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WO2025067343A1 - Composé cyclique fusionné et son utilisation - Google Patents

Composé cyclique fusionné et son utilisation Download PDF

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Publication number
WO2025067343A1
WO2025067343A1 PCT/CN2024/121459 CN2024121459W WO2025067343A1 WO 2025067343 A1 WO2025067343 A1 WO 2025067343A1 CN 2024121459 W CN2024121459 W CN 2024121459W WO 2025067343 A1 WO2025067343 A1 WO 2025067343A1
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Prior art keywords
membered
substituted
independently
alkyl
pharmaceutically acceptable
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Chinese (zh)
Inventor
贾海飞
陈德恒
申华琼
吴凌云
赵乐乐
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Neushen Therapeutics Shanghai Co Ltd
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Neushen Therapeutics Shanghai Co Ltd
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • 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
    • C07D471/06—Peri-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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the invention relates to a cyclic compound and application thereof.
  • NLRP3 inflammasome is a multiprotein complex that includes the sensor NLRP3, the adapter ASC and the effector caspase 1.
  • Cytokines, pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) can activate NLRP3 inflammasome, further activate caspase 1, promote the cleavage of pro-IL-1 ⁇ and pro-IL-18 and the release of cytokines IL-1 ⁇ and IL-18.
  • NLRP3 inflammasome plays an important role in autoimmune diseases, neurodegenerative diseases and various cardiovascular diseases.
  • NLRP3 inhibitors such as OLT-1177, DFV-890, and Selnoflast are in different stages of clinical research.
  • the development of NLRP3 inhibitors has broad application prospects.
  • the technical problem to be solved by the present invention is to overcome the defect of insufficient types of NLRP3 inhibitors in the prior art and provide a novel cyclopentadiene compound and its application.
  • the cyclopentadiene compound of the present invention has good inhibitory activity on NLRP3.
  • the present invention provides a compound as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:
  • R x-3 is -CHR x-1 R x-2 , C 3 -C 6 cycloalkyl, 3-7 membered heterocycloalkyl, C 3 -C 6 cycloalkyl substituted by one or more R x1 , or 3-7 membered heterocycloalkyl substituted by one or more R x2 ;
  • R x-1 and R x-2 together with the carbon atom to which they are commonly attached form a C 3 -C 6 cycloalkyl group, a 3-7 membered heterocycloalkyl group, a C 3 -C 6 cycloalkyl group substituted by one or more R x1 groups, or a 3-7 membered heterocycloalkyl group substituted by one or more R x2 groups ;
  • R x1 and R x2 are each independently C 1 -C 6 alkyl
  • R x3 is independently C 3 -C 6 cycloalkyl or 3-7 membered heterocycloalkyl
  • L 1 is NHR 2 , 8-10 membered cycloheterocycloalkyl, or 8-10 membered cycloheterocycloalkyl substituted by one or more R 3
  • L 2 is naphthyl, phenyl substituted by one or more R 4 , or 5-10 membered heteroaryl substituted by one or more R 5 ;
  • L 1 is naphthyl, phenyl substituted by one or more R 4 , or 5-10 membered heteroaryl substituted by one or more R 5
  • L 2 is NHR 2 , 8-10 membered paracycloheterocycloalkyl, or 8-10 membered paracycloheterocycloalkyl substituted by one or more R 3 ;
  • R 2 is C 3 -C 6 cycloalkyl, 3-7 membered heterocycloalkyl, 3-7 membered heterocycloalkyl substituted by one or more R 2-1 , C 1 -C 6 alkyl substituted by one or more R 2-2 , or C 3 -C 6 cycloalkyl substituted by one or more R 2-3 ;
  • R 2-1 and R 2-3 are each independently hydroxy, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-7 membered heterocycloalkyl, or C 1 -C 6 alkyl substituted by one or more R 2-1-1 ;
  • R 2-1-1 is independently halogen, C 3 -C 6 cycloalkyl or 3-7 membered heterocycloalkyl;
  • R 2-2 is independently 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl substituted by one or more R 2-2-1 ;
  • R 2-2-1 is independently C 1 -C 6 alkyl
  • R 3 is independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more halogens;
  • R4 and R5 are each independently hydrogen, halogen, hydroxyl, 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 halogen, or 5-6 membered heteroaryl substituted by one or more Rd ;
  • R d is independently C 1 -C 6 alkyl
  • two adjacent R 4 and the atoms to which they are attached together form a C 3 -C 6 cycloalkenyl, a 3-7 membered heterocycloalkenyl, a C 3 -C 6 cycloalkenyl substituted by one or more Re , or a 3-7 membered heterocycloalkenyl substituted by one or more Rf ;
