WO2021249337A1 - 二甲基亚磺酰亚胺衍生物 - Google Patents

二甲基亚磺酰亚胺衍生物 Download PDF

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WO2021249337A1
WO2021249337A1 PCT/CN2021/098601 CN2021098601W WO2021249337A1 WO 2021249337 A1 WO2021249337 A1 WO 2021249337A1 CN 2021098601 W CN2021098601 W CN 2021098601W WO 2021249337 A1 WO2021249337 A1 WO 2021249337A1
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compound
pharmaceutically acceptable
acceptable salt
ring
present
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PCT/CN2021/098601
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English (en)
French (fr)
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钱文远
廖勇刚
韦昌青
奚正英
肖瑶
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202180041378.4A priority Critical patent/CN115768749B/zh
Priority to JP2022575974A priority patent/JP7504234B2/ja
Priority to US18/009,440 priority patent/US20230219920A1/en
Priority to EP21820982.3A priority patent/EP4166541A4/en
Publication of WO2021249337A1 publication Critical patent/WO2021249337A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • 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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/54—Nitrogen and either oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/36—Nitrogen atoms

Definitions

  • the present invention relates to a series of dimethylsulfinimide derivatives, in particular to compounds represented by formula (II) and pharmaceutically acceptable salts thereof.
  • Inflammation is the basis for the occurrence and development of many diseases, and maintaining the balance of inflammatory response is of great significance to the prevention and treatment of infection, autoimmune diseases and cancer.
  • Inflammasome (inflammasome) plays an important role in the occurrence and development of inflammation-related diseases.
  • Nucleotide-binding oligomerization domain (NOD)-like receptor family contains pyrin domain protein 3 (NOD-like).
  • Receptor family, pyrin domain-containing protein 3, NLRP3) inflammasomes can be activated by a variety of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to activate them
  • PAMPs pathogen-associated molecular patterns
  • DAMPs damage-associated molecular patterns
  • Caspase-1 caspase-1
  • Caspase-1 which releases mature forms of pro-inflammatory factors interleukins IL-1 ⁇ and IL-18, causes the body's inflammatory response, although this response can be used to defend against foreign pathogens
  • abnormal or chronic activation of NLRP3 inflammasome can cause downstream negative effects and the onset and progression of many diseases.
  • NLRP3 inflammasome is composed of nucleotide-binding oligomerization domain-like receptors (NLRs) family member 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.
  • the core protein NLRP3 consists of 11 leucine at the C-terminal.
  • the acid repeat sequence (LRR), the middle NACHT domain and the N-terminal Pyrin domain (PYD) are composed.
  • NLRP3 interacts with the adaptor protein ASC through the PYD domain, and then ASC 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.
  • 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 to the outside of the cell to promote inflammation. happened.
  • 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 NLRP3 inflammasomes by inducing mitochondrial damage, potassium efflux, and increase in intracellular calcium ion concentration, and then activate NLRP3 inflammasomes to mediate the inflammatory response.
  • NLRP3 inflammasome is closely related to the occurrence and development of a variety of inflammatory diseases.
  • the first report pointed out that the NLRP3 inflammasome is related to the onset of some familial genetic diseases, such as familial Mediterranean fever and Muckle-Wells syndrome.
  • the Cias1 gene encoding NLRP3 on chromosome 1 of such patients was mutated, so that NLRP3 could not be inhibited by itself and was always in an activated state.
  • pro-IL-1 ⁇ and pro-IL were continuously combined.
  • -IL-18 is cleaved into mature IL-1 ⁇ and IL-18, leading to its massive secretion, causing excessive inflammation in the body.
  • joints and surrounding urate crystals are swallowed by macrophages, they may activate NLRP3 inflammasomes and promote the maturation and secretion of IL-1 ⁇ by promoting potassium efflux and inducing mitochondria to produce a large amount of reactive oxygen species.
  • the mature IL-1 ⁇ binds to the IL-1 receptor of the target cell and activates downstream signal transduction factors to generate a large number of inflammatory mediators to aggravate the inflammatory response.
  • ⁇ -amyloid protein can activate the NLRP3 inflammasome of microglia, causing inflammation in the brain, causing neuronal damage and death, and then causing neurodegenerative diseases such as Alzheimer's disease.
  • Endothelial cells and macrophages take up cholesterol from the blood to form tiny cholesterol crystals, activate NLRP3 inflammasomes, and play an important role in the occurrence and development of atherosclerosis.
  • Long-term high concentration of glucose in the body can stimulate pancreatic islet cells to activate NLRP3 inflammasomes, produce mature IL-1 ⁇ , trigger a series of inflammatory reactions, induce IL-1 ⁇ -dependent cell damage and death, and aggravate islet cell dysfunction, eventually leading to 2 The occurrence and 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 mouse encephalomyelitis (experimental autoimmune encephalomyelitis, EAE) by inhibiting the activity of NLRP3 inflammasomes.
  • CY-09 another small molecule antagonist, specifically blocks the assembly and activation of NLRP3 inflammasomes, 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 various phase I clinical studies.
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • X is selected from O and NR b ;
  • 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 is selected from 1, 2 or 3 substituents R a;
  • R 2 and R 3 are each independently selected from H, NH 2 , halogen and C 1-3 alkyl;
  • R 1 , R 2 and the carbon atoms to which they are attached together form a C 4-5 cycloalkyl group and a C 4-5 cycloalkenyl group;
  • R 3 and R 4 together with the carbon atoms to which they are attached form a C 4-5 cycloalkyl group and a C 4-5 cycloalkenyl group;
  • R 5 is selected from H, F, Cl, D and CN;
  • Each R a is independently selected from H, C 1-3 alkoxy, and the CN;
  • R b is selected from H, CN and C 1-3 alkyl
  • Ring A is selected from 5-membered heteroaryl groups
  • the 5-6 membered heteroaryl group and the 5 membered heteroaryl group include 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the above-mentioned compound has a structure represented by formula (II-1) or (II-2),
  • ring A, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the present invention.
  • the above-mentioned compound has a structure represented by formula (I-a) or (II-a),
  • ring A, R a and R 5 are as defined in the present invention.
  • the above-mentioned compound has a structure represented by formula (I-b) or (II-b),
  • Ring A and R 5 are as defined in the present invention.
  • the above-mentioned compound has a structure represented by formula (I-c) or (II-c),
  • Ring A, R a and R 5 are as defined in the present invention.
  • the above-mentioned compound has a structure represented by formula (III),
  • T 1 is selected from N and CH;
  • X and R 5 are as defined in the present invention.
  • R a is selected from H, OCH 3, and CN, the other variables are as defined in the present invention.
  • R 1 is selected from Other variables are as defined in the present invention.
  • 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 Other variables are as defined in the present invention.
  • R 1 and R 2 form together with the carbon atom to which they are attached
  • Other variables are as defined in the present invention.
  • R 3 and R 4 form together with the carbon atom to which they are attached
  • Other variables are as defined in the present invention.
  • R 1 and R 2 form together with the carbon atom to which they are attached
  • Other variables are as defined in the present invention.
  • R 3 and R 4 form together with the carbon atom to which they are attached
  • Other variables are as defined in the present invention.
  • the aforementioned ring A is selected from thienyl and thiazolyl, and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • X is selected from O and NR b ;
  • 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 is selected from 1, 2 or 3 substituents R a;
  • 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;
  • R a is selected from H, C 1-3 alkoxy and CN;
  • R b is selected from H, CN and C 1-3 alkyl
  • Ring A is selected from 5-membered heteroaryl groups
  • the 5-6 membered heteroaryl group and the 5 membered heteroaryl group include 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the above-mentioned compound has a structure represented by formula (II-1) or (II-2),
  • ring A, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the present invention.
  • 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 is selected from 1, 2 or 3 substituents R a;
  • 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;
  • R a is selected from H, C 1-3 alkoxy and CN;
  • Ring A is selected from 5-membered heteroaryl groups
  • the 5-6 membered heteroaryl group and the 5 membered heteroaryl group include 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.
  • the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is used in the preparation of a medicament for the treatment of NLRP3-related diseases.
  • the above application is characterized in that the NLRP3 antagonist-related disease drug is a drug for the treatment of inflammation-related diseases.
