Bicyclic substituted aromatic carboxylic acid deuterated compound

Abstract

Provided are a compound represented by formula (I) and a pharmaceutically acceptable salt thereof. # imgabs0 #

Description

Deuterated compounds of bicyclic substituted aromatic carboxylic acids

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese invention patent application No. 202210640584.3 filed with the State Intellectual Property Office of China on June 7, 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 a bicyclic substituted aromatic carboxylic acid deuterated compound, and in particular to a compound represented by formula (I) or a pharmaceutically acceptable salt 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, thereby 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 in the treatment of various diseases caused by complement abnormalities, providing new treatment options to meet 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, R7, R8 and R9 are each 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, said 3-6 membered heterocyclic group being 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, 3, 4 or 5 R a replace;

[0014] Each R a are independently selected from D, -F, -Cl, -Br or -I;

[0015] Each R b are independently selected from D, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, -C(=O)-C 1-3 Alkyl or -S(=O) m -C1-3 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;

[0016] Each R is independently selected from D, -F, -Cl, -Br, -I or -OH;

[0017] m is selected from 0, 1 or 2;

[0018] n is selected from 0 or 1;

[0019] The condition is that R1, R3, R4, R5, R6, R7, R8, R9, R a 、R b At least one of R and D is selected from D or a deuterated group.

[0020] In some embodiments of the present invention, T1 is selected from CH, T2 is selected from CH, and other variables are as defined in the present invention.

[0021] In some embodiments of the present invention, T1 is selected from CH, T2 is selected from N, and other variables are as defined in the present invention.

[0022] In some embodiments of the present invention, T1 is selected from N, T2 is selected from CH, and other variables are as defined in the present invention.

[0023] In some embodiments of the present invention, R1 is selected from D, and other variables are as defined herein.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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 deuterated C 1-3 Alkyl or deuterated C 1-3 Alkoxy, and other variables are as defined in the present invention.

[0029] 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 deuterated C 1-3 Alkoxy, and other variables are as defined in the present invention.

[0030] 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 -OCD3 or -OCD2CD3, and the other variables are as defined herein.

[0031] 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.

[0032] 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 or D, and the other variables are as defined in the present invention.

[0033] 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 the other variables are as defined in the present invention.

[0034] 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.

[0035] 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.

[0036] In some embodiments of the present invention, each R b Each 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.

[0037] 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.

[0038] 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 optionally substituted by 1, 2, 3, 4 or 5 D and F, respectively, and other variables are as defined in the present invention.

[0039] 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.

[0040] 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.

[0041] In some embodiments of the present invention, each R bEach is independently selected from D or -CD2CD3, and other variables are as defined in the present invention.

[0042] 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.

[0043] 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.

[0044] In some embodiments of the present invention, m is selected from 2, and other variables are as defined in the present invention.

[0045] In some embodiments of the present invention, n is selected from 1, and other variables are as defined in the present invention.

[0046] In some embodiments of the present invention, each R is independently selected from D or -F, and the other variables are as defined herein.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] It should be understood that when R1 is selected from H or D, the structural unit (R1)3C- in the compound shown in formula (I) is respectively -CH3 or -CD3; when R7 is selected from H or D, the structural unit -C(R7)3 in the compound shown in formula (I) is respectively -CH3 or -CD3, and other variables are as defined in the present invention.

[0052] 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.

[0053] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in the present invention.

[0054] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in the present invention.

[0055] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in the present invention.

[0056] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in the present invention.

[0057] In some embodiments of the present invention, the structural unit is selected from phenyl, pyridyl and pyridazinyl, and the other variables are as defined herein.

[0058] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined in the present invention.

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

[0060] In some embodiments of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0061] in,

[0062] R1, R4, R5, R6, R7, R8, R9, R b , n, T1 and T2 are as defined for the compound of formula (I) of the present invention;

[0063] When R4 and R5 are different, the carbon atom marked with "#" is a chiral carbon atom, existing in the form of a single enantiomer (R) or (S) or in a form enriched in one enantiomer;

[0064] 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.

