL of PBS or LPS to establish the model, and then gavage with the solvent or the test compound.

[0230] 3.4 One hour after administration, animals in Groups 1 to 5 were euthanized with CO2 or anesthetized with isoflurane, and then blood was collected from the heart. EDTA-K2 was used as the anticoagulant.

[0231] 3.5 Place blood on wet ice and centrifuge at 4500g for 10 minutes at 4°C. Collect plasma and aliquot into two tubes, 10-50 μl / tube. Store in a -80°C freezer for determination of C3d / iC3b / C3c / activated C3 levels.

[0232] 4. Statistical methods

[0233] The experimental data were expressed as mean ± standard error (Means ± SEM) and analyzed by one-way ANOVA using Graphpad Prism 8.0 software. A p < 0.05 was considered to indicate a statistically significant difference.

[0234] 5. Experimental results

[0235] The experimental results are shown in Table 4 and Figure 1.

[0236] Table 4

[0237] Experimental conclusion: The compound of the present invention has excellent activity in animals and can inhibit the activation of the complement alternative pathway (AP) in C57 mice induced by bacterial lipopolysaccharide (LPS).

[0238] The above describes exemplary embodiments of the present invention. It should be understood that the scope of protection of this application is not limited to the above exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention should be included in the scope of protection of this application.

Claims

1. A compound represented by formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof, in, X is selected from C(R5)2, O or N(R5); R1 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Heteroalkyl and C 3-9 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl or C 3-9 Cycloalkyl is optionally substituted with 1, 2 or 3 R; R2 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, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R; L is selected from a single bond, O, S, NH, The NH, Optionally substituted with 1, 2 or 3 R; R3 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, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R; R4 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, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Heteroalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R; Alternatively, R3 and R4 are connected together to form C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R; R5 is selected from H, F, Cl, CN, OH, C 1-6 Alkyl, C 1-6 Heteroalkyl and C 3-9 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl or C 3-9 Cycloalkyl is optionally substituted with 1, 2 or 3 R; R6 is selected from H, OH, CN, F, Cl, Br, I, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, the C 1-6 Alkyl, C 2-6 Alkenyl or C 2-6 Alkynyl 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 The heteroalkyl or 3-6 membered heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

2. The compound according to claim 1, its optical isomer or a pharmaceutically acceptable salt thereof, whose structure is shown below, in, L, R1, R2, R3, R4, R5 and R6 are as defined in claim 1.

3. The compound according to claim 1 or 2, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from H, OH, CN, F, Cl, Br, I, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino and C 3-6 Cycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino or C 3-6 The cycloalkyl group is optionally substituted with 1, 2 or 3 R groups.

4. The compound according to claim 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from H, OH, CN, F, Cl, Br, I, CH3, 5. The compound according to 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, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R groups.

6. The compound according to claim 5, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R2 is selected from H, OH, CN, F, Cl, Br, I, CH3, 7. The compound according to 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, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and 3-6 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, C 1-6 The alkylthio or 3-6 membered heterocycloalkyl group is optionally substituted with 1, 2 or 3 R groups.

8. The compound according to claim 7, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R3 is selected from H, OH, CN, F, Cl, Br, I, CH3, 9. The compound according to claim 8, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from H, OH, CN, F, Cl, Br, I, CH3, 10. The compound according to 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, C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino and 3-6 membered heterocycloalkyl, the C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 The alkylamino or 3-6 membered heterocycloalkyl group is optionally substituted with 1, 2 or 3 R groups.

11. The compound according to claim 10, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R4 is selected from H, OH, CN, F, Cl, Br, I, CH3, The CH3, Optionally substituted with 1, 2 or 3 R.

12. The compound according to claim 11, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R4 is selected from H, OH, CN, F, Cl, Br, I, CH3, 13. The compound according to claim 1 or 2, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R3 and R4 are connected together to form described Optionally substituted with 1, 2 or 3 R.

14. The compound according to claim 13, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R3 and R4 are connected together to form 15. The compound according to claim 1 or 2, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R5 is selected from H, F, Cl, CN, OH, CH3, 16. A compound of the following formula, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or an isotope thereof, selected from the group consisting of:

17. A pharmaceutical composition, wherein The invention comprises the compound according to any one of claims 1 to 16, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

18. Use of the compound according to any one of claims 1 to 16, its optical isomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating and / or preventing diseases related to complement factor B activity and expression.

19. The use according to claim 18, wherein: The diseases related to complement factor B activity and expression are selected from one or more of IgA nephropathy (IgAN), C3 glomerulopathy (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 diseases, inflammatory bowel disease and myasthenia gravis (MG).

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