  • two adjacent R 5 and the atoms to which they are attached together form a C 3 -C 6 cycloalkenyl, a 3-7 membered heterocycloalkenyl, a C 3 -C 6 cycloalkenyl substituted by one or more Re , or a 3-7 membered heterocycloalkenyl substituted by one or more Rf ;
  • R e and R f are each independently hydrogen, halogen, hydroxyl, 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 halogen, or 5-6 membered heteroaryl substituted by one or more R d ; each "8-10 membered heterocycloheteroalkyl" is independently 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 8-10 membered heterocycloheteroalkyl;
  • Each "5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl 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 membered heterocycloalkyl” is independently a 3-7 membered heterocycloalkyl 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 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 membered heterocycloalkenyl” is independently a 3-7 membered heterocycloalkenyl having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • L 1 is naphthyl, phenyl substituted by one or more R 4 or 5-10 membered heteroaryl substituted by one or more R 5
  • L 2 is NHR 2 , 8-10 membered cycloheterocycloalkyl or 8-10 membered cycloheterocycloalkyl substituted by one or more R 3 ;
  • L1 is NHR2 , 8-10 membered heterocycloalkyl or 8-10 membered heterocycloalkyl substituted by one or more R3
  • L2 is naphthyl, or a 5-10 membered monocyclic or bicyclic heteroaryl substituted by one or more R 5 , in which each ring of the monocyclic or bicyclic heteroaryl is aromatic
  • R 4-1 and R 4-5 are each independently hydrogen, halogen, 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 halogen, or 5-6 membered heteroaryl substituted by one or more R d
  • R 4-2 , R 4-3 and R 4-4 are each independently hydrogen, halogen, hydroxyl, cyano, C 1 -C
  • R 4-3 is a 5-6 membered heteroaryl group or a 5-6 membered heteroaryl group substituted by one or more R d
  • R 4-1 , R 4-2 , R 4-4 and R 4-5 are each independently hydrogen, halogen, hydroxyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 5-6 membered heteroaryl group, C 1 -C 6 alkyl substituted by one or more R c , C 1 -C 6 alkoxy substituted by one or more halogen, or 5-6 membered heteroaryl group substituted by one or more R d , or “R 4-1 and R 4-2 ”, “R 4-2 and R 4-3 ” respectively and the atoms to which they are connected together form a C 3 -C 6 cycloalkenyl group, a 3-7 membered heterocycloalkenyl group, a C 3 -C
  • the present invention provides a compound as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:
  • X 1 , X 5 , X 7 and X 11 are each independently
  • R x is -CHR x-1 R x-2 , C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted with one or more R x3 ;
  • R x-1 and R x-2 together with the carbon atom to which they are commonly attached form a C 3 -C 6 cycloalkyl group, a 3-7 membered heterocycloalkyl group, a C 3 -C 6 cycloalkyl group substituted by one or more R x1 groups, or a 3-7 membered heterocycloalkyl group substituted by one or more R x2 groups ;
  • R x1 and R x2 are each independently C 1 -C 6 alkyl
  • R x3 is independently C 3 -C 6 cycloalkyl or 3-7 membered heterocycloalkyl
  • L 1 is NHR 2 , 8-10 membered cycloheterocycloalkyl, or 8-10 membered cycloheterocycloalkyl substituted by one or more R 3
  • L 2 is naphthyl, phenyl substituted by one or more R 4 , or 5-10 membered heteroaryl substituted by one or more R 5 ;
  • L 1 is naphthyl, phenyl substituted by one or more R 4 or 5-10 membered heteroaryl substituted by one or more R 5
  • L 2 is NHR 2 , 8-10 membered cycloheterocycloalkyl, or 8-10 membered cycloheterocycloalkyl substituted by one or more R 3 ;
  • R 2 is C 3 -C 6 cycloalkyl, 3-7 membered heterocycloalkyl, 3-7 membered heterocycloalkyl substituted by one or more R 2-1 , C 1 -C 6 alkyl substituted by one or more R 2-2 , or C 3 -C 6 cycloalkyl substituted by one or more R 2-3 ;
  • R 2-1 and R 2-3 are each independently hydroxy, halogen, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-7 membered heterocycloalkyl, or C 1 -C 6 alkyl substituted by one or more R 2-1-1 ;
  • R 2-1-1 is independently halogen, C 3 -C 6 cycloalkyl or 3-7 membered heterocycloalkyl;
  • R 2-2 is independently 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl substituted by one or more R 2-2-1 ;
  • R 2-2-1 is independently C 1 -C 6 alkyl
  • R 3 is independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more halogens;
