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WO2025180453A1 - Dérivé de cycle pyridazine et son utilisation - Google Patents

Dérivé de cycle pyridazine et son utilisation

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Publication number
WO2025180453A1
WO2025180453A1 PCT/CN2025/079601 CN2025079601W WO2025180453A1 WO 2025180453 A1 WO2025180453 A1 WO 2025180453A1 CN 2025079601 W CN2025079601 W CN 2025079601W WO 2025180453 A1 WO2025180453 A1 WO 2025180453A1
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WO
WIPO (PCT)
Prior art keywords
independently
membered
substituted
mmol
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/079601
Other languages
English (en)
Chinese (zh)
Inventor
贾海飞
陈德恒
申华琼
吴凌云
赵乐乐
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Neushen Therapeutics Shanghai Co Ltd
Original Assignee
Neushen Therapeutics Shanghai Co Ltd
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Filing date
Publication date
Application filed by Neushen Therapeutics Shanghai Co Ltd filed Critical Neushen Therapeutics Shanghai Co Ltd
Publication of WO2025180453A1 publication Critical patent/WO2025180453A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to pyridazine ring derivatives and applications thereof.
  • the NLRP3 inflammasome is a multiprotein complex consisting of the sensor NLRP3, the adaptor ASC, and the effector caspase 1. Cytokines, pathogen-associated molecular patterns (PAMPs), or damage-associated molecular patterns (DAMPs) can activate the NLRP3 inflammasome, further activating caspase 1 and promoting the cleavage of pro-IL-1 ⁇ and pro-IL-18, as well as the release of the cytokines IL-1 ⁇ and IL-18.
  • PAMPs pathogen-associated molecular patterns
  • DAMPs damage-associated molecular patterns
  • the NLRP3 inflammasome plays a crucial role in neurodegenerative diseases.
  • NLRP3 inhibitors are available on the market.
  • several NLRP3 inhibitors including OLT-1177, DFV-890, and Selnoflast, are in various stages of clinical research.
  • the development of NLRP3 inhibitors holds broad promise for future applications.
  • the present invention aims to overcome the shortage of NLRP3 inhibitors in the prior art by providing novel pyridazine ring derivatives and their applications. These pyridazine ring derivatives exhibit excellent inhibitory activity against NLRP3 and are capable of effectively inhibiting IL-1 ⁇ secretion in THP-1 cells.
  • the present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:
  • R 1 is naphthyl substituted by one or more R 4 , phenyl substituted by one or more R 4 , or 5-10 membered heteroaryl substituted by one or more R 5 ;
  • R4 and R5 are each independently hydrogen, halogen, hydroxy, cyano, C1 - C6 alkyl, C1 - C6 alkoxy, C3 - C6 cycloalkyl, 5-6 membered heteroaryl, C1 - C6 alkyl substituted by one or more Rc , C1 - C6 alkoxy substituted by one or more Rd ' , or 5-6 membered heteroaryl substituted by one or more Rd ;
  • R c is independently deuterium, halogen or hydroxy
  • R d' is independently halogen
  • R d is independently halogen or C 1 -C 6 alkyl
  • two adjacent R 4 groups and the atoms to which they are attached together form a C 3 -C 7 cycloalkenyl group, a 3-7 membered heterocycloalkenyl group, a C 3 -C 7 cycloalkenyl group substituted by one or more R e , or a 3-7 membered heterocycloalkenyl group substituted by one or more R f ;
  • two adjacent R 5 groups and the atoms to which they are attached together form a C 3 -C 7 cycloalkenyl group, a 3-7 membered heterocycloalkenyl group, a C 3 -C 7 cycloalkenyl group substituted with one or more R e , or a 3-7 membered heterocycloalkenyl group substituted with one or more R f ;
  • R e and R f are each independently hydrogen, halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 5-6 membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R c , C 1 -C 6 alkoxy substituted by one or more R d' , or 5-6 membered heteroaryl substituted by one or more R d ;
  • R 2 is hydrogen, CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, 3-7 membered heterocycloalkyl, C 1 -C 6 alkoxy substituted by one or more R 2-1 , or C 1 -C 6 alkyl substituted by one or more R 2-2 ;
  • R 2-1 and R 2-2 are each independently halogen
  • a 1 , A 2 , A 3 and A 4 are each independently a linking bond, CR a R b , NR c , O or S;
  • the number of connecting bonds in A 1 , A 2 , A 3 and A 4 is 0, 1, 2 or 3;
  • Ra , Rb and Rc are each independently hydrogen, hydroxy, C1 - C6 alkyl, C3 - C6 cycloalkyl or C1 - C6 alkyl substituted by one or more Ra -1 , or Ra and Rb together with the carbon atom to which they are attached form a C3 - C6 cycloalkyl;
  • R 3 is C 3 -C 7 monocyclic cycloalkyl, C 5 -C 12 bicyclic cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, 5-12 membered bicyclic heterocycloalkyl, 3-7 membered monocyclic heterocycloalkyl substituted by one or more R 3-1 , 5-12 membered bicyclic heterocycloalkyl substituted by one or more R 3-1 , C 1 -C 6 alkyl substituted by one or more R 3-2 , C 3 -C 7 monocyclic cycloalkyl substituted by one or more R 3-3 , or C 5 -C 12 bicyclic cycloalkyl substituted by one or more R 3-3 ;
  • R 3-1-2 and R 3-1-3 are each independently a C 1 -C 6 alkyl group
  • R 3-2 is independently 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl substituted by one or more R 3-2-1 ;
  • R 3-2-1 is independently C 1 -C 6 alkyl
  • each "5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S; the number of heteroatoms is 1, 2 or 3;
  • Each "3-7 membered heterocycloalkyl” is independently a 3-7 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • Each "3-7 monocyclic heterocycloalkyl” is independently a 3-7 membered monocyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • Each "5-12 membered bicyclic heterocycloalkyl” is independently a 5-12 membered bicyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • Each "5-6 membered heteroaryl” is independently a 5-6 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • Each "3- to 7-membered heterocycloalkenyl group” is independently a 3- to 7-membered heterocycloalkenyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of the heteroatoms is 1, 2 or 3.