[0065] In some embodiments of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0066] in,

[0067] R1, R4, R5, R6, R9 and Rb As defined in the compound of formula (I) of the present invention;

[0068] When R4 and R5 are different, the carbon atom marked with "#" is a chiral carbon atom, existing in the form of a single enantiomer (R) or (S) or in a form enriched in one enantiomer;

[0069] 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.

[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, R4 is selected from deuterated C 1-3 Alkoxy; R6 and R9 are each independently selected from H or D.

[0072] In some embodiments of the present invention, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

[0073] wherein R4, R6 and R9 are as defined for the compound of formula (I) of the present invention.

[0074] Some other solutions of the present invention are derived from any combination of the above variables.

[0075] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0076] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] In some embodiments of the present invention, the complement factor B-related disease is selected from inflammatory disorders and autoimmune diseases.

[0083] In some embodiments of the present invention, the pharmaceutically acceptable salt is selected from pharmaceutically acceptable acid addition salts. In some embodiments of the present invention, the pharmaceutically acceptable salt is selected from pharmaceutically acceptable inorganic acid salts, organic acid salts, and amino acid salts.

[0084] In some embodiments of the present invention, examples of the pharmaceutically acceptable 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, etc.; and organic acid salts, such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, and salts of amino acids (such as arginine, etc.) and salts of organic acids such as glucuronic acid.

[0085] In some embodiments of the present invention, the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, nitrate, carbonate, bicarbonate, phosphate, monohydrogen phosphate, dihydrogen phosphate, sulfate, bisulfate, hydroiodide, phosphite, formate, acetate, propionate, trifluoroacetate, isobutyrate, maleate, malonate, benzoate, succinate, suberate, fumarate, lactate, mandelate, phthalate, benzenesulfonate, p-toluenesulfonate, citrate, tartrate, methanesulfonate, arginine and glucuronate.

[0086] In some embodiments of the present invention, the pharmaceutically acceptable salt is selected from hydrochloride, formate and trifluoroacetate.

[0087] In some embodiments of the present invention, the pharmaceutically acceptable salt is selected from hydrochloride.

[0088] Technical Effects

[0089] The compounds of the present invention have significant inhibitory activity on activation of the human serum bypass pathway and significantly inhibit complement activation stimulated by LPS. The compounds of the present invention also have good pharmacokinetic properties and can be developed into new small molecule inhibitors of complement system Factor B.

[0090] Related definitions

[0091] 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.

[0092] 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.

[0093] 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 compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or in 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, 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.

[0094] 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.

[0095] 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.

[0096] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0097] 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.

[0098] 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.

[0099] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0100] 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

[0101] 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).

[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] 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%.

[0104] 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%.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116]

[0026] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0117] 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.

[0118] 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.

[0119] Unless otherwise specified, the term "deuterated" means that 1, 2, 3 or more H atoms in a substituent are replaced with their isotope deuterium atoms.

[0120] 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.

[0121] 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 1-3 Examples of alkoxy groups include, but are not limited to, -OCD3, -OCD2CD3, and the like.

[0122] 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.

[0123] 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 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.

[0124] 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.

[0125] 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.

[0126] 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 the compounds, 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 on the cultured single crystal using a Bruker D8venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0127] 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

[0128] Figure 1 is a diagram of the PD model in mice induced by LPS complement activation. DETAILED DESCRIPTION

[0129] 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.

[0130] Reference Example 1: Synthesis of Intermediates N-1 and N-2

[0131] first step

[0132] To a solution of compound Na (0.5 g, 3.10 mmol, 1 eq) in tetrahydrofuran (5 mL) at 15°C, di-tert-butyl dicarbonate (812.33 mg, 3.72 mmol, 855.09 μL, 1.2 eq) and N,N-diisopropylethylamine (37.89 mg, 310.17 μmol, 0.1 eq) 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 layers were separated, and the aqueous phase was extracted three times with ethyl acetate (20 mL). The combined organic layers were washed twice with saturated brine (20 mL), 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.