  • R4 and R5 are each independently hydrogen, halogen, hydroxyl, cyano, C1 - C6 alkyl, C1 - C6 alkoxy, C3 - C6 cycloalkyl, C1 - C6 alkyl substituted by one or more Rc , or C1 - C6 alkoxy substituted by one or more halogen;
  • R c is independently deuterium or halogen
  • Each "8-10 membered cycloheterocycloalkyl” is independently 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 8-10 membered cycloheterocycloalkyl;
  • Each "5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • L 1 is naphthyl, phenyl substituted by one or more R 4 or 5-10 membered heteroaryl substituted by one or more R 5
  • L 2 is NHR 2 , 8-10 membered cycloheterocycloalkyl or 8-10 membered cycloheterocycloalkyl substituted by one or more R 3 ;
  • L1 is NHR2 , 8-10 membered heterocycloalkyl or 8-10 membered heterocycloalkyl substituted by one or more R3 , L2 is naphthyl, or a 5-10 membered heteroaryl substituted by one or more R 5 , R 4-1 and R 4-5 are each independently hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by one or more R c , or C 1 -C 6 alkoxy substituted by one or more halogen, R 4-2 , R 4-3 and R 4-4 are each independently hydrogen, halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by one or more R c , or C 1 -C 6 alk
  • certain groups in the compound as shown in 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”).
  • X 1 , X 5 , X 7 and X 11 are each independently
  • L 1 is NHR 2 , 8-10 membered cycloheterocycloalkyl, or 8-10 membered cycloheterocycloalkyl substituted by one or more R 3
  • L 2 is naphthyl, phenyl substituted by one or more R 4 , or 5-10 membered heteroaryl substituted by one or more R 5 ;
  • L 1 is naphthyl, phenyl substituted by one or more R 4 , or 5-10 membered heteroaryl substituted by one or more R 5
  • L 2 is NHR 2 , 8-10 membered paracycloheterocycloalkyl, or 8-10 membered paracycloheterocycloalkyl substituted by one or more R 3 ;
  • R 2 is 3-7 membered heterocycloalkyl, 3-7 membered heterocycloalkyl 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 is independently halogen, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-7 membered heterocycloalkyl, or C 1 -C 6 alkyl substituted by one or more R 2-1-1 ;
  • R 2-1-1 is independently halogen, C 3 -C 6 cycloalkyl or 3-7 membered heterocycloalkyl;
  • R 2-2 is independently 3-7 membered heterocycloalkyl or 3-7 membered heterocycloalkyl substituted by one or more R 2-2-1 ;
  • R 2-2-1 is independently C 1 -C 6 alkyl
  • R 3 is independently C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more halogens;
  • R4 and R5 are each independently hydrogen, halogen, hydroxyl, cyano, C1 - C6 alkyl, C1 - C6 alkoxy, C3 - C6 cycloalkyl, C1 - C6 alkyl substituted by one or more Rc , or C1 - C6 alkoxy substituted by one or more halogen;
  • R c is independently deuterium or halogen
  • Each "8-10 membered cycloheterocycloalkyl” is independently 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 8-10 membered cycloheterocycloalkyl;
  • Each "5-10 membered heteroaryl” is independently a 5-10 membered heteroaryl 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 membered heterocycloalkyl” is independently a 3-7 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • L 1 is naphthyl, phenyl substituted by one or more R 4 or 5-10 membered heteroaryl substituted by one or more R 5
  • L 2 is NHR 2 , 8-10 membered cycloheterocycloalkyl or 8-10 membered cycloheterocycloalkyl substituted by one or more R 3 ;
  • L1 is NHR2 , 8-10 membered heterocycloalkyl or 8-10 membered heterocycloalkyl substituted by one or more R3 , L2 is naphthyl, or a 5-10 membered heteroaryl substituted by one or more R 5 , R 4-1 and R 4-5 are each independently hydrogen, halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by one or more R c , or C 1 -C 6 alkoxy substituted by one or more halogen, R 4-2 , R 4-3 and R 4-4 are each independently hydrogen, halogen, hydroxyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by one or more R c , or C 1 -C 6 al
  • each "C 3 -C 6 cycloalkyl” is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • each "C 1 -C 6 alkyl” is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
  • each "8-10 membered heterocycloalkyl” is independently a 5-membered heterocycloalkyl, a 5-membered heterocycloalkyl or a 6-membered heterocycloalkyl, for example Ra and Rb, together with the N atom to which they are commonly attached, form a 5-membered and 5-membered heterocycloalkyl group, a 5-membered and 6-membered heterocycloalkyl group, or a 6-membered and 6-membered heterocycloalkyl group.
