WO2021114691A1 - Composé à cycles condensés contenant de l'azote, son procédé de préparation et son utilisation - Google Patents

Composé à cycles condensés contenant de l'azote, son procédé de préparation et son utilisation Download PDF

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WO2021114691A1
WO2021114691A1 PCT/CN2020/106220 CN2020106220W WO2021114691A1 WO 2021114691 A1 WO2021114691 A1 WO 2021114691A1 CN 2020106220 W CN2020106220 W CN 2020106220W WO 2021114691 A1 WO2021114691 A1 WO 2021114691A1
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compound
alkyl
group
membered
aryl
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Chinese (zh)
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游泽金
何云
李桂英
田强
宋宏梅
薛彤彤
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN202080071984.6A priority Critical patent/CN114555565B/zh
Publication of WO2021114691A1 publication Critical patent/WO2021114691A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a class of nitrogen-containing hexacyclic compounds, stereoisomers, tautomers or mixtures of said compounds, pharmaceutically acceptable salts, co-crystals, polymorphs or solvates of said compounds Or a stable isotope derivative, metabolite or prodrug of the compound.
  • the compounds of the present invention are used as NLRP3 (NLR family pyrin domain containing 3) modulators (such as agonists or partial agonists) and can be used for the treatment of abnormal cell proliferation diseases (such as cancer).
  • NLRP3 belongs to the family of NOD-like receptors. It is one of the most studied intracellular pattern recognition receptors in recent years. It is mainly expressed in macrophages and neutrophils. It participates in the body's innate immunity and resists pathogen infection and stress damage. NLRP3 inflammasome plays a very clear role in inflammatory and metabolic diseases, and its over-activation can lead to type 2 diabetes, immune diseases such as rheumatoid arthritis and atherosclerosis. However, recent studies have shown that NLRP3 has anti-tumor effects that inhibit tumor growth and metastasis.
  • NLRP3 protein recognizes pathogen-related molecular patterns (PAMP) or endogenous damage-related molecular patterns (DAMP), its NOD domain oligomerizes and recruits proteins such as ASC and pro-caspase-1 to form functional NLRP3 Inflammatory bodies.
  • pro-caspase-1 is cleaved and activated to caspase-1
  • caspase-1 cleaves pro-IL-1 ⁇ and pro-IL-18 in a large amount to convert them into active forms of IL-1 ⁇ and IL-18 and release them to Extracellular, amplify the inflammatory response.
  • NLRP3 inflammasome can significantly increase the levels of immune factors IL-1 ⁇ and IL-18 in the tumor microenvironment, initiate natural immune killing and subsequent adaptive immune responses to exert its anti-tumor effects.
  • IL-1 ⁇ can induce CD8+ T cells to secrete interferon ⁇ (IFN- ⁇ ) and CD4+ cells to secrete IL-17, leading to effective anti-tumor immune effects; while IL-18 can promote the maturation of NK cells Activates the downstream signaling pathway of STAT1 in immune cells and enhances the killing function of immune cells.
  • IFN- ⁇ interferon ⁇
  • IL-18 can promote the maturation of NK cells Activates the downstream signaling pathway of STAT1 in immune cells and enhances the killing function of immune cells.
  • Clinical studies have shown that the down-regulation of NLRP3 is significantly negatively correlated with the prognosis of liver cancer patients.
  • NLRP3-deficient mice have a higher rate of colorectal tumor formation and worsen liver metastasis of colorectal cancer. It can be seen that NLRP3 plays an important role in the tumor microenvironment and can be used as a key target of tumor immunotherapy, as well as a tumor prognostic marker.
  • NLRP3 modulators have the potential for tumor immunotherapy, and currently known compound BMS-986299 is in clinical phase I study. Therefore, it is necessary to develop new, high-efficiency and low-toxicity NLRP3 agonists to meet the needs of clinical treatment.
  • NLRP3 modulators such as agonists
  • directly binding or modifying NLRP3 at the protein level and by activating, stabilizing, and changing NLRP3 Distribution or other ways to enhance the function of NLRP3 inflammasome, thereby providing the following invention.
  • the present invention provides compounds having the structure represented by formula X, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts, co-crystals, polymorphs of the compounds Forms or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds:
  • L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 , L 2 and L 3 are the same or different and are each independently selected from C 1-8 alkylene, C 2 -8 alkenylene, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene, 5 -10 membered heteroarylene, O, S, NR 33 , S(O), S(O) 2 , C(O) and C(R 36a R 36b ), wherein the C 1-8 alkylene group, C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 arylene And 5-10 membered heteroarylene groups are each optionally substituted with one or more of the following substituents: halogen, OH
  • n, p and q are each independently 0, 1 or 2;
  • R 30 , R 37 , R 39 and R 40 are each independently selected from H, C 1-8 alkyl (e.g. C 1-6 alkyl or C 1-4 alkyl), C 1-8 alkoxy (e.g. C 1- 6 alkoxy or C 1-4 alkoxy), C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, -C 1-8 alkyl-C 6-12 aryl and -C 1-8 alkyl-(5-10 membered heteroaryl), wherein the C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl, -C 1-8 alkyl-C 6-12 aryl and -C 1-8 Alkyl-(5-10 membered heteroaryl) are each optionally substituted with one or more of the following substituents: OH, CN, NO 2
  • R 31 , R 32 , R 33 and R 34 are each independently selected from H, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl and 5-10 membered heteroaryl, or R 31 and R 32 together with the N atom to which they are attached form a 4-8 membered heterocyclic group, or R 33 and R 34 and the C to which they are each attached Together with the N atom to form a 4-8 membered heterocyclic group, wherein the C 1-8 alkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4-8 membered heterocyclic group, 4-10
  • Each of the membered heterocyclic group, C 6-12 aryl group and 5-10 membered heteroaryl group is optionally substituted by one or more of the following substituents: OH, CN, halogen, NO 2 , C 1-4 alkyl , C 1-4 alkoxy, C
  • R 35 is selected from C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl, -C 1-8 alkyl-C 6-12 aryl and -C 1-8 alkyl-(5-10 membered heteroaryl), wherein the C 1-8 alkyl, C 1-8 alkoxy , C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl are each optionally substituted by one or more of the following substituents: OH, CN , NO 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, C 1-4 haloalkoxy, CO 2 (C 1-6 alkyl), CONR 31 R 32 , NR 31 R 32 , NR 33 C(O)R 34 , S(O)Me, S(O
  • R 36a and R 36b are the same or different and are each independently selected from H, C 1-8 alkyl and C 1-8 alkoxy, wherein the C 1-8 alkyl and C 1-8 alkoxy are each independently Optionally substituted by one or more of the following groups: OH, CN, halogen, NH 2 , NHCH 3 and N(CH 3 ) 2 , or R 36a and R 36b together with the C atom to which they are attached form a 3- 7-membered cycloalkyl or heterocyclic group;
  • R 38 is selected from H, OH, CN, NO 2 , S(O)R 35 and S(O) 2 R 35 ;
  • each R 30 may be the same or different;
  • each R 31 may be the same or different;
  • each R 32 may be the same or different;
  • each R 33 may be the same or different;
  • each R 34 may be the same or different;
  • each R 35 may be the same or different;
  • each R 37 may be the same or different;
  • each R 38 may be the same or different;
  • each R 39 may be the same or different;
  • each R 40 may be the same or different;
  • R is selected from among them:
  • R 1 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl and 9-12 membered aryl and hetero Cyclic group, wherein the C 1-8 alkyl group, C 3-8 cycloalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group and 9-12 membered aryl group
  • the heterocyclic groups are each optionally substituted by one or more of the following substituents: halogen, CN, NO 2 , C 1-4 alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered heterocyclyl, and aryl group, CO 2 R 30, C ( O) R 30 , C(O)NR 31 R
  • R 2 is selected from H, NR 41a R 41b , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein said C 1- 8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and 4-10 membered heterocyclyl group each optionally substituted with a group of the following or One substitution: halogen, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O) NR 31 R 32 , NR 33 C(O)R 34 , C(O)OR 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 and NR 31 R 32 ;
  • R 5 is absent or selected from halogen, C 1-6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the C 1-6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, and 4-10 membered heterocyclic group are each optionally substituted with one or more of the following groups: halogen, OH, CN, C 1-4 alkane Oxy, C 1-4 hydroxyalkyl and NR 31 R 32 ;
  • n 0, 1 or 2, preferably 0 or 1;
  • X 1 is selected from CR 6 and N;
  • R 4 is selected from H, NR 41a R 41b , C 1-15 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and 4- 10-membered heterocyclic group, wherein the C 1-15 alkyl group, C 1-8 alkoxy group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-8 cycloalkyl group and 4-10 membered
  • the heterocyclic groups are each optionally substituted by one or more of the following substituents: halogen, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-7 membered heterocyclyl, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , C(O)OR 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33
  • R 6 is selected from H, halogen, C 1-6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the C 1-6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, and 4-10 membered heterocyclic group are each optionally substituted with one or more of the following groups: halogen, OH, CN, C 1-4 alkoxy Group, C 1-4 hydroxyalkyl group and NR 31 R 32 ;
  • R 41a and R 41b are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl, or R 41a and R 41b form together with the N atom to which they are attached 4-7 membered heterocyclic group, wherein the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group and 4-7 membered heterocyclic group are each optionally selected from the following groups One or more of the substitutions: OH, CN and NR 31 R 32 .
