WO2026032210A1 - Composé contenant de la pyrimidinone, composition pharmaceutique associée et utilisation associée - Google Patents

Composé contenant de la pyrimidinone, composition pharmaceutique associée et utilisation associée

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Publication number
WO2026032210A1
WO2026032210A1 PCT/CN2025/112448 CN2025112448W WO2026032210A1 WO 2026032210 A1 WO2026032210 A1 WO 2026032210A1 CN 2025112448 W CN2025112448 W CN 2025112448W WO 2026032210 A1 WO2026032210 A1 WO 2026032210A1
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Prior art keywords
alkyl
formula
mmol
groups
amino
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PCT/CN2025/112448
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English (en)
Chinese (zh)
Inventor
叶斌
唐悦
于军
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Shanghai Yidi Biotechnology Co Ltd
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Shanghai Yidi Biotechnology Co Ltd
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Publication of WO2026032210A1 publication Critical patent/WO2026032210A1/fr
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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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • 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

  • This invention relates to the pharmaceutical field, specifically to a pyrimidinone-containing compound, its preparation method, a pharmaceutical composition, and its application in the treatment of diseases caused by abnormal increases in neutrophil elastase.
  • HNE Human neutrophil elastase
  • elastin a serine proteolytic enzyme found in the aniline blue granules of neutrophils.
  • neutrophils are the first cells recruited to the site of inflammation, forming the earliest line of defense against invasion.
  • HNE can degrade various extracellular matrix proteins, such as elastin, proteoglycans, laminin, and fibronectin.
  • HNE can degrade or repair damaged tissue by degrading these structural proteins to maintain tissue homeostasis.
  • HNE can also help recruit neutrophils to the site of inflammation by degrading bacterial structural proteins, reducing bacterial infection and participating in inflammation regulation.
  • HNE HNE-induced hypertension
  • ARDS acute respiratory distress syndrome
  • sepsis sepsis
  • small-molecule HNE inhibitor compounds with different structural types. These include neovalerate derivatives, such as Sivelestat, the world's first drug used to treat and improve systemic inflammatory response syndrome (SIRS) in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS).
  • SIRS systemic inflammatory response syndrome
  • ALI acute lung injury
  • ARDS acute respiratory distress syndrome
  • Other types of small-molecule HNE inhibitors include pyridone derivatives (such as Alvelestat), dihydropyrimidinone derivatives (such as BAY 85-8501), and small-molecule peptides (such as POL6014).
  • This invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • W is selected from CH or N;
  • R1a or R1b is independently selected from hydroxyalkyl, aminoalkyl, carboxylalkyl, C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl or 3-6 membered heterocyclic groups;
  • R 1a may be selected from 5-6 heteroaryl groups
  • R1c or R1d is each independently selected from H, hydroxyalkyl, aminoalkyl, carboxylalkyl, C1-6 alkyl, or C1-6 alkoxy;
  • Q is selected from -NR 1c R 1d , hydroxyl, amino, carboxyl, C 3-6 cycloalkyl, 3-6 heterocyclic, phenyl, or 5-6 heteroaryl;
  • R3 is selected from phenyl or 5-6 heteroaryl, wherein the phenyl or 5-6 heteroaryl is optionally substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino, C1-6 alkyl, C1-6 alkoxy, pentafluorothio ( -SF5 ), C1-6 haloalkyl or C1-6 haloalkoxy.
  • R4 is selected from H, halogen, cyano, C1-6 alkyl, or C1-6 alkoxy;
  • A is selected from phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclic group;
  • Each Ra is independently selected from halogen, cyano, hydroxy, amino, nitro, carboxyl, oxo, C1-6 alkyl, C1-6 alkoxy, or TMS;
  • n1, n2, or m are each independently selected from 0, 1, 2, or 3;
  • the C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, 3-6 heterocyclic, phenyl, or 5-6 heteroaryl groups are optionally substituted by one or more substituents selected from halogen, cyano, hydroxyl, amino, carboxyl, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxycarbonyl groups.