  • X is independently CH 2 , NH, O or S
  • X′ is independently CH 2 or NH.
  • each "8-10 membered heterocycloalkyl” is independently
  • each "5-10 membered heteroaryl” is a 5-6 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl, and each ring of the 8-10 membered bicyclic heteroaryl is aromatic; preferably, each "5-10 membered heteroaryl” is a 5-6 membered monocyclic heteroaryl or an 8-10 membered bicyclic heteroaryl, wherein the heteroatom is one or two selected from N, O and S, and the number of heteroatoms is 1, 2 or 3, and each ring of the 8-10 membered bicyclic heteroaryl is aromatic, such as pyridyl, indolyl or benzothienyl, and further, for example
  • each "5-10 membered heteroaryl” is independently a 5-6 membered heteroaryl or an 8-10 membered bicyclic heteroaryl, such as pyridyl, further such as
  • each "3-7 membered heterocycloalkyl” is independently a 4-7 membered heterocycloalkyl, such as oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, piperidinyl, tetrahydropyranyl or azepanyl, for example
  • each "3-7 membered heterocycloalkyl” is independently a 4-7 membered heterocycloalkyl, such as oxetanyl, tetrahydropyrrolyl, piperidinyl, tetrahydropyranyl or azepanyl, for example
  • each "halogen” is independently F, Cl, Br or I, such as F or Cl.
  • each "C 3 -C 6 cycloalkyl” is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • each "C 1 -C 6 alkoxy group” is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy.
  • each "C 3 -C 6 cycloalkenyl” is independently cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl, for example cyclopentenyl.
  • each "3-7 membered heterocycloalkenyl” is independently a heteroatom of O, and the number of heteroatoms is 1 or 2
  • the "4-6 membered heterocycloalkenyl” is, for example, dihydrofuranyl.
  • condition II or III in condition II or III, for example
  • condition IV for example
  • condition IV for example
  • condition V for example
  • L2 is
  • L2 is
  • L2 is
  • L2 is
  • L2 is
  • L2 is
  • L2 is
  • L2 is
  • condition III the compound as shown in formula (I) satisfies condition III, wherein:
  • L1 is R 2-1 is C 1 -C 6 alkyl (e.g. methyl or ethyl);
  • L2 is R5 is hydrogen or methyl.
  • condition IV the compound as shown in formula (I) satisfies condition IV, wherein:
  • R x-3 is a 4-6 membered oxygen-containing heterocycloalkyl group, wherein the type of heteroatom is O and the number of heteroatom is 1;
  • R x-1 and R x-2 together with the carbon atom to which they are commonly attached form a 4-6-membered oxygen-containing heterocycloalkyl group or a 5-6-membered nitrogen-containing heterocycloalkyl group substituted with one or more methyl groups, wherein the type of heteroatom in the 4-6-membered oxygen-containing heterocycloalkyl group is O and the number of heteroatom is 1, and the type of heteroatom in the 5-6-membered nitrogen-containing heterocycloalkyl group is N and the number of heteroatom is 1;
  • L1 is R 2-1 is C 1 -C 6 alkyl (e.g. methyl or ethyl);
  • condition IV the compound as shown in formula (I) satisfies condition IV, wherein:
  • R x-1 and R x-2 together with the carbon atom to which they are commonly connected form a 4-6-membered oxygen-containing heterocycloalkyl group, wherein the type of heteroatom in the 4-6-membered oxygen-containing heterocycloalkyl group is O and the number of heteroatom is 1, and the type of heteroatom in the 5-6-membered nitrogen-containing heterocycloalkyl group is N and the number of heteroatom is 1;
  • L1 is R 2-1 is C 1 -C 6 alkyl (e.g. methyl or ethyl);
  • R 4-3 is a 5-6 membered heteroaryl group or a 5-6 membered heteroaryl group substituted by one or more R d ;
  • R d is independently C 1 -C 6 alkyl
  • R 4-1 and R 4-2 together with the atoms to which they are attached form a C 3 -C 6 cycloalkenyl group.
