WO2022022646A1 - 含硒五元杂芳环化合物 - Google Patents

含硒五元杂芳环化合物 Download PDF

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WO2022022646A1
WO2022022646A1 PCT/CN2021/109321 CN2021109321W WO2022022646A1 WO 2022022646 A1 WO2022022646 A1 WO 2022022646A1 CN 2021109321 W CN2021109321 W CN 2021109321W WO 2022022646 A1 WO2022022646 A1 WO 2022022646A1
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compound
pharmaceutically acceptable
acceptable salt
present
independently selected
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French (fr)
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廖勇刚
肖瑶
韦昌青
钱文远
陈曙辉
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Medshine Discovery Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
    • C07D421/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a series of selenium-containing five-membered heteroaromatic compounds, in particular to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • Inflammation is the basis for the occurrence and development of various diseases, and maintaining the balance of inflammatory response is of great significance for the prevention and treatment of infections, autoimmune diseases and cancer.
  • the inflammasome plays an important role in the occurrence and development of inflammation-related diseases.
  • the nucleotide-binding oligomerization domain (NOD)-like receptor family contains pyrin domain protein 3 (NOD-like protein 3).
  • Receptor family, pyrin domain-containing protein 3, NLRP3) inflammasome can be activated by a variety of pathogen-associated molecular patterns (pathogen-associated molecular patterns, PAMPs) and damage-associated molecular patterns (damage-associated molecular patterns, DAMPs), and then activated Caspase-1, which releases mature forms of the pro-inflammatory cytokines interleukins IL-1 ⁇ and IL-18, causes the body's inflammatory response, although this response can be used to defend against foreign pathogens , but aberrant or chronic activation of the NLRP3 inflammasome is known to cause negative downstream effects and the onset and progression of many diseases.
  • pathogen-associated molecular patterns PAMPs
  • damage-associated molecular patterns damage-associated molecular patterns
  • Caspase-1 which releases mature forms of the pro-inflammatory cytokines interleukins IL-1 ⁇ and IL-18, causes the body's inflammatory response, although this response can be used to defend against foreign pathogens ,
  • NLRP3 inflammasome is composed of nucleotide-binding oligomerization domain-like receptors (NLRs) family members NLRP3, adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD)
  • NLRs nucleotide-binding oligomerization domain-like receptors
  • ASC apoptosis-associated speck-like protein containing a CARD
  • a macromolecular multi-protein complex with a molecular weight of about 700kDa composed of the effector protein Caspase-1. It can be detected in a variety of immune cells such as granulocytes, macrophages, dendritic cells, B cells and non-immune cells such as epithelial cells and keratinocytes.
  • NLRP3 Its core protein NLRP3 consists of 11 leucines at the C-terminus Acid repeat sequence (LRR), NACHT domain in the middle and N-terminal Pyrin domain (PYD) composition. NLRP3 interacts with the adaptor protein ASC through its PYD domain, which then recruits and activates pro-Caspase-1 through its CARD domain to form a protein complex, the NLRP3 inflammasome. The recruited pro-Caspase-1 forms a heterotetramer through self-cleavage and hydrolysis, which is the active form of Caspase-1.
  • LRR C-terminus Acid repeat sequence
  • PYD N-terminal Pyrin domain
  • the activated form of Caspase-1 cleaves the cytokine precursors pro-IL-1 ⁇ and pro-IL-18 to produce mature pro-inflammatory cytokines IL-1 ⁇ and IL-18, which are then secreted extracellularly to promote inflammatory responses happened.
  • Activation of the NLRP3 inflammasome requires two signals, priming and activation.
  • the transcription factor NF- ⁇ B is activated by TLR or TNF receptors, thereby up-regulating the expression of NLRP3 and IL-1 ⁇ /IL-18 precursors, providing material reserves for the activation phase.
  • a variety of exogenous microorganisms or endogenous danger signals can act as activators, such as hyperglycemia, hyperlipidemia, uric acid crystals, cholesterol crystals, beta amyloid, and microbial toxins. These activators can effectively induce the assembly of the NLRP3 inflammasome by inducing mitochondrial damage, potassium efflux, and increased intracellular calcium concentration, thereby activating the NLRP3 inflammasome to mediate the inflammatory response.
  • NLRP3 inflammasome is closely related to the occurrence and development of various inflammatory diseases. It was first reported that the NLRP3 inflammasome is involved in the pathogenesis of some familial genetic diseases, such as familial Mediterranean fever and Muckle-Wells syndrome. Later studies found that the Cias1 gene encoding NLRP3 on chromosome 1 of these patients was mutated, so that NLRP3 could not be inhibited by itself and was always activated. Through the formation of NLRP3 inflammasomes, pro-IL-1 ⁇ and pro - IL-18 is spliced into mature IL-1 ⁇ and IL-18, leading to its massive secretion, causing an excessive inflammatory response in the body.
  • IL-1 ⁇ IL-1 receptor of target cells
  • ROS reactive oxygen species
  • Mature IL-1 ⁇ binds to the IL-1 receptor of target cells and activates downstream signal transduction factors, generating a large number of inflammatory mediators and aggravating the inflammatory response.
  • ⁇ -Amyloid can activate the NLRP3 inflammasome of microglia, leading to an inflammatory response in the brain, causing neuronal damage and death, and then causing neurodegenerative diseases such as Alzheimer's disease.
  • Long-term high concentrations of glucose in vivo can stimulate islet cells to activate the NLRP3 inflammasome, produce mature IL-1 ⁇ , trigger a series of inflammatory responses, induce IL-1 ⁇ -dependent cell damage and death, aggravate islet cell dysfunction, and ultimately lead to 2 development of type diabetes.
  • NLRP3 antagonists have been reported in patent applications such as WO2016131098, WO2019025467, WO2019121691 and WO2018015445.
  • MCC950 a derivative of diarylsulfonylurea, can reduce the severity of experimental autoimmune encephalomyelitis (EAE) in mice by inhibiting NLRP3 inflammasome activity.
  • Another small-molecule antagonist, CY-09 specifically blocks the assembly and activation of the NLRP3 inflammasome, and is critical for cryopyrin-associated auto-inflammatory syndrome (cAPS) and type II diabetes in mice The model has a significant therapeutic effect.
  • IFM-Tre's NLRP3 antagonist IFM-2427 is undergoing multiple Phase I studies.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 4 are each independently selected from H, C 1-3 alkyl, phenyl and 5-6 membered heteroaryl, the C 1-3 alkyl, phenyl and 5-6 membered heteroaryl being any is optionally substituted with 1, 2 or 3 Ra ;
  • R 2 and R 3 are each independently selected from H, NH 2 , halogen and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ;
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 4-5 cycloalkyl group optionally substituted with 1, 2 or 3 R c ;
  • R3 and R4 together with the carbon atom to which they are attached form a C4-5 cycloalkyl group optionally substituted with 1, 2 or 3 Rcs ;
  • R 5 is selected from H, F, Cl, D and CN;
  • each R is independently selected from H, F, Cl, Br, I, C 1-3 alkoxy and CN, said C 1-3 alkoxy optionally substituted with 1, 2 or 3 F;
  • Each R b and R c is independently selected from H, F, Cl, Br, I, C 1-3 alkoxy, and CN, said C 1-3 alkoxy optionally surrounded by 1, 2 or 3 F replace;
  • a 1 , A 2 and A 3 are each independently selected from CH, N and Se, and at least one of A 1 , A 2 and A 3 is selected from Se;
  • the 5-6 membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from -NH-, -O-, -S-, -Se- and N.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 4 are each independently selected from H, C 1-3 alkyl, phenyl and 5-6 membered heteroaryl, the C 1-3 alkyl, phenyl and 5-6 membered heteroaryl being any is optionally substituted with 1, 2 or 3 Ra ;
  • R 2 and R 3 are each independently selected from H, NH 2 , halogen and C 1-3 alkyl;
  • R 1 and R 2 together with the carbon atom to which they are attached form a C 4-5 cycloalkyl
  • R 5 is selected from H, F, Cl, D and CN;
  • each R is independently selected from H, C 1-3 alkoxy and CN;
  • a 1 , A 2 and A 3 are each independently selected from CH, N and Se, and at least one of A 1 , A 2 and A 3 is selected from Se;
  • the 5-6 membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from -NH-, -O-, -S-, -Se- and N.
  • the present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 and R 4 are each independently selected from H, C 1-3 alkyl, phenyl and 5-6 membered heteroaryl, the C 1-3 alkyl, phenyl and 5-6 membered heteroaryl being any is optionally substituted with 1, 2 or 3 Ra ;
  • R 2 and R 3 are each independently selected from H, NH 2 , halogen and C 1-3 alkyl;
  • R 5 is selected from H, F, Cl, D and CN;
  • each R is independently selected from H, C 1-3 alkoxy and CN;
  • a 1 , A 2 and A 3 are each independently selected from CH, N and Se, and at least one of A 1 , A 2 and A 3 is selected from Se, and the remaining two are selected from CH and N;
  • the 5-6 membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from -NH-, -O-, -S-, -Se- and N.