  • the compound represented by formula (I) is not the following compound and its stereoisomers:
  • certain groups in the compound of formula (I), its pharmaceutically acceptable salt or solvate of any of the foregoing are defined as follows, and the unmentioned groups are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment of the present invention”).
  • R 1 is naphthyl substituted by one or more R 4 , phenyl substituted by one or more R 4 , or 5-10 membered heteroaryl substituted by one or more R 5 ;
  • R4 and R5 are each independently hydrogen, halogen, hydroxy, cyano, C1 - C6 alkyl, C1 - C6 alkoxy, C3 - C6 cycloalkyl, 5-6 membered heteroaryl, C1 - C6 alkyl substituted by one or more Rc , C1 - C6 alkoxy substituted by one or more Rd ' , or 5-6 membered heteroaryl substituted by one or more Rd ;
  • R c is independently deuterium, halogen or hydroxy
  • R d' is independently halogen
  • R d is independently halogen or C 1 -C 6 alkyl
  • two adjacent R 4 groups and the atoms to which they are attached together form a C 3 -C 7 cycloalkenyl group, a 3-7 membered heterocycloalkenyl group, a C 3 -C 7 cycloalkenyl group substituted by one or more R e , or a 3-7 membered heterocycloalkenyl group substituted by one or more R f ;
  • two adjacent R 5 groups and the atoms to which they are attached together form a C 3 -C 7 cycloalkenyl group, a 3-7 membered heterocycloalkenyl group, a C 3 -C 7 cycloalkenyl group substituted with one or more R e , or a 3-7 membered heterocycloalkenyl group substituted with one or more R f ;
  • R e and R f are each independently hydrogen, halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 5-6 membered heteroaryl, C 1 -C 6 alkyl substituted by one or more R c , C 1 -C 6 alkoxy substituted by one or more R d' , or 5-6 membered heteroaryl substituted by one or more R d ;
  • R 2 is hydrogen, CN, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, 3-7 membered heterocycloalkyl, C 1 -C 6 alkoxy substituted by one or more R 2-1 , or C 1 -C 6 alkyl substituted by one or more R 2-2 ;
  • R 2-1 and R 2-2 are each independently halogen
  • a 1 , A 2 , A 3 and A 4 are each independently a linking bond, CR a R b , NR c , O or S;
  • the number of connecting bonds in A 1 , A 2 , A 3 and A 4 is 0, 1, 2 or 3;
  • Ra , Rb and Rc are each independently hydrogen, C1 - C6 alkyl, C3 - C6 cycloalkyl or C1- C6 alkyl substituted by one or more Ra -1 , or Ra and Rb together with the carbon atom to which they are attached form a C3 - C6 cycloalkyl ;
  • R a-1 is independently halogen
  • R 3 is C 3 -C 7 monocyclic cycloalkyl, C 5 -C 12 bicyclic cycloalkyl, 3-7 membered monocyclic heterocycloalkyl, 5-12 membered bicyclic heterocycloalkyl, 3-7 membered monocyclic heterocycloalkyl substituted by one or more R 3-1 , 5-12 membered bicyclic heterocycloalkyl substituted by one or more R 3-1 , C 1 -C 6 alkyl substituted by one or more R 3-2 , C 3 -C 7 monocyclic cycloalkyl substituted by one or more R 3-3 , or C 5 -C 12 bicyclic cycloalkyl substituted by one or more R 3-3 ;
  • R 3-1-1 is independently OH, halogen, C 3 -C 7 cycloalkyl or 3-7 membered heterocycloalkyl;
  • R 3-2 is independently 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl substituted by one or more R 3-2-1 ;
  • R 3-2-1 is independently C 1 -C 6 alkyl
  • each "5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S; the number of heteroatoms is 1, 2 or 3;
  • Each "3-7 membered heterocycloalkyl” is independently a 3-7 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • Each "3-7 monocyclic heterocycloalkyl” is independently a 3-7 membered monocyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • Each "5-12 membered bicyclic heterocycloalkyl” is independently a 5-12 membered bicyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • Each "5-6 membered heteroaryl” is independently a 5-6 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • Each "3- to 7-membered heterocycloalkenyl group” is independently a 3- to 7-membered heterocycloalkenyl group having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of the heteroatoms is 1, 2 or 3.
