Bicyclic substituted aromatic carboxylic ester compound

Abstract

The invention discloses a bicyclic substituted aromatic carboxylic ester compound, and particularly discloses a compound as shown in a formula (I) and pharmaceutically acceptable salts thereof. # imgabs0 #

Description

Bicyclic substituted aromatic carboxylate compounds

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese invention patent application No. 202210658423.7 filed with the State Intellectual Property Office of China on June 10, 2022, and all the contents disclosed in the application are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to bicyclic substituted aromatic carboxylic acid ester compounds, and in particular to compounds represented by formula (I) or pharmaceutically acceptable salts thereof. Background Art

[0004] The complement system is a crucial component of the human body's innate immune system, defending against infections by foreign pathogens, bacteria, and parasites. It also plays a crucial role in connecting innate and adaptive immunity. Complement is composed of plasma proteins, including soluble proteins, membrane-bound proteins, and complement receptors. Complement is primarily produced by membrane proteins expressed in the liver or on the cell surface, and exerts its effects in plasma, tissues, or cells. The complement system is activated primarily through three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).

[0005] Under normal physiological conditions in healthy individuals, the AP pathway maintains a low level of activation to monitor the invasion of foreign pathogens. Complement proteins are distributed on the surface of apoptotic cells, and complement activation is strictly regulated, serving only to clear apoptotic cells without further activating other innate or adaptive immune responses. In the event of infection by foreign pathogens, the complement system is fully activated, generating inflammatory responses, opsonization, or phagocytosis, destroying the pathogens and ultimately activating the adaptive immune response. Both inefficient and overstimulated complement can be harmful to the human body and are associated with increased susceptibility to infections and non-infectious diseases, such as autoimmune diseases, chronic inflammation, thrombotic microangiopathy, transplant rejection, and tumors.

[0006] Complement factor B (Factor B) acts on the AP pathway. Inhibiting Factor B activity can prevent activation of the API pathway without interfering with the CP and LP pathways, thus avoiding the increased risk of infection due to complement system inhibition. Currently, there are no small molecule Factor B inhibitors on the market. Novartis' Factor B inhibitor LNP023 is in Phase III clinical trials for the treatment of diseases such as PNH, IgAN, and C3G. Therefore, it is necessary to develop new small molecule inhibitors of the complement system Factor B, increase clinical research and verification, and use them for the treatment of various diseases caused by complement abnormalities, providing new treatment options for unmet clinical needs.

[0007] Summary of the Invention

[0008] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0009] in,

[0010] T1 and T2 are each independently selected from CH or N;

[0011] R1, R5, R6, R8, R9 and R 10 are independently selected from H or D;

[0012] R2 and R3 together with the atoms to which they are attached form a 3-6 membered heterocyclic group, in which case R4 is selected from H, D, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, deuterated C 1-3 Alkyl or deuterated C 1-3 alkoxy;

[0013] Alternatively, R2 and R4 together with the atoms to which they are attached form a 3-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R b Substitution, in this case, R3 is selected from H, D, halogen, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R a replace;

[0014] R7 is selected from C 1-6 Alkyl, phenyl, The C 1-6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 F groups, and the phenyl group is optionally substituted with 1, 2 or 3 R c replace;

[0015] R 11 Selected from C 1-6 Alkyl or C1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy is optionally substituted with 1, 2, 3, 4 or 5 Fs, each independently; a Each is independently selected from D, -F, -Cl, -Br or -I;

[0016] Each R b Each independently selected from D, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, -C(=O)-C 1-3 Alkyl or -S(=O) m -C 1-3 Alkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, -C(=O)-C 1-3 Alkyl or -S(=O) m -C 1-3 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 R groups, each independently;

[0017] Each R c Each independently selected from -F, -Cl, -Br, -I, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy is each independently optionally substituted with 1, 2, 3, 4 or 5 F;

[0018] Each R is independently selected from D, -F, -Cl, -Br, -I or -OH;

[0019] m is selected from 0, 1 or 2.

[0020] In some embodiments of the present invention, each R is independently selected from D, -F or -Cl, and the other variables are as defined herein.

[0021] In some embodiments of the present invention, each R is independently selected from D or -F, and the other variables are as defined herein.

[0022] In some embodiments of the present invention, each R a are each independently selected from D, -F or -Cl, and other variables are as defined in the present invention.

[0023] In some embodiments of the present invention, each R a are each independently selected from D or -F, and other variables are as defined in the present invention.

[0024] In some embodiments of the present invention, each R bEach is independently selected from D, -F, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -C(=O)CH3, -C(=O)CH2CH3, -SCH3, -SCH2CH3, -S(=O)CH3 or -S(=O)2CH3, and the -CH3, -CH2CH3, -OCH3, -OCH2CH3, -C(=O)CH3, -C(=O)-CH2CH3, -SCH3, -SCH2CH3, -S(=O)CH3 or -S(=O)2CH3 are each independently optionally substituted with 1, 2, 3, 4 or 5 R, and other variables are as defined herein.

[0025] In some embodiments of the present invention, each R b Each is independently selected from -CH3, -CD3, -CD2CD3, -CH2CH3, -CH2CH2F, -CH2CHF2, -CH2CF3, -C(=O)CH3 or -S(=O)2CH3, and other variables are as defined herein.

[0026] In some embodiments of the present invention, each R b Each is independently selected from D, -CH2CH3, -C(=O)CH3 or -S(=O)2CH3, and the -CH2CH3, -C(=O)CH3 or -S(=O)2CH3 are each independently optionally substituted by 1, 2, 3, 4 or 5 R, and other variables are as defined in the present invention.

[0027] In some embodiments of the present invention, each R b Each is independently selected from D, -CH2CH3, -CH2CH2F, -CH2CHF2, -CH2CF3, -C(=O)CH3, -S(=O)2CH3, -CD2CD3, -CD2CF3, -C(=O)CD3 or -S(=O)2CD3, and other variables are as defined herein.

[0028] In some embodiments of the present invention, each R b are each independently selected from D, -CH2CH3, -CH2CHF2, -CH2CF3 or -CD2CD3, and other variables are as defined herein.

[0029] In some embodiments of the present invention, each R b Each is independently selected from D or -CD2CD3, and other variables are as defined in the present invention.

[0030] In some embodiments of the present invention, each R b Each is independently selected from -CH2CH3, -CH2CHF2 or -CH2CF3, and the other variables are as defined herein.

[0031] In some embodiments of the present invention, each R b are each independently selected from -CH2CF3, and other variables are as defined herein.

[0032] In some embodiments of the present invention, T1 is selected from CH, T2 is selected from CH, and the other variables are as defined herein.

[0033] In some embodiments of the present invention, T1 is selected from CH, T2 is selected from N, and the other variables are as defined herein.