  • the compound of formula (I) is selected from compounds represented by formulas (II-a), (II-b), (II-c), or (II-d).
  • R1 , R2 , R3 , R4 , W, A, Y, Z, Ra , m, or r have the same range of definition as in equation (I);
  • R1a or R1b is each independently selected from C1-3 alkyl or C2-4 alkenyl;
  • R1c or R1d is each independently selected from H or C1-3 alkyl groups;
  • R1a or R1b is each independently selected from methyl, ethyl, vinyl, or propenyl;
  • R1c or R1d is each independently selected from H, methyl, or ethyl; or
  • R1a is selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or
  • R1a is selected from furanyl, thiophenyl, pyrroleyl, pyrazolyl, imidazolyl, or oxazolyl.
  • R1 is selected from
  • R1 is selected from cyano
  • R2 is selected from C1-3 alkyl or -( CH2 ) n1 -Q; n1 is selected from 0, 1, 2 or 3; Q is selected from -NR1c R1d , hydroxyl, C3-6 cycloalkyl or 3-6 membered heterocyclic group; R1c or R1d is each independently selected from H or C1-3 alkyl;
  • R 1c or R 1d is each independently selected from H, methyl or ethyl
  • R2 is selected from methyl, ethyl, -CH2 - NH2 , -CH2 -NH- CH3 , -CH2 -N( CH3 ) 2 , or...
  • R2 is selected from methyl
  • R2 is selected from -CH2 -N( CH3 ) 2 ;
  • R2 is selected from...
  • R1 and R2 are linked to form a C5-6 cycloalkyl or a 5-6 membered heterocyclic group; the C5-6 cycloalkyl or 5-6 membered heterocyclic group is optionally substituted by one or more substituents selected from oxo, C1-3 alkyl or C1-3 alkoxy groups;
  • R1 and R2 are linked to form a C5-6 cycloalkyl or a 5-6 membered heterocyclic group; the C5-6 cycloalkyl or 5-6 membered heterocyclic group may optionally be substituted with one or more oxo groups, methyl groups, or ethyl groups;
  • R1 and R2 are linked to form cyclopentenyl, cyclohexenyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyridazinyl, dihydropyridazinyl, tetrahydropyrimidinyl or dihydropyrimidinyl, optionally substituted by one or more oxo groups or methyl groups.
  • R1 and R2 are connected to form It may be substituted with one or two methyl groups.
  • R3 is selected from phenyl or 6-membered heteroaryl; the phenyl or 6-membered heteroaryl may optionally be substituted by one or more substituents selected from halogen, cyano, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl or C1-3 haloalkoxy;
  • R3 is selected from phenyl, pyridinyl, pyridinyl, pyrimidinyl, or pyrazinyl, and is optionally substituted by one or more substituents selected from halogen, cyano, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, or fluorinated methoxy.
  • R3 is selected from phenyl or pyridyl, optionally substituted with a methyl, trifluoromethyl or difluoromethyl group;
  • R3 is selected from phenyl or pyridyl, optionally substituted with an F, Cl, Br or I;
  • R3 is selected from a phenyl group substituted with a Br
  • R3 is selected from phenyl or pyridinyl, optionally substituted with a pentafluorothio group ( -SF5 );
  • R3 is selected from trifluoromethylphenyl
  • R3 is selected from trifluoromethylpyridinyl
  • R3 is selected from difluoromethylphenyl.
  • R4 is selected from H.
  • X, Y, or Z is selected from one of the following conditions:
  • X, Y, or Z is selected from one of the following conditions:
  • Z is selected from -( CH2 ) n2- ;
  • Y is selected from -(CH 2 ) n2 - or -NH-
  • Z is selected from -(CH 2 ) n2 -;
  • Y is selected from -(CH 2 ) n2 - or -NH-;
  • X is selected from -NH-
  • Z is selected from -( CH2 ) n2- .