  • each "5-10 membered heteroaryl” is independently a 8-10 membered bicyclic heteroaryl group having one heteroatom selected from N, O and S, for example
  • each "C 1 -C 6 alkyl” is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl; for example, methyl, ethyl or isopropyl, further for example, methyl.
  • each "halogen" is independently fluorine, chlorine, bromine or iodine; for example, fluorine or chlorine, further for example fluorine.
  • each "C 1 -C 6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; for example, methoxy.
  • each "C 3 -C 6 cycloalkyl” is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; for example, cyclopropyl, cyclobutyl or cyclohexyl.
  • each "5-6 membered heteroaryl group” is independently a 5-membered heteroaryl group in which the heteroatoms are S and N and the number of heteroatoms is 3; for example,
  • each "C 3 -C 7 cycloalkenyl” is independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, for example, cyclopentenyl.
  • each "3-7 membered heterocycloalkenyl” is independently a "4-6 membered heterocycloalkenyl" wherein the heteroatom is O and the number of heteroatoms is 1 or 2, for example, dihydrofuranyl.
  • each "C 3 -C 7 cycloalkyl” is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • each "3-7 membered heterocycloalkyl” is independently a 4-9 membered heterocycloalkyl group in which the heteroatom is O or N and the number of heteroatoms is 1 or 2, for example, any of the following:
  • each "C 3 -C 7 membered monocyclic cycloalkyl” is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, Among them, the configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof; for example,
  • each "3-7 membered monocyclic heterocycloalkyl” is independently a “4-7 membered monocyclic heterocycloalkyl” wherein the heteroatom is N and/or O, and the number of heteroatoms is 1 or 2, for example, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl; for example,
  • the configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof, and X is O, NH or CH 2 ; for example,
  • each "C 5 -C 12 bicyclic cycloalkyl” is independently a C 5 -C 12 bicyclic cycloalkyl, a C 5 -C 12 bridged cycloalkyl or a C 5 -C 12 spirocyclic cycloalkyl.
  • R 1 is a phenyl group substituted by one or more R 4 groups or a 5-10 membered heteroaryl group substituted by one or more R 5 groups; preferably, it is a phenyl group substituted by one or more R 4 groups .
  • R4 and R5 are each independently hydrogen, halogen, hydroxyl, cyano, C1 - C6 alkyl, C1 - C6 alkoxy, 5-6 membered heteroaryl, C1 - C6 alkyl substituted by one or more Rc , or 5-6 membered heteroaryl substituted by one or more Re ;
  • two adjacent R 4 groups and the atoms to which they are attached together form a C 3 -C 7 cycloalkenyl group or a 3-7 membered heterocycloalkenyl group.
  • R c is independently halogen
  • R e is independently C 1 -C 6 alkyl.
  • the number of connecting bonds in A 1 , A 2 , A 3 and A 4 is 0 or 1, preferably 1.
  • Ra , Rb and Rc are each independently H, hydroxyl or C1 - C6 alkyl; or, Ra and Rb together with the carbon atom to which they are attached form a C3 - C6 cycloalkyl.
  • Ra , Rb and Rc are each independently H or C1 - C6 alkyl; or, Ra and Rb together with the carbon atom to which they are attached form a C3 - C6 cycloalkyl.
  • R 3 is a 5-12 membered bicyclic heterocycloalkyl, a 3-7 membered monocyclic heterocycloalkyl substituted by one or more R 3-1 , a C 1 -C 6 alkyl substituted by one or more R 3-2 , or a C 3 -C 7 monocyclic cycloalkyl substituted by one or more R 3-3 ; preferably a 3-7 membered monocyclic heterocycloalkyl substituted by one or more R 3-1 .
  • R 3-1-1 is independently C 3 -C 7 cycloalkyl.
  • R 3-1-2 is independently C 1 -C 6 alkyl.
  • R 3-1 and R 3-3 are each independently hydroxyl, halogen or C 1 -C 6 alkyl, preferably C 1 -C 6 alkyl.
  • R 3-2 is independently a 3-7 membered heterocycloalkyl group substituted by one or more R 3-2-1 .
  • R 3-2-1 is independently C 1 -C 6 alkyl.
  • R1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R1 is Preferably
  • R2 is hydrogen, methyl or For example, hydrogen.