[0133] 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] + .

[0134] Step 2

[0135] To a solution of N-methyl-N-formylaniline (459.93 mg, 3.40 mmol, 418.12 μL, 1.3 eq) in dichloromethane (2.7 mL) under nitrogen at 15°C was slowly added dropwise oxalyl chloride (431.90 mg, 3.40 mmol, 297.86 μL, 1.3 eq). After the addition was complete, the reaction solution was stirred at 15°C for 12 hours and then added dropwise to a solution of compound Nb (0.684 g, 2.62 mmol, 1 eq) 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 three times with ethyl acetate (20 mL). The combined organic phases were washed three times with saturated brine (20 mL), 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.

[0136] 1H 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] + .

[0137] Step 3

[0138] At 0°C, sodium borohydride (1.71 g, 45.28 mmol, 2.5 eq) was slowly added to a solution of compound Nc (5.24 g, 18.11 mmol, 1 eq) in tetrahydrofuran (20 mL) and methanol (20 mL) under nitrogen. After the addition was complete, the reaction solution was stirred at 15°C for 0.5 hour, and then dilute hydrochloric acid (0.5 M, 20 mL) was slowly added. After the addition was complete, the reaction solution was stirred for 20 minutes. The mixture was extracted three times with ethyl acetate (60 mL), and the combined organic phases were washed twice with saturated brine (60 mL), 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 = 1:10 to 1:3) to obtain compound N-1.

[0139] 1 H NMR (400MHz, CDCl3) δppm 7.59-7.50(m,1H),6.80-6.70(m,1H),6.66-6.60(m,1H),4.97-4.85(m,2H),3.96-3.86(m,3H),2.68-2.58(m,3H),1.65-1.63(m,9H).

[0140] Step 4

[0141] To a nitrogen-protected solution of compound N-1 (0.3 g, 1.03 mmol, 1 eq) in dichloromethane (6.87 mL) at 15°C was added (chloromethylene)dimethylammonium chloride (197.71 mg, 1.54 mmol, 1.5 eq). After the addition, the reaction mixture was stirred at 15°C for 1 hour. The reaction mixture was cooled to 0°C, and aqueous sodium bicarbonate solution (5%, 30 mL) was added. The mixture was then extracted three times with dichloromethane (20 mL). The combined organic phases were washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield compound N-2.

[0142] 1H NMR(400MHz,DMSO-d6)δppm 7.73-7.61(m,1H),6.91-6.86(m,1H),6.82-6.75(m,1H),4.99-4.91(m,2H),3.89-3.82(m,3H),2.56-2.54(m,3H),1.60-1.57(m,9H).

[0143] Reference Example 2: Synthesis of intermediate Md

[0144] first step

[0145] Benzylamine (194.62 g, 1.82 mol, 2 eq) was slowly added to acetic acid (103.88 mL, 1.82 mol, 2 eq) in water (850 mL). The reaction system was cooled to 0-10°C, and 1,3-acetonedicarboxylic acid (265.36 g, 1.82 mol, 2 eq) was then slowly added portionwise. The reaction solution was allowed to react at 0°C for 0.5 hours. A solution of compound Ma (170 g, 908.15 mmol, 1 eq) in dioxane (850 mL) was slowly added to the reaction system. The reaction solution was slowly allowed to return to room temperature and then reacted 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 aqueous solution (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 mixed solvent of n-heptane and methyl tert-butyl ether (1:1, 500 mL) for 0.5 h, and the solid was collected by filtration to obtain compound Mb. LC-MS: m / z = 317.1 [M+H] + .