  • 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 shown in 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 a disease associated with NLRP3.
  • the NLRP3-related diseases are autoimmune diseases (such as osteoarthritis, gout, Schnitzler syndrome, cryopyrin-related periodic syndrome or ulcerative colitis, etc.), neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease), cardiovascular disease or chronic obstructive pulmonary disease.
  • autoimmune diseases such as osteoarthritis, gout, Schnitzler syndrome, cryopyrin-related periodic syndrome or ulcerative colitis, etc.
  • neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease
  • cardiovascular disease or chronic obstructive pulmonary disease.
  • 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 autoimmune diseases (such as osteoarthritis, gout, Schnitzler syndrome, cryopyrin-related periodic syndrome or ulcerative colitis, etc.), neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease, etc.), cardiovascular diseases or chronic obstructive pulmonary disease.
  • autoimmune diseases such as osteoarthritis, gout, Schnitzler syndrome, cryopyrin-related periodic syndrome or ulcerative colitis, etc.
  • neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease, etc.
  • cardiovascular diseases or chronic obstructive pulmonary disease such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral
  • 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, wherein the disease associated with NLRP3 is preferably an autoimmune disease (such as osteoarthritis, gout, Schnitzler syndrome, cryopyrin-associated periodic syndrome or ulcerative colitis, etc.), a neurodegenerative disease (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease, etc.), a cardiovascular disease or chronic obstructive pulmonary disease, etc.
  • an autoimmune disease such as osteoarthritis, gout, Schnitzler syndrome, cryopyrin-associated periodic syndrome or ulcerative colitis, etc.
  • a neurodegenerative disease such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease, etc.
  • the present invention also provides a method for preventing and/or treating a disease, comprising: administering a therapeutically effective amount of the substance X or the pharmaceutical composition to an individual in need thereof, wherein the disease is an autoimmune disease (such as osteoarthritis, gout, Schnitzler syndrome, cryopyrin-associated periodic syndrome or ulcerative colitis, etc.), a neurodegenerative disease (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease, etc.), a cardiovascular disease or chronic obstructive pulmonary disease, etc.
  • an autoimmune disease such as osteoarthritis, gout, Schnitzler syndrome, cryopyrin-associated periodic syndrome or ulcerative colitis, etc.
  • a neurodegenerative disease such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis or Huntington's disease, etc.
  • a cardiovascular disease or chronic obstructive pulmonary disease etc.
  • 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 shown in 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 (eg, C 1 -C 6 ).
  • 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 saturated cyclic group having a specified number of ring atoms (e.g., 3-7 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).
  • heteroaryl refers to a cyclic, unsaturated, monovalent group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic or polycyclic, with two atoms and one bond shared between the monocyclic rings, and (at least one ring or each ring) aromatic.
  • ring atoms e.g., 5-10 members
  • heteroatoms e.g., 1, 2, or 3
  • a specified type of heteroatoms one or more of N, O, and S
  • the carbon atom or heteroatom is connected to the rest of the molecule; the heteroaryl group is connected to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms; the heteroaryl group is connected to the rest of the molecule through a ring with aromatic properties.
  • cycloalkyl refers to a saturated cyclic group having a specified number of ring carbon atoms (eg, C 3 -C 6 ) wherein the ring atoms consist only of carbon atoms.
  • ring carbon atoms eg, C 3 -C 6
  • examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • variable e.g, R c
  • the definition of the variable at each position is independent of the definition at the remaining positions, and their meanings are independent of each other and do not affect each other.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound of the present invention and a relatively nontoxic, pharmaceutically acceptable acid or base.
  • a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent.
  • an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.