  • R3 is (For example, ), R 3a and R 3b together with the carbon atom to which they are attached form a C 3 -C 7 monocyclic cycloalkyl, a C 5 -C 12 bicyclic cycloalkyl, a 3-7 membered monocyclic heterocycloalkyl, a 5-12 membered bicyclic heterocycloalkyl, a 3-7 membered monocyclic heterocycloalkyl substituted by one or more R 3-1 , a 5-12 membered bicyclic heterocycloalkyl substituted by one or more R 3-1 , a C 3 -C 7 monocyclic cycloalkyl substituted by one or more R 3-3 , or a C 5 -C 12 bicyclic cycloalkyl substituted by one or more R 3-3 , R 3c and R 3d together with the carbon atom to which they are attached form a 3-7 membered heterocycloalkyl substituted by one or more
  • R3 is (For example, ), wherein the configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof; m is 0 or 1; R 3-1 , R 3-3 and R 3-2-1 are defined as described in any one of the present invention.
  • R3 is The configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof; m is 0 or 1; and R 3-1 is defined as described in any one of the present invention.
  • R3 is The configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof; m is 0 or 1; and R 3-1 is defined as described in any one of the present invention.
  • R3 is The configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof; m is 0 or 1; and R 3-1 is defined as described in any one of the present invention.
  • R3 is The configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof; m is 0 or 1; and R 3-2-1 is defined as described in any one of the present invention.
  • R3 is The configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof; m is 0 or 1; and R 3-3 is defined as described in any one of the present invention.
  • R3 is The configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof; m is 0 or 1; and R 3-3 is defined as described in any one of the present invention.
  • R3 is The configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof; m is 0 or 1; and R 3-3 is defined as described in any one of the present invention.
  • R3 is The configuration of the carbon atom marked with "*" is R configuration, S configuration or a mixture thereof; m is 0 or 1; and R 3-3 is defined as described in any one of the present invention.
  • R3 is (For example, Further example ), wherein m is 0 or 1; R 3-1 , R 3-3 and R 3-2-1 are as defined in any one of the present invention.
  • R3 is Preferably
  • R3 is Preferably
  • R a , R b and R c are as defined in any one of the present invention.
  • R a , R b and R c are as defined in any one of the present invention.
  • R a , R b and R c are as defined in any one of the present invention.
  • R c is defined as described in any one of the present invention.
  • R c is defined as described in any one of the present invention.
  • Ra and Rb are as defined in any one of the present invention.
  • Ra and Rb are as defined in any one of the present invention.
  • the compound represented by formula (I) is any one of the following compounds:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a substance X and a pharmaceutically acceptable excipient, wherein the substance X is a compound as represented by formula (I) as described in any of the above schemes, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.
  • the present invention also provides a use of the above-mentioned pharmaceutical composition or the above-mentioned substance X in the preparation of an NLRP3 inhibitor.
  • the present invention also provides a use of the above-mentioned pharmaceutical composition or the above-mentioned substance X in the preparation of a drug for preventing and/or treating diseases related to NLRP3;
  • the NLRP3-related disease is a neurodegenerative disease (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease).
  • a neurodegenerative disease such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease.
  • the present invention also provides a pharmaceutical composition or substance X for use in the preparation of a method for preventing and/or treating neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease).
  • neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease.
  • the present invention also provides a method for preventing and/or treating a disease associated with NLRP3, comprising administering a therapeutically effective amount of the substance X or the pharmaceutical composition to an individual in need thereof.
  • the NLRP3-associated disease is preferably a neurodegenerative disease (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease).
  • the present invention also provides a method for preventing and/or treating a disease, comprising: administering a therapeutically effective amount of the aforementioned substance X or the aforementioned pharmaceutical composition to an individual in need thereof, wherein the disease is a neurodegenerative disease (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease).
  • a neurodegenerative disease such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, or Huntington's disease.
  • the present invention also provides a method for inhibiting NLRP3, comprising administering to an individual in need thereof a therapeutically effective amount of a compound as represented by formula (I) as described in any embodiment of the present invention, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.
  • a substituent may be preceded by a single dash "-" to indicate that the named substituent is bonded to the parent moiety through a single bond.
  • halogen refers to F, Cl, Br or I.
  • alkyl refers to a straight or branched chain alkyl group having a specified number of carbon atoms (e.g., C1 - C6 ).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, and the like.
  • alkoxy refers to the group R X -O-, where R X is defined as the term “alkyl”.
  • heterocycloalkyl refers to a monocyclic or bicyclic saturated cyclic group having a specified number of ring atoms (e.g., 3-7 members, 5-12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatoms (1, 2, or 3 of N, O, and S).
  • heterocycloalkenyl refers to a cyclic, unsaturated, monovalent hydrocarbon group having a specified number of ring atoms (e.g., 3-7 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one or more of N, O, and S), which has one or more (e.g., 1 or 2) carbon-carbon sp2 double bonds and is not aromatic.