  • the present invention provides a compound having a structure represented by formula I, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, Polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds:
  • R 1 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl and 9-12 membered aryl and hetero Cyclic group, wherein the C 1-8 alkyl group, C 3-8 cycloalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group and 9-12 membered aryl group
  • the heterocyclic groups are each optionally substituted by one or more of the following substituents: halogen, CN, NO 2 , C 1-4 alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered heterocyclyl, and aryl group, CO 2 R 30, C ( O) R 30 , C(O)NR 31 R
  • R 2 is selected from H, NR 41a R 41b , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein said C 1- 8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and 4-10 membered heterocyclyl group each optionally substituted with a group of the following or One substitution: halogen, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-7 membered heterocyclic group, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O) NR 31 R 32 , NR 33 C(O)R 34 , C(O)OR 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33 C(O)NR 31 R 32 and NR 31 R 32 ;
  • R 5 is absent or selected from halogen, C 1-6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the C 1-6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, and 4-10 membered heterocyclic group are each optionally substituted with one or more of the following groups: halogen, OH, CN, C 1-4 alkane Oxy, C 1-4 hydroxyalkyl and NR 31 R 32 ;
  • n 0, 1 or 2, preferably 0 or 1;
  • L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 , L 2 and L 3 are the same or different and each is independently selected from C 1-8 sub Alkyl, C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, O, S, NR 33 , S(O), S(O) 2 , C(O) and C(R 36a R 36b ), wherein the C 1- 8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6
  • the -12 arylene group and the 5-10 membered heteroarylene group are each optionally substituted with one or more of the following substituents: hal
  • n, p, and q are each independently 0, 1 or 2 each time they appear;
  • R 30 , R 37 , R 39 and R 40 are each independently selected from H, C 1-8 alkyl (e.g. C 1-6 alkyl or C 1-4 alkyl), C 1-8 alkoxy (e.g. C 1- 6 alkoxy or C 1-4 alkoxy), C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, -C 1-8 alkyl-C 6-12 aryl and -C 1-8 alkyl-(5-10 membered heteroaryl), wherein the C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl, -C 1-8 alkyl-C 6-12 aryl and -C 1-8 Alkyl-(5-10 membered heteroaryl) are each optionally substituted with one or more of the following substituents: OH, CN, NO 2
  • R 31 , R 32 , R 33 and R 34 are each independently selected from H, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl and 5-10 membered heteroaryl, or R 31 and R 32 together with the N atom to which they are attached form a 4-8 membered heterocyclic group, or R 33 and R 34 and the C to which they are each attached Together with the N atom to form a 4-8 membered heterocyclic group, wherein the C 1-8 alkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4-8 membered heterocyclic group, 4-10
  • Each of the membered heterocyclic group, C 6-12 aryl group and 5-10 membered heteroaryl group is optionally substituted by one or more of the following substituents: OH, CN, halogen, NO 2 , C 1-4 alkyl , C 1-4 alkoxy, C
  • R 35 is selected from C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl, -C 1-8 alkyl-C 6-12 aryl and -C 1-8 alkyl-(5-10 membered heteroaryl), wherein the C 1-8 alkyl, C 1-8 alkoxy , C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl are each optionally substituted by one or more of the following substituents: OH, CN , NO 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, C 1-4 haloalkoxy, CO 2 (C 1-6 alkyl), CONR 31 R 32 , NR 31 R 32 , NR 33 C(O)R 34 , S(O)Me, S(O
  • R 36a and R 36b are the same or different and are each independently selected from H, C 1-8 alkyl and C 1-8 alkoxy, wherein the C 1-8 alkyl and C 1-8 alkoxy are each independently Optionally substituted by one or more of the following groups: OH, CN, halogen, NH 2 , NHCH 3 and N(CH 3 ) 2 , or R 36a and R 36b together with the C atom to which they are attached form a 3- 7-membered cycloalkyl or heterocyclic group;
  • R 38 is selected from H, OH, CN, NO 2 , S(O)R 35 and S(O) 2 R 35 ;
  • R 41a and R 41b are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl, or R 41a and R 41b form together with the N atom to which they are attached 4-7 membered heterocyclic group, wherein the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group and 4-7 membered heterocyclic group are each optionally selected from the following groups One or more of the substitutions: OH, CN and NR 31 R 32 ; and
  • each R 30 may be the same or different;
  • each R 31 may be the same or different;
  • each R 32 may be the same or different;
  • each R 33 may be the same or different;
  • each R 34 may be the same or different;
  • each R 35 may be the same or different;
  • each R 37 may be the same or different;
  • each R 38 may be the same or different;
  • each R 39 may be the same or different;
  • each R 40 may be the same or different.
  • the present invention provides a compound having a structure represented by Formula II, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, Polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds:
  • R 1 , L 2 and R 3 are as defined in formula I.