  • the above-mentioned compound has the structure represented by formula (I-a)
  • a 1 , A 2 , A 3 , Ra and R 5 are as defined in the present invention.
  • a 1 , A 2 , A 3 and R 5 are as defined in the present invention.
  • a 1 , A 2 , A 3 , Ra and R 5 are as defined in the present invention.
  • R a and R 5 are as defined in the present invention.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the present invention.
  • each of the above R a is independently selected from H, F, Cl, OCH 3 , OCH 2 CH 3 and CN, and other variables are as defined in the present invention.
  • each of the above R a is independently selected from H, OCH 3 and CN, and other variables are as defined in the present invention.
  • each of the above R b is independently selected from H, F, Cl, OCH 3 , OCH 2 CH 3 and CN, and other variables are as defined in the present invention.
  • each of the above R c is independently selected from H, F, Cl, OCH 3 , OCH 2 CH 3 and CN, and other variables are as defined in the present invention.
  • the above R 1 is selected from pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl and oxazolyl, said pyridyl, pyrimidinyl, pyrrolyl, pyrazolyl, Imidazolyl, thiazolyl and oxazolyl are optionally substituted with 1, 2 or 3 R a , other variables are as defined herein.
  • R 1 is selected from Other variables are as defined in the present invention.
  • R 2 is selected from H, and other variables are as defined in the present invention.
  • R 3 is selected from H, and other variables are as defined in the present invention.
  • R 4 is selected from H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH3 and CH( CH3 ) 2 are optionally substituted with 1, 2 or 3 R a , other variables are as defined in the present invention.
  • R 4 is selected from Other variables are as defined in the present invention.
  • R 1 and R 2 together with the carbon atom to which they are attached form a cyclopentyl group optionally substituted with 1, 2 or 3 R c , other variables as defined herein .
  • the above R1 and R2 together with the carbon atom to which they are attached make a structural unit selected from Other variables are as defined in the present invention.
  • the above R3 and R4 together with the carbon atom to which they are attached form a cyclopentyl group optionally substituted with 1, 2 or 3 Rc , other variables as defined herein .
  • the above R3 and R4 together with the carbon atom to which they are attached form a structural unit selected from Other variables are as defined in the present invention.
  • R1 and R2 are formed together with the carbon atom to which they are attached
  • Other variables are as defined in the present invention.
  • R1 and R2 are formed together with the carbon atom to which they are attached
  • Other variables are as defined in the present invention.
  • R3 and R4 are formed together with the carbon atom to which they are attached
  • Other variables are as defined in the present invention.
  • R3 and R4 are formed together with the carbon atom to which they are attached
  • Other variables are as defined in the present invention.
  • the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
  • the compound of the present invention exhibits good NLRP3 inhibitory activity, good oral bioavailability, high exposure, good in vivo efficacy, and has a large effect in the treatment of inflammation-related diseases. application prospects.
  • the exposure of some of these compounds in the gut is much higher than that in the plasma, and can be targeted for development for the treatment of intestinal inflammation-related indications.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such 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.
  • acid addition salts can be obtained by contacting such 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 including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • 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 isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
  • the enantiomer content is less than 100%, and the isomer or enantiomer content 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%.
  • isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of 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% .
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • the substituent can bond to any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene.
  • substituents do not specify through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine rings. The carbon atom is attached to the substituted group.
  • the direction of attachment is arbitrary, for example,
  • the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
  • Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites in the group can be linked to other groups by chemical bonds.
  • connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
  • the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines Express.
  • a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
  • the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” refers to a “ring” of 5-7 atoms arranged around it.
  • 3-10 membered ring means cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl consisting of 3 to 10 ring atoms.
  • Said ring includes a single ring, and also includes a bicyclic or polycyclic ring system such as a spiro ring, a paracyclic ring and a bridged ring.
  • the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the 3-10-membered ring includes 3-10 yuan, 3-9 yuan, 3-8 yuan, 3-7 yuan, 3-6 yuan, 3-5 yuan, 4-10 yuan, 4-9 yuan, 4- 8 yuan, 4-7 yuan, 4-6 yuan, 4-5 yuan, 5-10 yuan, 5-9 yuan, 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6- 9 yuan, 6-8 yuan and 6-7 yuan ring, etc.
  • the term "5-7 membered heterocycloalkyl” includes piperidinyl and the like, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, wherein each "ring" independently meets the above definition.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • C 1-6 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl and the like; it can be Is monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methine).
  • C 1-6 alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
  • Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C1-6alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-6 alkoxy groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy groups, etc. .
  • C 1-6 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) oxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy and the like.
  • C1-3alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 3-5 cycloalkyl means a saturated or partially unsaturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, the C 3-5 ring
  • the alkyl group includes C3-4 and C4-5 cycloalkyl and the like; it may be monovalent, divalent or polyvalent.
  • Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • C 4-5 cycloalkyl means a saturated or partially unsaturated cyclic hydrocarbon group consisting of 4 to 5 carbon atoms, which is a monocyclic ring system; it may be monovalent, divalent price or multi-price.
  • Examples of C4-5 cycloalkyl groups include, but are not limited to, cyclobutyl, cyclopentyl, and the like.
  • the terms “5-6 membered heteroaryl ring” and “5-6 membered heteroaryl” are used interchangeably in the present invention, and the term “5-6 membered heteroaryl” means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated ⁇ electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4
  • 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 enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structure of the compound 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 compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • the solvent used in the present invention is commercially available.
  • CO2 represents carbon dioxide
  • ATP represents adenosine triphosphate
  • LPS represents lipopolysaccharide
  • CBA represents cytokine microsphere detection technology
  • PMA represents crotyl alcohol-12-tetradecanoate-13-acetate
  • NEAA stands for non-essential amino acids
  • FBS stands for fetal bovine serum
  • IL-1 ⁇ stands for interleukin-1 ⁇
  • Human IL-1 ⁇ Flex Set stands for human interleukin-1 ⁇ detection kit.
  • Step 2 tert-butyl nitrite (2.8 g, 28.0 mmol) and copper bromide (4.5 g, 20.2 mmol) were added to acetonitrile (30 mL), and compound 1-3 (3.7 g, 16.8 mmol) in acetonitrile ( 30 mL) solution and the reaction was stirred at 25°C for 1 hour.
  • Step 6 Compound 1-7 (1.0 g, 2.3 mmol) was dissolved in acetonitrile (24 mL), acetic acid (0.3 mL) and water (0.6 mL), 1,3-dichloro-5,5 was added at 0°C - Dimethyl hydantoin (0.9 g, 4.6 mmol), the reaction was stirred at 25°C for 5 minutes. After cooling the reaction system to 0°C, ammonia water (4.7 mL, 46.8 mmol, 38%) was added, and the temperature was raised to 25°C and stirring was continued for 0.5 hours.
  • Step 1 Compound 2-1 (500.0 mg, 2.3 mmol) and compound 2-2 (357.0 mg, 2.3 mmol) were dissolved in dioxane (40 mL)/water (8 mL), followed by [1,1' -Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (191.1 mg, 234.0 ⁇ mol) and potassium carbonate (646.8 mg, 4.7 mmol), the reaction was stirred at 100°C for 2 After 1 hour, it was cooled to room temperature, and extracted with water (50 mL) and ethyl acetate (150 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated.
  • Step 2 Compound 2-3 (95.0 mg, 392.1 mmol) was dissolved in tetrahydrofuran (10 mL), triphosgene (50.0 mg, 168.6 ⁇ mol) and triethylamine (119.0 g, 1.2 mmol) were added at 25° C., 25 Stir at °C for 0.5 hour. After the completion of the reaction, the reaction solution was filtered to obtain the tetrahydrofuran solution of compound 2-4, which was directly used in the next step.
  • Step 2 Compound 3-2 (10.0 g, 37.5 mmol) and tert-butyl carbamate (8.8 g, 75.1 mmol) were dissolved in dioxane (150 mL), and cesium carbonate (24.48 g, 75.12 g) was added under nitrogen protection mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (4.3g, 7.5mmol) and tris(dibenzylideneacetone)dipalladium (3.4g, 3.7mmol), react Stir at 80°C for 1 hour.
  • Step 3 Compound 3-3 (6.0 g, 25.7 mmol) was dissolved in dichloromethane (50 mL), trifluoroacetic acid (17.6 g, 154.3 mmol) was added dropwise at 25 °C, and the reaction was stirred at 25 °C for 1 hour, Saturated sodium bicarbonate (200 mL) was added to quench, and then extracted with dichloromethane (200 mL). The organic phase was concentrated to obtain compound 3-4, which was directly used in the next step. MS ESI calcd for C9H11N [M+H] + 134, found 134.