  • the compound of the present invention exhibits good NLRP3 inhibitory activity, has good oral bioavailability and high exposure, and has excellent efficacy in vivo; it is more effective against MSU-induced C57BL/6 mouse Air Pouch gout model Good therapeutic effect, has the potential to treat gout and other diseases related to inflammatory cytokines, and has great application prospects.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or 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, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; 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 basic and
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of both.
  • 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 their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in 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” is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
  • diastereomer refers to a stereoisomer in which a molecule has two or more chiral centers and the relationship between the molecules is non-mirror mirror image.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a three-dimensional center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key Or straight dashed key
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
  • the content of the enantiomer is less than 100%, and the content of the 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 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
  • 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 enantiomer excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one wants to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterium can be substituted for hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent.
  • the substituent may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the compound after substitution Is stable.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted 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 be bonded to any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • connection mode of the chemical bond is not positioned, and there is a H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will correspondingly decrease with the number of chemical bonds connected to become the corresponding valence number ⁇ The group.
  • the chemical bond between the site and other groups can be a straight solid bond Straight dashed key Or wavy line Express.
  • the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in indicates that the phenyl group is connected to other groups through the 1 and 2 carbon atoms;
  • aromatic ring refers to a cyclic group with a conjugated ⁇ -electron system, the atoms of which are covered by a cloud of delocalized ⁇ electrons.
  • it can be written in the form of alternating single and double bonds when it conforms to the atomic valence and covalent bond formation rules, or it can be used Represents the delocalized ⁇ electron cloud.
  • structural formula The structure shown is the same, the structural formula The structures shown are all the same. It can be a monocyclic or fused polycyclic system, where each ring is aromatic. Unless otherwise specified, the ring optionally contains 0, 1, or more heteroatoms independently selected from O, S, and N.
  • the number of atoms in a ring is generally defined as the number of ring members.
  • “5-7 membered ring” refers to a “ring” in which 5-7 atoms are arranged around.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed 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 (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest 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 groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 5 carbon atoms, which is a monocyclic ring system, and the C 3-5 cycloalkyl includes C 3 -4 and C 4-5 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and the like.
  • C 4-5 cycloalkyl means a saturated cyclic hydrocarbon group composed of 4 to 5 carbon atoms, which is a monocyclic ring system; it can be monovalent, divalent or multivalent.
  • Examples of C 4-5 cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl and the like.
  • C 4-5 cycloalkenyl means a partially unsaturated cyclic hydrocarbon group composed of 4 to 5 carbon atoms containing at least one carbon-carbon double bond, which is a monocyclic ring system.
  • the C 4-5 cycloalkenyl group includes a C 4 or C 5 cycloalkenyl group; it may be monovalent, divalent or multivalent.
  • Examples of C 4-5 cycloalkenyl include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and the like.
  • 5-6 membered heteroaryl ring and “5-6 membered heteroaryl group” can be used interchangeably in the present invention.
  • the term “5-6 membered heteroaryl group” means a ring consisting of 5 to 6 ring atoms. It is composed of a monocyclic group with a conjugated ⁇ -electron system, in which 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 optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
  • the 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 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,
  • the term "5-membered heteroaryl” in the present invention means a monocyclic group consisting of 5 ring atoms with a conjugated ⁇ -electron system, and 1, 2, 3, or 4 ring atoms are independently selected from Heteroatoms of O, S and N, the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
  • the 5-membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • Examples of the 5-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.) Etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazole Group, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4
  • 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, the embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations 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.
  • SXRD single crystal X-ray diffraction
  • the cultivated single crystal is collected with the Bruker D8 venture diffractometer to collect the diffraction intensity data
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • the solvent used in the present invention is commercially available.
  • DMSO dimethyl sulfoxide
  • CO 2 stands for carbon dioxide
  • ATP adenosine triphosphate
  • LPS lipopolysaccharide
  • CBA cytokine microsphere detection technology
  • PMA crotyl alcohol-12-tetradecane Ester-13-acetate
  • NEAA non-essential amino acids
  • FBS fetal bovine serum
  • IL-1 ⁇ interleukin-1 ⁇
  • Human IL-1 ⁇ Flex Set stands for human interleukin-1 ⁇ detection kit.
  • the compound is used according to the conventional naming principle in the field or The software is named, and the commercially available compounds use the supplier catalog name.
  • Figure 1 Experimental results of inhibition of the inflammatory cytokine IL-6 in APLV;
  • Figure 2 Inhibition test results of the inflammatory cytokine IL-1 ⁇ in APLV.
  • Step 3 Dissolve compound 1-5 (1.0g, 2.3mmol) in dichloromethane (10mL), add sulfuric acid (concentration 98%, 3.5mL) dropwise at 0°C, and stir at 25°C for 1 hour.
  • MS ESI calculated value C 6 H 10 N 2 O 3 S 3 [M+H] + 255, measured value 255.
  • Step 4 Sodium hydride (30.3mg, 758.3 ⁇ mol, 60% purity) was added to compound 1-6 (150.0mg, 589.7 ⁇ mol) in tetrahydrofuran (10mL) solution, stirred at 0°C for 10 minutes, and then compound 1 A solution of -7 (123.3 mg, 619.2 ⁇ mol) in tetrahydrofuran (10 mL) was added to the system and stirred at 25° C. for 0.5 hours.
  • Step 1 Dissolve compound 2-1 (500.0mg, 2.3mmol) and compound 2-2 (357.0mg, 2.3mmol) in dioxane (40mL)/water (8mL), and then add [1,1' -Bis(diphenylphosphino)ferrocene]dichloride palladium(II) dichloromethane adduct (191.1mg, 234.0 ⁇ mol) and potassium carbonate (646.8mg, 4.7mmol), the reaction was stirred at 100°C for 2 After hours, it was cooled to room temperature, and water (50 mL) and ethyl acetate (150 mL) were added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated.
  • Step 2 Dissolve compound 2-3 (95.0mg, 392.1mmol) in tetrahydrofuran (10mL), add triphosgene (50.0mg, 168.6 ⁇ mol) and triethylamine (119.m0g, 1.2mmol) at 25°C. Stir for 0.5 hour at °C. After the completion of the reaction, the reaction solution was filtered to obtain a tetrahydrofuran solution of compound 2-4, which was directly used in the next step. MS ESI calculated value for C 16 H 16 N 2 O 2 [M+H] + 269, measured value 269.
  • Step 3 Add sodium hydride (39.3 mg, 982.9 ⁇ mol, 60% purity) to a solution of compound 1-6 (100.0 mg, 393.2 ⁇ mol) in tetrahydrofuran (10 mL), stir at 0°C for 10 minutes, and then add compound 2 A solution of -4 (105.49 mg, 393.16 ⁇ mol) in tetrahydrofuran (10 mL) was added to the system and stirred at 25° C. for 0.5 hours.
  • Step 2 Dissolve compound 3-2 (10.0g, 37.5mmol) and tert-butyl carbamate (8.8g, 75.1mmol) in dioxane (150mL), add cesium carbonate (24.48g, 75.12) under nitrogen protection mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (4.3g, 7.5mmol) and tris(dibenzylideneacetone) dipalladium (3.4g, 3.7mmol), reaction Stir at 80°C for 1 hour.
  • Step 3 Dissolve compound 3-3 (6.0 g, 25.7 mmol) in dichloromethane (50 mL), add trifluoroacetic acid (17.6 g, 154.3 mmol) dropwise at 25°C, and stir the reaction at 25°C for 1 hour. It was quenched by adding saturated sodium bicarbonate (200 mL), and then extracted with dichloromethane (200 mL). After the organic phase was concentrated, compound 3-4 was directly used in the next step. MS ESI calculated value C 9 H 11 N[M+H] + 134, measured value 134.
  • Step 5 Dissolve compound 3-5 (2.9g, 16.5mmol) in tetrahydrofuran (50mL), add p-toluenesulfonic acid (1.6g, 9.1mmol) and palladium acetate (185.7mg, 827.5 ⁇ mol) at 20°C After stirring for 0.5 hours, N-bromosuccinimide (3.2g, 18.2mmol) was added, and the reaction was continued to stir at 20°C for 2 hours.