  • the present invention provides a compound having a structure represented by Formula II-A, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, or a mixture of the compound Crystals, polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds:
  • the present invention provides a compound having a structure represented by formula III, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, Polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds:
  • X 1 is selected from CR 6 and N,
  • R 1 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl and 9-12 membered aryl and hetero Cyclic group, wherein the C 1-8 alkyl group, C 3-8 cycloalkyl group, 4-10 membered heterocyclic group, C 6-12 aryl group, 5-10 membered heteroaryl group and 9-12 membered aryl group
  • the heterocyclic groups are each optionally substituted by one or more of the following substituents: halogen, CN, NO 2 , C 1-4 alkyl, C 3-8 cycloalkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, 9-12 membered heterocyclyl, and aryl group, CO 2 R 30, C ( O) R 30 , C(O)NR 31 R
  • R 4 is selected from H, NR 41a R 41b , C 1-15 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and 4- 10-membered heterocyclic group, wherein the C 1-15 alkyl group, C 1-8 alkoxy group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-8 cycloalkyl group and 4-10 membered
  • the heterocyclic groups are each optionally substituted by one or more of the following substituents: halogen, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, 4-7 membered heterocyclyl, CN, NO 2 , OR 37 , SR 37 , C(O)R 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , C(O)OR 30 , OC(O)R 30 , OC(O)NR 31 R 32 , NR 33
  • R 6 is selected from H, halogen, C 1-6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl and 4-10 membered heterocyclic group, wherein the C 1-6 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, and 4-10 membered heterocyclic group are each optionally substituted with one or more of the following groups: halogen, OH, CN, C 1-4 alkoxy Group, C 1-4 hydroxyalkyl group and NR 31 R 32 ;
  • L is -(L 1 ) n -(L 2 ) p -(L 3 ) q -, wherein L 1 , L 2 and L 3 are the same or different and each is independently selected from C 1-8 sub Alkyl, C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, O, S, NR 33 , S(O), S(O) 2 , C(O) and C(R 36a R 36b ), wherein the C 1- 8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, C 1-8 alkyleneoxy, C 3-8 cycloalkylene, 4-10 membered heterocyclylene, C 6
  • the -12 arylene group and the 5-10 membered heteroarylene group are each optionally substituted with one or more of the following substituents: hal
  • n, p, and q are each independently 0, 1 or 2 each time they appear;
  • R 30 , R 37 , R 39 and R 40 are each independently selected from H, C 1-8 alkyl (e.g. C 1-6 alkyl or C 1-4 alkyl), C 1-8 alkoxy (e.g. C 1- 6 alkoxy or C 1-4 alkoxy), C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl, 5-10 membered heteroaryl, -C 1-8 alkyl-C 6-12 aryl and -C 1-8 alkyl-(5-10 membered heteroaryl), wherein the C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl, -C 1-8 alkyl-C 6-12 aryl and -C 1-8 Alkyl-(5-10 membered heteroaryl) are each optionally substituted with one or more of the following substituents: OH, CN, NO 2
  • R 31 , R 32 , R 33 and R 34 are each independently selected from H, C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl and 5-10 membered heteroaryl, or R 31 and R 32 together with the N atom to which they are attached form a 4-8 membered heterocyclic group, or R 33 and R 34 and the C to which they are each attached Together with the N atom to form a 4-8 membered heterocyclic group, wherein the C 1-8 alkyl group, C 1-8 alkoxy group, C 3-8 cycloalkyl group, 4-8 membered heterocyclic group, 4-10
  • Each of the membered heterocyclic group, C 6-12 aryl group and 5-10 membered heteroaryl group is optionally substituted by one or more of the following substituents: OH, CN, halogen, NO 2 , C 1-4 alkyl , C 1-4 alkoxy, C
  • R 35 is selected from C 1-8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6-12 aryl, 5-10 membered heteroaryl, -C 1-8 alkyl-C 6-12 aryl and -C 1-8 alkyl-(5-10 membered heteroaryl), wherein the C 1-8 alkyl, C 1-8 alkoxy , C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-12 aryl and 5-10 membered heteroaryl are each optionally substituted by one or more of the following substituents: OH, CN , NO 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, halogen, C 1-4 haloalkoxy, CO 2 (C 1-6 alkyl), CONR 31 R 32 , NR 31 R 32 , NR 33 C(O)R 34 , S(O)Me, S(O
  • R 36a and R 36b are the same or different and are each independently selected from H, C 1-8 alkyl and C 1-8 alkoxy, wherein the C 1-8 alkyl and C 1-8 alkoxy are each independently Optionally substituted by one or more of the following groups: OH, CN, halogen, NH 2 , NHCH 3 and N(CH 3 ) 2 , or R 36a and R 36b together with the C atom to which they are attached form a 3- 7-membered cycloalkyl or heterocyclic group;
  • R 38 is selected from H, OH, CN, NO 2 , S(O)R 35 and S(O) 2 R 35 ;
  • R 41a and R 41b are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy and C 3-8 cycloalkyl, or R 41a and R 41b form together with the N atom to which they are attached 4-7 membered heterocyclic group, wherein the C 1-6 alkyl group, C 1-6 alkoxy group, C 3-8 cycloalkyl group and 4-7 membered heterocyclic group may optionally be selected from the following groups One or more of the substitutions: OH, CN and NR 31 R 32 ; and
  • each R 30 may be the same or different;
  • each R 31 may be the same or different;
  • each R 32 may be the same or different;
  • each R 33 may be the same or different;
  • each R 34 may be the same or different;
  • each R 35 may be the same or different;
  • each R 37 may be the same or different;
  • each R 38 may be the same or different;
  • each R 39 may be the same or different;
  • each R 40 may be the same or different.
  • the present invention provides a compound having a structure represented by formula IV, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts, co-crystals, Polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds:
  • R 1 , L 2 and R 3 are as defined in formula III.
  • the present invention provides a compound having a structure represented by formula IV-A, a stereoisomer, a tautomer of the compound, or a mixture thereof, a pharmaceutically acceptable salt, or a mixture of the compound Crystals, polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds:
  • R 3 is preferably independently selected from H, halogen, CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclic group, C 6 each occurrence -10 aryl, 5-6 membered heteroaryl, CO 2 R 30 , C(O)NR 31 R 32 , NR 33 C(O)R 34 , NR 31 R 32 , S(O) 2 R 35 , OR 37 , SR 37 , C(O)R 30 , OC(O)R 30 , NR 33 C(O)NR 31 R 32 and S(O) 2 NR 31 R 32 , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl are each optionally substituted with one or more of the following substituents: halogen, CN, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4
  • each occurrence of R 3 is independently selected from H, CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl, 5- 6-membered heteroaryl, NR 33 C(O)R 34 , OR 37 , SR 37 , C(O)R 30 and OC(O)R 30 , wherein the C 1-6 alkyl group, C 3-6 ring
  • the alkyl group, 4-7 membered heterocyclic group, C 6-10 aryl group and 5-6 membered heteroaryl group are each optionally substituted with one or more of the following substituents: CN, C 1-4 alkyl and CO 2 R 30 , R 30 and R 37 are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 4-10 membered heterocyclic group, C 6 -12 aryl group and 5-10 membered heteroaryl group, wherein the C 1-6 alkyl group
  • R 3 is independently selected from H, OH, CN, N(CH 3 )C(O)CH 3 , N(CH 3 )C(O)CH 2 CH 3 , N(CH 3 ) C(O)-cyclopropyl and the following groups each optionally substituted with one or more of hydroxy, methyl and CN: methyl, ethyl, propyl, cyclopropyl, cyclobutyl , Cyclopentyl, tetrahydrofuranyl, morpholino, tetrahydropyranyl, isoxazolyl, pyrazolyl and piperidinyl.
  • L does not exist or is -L 1 -L 2 -, wherein L 1 is NH or N(CH 3 ), and L 2 does not exist or is selected from C 1-4 alkylene , C 1-4 alkyleneoxy and C 3-6 cycloalkylene.
  • L does not exist or is -L 1 -L 2 -, where L 1 is NH or N(CH 3 ), and L 2 does not exist or is selected from methylene, ethylene , Propylene, butylene, methyleneoxy, ethyleneoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, ring Propyl, cyclobutylene, cyclopentylene and cyclohexylene.
  • -LR 3 or -NH-L 2 -R 3 is preferably selected from:
  • the compounds of the present invention and pharmaceutically acceptable salts thereof include, but are not limited to:
  • composition preparation and use
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described above, a stereoisomer, a tautomer of the compound, or a mixture thereof, a pharmaceutically acceptable salt, or a mixture of the compound Crystals, polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds.
  • the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition is used to prevent and/or treat diseases related to NLRP3 inflammasome activity (e.g., tumor diseases).
  • diseases related to NLRP3 inflammasome activity e.g., tumor diseases.
  • the present invention provides a pharmaceutical preparation, which comprises the compound as described above, a stereoisomer, a tautomer of the compound, or a mixture thereof, a pharmaceutically acceptable salt, a co-crystal of the compound , Polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of the compound, or comprise the above-mentioned pharmaceutical composition.