  • solvate refers to a substance formed by combining a compound of the present invention 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 from the compounds of the present invention and 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 drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. Please refer to Part IV of the Pharmacopoeia of the People's Republic of China (2020 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
  • the "inhibitor” can be used in mammals; 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) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing 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 and progressive effects of the present invention are that the cyclopentadiene compounds of the present invention have good inhibitory activity on NLRP3 and the compounds of the present invention can well inhibit the secretion of IL-1 ⁇ in THP-1 cells.
  • reaction solution was cooled to room temperature, and water (30 mL) and saturated ammonium chloride solution (30 mL) were slowly added, stirred at room temperature for one hour, filtered, and the filter cake was washed with saturated ammonium chloride solution (20 mL x 2) and water (20 mL x 2) in sequence, and the filter cake was dried to obtain compound 1-4.
  • reaction solution was filtered, and the filtrate was directly purified by high performance liquid chromatography (C18 spherical 30-35 ⁇ m 100A 40g, mobile phase: acetonitrile-10mmol/L 0.1% formic acid aqueous solution, gradient: 10-50%, retention time: 30min) to obtain the formate salt of 5.
  • reaction solution was cooled to room temperature, the pH was adjusted to 6 with dilute hydrochloric acid, extracted with ethyl acetate (300 mL), the organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. After the reaction solution was concentrated under reduced pressure, it was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1, v/v) to obtain 10-2.
  • 11-1 (165 mg, 0.53 mmol), 11-2 (163 mg, 0.64 mmol) and methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (45 mg, 0.05 mmol) were added to 1,4-dioxane (2 mL), and potassium phosphate (337 mg, 1.59 mmol) and water (0.4 mL) were added. The mixture was heated to 100 °C and stirred for 12 hours under nitrogen protection.
  • 11-1 200 mg, 0.62 mmol
  • 12-1 (332 mg, 0.93 mmol)
  • methanesulfonic acid (2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (52 mg, 0.06 mmol)
  • 1,4-dioxane 2 mL
  • potassium phosphate 263 mg, 1.24 mmol
  • water 0.5 mL
  • reaction solution was added to water (20 mL), extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound.
  • the reaction solution was filtered and the filtrate was directly subjected to silica gel column chromatography (stone The product was purified by ethanol/ethyl acetate (3/1, v/v) to give 12-2.
  • ESI-MS theoretical calculated value: [M+H] + 462.24, found value 462.3.
  • reaction solution was added to water (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product containing the target compound.
  • the reaction solution was filtered, and the filtrate was directly purified by silica gel column chromatography (petroleum ether/ethyl acetate, 2/1, v/v) to obtain 16-2.
  • 17-1 (50.0 mg, 0.08 mmol) was dissolved in ethylene glycol dimethyl ether (3 mL), and 3-bromobutylene oxide (32.4 mg, 0.24 mmol), tris(trimethylsilyl)silane (58.9 mg, 0.24 mmol), sodium carbonate (16.8 mg, 0.16 mmol), nickel chloride dimethoxyethane (0.55 mg, 2.5 ⁇ mol), 4,4'-di-tert-butyl-2,2'-bipyridine (0.67 mg, 2.5 ⁇ mol) and [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridylN]phenyl-C]iridium(III)hexafluorophosphate (0.89 mg, 0.8 ⁇ mol) were added.
  • Dissolve 20-4 (900 mg, 5.51 mmol) in concentrated hydrochloric acid (10 mL) and water (10 mL) and cool to 0°C.
  • Dissolve sodium nitrite (760 mg, 11.02 mmol) in water (2 mL) and slowly drip into the reaction solution at 0°C, and continue stirring for 2 hours.
  • Dissolve potassium iodide (4.57 g, 27.55 mmol) in water (2 mL) and slowly drip into the reaction solution at 0°C, continue stirring for 30 minutes, warm to room temperature and stir for 1 hour, then warm to 60°C and stir for 1 hour.
  • the filtrate was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 3767/QDA, Column: Agilent C18, 19*250mm, 10um; mobile phase: acetonitrile-0.1% formic acid aqueous solution, gradient: 23-33%, retention time: 7 min) to obtain 20.