  • X is selected from -(CH 2 ) n2 -
  • Z is selected from -(CH 2 ) n2 -;
  • X, Y, or Z is selected from one of the following conditions:
  • Y is selected from -( CH2 ) n2- or -NH-
  • Z is selected from -( CH2 ) n2- ;
  • r is selected from 0, 1, or 2; n2 is selected from 0, 1, 2, or 3.
  • A is selected from phenyl or 5-6 heteroaryl groups
  • A is selected from phenyl or 5-membered heteroaryl
  • A is selected from 5-membered heteroaryl groups
  • A is selected from furanyl, thiophenyl, pyrroleyl, pyrazolyl, methylpyrazolyl, imidazolyl, methylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or triazolyl.
  • A is selected from pyrazolyl, methylpyrazolyl, imidazoleyl, methylimidazolyl, triazoleyl, or thiazolyl.
  • each Ra is independently selected from halogen, cyano, hydroxy, amino, nitro, oxo, C1-3 alkyl, C1-3 alkoxy, or TMS; m is selected from 0, 1 , 2, or 3.
  • Ra atoms together with the carbon atom they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • each Ra is independently selected from hydroxyl, amino, nitro, oxo, methyl, or TMS; m is selected from 0, 1, 2, or 3.
  • each Ra is independently selected from amino, oxo, methyl, or TMS; m is selected from 0, 1, 2, or 3.
  • the compound of formula (I) is selected from any of the following compounds:
  • the compound of the present invention when the compound of the present invention has a chiral center, the compound further includes its stereoisomers and racemates; the stereoisomers include R or S enantiomers.
  • This invention provides an intermediate compound of formula (V) or a pharmaceutically acceptable salt thereof.
  • R5a and R5b are each independently selected from hydroxyalkyl, aminoalkyl, carboxylalkyl, C1-6 alkyl, or C2-6 alkenyl;
  • R5c or R5d are each independently selected from H, hydroxyalkyl, aminoalkyl, carboxylalkyl, C1-6 alkyl, or C1-6 alkoxy;
  • R5e is selected from halogen, hydroxyl, amino, or carboxyl;
  • R5f is selected from TMS, TBS, or SEM;
  • R6a or R6b is independently selected from A( R5g ) u , hydroxyl, amino, C1-6 alkyl or C2-6 alkenyl;
  • R6c is selected from hydroxyl, amino or carboxyl.
  • the hydrogen atom of -CH2- is optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, nitro, carboxyl, oxo, C1-6 alkyl, and C1-6 alkoxy groups;
  • n3, n4, or u are each independently selected from 0, 1, 2, or 3.
  • R5 is selected from halogen, hydroxyl, amino, nitro or carboxyl groups
  • R5a and R5b are each independently selected from C1-3 alkyl or C2-6 alkenyl; preferably, R5a and R5b are each independently selected from methyl, ethyl, vinyl or propenyl.
  • R5c or R5d is each independently selected from H, hydroxyalkyl or C1-3 alkyl; preferably, R5c or R5d is each independently selected from H, methyl, -CH2-OH, -( CH2 ) 2 - OH or -( CH2 ) 3 -OH;
  • R5e is selected from halogens or hydroxyl groups;
  • R5 is selected from...
  • R5 is selected from -C2-6 ynynyl- R5f ;
  • R5f is selected from TMS, TBS, or SEM; preferably, the C2-6 ynynyl is selected from ethynyl or propynyl.
  • R6 is selected from H
  • R6a is selected from -A( R5g ) u , hydroxyl or amino;
  • R6 is selected from -( CH2 ) n4 - R6c ;
  • R6c is selected from hydroxyl, amino, nitro, or carboxyl groups;
  • R6 is selected from -( CH2 ) n4 -A( R5g ) u ; n4 is selected from 0, 1, 2 or 3; u is selected from 0, 1 or 2;
  • the intermediate compound represented by formula (V) is selected from compounds represented by formulas (Va), (Vb), (Vc), (Vd), (Ve), (Vf), or (Vg):
  • R6 ' is selected from R6 and is not H;
  • R7 is selected from hydroxyl, amino, C1-6 alkyl, -OR7a or -NR7b R7c ;
  • R7a is selected from C1-6 alkyl or C2-4 alkenyl;
  • one of R7b or R7c is selected from H or C1-6 alkyl, and the other is selected from hydroxyalkyl, aminoalkyl or carboxylalkyl; or, R7 is connected to R2 to form a 5-6 membered ring substituted with an oxo group;
  • R7 is selected from hydroxyl, amino, or -OR7a ; R7a is selected from methyl, ethyl, vinyl, or propenyl.