[0146] Step 2

[0147] Compound Mb (220 g, 1 eq) was dissolved in acetonitrile (1700 mL), then heated to 70°C and stirred for 2 hours. L-dibenzoyltartaric acid (200 g, 0.8 eq) was slowly added with stirring. The reaction mixture was stirred at 70°C for another 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 x 2). The filtered solid was added to 1000 mL of water, and the pH was adjusted to 8 with 1 M NaOH aqueous solution. The mixture was then extracted with ethyl acetate (2000 mL x 2). The organic phases were combined and washed with saturated brine (2000 mL x 2). The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 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%.

[0148] Step 3

[0149] Compound Mc (94 g, 297.10 mmol, 1 eq) was dissolved in tetrahydrofuran (750 mL), followed by the addition of water (10.71 mL, 594.19 mmol, 2 eq). 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, 1.2 eq) was slowly added dropwise. After the addition was complete, stirring was continued at this temperature for 30 minutes. Hydrogen peroxide (102.77 mL, 1.07 mol, 30% purity, 3.6 eq) 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 twice with methyl tert-butyl ether (500 mL). The organic phase was washed twice with saturated brine (1000 mL), dried, filtered, and concentrated under reduced pressure to obtain compound Md (retention time: 1.197 min, ee = 96.9%). LC-MS: m / z = 319.1 [M+H] + SFC analysis method: chromatographic column: Chiralcel OJ 50×4.6 mm ID, 3 μm, mobile phase: A: CO2, B: methanol (0.05% diethylamine), gradient B%: 5%-40%.

[0150] Example 1

[0151] first step

[0152] To a solution of compound Md (5 g, 15.70 mmol, 1 eq) in N,N-dimethylformamide (25 mL) at 0°C was added sodium tert-butoxide (4.53 g, 47.11 mmol, 3 eq). The reaction mixture was stirred for 0.5 hours, then cooled to -10°C, deuterated iodomethane (2.23 g, 15.70 mmol, 1 eq) was added, and stirring continued for 2 hours. After the reaction mixture was cooled to room temperature, it was quenched by the addition of water (50 mL) at 0°C. The pH was adjusted to 5-6 with citric acid, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), 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 1-1. LC-MS: m / z = 336.2 [M+H] + .

[0153] Step 2

[0154] To a solution of compound 1-1 (2.1 g, 6.26 mmol, 1 eq) in dimethyl sulfoxide (20 mL) at 0°C, potassium carbonate (951.71 mg, 6.89 mmol, 1.1 eq) was added dropwise, followed by hydrogen peroxide solution (902.27 μL, 9.39 mmol, 30% purity, 1.5 eq). 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 1-2, which was used directly in the next step. LC-MS: m / z = 354.2 [M+H] + .

[0155] Step 3

[0156] At 25°C, N,N-dimethylformamide dimethyl acetal (1.08g, 9.05mmol, 2eq) was added to a solution of compound 1-2 (1.6g, 4.53mmol, 1eq) 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 product of compound 1-3, which was used directly in the next step. LC-MS: m / z=369.2[M+H] + .

[0157] Step 4

[0158] To a solution of compound 1-3 (1.46 g, 3.96 mmol, 1 eq) in anhydrous methanol (15 mL) at 25°C, hydrochloric acid (472.11 μL, 4.75 mmol, 36% purity, 1.2 eq) 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 filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 1-4, which was used directly in the next step. LC-MS: m / z = 279.1 [M+H] + .

[0159] Step 5

[0160] To a solution of compound 1-4 (0.8 g, 2.87 mmol, 1 eq) in N,N-dimethylformamide (10 mL) at 25°C were added compound Nc (831.51 mg, 2.87 mmol, 1 eq), pyridine (695.91 μL, 8.62 mmol, 3 eq), phenylsilane (466.50 mg, 4.31 mmol, 1.5 eq), and trimethylsilyl chloride (780.58 mg, 7.18 mmol, 2.5 eq). After addition, the atmosphere was purged with nitrogen three times. The reaction mixture was stirred at 60°C for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted twice with ethyl acetate (10 mL). The organic phases were combined, washed with saturated brine (10 mL), 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 yield compound 1-5. LC-MS: m / z = 552.3 [M+H] + .