  • Step 5 Compound 3-5 (2.9g, 16.5mmol) was dissolved in tetrahydrofuran (50ml), p-toluenesulfonic acid (1.6g, 9.1mmol) and palladium acetate (185.7mg, 827.5 ⁇ mol) were added at 20°C After stirring for 0.5 hours, N-bromosuccinimide (3.2 g, 18.2 mmol) was added, and the reaction was stirred at 20° C. for 2 hours. After the reaction was completed, water (50 mL) was added to quench, and ethyl acetate (150 mL) was used for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated.
  • Step 8 Compound 3-8 (103.7 mg, 431.8 ⁇ mol) was dissolved in tetrahydrofuran (10 ml), triphosgene (55.1 mg, 185.6 ⁇ mol) and triethylamine (131.2 mg, 1.3 mmol) were added at 25° C., at 25° C. under stirring for 0.5 hours. After the reaction was completed, the tetrahydrofuran solution of compound 3-9 was obtained by filtration, which was directly used in the next step.
  • the human monocytic cell line THP1 was used to study the inhibitory activity (IC 50 ) of NLRP3 antagonists on cellular IL-1 ⁇ secretion.
  • the monocyte line THP1 was differentiated into mature macrophages using PMA (crotyl alcohol-12-tetradecanoate-13-acetate), and then LPS (lipopolysaccharide), an agonist of the Toll-like receptor TLR4, was used to Stimulation of cells activates the transcriptional activity of the inflammasome NLRP3 and the expression of the IL-1 ⁇ precursor pro-IL-1 ⁇ .
  • an antagonist of NLRP3 is added, followed by ATP to further mature and activate NLRP3 and activate downstream caspase-1.
  • Activated caspase-1 can digest pro-IL-1 ⁇ into mature IL-1 ⁇ that can be secreted.
  • NLRP3 antagonists can effectively inhibit the ATP-induced maturation and activation of NLRP3 and the activation of downstream caspase-1, thereby inhibiting the maturation and secretion of IL-1 ⁇ .
  • THP1 cells were adjusted to 5*10 5 cells/mL, then PMA was added, and the final concentration was adjusted to 100 ng/mL, 200 ⁇ L/well was seeded into a 96-well flat bottom plate, stimulated at 37°C, 5% CO 2 Overnight (try ⁇ 16 hours).
  • test compounds were added into the wells, and the screening concentrations were: 5 ⁇ M, 1 ⁇ M, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, and 0.064 nM, respectively. Incubate for 1 h in a 37°C, 5% CO2 incubator.
  • mice To test the pharmacokinetics of the compounds of the present invention in mice.
  • the clear solution obtained after dissolving test compound 1 was administered to male C57BL/6 mice (C57BL/6) by tail vein injection and gavage respectively (fasted overnight, resumed eating 4 hours after administration, 7-10 weeks old) ).
  • the dose of intravenous injection was 0.5 mg/kg, and the dose of intragastric administration was 2.0 mg/kg.
  • the intravenous injection group at 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 hours, the gavage group at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours, respectively, from Blood was collected from the saphenous vein and centrifuged to obtain plasma.
  • the plasma concentration was determined by LC-MS/MS method, and the relevant pharmacokinetic parameters were calculated by non-compartmental model linear logarithmic trapezoid method using WinNonlin TM Version 6.3 pharmacokinetic software. Relevant parameters: T 1/2 : half-life; Vd: apparent volume of distribution; Cl: clearance rate; C max : peak concentration; AUC 0-inf : time from 0 time to the last detectable drug concentration, this experiment In is the area under the plasma concentration-time curve from 0 to 24 hours; F%: bioavailability. The test results are shown in Table 2:
  • mice supplier is Shanghai Lingchang Biotechnology Co., Ltd.
  • the clear solution obtained after dissolving the test compound 2 is 10% DMSO/10% Solutol/80% Water
  • two mice were injected through the tail vein respectively, the injection dose was 3 mg/kg, at 0.0833, 0.25, 0.5
  • Blood was collected from saphenous vein at 1, 2, 4, 8 and 24 hours and the plasma was obtained after centrifugation; eight mice were given intragastrically at a dose of 20 mg/kg, two of which were administered at 0.25, 0.5, 1, 2, 4, At 6, 8, and 24 hours, blood was collected from the saphenous vein and centrifuged to obtain plasma, and the other six animals were euthanized at 0.25, 2, and 6 hours after administration. Rinse with saline and place on soft absorbent paper to drain any remaining fluid.
  • Plasma and colorectal concentrations were determined by LC-MS/MS method, and relevant pharmacokinetic parameters were calculated by non-compartmental model linear logarithmic trapezoidal method using WinNonlin TM Version 6.3 pharmacokinetic software. The test results are shown in Table 3:
  • the compounds of the present invention have good oral bioavailability in mice, and high exposure is conducive to producing good in vivo efficacy. Some of the compounds have intestinal exposures far greater than plasma exposures, and can be developed for targeted use. Treatment of Intestinal Inflammation-Related Indications.
  • the murine air pouch (AirPouch) is a sac-like space similar to the human synovium, and the injection of monosodium urate crystals (MSU) into the air pouch causes an acute inflammatory response similar to that of human gout.
  • MSU monosodium urate crystals
  • mice Air Pouch gout model was used to evaluate the effect of the compounds of the present invention in the treatment of acute gout.
  • mice C57BL/6 mice, male, 7-8 weeks old, Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.
  • mice Healthy mice were used for numbering and grouping, and sterile air was injected into the back of the mice on the day (Day 1) and day 4 (Day 4) to generate air sacs.
  • day 7 On day 7 (Day 7), administration was performed first, MSU crystalloid solution was injected into the balloon 1 hour later, and balloon flushing fluid (APLV) was collected and analyzed 7 hours later.
  • APLV balloon flushing fluid
  • uric acid 1 g was dissolved in 0.2 liters of boiling water containing 6 mL of 1N sodium hydroxide. After adjusting the pH to 7.4, the solution was gradually cooled at room temperature and then left at 4 °C overnight. MSU crystals were recovered by centrifugation, dried by evaporative drying, dispensed into individual vials (3 mg), and sterilized by autoclaving.
  • mice Healthy C57BL/6 mice were used for numbering and grouping, and a pouch was created by subcutaneous injection of 5 mL of sterile air into the back of the mice on the day of grouping (Day 1 ) and the fourth day (Day 4).
  • Day 7 On the seventh day (Day 7), the group mice were given vehicle or test substance, respectively, and 1 hour later, a suspension of MSU crystals (saline, 3 mg/mL) was injected into the balloon. After 6 hours, the balloon flushing fluid (APLV) will be collected and the levels of IL-6 and IL-1 ⁇ in APLV will be tested using ELISA kits. Results are expressed as mean ⁇ SEM. Statistical analysis was performed using a method of analysis of variance (ANOVA) followed by Dunnett's test and differences were considered significant when p ⁇ 0.05. test results
  • MSU injection produced an acute inflammatory response in the air sacs of the mice, as manifested by significantly elevated concentrations of inflammatory cytokines IL-6 and IL-1 ⁇ in APLV.
  • the inflammatory response was significantly inhibited, and the levels of IL-6 and IL-1 ⁇ in APLV were decreased.
  • Compound 1 has a better effect on reducing IL-6 than MCC950 at the same dose, and has a similar effect on reducing IL-1 ⁇ as MCC950.
  • Figure 1 shows the results of the inhibition experiment of the inflammatory cytokine IL-6 in APLV
  • Figure 2 shows the results of the inhibition experiment of the inflammatory cytokine IL-1 ⁇ in APLV.
  • p indicates a significant difference, *: p ⁇ 0.05; **: p ⁇ 0.01; ***p ⁇ 0.001.
  • the compound of the present invention has a good therapeutic effect on MSU-induced C57BL/6 mouse Air Pouch gout model, and has the potential to treat gout and other diseases related to inflammatory cytokines.