  • heteroaryl refers to a cyclic, aromatic, monovalent group having a specified number of ring atoms (e.g., 5-6 members, 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one or more of N, O, and S), which is monocyclic or polycyclic, with two atoms and one bond shared between the individual rings.
  • a heteroaryl group is attached to the rest of the molecule through a carbon atom or a heteroatom; a heteroaryl group is attached to the rest of the molecule through a ring with a heteroatom or a ring without a heteroatom.
  • cycloalkyl refers to a saturated cyclic group having a specified number of ring carbon atoms (e.g., C 3 -C 6 or C 3 -C 7 ), wherein the ring atoms consist only of carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • cycloalkenyl refers to a cyclic, unsaturated, monovalent hydrocarbon radical having a specified number of carbon atoms (e.g., C 3 -C 7 ), having one or more (e.g., 1 or 2) carbon-carbon sp 2 double bonds, and not being aromatic.
  • R c any variable (e.g., R c ) appears multiple times in a compound definition, the definition of that variable at each occurrence is independent of the definitions at the remaining occurrences, and their meanings are independent of each other and do not affect each other.
  • pharmaceutically acceptable salt refers to salts prepared from compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
  • solvate refers to a compound of the present invention combined with a stoichiometric or non-stoichiometric amount of a solvent.
  • the solvent molecules in the solvate may be present in an ordered or non-ordered arrangement.
  • pharmaceutically acceptable salt and solvate in the term “pharmaceutically acceptable salt solvate” as described above refer to substances prepared by the compounds of the present invention with relatively non-toxic, pharmaceutically acceptable acids or bases; and formed in combination with stoichiometric or non-stoichiometric solvents.
  • pharmaceutically acceptable excipients refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. These excipients are all substances, other than the active ingredient, contained in a pharmaceutical preparation. For a list of excipients, see Part IV of the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C. Rowe, 2009, Sixth Edition).
  • the "inhibitor" can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art.
  • treatment refers to therapeutic treatment.
  • treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that leads to or causes the condition or (b) one or more biological manifestations of the condition, (3) ameliorating one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing the progression of the condition or one or more biological manifestations of the condition.
  • prevent refers to the reduction of the risk of acquiring or developing a disease or disorder.
  • the reagents and raw materials used in the present invention are commercially available.
  • the positive progress of the present invention is that the present invention has one or more of the following effects: 1
  • the pyridazine ring derivative of the present invention has good inhibitory activity against NLRP3 and can effectively inhibit the secretion of IL-1 ⁇ in THP-1 cells: the IC50 value is 1-160nM; 2
  • the compound of the present invention has good pharmacokinetic properties: the bioavailability F is 35%-130%; 3
  • the compound of the present invention has the characteristics of high permeability and low efflux: the efflux ratio is 0.5-1.4; 4
  • the compound of the present invention can effectively inhibit the secretion of IL-1 ⁇ in PBMC cells: the IC50 value is 1-12nM; 5
  • the compound of the present invention can significantly reduce the serum IL-1 ⁇ concentration in a mouse inflammation model, showing a good anti-inflammatory effect.
  • the crude product was purified by high-performance liquid chromatography (Waters-Sunfire-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L 0.1% formic acid in water, gradient: 15-25%, retention time: 10 minutes) to obtain the monoformate salt of compound 2.
  • the crude product was purified by high-performance liquid chromatography (Waters-Sunfire-C18-10 ⁇ m-19*250mm, mobile phase: acetonitrile-10mmol/L 0.1% formic acid in water, gradient: 20-30%, retention time: 17 minutes) to obtain the monoformate salt of compound 3.
  • reaction solution was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (30 mL ⁇ 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high-performance liquid chromatography (Waters 3767/QDA Column: SunFire C18, 19*250 mm, 10 ⁇ m; mobile phase: acetonitrile-0.1% aqueous ammonia, gradient: 20-30%, retention time: 11 min) to obtain 10.
  • high-performance liquid chromatography Waters 3767/QDA Column: SunFire C18, 19*250 mm, 10 ⁇ m; mobile phase: acetonitrile-0.1% aqueous ammonia, gradient: 20-30%, retention time: 11 min
  • 17-1 (150 mg, 0.56 mmol) was dissolved in methanol (6 mL) and tetrahydrofuran (6 mL).
  • 27-1 (195 mg, 1.12 mmol), acetic acid (148 mg, 2.8 mmol), and sodium triacetoxyborohydride (180 mg, 0.84 mmol) were added sequentially, and the mixture was stirred at 60°C for 16 hours. After completion of the reaction, the pH was adjusted to greater than 8 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (50 mL ⁇ 3).
  • 29-1 (350 mg, 1.37 mmol) was dissolved in 1,2-dichloroethane (5 mL).
  • Acetaldehyde (5.0 mol/L tetrahydrofuran solution, 0.08 mL, 0.37 mmol) and sodium triacetoxyborohydride (871 mg, 4.11 mmol) were added sequentially at 0°C, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (20 mL x 3).