[0034] In some embodiments of the present invention, T1 is selected from N, T2 is selected from CH, and the other variables are as defined herein.

[0035] In some embodiments of the present invention, R2 and R3 together with the atoms to which they are attached form azetidinyl, azetyl or azacyclohexyl, in which case R4 is selected from H, D, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -CD3, -CD2CD3, -OCD3 or -OCD2CD3, and other variables are as defined herein.

[0036] In some embodiments of the present invention, R2 and R3 together with the atoms to which they are attached form an azacyclopentyl group, in which case R4 is selected from -OCH3, -OCH2CH3, -OCD3 or -OCD2CD3, and other variables are as defined herein.

[0037] In some embodiments of the present invention, the R2 and R3 together with the atoms to which they are attached form an azacyclopentyl group, in which case the R4 is selected from -OCH3 or -OCD3, and the other variables are as defined herein.

[0038] In some embodiments of the present invention, the R2 and R3 together with the atoms to which they are attached form an azacyclopentyl group, in which case the R4 is selected from -OCH2CH3 or -OCD2CD3, and the other variables are as defined herein.

[0039] In some embodiments of the present invention, the R2 and R4 together with the atoms to which they are attached form an oxetane, an oxolanyl, an oxhexyl, an azetidinyl, an azetyl or an azetyl group, wherein the oxetane, an oxolanyl, an oxhexyl, an azetidinyl, an azetyl or an azetyl group are independently optionally replaced by 1, 2 or 3 R b In this case, R3 is selected from H or D, and the other variables are as defined in the present invention.

[0040] In some embodiments of the present invention, the R2 and R4 together with the atoms to which they are attached form an oxacyclohexyl or an azacyclohexyl group, wherein the oxacyclohexyl or the azacyclohexyl group are independently optionally replaced by 1, 2 or 3 R bIn this case, R3 is selected from H or D, and the other variables are as defined in the present invention.

[0041] In some embodiments of the present invention, the R2 and R4 together with the atoms to which they are attached form an oxacyclohexyl or an azacyclohexyl group, wherein the oxacyclohexyl or the azacyclohexyl group are independently optionally replaced by 1, 2 or 3 R b In this case, R3 is selected from H, and other variables are as defined in the present invention.

[0042] In some embodiments of the present invention, "R2 and R3 together with the atoms to which they are attached form" means that R2 and R3 together with the carbon atoms to which they are attached and the N atom between the two carbon atoms form.

[0043] In some embodiments of the present invention, "R2 and R4 together with the atoms to which they are attached form" means that R2 and R4 together with the carbon atoms to which they are attached and the methylene group between the two carbon atoms form.

[0044] In some embodiments of the present invention, R 11 Selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(CH3)3, wherein -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(CH3)3 are each independently optionally substituted with 1, 2, 3, 4 or 5 F, and other variables are as defined herein.

[0045] In some embodiments of the present invention, R 11 is selected from -C(CH3)3, and other variables are as defined herein.

[0046] In some embodiments of the present invention, R7 is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, phenyl, The -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2 are each independently optionally substituted with 1, 2, 3, 4 or 5 F, and other variables are as defined in the present invention.

[0047] In some embodiments of the present invention, R7 is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, The -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2 are each independently optionally substituted with 1, 2, 3, 4 or 5 F, and other variables are as defined in the present invention.

[0048] In some embodiments of the present invention, R7 is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, Other variables are as defined in the present invention.

[0049] In some embodiments of the present invention, R7 is selected from -CH3, -CH2CH3, Other variables are as defined in the present invention.

[0050] In some embodiments of the present invention, R7 is selected from -CH3 or -CH2CH3, and the other variables are as defined herein.

[0051] In some embodiments of the present invention, R7 is selected from -CH3, and the other variables are as defined herein.

[0052] In some embodiments of the present invention, m is selected from 2, and other variables are as defined herein.

[0053] In some embodiments of the present invention, the 3-6 membered heterocyclic group is selected from a 3-6 membered saturated heterocyclic group containing N or O.

[0054] In some embodiments of the present invention, the 3-6 membered heterocyclic group is selected from a 4-6 membered saturated heterocyclic group containing one N or one O.

[0055] In some embodiments of the present invention, the 3-6 membered heterocyclic group is selected from a 4-6 membered saturated heterocyclic group containing one N.

[0056] In some embodiments of the present invention, the 3-6 membered heterocyclic group is selected from a 4-6 membered saturated heterocyclic group containing one O.

[0057] It should be understood that when R1 is selected from H or D, the structural unit (R1)3C- in the compound represented by formula (I) is respectively -CH3 or -CD3; when R 10 When selected from H or D, the structural unit -C(R 10 )3 respectively represents -CH3 or -CD3, and other variables are as defined in the present invention.

[0058] It should be understood that the two R8 in the compound represented by formula (I) are the same, that is, when one R8 is H or D, the other R8 is H or D respectively, and other variables are as defined in the present invention.

[0059] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in the present invention.

[0060] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in the present invention.

[0061] In some embodiments of the present invention, the structural unit is selected from phenyl, pyridyl or pyridazinyl, and other variables are as defined in the present invention.

[0062] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in the present invention.

[0063] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in the present invention.

[0064] In some embodiments of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0065] in,

[0066] R1, R4, R7, R b , T1 and T2 are as defined in the present invention;

[0067] When R4 is not H, the carbon atom marked with "#" is a chiral carbon atom, existing in the form of a single enantiomer (R) or (S) or in the form enriched in one enantiomer; the carbon atom marked with "*" is a chiral carbon atom, existing in the form of a single enantiomer (R) or (S) or in the form enriched in one enantiomer.

[0068] In some embodiments of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0069] wherein R1, R4, R7, T1 and T2 are as defined in the present invention.

[0070] In some embodiments of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0071] wherein R1, R4 and R7 are as defined in the present invention.

[0072] Some other solutions of the present invention are derived from any combination of the above variables.

[0073] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0074] In some embodiments of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0075] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and further comprising a pharmaceutically acceptable carrier.

[0076] The present invention also provides use of the compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diseases associated with complement factor B.

[0077] The present invention also provides a method for treating diseases associated with complement factor B, comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a mammal (preferably a human) in need of such treatment.

[0078] The present invention also provides use of the compound of the present invention or a pharmaceutically acceptable salt thereof in treating diseases related to complement factor B.

[0079] The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating a disease associated with complement factor B.

[0080] In some embodiments of the present invention, the complement factor B-related disease is selected from inflammatory disorders and autoimmune diseases.

[0081] On the other hand, the present invention also provides a method for preparing a compound of formula (I), comprising: reacting a compound of formula (II) with R7-OH to obtain a compound of formula (I),

[0082] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , T1 and T2 are as described for the compound of formula (I) of the present invention.