  • the present invention provides a compound as described above, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, and polymorph of the compound Or solvates, stable isotope derivatives, metabolites or prodrugs of the compounds, or the use of the above-mentioned pharmaceutical composition for the preparation of medicines for the prevention and/or treatment of NLRP3 inflammasomes Activity-related diseases (e.g. tumor diseases).
  • NLRP3 inflammasomes Activity-related diseases (e.g. tumor diseases).
  • the present invention provides a compound as described above, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, and polymorph of the compound Or solvates, stable isotope derivatives, metabolites or prodrugs of the compounds, or pharmaceutical compositions as described above, which are used to prevent and/or treat diseases related to NLRP3 inflammasome activity (such as tumor diseases) ).
  • the present invention provides a compound as described above, a stereoisomer, a tautomer or a mixture of the compound, a pharmaceutically acceptable salt, co-crystal, and polymorph of the compound Or solvates, stable isotope derivatives, metabolites or prodrugs of the compounds, or the use of the pharmaceutical composition as described above for the preparation of preparations for regulating (for example, increasing) NLRP3 inflammasome active.
  • the formulation is administered to a subject (e.g., a mammal, including, for example, bovine, equine, ovine, swine, canine, feline, rodent, Primates (such as humans) in vivo to increase the NLRP3 inflammasome activity in the cells of the subject.
  • a subject e.g., a mammal, including, for example, bovine, equine, ovine, swine, canine, feline, rodent, Primates (such as humans) in vivo to increase the NLRP3 inflammasome activity in the cells of the subject.
  • cells in vitro e.g., cell lines or cells from a subject
  • the present invention provides a method for modulating (e.g. increasing) the activity of NLRP3 inflammasome in a cell, which comprises administering to the cell an effective amount of a compound as described above, stereoisomers, tautomers of the compound Isomers or mixtures thereof, pharmaceutically acceptable salts, co-crystals, polymorphs or solvates of said compounds, stable isotope derivatives, metabolites or prodrugs of said compounds, drugs as described above Composition, or pharmaceutical formulation as described above.
  • the present invention provides a kit for modulating (for example, increasing) the activity of NLRP3 inflammasomes, the kit comprising a compound as described above, stereoisomers and tautomers of the compound Or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, a stable isotope derivative, metabolite or prodrug of the compound, the pharmaceutical composition as described above, Or a pharmaceutical formulation as described above.
  • the present invention provides a method for treating and/or preventing diseases (such as tumor diseases) associated with NLRP3 inflammasome activity, which comprises administering to a subject in need thereof a therapeutically and/or preventively effective amount of the above
  • diseases such as tumor diseases
  • the tumor diseases include, but are not limited to: brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, intrauterine cancer Membranous cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female reproductive tract cancer, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer, bone cancer, skin cancer, brain Cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma or sarcoma.
  • the compounds of the invention are NLRP3 full agonists. In some embodiments, the compounds of the invention are NLRP3 partial agonists.
  • agonist refers to a compound that binds to a receptor and activates it to trigger a downstream biological effect or response, including full agonist and partial agonist.
  • Full agonists can activate the receptor and produce the greatest effect (maximal effect or E max ).
  • a partial agonist can bind to the receptor and activate it, but compared to a full agonist, it only produces a partial effect.
  • the partial agonist can sometimes become a partial antagonist by competing with the full agonist for binding sites on the receptor or by other mechanisms.
  • Efficacy potential, when by EC 50 (producing 50% of the concentration of compound E max) measure) a possible partial agonist potency higher or lower than a full agonist.
  • the NLRP3 agonists of the present invention include NLRP3 full agonists and NLRP3 partial agonists.
  • NLRP3 NLR family pyrin domain containing 3, which is an inflammasome.
  • the meaning includes NLRP3 nucleic acid, polynucleotide, oligonucleotide, sense and antisense polynucleotide chain, complementary sequence, short peptide, polypeptide , Proteins, homologous or heterologous molecules, subtypes, precursors, mutants, variants, derivatives, various splicing bodies, alleles, different species and activation fragments, etc.
  • halo refers to substitution by a halogen atom, and the “halogen” includes F, Cl, Br, or I.
  • alkyl refers to a linear or branched saturated aliphatic hydrocarbon group.
  • C 1-15 alkyl C 1-8 alkyl
  • C 1-6 alkyl C 1-6 alkyl
  • C 1-4 alkyl respectively refer to having 1 to 15 carbon atoms, 1 to 8 Carbon atoms, linear or branched alkyl groups of 1 to 6 carbon atoms and 1-4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl Group, tert-butyl, n-pentyl or n-hexyl.
  • the alkyl group may be optionally substituted with one or more (such as 1 to 3) substituents which are the same or different.
  • alkylene refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a linear or branched saturated hydrocarbon group, which contains the specified number of carbon atoms.
  • C 1-8 alkylene refers to an alkylene group having 1 to 8 carbon atoms, such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), isopropylidene Group (-CH(CH 3 )CH 2 -) and so on.
  • the alkylene group may be optionally substituted with one or more (such as 1 to 3) substituents which are the same or different.
  • haloalkyl refers to an alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms.
  • C 1-8 haloalkyl refers to having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1-4 carbon atoms, respectively For example, -CF 3 , -C 2 F 5 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CH 2 Cl, -CH 2 CH 2 CF 3 and the like.
  • hydroxyalkyl refers to a group formed by replacing the hydrogen atom of an alkyl group with one or more hydroxy groups, such as a C 1-4 hydroxyalkyl group or a C 1-3 hydroxyalkyl group, examples of which include but are not limited to hydroxy Methyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH)CH 3 and so on.
  • the alkenyl group may be optionally substituted with one or more (such as 1 to 3) substituents which are the same or different.
  • the alkenylene group may be optionally substituted with one or more (such as 1 to 3) substituents which are the same or different.
  • alkynyl refers to a monovalent linear or branched hydrocarbon group with one or more carbon-carbon triple bonds, including but not limited to ethynyl, 2-propynyl, 2-butynyl and 1,3-butynyl Dialkynyl and so on.
  • the alkynyl group may be optionally substituted with one or more (such as 1 to 3) substituents which are the same or different.
  • alkynylene refers to a divalent straight or branched chain hydrocarbon group with one or more carbon-carbon triple bonds, which contains the specified number of carbon atoms, such as 2 to 8 carbon atoms, including but not limited to Wait.
  • the alkynylene group may be optionally substituted with one or more (such as 1 to 3) substituents which are the same or different.
  • alkoxy means a group in which an oxygen atom is inserted at any reasonable position of an alkyl group (as defined above), for example, C 1-8 alkoxy, C 1-6 alkoxy, C 1-4 Alkoxy or C 1-3 alkoxy.
  • Representative examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy Group, hexyloxy group, -CH 2 -OCH 3 and so on.
  • the alkoxy group may be optionally substituted with one or more (such as 1 to 3) substituents which are the same or different.
  • alkyleneoxy refers to a divalent alkoxy group, such as -OCH 2 -, -OCH(CH 3 )CH 2 -, -OCH 2 CH 2 O-, -CH 2 CH 2 O-, etc.
  • the alkyleneoxy group may be optionally substituted with one or more (such as 1 to 3) substituents which are the same or different.
  • condensed ring or “fused ring” refers to a ring system formed by two or more ring structures sharing two adjacent atoms with each other.
  • spirocyclic ring refers to a ring system formed by two or more cyclic structures sharing one ring atom with each other.
  • bridged ring refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.