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Abstract

涉及如式(I)所示的含硒五元杂芳环化合物、及其药学上可接受的盐；式(I)中，A1、A2和A3各自独立地选自CH、N和Se，且A1、A2和A3中至少有一个选自Se。所述化合物作为NLRP3拮抗剂，展示了良好的NLRP3抑制活性，有良好的口服生物利用度，较高的暴露量，有利于产生良好的体内药效，在治疗炎症相关的疾病中具有应用前景。

Description

含硒五元杂芳环化合物
本发明主张如下优先权：
CN 202010743475.5，2020年07月29日；
CN 202110757415.3，2021年07月05日。
技术领域
本发明涉及一系列含硒五元杂芳环化合物，具体涉及式(I)所示化合物或其药学上可接受的盐。
背景技术
炎症是多种疾病发生、发展的基础，维持炎症应答平衡对防治感染、自身免疫疾病和癌症等有重要意义。炎症小体(inflammasome)在炎症相关疾病的发生发展中发挥重要作用，核苷酸结合寡聚化结构域(nucleotide-binding oligomerization domain，NOD)样受体家族含pyrin结构域蛋白3(NOD-like receptor family，pyrin domain-containing protein 3，NLRP3)炎症小体能够被多种病原相关分子模式(pathogen-associated molecular patterns，PAMPs)和损伤相关分子模式(damage-associated molecular patterns，DAMPs)激活，进而活化半胱氨酸天冬氨酸蛋白酶-1(caspase-1)，释放成熟形式的促炎因子白细胞介素IL-1β和IL-18，引起机体的炎症反应，虽然这种反应可用于抵御外来病原体，但已知NLRP3炎性体的异常或慢性激活会引起下游的负面影响以及许多疾病的发作和进展。
NLRP3炎性小体是由核苷酸结合寡聚化结构域样受体(nucleotide-binding oligomerization domain-like receptors，NLRs)家族成员NLRP3、接头蛋白ASC(apoptosis-associated speck-like protein containing a CARD)和效应蛋白Caspase-1组成的一种分子量约为700kDa的大分子多蛋白复合体。在多种免疫细胞如粒细胞、巨噬细胞、树突状细胞、B细胞和非免疫细胞如上皮细胞和角细胞等都能够被检测到，其核心蛋白NLRP3由C-末端的11个亮氨酸重复序列(LRR)，中间的NACHT结构域以及N-末端的Pyrin结构域(PYD)组成。NLRP3通过PYD结构域与接头蛋白ASC相互作用，然后ASC通过其CARD结构域募集并激活pro-Caspase-1，形成蛋白复合物，即NLRP3炎症小体。被招募的pro-Caspase-1通过自切割、水解形成异四聚体，即为Caspase-1的活性形式。激活形式的Caspase-1对细胞因子前体pro-IL-1β与pro-IL-18进行切割产生成熟的促炎性细胞因子IL-1β和IL-18，继而分泌到胞外，从而促进炎症反应的发生。
NLRP3炎症小体的活化需要引发(priming)和激活(activation)两个信号。在引发阶段，由TLR或者TNF受体活化转录因子NF-κB，从而上调NLRP3以及IL-1β/IL-18前体的表达，为激活阶段提供物质储备。在激活阶段，多种外源性微生物或内源性危险信号可充当激活剂，如高血糖、高血脂、尿酸结晶、胆固醇结晶、β淀粉样蛋白和微生物毒素等多种物质。这些激活剂可通过诱导线粒体损伤、钾离子外流和细胞内钙离子浓度升高等途径有效诱导NLRP3炎症小体组装，从激活NLRP3炎症小体进而介导炎症反应。
越来越多的研究证实NLRP3炎性小体与多种炎症性疾病的发生发展密切相关。最早有报道指出NLRP3炎性小体与一些家族性遗传性疾病的发病有关，如家族性地中海发热和Muckle-Wells综合征等。后经研究发现这类患者1号染色体上编码NLRP3的Cias1基因发生了突变，使NLRP3不能被自身抑制，始终处于激活状态，通过形成NLRP3炎性小体，持续地将pro-IL-1β和pro-IL-18剪切为成熟的IL-1β和IL-18，导致其大量分泌，引起机体过度的炎症反应。痛风病人关节及周围的尿酸盐晶体被巨噬细胞吞噬后可能通过促进钾离子外流和诱导线粒体产生大量活性氧ROS，使NLRP3炎性小体活化，促使IL-1β成熟和分泌。成熟的IL-1β与靶细胞的IL-1受体结合后激活下游信号转导因子，生成大量炎症介质从而加重炎症反应。β-淀粉样蛋白可通过激活小胶质细胞的NLRP3炎性小体，导致脑内炎症反应，引起神经元的损伤和死亡，进而引起阿尔兹海默病等神经退行性疾病的发生。内皮细胞和巨噬细胞从血液中摄取的胆固醇，形成微小胆固醇结晶，激活NLRP3炎性小体，在动脉粥样硬化的发生与发展过程中起着重要作用。体内长期高浓度的葡萄糖能刺激胰岛细胞激活NLRP3炎性小体，产生成熟的IL-1β，引发一系列炎症反应，诱导IL-1β依赖的细胞损伤和死亡，加重胰岛细胞功能障碍，最终导致2型糖尿病的发生发展。
有多种NLRP3拮抗剂在WO2016131098、WO2019025467、WO2019121691和WO2018015445等专利申请中被报道。二芳基磺酰脲的衍生物MCC950通过抑制NLRP3炎症小体活性，可以减轻小鼠脑脊髓炎(experimental autoimmune encephalomyelitis，EAE)的严重程度。另一种小分子拮抗剂CY-09，特异性地阻断NLRP3炎症小体的组装与活化，对于小鼠低温相关的自身炎症综合征(cryopyrin-associated auto-inflammatory syndrome，cAPS)和II型糖尿病模型有显著的治疗效果。IFM-Tre公司的NLRP3拮抗剂IFM-2427正在开展多种临床I期研究。
Figure PCTCN2021109321-appb-000001
探究NLRP3炎症小体的活化机制，开发靶向的NLRP3小分子拮抗剂，能为与其相关的炎症性疾病提供潜在的治疗手段，有着重要意义和广阔的前景。目前，仍然存在开发新的NLRP3拮抗剂用于治疗炎症性疾病的需求。
发明内容
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2021109321-appb-000002
其中，
R 1和R 4各自独立地选自H、C 1-3烷基、苯基和5-6元杂芳基，所述C 1-3烷基、苯基和5-6元杂芳基任选被1、2或3个R a取代；
R 2和R 3各自独立地选自H、NH 2、卤素和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代；
或者，R 1和R 2与它们连接的碳原子一起形成C 4-5环烷基，所述C 4-5环烷基任选被1、2或3个R c取代；
或者，R 3和R 4与它们连接的碳原子一起形成C 4-5环烷基，所述C 4-5环烷基任选被1、2或3个R c取代；
R 5选自H、F、Cl、D和CN；
各R a独立地选自H、F、Cl、Br、I、C 1-3烷氧基和CN，所述C 1-3烷氧基任选被1、2或3个F取代；
各R b和R c分别独立地选自H、F、Cl、Br、I、C 1-3烷氧基和CN，所述C 1-3烷氧基任选被1、2或3个F取代；
A 1、A 2和A 3各自独立地选自CH、N和Se，且A 1、A 2和A 3中至少有一个选自Se；
所述5-6元杂芳基包含1、2、3或4个独立选自-NH-、-O-、-S-、-Se-和N的杂原子或杂原子团。
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2021109321-appb-000003
其中，
R 1和R 4各自独立地选自H、C 1-3烷基、苯基和5-6元杂芳基，所述C 1-3烷基、苯基和5-6元杂芳基任选被1、2或3个R a取代；
R 2和R 3各自独立地选自H、NH 2、卤素和C 1-3烷基；
或者R 1和R 2与它们连接的碳原子一起形成C 4-5环烷基；
或者R 3和R 4与它们连接的碳原子一起形成C 4-5环烷基；
R 5选自H、F、Cl、D和CN；
各R a独立地选自H、C 1-3烷氧基和CN；
A 1、A 2和A 3各自独立地选自CH、N和Se，且A 1、A 2和A 3中至少有一个选自Se；
所述5-6元杂芳基包含1、2、3或4个独立选自-NH-、-O-、-S-、-Se-和N的杂原子或杂原子团。
本发明还提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2021109321-appb-000004
其中，
R 1和R 4各自独立地选自H、C 1-3烷基、苯基和5-6元杂芳基，所述C 1-3烷基、苯基和5-6元杂芳基任选被1、2或3个R a取代；
R 2和R 3各自独立地选自H、NH 2、卤素和C 1-3烷基；
或者R 1、R 2与它们连接的碳原子一起形成C 4-5环烷基；
或者R 3、R 4与它们连接的碳原子一起形成C 4-5环烷基；
R 5选自H、F、Cl、D和CN；
各R a独立地选自H、C 1-3烷氧基和CN；
A 1、A 2和A 3各自独立地选自CH、N和Se，且A 1、A 2和A 3中至少有一个选自Se，其余两个选自CH和N；
所述5-6元杂芳基包含1、2、3或4个独立选自-NH-、-O-、-S-、-Se-和N的杂原子或杂原子团。
本发明的一些方案中，上述化合物具有式(I-a)所示结构
Figure PCTCN2021109321-appb-000005
其中，A 1、A 2、A 3、R a和R 5如本发明所定义。
本发明的一些方案中，上述化合物具有式(I-b)所示结构：
Figure PCTCN2021109321-appb-000006
其中，A 1、A 2、A 3和R 5如本发明所定义。