  • Step 8 Dissolve compound 3-8 (103.7mg, 431.8 ⁇ mol) in tetrahydrofuran (10mL), add triphosgene (55.1mg, 185.6 ⁇ mol) and triethylamine (131.2mg, 1.3mmol) at 25°C, 25°C Stir for 0.5 hour. After the reaction is completed, the tetrahydrofuran solution of compound 3-9 is obtained by filtration, which is directly used in the next step. MS ESI calculated value C 16 H 14 N 2 O 2 [M+H] + 267, measured value 267.
  • Step 9 Add sodium hydride (39.3 mg, 982.9 ⁇ mol, 60% purity) to a solution of compound 1-6 (100.0 mg, 393.2 ⁇ mol) in tetrahydrofuran (10 mL), stir at 0°C for 10 minutes, and then add compound 3 A solution of -9 (104.7 mg, 393.2 ⁇ mol) in tetrahydrofuran (10 mL) was added to the system and stirred at 25° C. for 0.5 hours.
  • Step 1 Slowly add dibenzylamine (4.0g, 20.1mmol) and triethylamine (2.3g, 22.9mmol) to the dichloromethane (5.0g, 19.1mmol) of compound 4-1 (5.0g, 19.1mmol) at 0°C. 25mL) solution, the reaction was stirred at 25°C for 12 hours.
  • Step 2 Dissolve compound 4-2 (3.4g, 8.1mmol) in 1,4-dioxane (40mL), add compound 1-4 (824.8mg, 8.9mmol), tris(dibenzylidene Acetone) two palladium (737.2mg, 805.0 ⁇ mol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (931.5mg, 1.6mmol), cesium carbonate (5.3g, 16.1mmol), Replace with nitrogen three times. The reaction was stirred at 110°C for 12 hours and then cooled to 25°C and filtered.
  • Step 4 Cool compound 4-4 (1.0g, 3.9mmol) in tetrahydrofuran (20mL) solution to 0°C, add sodium hydride (346.0mg, 8.7mmol, 60% purity) and stir for 0.5 hour, add tert-butyl di Methylchlorosilane (711.1mg, 4.7mmol) was then raised to 25°C and stirring was continued for 12 hours.
  • the reaction was cooled to 0°C, quenched by adding saturated aqueous ammonium chloride solution (10mL), extracted with ethyl acetate (20mL*3), and the organic phase was washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 5 Dissolve dichlorotriphenylphosphine (2.0g, 6.1mmol) in chloroform (20mL), add triethylamine (1.1g, 10.8mmol) at 0°C, stir for 15 minutes, add compound 4-5 ( 1.0 g, 2.7 mmol), stirred at 0°C for 0.5 hours, added to a saturated ammonia tetrahydrofuran solution (20 mL) previously cooled to -40°C, and naturally heated to 25°C and stirred for 12 hours.
  • Step 6 Dissolve compound 4-6 (150.0 mg, 408.0 ⁇ mol) in tetrahydrofuran (10 mL), add sodium hydride (32.6 mg, 816.1 ⁇ mol, 60% purity) at 0°C and stir for 0.5 hours, then add compound 1-7 ( 81.3mg, 408.0 ⁇ mol) in tetrahydrofuran (10mL) solution, the reaction was continued at 25°C for 1 hour. The reaction solution was cooled to 0°C and quenched by adding water (2 mL) to obtain the compound 4-7 solution directly used in the next step. MS ESI calculated value C 25 H 38 N 4 O 3 S 3 Si[M+H] + 567, measured value 567.
  • Step 7 Add dilute hydrochloric acid (1mol/L, 10mL) to the above 4-7 solution and stir at 25°C for 0.5 hours. The solvent was removed by concentration under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: Welch Xtimate C18 250*70mm#10 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 27%-47 %, 25min) to give compound 4.
  • MS ESI calculated value C 19 H 24 N 4 O 3 S 3 [M+H] + 453, measured value 453.
  • Step 8 Compound 4 (100mg) was separated by preparative supercritical fluid chromatography (column: Chiralcel OD-3 100mm*4.6mm ID, 3 ⁇ m); mobile phase: [A: carbon dioxide, B: methanol (0.05% diethylamine) )], gradient: B: 5%-40%, 4min; B%: 40%, 2.5min; B%: 5%, 1.5min) to obtain compound 4a (retention time 4.68min) and compound 4b (retention time 5.24min ).
  • Step 1 Add sodium hydride (43.5mg, 1.1mmol, 60% purity) to compound 4-6 (100.0mg, 272.0 ⁇ mol) in tetrahydrofuran (10.0mL) solution, stir at 25°C for 0.5 hours, then add compound 3 -9 (72.4 mg, 272.0 ⁇ mol) was added to the system and the stirring was continued for 1 hour to obtain the reaction solution of compound 5-1 and used directly in the next step.
  • Step 3 Compound 5 (90mg) was separated by preparative chromatography (Column: Column: Cellulose-2 100mm*4.6mm ID, 3 ⁇ m; mobile phase A: carbon dioxide; B: [0.05% diethylamine-methanol]; gradient: B%: 50%-50%, 25min) to obtain compound 5a (retention time 2.58min) and compound 5b (retention time 3.82min).
  • Step 1 Potassium carbonate (5.1g, 37.0mmol) was added to a solution of benzyl mercaptan (1.5g, 12.3mmol) in dimethylformamide (30mL), stirred at 25°C for 5 minutes, and compound 6-1 (3.0 g, 12.4 mmol). The reaction was heated to 100°C and continued to stir for 5 hours and then dropped to 25°C, quenched by adding water (60mL), extracted with ethyl acetate (60mL*3), and the combined organic phase was washed with saturated brine (200mL), anhydrous sodium sulfate After drying, filtering, and concentrating under reduced pressure, compound 6-2 was directly used in the next reaction.
  • Step 2 Add compound 6-2 (1.0g, 3.5mmol), acetic acid (10mL), water (5mL) and dichlorohydantoin (2.8g, 14.0mmol) into the pre-dried reaction flask, and the reaction was stirred at 40°C 1.5 hours. After the completion of the reaction, the reaction solution was quenched by adding water (20mL), extracted with dichloromethane (20mL*3), the combined organic phase was washed with saturated brine (30mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was reduced Pressure concentration. Petroleum ether (1 mL) and ethyl acetate (1 mL) were added to the residue, stirred for 10 minutes and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6-3 and used immediately in the next step.
  • Step 4 Add compound 6-4 (390.0 mg, 992.1 ⁇ mol), 1,4-dioxane (10 mL), compound 1-4 (138.6 mg, 1.5 mmol) and cesium carbonate ( 969.7mg, 2.9mmol), and finally 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (114.8mg, 198.4 ⁇ mol) and tris(dibenzylideneacetone)dipalladium (90.8mg) , 99.2 ⁇ mol). The reaction was stirred at 110°C for 2 hours and cooled to 25°C under the protection of nitrogen.
  • Step 1 Dissolve compound 6-6 (200.0mg, 783.3 ⁇ mol) in tetrahydrofuran (20mL), add sodium hydride (78.3mg, 1.9mmol, 60% purity) at 0°C and stir for 0.5 hours, then add tert-butyl Dimethylchlorosilane (141.6mg, 939.9 ⁇ mol) was stirred at 25°C for 1 hour.
  • Step 2 Triethylamine (260.7mg, 2.5mmol) was added dropwise to a solution of dichlorotriphenylphosphine (429.3mg, 1.3mmol) in chloroform (10mL) at 25°C, stirred for 10 minutes and then cooled to 0°C A solution of compound 7-1 (190.0 mg, 515.5 ⁇ mol) in chloroform (3 mL) was added, and the reaction was stirred at 0° C. for 0.5 hours. Ammonia gas was passed through the system for 15 minutes, and then the temperature was raised to 25°C and stirred for 1 hour. After the reaction is completed, the compound 7-2 is obtained by concentration, which is directly used in the next reaction. MS ESI calculated value C 11 H 24 N 4 O 2 S 3 Si[M+H] + 369, measured value 369.
  • Step 3 Add sodium hydride (78.13 mg, 1.95 mmol, 60% purity) to a solution of compound 7-2 (180.0 mg, 488.32 ⁇ mol) in tetrahydrofuran (20 mL), stir at 25° C. for 0.5 hours, and then add compound 1 -7 (97.3mg, 488.3 ⁇ mol) was added to the system and stirred for 1 hour. After the reaction is completed, the reaction solution of compound 7-3 is directly used in the next step.