  • cycloalkyl refers to saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring groups, including but not limited to monocyclic alkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl) and bicyclic alkyl groups, including spirocyclic, fused ring (fused ring) or bridged ring systems (ie, spirocyclic alkyl, fused ring (fused ring) alkyl And bridged cycloalkyl groups, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, etc.).
  • monocyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl,
  • the cycloalkyl group may be optionally substituted by one or more (such as 1 to 3) substituents which are the same or different.
  • 3-7 membered cycloalkyl refers to a cycloalkyl group having 3 to 7 ring-forming carbon atoms, which may be a monocyclic alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclo
  • the heptyl group may also be a bicyclic alkyl group, such as a C 5-7 spirocycloalkyl group, a C 5-7 bridged cycloalkyl group or a C 4-7 condensed cycloalkyl group.
  • C 3-8 cycloalkyl refers to a cycloalkyl group having 3 to 8 ring-forming carbon atoms, such as a C 3-6 cycloalkyl group, which may be a monocyclic alkyl group, such as cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, it can also be a bicyclic alkyl group, such as C 3-8 spirocycloalkyl, C 3-8 bridged cycloalkyl, C 3-8 condensed cycloalkyl , C 3-6 spirocycloalkyl, C 3-6 bridged cycloalkyl or C 3-6 condensed cycloalkyl.
  • cycloalkylene refers to a cycloalkyl group as defined herein, which has two monovalent group centers obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent cycloalkyl group.
  • Typical cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, cyclononylidene, cyclohexenylene, etc. .
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated ⁇ -electron system.
  • C 6-12 aryl group means an aryl group containing 6 to 12 carbon atoms, such as a C 6-10 aryl group, and specific examples are phenyl or naphthyl.
  • the aryl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents (for example, halogen, OH, CN, NO 2 , C 1 -C 6 alkyl, etc.).
  • arylene refers to an aryl group as defined herein, which has two monovalent group centers obtained by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent aryl group.
  • Typical arylene groups include, but are not limited to, phenylene and naphthylene.
  • aryl and cycloalkyl refers to a fused ring group formed by aryl and cycloalkyl (such as monocyclic alkyl) sharing two adjacent atoms with each other, wherein the point of attachment to other groups can be at the aromatic On the base or on the cycloalkyl group.
  • 9-12 membered aryl and cycloalkyl refers to an aryl and cycloalkyl group containing 9-12 ring atoms in total, such as phenyl and cyclopentyl, phenyl and cyclohexyl, such as
  • heterocyclylene refers to a heterocyclic group as defined herein, which has the same carbon atom or two different carbon atoms, one carbon atom and one heteroatom, or two heteroatoms removed from the parent heterocyclic group. Two monovalent group centers derived from a hydrogen atom.
  • 3-14 membered heterocyclic group means a heterocyclic group containing 3-14 ring atoms, including but not limited to 4-10 membered heterocyclic group, 4-7 membered heterocyclic group, 5-6 membered heterocyclic group Group, 4-7 membered nitrogen-containing heterocyclic group, 4-7 membered oxygen-containing heterocyclic group, 4-7 membered sulfur-containing heterocyclic group, 5-6 membered nitrogen-containing heterocyclic group, 5-6 membered oxygen-containing heterocyclic group Group, 5-6 membered sulfur-containing heterocyclic group, etc., the "nitrogen-containing heterocyclic group", "oxygen-containing heterocyclic group” and "sulfur-containing heterocyclic group” each optionally further contain one or more Other heteroatoms of oxygen, nitrogen and sulfur.
  • 3-14 membered heterocyclic groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, Pyrazolyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, Wait.
  • the heterocyclic group also includes a fused ring structure, and the point of connection between the fused ring structure and other groups can be on any ring in the fused ring structure. Therefore, the heterocyclic group of the present invention also includes (but is not limited to) heterocyclic group and heterocyclic group, heterocyclic group and cycloalkyl group, single heterocyclic group and single heterocyclic group, single heterocyclic group and monocyclic alkyl group.
  • heterocyclic groups also include bridged heterocyclic groups and spiro heterocyclic groups.
  • bridged heterocyclyl refers to two saturated rings that share two ring atoms that are not directly connected and contain one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, Nitrogen atom or sulfur atom), including but not limited to 7-10 membered heterocyclic group, 8-10 membered heterocyclic group, 7-10 membered nitrogen-containing bridged heterocyclic group, 7-10 membered oxygen-containing Bridged heterocyclic group, 7-10 membered sulfur-containing bridged heterocyclic group, etc., for example Wait.
  • the "nitrogen-containing bridged heterocyclic group", "oxygen-containing bridged heterocyclic group” and “sulfur-containing bridged heterocyclic group” each optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.
  • spiroheterocyclic group refers to two or more saturated rings that share one ring atom and contain one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, Nitrogen atom, sulfur atom) ring structure, including but not limited to 5-10 membered spiro heterocyclic group, 6-10 membered spiro heterocyclic group, 6-10 membered nitrogen-containing spiro heterocyclic group, 6-10 membered oxygen-containing Spiro heterocyclic group, 6-10 membered sulfur-containing spiro heterocyclic group, etc., for example Wait.
  • heteroatoms e.g., oxygen atoms, Nitrogen atom, sulfur atom
  • nitrogen-containing spiro heterocyclic group each optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.
  • oxygen-containing spiro heterocyclic group refers to a spiroheterocyclic group containing 6-10 ring atoms in total and at least one of which is a nitrogen atom.
  • aryl and heterocyclic group refers to a cyclic group formed by an aryl group and a heterocyclic group sharing two adjacent carbon atoms with each other (wherein the aryl group and the heterocyclic group are as defined above), which is combined with other groups.
  • the point of attachment of the group may be on an aryl group or a heterocyclic group.
  • 9-12 membered aryl and heterocyclyl means an aryl and heterocyclyl group containing a total of 9-12 ring atoms, including but not limited to 9-10 membered Benzoheterocyclic group, such as benzo 5-8 membered heterocyclic group, such as benzo 5-6 membered heterocyclic group, such as benzo 5-6 membered monoheterocyclic group, benzo 5-6 membered nitrogen-containing monohetero Cyclic group, benzo 5-6 membered oxygen-containing monoheterocyclic group, benzo 5-6 membered sulfur-containing heterocyclic group, etc.
  • Benzoheterocyclic group such as benzo 5-8 membered heterocyclic group
  • benzo 5-6 membered heterocyclic group such as benzo 5-6 membered monoheterocyclic group, benzo 5-6 membered nitrogen-containing monohetero Cyclic group, benzo 5-6 membered oxygen-containing monoheterocyclic group, benzo 5-6 membere
  • Each of the "nitrogen-containing heterocyclic group", “oxygen-containing heterocyclic group” and “sulfur-containing heterocyclic group” optionally further contains one or more other heteroatoms selected from oxygen, nitrogen and sulfur.
  • aryl and heterocyclic groups include, but are not limited to: indazolyl,
  • heteroaryl refers to a monocyclic or polycyclic aromatic group containing one or more identical or different heteroatoms, including monocyclic heteroaryl groups and aromatic groups containing at least one heteroaromatic ring (an aromatic group containing at least one heteroatom Ring system), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, such as 5, 6, 7, 8, 9 or 10 Ring atom.
  • the heteroatom may be oxygen, nitrogen or sulfur.
  • heteroarylene refers to a heteroaryl group as described above, which has two hydrogen atoms removed from the same carbon atom or two different carbon atoms of the parent heteroaryl group or one hydrogen atom removed from the carbon atom And two monovalent group centers are obtained by removing one hydrogen atom from the nitrogen atom.