[0083] The present invention also provides a method for preparing compound M1, comprising: (1) reacting compound Ma with compound R p -NH2 reacts with 1,3-acetone dicarboxylic acid to obtain compound M-b'; (2) compound M-b' is resolved with a chiral reagent to obtain compound M-c'; (3) compound M-c' undergoes a reduction reaction to obtain compound M-d'; (4) compound M-d' reacts with an ethylating agent to obtain compound M-e'; (5) compound M-e' undergoes a hydrolysis reaction to obtain compound M-f'; (6) compound M-f' reacts with a methylating agent to obtain compound M-g'; (7) compound M-g' undergoes a deprotection reaction to obtain compound Mh; (8) compound Mh reacts with compound Nc to obtain compound Mi; (9) compound Mi undergoes a deprotection reaction to obtain compound M1.

[0084] Wherein, Rp is selected from Bn or PMB.

[0085] In some embodiments of the present invention, in the method for preparing compound M1, the chiral reagent in step (2) is selected from L-di-p-benzoyltartaric acid or D-di-p-benzoyltartaric acid.

[0086] In some embodiments of the present invention, in the method for preparing compound M1, the reducing agent in step (3) is selected from diisobutylaluminum hydride, sodium borohydride, lithium tri-sec-butylborohydride or diisobutylaluminum hydride.

[0087] In some embodiments of the present invention, in the method for preparing compound M1, the ethylating agent in step (4) is selected from iodoethane, bromoethane or diethyl sulfate.

[0088] In some embodiments of the present invention, in the method for preparing compound M1, the methylating agent in step (6) is selected from thionyl chloride / methanol, hydrochloric acid-methanol or DMF-DMA / methanol.

[0089] The present invention also provides a method for preparing a compound Me, an intermediate for preparing compound M1, comprising: (1) reacting compound Ma with benzylamine and 1,3-acetonedicarboxylic acid to obtain compound Mb; (2) resolving compound Mb with a chiral reagent to obtain compound Mc; (3) subjecting compound Mc to a reduction reaction to obtain compound Md; (4) reacting compound Md with an ethyl ester reagent to obtain compound Me;

[0090] In some embodiments of the present invention, the method for preparing compound Me, wherein the reaction conditions are the same as those described in the method for preparing compound M1.

[0091] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0092] The present invention also provides use of the above compounds Me, Mf, Mg, and Mh in the preparation of compound M1.

[0093] Technical Effects

[0094] The compound of the present invention can significantly inhibit complement activation stimulated by LPS, has good pharmacokinetic properties, and can be developed into a new small molecule inhibitor of complement system Factor B.

[0095] Related definitions

[0096] 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.

[0097] 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.

[0098] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which are prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases, having specific substituents. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or a suitable inert solvent. 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.

[0099] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0100] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0101] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0102] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0103] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0104] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0105] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0106] Unless otherwise specified, when a compound contains a double bond structure, such as a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond, and each atom on the double bond is connected to two different substituents (in a double bond containing a nitrogen atom, a lone pair of electrons on the nitrogen atom is considered as a substituent to which it is connected), if a wavy line is used between the atom on the double bond and its substituent in the compound, When connected, it represents the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound. For example, the following formula (A) represents that the compound exists in the form of a single isomer of formula (A-1) or formula (A-2) or in the form of a mixture of two isomers of formula (A-1) and formula (A-2); the following formula (B) represents that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of a mixture of two isomers of formula (B-1) and formula (B-2). The following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of a mixture of two isomers of formula (C-1) and formula (C-2).

[0107] 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.

[0108] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0109] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0110] 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.

[0111] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0112] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0113] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0114] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0115] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0116] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.

[0117] 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.

[0118] When the listed linking groups do not specify their linking direction, their linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0119] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0120] When a variable (e.g., R) is substituted on one ring of a polycyclic ring system, unless otherwise specified, the variable (e.g., R) is designated as substituted on that ring and not on other rings of the polycyclic ring system, e.g., represents that ring A and ring B are fused together, substituent R1 is a substituent of ring A, and substituent R2 is a substituent of ring B, It means that the five-membered ring in the spirocyclic system is replaced by n Rs.

[0121]

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

[0122] 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 1-4 、C 1-3 、C 2-4 、C 2-3 , C1, C2, C3, C4, C5 and C6 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).1-5 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0123] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1- Examples of 3-alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0124] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0125] 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 2-4 、C 2-3 , C1, C2, C3, C4, C5 and C6 alkoxy, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0126] Unless otherwise specified, the term "deuterated C 1-3 "Alkyl" means C 1-3 1, 2, 3 or more H atoms in an alkyl group are replaced by their isotope deuterium atoms, deuterated C 1-3 Examples of alkyl groups include, but are not limited to, -CD3, -CD2CD3, and the like.

[0127] Unless otherwise specified, the term "deuterated C 1-3 "Alkoxy" means C 1-3 1, 2, 3 or more H atoms in an alkoxy group are replaced by their isotope deuterium atoms, deuterated C 1-3Examples of alkoxy groups include, but are not limited to, -OCD3, -OCD2CD3, and the like.

[0128] Unless otherwise specified, the term "3-6 membered heterocyclyl" by itself or in combination with other terms means a saturated or partially unsaturated monocyclic 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). In addition, with respect to the "3-6 membered heterocyclyl", a heteroatom may occupy the position at which the heterocyclyl is attached to the rest of the molecule. The 3-6 membered heterocyclyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocyclyls. Examples of 3-6 membered heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, wait.

[0129] Unless otherwise specified, the term "4-6 membered saturated heterocyclyl" by itself or in combination with other terms means a saturated monocyclic cyclic group consisting of 4 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). In addition, with respect to the “3-6 membered heterocyclic radical”, a heteroatom may occupy the position at which the heterocyclic radical is connected to the rest of the molecule. Examples of 4-6 membered saturated heterocyclic radicals include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-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, etc.

[0130] Unless otherwise specified, C n-n+m or C n -C n+mAny 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 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 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0131] 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.

[0132] Abbreviations: psi stands for pounds-force per square inch, a unit of pressure; eq stands for equivalent; mol stands for mole; mmol stands for millimole; g stands for gram; mg stands for milligram; mL stands for milliliter; mm stands for millimeter; h stands for hour; min stands for minute.

[0133] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data from a cultured single crystal using a Bruker D8venture diffractometer, using CuKα radiation and a φ / ω scanning mode. After collecting relevant data, the crystal structure can be further analyzed using a direct method (Shelxs97) to confirm the absolute configuration.

[0134] The solvents used in the present invention can be obtained commercially. Software naming, commercially available compounds use supplier catalog names. BRIEF DESCRIPTION OF THE DRAWINGS

[0135] Figure 1 is a diagram of the PD model in mice induced by LPS complement activation. DETAILED DESCRIPTION

[0136] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. While the present invention 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 invention without departing from the spirit and scope of the present invention.