  • R7 and R2 are linked to form a C5-6 cycloalkyl or 5-6 membered heterocyclic group substituted with an oxo group; the C5-6 cycloalkyl or 5-6 membered heterocyclic group is optionally substituted with one or more C1-3 alkyl or C1-3 alkoxy groups; preferably, the C5-6 cycloalkyl or 5-6 membered heterocyclic group is optionally substituted with one or more methyl or ethyl groups;
  • R7 and R2 are linked to form a cyclopentenyl, cyclohexenyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyridazinyl, tetrahydropyrimidinyl, or dihydropyrimidinyl group substituted with an oxo group, optionally substituted with one or more methyl groups.
  • R7 and R2 are connected to form Alternatively, it may be substituted with one or two methyl groups;
  • R8 is selected from H, C1-6 alkyl or C2-4 alkenyl
  • R8 is selected from H, methyl, ethyl, vinyl, or propenyl
  • R9 and R10 are each independently selected from H, halogen, hydroxyl, amino, nitro, carboxyl, C1-6 alkyl or C1-6 alkoxy; or R9 and R10 are linked to form an oxo group;
  • R9 and R10 are each independently selected from H, hydroxyl, amino, nitro, carboxyl, methyl, ethyl, or methoxy; or R9 and R10 are linked to form an oxo group;
  • R9 and R10 are each independently selected from H or amino groups
  • p is selected from 0, 1, or 2;
  • R 11 is selected from -A(R 5g ) u .
  • the intermediate compound represented by formula (V) is selected from any of the following compounds:
  • This invention provides a method for preparing the compound of formula (II-b 1 ) or a salt thereof.
  • R1 , R2 , R3 , R4 , R6 , R8 , W, Z, Ra or m are as described above;
  • R5 is selected from halogens, preferably from F or Br;
  • formula (V) undergoes a carbonylation reaction under palladium catalysis to obtain formula (Ve), and formula (Ve) undergoes hydrolysis, deprotection and intramolecular cyclization reaction to obtain formula (II-b 1 ).
  • This invention provides a method for preparing a compound of formula (II-a 2 ) or a salt thereof.
  • R2 , R3 , R4 , R7 , R9 , R10 , W or p are as described above;
  • R5 is selected from halogens, preferably from F or Br;
  • formula (Vc) reacts with thiol under alkaline conditions to obtain formula (Vf), formula (Vf) undergoes an intramolecular cyclization reaction to obtain formula (II- a1 ), and formula (II- a1 ) is further oxidized to obtain formula (II- a2 ).
  • This invention provides a method for preparing a compound of formula (II-d) or a salt thereof.
  • R1 , R2 , R3 , R4 , R11 , W, A, Y, Z, Ra or m are as described above;
  • R5 is selected from halogens, preferably from F or Br;
  • formula (V-a) reacts with formula (VI) to obtain formula (V-g), and formula (V-g) undergoes an intramolecular cyclization reaction to obtain formula (II-d).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the compounds described herein or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for diseases caused by an abnormal increase in neutrophil elastase.
  • the diseases mentioned include acute lung injury, acute respiratory distress syndrome, systemic inflammatory response syndrome, bronchiectasis, sepsis, etc.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12), more preferably an alkyl group containing 1 to 6 carbon atoms (C 1-6 alkyl), and even more preferably an alkyl group containing 1 to 3 carbon atoms (C 1-3 alkyl).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, and their various branched isomers.
  • Alkyl groups can be substituted or unsubstituted.
  • alkoxy refers to -O- (alkyl), where alkyl is defined as described herein.