  • 5-10 membered heteroaryl means a heteroaryl group containing 5 to 10 ring atoms, including 5-6 membered heteroaryl, 5-6 membered monoheteroaryl, 5-10 membered nitrogen-containing heteroaryl Group, 5-10 member oxygen-containing heteroaryl group, 5-10 member sulfur-containing heteroaryl group, 5-6 member nitrogen-containing heteroaryl group, 5-6 member oxygen-containing heteroaryl group, 5-6 member sulfur-containing heteroaryl group Group, 5-6 membered nitrogen-containing monoheteroaryl group, 5-6 membered oxygen-containing monoheteroaryl group, 5-6 membered sulfur-containing monoheteroaryl group.
  • the “nitrogen-containing heteroaryl group”, “oxygen-containing heteroaryl group”, “sulfur-containing heteroaryl group”, “nitrogen-containing monoheteroaryl group”, “oxygen-containing monoheteroaryl group” and “sulfur-containing monoheteroaryl group” optionally further contains one or more other heteroatoms selected from oxygen, nitrogen, and sulfur.
  • Examples of 5-10 membered heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, Azolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and 5-10 membered cyclic groups containing these groups.
  • heteroaryl encompasses a bicyclic structure, that is, heteroaryl (e.g., monoheteroaryl) can be combined with aryl (e.g., monocyclic aryl, e.g., phenyl), heterocyclic group (e.g., monoheterocyclic group). Group), cycloalkyl (e.g. monocycloalkyl) or another heteroaryl group (e.g.
  • Another monoheteroaryl sharing two adjacent atoms with each other to form a combined ring structure, which is the point of attachment to other groups
  • It can be on any heteroaromatic ring or other ring, including but not limited to (mono)heteroaryl and (mono)heteroaryl, (mono)heteroaryl and (monocyclic)aryl, (mono)heteroaryl And (mono)heterocyclyl or (mono)heteroaryl and (mono)cycloalkyl, for example 5-6 membered (mono)heteroaryl and 5-6 membered (mono)heteroaryl, 5-6 membered ( Mono) heteroaryl phenyl, 5-6 membered (mono) heteroaryl and 5-6 membered (mono) heterocyclic group or 5-6 membered (mono) heteroaryl and C 4-6 (mono) ring Alkyl groups (e.g.
  • heteroaryl encompasses aryl-containing fused ring structures, which are also referred to as "aryl and heteroaryl", which refers to aryl (e.g., monocyclic aryl, e.g., phenyl) and heteroaryl (e.g., monocyclic aryl) Heteroaryl groups, such as 5-6 membered mono-heteroaryl groups, can be connected to other groups on the aromatic ring or on the heteroaromatic ring.
  • aryl and heteroaryl includes, but is not limited to, monocyclic aryl and monoheteroaryl.
  • 9-12 membered aryl and heteroaryl group refers to an aryl and heteroaryl group containing a total of 9 to 12 ring atoms, such as a benzo 5-6 membered nitrogen-containing monoheteroaryl group.
  • heteroaryl includes a cycloalkyl-containing bicyclic structure, which is also referred to as “heteroaryl and cycloalkyl", which refers to a heteroaryl group (such as a monoheteroaryl group, such as a 5-6 membered monoheteroaryl group). Group) and a cycloalkyl group (for example, a C 4-6 cycloalkyl group).
  • a heteroaryl group such as a monoheteroaryl group, such as a 5-6 membered monoheteroaryl group).
  • a cycloalkyl group for example, a C 4-6 cycloalkyl group.
  • the point of connection with other groups can be on the heteroaromatic ring or on the cycloalkyl group.
  • the "heteroaryl and cycloalkyl” includes, but is not limited to, monoheteroaryl and monocycloalkyl.
  • 9-10 membered heteroaryl and cycloalkyl refers to a heteroaryl and cycloalkyl group containing a total of 9-10 ring atoms, such as 4-6 membered nitrogen-containing monoheteroaryl and C 4-6 mono Cycloalkyl.
  • substitution means that one or more (for example, 1, 2, 3, or 4) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is The normal valence in the current situation and the substitution forms a stable compound. Combinations of substituents and/or variables are only permissible when such combinations form stable compounds.
  • substituent can be (1) unsubstituted or (2) substituted. If the carbon of a substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may each be independently selected optionally Substituent replacement. If the nitrogen of a substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected optionally Substituent replacement.
  • each substituent is selected independently of the other. Therefore, each substituent may be the same or different from another (other) substituent.
  • one or more means one or more than one under reasonable conditions, such as two, three, four, five, six, seven, eight, nine Or 10.
  • the point of attachment of a substituent can be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopic compounds of the compounds of the present invention, which are the same as the compounds of the present invention, except that one or more atoms have the same atomic number but the atomic mass or mass number is different from the one that is predominant in nature. Atomic substitution of atomic mass or mass number.
  • isotopes suitable for inclusion in the compounds of the present invention include (but are not limited to) isotopes of hydrogen (e.g. 2 H, 3 H); isotopes of carbon (e.g. 11 C, 13 C, and 14 C); isotopes of chlorine (e.g.
  • stable isotope derivative means that one or more atoms in the compound of the present invention are replaced by atoms having the same atomic number but whose atomic mass or mass number is different from the predominant atomic mass or mass number in nature. The stable compound.
  • stereoisomer refers to an isomer formed by a compound containing at least one asymmetric center. In compounds with one or more (for example, 1, 2, 3, or 4) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and Individual diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the present invention may exist in a mixture of two or more different structural forms (commonly referred to as tautomers) in rapid equilibrium.
  • Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait.
  • nitroso-oximes can exist in equilibrium in the following tautomeric forms in solution:
  • the pyrazole ring can exist in equilibrium in the following tautomeric forms:
  • the compounds of the present invention are intended to be stereoisomers (including cis and trans isomers), optical isomers (such as R and S enantiomers), and diastereomers. , Geometric isomers, rotamers, conformational isomers, atropisomers or mixtures thereof.
  • the compounds of the present invention can exhibit more than one type of isomerism, and are composed of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
  • the present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which can be a single polymorph or a mixture of more than one polymorph in any ratio. It should also be understood that certain compounds of the present invention may exist in free form for treatment, or, when appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to: pharmaceutically acceptable salts, solvates, metabolites or prodrugs, which can be directly or indirectly administered to patients in need thereof.
  • the compound of the present invention or its metabolite or residue is provided. Therefore, when the "compound of the present invention" is referred to herein, it is also intended to encompass the above-mentioned various derivative forms of the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • acid addition salts for example, hexafluorophosphate, meglumine salt and the like.
  • suitable salts see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, 2002).
  • pharmaceutically acceptable carrier refers to a diluent, adjuvant, excipient or vehicle administered with the therapeutic agent, and it is suitable for contact with humans and/or within the scope of reasonable medical judgment Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • the pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, and mineral oil. Oil, sesame oil, etc.
  • sterile liquids such as water and oils
  • oils including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, and mineral oil. Oil, sesame oil, etc.
  • water is an exemplary carrier. It is also possible to use physiological saline and aqueous glucose and glycerol solutions as liquid carriers, especially for injections.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol, etc.
  • the composition may also contain small amounts of wetting agents, emulsifiers or pH buffering agents as needed.
  • Oral preparations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • the pharmaceutical composition of the present invention can act systemically and/or locally.
  • they can be administered by suitable routes, such as by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, transnasal, transmucosal, topical, It is administered in the form of ophthalmic preparations or by inhalation.
  • the pharmaceutical composition of the present invention can be administered in a suitable dosage form.
  • the dosage form includes but not limited to tablet, capsule, lozenge, hard candy, powder, spray, cream, ointment, suppository, gel, paste, lotion, ointment, aqueous suspension , Injectable solutions, elixirs, syrups.
  • an effective dose refers to the amount of a compound that will relieve one or more symptoms of the condition being treated to a certain extent after being administered.