  • MS ESI calculated value C 24 H 37 N 5 O 3 S 3 Si[M+H] + 568, measured value 568.
  • Step 5 Compound 7 (20mg) was separated by preparative supercritical fluid chromatography (column: Chiralpak AS-3 150mm*4.6mm ID, 3 ⁇ m); mobile phase: [A: carbon dioxide, B: ethanol (0.05% diethylamine) )]; Gradient: B%: 5%-40%, 5min; B%: 40%, 2.5min; B%: 5%, 2.5min) to obtain compounds 7a (retention time 5.53min) and 7b (retention time 6.15min ).
  • Step 2 Dissolve compound 8-2 (1.0g, 4.2mmol) in tetrahydrofuran (60mL), add triphosgene (537.7mg, 1.8mmol) and triethylamine (1.3g, 12.6mmol) at 25°C, 25°C Stir for 0.5 hour. After the completion of the reaction, the reaction solution was filtered to obtain a tetrahydrofuran solution of compound 8-3, which was directly used in the next step.
  • the calculated value of MS ESI is C 16 H 13 N 3 O[M+H] + 264, and the measured value is 264.
  • Step 3 Add sodium hydride (43.5 mg, 1.1 mmol, 60% purity) to a solution of compound 4-6 (100.0 mg, 272.0 ⁇ mol) in tetrahydrofuran (10.0 mL) at 25° C. and stir for 0.5 hours, then add the compound 8-3 (71.1mg, 272.0 ⁇ mol) was added to the system and stirring was continued for 1 hour. After the reaction is completed, the reaction solution of compound 8-4 is directly used in the next step.
  • MS ESI calculated value C 28 H 36 N 6 O 3 S 3 Si[M+H] + 629, measured value 629.
  • Experimental example 1 IC 50 experiment for detecting NLRP3 antagonist using THP-1 cells
  • Activated caspase-1 can digest pro-IL-1 ⁇ into mature IL-1 ⁇ that can be secreted.
  • NLRP3 antagonists can effectively inhibit the maturation and activation of NLRP3 induced by ATP and the activation of downstream caspase-1, thereby inhibiting the maturation and secretion of IL-1 ⁇ .
  • the final concentration of LPS is: 100ng/mL, 200 ⁇ L/well in 96-well plate, 37°C, 5% CO 2 incubate for 3h.
  • test compound added to the well, and the screening concentrations are: 5 ⁇ M, 1 ⁇ M, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, 0.064 nM. Incubate for 1 hour at 37°C and 5% CO 2 in an incubator.
  • mice The clear solution obtained by dissolving the test compound was injected into the tail vein and gavage (the solvent is 10% DMSO/10% solutol/80% water) into female C57BL/6J mice (overnight fasting, 6- 8 weeks old).
  • the intravenous group (IV) was at 0.0833, 0.25, 0.5, 1, 2, 4, 8 and 24 hours
  • the intragastric group (PO) was at 0.25, 0.5, 1, 2, 4, At 6, 8 and 24 hours
  • blood was collected from the mandibular vein and centrifuged to obtain plasma.
  • the compound of the present invention has good oral bioavailability, higher exposure, and good in vivo efficacy properties.
  • Air Pouch is a sac-like space similar to the human synovial membrane. Injecting monosodium urate crystals (MSU) into the air pouch can cause an acute inflammatory response similar to human gout.
  • MSU monosodium urate crystals
  • APLV airbag flushing fluid
  • mice Air Pouch gout model to evaluate the effect of the compound 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 in the experiment, and sterile air was injected into the back of the mice on the same day (Day 1) and the fourth day (Day 4) to generate air sacs.
  • Day 1 the drug was administered first, the MSU crystal solution was injected into the balloon after 1 hour, and the balloon washing fluid (APLV) was collected and analyzed after 7 hours.
  • APLV balloon washing fluid
  • mice healthy C57BL/6 mice were used for numbering and grouping.
  • Day 1 On the day of grouping (Day 1) and the fourth day (Day 4), 5 mL of sterile air was subcutaneously injected into the back of the mice to generate an air sac.
  • Day 7 On the seventh day (Day 7), the mice were given vehicle or test substance respectively.
  • a suspension of MSU crystals saline, 3 mg/mL was injected into the balloon.
  • the airbag rinsing fluid APLV
  • the results are expressed as mean ⁇ SEM.
  • the statistical analysis was performed using a method of analysis of variance (ANOVA), followed by Dunnett's test. When p ⁇ 0.05, the difference was considered significant.
  • MSU injection caused acute inflammation in the mouse air sacs, which was manifested by a significant increase in the inflammatory cytokines IL-6 and IL-1 ⁇ concentrations in APLV.
  • compound 7a and dexamethasone After administration of compound MCC950, compound 7a and dexamethasone, the IL-6 level and IL-1 ⁇ level in APLV decreased rapidly.
  • compound 7a is better than dexamethasone (10mg/kg dose) in reducing IL-6 at the three doses of high, medium and low.
  • the reduction effect of MCC950 is better than MCC950 (50mg/kg dose).
  • Compound 7a has a significant reduction effect on IL-1 ⁇ .
  • the compound of the present invention has a good therapeutic effect on the C57BL/6 mouse Air Pouch gout model induced by MSU, and has the potential to treat gout and other diseases related to inflammatory cytokines.

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Abstract

本发明公开了一系列二甲基亚磺酰亚胺衍生物，具体公开了式(II)所示化合物及其药学上可接受的盐。

Description

二甲基亚磺酰亚胺衍生物
本发明主张如下优先权：
CN202010528855.7，2020年06月11日；