[0137] Reference Example 1: Intermediate Nc

[0138] first step

[0139] To a solution of compound Na (0.5 g) in tetrahydrofuran (5 mL) at 15°C, di-tert-butyl dicarbonate (812.33 mg) and N,N-diisopropylethylamine (37.89 mg) were added. The reaction solution was stirred at 15°C for 1 hour. The reaction solution was added to water (15 mL) and stirred for 5 minutes. The liquid was separated, and the aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic layer was washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:10) to obtain compound Nb.

[0140] 1 H NMR (400MHz, CDCl3) δppm 7.54-7.48(m,1H),6.90-6.84(m,1H),6.77-6.70(m,1H),6.50-6.43(m,1H),3.9 0-3.77(m,3H),2.70-2.55(m,3H),1.66-1.61(m,9H); LC-MS: m / z=206.1[M-56+H] + .

[0141] Step 2

[0142] At 15°C, oxalyl chloride (431.90 mg) was slowly added dropwise to a solution of N-methyl-N-formylaniline (459.93 mg) in dichloromethane (2.7 mL) under nitrogen. After the addition was complete, the reaction solution was stirred at 15°C for 12 hours, then added dropwise to a solution of compound Nb (0.684 g) in dichloromethane (2.8 mL) at -14°C. After the addition was complete, the reaction solution was stirred at -15°C for 1.5 hours. The reaction solution was poured into ice water (20 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (20 mL*3), and the combined organic phases were washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0:1 to 1:10) to obtain compound Nc.

[0143] 1 H NMR(400MHz,DMSO-d6)δppm 10.61-10.41(m,1H),7.91-7.71(m,1H),7.38-7.21(m,1H),7.07-6.97(m,1H),3 .97-3.93(m,3H),2.63-2.59(m,3H),1.60-1.58(m,9H); LC-MS: m / z=290.1[M+H] + .

[0144] Reference Example 2: Synthesis of Intermediate M1

[0145] first step

[0146] Benzylamine (194.62 g) was slowly added to acetic acid (103.88 mL) in water (850 mL). The reaction system was cooled to 0-10°C, and 1,3-acetonedicarboxylic acid (265.36 g) was slowly added in portions. The reaction solution was allowed to react at 0°C for 0.5 hours. A solution of compound Ma (170 g) in dioxane (850 mL) was slowly added to the reaction system. The reaction solution was slowly allowed to return to room temperature and then allowed to react at 45°C for 12 hours. The reaction solution was cooled to room temperature and then extracted with ethyl acetate (500 mL x 2). The organic phases were combined and washed sequentially with saturated sodium bicarbonate (500 mL) and saturated sodium chloride (500 mL). After drying over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was stirred in a mixture of n-heptane and methyl tert-butyl ether (1:1, 500 mL) for 0.5 hours. The solid was then filtered and collected to obtain compound Mb. LC-MS: m / z=317.1[M+H] + .

[0147] Step 2

[0148] Compound Mb (220 g) was dissolved in acetonitrile (1700 mL), then heated to 70°C and stirred for 2 hours. L-di-p-benzoyltartaric acid (200 g) was slowly added with stirring. The reaction solution was stirred at 70°C for 2 hours, then slowly returned to 25°C and stirred for 12 hours. The solid was collected by filtration, and the filter cake was washed with acetonitrile (400 mL*2). The filtered solid was added to 1000 mL of water, and 1 M NaOH aqueous solution was added with stirring to adjust the pH to 8. Ethyl acetate was then added for extraction (2000 mL*2). The organic phases were combined and washed with saturated brine (2000 mL*2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound Mc (retention time: 2.175 min, ee=99.1%). LC-MS: m / z=317.1 [M+H] + SFC analysis method: chromatographic column: Chiralpak AD 50×4.6 mm ID, 3 μm, mobile phase: A: CO2, B: methanol (0.05% diethylamine), gradient B%: 5%-40%.

[0149] Step 3

[0150] Compound Mc (94 g) was dissolved in tetrahydrofuran (750 mL), followed by the addition of water (10.71 mL). The atmosphere was replaced with nitrogen three times, and the temperature was lowered to -40°C. At this temperature, lithium tri-sec-butylborohydride (1 M, 356.52 mL) was slowly added dropwise. After the addition was complete, stirring was continued at this temperature for 30 minutes. Hydrogen peroxide (102.77 mL, 30% purity) was slowly added dropwise to the reaction solution, maintaining the temperature below 0°C. A solution of sodium sulfite (135 g) in water (1000 mL) was then slowly added, and extraction was performed with methyl tert-butyl ether (500 mL*2). The organic phase was washed with saturated brine (1000 mL*2), dried, filtered, and concentrated under reduced pressure to yield compound Md (retention time: 1.197 min, ee = 96.9%). LC-MS: m / z = 319.1 [M+H] + SFC analysis method: Column: Chiralcel OJ 50×4.6 mm ID, 3 μm, Mobile phase: A: CO2, B: methanol (0.05% diethylamine), Gradient B%: 5%-40%.

[0151] Step 4

[0152] Compound Md (7 g) was dissolved in N,N-dimethylformamide (35 mL), replaced with nitrogen three times, cooled to 0°C, then sodium tert-butoxide (6.34 g) was added and stirred for 30 min. The temperature was lowered to -10°C and diethyl sulfate (6.78 g) was slowly added dropwise at this temperature. After the addition was complete, stirring was continued at this temperature for 2 hours. The reaction solution was added to water (160 mL), the pH was adjusted to 5-6 with solid citric acid, and ethyl acetate (100 mL) was added for extraction. The organic phase was washed with saturated sodium carbonate aqueous solution (50 mL) and brine (100 mL) in sequence, dried and filtered, and the filtrate was concentrated under reduced pressure to obtain compound Me. LC-MS: m / z=347.2[M+H] + .

[0153] Step 5

[0154] Potassium carbonate (3.51 g) was added to a solution of compound Me (8 g) in dimethyl sulfoxide (40 mL) at 20°C, followed by the slow dropwise addition of hydrogen peroxide (3.33 mL, 30% purity). After the addition was complete, the reaction mixture was heated to 40°C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was slowly added to ice water (150 mL) and stirred at 0°C for 1 hour. The precipitated solid was filtered and the filter cake dried to obtain compound Mf. LC-MS: m / z = 365.2 [M+H] + .

[0155] Step 6

[0156] At room temperature, N,N-dimethylformamide dimethyl acetal (59.81 g) was added to a solution of compound Mf (99 g) in methanol (1000 mL). The reaction solution was heated to 40°C and stirred for 16 hours. The reaction solution was directly concentrated under reduced pressure to obtain a residue. Ethyl acetate (1000 mL) was added to the residue, and then washed with water (500 mL) and saturated brine (500 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound Mg, which was directly used in the next step. LC-MS: m / z = 380.2 [M+H] + .