本发明的一些方案中，上述化合物具有式(I-c)所示结构：
Figure PCTCN2021109321-appb-000007
其中，A 1、A 2、A 3、R a和R 5如本发明所定义。
本发明的一些方案中，上述化合物具有式(I-c-1)所示结构：
Figure PCTCN2021109321-appb-000008
其中，R a和R 5如本发明所定义。
本发明的一些方案中，上述化合物具有式(I-d)所示结构：
Figure PCTCN2021109321-appb-000009
其中，R 1、R 2、R 3、R 4和R 5如本发明所定义。
本发明的一些方案中，上述各R a独立地选自H、F、Cl、OCH 3、OCH 2CH 3和CN，其他变量如本发明所定义。
本发明的一些方案中，上述各R a独立地选自H、OCH 3和CN，其他变量如本发明所定义。
本发明的一些方案中，上述各R b独立地选自H、F、Cl、OCH 3、OCH 2CH 3和CN，其他变量如本发明所定义。
本发明的一些方案中，上述各R c独立地选自H、F、Cl、OCH 3、OCH 2CH 3和CN，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自吡啶基、嘧啶基、吡咯基、吡唑基、咪唑基、噻唑基和噁唑基，所述吡啶基、嘧啶基、吡咯基、吡唑基、咪唑基、噻唑基和噁唑基任选被1、2或3个R a取代，其他变量如 本发明所定义。
本发明的一些方案中，上述R 1选自
Figure PCTCN2021109321-appb-000010
其他变量如本发明所定义。
本发明的一些方案中，上述R 2选自H，其他变量如本发明所定义。
本发明的一些方案中，上述R 3选自H，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自H、CH 3、CH 2CH 3、CH 2CH 2CH 3和CH(CH 3) 2，所述CH 3、CH 2CH 3、CH 2CH 2CH 3和CH(CH 3) 2任选被1、2或3个R a取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自
Figure PCTCN2021109321-appb-000011
其他变量如本发明所定义。
本发明的一些方案中，上述R 1和R 2与它们连接的碳原子一起形成环戊基，所述环戊基任选被1、2或3个R c取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 1和R 2与它们连接的碳原子一起使结构单元
Figure PCTCN2021109321-appb-000012
选自
Figure PCTCN2021109321-appb-000013
其他变量如本发明所定义。
本发明的一些方案中，上述R 3和R 4与它们连接的碳原子一起形成环戊基，所述环戊基任选被1、2或3个R c取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 3和R 4与它们连接的碳原子一起使结构单元
Figure PCTCN2021109321-appb-000014
选自
Figure PCTCN2021109321-appb-000015
其他变量如本发明所定义。
本发明的一些方案中，上述R 1和R 2与它们连接的碳原子一起形成
Figure PCTCN2021109321-appb-000016
其他变量如本发明所定义。
本发明的一些方案中，上述R 1和R 2与它们连接的碳原子一起形成
Figure PCTCN2021109321-appb-000017
其他变量如本发明所定义。
本发明的一些方案中，上述R 3和R 4与它们连接的碳原子一起形成
Figure PCTCN2021109321-appb-000018
其他变量如本发明所定义。
本发明的一些方案中，上述R 3和R 4与它们连接的碳原子一起形成
Figure PCTCN2021109321-appb-000019
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2021109321-appb-000020
选自
Figure PCTCN2021109321-appb-000021
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2021109321-appb-000022
选自
Figure PCTCN2021109321-appb-000023
其他变量如本发明所定义。
本发明还有一些方案由上述变量任意组合而来。
本发明还提供了下式所示化合物或其药学上可接受的盐，
Figure PCTCN2021109321-appb-000024
技术效果
本发明化合物作为NLRP3拮抗剂，展示了良好的NLRP3抑制活性，有良好的口服生物利用度，较高的暴露量，有利于产生良好的体内药效，在治疗炎症相关的疾病中具有较大的应用前景。其中部分化合物 在肠道中暴露量远高于血浆中的暴露量，可以针对性的开发用于肠道炎症相关适应症的治疗。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2021109321-appb-000025
和楔形虚线键
Figure PCTCN2021109321-appb-000026
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2021109321-appb-000027
和直形虚线键
Figure PCTCN2021109321-appb-000028
表示立体中心的相对构型，用波浪线
Figure PCTCN2021109321-appb-000029
表示楔形实线键
Figure PCTCN2021109321-appb-000030
或楔形虚线键
Figure PCTCN2021109321-appb-000031
或用波浪线
Figure PCTCN2021109321-appb-000032
表示直形实线键
Figure PCTCN2021109321-appb-000033
或直形虚线键
Figure PCTCN2021109321-appb-000034
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物 的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当一个取代基数量为0时，表示该取代基是不存在的，比如-A-(R) 0表示该结构实际上是-A。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基的键可以交叉连接到一个环上的两一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2021109321-appb-000035
表示其取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2021109321-appb-000036
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2021109321-appb-000037
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2021109321-appb-000038
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2021109321-appb-000039
直形虚线键
Figure PCTCN2021109321-appb-000040
或波浪线
Figure PCTCN2021109321-appb-000041
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2021109321-appb-000042
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2021109321-appb-000043
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
Figure PCTCN2021109321-appb-000044
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2021109321-appb-000045
Figure PCTCN2021109321-appb-000046
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2021109321-appb-000047
仍包括
Figure PCTCN2021109321-appb-000048
这种连接方式的基团，只是在连接1个化学键时，该位点的H会对应减少1个变成相应的一价哌啶基。
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。
除非另有规定，“3-10元环”表示由3至10个环原子组成的环烷基、杂环烷基、环烯基或杂环烯基。所述的环包括单环，也包括螺环、并环和桥环等双环或多环体系。除非另有规定，该环任选地包含1、2或3个独立选自O、S和N的杂原子。所述3-10元环包括3-10元、3-9元、3-8元、3-7元、3-6元、3-5元、4-10元、4-9元、4-8元、4-7元、4-6元、4-5元、5-10元、5-9元、5-8元、5-7元、5-6元、6-10元、6-9元、6-8元和6-7元环等。术语“5-7元杂环烷基”包括哌啶基等，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。