CN202010779149.X，2020年08月05日。
技术领域
本发明涉及一系列二甲基亚磺酰亚胺衍生物，具体涉及式(II)所示化合物及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 PCTCN2021098601-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(II)所示化合物或其药学上可接受的盐，
Figure PCTCN2021098601-appb-000002
其中，X选自O和NR b；
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环烷基和C 4-5环烯基；
或者R 3、R 4与它们连接的碳原子一起形成C 4-5环烷基和C 4-5环烯基；
R 5选自H、F、Cl、D和CN；
各R a分别独立地选自H、C 1-3烷氧基和CN；
R b选自H、CN和C 1-3烷基；
环A选自5元杂芳基；
所述5-6元杂芳基和5元杂芳基包含1、2、3或4个独立选自-NH-、-O-、-S-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(II-1)或(II-2)所示结构，
Figure PCTCN2021098601-appb-000003
其中，环A、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，上述化合物具有式(I-a)或(II-a)所示结构，
Figure PCTCN2021098601-appb-000004
其中，环A、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)或(II-b)所示结构，
Figure PCTCN2021098601-appb-000005
环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)或(II-c)所示结构，
Figure PCTCN2021098601-appb-000006
环A、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(III)所示结构，
Figure PCTCN2021098601-appb-000007
其中，
T 1选自N和CH；
X和R 5如本发明所定义。
本发明的一些方案中，上述R a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R 1选自
Figure PCTCN2021098601-appb-000008
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 PCTCN2021098601-appb-000009
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
Figure PCTCN2021098601-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 1、R 2与它们连接的碳原子一起形成
Figure PCTCN2021098601-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 3、R 4与它们连接的碳原子一起形成
Figure PCTCN2021098601-appb-000012
其他变量如本发明所定义。
本发明的一些方案中，上述R 1、R 2与它们连接的碳原子一起形成
Figure PCTCN2021098601-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、R 4与它们连接的碳原子一起形成
Figure PCTCN2021098601-appb-000014
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 PCTCN2021098601-appb-000015
选自
Figure PCTCN2021098601-appb-000016
Figure PCTCN2021098601-appb-000017
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 PCTCN2021098601-appb-000018
选自
Figure PCTCN2021098601-appb-000019
Figure PCTCN2021098601-appb-000020
其他变量如本发明所定义。
本发明的一些方案中，上述环A选自噻吩基和噻唑基，其他变量如本发明所定义。
本发明的一些方案中，上述环A选自
Figure PCTCN2021098601-appb-000021
其他变量如本发明所定义。
本发明的一些方案中，上述环A选自
Figure PCTCN2021098601-appb-000022
其他变量如本发明所定义。
本发明提供了式(II)所示化合物或其药学上可接受的盐，
Figure PCTCN2021098601-appb-000023
其中，
X选自O和NR b；
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；
R a选自H、C 1-3烷氧基和CN；
R b选自H、CN和C 1-3烷基；
环A选自5元杂芳基；
所述5-6元杂芳基和5元杂芳基包含1、2、3或4个独立选自-NH-、-O-、-S-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(II-1)或(II-2)所示结构，
Figure PCTCN2021098601-appb-000024
其中，环A、R 1、R 2、R 3、R 4和R 5如本发明所定义。
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 PCTCN2021098601-appb-000025
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；
R a选自H、C 1-3烷氧基和CN；
环A选自5元杂芳基；
所述5-6元杂芳基和5元杂芳基包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
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 PCTCN2021098601-appb-000026
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自，
Figure PCTCN2021098601-appb-000027
本发明的一些方案中，上述化合物或其药学上可接受的盐在制备治疗NLRP3相关疾病的药物中的应用。
本发明的一些方案中，上述的应用，其特征在于，所述NLRP3拮抗剂相关疾病的药物是用于治疗与炎症相关的疾病的药物。
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，具良好的口服生物利用度和较高的暴露量，体内药效优良；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，具有较大的应用前景。
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 PCTCN2021098601-appb-000028
和楔形虚线键
Figure PCTCN2021098601-appb-000029
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2021098601-appb-000030
和直形虚线键
Figure PCTCN2021098601-appb-000031
表示立体中心的相对构型，用波浪线
Figure PCTCN2021098601-appb-000032
表示楔形实线键
Figure PCTCN2021098601-appb-000033
或楔形虚线键
Figure PCTCN2021098601-appb-000034
或用波浪线
Figure PCTCN2021098601-appb-000035
表示直形实线键
Figure PCTCN2021098601-appb-000036
或直形虚线键
Figure PCTCN2021098601-appb-000037
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％。
可以通过的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 PCTCN2021098601-appb-000038
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 PCTCN2021098601-appb-000039
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 PCTCN2021098601-appb-000040
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 PCTCN2021098601-appb-000041
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 PCTCN2021098601-appb-000042
直形虚线键
Figure PCTCN2021098601-appb-000043
或波浪线
Figure PCTCN2021098601-appb-000044
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 PCTCN2021098601-appb-000045
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 PCTCN2021098601-appb-000046
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 PCTCN2021098601-appb-000047
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 PCTCN2021098601-appb-000048
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2021098601-appb-000049
仍包括
Figure PCTCN2021098601-appb-000050
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，术语“芳香性环”为具有共轭π电子体系的环状基团，其原子间被离域π电子云覆盖。在结构式中，在符合原子价态和共价键成键规则时，可以书写为单双键交替的形式，也可以用
Figure PCTCN2021098601-appb-000051
表示离域π电子云。例如，结构式
Figure PCTCN2021098601-appb-000052
所表示的结构均相同，结构式
Figure PCTCN2021098601-appb-000053
所表示的结构均相同。其可以是单环或稠合多环体系，其中各个环均为芳香性的。除非另有规定，该环任选地包含0、1或多个独立选自O、S和N的杂原子。