  • 29-2 (70 mg, 0.25 mmol), 29-3 (85 mg, 0.50 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (20 mg, 0.03 mmol), and potassium carbonate (173 mg, 1.25 mmol) were added to 1,4-dioxane (5 mL) and 1 mL. The mixture was heated to 90°C and stirred for 16 hours under nitrogen protection.
  • 3-1 (610 mg, 2.90 mmol) and 32-1 (410 mg, 2.90 mmol) were dissolved in acetonitrile (20 mL), and N,N-diisopropylethylamine (2.4 mL, 14.5 mmol) was added. The mixture was heated to 70°C and stirred for 18 hours. After the reaction, the mixture was cooled to room temperature, and 3-3 (820 mg, 5.40 mmol) and N,N-diisopropylethylamine (2.2 mL, 13.5 mmol) were added. Stirring was continued at room temperature for another 18 hours.
  • 33-3 (47 mg, 0.13 mmol) was dissolved in methanol (5 mL), and acetaldehyde (5.0 mol/L tetrahydrofuran solution, 0.04 mL, 0.2 mmol), acetic acid (0.1 mL), and sodium triacetoxyborohydride (83 mg, 0.39 mmol) were added sequentially. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by HPLC (Waters 3767/QDA Column: SunFire C18, 19*250 mm, 10 ⁇ m; mobile phase: acetonitrile-0.05% ammonia monohydrate, gradient: 34-44%, retention time: 8 min) to afford 33.
  • HPLC Waters 3767/QDA Column: SunFire C18, 19*250 mm, 10 ⁇ m; mobile phase: acetonitrile-0.05% ammonia monohydrate, gradient: 34-44%, retention time: 8 min
  • 34-1 (5.0 g, 71.34 mmol) was dissolved in N,N-dimethylformamide (150 mL). Sodium hydride (60%, 3.71 g, 92.74 mmol) was added portionwise at 0°C. After stirring for 1 hour, 34-2 (25.60 g, 107.01 L) was added dropwise. The mixture was warmed to room temperature and stirred for 16 hours. After completion of the reaction, water (400 mL) was slowly added to quench the reaction. The mixture was extracted with ethyl acetate/petroleum ether (1/4, v/v, 300 mL x 3).
  • 34-3 (4.5 g, 39.43 mmol) was dissolved in tetrahydrofuran (180 mL), and triphenylphosphine (12.41 g, 47.32 mmol) and imidazole (8.05 g, 118.29 mmol) were added. The mixture was cooled to -10°C, and iodine (12.01 g, 47.32 mmol) was added. The mixture was stirred at 25°C for 3 hours. After the reaction, the mixture was diluted with water (250 mL) and extracted with petroleum ether (200 mL ⁇ 3).
  • 34-7 (380 mg, 0.92 mmol) was dissolved in toluene (15 mL), heated to 130°C, and stirred for 16 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1, v/v) to afford 34-8.
  • ESI-MS calculated value [M+H] + 383.2, found 383.2.
  • 39-3 (300 mg, 0.86 mmol) was dissolved in toluene (10 mL), heated to 130°C, and stirred for 24 hours. After the reaction, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1, v/v) to obtain 39-4.
  • reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (50 mL ⁇ 3). The organic phases were combined, washed with saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high-performance liquid chromatography (Waters 3767/QDA Column: SunFire C18, 19*250 mm, 10 ⁇ m; mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 24-34%, retention time: 6 min) to obtain 39.
  • high-performance liquid chromatography Waters 3767/QDA Column: SunFire C18, 19*250 mm, 10 ⁇ m; mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 24-34%, retention time: 6 min
  • Dissolve 40-1 (1.1 g, 3.0 mmol) in tetrahydrofuran (15 mL), cool to 0°C, and slowly add methylmagnesium bromide (1.0 mol/L tetrahydrofuran solution, 5.4 mL, 5.54 mmol) dropwise under nitrogen. Stirring is continued at 0°C for 3 hours. After completion of the reaction, saturated ammonium chloride solution (20 mL) is added dropwise to quench the reaction. Extraction is then performed with ethyl acetate (20 mL x 3).
  • reaction solution was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (100 mL ⁇ 3), and the organic phases were combined, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1, v/v) to obtain 40-3.
  • Activity Test 1 Evaluation of the compound's ability to inhibit IL-1 ⁇ secretion from THP-1 cells
  • the ELISA kit was used to detect the secretion of IL-1 ⁇ to evaluate the activity of the compound in inhibiting the secretion of IL-1 ⁇ by THP-1 cells.
  • THP-1 cells were cultured in 1640 medium supplemented with 10% heat-inactivated fetal bovine serum at 37°C and 5% CO2. The cell suspension was gently shaken and transferred to a centrifuge tube for counting. The required volume was removed and added to fresh subculture medium.