  • alkoxy groups contain 1 to 12 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) (C 1-12 alkoxy groups), more preferably alkoxy groups contain 1 to 6 carbon atoms (C 1-6 alkoxy groups), and even more preferably alkoxy groups contain 1 to 3 carbon atoms (C 1-3 alkoxy groups).
  • Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy groups.
  • Alkoxy groups can be substituted or unsubstituted.
  • alkenyl refers to a linear or branched hydrocarbon group containing one or more double bonds and having 2 to 20 carbon atoms, preferably “C 2-6 alkenyl”.
  • C 2-6 alkenyl should be understood to preferably represent a linear or branched monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, or 6 carbon atoms, preferably having 2 or 3 carbon atoms (i.e., C 2-3 alkenyl).
  • Non-limiting examples of alkenyl groups include vinyl, propenyl, and butenyl.
  • the alkenyl group may be substituted or unsubstituted.
  • alkynyl refers to a linear or branched hydrocarbon group containing one or more triple bonds and having 2 to 20 carbon atoms, preferably “C 2-6 alkynyl”.
  • C 2-6 alkynyl should be understood to preferably represent a linear or branched monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, or 6 carbon atoms, preferably having 2 or 3 carbon atoms (i.e., C 2-3 alkynyl).
  • Non-limiting examples of alkynyl include ethynyl and propynyl.
  • the alkynyl group may be substituted or unsubstituted.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring comprises 3 to 20 carbon atoms, preferably 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms (C 3-6 cycloalkyl), and even more preferably 5 to 6 carbon atoms (C 5-6 cycloalkyl).
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc. etc.; cycloalkyl groups can be substituted or unsubstituted.
  • it comprises 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it comprises 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; even more preferably, it comprises 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms; most preferably, it comprises 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms.
  • 3 to 14 e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14
  • 1 to 4 e.g., 1, 2, 3, and 4
  • 3 to 8 ring atoms e.g., 3, 4, 5, 6, 7, and 8
  • 1 to 3 e.g., 1, 2, and 3
  • it comprises 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms;
  • heterocyclic groups include pyrrolyl, dihydropyrrolyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridyl, dihydropyridyl, piperidyl, piperazinyl, tetrahydropyridazinyl, dihydropyridazinyl, tetrahydropyrazinyl, dihydropyrazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.
  • the heterocyclic group can be substituted or unsubstituted.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated ⁇ -electron system, preferably 6- to 10-membered, such as phenyl and naphthyl, more preferably phenyl.
  • the aryl group may be substituted or unsubstituted.
  • heteroaryl refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • the heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyrrole, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc.
  • the heteroaryl group can be substituted or unsubstituted.
  • alkyl alkoxy
  • alkenyl alkynyl
  • cycloalkyl heterocyclic
  • aryl and “heteroaryl,” etc., used herein may be substituted or unsubstituted; when substituted, they may be substituted at any usable linking point, and the substituents are preferably each independently selected from one or more of the same or different substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, aminoalkyl, nitro, carboxyl, cycloalkyl, heterocyclic, aryl, and heteroaryl.
  • halogenated alkyl refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined herein.
  • Non-limiting examples include: trifluoromethyl, difluoromethyl, and monofluoromethyl.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined herein.
  • hydroxyalkyl means an alkyl group substituted with one or more hydroxyl groups, wherein the alkyl group is as defined herein, and non-limiting examples of hydroxyalkyl groups include -CH2 - OH, -( CH2 ) 2 -OH or -( CH2 ) 3 -OH, etc.
  • aminoalkyl refers to an alkyl group substituted with one or more amino groups, wherein the alkyl group is as defined herein, and non-limiting examples of aminoalkyl groups include -CH2- NH2 , -( CH2 ) 2 - NH2 , or -( CH2 ) 3 - NH2 , etc.
  • halogen refers to F, Cl, Br, or I.
  • cyano refers to -CN.
  • hydroxyl group refers to -OH.
  • amino refers to -NH2 .