  • 17-1 50 mg, 0.08 mmol
  • 25-1 29 mg, 0.40 mmol
  • cuprous iodide (30 mg, 0.02 mmol)
  • 3,4,7,8-tetramethyl-1,10-phenanthroline 8 mg, 0.03 mmol
  • cesium carbonate 120 mg, 0.37 mmol
  • Activity test 1 Evaluation of the activity of compounds in inhibiting IL-1 ⁇ secretion from THP-1 cells
  • the secretion of IL-1 ⁇ was detected using ELISA kit to evaluate the activity of compounds in inhibiting the secretion of IL-1 ⁇ from THP-1 cells.
  • THP-1 cells were cultured in 1640 medium containing 10% heat-inactivated fetal bovine serum at 37°C and 5% carbon dioxide. The cell suspension was gently shaken and transferred to a centrifuge tube for counting. The required volume was removed and added to new subculture medium.
  • the compounds 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 prepared into a clear solution or suspension with a specified solvent and given a single intravenous injection and oral administration to three mice.
  • the solvents for intravenous injection and oral administration were both aqueous solutions containing 10% sulfobutyl- ⁇ -cyclodextrin.
  • the drug concentration was 0.4 mg/ml for intravenous injection and 0.5 mg/ml for oral administration.
  • Whole blood samples were collected within 24 hours into commercial EDTA2K anticoagulant tubes, centrifuged to obtain the upper plasma sample, and acetonitrile solution containing internal standard was added to precipitate protein. The supernatant was centrifuged and added with an equal volume of water. After centrifugation, the supernatant was sampled and the blood drug concentration was quantitatively analyzed by LCMS/MS analysis method and pharmacokinetic parameters were calculated.

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Abstract

L'invention concerne un composé cyclique fusionné et son utilisation. Plus particulièrement, l'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 d'un sel pharmaceutiquement acceptable de celui-ci. Le présent composé cyclique fusionné a une bonne activité inhibitrice sur NLRP3.
PCT/CN2024/121459 2023-09-27 2024-09-26 Composé cyclique fusionné et son utilisation Pending WO2025067343A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020140052A1 (fr) * 2018-12-28 2020-07-02 Spv Therapeutics Inc. Inhibiteurs de kinases dépendantes des cyclines
WO2023066825A1 (fr) * 2021-10-19 2023-04-27 F. Hoffmann-La Roche Ag Composés hétéroaryle bicycliques fusionnés utiles en tant qu'inhibiteurs de nlrp3
EP4265247A1 (fr) * 2022-04-22 2023-10-25 Université Paris Cité Composés induisant la production de protéines par les cellules immunitaires
WO2024057013A1 (fr) * 2022-09-12 2024-03-21 Exscientia Ai Limited Modulateurs de nlrp3
US20240101563A1 (en) * 2022-07-28 2024-03-28 Ac Immune Sa Novel compounds
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
CN118546161A (zh) * 2023-05-13 2024-08-27 成都赜灵生物医药科技有限公司 并氮杂环类化合物及其用途
WO2024218100A1 (fr) * 2023-04-19 2024-10-24 F. Hoffmann-La Roche Ag Dérivés d'oxazolo[4,5-b]pyrazine et d'oxazolo[4,5-b]pyridine utilisés en tant qu'inhibiteurs de nlrp3 pour le traitement, par exemple de maladies inflammatoires

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020140052A1 (fr) * 2018-12-28 2020-07-02 Spv Therapeutics Inc. Inhibiteurs de kinases dépendantes des cyclines
WO2023066825A1 (fr) * 2021-10-19 2023-04-27 F. Hoffmann-La Roche Ag Composés hétéroaryle bicycliques fusionnés utiles en tant qu'inhibiteurs de nlrp3
EP4265247A1 (fr) * 2022-04-22 2023-10-25 Université Paris Cité Composés induisant la production de protéines par les cellules immunitaires
US20240101563A1 (en) * 2022-07-28 2024-03-28 Ac Immune Sa Novel compounds
WO2024057013A1 (fr) * 2022-09-12 2024-03-21 Exscientia Ai Limited Modulateurs de nlrp3
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
WO2024218100A1 (fr) * 2023-04-19 2024-10-24 F. Hoffmann-La Roche Ag Dérivés d'oxazolo[4,5-b]pyrazine et d'oxazolo[4,5-b]pyridine utilisés en tant qu'inhibiteurs de nlrp3 pour le traitement, par exemple de maladies inflammatoires
CN118546161A (zh) * 2023-05-13 2024-08-27 成都赜灵生物医药科技有限公司 并氮杂环类化合物及其用途

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