  • the dosage regimen can be adjusted to provide the best desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgent need of the treatment situation. It should be noted that the dose value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It should be further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • the amount of the compound of the present invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the treatment of the compound, and the judgment of the prescribing physician.
  • the effective dose is about 0.0001 to about 50 mg per kg body weight per day, for example, about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, for example, about 0.7 mg/day to about 700 mg/day.
  • a dose level not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose can still be used without causing any harmful side effects, provided that the larger dose is first
  • the dose is divided into several smaller doses to be administered throughout the day.
  • the content or amount of the compound of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg.
  • treating means reversing, alleviating, or inhibiting the progress of one or more symptoms of the disorder or condition to which such term is applied.
  • prevention means being able to avoid the occurrence of the disease or condition to which such a term is applied.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from diseases such as those described herein.
  • non-human animals include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs). , Cats, cows, pigs, etc.).
  • the compound of the present invention may exist in the form of a solvate (preferably a hydrate), wherein the compound of the present invention contains a polar solvent as a structural element of the compound crystal lattice, in particular, for example, water, methanol or ethanol.
  • a polar solvent as a structural element of the compound crystal lattice, in particular, for example, water, methanol or ethanol.
  • the amount of polar solvent, especially water, can be present in a stoichiometric or non-stoichiometric ratio.
  • metabolites of the compounds of the present invention that is, substances formed in the body when the compounds of the present invention are administered.
  • Such products can be produced by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic hydrolysis, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds obtained by contacting the compound of the present invention with a mammal for a time sufficient to produce its metabolites.
  • the present invention further includes within its scope the prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity, when administered to the body or The above can be converted into the compound of the present invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compound, which are easily converted into the desired therapeutically active compound in vivo.
  • prodrugs please refer to "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by EBRoche, American Pharmaceutical Association).
  • prodrugs of the present invention can be used, for example, by using certain parts known to those skilled in the art as “pro-moiety (for example, “Design of Prodrugs", described in H. Bundgaard (Elsevier, 1985))" It can be prepared by substituting appropriate functional groups present in the compounds of the present invention.
  • the present invention also encompasses compounds of the present invention containing protecting groups.
  • protection of sensitive groups or reactive groups on any relevant molecule may be necessary and/or desirable, thereby forming a chemically protected form of the compounds of the present invention.
  • This can be achieved through conventional protective groups, such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GMWuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 Protective base. These references are incorporated herein by reference.
  • the protecting group can be removed at an appropriate subsequent stage.
  • R 1 , R 3 and L 2 are as defined in the above formula I, and X is selected from chlorine, bromine and iodine.
  • the first step compound II-1 and guanidine carbonate undergo ring closure reaction to produce compound II-2.
  • the solvent that can be used is 1,4-dioxane, dimethyl sulfoxide, DMF, N,N-dimethylacetamide, and the like.
  • the reaction temperature is 0°C to 200°C.
  • the second step Compound II-2 and R 1 -boronic acid or R 1 -boronic acid ester or R 1 -organotin compound (such as R 1 Sn(n-Bu) 3 ) undergo a coupling reaction (such as Suzuki reaction or Stille reaction) ) To produce compound II-3.
  • a coupling reaction such as Suzuki reaction or Stille reaction
  • the catalysts that can be used are Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 and the like.
  • the bases that can be used are Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , AcOK, NaHCO 3 , K 2 CO 3 and the like.
  • the solvents that can be used are 1,4-dioxane/H 2 O, DMF/H 2 O, DMSO/H 2 O, CH 3 CN/H 2 O, toluene/H 2 O Wait.
  • the reaction temperature is between 60°C and 180°C.
  • the third step Compound II-3 and R 3 -L 2 -PG undergo substitution reaction to produce compound II, where PG is a leaving group, which can be halogen (for example, F, Cl, Br or I) or sulfonate.
  • PG is a leaving group, which can be halogen (for example, F, Cl, Br or I) or sulfonate.
  • the solvent that can be used is DMF, DMSO, THF, CH 3 CN, DCM, and the like.
  • the base that can be used is sodium hydride, triethylamine, N,N-diisopropylethylamine, potassium tert-butoxide, sodium hydroxide, and the like.
  • the reaction temperature is -20°C to 180°C.
  • R 1 , R 3 and L 2 are as defined in the above formula I, and X is selected from chlorine, bromine and iodine.
  • the first step compound II-4 and chloroformamidine hydrochloride undergo ring closure reaction to produce compound II-5.
  • the solvent that can be used is 1,4-dioxane, dimethyl sulfone, and the like.
  • the reaction temperature is 0°C to 200°C.
  • the second step Compound II-5 and R 3 -L 2 -NH 2 undergo condensation reaction to produce compound II-6.
  • condensing agents that can be used are BOP, pyBOP, HOBT, HATU, HBTU, TBTU, and the like.
  • the bases that can be used are DBU, DIPEA, K 3 PO 4 , Na 2 CO 3 , AcOK, NaHCO 3 and the like.
  • the reaction temperature is 0°C to 180°C.
  • the third step Compound II-6 and R 1 -boronic acid or R 1 -boronic acid ester or R 1 -organotin compound (such as R 1 Sn(n-Bu) 3 ) undergo a coupling reaction (such as Suzuki reaction or Stille reaction) ), to produce compound II.
  • a coupling reaction such as Suzuki reaction or Stille reaction
  • the catalysts that can be used are Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 and the like.
  • the bases that can be used are Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , AcOK, NaHCO 3 , K 2 CO 3 and the like.
  • the solvents that can be used are 1,4-dioxane/H 2 O, DMF/H 2 O, DMSO/H 2 O, CH 3 CN/H 2 O, toluene/H 2 O Wait.
  • the reaction temperature is 60°C to 180°C.
  • R 1 , R 3 and L 2 are as defined in the above formula III, and X is selected from chlorine, bromine and iodine.
  • the first step compound IV-1 and chloroformamidine hydrochloride undergo ring closure reaction to produce compound IV-2.
  • the solvent that can be used is 1,4-dioxane, dimethyl sulfone, and the like.
  • the reaction temperature is 0°C to 200°C.
  • the second step Compound IV-2 and R 3 -L 2 -NH 2 undergo condensation reaction to produce compound IV-3.
  • condensing agents that can be used are BOP, pyBOP, HOBT, HATU, HBTU, TBTU, and the like.
  • the bases that can be used are DBU, DIPEA, K 3 PO 4 , Na 2 CO 3 , AcOK, NaHCO 3 and the like.
  • the reaction temperature is 0°C to 180°C.
  • the third step Compound IV-3 and R 1 -boronic acid or R 1 -boronic acid ester or R 1 -organotin compound (such as R 1 Sn(n-Bu) 3 ) undergo coupling reaction (such as Suzuki reaction or Stille reaction ) To generate compound IV.
  • R 1 -boronic acid or R 1 -boronic acid ester or R 1 -organotin compound such as R 1 Sn(n-Bu) 3
  • coupling reaction such as Suzuki reaction or Stille reaction
  • the catalysts that can be used are Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 and the like.
  • the bases that can be used are Cs 2 CO 3 , K 3 PO 4 , Na 2 CO 3 , AcOK, NaHCO 3 , K 2 CO 3 and the like.
  • the solvents that can be used are 1,4-dioxane/H 2 O, DMF/H 2 O, DMSO/H 2 O, CH 3 CN/H 2 O, toluene/H 2 O Wait.
  • the reaction temperature is between 60°C and 180°C.
  • the compound of the present invention has obvious agonistic activity on NLRP3 and its signal pathway, without obvious toxic side effects, and can be used for the treatment of diseases related to NLRP3 inflammatory body activity, such as abnormal cell proliferation diseases (e.g. cancer).
  • diseases related to NLRP3 inflammatory body activity such as abnormal cell proliferation diseases (e.g. cancer).