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，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“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 1-3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，“C 4-5环烯基”表示包含至少一个碳-碳双键的由4至5个碳原子组成的部分不饱和的环状碳氢基团，其为单环体系。所述C 4-5环烯基包括C 4或C 5环烯基；其可以是一价、二价或者多价。C 4-5环烯基的实例包括但不限于，环丁烯基、环戊烯基、环戊二烯基等。
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)。
除非另有规定，本发明术语“5元杂芳基”表示由5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)或噻吩基(包括2-噻吩基和3-噻吩基等)。
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 PCTCN2021098601-appb-000054
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：DMSO代表二甲基亚砜；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-1βFlex 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 PCTCN2021098601-appb-000055
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 PCTCN2021098601-appb-000056
步骤1：将化合物1-1(3.2g，12.2mmol)和三乙胺(1.9g，18.4mmol)溶于二氯甲烷(100mL)中，加入化合物1-2(2.66g，13.46mmol)，反应在25℃下搅拌2小时。反应完毕后将反应液浓缩，粗品经柱层析分离(石油醚∶乙酸乙酯＝3∶1)得化合物1-3。MS ESI计算值C 18H 16BrNO 2S 2[M+H，M+H+2] +422，424，实测值422，424。
步骤2：将化合物1-3(2.8g，22.6mmol)溶于二氧六环(30mL)中，加入2-(二叔丁基膦)联苯(282.6mg，947.1μmol)，化合物1-4(661.6mg，7.1mmol)，叔丁醇钠(682.6mg，7.1mmol)和三(二苄亚基丙酮)钯(433.6mg，473.5μmol)，80℃搅拌1小时。反应完毕后，将反应液冷却过滤，滤液浓缩后，粗品经柱层析分离(石油醚∶乙酸乙酯＝3∶1)得化合物1-5。MS ESI计算值C 20H 22N 2O 3S 3[M+H] +435，实测值435。
步骤3：将化合物1-5(1.0g，2.3mmol)溶于二氯甲烷(10mL)中，在0℃下滴加硫酸(浓度98％，3.5mL)，反应于25℃搅拌1小时后将反应液倒入冰水(50mL)中，然后用二氯甲烷萃取(150mL)，有机相浓缩，粗品经柱层析分离(石油醚∶乙酸乙酯＝1∶1)得化合物1-6。MS ESI计算值C 6H 10N 2O 3S 3[M+H] +255，实测值255。
步骤4：将氢化钠(30.3mg，758.3μmol，60％纯度)加入到化合物1-6(150.0mg，589.7μmol)的四氢呋喃(10mL)溶液中，在0℃下搅拌10分钟，再将化合物1-7(123.3mg，619.2μmol)的四氢呋喃(10mL)溶液加到体系中并于25℃下搅拌0.5小时。反应完毕后用稀盐酸(1mol/L，1mL)淬灭，再用乙酸乙酯萃取(50mL*2)，有机相浓缩，粗品经柱层析分离(乙酸乙酯∶乙醇＝10∶1)得化合物1。MS ESI计算值C 19H 23N 3O 4S 3[M+H] +454，实测值454。 1H NMR(400MHz，CD 3CN)δppm 8.42(brs，1H)，8.19(s，1H)，8.09(s，1H)，7.01(d，J＝4.0Hz，1H)，6.38(d，J＝4.0Hz，1H)，3.23(s，6H)，2.87(brt，J＝7.4Hz，4H)，2.66(brt，J＝7.4Hz，4H)，2.00-2.07(m，4H)。
实施例2
Figure PCTCN2021098601-appb-000057
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。MS ESI计算值C 16H 16N 2O 2[M+H] +269，实测值269。
步骤3：将氢化钠(39.3mg，982.9μmol，60％纯度)加入到化合物1-6(100.0mg，393.2μmol)的四氢呋喃(10mL)溶液中，在0℃下搅拌10分钟，再将化合物2-4(105.49mg，393.16μmol)的四氢呋喃(10mL)溶液加到体系中并于25℃下搅拌0.5小时。反应完毕后反应完毕后用稀盐酸(1mol/L，1mL)淬灭，再用乙酸乙酯萃取(50mL*2)，有机相浓缩，粗品经制备高效液相色谱分离(色谱柱：Welch Xtimate C18 150*25mm*5μm；流动相：[水(10mM碳酸氢铵)-乙腈]；乙腈％：15％-40％，9.5min)得化合物2。MS ESI计算值C 22H 26N 4O 5S 3[M+H] +523，实测值523。 1H NMR(400MHz，CD 3OD)δppm 8.04(d，J＝5.3Hz，1H)，7.41-7.43(m，2H)，7.17-7.19(m，1H)，6.85-6.87(m，2H)，6.75(s，1H)，6.40(d，J＝4.3Hz，1H)，3.94(s，3H)，3.13(s，6H)，3.04-3.13(m，1H)，1.21(d，J＝6.8Hz，6H)。
实施例3
Figure PCTCN2021098601-appb-000058
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(100mL)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，M+2] +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，M+2] +212，214，实测值212，214。
步骤7：将化合物3-7(200.0mg，943.0μmol l)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。MS ESI计算值C 16H 14N 2O 2[M+H] +267，实测值267。
步骤9：将氢化钠(39.3mg，982.9μmol，60％纯度)加入到化合物1-6(100.0mg，393.2μmol)的四氢呋喃(10mL)溶液中，在0℃下搅拌10分钟，再将化合物3-9(104.7mg，393.2μmol)的四氢呋喃(10mL)溶液加到体系中并于25℃下搅拌0.5小时。反应完毕后用稀盐酸(1mol/L，1mL)淬灭，再用乙酸 乙酯萃取(50mL*2)，有机相浓缩，粗品经制备高效液相色谱分离(色谱柱：Welch Xtimate C18 150*25mm*5μm；流动相：[水(10mM碳酸氢铵)-乙腈]；乙腈％：15％-40％，9.5min)得化合物3。MS ESI计算值C 22H 24N 4O 5S 3[M+H] +521，实测值521。 1H NMR(400MHz，CD 3OD)δppm 8.07(d，J＝5.3Hz，1H)，7.40-7.44(m，2H)，7.12-7.22(m，1H)，6.84(d，J＝4.3Hz，1H)，6.76(s，1H)，6.40(d，J＝4.3Hz，1H)，3.93(s，3H)，3.13(s，6H)，3.00(t，J＝7.4Hz，2H)，2.80-2.83(m，2H)，2.12(t，J＝7.4Hz，2H)。
实施例4
Figure PCTCN2021098601-appb-000059
步骤1：在0℃下依次将二苄胺(4.0g，20.1mmol)，三乙胺(2.3g，22.9mmol)缓慢加到将化合物4-1(5.0g，19.1mmol)的二氯甲烷(25mL)溶液中，反应于25℃搅拌12小时。将反应液加入水(25mL)中，二氯甲烷(50mL*3)萃取，有机相经饱和食盐水(25mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩后经柱层析分离纯化(石油醚∶乙酸乙酯＝20∶1～1∶1)得化合物4-2直接用于下一步反应。MS ESI计算值C 18H 16BrNO 2S 2[M+H；M+H+2] +422；424，实测值422；424。
步骤2：将化合物4-2(3.4g，8.1mmol)溶于1，4-二氧六环(40mL)中，依次加入化合物1-4(824.8mg，8.9mmol)，三(二亚苄基丙酮)二钯(737.2mg，805.0μmol)，4，5-双二苯基膦-9，9-二甲基氧杂蒽(931.5mg，1.6mmol)，碳酸铯(5.3g，16.1mmol)，氮气置换三次，反应于110℃搅拌12小时后冷却至25℃过滤，滤液浓缩后经柱层析分离纯化(石油醚∶乙酸乙酯＝10∶1～0∶1)得化合物4-3直接用于下一步反应。MS ESI计算值C 20H 22N 2O 3S 3[M+H] +435，实测值435。
步骤3：在0℃向化合物4-3(2.4g，5.4mmol)的二氯甲烷(20mL)溶液加入浓硫酸(5.4g，54.0mmol，浓度98％)，反应于20℃搅拌2小时。向反应液加入约30g冰，用氢氧化钠固体调节pH＝5～6后使用二氯甲烷∶甲醇＝10∶1的混合溶剂(30mL*3)萃取，有机相无水硫酸钠干燥，浓缩后经柱层析分离纯化(二氯甲烷∶甲醇＝30∶1～10∶1)得化合物4-4直接用于下一步反应。MS ESI计算值C 6H 10N 2O 3S 3 [M+H] +255，实测值255。
步骤4：将化合物4-4(1.0g，3.9mmol)的四氢呋喃(20mL)溶液冷却到0℃，加入氢化钠(346.0mg，8.7mmol，60％纯度)后搅拌0.5小时，加入叔丁基二甲基氯硅烷(711.1mg，4.7mmol)后升温至25℃继续搅拌12小时。反应降温至0℃，加入饱和氯化铵水溶液(10mL)淬灭，乙酸乙酯(20mL*3)萃取，有机相经饱和食盐水(20mL)洗涤，无水硫酸钠干燥，减压浓缩后经柱层析分离纯化(石油醚∶乙酸乙酯＝3∶1～0∶1)到化合物4-5直接用于下一步反应。MS ESI计算值C 12H 24N 2O 3S 3Si[M+H] +369，实测值369。
步骤5：将二氯三苯基膦(2.0g，6.1mmol)溶于氯仿(20mL)，0℃下加入三乙胺(1.1g，10.8mmol)，搅拌15分钟后，加入化合物4-5(1.0g，2.7mmol)，0℃搅拌0.5小时后，加入到预先冷却至-40℃的饱和的氨气四氢呋喃溶液(20mL)中，自然升温至25℃搅拌12小时。反应完成后直接浓缩，残余物经制备高效液相色谱纯化(色谱柱：Welch Xtimate C18 250*70mm：10μm；流动相：[水(10mM碳酸氢铵)-乙腈]；乙腈％：30％-57％，30min)化得化合物4-6直接用于下一步反应。MS ESI计算值C 12H 25N 3O 2S 3Si[M+H] +368，实测值368。
步骤6：将化合物4-6(150.0mg，408.0μmol)溶于四氢呋喃(10mL)，0℃下加入氢化钠(32.6mg，816.1μmol，60％纯度)搅拌0.5小时，然后加入化合物1-7(81.3mg，408.0μmol)的四氢呋喃(10mL)溶液，反应于25℃继续反应1小时。反应液降温至0℃，加水(2mL)淬灭，得化合物4-7溶液直接用于下一步。MS ESI计算值C 25H 38N 4O 3S 3Si[M+H] +567，实测值567。