[0161] Step 6

[0162] To a mixture of compound 1-5 (0.4 g, 725.05 μmol, 1 eq) in tetrahydrofuran (2 mL) and anhydrous methanol (2 mL) was added lithium hydroxide monohydrate (1 M, 3.63 mL, 5 eq) at 25°C. After the addition, the reaction mixture was heated to 50°C and reacted 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 HPLC (column: Phenomenex Luna C18 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 1. 1 H 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] + .

[0163] Example 2

[0164] first step

[0165] To a solution of compound Md (6 g, 18.84 mmol, 1 eq) in N,N-dimethylformamide (30 mL) was added sodium tert-butoxide (5.43 g, 56.53 mmol, 3 eq) and then deuterated bromoethane (2.58 g, 22.61 mmol, 1.2 eq) at 0°C for 1 hour. The reaction solution was slowly added dropwise to ice water (150 mL), then the pH was adjusted to 5-6 with citric acid and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with saturated brine (100 mL x 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 = 1:3) to obtain compound 2-1. LCMS: m / z = 352.2 [M+H] + .

[0166] Step 2

[0167] To a solution of compound 2-1 (3.3 g, 9.39 mmol, 1 eq) in dimethyl sulfoxide (30 mL) were added potassium carbonate (1.43 g, 10.33 mmol, 1.1 eq) and hydrogen peroxide (1.35 mL, 14.08 mmol, 30% purity, 1.5 eq). The mixture was stirred at 40°C for 16 hours. The reaction solution was slowly added dropwise to stirred ice water (150 mL). Stirring was continued for 0.5 hours, filtered, and the filter cake was rinsed with water (50 mL x 3). The filter cake was dried under reduced pressure to yield compound 2-2. LCMS: m / z = 370.2 [M+H] + .

[0168] Step 3

[0169] To a solution of compound 2-2 (240.00 mg, 649.51 μmol, 1 eq) in methanol (5 mL) was added N,N-dimethylformamide dimethyl acetal (154.79 mg, 1.30 mmol, 2 eq), and the mixture was stirred at 70°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in ethyl acetate (50 mL), washed with water (30 mL*3), washed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 2-3. LCMS: m / z = 385.1 [M+H] + .

[0170] Step 4

[0171] Compound 2-3 (220.00 mg, 572.14 μmol, 1 eq), wet palladium on carbon (100 mg, 10% content), and concentrated hydrochloric acid (68.17 μL, 686.57 μmol, 36% purity, 1.2 eq) were dissolved in methanol (10 mL) and replaced with nitrogen three times. The reaction solution was stirred at 50°C under nitrogen for 2 hours. The reaction solution was cooled and filtered, and the filtrate was concentrated under reduced pressure. The residue was added to water (50 mL), and the pH was adjusted to 9-10 with 1 M sodium hydroxide solution. The residue was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 2-4. LCMS: m / z = 295.2 [M+H] + .

[0172] Step 5

[0173] To a solution of compound 2-4 (0.16 g, 543.48 μmol, 1 eq) and compound Nc (157.24 mg, 543.48 μmol, 1 eq) in N,N-dimethylformamide (5 mL) were added pyridine (131.60 μL, 1.63 mmol, 3 eq), trimethylsilyl chloride (147.61 mg, 1.36 mmol, 2.5 eq), and phenylsilane (88.21 mg, 815.22 μmol, 1.5 eq). The reaction mixture was stirred at 100°C under nitrogen for 3 hours. Water (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, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (ethyl acetate:petroleum ether = 1:3) to obtain compound 2-5. LCMS: m / z=568.3[M+H] + .