除非另有规定，术语“C 1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C 1-6烷氧基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、C 4和C 3烷氧基等。C 1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，“C 3-5环烷基”表示由3至5个碳原子组成的饱和或部分不饱和的环状碳氢基团，其为单环体系，所述C 3-5环烷基包括C 3-4和C 4-5环烷基等；其可以是一价、二价或者多价。C 3-5环烷基的实例包括，但不限于，环丙基、环丁基、环戊基等。
除非另有规定，“C 4-5环烷基”表示由4至5个碳原子组成的饱和或部分不饱和的环状碳氢基团，其为单环体系；其可以是一价、二价或者多价。C 4-5环烷基的实例包括，但不限于，环丁基、环戊基等。
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1，2，3-三唑基、2H-1，2，3-三唑基、1H-1，2，4-三唑基和4H-1，2，4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2021109321-appb-000049
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明所使用的溶剂可经市售获得。
本发明采用下述缩略词：CO 2代表二氧化碳；ATP代表三磷酸腺苷；LPS代表脂多糖；CBA代表细胞因子微球检测技术；PMA代表巴豆醇-12-十四烷酸酯-13-乙酸酯；NEAA代表非必须氨基酸；FBS代表胎牛血清；IL-1β代表白介素-1β；Human IL-1β Flex Set代表人白介素-1β检测试剂盒。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2021109321-appb-000050
软件命名，市售化合物采用供应商目录名称。
附图说明
图1.APLV中的炎性细胞因子IL-6的抑制实验结果。
图2.APLV中的炎性细胞因子IL-1β的抑制实验结果。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
Figure PCTCN2021109321-appb-000051
步骤1：将化合物1-1(5.0g，40.6mmol)和化合物1-2(7.9g，40.6mmol)混合，加热到80℃搅拌2小时，加入乙酸乙酯(200mL)/水(200mL)萃取，有机相经无水硫酸钠干燥后浓缩，粗品经柱层析纯化(石油醚∶乙酸乙酯＝1∶1)得化合物1-3。MS ESI计算值C 6H 8N 2O 2Se[M+H] +221，实测值221。
步骤2：将亚硝酸叔丁酯(2.8g，28.0mmol)和溴化铜(4.5g，20.2mmol)加入乙腈(30mL)中，滴加化合物1-3(3.7g，16.8mmol)的乙腈(30mL)溶液，反应于25℃下搅拌1小时。反应完毕后，加入稀盐酸(1mol/L，30mL)淬灭反应，用二氯甲烷(100mL)萃取，有机相经无水硫酸钠干燥后浓缩，粗品经柱层析纯化(石油醚∶乙酸乙酯＝10∶1)得化合物1-4。MS ESI计算值C 6H 6BrNO 2Se[M+H，M+2+H] +284，286，实测值284，286。
步骤3：将苄硫醇(1.2g，9.7mmol)溶于四氢呋喃(100mL)，在0℃下加入钠氢(494.7mg，12.37mmol，60％含量)后搅拌5分钟，然后加入化合物1-4(2.5g，8.8mmol)，25℃搅拌30分钟，加入稀盐酸(1mol/L，1.5mL)淬灭反应，然后用乙酸乙酯(50mL)/水(25mL)萃取，有机相经无水硫酸钠干燥后浓缩，粗品经柱层析纯化(石油醚∶乙酸乙酯＝10∶1)得化合物1-5。MS ESI计算值C 13H 13NO 2SSe[M+H] +328，实测值328。
步骤4：将化合物1-5(3.2g，9.81mmol)溶于四氢呋喃(100mL)中，在-78℃下加入甲基溴化镁(13.0mL，39.2mmol，3mol/L)后在25℃搅拌30分钟，加入水(5mL)淬灭反应，然后用乙酸乙酯(50mL)/水(25mL)萃取，有机相经无水硫酸钠干燥后浓缩，粗品经柱层析纯化(石油醚∶乙酸乙酯＝10∶1)得化合物1-6。MS ESI计算值C 13H 15NOSSe[M+H] +314，实测值314。
步骤5：将化合物1-6(1.8g，5.8mmol)和2，6-二甲基吡啶(3.1g，29.30mmol)溶于二氯甲烷(50mL)，缓慢加入三氟甲磺酸三甲基硅酯(4.6g，17.5mmol)，反应于25℃搅拌0.5小时。反应完毕后，用二氯甲烷(50mL)/水(25mL)萃取，有机相浓缩后粗品经柱层析纯化(石油醚∶乙酸乙酯＝10∶1)得化合物1-7。MS ESI计算值C 19H 29NOSSeSi[M+H] +428，实测值428。
步骤6：将化合物1-7(1.0g，2.3mmol)溶于乙腈(24mL)、醋酸(0.3mL)和水(0.6mL)中，在0℃下加入1，3-二氯-5，5-二甲基海因(0.9g，4.6mmol)，反应于25℃下搅拌5分钟。将反应体系冷却到0℃后加入氨水 (4.7mL，46.8mmol，38％)，升温到25℃继续搅拌0.5小时。加入稀盐酸(3mol/L，5mL)淬灭反应，浓缩后粗品经柱层析纯化(石油醚∶乙酸乙酯＝10∶1)得化合物1-8。MS ESI计算值C 12H 24N 2O 3SSeSi[M+H] +385，实测值385。
步骤7：将化合物1-8(280.0mg，730.2μmol)溶于四氢呋喃(30mL)中，在0℃下加入钠氢(72.0mg，1.83mmol，60％含量)后搅拌30分钟，然后加入化合物1-9(160.0mg，803.2μmol)的四氢呋喃溶液(20mL)，25℃搅拌1小时，加入水(10mL)淬灭反应，然后用乙酸乙酯(50mL)/水(25mL)萃取，有机相经无水硫酸钠干燥后浓缩，粗品经制备薄层色谱法纯化(二氯甲烷∶甲醇＝10∶1)得化合物1-10。MS ESI计算值C 25H 37N 3O 4SSeSi[M+H] +584，实测值584。
步骤8：将化合物1-10(280.0mg，480.5μmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(1mL)后在25℃搅拌10分钟，用饱和碳酸氢钠水溶液(3mL)淬灭，然后用乙酸乙酯(50mL)/水(25mL)萃取，有机相经无水硫酸钠干燥后浓缩，粗品经制备薄层色谱法纯化(乙酸乙酯∶乙醇＝20∶1)得化合物1。MS ESI计算值C 19H 23N 3O 4SSe[M+H] +470，实测值470。 1H NMR(400MHz，CD 3OD)δppm 8.05(s，1H)，6.80(s，1H)，2.74(br t，J＝7.38Hz，4H)，2.67(br t，J＝7.32Hz，4H)，1.92(quin，J＝7.38Hz，4H)，1.49(s，6H)。
实施例2
Figure PCTCN2021109321-appb-000052
步骤1：将化合物2-1(500.0mg，2.3mmol)和化合物2-2(357.0mg，2.3mmol)溶于二氧六环(40mL)/水(8mL)中，再加入[1，1′-双(二苯基膦基)二茂铁]二氯化钯(II)二氯甲烷加合物(191.1mg，234.0μmol)和碳酸钾(646.8mg，4.7mmol)，反应于100℃搅拌2小时后冷却至室温，加水(50mL)和乙酸乙酯(150mL)萃取，有机相经无水硫酸钠干燥后浓缩，粗品经柱层析纯化(石油醚∶乙酸乙酯＝10∶1)得化合物2-3。MS ESI计算值C 15H 18N 2O[M+H] +243，实测值243。
步骤2：将化合物2-3(95.0mg，392.1mmol)溶于四氢呋喃(10mL)中，25℃下加入三光气(50.0mg，168.6μmol)和三乙胺(119.m0g，1.2mmol)，25℃下搅拌0.5小时。反应完毕后，将反应液过滤得化合物2-4的四 氢呋喃溶液，直接用于下一步。
步骤3：将化合物1-8(100.0mg，260.8μmol)溶于四氢呋喃(10mL)中，在0℃下加入钠氢(26.0mg，652.0μmol，60％含量)后搅拌10分钟，然后加入化合物2-4(76.9mg，286.9μmol)的四氢呋喃溶液(10mL)，25℃搅拌1小时，加入水(10mL)淬灭反应，然后用乙酸乙酯(50mL)/水(25mL)萃取，有机相经无水硫酸钠干燥后浓缩，粗品经制备薄层色谱法纯化(二氯甲烷∶甲醇＝10∶1)得化合物2-5。MS ESI计算值C 28H 40N 4O 5SSeSi[M+H] +653，实测值653。
步骤4：将化合物2-5(130.0mg，199.5μmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(1mL)后在25℃搅拌30分钟，用饱和碳酸氢钠水溶液(3mL)淬灭，然后用乙酸乙酯(50mL)/水(25mL)萃取，有机相经无水硫酸钠干燥后浓缩，粗品经制备薄层色谱法纯化(乙酸乙酯∶乙醇＝20∶1)得化合物2。MS ESI计算值C 22H 26N 4O 5SSe[M+H] +539，实测值539。
1H NMR(400MHz，CD 3CN)δppm 8.11(s，1H)，7.92(d，J＝5.27Hz，1H)，7.31-7.44(m，2H)，7.15(br d，J＝7.28Hz，1H)，6.78-6.95(m，2H)，6.67-6.76(m，1H)，3.90(s，3H)，3.05-3.23(m，1H)，1.50(s，6H)，1.14(br d，J＝7.03Hz，6H)。
实施例3
Figure PCTCN2021109321-appb-000053