[0157] Step 7

[0158] To a solution of compound Mg (4 g) in methanol (40 mL) at 20°C under a nitrogen atmosphere, concentrated hydrochloric acid (975 μL, 36% purity) and wet palladium on carbon (1 g, 10% content) were added sequentially. The atmosphere was replaced with hydrogen three times, and the reaction mixture was stirred at 50°C for 1.5 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain crude compound Mh, which was used directly in the next step. LC-MS: m / z = 290.1 ​​[M+H] + .

[0159] Step 8

[0160] At 15°C under a nitrogen atmosphere, pyridine (836.80 μL), trimethylsilyl chloride (938.60 mg), and phenylsilane (560.93 mg) were added to a solution of compound Mh (1 g) and compound Nc (999.85 mg) in acetonitrile (15 mL). The reaction solution was stirred at 70°C for 16 hours, then added to water (100 mL) and extracted with ethyl acetate (100 mL*2). The organic phases were combined, washed with saturated brine (100 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Mi. LC-MS: m / z = 563.5 [M+H] + .

[0161] Step 9

[0162] Under nitrogen protection at 15°C, lithium hydroxide (1M, 50.00 mL) was added to a mixed solution of compound Mi (5 g) in tetrahydrofuran (50 mL) and methanol (50 mL) in water. The reaction solution was heated to 50°C and stirred for 16 hours. The reaction solution was cooled to room temperature and the pH was adjusted to 6-7 with glacial acetic acid. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (chromatographic column: Phenomenex Luna C18 (250*80mm*15μm); mobile phase: A: water (0.05% hydrochloric acid), B: acetonitrile, method B: 20%-50%) to obtain compound M1.

[0163] 1 H NMR (400MHz, DMSO-d6) δ=13.21(br s,1H),11.29-11.18(m,1H),9.86-9.62(m,1H),8.13(br d,J=

[0164] 7.8Hz,2H),8.04-7.82(m,2H),7.43(br s,1H),6.82(s,1H),6.38(br s,1H),4.07-3.93(m,3H),3.86(s,3H),3.60(br s,1H),3.40(q,J=7.2Hz,2H),3.33(s,3H),2.92-2.80(m,2H),2.80-2.65(m,2H),2.64-2.55(m,

[0165] 1H), 2.39-2.26 (m, 1H), 2.04 (br d, J=15.2Hz, 2H), 1.13 (t, J=7.2Hz, 3H); LC-MS: m / z=449.3[M+H] + .

[0166] Reference Example 3: Synthesis of Intermediates M2 and M3

[0167] first step

[0168] At 0°C, sodium tert-butoxide (4.53g) was added to a solution of compound Md (5g) in N,N-dimethylformamide (25mL). The reaction solution was stirred for 0.5 hours, then cooled to -10°C, deuterated iodomethane (2.23g) was added and stirring continued for 2 hours. After the reaction solution was cooled to room temperature, water (50mL) was added at 0°C to quench the mixture, the pH was adjusted to 5-6 with citric acid, and the mixture was extracted with ethyl acetate (50mL*2). The organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:4) to obtain compound D-1. LC-MS: m / z = 336.2 [M+H] + .

[0169] Step 2

[0170] Potassium carbonate (951.71 mg) was added to a dimethyl sulfoxide solution (20 mL) of compound D-1 (2.1 g) at 0°C, followed by a dropwise addition of hydrogen peroxide solution (902.27 μL, 30% purity). After the addition was complete, the reaction mixture was heated to 40°C and stirred for 1 hour. Water (30 mL) was added to the reaction mixture to precipitate a solid, which was filtered and the filter cake collected to obtain crude compound D-2, which was used directly in the next step. LC-MS: m / z = 354.2 [M+H] + .

[0171] Step 3

[0172] At 25°C, N,N-dimethylformamide dimethyl acetal (1.08g) was added to a solution of compound D-2 (1.6g) in anhydrous methanol (16mL). After the addition, the reaction solution was heated to 75°C and stirred under nitrogen for 16 hours. The reaction solution was concentrated under reduced pressure, water (16mL) was added, and ethyl acetate (16mL*2) was added. The organic phases were combined, washed with saturated brine (16mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude compound D-3, which was used directly in the next step. LC-MS: m / z=369.2[M+H] + .

[0173] Step 4

[0174] To a solution of compound D-3 (1.46 g) in anhydrous methanol (15 mL) at 25°C, hydrochloric acid (472.11 μL, 36% purity) and wet palladium on carbon (0.2 g, 10% content) were added. The atmosphere was purged with nitrogen three times, and the reaction mixture was heated to 50°C under hydrogen (15 Psi) for 2 hours. The reaction mixture was poured into celite and filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain crude compound D-4, which was used directly in the next step. LC-MS: m / z = 279.1 [M+H] + .

[0175] Step 5

[0176] At 25°C, to a solution of compound D-4 (0.8g) in N,N-dimethylformamide (10mL) were added intermediate compound Nc (831.51mg), pyridine (695.91μL), phenylsilane (466.50mg), and trimethylsilyl chloride (780.58mg). After the addition was complete, the atmosphere was purged with nitrogen three times, and the reaction solution was stirred at 60°C for 16 hours. After the reaction solution was cooled to room temperature, it was quenched by the addition of water (10mL) and extracted with ethyl acetate (10mL*2). The organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:1) to obtain compound M2. LC-MS: m / z = 552.3 [M+H] + .

[0177] Step 6

[0178] To a mixture of compound M2 (0.4 g) in tetrahydrofuran (2 mL) and anhydrous methanol (2 mL) was added a 1 M aqueous lithium hydroxide solution (3.63 mL) at 25°C. After the addition, the reaction mixture was heated to 50°C and allowed to react for 16 hours. After cooling to room temperature, the pH was adjusted to 6-7 with acetic acid and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography (Phenomenex Luna C18 column, 75 × 30 mm × 3 μm; mobile phase: A: water (0.05% hydrochloric acid), B: acetonitrile, method B: 16%-36%) to obtain the hydrochloride salt of compound M3.

[0179] 1H NMR (400MHz, DMSO-d6)δ=13.35-13.05(m,1H),11.32-11.15(m,1H),9.67-9.50(m,1H),8.15(br d,J=7.9Hz,3H),8.02-7.97(m,1H),7.60-7.37(m,1H),6.90(d,J=1.4Hz,1H),6.40-6.27(m,1H),3.87(s,3H),3.76-3.72(m,1 H),3.55-3.49(m,1H),2.95-2.82(m,2H),2.82-2.73(m,2H),2.73-2.65(m,2H),2.48-2.41(m,2H),2.37-2.24(m,2H),2.09(br d, J=15.6Hz, 3H); LC-MS: m / z=438.2[M+H] + .