[0174] Step 6

[0175] To a solution of compound 2-5 (180.96 mg, 318.75 μmol, 1 eq) in tetrahydrofuran (3 mL) and methanol (3 mL) was added aqueous lithium hydroxide solution (1 M, 3 mL, 9.41 eq), and the mixture was stirred at 50°C for 16 hours. The reaction solution was cooled to room temperature, the pH was adjusted to 7 with acetic acid, and then concentrated under reduced pressure. The resulting residue was purified by high-performance liquid chromatography (column: Phenomenex C18 75×30 mm×3 μm; mobile phase: A: water (0.05% hydrochloric acid), B: acetonitrile, gradient: B: 22%-42%) to obtain the hydrochloride salt of compound 2. 1H NMR (400MHz, DMSO-d6)δ=13.22(br s,1H),11.25(br s,1H),9.75(br s,1H),8.13(br d,J=8.0Hz,2H),8.06-7.75(m,2H),7.43(t,J=2.8Hz,1H),6.82(s,1H),6.39(br s,1H),4.06-3.93(m,3H),3.86(s,3H),3.60(br s,1H),2.93-2.79(m,2H),2.74-2.71(m,1H),2.64-2.55(m,1H),2.53-2.51(m,2H),2.47-2.45(m,1H),2.40-2.27(m,2H),2.03(br d, J=16Hz, 2H); LC-MS: m / z=454.2[M+H] + .

[0176] Referring to the methods of Examples 1 and 2, the compounds in Table 1 below were prepared from Fragment A and Fragment B:

[0177] Table 1

[0178] Biochemical testing

[0179] Experimental Example 1: Inhibition of Wieslab Complement Alternative Pathway Activation (Enzyme Activity Test)

[0180] Purpose of the experiment:

[0181] pass Complement System Alternative Pathway Kit is used to determine the inhibitory activity of test compounds against the complement alternative pathway in human serum. Experimental plan:

[0182] Dilute the serum with diluent (1:23). Add the drug to the diluted serum, with 8 concentration gradients, up to 10mM or 50mM, and 5-fold gradient dilution. Incubate at room temperature for 15 minutes. Add the compound and serum mixture to the 96-well plate provided by the kit (100μL / well) and activate at 37 degrees for 1 hour. Wash three times with wash buffer. Add the detection antibody provided by the kit (100μL) and incubate at room temperature for 30 minutes. Wash three times with wash buffer. Add the substrate (100μL) and incubate at room temperature for 30 minutes. Detect the absorbance at 405nM using an enzyme reader.

[0183] Experimental results:

[0184] The results of the inhibitory activity of the test compounds on the complement alternative pathway are shown in Table 2. Where A represents: IC 50 Value < 100nM; B represents: 100nM ≤ IC 50 Value ≤ 1000nM; C represents: IC 50 Value>1000nM.

[0185] Table 2: Results of in vitro enzyme activity screening test of the compounds of the present invention

[0186] Conclusion: The compounds of the present invention have significant inhibitory activity on the activation of human serum bypass pathway.

[0187] Experimental Example 2: Pharmacokinetic Study in Rats

[0188] Purpose of the experiment:

[0189] Male SD rats were used as test animals, and the drug concentrations in the plasma of the rats at different time points after oral gavage of the compound of the present invention were determined by LC / MS / MS to study the pharmacokinetic behavior of the compound of the present invention in rats and evaluate its pharmacokinetic characteristics.

[0190] Test plan:

[0191] Healthy male rats weighing 200-300 g were used, with 2 rats in each group.

[0192] 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:

[0193] The pharmacokinetic parameters are shown in Table 3.

[0194] Table 3: Pharmacokinetic data of the compounds of the present invention in rats

[0195] 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.

[0196] Conclusion: The compound of the present invention has good oral exposure and long half-life, and has excellent pharmacokinetic properties.