步骤1：将化合物3-1(9.0g，67.1mmol)溶于二氯甲烷(50mL)，0℃下缓慢加入三氟甲磺酸酐(37.8g，134.1mmol)和吡啶(15.9g，201.23mmol)，反应于25℃搅拌1小时后加水(50mL)淬灭，用二氯甲烷(100 mL)萃取，有机相浓缩后粗品经柱层析纯化(石油醚∶乙酸乙酯＝20∶1)得化合物3-2。
步骤2：将化合物3-2(10.0g，37.5mmol)和氨基甲酸叔丁酯(8.8g，75.1mmol)溶于二氧六环(150mL)中，氮气保护下加入碳酸铯(24.48g，75.12mmol)，4，5-双二苯基膦-9，9-二甲基氧杂蒽(4.3g，7.5mmol)和三(二亚苄基丙酮)二钯(3.4g，3.7mmol)，反应于80℃下搅拌1小时。反应完毕后加水(50mL)淬灭反应，用乙酸乙酯(150mL)萃取，有机相浓缩所得粗品经柱层析纯化(石油醚∶乙酸乙酯＝5∶1)得化合物3-3。MS ESI计算值C 14H 19NO 2[M+H] +234，实测值234。
步骤3：将化合物3-3(6.0g，25.7mmol)溶于二氯甲烷(50mL)，25℃下滴加三氟乙酸(17.6g，154.3mmol)，反应于25℃下搅拌1小时后，加饱和碳酸氢钠(200mL)淬灭，再用二氯甲烷(200mL)萃取，有机相浓缩后得化合物3-4直接用于下一步。MS ESI计算值C 9H 11N[M+H] +134，实测值134。
步骤4：将化合物3-4(2.6g，19.5mmol)和三乙胺(2.6g，25.4mmol)溶于二氯甲烷(30mL)中，再滴加乙酸酐(2.3g，22.5mmol)，反应于25℃搅拌16小时。反应完毕后加水(50mL)淬灭，再用二氯甲烷(150mL)萃取，有机相浓缩所得粗品经柱层析(石油醚∶乙酸乙酯＝2∶1)纯化得化合物3-5。MS ESI计算值C 11H 13NO[M+H] +176，实测值176。
步骤5：将化合物3-5(2.9g，16.5mmol)溶于四氢呋喃(50ml)中，加入对甲基苯磺酸(1.6g，9.1mmol)和醋酸钯(185.7mg，827.5μmol)，20℃下搅拌0.5小时后加入N-溴代丁二酰亚胺(3.2g，18.2mmol)，反应于20℃下继续搅拌2小时。反应完毕后加水(50mL)淬灭，乙酸乙酯(150mL)萃取，有机相经无水硫酸钠干燥后浓缩，粗品经柱层析纯化(石油醚∶乙酸乙酯＝2∶1)得化合物3-6。MS ESI计算值C 11H 12BrNO[M+H，M+2+H] +254，256，实测值254，256。
步骤6：将化合物3-6(2.3g，9.1mmol)溶于乙醇(20mL)和浓盐酸(7mL，浓度37％)中，反应于80℃下搅拌12小时。反应完毕后加饱和碳酸氢钠(200mL)淬灭，然后用乙酸乙酯(200mL)萃取，有机相经无水硫酸钠干燥后浓缩，粗品经柱层析纯化(石油醚∶乙酸乙酯＝2∶1)得化合物3-7。MS ESI计算值C 9H 10BrN[M+H，M+2+H] +212，214，实测值212，214。
步骤7：将化合物3-7(200.0mg，943.0μmoll)和化合物2-2(158.6mg，1.0mmol)溶于二氧六环(16mL)/水(4mL)中，再加入碳酸钾(325.8mg，2.3mmol)和[1，1′-双(二苯基膦)二茂铁]二氯化钯(II)(69.0mg，94.3μmol)，反应在氮气保护下于80℃搅拌2小时后浓缩，粗品经柱层析纯化(石油醚∶乙酸乙酯＝1∶1)得化合物3-8。MS ESI计算值C 15H 16N 2O[M+H] +241，实测值241。
步骤8：将化合物3-8(103.7mg，431.8μmol)溶于四氢呋喃(10ml)中，25℃下加入三光气(55.1mg，185.6μmol)和三乙胺(131.2mg，1.3mmol)，25℃下搅拌0.5小时。反应完毕后过滤得化合物3-9的四氢呋喃溶液，直接用于下一步。
步骤9：将化合物1-8(100.0mg，260.8μmol)溶于四氢呋喃(30mL)中，在0℃下加入钠氢(26.0mg，652.0μmol，60％含量)后搅拌30分钟，然后加入化合物3-9(76.4mg，286.9μmol)的四氢呋喃溶液(20mL)，25℃ 搅拌1小时，加入水(10mL)淬灭反应，然后用乙酸乙酯(50mL)/水(25mL)萃取，有机相经无水硫酸钠干燥后浓缩，粗品经制备薄层色谱法纯化(二氯甲烷∶甲醇＝10∶1)得化合物3-10。MS ESI计算值C 28H 38N 4O 5SSeSi[M+H] +651，实测值651。
步骤10：将化合物3-10(45.0mg，69.3μmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(1mL)后在25℃搅拌10分钟，用饱和碳酸氢钠水溶液中和至pH＝7，然后用乙酸乙酯(50mL)/水(25mL)萃取，有机相经无水硫酸钠干燥后浓缩，粗品经制备薄层色谱法纯化(乙酸乙酯∶乙醇＝20∶1)得化合物3。MS ESI计算值C 22H 24N 4O 5SSe[M+H] +537，实测值537。
1H NMR(400MHz，CD 3CN)δppm 7.94(s，1H)，7.86(d，J＝5.27Hz，1H)，7.04-7.10(m，1H)，6.96-7.03(m，1H)，6.72(br d，J＝4.77Hz，1H)，6.60(s，1H)，3.78(s，3H)，2.83(br t，J＝7.28Hz，2H)，2.66(br t，J＝7.28Hz，2H)，1.86(td，J＝2.42，4.96Hz，3H)，1.37(s，6H)。
生物测试数据：
实验例1：利用THP-1细胞检测NLRP3拮抗剂的IC 50实验
供实验用的本发明化合物其化学名称和结构式见各化合物的制备实施例。
1.实验原理：本实验利用人源的单核细胞系THP1，来研究NLRP3拮抗剂对细胞IL-1β分泌的抑制活性(IC 50)。利用PMA(巴豆醇-12-十四烷酸酯-13-乙酸酯)分化单核细胞系THP1变成成熟的巨噬细胞，然后利用Toll样受体TLR4的激动剂LPS(脂多糖)来对细胞进行刺激，激活炎症小体NLRP3的转录活性，以及IL-1β前体pro-IL-1β的表达。在此时，加入NLRP3的拮抗剂，然后再加入ATP来使得NLRP3进一步成熟和活化，并激活下游的caspase-1。活化的caspase-1可以对pro-IL-1β进行酶切加工成为可被分泌的成熟IL-1β。NLRP3拮抗剂可以有效抑制ATP诱导的NLRP3的成熟和活化，以及下游caspase-1的活化，从而抑制IL-1β的成熟和分泌。
2.实验材料：
2.1试剂：
名称 供应商 货号或编号 储存条件
PMA Sigma 79346 -20℃
LPS InvivoGen tlrl-eblps -20℃
ATP - - -20℃
1640培养基 Gibco 22400-089 42
FBS HyClone SV30087.03 -80℃
青链霉素 HyClone SV30010 4℃
名称 供应商 货号或编号 储存条件
β-巯基乙醇 Sigma M3148 室温
NEAA非必需氨基酸 Gibco 1140-050 4℃
人可溶性蛋白试剂盒 BD 558265 室温
Human IL-1β Flex Set BD 558279 室温
96孔平底板 Corning 3599 室温
96孔U底板 Corning 3799 室温
2.2仪器：
名称 供应商 货号或编号
流式细胞仪 BD LSRFortessa
2.3实验步骤：
(1)将THP1细胞的密度调整到5*10 5细胞/mL，然后加入PMA，并且将终浓度调整为100ng/mL，200μL/孔接种至96孔平底板，37℃、5％CO 2刺激过夜(尽量＜16小时)。
(2)第二天，将上清弃掉，然后小心用杜氏磷酸盐缓冲液清洗两次(200μL/次)。
(3)用LPS刺激细胞，LPS终浓度为：100ng/mL，200μL/孔加入96孔板，37℃、5％CO 2培养3h。
(4)将测试化合物加入孔内，筛选浓度分别为：5μM、1μM、200nM、40nM、8nM、1.6nM、0.32nM、0.064nM。在37℃、5％CO 2培养箱内孵育1h。
(5)每孔加入ATP，终浓度为5mM，37℃、5％CO 2培养过夜(＞18小时)。
(6)第三天，取出上清5μL，稀释10倍，并利用CBA检测上清中IL-1β的含量。
3.实验结果：
化合物活性结果见表1。
表1 化合物NLRP3拮抗剂抑制活性结果
化合物 THP-1细胞IL-1β抑制活性IC 50(nM)
1 37.9
2 11.3
3 11.6
实验结论：本发明化合物展示了良好的NLRP3抑制活性。
实验例2：本发明化合物的药代动力学评价
实验目的：测试本发明化合物在小鼠体内的药代动力学。
实验材料：
C57BL/6小鼠(雄性，7～10周龄)
实验操作：
将试验化合物1溶解后得到的澄清溶液分别经尾静脉注射和灌胃给予雄性C57BL/6小鼠(C57BL/6)体内(过夜禁食，给药后4小时后恢复进食，7～10周龄)。静脉注射给药剂量为0.5mg/kg，灌胃给药剂量为2.0mg/kg。给予受试化合物后，静脉注射组在0.0833，0.25，0.5，1，2，4，8和24小时，灌胃组在0.25，0.5，1，2，4，6，8和24小时，分别从隐静脉采血并离心后获得血浆。采用LC-MS/MS法测定血药浓度，使用WinNonlin TM Version6.3药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。相关参数：T 1/2：半衰期；Vd：表观分布容积；Cl：清除率；C max：达峰浓度；AUC 0-inf：从0时间到最后一次能检测到药物浓度的时间，本实验中为0-24小时的血浆浓度-时间曲线下面积；F％：生物利用度。测试结果如表2所示：
表2 化合物1在小鼠*中血浆的PK测试结果
Figure PCTCN2021109321-appb-000054
注*：小鼠供应商为上海灵畅生物科技有限公司。