[0180] Example 1

[0181] To a solution of compound M1 (2 g) in dichloromethane (20 mL) at 15°C were added methanol (1.67 mL), 4-dimethylaminopyridine (1.51 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (790.49 mg). The reaction mixture was stirred at 10°C for 16 hours, then concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography (Phenomenex luna C18 150*40mm*15μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile, mobile phase: B: 20%-50%). The resulting solution was adjusted to a pH of approximately 8 with saturated sodium bicarbonate aqueous solution, concentrated under reduced pressure to remove the acetonitrile solvent, and the aqueous phase was extracted with ethyl acetate (300 mL x 2). The combined organic phases were washed with saturated brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 1.

[0182] LC-MS: m / z = 463.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ=10.81(br s,1H),7.98(br d,J=8.4Hz,2H),7.78(br d,J=8.4Hz,2H),7.26(br s,1H),6.66(s,1H),6.52(br s,1H),3.85(s,3H),3.78-3.65(m,5H),3.39(q,J=6.8Hz,2H),3.33(s,1H),3.19(br d,J=12.4Hz,1H),3.06(br s,1H),2.42(s,3H),2.20(br dd,J=4.8,14.0Hz,1H),2.10-1.91(m,5H),1.51(br d, J=14.0Hz, 1H), 1.11 (t, J=7.2Hz, 3H).

[0183] Example 2

[0184] To a solution of compound M1 (0.5 g) in dichloromethane (10 mL) at 15°C were added ethanol (474.92 mg), 4-dimethylaminopyridine (503.78 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (395.25 mg). The reaction mixture was stirred at 10°C for 16 hours, then concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography (Phenomenex luna C18 150*25mm*10μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile, mobile phase: B: 27%-47%). The resulting solution was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution, concentrated under reduced pressure to remove the acetonitrile solvent, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 2.

[0185] LC-MS: m / z = 477.3 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ=10.82(br s,1H),7.98(d,J=8.4Hz,2H),7.78(d,J=8.4Hz,2H),7.26(t,J=2.4Hz,1H),6. 66(s,1H),6.52(d,J=2.4Hz,1H),4.32(q,J=7.2Hz,2H),3.72(s,3H),3.70(br s,2H),3.39(q,J=7.2Hz,2H),3.30(s,1H),3.19(d,J=12.0Hz,1H),3.05(br s,1H),2.42(s,3H),2.20(br dd,J=4.8,14.4Hz,1H),2.10-1.92(m,5H),1.51(br d,J=14.0Hz,1H),1.32(t,J=7.2Hz,3H),1.11(t,J=7.2Hz,3H).

[0186] Example 3

[0187] To a solution of compound M1 (0.5 g) in dichloromethane (10 mL) at 15°C were added compound 3-1 (268.24 mg), 4-dimethylaminopyridine (503.78 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (395.25 mg). The reaction mixture was stirred at 10°C for 16 hours, then concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography (Phenomenex C18 75*30 mm*3 μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile, mobile phase: B: 20%-50%). The resulting solution was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution, concentrated under reduced pressure to remove the acetonitrile solvent, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield compound 3.

[0188] LC-MS: m / z = 561.4 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ = 10.82 (br s, 1H), 8.00 (d, J = 8.4Hz, 2H), 7.79 (br d,J=8.4Hz,2H),7.26(t,J=2.8Hz,1H),6.65(s,1H),6.56-6.50(m,1H),5.22(s,2H),3 .76-3.66(m,5H),3.39(q,J=7.2Hz,2H),3.31(s,2H),3.18(d,J=12.4Hz,1H),3.05(br s,1H),2.42(s,3H),2.24-2.16(m,4H),2.08-2.03(m,1H),2.02-1.94(m,3H),1.51(br d,J=14.4Hz,1H),1.11(t,J=7.2Hz,3H).

[0189] Example 4

[0190] To a solution of compound M1 (0.2 g) in acetonitrile (3 mL) at 15°C, N,N-diisopropylethylamine (159.88 mg) and chloromethyl pivalate (124.21 mg) were added. The reaction mixture was stirred at 60°C for 2 hours, then concentrated under reduced pressure to remove the solvent. The crude product was purified by column chromatography (3-Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: A: water (0.05% hydrochloric acid), B: acetonitrile, mobile phase: B: 34%-54%). The resulting solution was adjusted to pH 8 with saturated sodium bicarbonate aqueous solution, concentrated under reduced pressure to remove the acetonitrile solvent, and the aqueous phase was extracted twice with ethyl acetate (50 mL). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After addition of water, the product was freeze-dried and concentrated to yield compound 4.

[0191] LC-MS: m / z=563.3[M+H] + ; 1H NMR(400MHz,DMSO-d6)δ=10.82(br s,1H),7.99(d,J=8.4Hz,2H),7.81(d,J=8.4Hz,2H),7.26(t,J=2.8Hz,1H),6.65(s,1H),6.52 (d,J=2.8Hz,1H),5.97(s,2H),3.75-3.64(m,5H),3.40(q,J=6.8Hz,2H),3.30(s,3H),3.20(br d,J=12.0Hz,1H),3.07(br d,J=2.4Hz,1H),2.42(s,3H),2.20(br dd,J=4.4,14.0Hz,1H),2.11–1.95(m,3H),1.56-1.47(m,1H),1.18-1.06(m,12H).

[0192] Example 5

[0193] To compound M2 (300.00 mg) at 20°C, a 4M solution of hydrochloric acid in methanol (2.45 mL) was added. The reaction mixture was stirred at 20°C for 2 hours. After cooling to room temperature, a saturated aqueous sodium bicarbonate solution (50 mL) was added. The reaction mixture was filtered under reduced pressure and purified using a chromatographic column (Phenomenex Luna C18 75*30mm*3μm; mobile phase: A: water (0.05% hydrochloric acid), B: acetonitrile, method: B: 24%-44%). The reaction mixture was then added with a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (50 mL*2). The combined organic phases were washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield compound 5.

[0194] LC-MS: m / z = 452.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ=10.82(br s,1H),7.99(d,J=8.4Hz,2H),7.79(d,J=8.4Hz,2H),7.27(t,J=2.4Hz,1H), 6.66(s,1H),6.50(dd,J=2.0,2.8Hz,1H),3.86(s,3H),3.73(s,3H),3.60(br t,J=4.4Hz,1H),3.19(d,J=12.0Hz,1H),3.11-3.03(m,1H),2.43(s,3H),2.39(br s,1H),2.36(br d,J=7.2Hz,1H),2.21(br dd,J=5.2,14.8Hz,1H),2.08-1.97(m,4H),1.92(br d,J=6.8Hz,1H),1.62-1.48(m,1H).