  • the structure of the compound was identified by nuclear magnetic resonance spectroscopy ( 1 H NMR) and/or mass spectrometry (MS).
  • the monitoring of the reaction is carried out by TLC or LC-MS.
  • TLC uses silica gel GF 254 as the stationary phase.
  • LC-MS uses Aglient 1260 Infinity/Aglient 6120 Quadrupole mass spectrometer to record.
  • the compound can be separated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and/or flash column chromatography (Flash column chromatography).
  • Prep-HPLC uses Agilent 1260 preparative liquid chromatograph, the detection wavelength is 214nm or 254nm; the chromatographic column is Waters SunFire Prep C18 OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); the column temperature is 25°C, and the elution conditions are as follows:
  • Condition 1 10%-90% acetonitrile and 90%-10% ammonium formate aqueous solution (0.05%), 0-16min; flow rate: 24mL/min;
  • Condition 3 10%-90% acetonitrile and 90%-10% formic acid aqueous solution (0.05%), 0-16min; flow rate: 28mL/min;
  • Condition 4 10%-90% acetonitrile and 90%-10% ammonium bicarbonate aqueous solution (0.05%), 0-16min; flow rate: 28mL/min;
  • Condition 7 0%-50% acetonitrile and 100%-50% ammonium bicarbonate aqueous solution (0.05%), 0-20min; flow rate: 28mL/min.
  • Silica gel column chromatography generally uses 200-300 mesh silica gel (Qingdao Ocean) as the stationary phase.
  • Eluent system A dichloromethane and methanol
  • eluent system B petroleum ether and ethyl acetate; the volume ratio of the solvent is adjusted according to the polarity of the compound.
  • the flash column chromatography uses the Biotage flash column chromatograph.
  • the microwave reaction was carried out using BiotageInitiator+microwave reactor.
  • reaction temperature is room temperature (15°C to 30°C).
  • the reagents used in this application are purchased from companies such as Acros Organics, Aldrich Chemical Company, or Terb Chemical.
  • the first step 7-bromoquinazoline-2,4-diamine (compound 1b)
  • the fourth step 3-((2-amino-7-(1H-pyrazol-5-yl)quinazolin-4-yl)amino)-1-propanol formate (compound 1s)
  • compound 2b 55 mg was added to DMF (3 mL), DBU (104.64 mg) and BOP (121.60 mg) were added successively, and the mixture was stirred for 5 min. Add 2-methoxyethylamine (127mg) and react for 16h. The reaction solution was suction filtered, and the filtrate was separated and purified by Prep-HPLC (elution condition 4), and lyophilized to obtain compound 2c (8 mg).
  • the first step 3-((2-amino-7-bromoquinazolin-4-yl)amino)-2,2-dimethyl-1-propanol (compound 13a)
  • the first step 4-((2-amino-7-bromoquinazolin-4-yl)amino)cyclohexanol (compound 14a)
  • the first step 7-bromo-4-((2R,6R)-2,6-dimethylmorpholino)quinazolin-2-amine (compound 29a)
  • the first step 7-bromo-N 4 -(cyclobutylmethyl)quinazoline-2,4-diamine (compound 30a)
  • Step 2 4-((2-Amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)cyclohexanol (Compound 38)
  • Step 2 cis-3-((2-amino-6-(1H-pyrazol-5-yl)thieno[3,2-d]pyrimidin-4-yl)amino)-1-methyl ring Butanol (Compound 41)
  • HTRF time-resolved fluorescence
  • RPMI 1640 Hyclone
  • FBS fetal bovine serum
  • PMA Biyuntian
  • Kit IL-1 ⁇ assay kit (CISBIO)
  • THP-1 cells in the logarithmic growth phase were seeded in a T75 culture flask at a density of 5 ⁇ 10 5 cells/well, and then cultured in a 37°C, 5% CO 2 cell incubator for 24 hours.
  • 1 ⁇ M PMA induces THP-1 suspension cells to become adherent macrophages.
  • the medium was RPMI 1640 containing 10% heat-inactivated FBS and 0.05 mM ⁇ -mercaptoethanol.
  • the HTRF detection method was used to test the effect of the compound of the present invention on the level of IL-1 ⁇ in THP1-def NLRP3 cells to evaluate the specificity of the compound on hNLRP3 inflammasome or hNLRP3 inflammasome pathway agonism.
  • Kit IL-1 ⁇ assay kit (CISBIO)
  • THP1-def NLRP3 cells in the logarithmic growth phase were seeded in a T75 culture flask at a density of 5 ⁇ 10 5 cells/well, and then cultured in a cell incubator at 37°C and 5% CO 2 for 24 hours.
  • 1 ⁇ M PMA was used to induce THP1- def NLRP3 suspension cells to become adherent macrophages.
  • the medium was RPMI 1640 containing 10% heat-inactivated FBS and 0.05 mM ⁇ -mercaptoethanol.
  • the luciferase in HEK-hTLR7-NF- ⁇ B-luciferase reporter gene cells was tested to test the activating effect of the compound of the present invention on the TLR7 signaling pathway, so as to evaluate the specificity of the compound's agonistic effect on the NLRP3 pathway.
  • DMEM High glucose
  • FBS Gabco
  • HEK-hTLR7-NF- ⁇ B-Luciferase reporter cells human TLR7NF- ⁇ B-luciferase reporter cells (Nanjing Kebai)
  • DMEM High glucose
  • FBS Gabco
  • QUANTI-Blue InvivoGen
  • HEK-Blue TM hTLR8 cells human TLR 8 cells (InvivoGen)
  • the compounds of the present invention represented by the compounds listed in Table 1 have a significant agonistic effect on the expression of IL-1 ⁇ in THP-1 cells after PMA-induced differentiation, but on IL-1 ⁇ in THP-1 def NLRP3 cells.
  • the expression has no agonistic effect even at the highest compound tested concentration (30 ⁇ M). All the compounds tested had no activating effect on hTLR7 and hTLR8 at 100 ⁇ M.
  • the compounds of the present invention represented by the compounds listed in Table 1 have obvious specific agonistic activity on hNLRP3 and/or its signal pathway.
  • HEK-293 human embryonic kidney cells
  • Negative control extracellular fluid containing 0.1% DMSO (Sigma)
  • CYP450 is the most important enzyme system in drug metabolism. Enzymes involved in metabolism interact with drugs, and the most important ones are CYP1A2, CYP2D6 and CYP3A4.
  • This experiment uses P450-Glo TM CYP1A2 Screening System, CYP2D6Cyan Screening Kit and CYP3A4 Red Screening Kit, according to the kit instructions to determine the compound's inhibitory activity on CYP1A2, CYP2D6 and CYP3A4. The results are shown in Table 4.

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Abstract

La présente invention concerne un composé à cycles condensés contenant de l'azote, son procédé de préparation et son utilisation. Plus particulièrement, la présente invention concerne un composé ayant une structure représentée par la formule (X), un stéréoisomère ou un tautomère du composé ou un mélange de ceux-ci, un sel pharmaceutiquement acceptable, un co-cristal, un polymorphe ou un solvate du composé, ou un dérivé isotopique stable, un métabolite ou un promédicament du composé. Le composé selon la présente invention peut avoir une structure représentée par la formule (I) ou la formule (III). Les composés peuvent être utilisés pour le traitement de maladies associées à une prolifération cellulaire anormale (telles que les cancers).
PCT/CN2020/106220 2019-12-13 2020-07-31 Composé à cycles condensés contenant de l'azote, son procédé de préparation et son utilisation WO2021114691A1 (fr)

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WO2021057256A1 (fr) * 2019-09-29 2021-04-01 四川科伦博泰生物医药股份有限公司 Composé azoté hétérocyclique, composition pharmaceutique le contenant, son procédé de préparation et utilisation associée

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