将试验化合物2溶解后得到的澄清溶液，溶媒为10％DMSO/10％Solutol/80％Water，取两只小鼠分别经尾静脉注射，注射剂量为3mg/kg，于0.0833，0.25，0.5，1，2，4，8和24小时从隐静脉采血并离心后获得血浆；取八只小鼠灌胃，灌胃剂量为20mg/kg，其中两只在0.25，0.5，1，2，4，6，8和24小时，分别从隐静脉采血并离心后获得血浆，另外六只动物，分别在给药后0.25，2，6小时对实验动物安乐死，收集结直肠，取出内容物，用预冷盐水冲洗并放在柔软的可吸收纸上以排出所有剩余的液体。组织称重并转移到匀浆管中，加入9倍匀浆溶液(15mM PBS(pH＝7.4)缓冲液：MeOH(v∶v，2∶1))后样品将被匀浆用于分析。采用LC-MS/MS法测定血浆和结直肠浓度，使用WinNonlin TM Version6.3药动学软件，以非房室模型线性对数梯形法计算相关药代动力学参数。测试结果如表3所示：
表3 化合物2在小鼠*血浆和肠道PK测试结果
Figure PCTCN2021109321-appb-000055
注*：小鼠供应商为北京维通利华实验动物技术有限公司；--：表示未测试。
结论：
本发明的化合物在小鼠体内有良好的口服生物利用度，较高的暴露量，有利于产生良好的体内药效，其中部分化合物肠道暴露量远大于血浆暴露量，可以针对性开发用于肠道炎症相关的适应症的治疗。
实验例3：化合物对MSU诱导的C57BL/6小鼠气囊急性痛风模型的治疗效果评价
鼠气囊(AirPouch)是类似于人滑膜的囊状空间，将尿酸单钠晶体(MSU)注入气囊会引起类似于人类痛风的急性炎症反应。通过对气囊冲洗液(APLV)中的炎性细胞因子IL-6和IL-1β分析，以MCC950为参照化合物，测试本发明化合物在雄性C57BL/6小鼠的MSU诱导的气囊痛风模型中的功效。
实验目的：小鼠Air Pouch痛风模型评价本发明化合物的治疗急性痛风的效果。
实验动物：C57BL/6小鼠，雄性，7-8周龄，北京维通利华实验动物技术有限公司。
实验设计：
实验用健康小鼠进行编号和分组，当天(Day1)和第4天(Day4)向小鼠背部注射无菌空气产生气囊。在第7天(Day7)，先给药，1小时后将MSU晶体溶液注入气囊中，7小时后收集气囊冲洗液(APLV)并进行分析。分组及给药方案如表4所示。
表4 分组及给药方案
组别 动物数 免疫原 受试药品 给药剂量和途径 溶媒
1 5 无 Navie - -
2 8 MSU(3mg) Vehicle - -
3 8 MSU(3mg) MCC950 50mg/kg；po 10％DMSO/10％solutol/80％水
4 8 MSU(3mg) 化合物1 50mg/kg；po 10％DMSO/10％solutol/80％水
注：Navie：健康对照组；Vehicle：溶媒对照组；MCC950：参比化合物；po：口服给药；
实验方法与步骤：
1.1 MSU制备
将1g尿酸溶解在0.2升含有6mL 1N氢氧化钠的沸水中，将pH值调节至7.4后，将溶液在室温下逐渐冷却，然后在4℃下放置过夜。通过离心回收MSU晶体，并通过蒸发干燥进行干燥，分配到单个小瓶中(3mg)，并通过高压灭菌进行灭菌。
1.2分组和给药以及IL-6和IL-1β检测
实验用健康C57BL/6小鼠进行编号和分组，分组当天(Day1)和第四天(Day4)通过向小鼠的背部皮下注射5mL无菌空气，产生一个气囊。在第七天(Day7)，分别给予分组小鼠溶媒或者受试物，1小时后，将MSU晶体的悬浮液(盐水，3mg/mL)注入气囊中。6小时后，将收集气囊冲洗液(APLV)，使用ELISA试剂盒测试APLV中IL-6和IL-1β的水平。结果表示为平均值±SEM。统计分析是使用方差分析(ANOVA)的一种方法进行的，随后进行了Dunnett)检验，当p＜0.05时，差异被认为是显着的。试验结果
与健康对照组相比，MSU注射使得小鼠气囊中产生急性炎症反应，表现为APLV中的炎性细胞因子IL-6和IL-1β浓度显著升高。给予化合物MCC950或者化合物1治疗后，炎症反应均得到明显抑制，APLV中的IL-6水平和IL-1β水平降低。化合物1同等给药剂量下对IL-6的降低效果优于MCC950，对IL-1β的降低效果与MCC950相当。APLV中的炎性细胞因子IL-6的抑制实验结果见附图1，APLV中的炎性细胞因子IL-1β的抑制实验结果见附图2，p表示显著性差异，*：p＜0.05；**：p＜0.01；***p＜0.001。
结论：
本发明化合物对MSU诱导的C57BL/6小鼠Air Pouch痛风模型有较好的治疗效果，具有治疗痛风等其他与炎性细胞因子相关疾病的潜力。

Claims (16)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2021109321-appb-100001
    其中，
    R 1和R 4各自独立地选自H、C 1-3烷基、苯基和5-6元杂芳基，所述C 1-3烷基、苯基和5-6元杂芳基任选被1、2或3个R a取代；
    R 2和R 3各自独立地选自H、NH 2、卤素和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代；
    或者，R 1和R 2与它们连接的碳原子一起形成C 4-5环烷基，所述C 4-5环烷基任选被1、2或3个R c取代；
    或者，R 3和R 4与它们连接的碳原子一起形成C 4-5环烷基，所述C 4-5环烷基任选被1、2或3个R c取代；
    R 5选自H、F、Cl、D和CN；
    各R a独立地选自H、F、Cl、Br、I、C 1-3烷氧基和CN，所述C 1-3烷氧基任选被1、2或3个F取代；
    各R b和R c分别独立地选自H、F、Cl、Br、I、C 1-3烷氧基和CN，所述C 1-3烷氧基任选被1、2或3个F取代；
    A 1、A 2和A 3各自独立地选自CH、N和Se，且A 1、A 2和A 3中至少有一个选自Se；
    所述5-6元杂芳基包含1、2、3或4个独立选自-NH-、-O-、-S-、-Se-和N的杂原子或杂原子团。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，所述化合物具有式(I-a)所示结构：
    Figure PCTCN2021109321-appb-100002
    其中，A 1、A 2、A 3、R a和R 5如权利要求1所定义。
  3. 根据权利要求1所述化合物或其药学上可接受的盐，其中，所述化合物具有式(I-b)所示结构：
    Figure PCTCN2021109321-appb-100003
    其中，A 1、A 2、A 3和R 5如权利要求1所定义。
  4. 根据权利要求1所述化合物或其药学上可接受的盐，其中，所述化合物具有式(I-c)所示结构：
    Figure PCTCN2021109321-appb-100004
    其中，A 1、A 2、A 3、R a和R 5如权利要求1所定义。
  5. 根据权利要求4所述化合物或其药学上可接受的盐，其中，所述化合物具有式(I-c-1)所示结构：
    Figure PCTCN2021109321-appb-100005
    其中，R a和R 5如权利要求1所定义。
  6. 根据权利要求1所述化合物或其药学上可接受的盐，其中，所述化合物具有式(I-d)所示结构：
    Figure PCTCN2021109321-appb-100006
    其中，R 1、R 2、R 3、R 4和R 5如权利要求1所定义。
  7. 根据权利要求1、2或4任一项所述化合物或其药学上可接受的盐，其中，各R a独立地选自H、OCH 3和CN。
  8. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 1选自
    Figure PCTCN2021109321-appb-100007
  9. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 2选自H。
  10. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 3选自H。
  11. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 4选自
    Figure PCTCN2021109321-appb-100008
  12. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 1和R 2与它们连接的碳原子一起使结构单元
    Figure PCTCN2021109321-appb-100009
    选自
    Figure PCTCN2021109321-appb-100010
  13. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 3和R 4与它们连接的碳原子一起使结构单元
    Figure PCTCN2021109321-appb-100011
    选自
    Figure PCTCN2021109321-appb-100012
  14. 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2021109321-appb-100013
    选自
    Figure PCTCN2021109321-appb-100014
    Figure PCTCN2021109321-appb-100015
  15. 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2021109321-appb-100016
    选自
    Figure PCTCN2021109321-appb-100017
  16. 下式化合物或其药学上可接受的盐：
    Figure PCTCN2021109321-appb-100018
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