步骤7：向上述4-7溶液中加入稀盐酸(1mol/L，10mL)并于25℃搅拌0.5小时。减压浓缩除去溶剂，残余物经制备高效液相色谱纯化(色谱柱：Welch Xtimate C18 250*70mm#10μm；流动相：[水(10mM碳酸氢铵)-乙腈]；乙腈％：27％-47％，25min)得化合物4。MS ESI计算值C 19H 24N 4O 3S 3[M+H] +453，实测值453。
步骤8：化合物4(100mg)经制备超临界流体色谱法分离(色谱柱：Chiralcel OD-3 100mm*4.6mm I.D.，3μm)；流动相：[A：二氧化碳，B：甲醇(0.05％二乙胺)]，梯度：B：5％～40％，4min；B％：40％，2.5min；B％：5％，1.5min)得化合物4a(保留时间4.68min)和化合物4b(保留时间5.24min)。
化合物4a， 1H NMR(400MHz，DMSO-d 6)δ＝8.26(s，1H)，7.47(s，2H)，7.29(d，J＝4.0Hz，1H)，6.86(s，1H)，6.28(d，J＝4.0Hz，1H)，3.29(s，6H)，2.78(t，J＝7.4Hz，4H)，2.69(t，J＝7.4Hz，4H)，1.93(t，J＝7.4Hz，4H)。MS ESI计算值C 19H 24N 4O 3S 3[M+H] +453，实测值453。
化合物4b， 1H NMR(400MHz，DMSO-d 6)δ＝8.30(s，1H)，7.49(s，2H)，7.30(d，J＝4.0Hz，1H)，6.88(s，1H)，6.30(d，J＝4.0Hz，1H)，3.32(s，6H)，2.79(t，J＝7.4Hz，4H)，2.71(t，J＝7.4Hz，4H)，1.94(t，J＝7.4Hz，4H)。MS ESI计算值C 19H 24N 4O 3S 3[M+H] +453，实测值453。
实施例5
Figure PCTCN2021098601-appb-000060
步骤1：将氢化钠(43.5mg，1.1mmol，60％纯度)加入到化合物4-6(100.0mg，272.0μmol)的四氢呋喃(10.0mL)溶液中，25℃下搅拌0.5小时后再将化合物3-9(72.4mg，272.0μmol)加到体系中继续搅拌1小时得化合物5-1的反应液直接用于下一步。MS ESI计算值C 28H 39N 5O 4S 3Si[M+H] +634，实测值634。
步骤2：向上述化合物5-1的反应液中于0℃滴加浓盐酸(5.0mL，浓度37％)并搅拌10分钟，反应完毕后用乙酸乙酯(30mL)萃取，有机相用无水硫酸钠干燥。得的粗品经柱层析分离(二氯甲烷∶甲醇＝10∶1)得化合物5。MS ESI计算值C 22H 25N 5O 4S 3[M+H] +520，实测值520。
步骤3：化合物5(90mg)经制备色谱法分离(色谱柱：Column：Cellulose-2 100mm*4.6mm I.D.，3μm；流动相A：二氧化碳；B：[0.05％二乙胺-甲醇]；梯度：B％：50％-50％，25min)得化合物5a(保留时间2.58min)和化合物5b(保留时间3.82min)。
化合物5a， 1H NMR(400MHz，DMSO-d 6)δppm 8.26(brs，1H)，8.12(d，J＝5.3Hz，1H)，7.42(brs，2H)，7.15-7.25(m，1H)，7.06-7.14(m，2H)，6.95(brd，J＝4.8Hz，1H)，6.76(s，1H)，6.25(d，J＝4.0Hz，1H)，3.88(s，3H)，3.32(s，6H)，2.92(t，J＝7.4Hz，2H)，2.79(brs，2H)，1.96-2.03(m，2H).MS ESI计算值C 22H 25N 5O 4S 3[M+H] +520，实测值520。
化合物5b， 1H NMR(400MHz，DMSO-d 6)δppm 8.26(brs，1H)，8.12(d，J＝5.3Hz，1H)，7.42(brs，2H)，7.15-7.21(m，1H)，7.06-7.16(m，2H)，6.95(brd，J＝4.8Hz，1H)，6.76(s，1H)，6.25(d，J＝4.0Hz，1H)，3.88(s，3H)，3.32(s，6H)，2.92(brt，J＝7.4Hz，2H)，2.79(brs，2H)，1.98-2.03(m，2H)；MS ESI计算值C 22H 25N 5O 4S 3[M+H] +520，实测值520。
实施例6
Figure PCTCN2021098601-appb-000061
步骤1：将碳酸钾(5.1g，37.0mmol)加入到苄硫醇(1.5g，12.3mmol)的二甲基甲酰胺(30mL)溶液中，25℃搅拌5分钟后加入化合物6-1(3.0g，12.4mmol)。反应升温至100℃继续搅拌5小时后降至25℃，加入水(60mL)淬灭，乙酸乙酯萃取(60mL*3)，合并后有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩得化合物6-2直接用于下一步反应。 1H NMR(400MHz，CDCl 3)δ＝7.51(s，1H)，7.20-7.33(m，5H)，4.35(s，2H)。MS ESI计算值C 10H 8BrNS 2[M+H；M+H+2] +286；288，实测值286；288。
步骤2：在预先干燥的反应瓶中加入化合物6-2(1.0g，3.5mmol)，乙酸(10mL)，水(5mL)和二氯海因(2.8g，14.0mmol)，反应在40℃搅拌1.5小时。反应完成后向反应液加入水(20mL)淬灭，二氯甲烷(20mL*3)萃取，合并后的有机相用饱和食盐水(30mL)洗涤，有机相无水硫酸钠干燥，过滤，滤液减压浓缩。残余物中加入石油醚(1mL)和乙酸乙酯(1mL)，搅拌10分钟后过滤，滤液减压浓缩得化合物6-3立即用于下一步。
步骤3：将化合物6-3(800.0mg，3.1mmol)溶于1，2-二氯乙烷(10mL)中，加入二苄胺(2.4g，12.2mmol)。反应于80℃搅拌12小时后降至25℃，向反应液中加入水(40mL)淬灭，用乙酸乙酯(40mL*3)萃取，合并后有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物经柱层析分离(二氯甲烷∶甲醇＝20∶1)得化合物6-4。MS ESI计算值C 17H 15BrN 2O 2S 2[M+H；M+H+2] +423；425，实测值423；425。
步骤4：在预先干燥的反应瓶中加入化合物6-4(390.0mg，992.1μmol)，1，4-二氧六环(10mL)，化合物1-4(138.6mg，1.5mmol)和碳酸铯(969.7mg，2.9mmol)，最后加入4，5-双二苯基膦-9，9-二甲基氧杂蒽(114.8mg，198.4μmol)和三(二亚苄基丙酮)二钯(90.8mg，99.2μmol)。反应在氮气保护下于110℃搅拌2小时降温至25℃，向反应液中加水(20mL)淬灭，用乙酸乙酯(20mL*3)萃取，合并后有机相用饱和食盐水(20mL*3)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残余物经柱层析分离(二氯甲烷∶甲醇＝10∶1)得化合物6-5。MS ESI计算值C 19H 21N 3O 3S 3[M+H] +436，实测值436。
步骤5：将化合物6-5(150mg，344.3μmol)溶于二氯甲烷(1mL)中，加入浓硫酸(1mL，浓度98％)。25℃反应0.5小时。反应完成后将反应液缓慢倒入冰水(5mL)中，用2mol/L的氢氧化钠溶液调节 pH＝4～5，减压浓缩得残余物经柱层析分离(二氯甲烷∶甲醇＝20∶1)得化合物6-6。MS ESI计算值C 5H 9N 3O 3S 3[M+H] +256，实测值256。
步骤6：将化合物6-6(220.0mg，86.1μmol)溶于四氢呋喃(1mL)中，0℃下加入氢化钠(10.3mg，258.4μmol，60％纯度)搅拌0.5小时后加入化合物1-7(20.6mg，103.3μmol)。反应升温至25℃继续搅拌0.5小时后加入水(0.5mL)淬灭，减压浓缩反应液，残余物通过制备薄层色谱法纯化(二氯甲烷∶甲醇＝10∶1)得化合物6。 1H NMR(400MHz，CD 3OD)δppm 7.10(brs，1H)，6.89(s，1H)，3.27(s，6H)，2.82(t，J＝7.1Hz，4H)，2.69-2.76(m，4H)，1.96-2.03(m，4H)；MS ESI计算值C 18H 22N 4O 4S 3[M+H] +455，实测值455。
实施例7
Figure PCTCN2021098601-appb-000062
步骤1：将化合物6-6(200.0mg，783.3μmol)溶于四氢呋喃(20mL)中，在0℃下加入氢化钠(78.3mg，1.9mmol，60％纯度)搅拌0.5小时，然后加入叔丁基二甲基氯硅烷(141.6mg，939.9μmol)，25℃搅拌1小时，反应完毕后用饱和氯化铵溶液(5mL)淬灭，乙酸乙酯(30mL*2)萃取，合并后有机相用无水硫酸钠干燥，浓缩后残余物经柱层析分离(二氯甲烷∶甲醇＝20∶1)得化合物7-1。MS ESI计算值C 11H 23N 3O 3S 3Si[M+H] +370，实测值370。
步骤2：将三乙胺(260.7mg，2.5mmol)于25℃下滴加到二氯三苯基膦(429.3mg，1.3mmol)的氯仿(10mL)溶液中，搅拌10分钟后降温至0℃加入化合物7-1(190.0mg，515.5μmol)的氯仿(3mL)溶液，反应于0℃下继续搅拌0.5小时。往该体系中通氨气15分钟后升温至25℃搅拌1小时。反应完毕后，将浓缩得化合物7-2，直接用于下一步反应。MS ESI计算值C 11H 24N 4O 2S 3Si[M+H] +369，实测值369。
步骤3：将氢化钠(78.13mg，1.95mmol，60％纯度)加入到化合物7-2(180.0mg，488.32μmol)的四氢呋喃(20mL)溶液中，在25℃下搅拌0.5小时，再将化合物1-7(97.3mg，488.3μmol)加到体系中继续搅拌1小时。反应完毕后得化合物7-3的反应液直接用于下一步。MS ESI计算值C 24H 37N 5O 3S 3Si[M+H] +568，实测值568。
步骤4：于0℃下向上述化合物7-3的反应液中滴加浓盐酸(5.0mL，浓度37％)并搅拌10分钟，反应完毕后用乙酸乙酯(30mL)萃取，有机相用无水硫酸钠干燥。得的粗品经柱层析分离(二氯甲烷∶甲醇＝10∶1)得化合物7。MS ESI计算值C 18H 23N 5O 3S 3[M+H] +454，实测值454。
步骤5：化合物7(20mg)经制备超临界流体色谱法分离(色谱柱：Chiralpak AS-3 150mm*4.6mm I.D.，3μm)；流动相：[A：二氧化碳，B：乙醇(0.05％二乙胺)]；梯度：B％：5％～40％，5min；B％：40％，2.5min；B％：5％，2.5min)得化合物7a(保留时间5.53min)和7b(保留时间6.15min)。
化合物7a： 1H NMR(400MHz，DMSO-d 6)δppm 8.41(brs，1H)，7.73(brs，2H)，7.23(s，1H)，6.87(s，1H)，3.35(s，6H)，2.78(brt，J＝7.3Hz，4H)，2.67(brs，4H)，1.86-1.97(m，4H).MS ESI计算值C 18H 23N 5O 3S 3[M+H] +454，实测值454。
化合物7b： 1H NMR(400MHz，DMSO-d 6)δppm 8.42(brs，1H)，7.73(brs，2H)，7.23(s，1H)，6.87(s，1H)，3.35(brs，6H)，2.78(brt，J＝7.0Hz，4H)，2.68(brs，4H)，1.93(brt，J＝7.3Hz，4H).MS ESI计算值C 18H 23N 5O 3S 3[M+H] +454，实测值454。