  • the compound of the present invention can effectively inhibit the secretion of IL-1 ⁇ in THP-1 cells.
  • the pharmacokinetic properties of the compounds obtained in the examples of the present invention were evaluated in CD-1 mice.
  • the candidate compound was formulated into a clear solution or suspension in a designated solvent and administered intravenously or orally to three mice. Both intravenous and oral administration were performed in an aqueous solution containing 10% sulfobutyl- ⁇ -cyclodextrin. The drug concentration was 0.4 mg/ml for intravenous administration and 0.5 mg/ml for oral administration.
  • Whole blood samples were collected over a 24-hour period into commercially available EDTA2K anticoagulant tubes (ethylenediaminetetraacetic acid dipotassium anticoagulant tubes). The supernatant was centrifuged to obtain the upper plasma layer. Protein was precipitated by the addition of acetonitrile containing an internal standard.
  • the supernatant was centrifuged, an equal volume of water was added, and the supernatant was centrifuged again. The supernatant was sampled and injected for quantitative analysis of plasma concentrations and calculation of pharmacokinetic parameters using LCMS/MS.
  • test samples were prepared according to the corresponding examples, and the results showed that the compounds of the present application have good pharmacokinetic properties.
  • MDR1-MDCK II cells obtained from the Netherlands Cancer Institute will be seeded onto PET membranes in 96-well inserts and cultured for 4–7 days before use in experiments.
  • Validation was performed in duplicate wells by measuring the unidirectional (A ⁇ B) permeability of nadolol (low permeability marker), metoprolol (high permeability marker), and the bidirectional permeability of digoxigenin (P-glycoprotein substrate marker).
  • HBSS Hank's balanced salt solution
  • HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
  • Test compound concentration 2.0 ⁇ M
  • n 2;
  • Direction including bidirectional transportation from A to B and from B to A;
  • Incubation conditions 37 ⁇ 1°C, 5% CO 2 , relative saturated humidity.
  • the dosing solution (2.0 ⁇ M solution of the test compound) was mixed with 100 ⁇ L of buffer and 250 ⁇ L of a stop solution containing an appropriate internal standard (IS) (usually 250 nM tolbutamide and 100 nM labetalol in methanol or acetonitrile) to serve as the T0 sample.
  • IS internal standard
  • All samples (including T0 samples, dosing samples, receiving samples, and blank samples) will be analyzed using LC-MS/MS.
  • concentration of the test compound will be expressed as the peak area ratio of the analyte to the IS, without the need for a standard curve.
  • test samples were prepared according to the corresponding examples.
  • the results showed that the compounds of the present application have the characteristics of high permeability and low efflux.
  • Activity Test 4 Evaluation of the compound's ability to inhibit IL-1 ⁇ secretion from PBMCs
  • LPS lipopolysaccharide
  • test plate Five hours later, centrifuge the test plate at 350g for 5 minutes, discard the supernatant, add 100 ⁇ L serum-free RPMI1640 medium and 50 ⁇ L 4 ⁇ test compound to each well and treat for 30 minutes.
  • the compound of the present invention can effectively inhibit the secretion of IL-1 ⁇ in PBMC cells.
  • Activity test 5 Evaluation of the compound's efficacy in an inflammation model induced by intraperitoneal injection of LPS and ATP in mice
  • mice Male C57BL/6 mice were randomly divided into 5 groups according to body weight before administration, with 6 mice in each group.
  • Group 1 was the vehicle control group
  • Group 2 was the model group
  • Groups 3 to 5 were the test sample administration groups (Group 3: the test sample was prepared by Example 2;
  • Group 4 the test sample was prepared by Example 6;
  • Group 5 the test sample was prepared by Example 17).
  • the animals in Group 1 were first orally gavaged with the test vehicle (aqueous solution containing 10% sulfobutyl- ⁇ -cyclodextrin), and then intraperitoneally injected with phosphate buffered saline one hour later.
  • test vehicle aqueous solution containing 10% sulfobutyl- ⁇ -cyclodextrin
  • phosphate buffered saline was injected, and 300 ⁇ L of whole blood was collected from the inner canthus half an hour later; the animals in Group 2 were first orally gavaged with the test vehicle (aqueous solution containing 10% sulfobutyl- ⁇ -cyclodextrin), and then intraperitoneally injected with LPS (dissolved in phosphate buffered saline) at a dose of 5 mg/kg one hour later. After another two hours, 0.5 mL of LPS was injected. ATP (30 mM phosphate buffer) was administered, and 300 ⁇ L of whole blood was collected from the medial canthus half an hour later.
  • test vehicle aqueous solution containing 10% sulfobutyl- ⁇ -cyclodextrin
  • mice in Groups 3 to 5 were first orally gavaged with the test article (dissolved in an aqueous solution containing 10% sulfobutyl- ⁇ -cyclodextrin) at a dose of 5 mg/kg.