[0195] Example 6

[0196] To a solution of the hydrochloride salt of compound M3 (300.00 mg) in dichloromethane (10 mL) at 20°C were added 4-dimethylaminopyridine (251.29 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (262.88 mg), and ethanol (371.60 μL). The reaction mixture was stirred at 20°C for 2 hours. After cooling to room temperature, the reaction mixture was filtered under reduced pressure and purified using a Unisil 3-100 C18 Ultra 150*50mm*3μm column; mobile phase: A: water (0.025% formic acid), B: acetonitrile, method B: 20%-50%). Saturated aqueous sodium bicarbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 6.

[0197] LC-MS: m / z = 466.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ=10.90-10.74(m,1H),8.05-7.92(m,2H),7.78(br d,J=8.4Hz,2H),7.33-7.21(m,1H),6.72-6.61(m,1H),6.52(br s,1H),4.44-4.23(m,2H),3.73(s,4H),3.62-3.54(m,1H),3.23-3.16(m,1H),3.11-3.01(m,1H),2.45-2.40(m,3H),2 .40-2.33(m,1H),2.26-2.14(m,1H),2.11-1.97(m,4H),1.96-1.86(m,1H),1.63-1.50(m,1H),1.33(t,J=7.2Hz,3H).

[0198] Example 7

[0199] At 20°C, 4-dimethylaminopyridine (251.29 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (262.88 mg), and compound 7-1 (223.00 mg) were added to a solution of the hydrochloride salt of compound M3 (300.00 mg) in dichloromethane (10 mL). The reaction solution was stirred at 20°C for 2 hours. After the reaction solution was cooled to room temperature, saturated aqueous sodium bicarbonate solution (10 mL) was added and the reaction solution was filtered under reduced pressure. The residue was separated and purified by preparative chromatography (petroleum ether:ethyl acetate = 0:1) to obtain compound 7.

[0200] LC-MS: m / z = 550.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.91-10.76 (m, 1H), 8.04-7.97 (m, 2H), 7.80 (br d,J=8.4Hz,2H),7.38-7.21(m,1H),6.72-6.60(m,1H),6.58-6.44(m,1H),5.26-5.19(m,2H),3.79-3.69(m,4H),3.63-3.56(m,1H),3.19(br d,J=12.0Hz,1H),3.07(br s,1H),2.43(s,3H),2.38-2.31(m,1H),2.23(s,3H),2.21-2.14(m,1H),2.10-1.97(m,4H),1.94-1.85(m,1H),1.60-1.49(m,1H).

[0201] Example 8

[0202] To a solution of the hydrochloride salt of compound M3 (0.3 g) in acetonitrile (5 mL) at 25°C, N,N-diisopropylethylamine (179.14 μL) and chloromethyl pivalate (154.89 mg) were added. The reaction mixture was heated to 60°C and stirred for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Purification was continued using a chromatographic column (Phenomenex luna C18 150*25mm*10μm; mobile phase: A: water (0.025% formic acid), B: acetonitrile, step B: 26%-56%). The reaction mixture was adjusted to pH 8 by adding saturated sodium bicarbonate aqueous solution. The acetonitrile solvent was removed by concentration under reduced pressure and extracted with ethyl acetate (50 mL*2). The combined organic phases were washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to yield compound 8.

[0203] LC-MS: m / z = 552.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ=10.83(br s,1H),7.99(d,J=8.4Hz,2H),7.80(d,J=8.4Hz,2H),7.25(t,J=2.4Hz,1H) ,6.65(s,1H),6.53-6.46(m,1H),5.96(s,2H),3.76-3.68(m,4H),3.59(br t,J=4.4Hz,1H),3.31(s,1H),3.18(d,J=12.0Hz,1H),3.06(br s,1H),2.42(s,3H),2.39-2.32(m,1H),2.19(br dd,J=5.2,14.8Hz,1H),2.05-1.95(m,3H),1.93-1.85(m,1H),1.54(br d,J=14.0Hz,1H),1.15(s,9H).

[0204] Biochemical testing

[0205] Experimental Example 1: Pharmacokinetic Study in Rats

[0206] Purpose of the experiment:

[0207] Male SD rats were used as test subjects. LC / MS / MS was used to determine the plasma concentrations of the compound of the present invention and its carboxylic acid metabolites at different time points after oral gavage. The pharmacokinetic behavior of the compound of the present invention and its carboxylic acid metabolites in rats was studied and their pharmacokinetic characteristics were evaluated.

[0208] Test plan:

[0209] Healthy male rats weighing 200-300 g were used, with 2 rats in each group.

[0210] The compound of the present invention was prepared into a 3 mg / mL clear solution using 20% ​​PEG400 / 10% solutol / 70% water. The rats were fasted overnight and given the drug at a dose of 30 mg / kg by oral gavage. Blood was collected before and 0.25, 0.5, 1, 2, 4, 7, and 24 hours after administration, placed in a heparinized anticoagulant tube, centrifuged at 7000 rpm (5204 g) at 4°C, and the plasma was separated and stored at -80°C. Food was consumed 4 hours after administration. The content of the test compound in the plasma of rats after oral administration was determined by LC / MS / MS. The plasma samples were pretreated with precipitated proteins and then analyzed. Experimental results: The pharmacokinetic parameters are shown in Table 1.

[0211] Table 1: Pharmacokinetic data of the compounds of the present invention in rats

[0212] Note: C max : peak concentration; T maax : peak time; T 1 / 2 : Drug elimination half-life; AUC 0-last : Area under the drug-time curve from 0 to the last sampling time. ND: Blood drug concentration is below the detection limit and not fitted; ND*: Not fitted within 24 hours.

[0213] Conclusion: After oral administration, the compound of the present invention has a high exposure of its carboxylic acid metabolite in vivo and has excellent pharmacokinetic properties.

[0214] Experimental Example 2: LPS-induced complement activation in PD mouse model

[0215] Experimental purpose: To investigate the inhibitory effect of the compounds of the present invention on complement activation induced by LPS stimulation in mice.

[0216] Experimental animals: Female C57BL / 6J mice, 7-9 weeks old, weighing 17-23 g; Supplier: Shanghai Xipu-Bikai Laboratory Animal Co., Ltd. Experimental procedure:

[0217] Four hours before administration, 100 μg of lipopolysaccharide (LPS) from Salmonella typhimurium (Sigma) was dissolved in 100 μL of sterile PBS (phosphate buffer pH 7.2-7.4) and injected intraperitoneally to induce complement activation in mice. Normal mouse group (negative control): Animals received an intraperitoneal injection of 100 μL of sterile PBS and were administered the vehicle alone by gavage (PO). Model group (positive control): Animals received intraperitoneal LPS and PO administration of the vehicle (20% PEG400 / 10% solutol / 70% water). Drug group: Samples were collected 4 hours after administration of the compound (vehicle: 20% PEG400 / 10% solutol / 70% water, administration volume: 5 mL / kg, dose: 10 mg / kg).