  • nitro refers to -NO2 .
  • TMS trimethylsilyl
  • SEM refers to (trimethylsilyl)ethoxymethyl.
  • TBS tert-butyldimethylsilyl
  • pentafluorosulfonyl refers to -SF5 .
  • Optional or “optionally” means that the event or environment described below may but does not have to occur, and the description includes the possibility or absence of such event or environment.
  • “optionally alkyl-substituted heterocyclic group” means that the alkyl group may but does not have to be present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
  • One or more means 1, 2, 3, 4, 5, 6, 7, 8, 9 or more, preferably 1, 2, 3 or 4.
  • Substituted refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically/pharmacologically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertion of its biological activity.
  • “Pharmaceutical acceptable” means relatively non-toxic, safe, and suitable for patient use.
  • a “pharmaceutically acceptable salt” is a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base.
  • a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent.
  • an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.
  • Option 1 The intermediate formula (Va) or formula (Vb) can be synthesized according to the method of Route 1, wherein R1 , R2 , R3 , R4 , R5 , R6 ' or W are as described above;
  • the intermediate compound of general formula (Va) can be obtained by heating a commercially available or synthetically obtained aldehyde (III-1), urea (III-2), and ketone (III-3) in a stable organic solvent in the presence of an acid (such as acetic acid, trifluoroacetic acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, polyphosphoric acid) in the presence of an acid.
  • the intermediate compound of general formula (Vb) can be obtained by alkylation of (Va) under basic conditions or by reaction with an alcohol (R 6 'OH) (Mitsunobu).
  • the intermediate (Vc) or (Vd) can be synthesized according to the method of Route 2, wherein R1 , R2 , R3 , R4 , R5 , R6 ', R7 or W are as described above;
  • intermediate compound (VII) can be prepared by reacting a commercially available or synthetically obtained aldehyde (III-1) with sodium benzenesulfmate and BocNH2 in the presence of formic acid (J. Am. Chem. Soc., 2012, 134, 18193-18196, Org. Syn., 2009, 86-11-17).
  • Intermediate compound (IX) can be prepared by reacting (VIII) with R3 - NH2 in the presence of ytterbium trifluoromethanesulfonate (Synth. Commun. 2010, 40, 2506-2510, J. Heterocyclic Chem., 2002, 39-965-973).
  • Intermediate compound (XI) can be prepared by reacting (VII) with (IX) in the presence of an inorganic base such as NaH or potassium tert-butoxide.
  • Intermediate compound of general formula (XII) can be obtained by deprotection treatment of (XI) with an acid (such as hydrochloric acid).
  • Intermediate compound of general formula (Vc) can be prepared by reacting (XII) with phosgene, triphogene, or carbonyl diimidazole in the presence of a suitable inorganic or organic base such as sodium carbonate, DIEPA, or pyridine (Tetrahedron Lett, 2011, 67, 8564-8571).
  • Intermediate compound of general formula (Vd) can be obtained by alkylation of (Vc) under basic conditions or by reaction with an alcohol (R 6 'OH) (Mitsunobu).
  • Equation (Ib 1 ) can be synthesized according to the method of route 3, wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 8 , W, Z, Ra or m are as described above;
  • R5 is selected from halogens, preferably from F or Br;
  • Equation (II-a 1 ) or (II-a 2 ) can be synthesized according to the method of route 4, wherein R 2 , R 3 , R 4 , R 7 , R 9 , R 10 , W or p are as described above;
  • R5 is selected from halogens, preferably from F or Br;
  • Formula (Vc) reacts with thiol under alkaline conditions to give (Vf), and formula (Vf) undergoes intramolecular cyclization (Mitsunobu) to give formula (II- a1 ).
  • Formula (II- a1 ) is further oxidized to give formula (II- a2 ).
  • Equation (II-c) can be synthesized according to the method of route 5, wherein R1 , R2 , R3 , R4 , R11 , W, Ra or m are as described above;
  • R5 is selected from halogens, preferably from F or Br;
  • Formula (V-a) reacts with formula (VI) Suzuki of heterocyclic boron ester to give formula (V-g), and formula (V-g) undergoes intramolecular cyclization (Mitsunobu) to give formula (II-d).