实施例8
Figure PCTCN2021098601-appb-000063
步骤1：将化合物2-1(2.0g，9.3mmol)和化合物8-1(2.2g，9.3mmol)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(762.8mg，934.1μmol)和碳酸钾(2.6g，18.6mmol)，反应于100℃搅拌2小时后冷却至25℃，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，粗品经柱层析分离(石油醚∶乙酸乙酯＝2∶1)得化合物8-2。MS ESI计算值C 15H 15N 3[M+H] +238，实测值238。
步骤2：将化合物8-2(1.0g，4.2mmol)溶于四氢呋喃(60mL)中，25℃下加入三光气(537.7mg，1.8mmol)和三乙胺(1.3g，12.6mmol)，25℃下搅拌0.5小时。反应完毕后，将反应液过滤得化合物8-3的四氢呋喃溶液，直接用于下一步。MS ESI计算值C 16H 13N 3O[M+H] +264，实测值264。
步骤3：在25℃下将氢化钠(43.5mg，1.1mmol，60％纯度)加入到化合物4-6(100.0mg，272.0μmol)的四氢呋喃(10.0mL)溶液中并搅拌0.5小时，再将化合物8-3(71.1mg，272.0μmol)加到体系中继续下搅拌1小时。反应完毕后得化合物8-4的反应液直接用于下一步。MS ESI计算值C 28H 36N 6O 3S 3Si[M+H] +629，实测值629。
步骤4：向上述化合物8-4的反应液中于0℃滴加浓盐酸(5mL，浓度37％)并搅拌10分钟，反应完毕后用乙酸乙酯(30mL)萃取，有机相用无水硫酸钠干燥，过滤，浓缩所得粗品经柱层析分离(二氯甲烷∶甲醇＝20∶1)得化合物8。 1H NMR(400MHz，CD 3OD)δppm 8.67(d，J＝5.5Hz，1H)，7.90(brs，1H)，7.87-8.01(m，1H)，7.62-7.74(m，1H)，7.23-7.33(m，2H)，7.17-7.21(m，1H)，6.38(d，J＝4.5Hz，1H)，3.34-3.40(s，6H)，2.91-3.06(m，4H)，2.12(brt，J＝7.0Hz，2H).MS ESI计算值C 22H 22N 6O 3S 3[M+H] +515，实测值515。
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试剂如下表1所示：
表1
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 4℃
FBS HyClone SV30087.03 -80℃
青链霉素 HyClone SV30010 4℃
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-1βFlex 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仪器如下表2所示：
表2
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3。
表3化合物NLRP3拮抗剂抑制活性结果
Figure PCTCN2021098601-appb-000064
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：化合物药代动力学评价
实验目的：测试化合物在小鼠体内药代动力学
实验材料：C57BL/6J小鼠(雄性，6-8周龄)
实验操作：将试验化合物溶解后得到的澄清溶液分别经尾静脉注射和灌胃(溶媒为10％DMSO/10％solutol/80％水)给予雌性C57BL/6J小鼠体内(过夜禁食，6-8周龄)。给予受试化合物或对照化合物后，静脉注射组(IV)在0.0833，0.25，0.5，1，2，4，8和24小时，灌胃组(PO)在0.25，0.5，1，2，4，6，8和24小时，分别从下颌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 TMVersion 6.3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。各参数含义：T 1/2：半衰期；C max：达峰浓度；AUC 0-inf：从0时间到外推至无穷大时的血浆浓度-时间曲线下面积；F：生物利用度，Vd：表观分布容积，Cl：清除率T max：达峰时间。测试结果如 表4所示：
表4化合物7a的药代动力学测试结果
Figure PCTCN2021098601-appb-000065
结论：本发明的化合物具良好的口服生物利用度，较高的暴露量，体内药效性质良好。
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(Air Pouch)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：
如图1，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，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5所示。
表5分组及给药方案
Figure PCTCN2021098601-appb-000066
Figure PCTCN2021098601-appb-000067
注：Navie：健康对照组；Vehicle：溶媒对照组；MCC950：参比化合物；Dex.：地塞米松；po：口服给药；ip：腹腔注射给药；
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、化合物7a和地塞米松治疗后，APLV中的IL-6水平和IL-1β水平迅速降低。其中，化合物7a在高、中和低三个剂量下对IL-6的降低效果都优于地塞米松(10mg/kg剂量)，在15mg/kg和50mg/kg给药剂量下对IL-6的降低效果都优于MCC950(50mg/kg剂量)。化合物7a对IL-1β的降低效果显著，在15mg/kg和50mg/kg给药剂量下对IL-1β的降低效果都显著优于MCC950(50mg/kg剂量)，IL-1β水平极低，达到地塞米松(10mg/kg)同等效果。APLV中的炎性细胞因子IL-6的抑制实验结果见图1，APLV中的炎性细胞因子IL-1β的抑制实验结果见图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 (20)

  1. 式(II)所示化合物或其药学上可接受的盐，
    Figure PCTCN2021098601-appb-100001
    其中，X选自O和NR b；
    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环烷基和C 4-5环烯基；
    或者R 3、R 4与它们连接的碳原子一起形成C 4-5环烷基和C 4-5环烯基；
    R 5选自H、F、Cl、D和CN；
    各R a分别独立地选自H、C 1-3烷氧基和CN；
    R b选自H、CN和C 1-3烷基；
    环A选自5元杂芳基；
    所述5-6元杂芳基和5元杂芳基包含1、2、3或4个独立选自-NH-、-O-、-S-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(II-1)或(II-2)所示结构：
    Figure PCTCN2021098601-appb-100002
    其中，环A、R 1、R 2、R 3、R 4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-a)或(II-a)所示结构：
    Figure PCTCN2021098601-appb-100003
    其中，环A、R a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-b)或(II-b)所示结构：
    Figure PCTCN2021098601-appb-100004
    其中，环A和R 5如权利要求1所定义。
  5. 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)或(II-c)所示结构：
    Figure PCTCN2021098601-appb-100005
    其中，环A、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(III)所示结构：
    Figure PCTCN2021098601-appb-100006
    其中，
    T 1选自N和CH；
    X和R 5如权利要求1所定义。
  7. 根据权利要求1～3或5任意一项所述化合物或其药学上可接受的盐，其中，R a选自H、OCH 3和CN。
  8. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 1选自
    Figure PCTCN2021098601-appb-100007
  9. 根据权利要求1或2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或2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或2所述化合物或其药学上可接受的盐，其中，R 4选自
    Figure PCTCN2021098601-appb-100008
  12. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 1、R 2与它们连接的碳原子一起形成
    Figure PCTCN2021098601-appb-100009
  13. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R 3、R 4与它们连接的碳原子一起形成
    Figure PCTCN2021098601-appb-100010
  14. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2021098601-appb-100011
    选自
    Figure PCTCN2021098601-appb-100012
  15. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，环A选自噻吩基和噻唑基。
  16. 根据权利要求15所述化合物或其药学上可接受的盐，其中，环A选自
    Figure PCTCN2021098601-appb-100013
  17. 下式化合物或其药学上可接受的盐：
    Figure PCTCN2021098601-appb-100014
  18. 根据权利要求17所述化合物或其药学上可接受的盐，其选自，
    Figure PCTCN2021098601-appb-100015
  19. 根据权利要求1～18任一项所述的化合物或其药学上可接受的盐在制备治疗NLRP3相关疾病的药物中的应用。
  20. 根据权利要求19所述的应用，其中，所述NLRP3拮抗剂相关疾病的药物是用于治疗与炎症相关的疾病的药物。
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