  • test article dissolved in an aqueous solution containing 10% sulfobutyl- ⁇ -cyclodextrin
  • LPS dissolved in phosphate buffer
  • 0.5 mL of ATP (30 mM phosphate buffer) was injected, and 300 ⁇ L of whole blood was collected from the medial canthus half an hour later. After the collected whole blood was allowed to naturally separate into serum, it was centrifuged at 7500 rpm for 5 minutes, and the serum was aspirated and frozen at -80°C.
  • Serum IL-1 ⁇ concentrations were measured using a mouse IL-1 ⁇ enzyme-linked immunosorbent assay (ELISA) kit.
  • ELISA enzyme-linked immunosorbent assay
  • the compound of the present invention can significantly reduce the IL-1 ⁇ concentration in the serum of a mouse inflammation model, showing a good anti-inflammatory effect.

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Abstract

Sont divulgués dans la présente invention un nouveau dérivé de cycle pyridazine et son utilisation. Spécifiquement, la présente invention concerne un composé tel que représenté par la formule (I), un sel pharmaceutiquement acceptable de celui-ci, un solvate de celui-ci, ou un solvate du sel pharmaceutiquement acceptable de celui-ci. Le dérivé de cycle pyridazine de la présente invention a une bonne activité inhibitrice contre NLRP3, et peut mieux inhiber la sécrétion d'IL-1 bêta dans des cellules THP-1.
PCT/CN2025/079601 2024-02-28 2025-02-27 Dérivé de cycle pyridazine et son utilisation Pending WO2025180453A1 (fr)

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CN116867769A (zh) * 2021-02-08 2023-10-10 南京明德新药研发有限公司 取代的哒嗪苯酚类衍生物
WO2024090469A1 (fr) * 2022-10-26 2024-05-02 アステラス製薬株式会社 Dérivé de pyridazine condensé
WO2024094150A1 (fr) * 2022-11-04 2024-05-10 Insilico Medicine Ip Limited Inhibiteurs de l'inflammasome nlrp3 et leurs utilisations
WO2024121184A1 (fr) * 2022-12-08 2024-06-13 F. Hoffmann-La Roche Ag Inhibiteurs de nlrp3
WO2024137319A1 (fr) * 2022-12-19 2024-06-27 Merck Sharp & Dohme Llc Hétérocyles bicycliques 6,6 utiles comme inhibiteurs de la protéine réceptrice de type nod 3
WO2024138045A1 (fr) * 2022-12-23 2024-06-27 Neumora Therapeutics, Inc. Modulateurs de l'inflammasome nlrp3 et produits et procédés associés
WO2024148029A2 (fr) * 2023-01-03 2024-07-11 Kodiak Sciences Inc. Composés organiques en tant qu'inhibiteurs de nlrp3
WO2024157953A1 (fr) * 2023-01-24 2024-08-02 第一三共株式会社 Composé benzène substitué
WO2024169895A1 (fr) * 2023-02-14 2024-08-22 深圳众格生物科技有限公司 Composé pour inhiber nlrp3, procédé de préparation et utilisation
WO2024251073A1 (fr) * 2023-06-03 2024-12-12 成都赜灵生物医药科技有限公司 Composé de pyridazine et son utilisation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113840602A (zh) * 2019-03-15 2021-12-24 斯基霍克疗法公司 用于校正异常剪接的组合物和方法
CN116867769A (zh) * 2021-02-08 2023-10-10 南京明德新药研发有限公司 取代的哒嗪苯酚类衍生物
WO2024090469A1 (fr) * 2022-10-26 2024-05-02 アステラス製薬株式会社 Dérivé de pyridazine condensé
WO2024094150A1 (fr) * 2022-11-04 2024-05-10 Insilico Medicine Ip Limited Inhibiteurs de l'inflammasome nlrp3 et leurs utilisations
WO2024121184A1 (fr) * 2022-12-08 2024-06-13 F. Hoffmann-La Roche Ag Inhibiteurs de nlrp3
WO2024137319A1 (fr) * 2022-12-19 2024-06-27 Merck Sharp & Dohme Llc Hétérocyles bicycliques 6,6 utiles comme inhibiteurs de la protéine réceptrice de type nod 3
WO2024138045A1 (fr) * 2022-12-23 2024-06-27 Neumora Therapeutics, Inc. Modulateurs de l'inflammasome nlrp3 et produits et procédés associés
WO2024148029A2 (fr) * 2023-01-03 2024-07-11 Kodiak Sciences Inc. Composés organiques en tant qu'inhibiteurs de nlrp3
WO2024157953A1 (fr) * 2023-01-24 2024-08-02 第一三共株式会社 Composé benzène substitué
WO2024169895A1 (fr) * 2023-02-14 2024-08-22 深圳众格生物科技有限公司 Composé pour inhiber nlrp3, procédé de préparation et utilisation
WO2024251073A1 (fr) * 2023-06-03 2024-12-12 成都赜灵生物医药科技有限公司 Composé de pyridazine et son utilisation

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