  • the stereoisomers can be obtained by methods known in the art.
  • the compound of the present invention can be purified by SFC to obtain two enantiomers (R and S).
  • the specific SFC purification conditions are: Chiracel AD-3 column (460 mm ID x 5 cm L); eluent CO2 : Ethanol (0.05% DEA) (70:30 v/v); detection wavelength: 254 nm; flow rate: 2.5 ml/min.
  • n-BuLi 2.5M in THF, 2ml, 5mmol
  • a 20mL THF solution of 31e 1.1g, 3.5mmol
  • a 5mL THF solution containing 1.3g, 7mmol of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborane 1.3g, 7mmol was added dropwise.
  • the mixture was brought to room temperature and stirred for 1 hour, then saturated NH4Cl (20mL) was added.
  • FLU reference wells were those with only enzyme added and no inhibitor added, while FLU positive wells were those with both enzyme and 3000 nM Sivelestat-2.

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Abstract

La présente invention concerne un composé contenant de la pyrimidinone, une composition pharmaceutique associée et une utilisation associée. Plus particulièrement, l'invention concerne un composé tel que représenté dans la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci. Le composé de la présente invention présente une forte activité inhibitrice contre l'ENh, et le composé ou la composition pharmaceutique associée peut être utilisé pour traiter des maladies associées provoquées par une augmentation anormale de l'élastase neutrophile.
PCT/CN2025/112448 2024-08-05 2025-08-04 Composé contenant de la pyrimidinone, composition pharmaceutique associée et utilisation associée Pending WO2026032210A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102482231A (zh) * 2009-04-06 2012-05-30 拜耳制药股份公司 磺酰胺和磺基肟-取代的二芳基-二氢嘧啶酮和其应用
CN104995186A (zh) * 2013-02-06 2015-10-21 勃林格殷格翰国际有限公司 经取代的双环二氢嘧啶酮及其作为嗜中性粒细胞弹性蛋白酶活性的抑制剂的用途
WO2016016363A1 (fr) * 2014-07-31 2016-02-04 Boehringer Ingelheim International Gmbh Dihydropyrimidinones bicycliques substituées et leur utilisation en tant qu'inhibiteurs de l'activité de l'élastase neutrophile
WO2016016366A1 (fr) * 2014-07-31 2016-02-04 Boehringer Ingelheim International Gmbh Dihydropyrimidinones substituées et leur utilisation en tant qu'inhibiteurs de l'activité de l'élastase neutrophile
CN106660988A (zh) * 2014-07-31 2017-05-10 勃林格殷格翰国际有限公司 经取代的双环二氢嘧啶酮及其作为嗜中性粒细胞弹性蛋白酶活性的抑制剂的用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102482231A (zh) * 2009-04-06 2012-05-30 拜耳制药股份公司 磺酰胺和磺基肟-取代的二芳基-二氢嘧啶酮和其应用
CN104995186A (zh) * 2013-02-06 2015-10-21 勃林格殷格翰国际有限公司 经取代的双环二氢嘧啶酮及其作为嗜中性粒细胞弹性蛋白酶活性的抑制剂的用途
WO2016016363A1 (fr) * 2014-07-31 2016-02-04 Boehringer Ingelheim International Gmbh Dihydropyrimidinones bicycliques substituées et leur utilisation en tant qu'inhibiteurs de l'activité de l'élastase neutrophile
WO2016016366A1 (fr) * 2014-07-31 2016-02-04 Boehringer Ingelheim International Gmbh Dihydropyrimidinones substituées et leur utilisation en tant qu'inhibiteurs de l'activité de l'élastase neutrophile
CN106660988A (zh) * 2014-07-31 2017-05-10 勃林格殷格翰国际有限公司 经取代的双环二氢嘧啶酮及其作为嗜中性粒细胞弹性蛋白酶活性的抑制剂的用途

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