[0218] Sample Collection: 0.3 mL of blood was collected from the orbital venous plexus. All blood samples were placed in 1.5 mL commercial EDTA-K2 anticoagulant tubes (supplier: Jiangsu Kangjian Medical Supplies Co., Ltd.). Within half an hour of blood collection, the tubes were centrifuged at 3000 g for 10 minutes at 4°C. The supernatant plasma was aspirated, quickly placed on dry ice, and stored at -80°C for Western blot analysis of C3d protein levels downstream of complement activation.

[0219] Sample Analysis: Mix mouse plasma (5 μL) with lysis buffer (27.5 μL), loading buffer (12.5 μL), and reducing buffer (5 μL). Incubate at 100°C for 20 min. Load 5 μL / well, for a total of 0.025 μL of serum per well. C3d and transferrin protein levels were assayed by Western blotting.

[0220] Experimental results:

[0221] After complement activation was induced in mice via intraperitoneal injection, serum C3d protein levels in the model group increased by 45% to 55% compared to the normal group. After oral administration of the compound of this invention, serum C3d protein levels in the mice in each drug group decreased by 60% to 80% compared to the model group, demonstrating a significant decrease in C3d protein levels. Specific experimental results are shown in Figure 1.

[0222] Experimental conclusion: Compared with the normal group and the model group, the compound of the present invention can or can significantly inhibit LPS-stimulated complement activation.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, T1 and T2 are each independently selected from CH or N; R1, R5, R6, R8, R9 and R 10 are independently selected from H or D; R2 and R3 together with the atoms to which they are attached form a 3-6 membered heterocyclic group, in which case R4 is selected from H, D, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, deuterated C 1-3 Alkyl or deuterated C 1-3 alkoxy; Alternatively, R2 and R4 together with the atoms to which they are attached form a 3-6 membered heterocyclic group, which is optionally substituted by 1, 2 or 3 R b Substitution, in this case, R3 is selected from H, D, halogen, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl or C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R a replace; R7 is selected from C 1-6 Alkyl, phenyl, The C 1-6 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 F groups, and the phenyl group is optionally substituted with 1, 2 or 3 R c replace; R 11 Selected from C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy is optionally substituted with 1, 2, 3, 4 or 5 Fs, each independently; a Each is independently selected from D, -F, -Cl, -Br or -I; Each R b Each independently selected from D, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, -C(=O)-C 1-3 Alkyl or -S(=O) m -C 1-3 Alkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, -C(=O)-C 1-3 Alkyl or -S(=O) m -C 1-3 The alkyl group is optionally substituted with 1, 2, 3, 4 or 5 R groups, each independently; Each R c Each independently selected from -F, -Cl, -Br, -I, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl or C 1-6 Alkoxy is each independently optionally substituted with 1, 2, 3, 4 or 5 F; Each R is independently selected from D, -F, -Cl, -Br, -I or -OH; m is selected from 0, 1 or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Each R is independently selected from D, -F or -Cl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Each R a are each independently selected from D, -F or -Cl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Each R b each independently selected from D, -F, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -C(=O)CH3, -C(=O)CH2CH3, -SCH3, -SCH2CH3, -S(=O)CH3, or -S(=O)2CH3, wherein -CH3, -CH2CH3, -OCH3, -OCH2CH3, -C(=O)CH3, -C(=O)-CH2CH3, -SCH3, -SCH2CH3, -S(=O)CH3, or -S(=O)2CH3 are each independently selected from D, -F, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -C(=O)CH3, -C(=O)-CH2CH3, -SCH3, -SCH2CH3, -S(=O)CH3, or -S(=O)2CH3 are each independently optionally substituted with 1, 2, 3, 4, or 5 R; Or, each R b Each is independently selected from -CH3, -CD3, -CD2CD3, -CH2CH3, -CH2CH2F, -CH2CHF2, -CH2CF3, -C(=O)CH3 or -S(=O)2CH3; Or, each R b Each independently selected from D, -CH2CH3, -CH2CH2F, -CH2CHF2, -CH2CF3, -C(=O)CH3, -S(=O)2CH3, -CD2CD3, -CD2CF3, -C(=O)CD3 or -S(=O)2CD3; Or, each R b Each is independently selected from -CH2CF3.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 and R3 together with the atoms to which they are attached form azetidinyl, azetyl or azacyclohexyl, in which case R4 is selected from H, D, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -CD3, -CD2CD3, -OCD3 or -OCD2CD3; Alternatively, R2 and R3 together with the atoms to which they are attached form an azacyclopentyl group, in which case R4 is selected from -OCH3, -OCH2CH3, -OCD3 or -OCD2CD3.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 and R4 together with the atoms to which they are attached form an oxetanyl, oxolanyl, oxhexyl, azetidinyl, azetyl or azetyl group, wherein the oxetanyl, oxolanyl, oxhexyl, azetidinyl, azetyl or azetyl group are each independently optionally substituted by 1, 2 or 3 R b Substitution, in this case, said R3 is selected from H or D; Alternatively, R2 and R4 together with the atoms to which they are attached form an oxacyclohexyl or an azacyclohexyl group, wherein the oxacyclohexyl or the azacyclohexyl group are each independently optionally substituted by 1, 2 or 3 R b Substitution, in this case, said R3 is selected from H.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 11 -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(CH3)3, wherein -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2 or -C(CH3)3 are each independently optionally substituted with 1, 2, 3, 4 or 5 F; Or, R 11 Selected from -C(CH3)3.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R7 is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, The -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2 are each independently optionally substituted with 1, 2, 3, 4 or 5 F; Alternatively, R7 is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, The -CH3, -CH2CH3, -CH2CH2CH3 or -CH(CH3)2 are each independently optionally substituted with 1, 2, 3, 4 or 5 F; Alternatively, R7 is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, 9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Structural unit Selected from Alternatively, the structural unit Selected from 10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Structural unit is selected from phenyl, pyridyl or pyridazinyl; Alternatively, the structural unit Selected from 11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from Among them, R1, R4, R7, R b , T1 and T2 are as defined in claim 1; When R4 is not H, the carbon atom marked with "#" is a chiral carbon atom, existing in the form of a single enantiomer (R) or (S) or in the form enriched in one enantiomer; The carbon atom marked with "*" is a chiral carbon atom, existing in the form of a single enantiomer (R) or (S) or in the form enriched in one enantiomer.

12. The following compound or a pharmaceutically acceptable salt thereof:

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from 14. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

15. Use of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14, in the preparation of a medicament for treating diseases associated with complement factor B.

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