[0197] Experimental Example 3: LPS-induced complement activation in PD mouse model

[0198] Purpose of the experiment:

[0199] The inhibitory effect of the compounds of the present invention on complement activation induced by LPS stimulation in mice was investigated.

[0200] Experimental animals:

[0201] Female C57BL / 6J mice, 7-9 weeks old, weighing 17-23 g; supplier: Shanghai Xipu-Bikai Laboratory Animal Co., Ltd.

[0202] Experimental process:

[0203] 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 (IO). Model group (positive control): animals received intraperitoneal LPS and PO administration of the vehicle (20% PEG400 / 10% solutol / 70% water). Drug group: 4 hours after administration of the compound (vehicle: 20% PEG400 / 10% solutol / 70% water, administration volume: 5 mL / kg, dose: 10 mg / kg), samples were collected.

[0204] 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.

[0205] Sample analysis: Mix mouse plasma (5 μL) + Lysis buffer (27.5 μL) + Loading buffer (12.5 μL) + Reducing buffer (5 μL) and incubate at 100°C for 15 min. The sample volume is 5 μL / well, i.e., the plasma sample volume per well is 0.5 μL.

[0206] Experimental results:

[0207] After inducing complement activation in mice by intraperitoneal injection, the C3d protein level in the serum of the model group mice increased by 40% to 50% compared with the normal group. After oral administration of the compound of the present invention, the C3d protein level in the serum of the mice in each drug group decreased by 60% to 80% relative to the modeling group, and the C3d protein level decreased significantly. The specific experimental results are shown in Figure 1.

[0208] Experimental conclusion: Compared with the normal group and the model group, the compound of the present invention 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, R7, R8 and R9 are each 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, 3, 4 or 5 R a replace; Each R a are independently selected from D, -F, -Cl, -Br or -I; Each R b are 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 is independently selected from D, -F, -Cl, -Br, -I or -OH; m is selected from 0, 1 or 2; n is selected from 0 or 1; The condition is that R1, R3, R4, R5, R6, R7, R8, R9, R a 、R b At least one of R and D is selected from a deuterated group.

2. The compound of formula (I) according to claim 1, wherein T1 is selected from CH, T2 is selected from CH; or T1 is selected from CH, T2 is selected from N; or T1 is selected from N, T2 is selected from CH.

3. The compound of formula (I) according to claim 1, wherein R2 and R3 together with the atoms to which they are attached form azetidinyl, azepanyl or azahexyl, in which case R4 is selected from H, D, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -CD3, -CD2CD3, -OCD3 or -OCD2CD3.

4. The compound of formula (I) according to claim 1, 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.

5. The compound of formula (I) according to claim 1, wherein Each R b Each 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 by 1, 2, 3, 4 or 5 R.

6. The compound of formula (I) according to claim 1, wherein Each R is independently selected from D or -F.

7. The compound of formula (I) according to claim 1, wherein Structural unit Selected from 8. The compound of formula (I) according to claim 1, wherein Structural unit is selected from phenyl, pyridyl and pyridazinyl.

9. The compound of formula (I) according to claim 1, wherein The compound is selected from in, R1, R4, R5, R6, R7, R8, R9, R b , n, T1 and T2 are as defined in claim 1; When R4 and R5 are different, the carbon atom marked with "#" is a chiral carbon atom, existing in the form of a single enantiomer (R) or (S) or in a 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.

10. The compound of formula (I) according to claim 1, wherein The compound is selected from in, R1, R4, R5, R6, R9 and R b As defined in claim 1; When R4 and R5 are different, the carbon atom marked with "#" is a chiral carbon atom, existing in the form of a single enantiomer (R) or (S) or in a 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.

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

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

13. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

14. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or the pharmaceutical composition according to claim 13 in the preparation of a medicament for treating diseases associated with complement factor B.

15. Use of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or the pharmaceutical composition according to claim 13 in treating diseases related to complement factor B.

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