WO2022216097A1 - Nouvel inhibiteur de lrrk2 - Google Patents

Nouvel inhibiteur de lrrk2 Download PDF

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WO2022216097A1
WO2022216097A1 PCT/KR2022/005074 KR2022005074W WO2022216097A1 WO 2022216097 A1 WO2022216097 A1 WO 2022216097A1 KR 2022005074 W KR2022005074 W KR 2022005074W WO 2022216097 A1 WO2022216097 A1 WO 2022216097A1
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heptanyl
octanyl
disease
azabicyclo
azaspiro
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PCT/KR2022/005074
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English (en)
Korean (ko)
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강은지
김현진
조대현
이재영
고은
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주식회사 스탠다임
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Priority to KR1020237025046A priority Critical patent/KR102585193B1/ko
Publication of WO2022216097A1 publication Critical patent/WO2022216097A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D401/02—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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a leucine-rich repeat kinase 2 (leucine-rich repeat kinase 2: LRRK2) inhibitor of Formula 1, a pharmaceutical composition for preventing or treating a disease or disorder mediated by or related to LRRK2 including the same, and a disease using the same or to a method for treating and preventing a disease.
  • LRRK2 leucine-rich repeat kinase 2
  • Parkinson's disease affect millions of people. Parkinson's disease is caused by progressive deficits in midbrain dopamine neurons, impairing the patient's ability to direct and control movement.
  • Leucine-rich repeat kinase 2 (leucine-rich repeat kinase 2: LRRK2) is implicated in hereditary Parkinson's disease.
  • LRRK2 Gly2019Ser mutation causes an increase in kinase activity, resulting in hereditary Parkinson's disease.
  • LRRK2 is also associated with Crohn's disease through genomic association analysis (Teri A. Manolio, N Engl J Med 2010;363:166-176).
  • modulators or inhibitors of LRRK2 are being developed (eg, Patent Publication No. 2020-0085779 (July 15, 2020)).
  • an object of the present invention is to provide a compound of Formula 1 that exhibits excellent inhibitory activity against LRRK2, and using the same, a disease or disorder mediated by or related to LRRK2, for example, high efficacy in the treatment and prevention of neurodegenerative diseases is to achieve
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease or disorder mediated by or related to LRRK2.
  • Another object of the present invention is to provide a method for preventing or treating a disease or disorder mediated by or related to LRRK2 using an LRRK2 inhibitor.
  • One aspect of the present invention provides a compound represented by the following formula (1), a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:
  • R 1 may be C 1-6 alkyl substituted with halogen.
  • R 1 may be C 1-3 alkyl substituted with 1 to 3 halogen atoms each independently selected from the group consisting of F, Cl, Br, and I.
  • R 1 is CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 CHF 2 , CH 2 CH 2 F, CH 2 CH 2 CF 3 , CH 2 CH 2 CHF 2 , CH 2 CH 2 CH 2 F, CCl 3 , CHCl 2 , CH 2 Cl, CH 2 CCl 3 , CH 2 CHCl 2 , CH 2 CH 2 Cl, CH 2 CH 2 CCl 3 , CH 2 CH 2 CHCl 2 , CH 2 CH 2 CH 2 Cl , CBr 3 , CHBr 2 , CH 2 Br, CH 2 CBr 3 , CH 2 CHBr 2 , CH 2 CH 2 Br, CH 2 CH 2 CBr 3 , CH 2 CH 2 CHBr 2 , CH 2 CH 2 CH
  • R 2 Is halogen; OH; CN; amino; nitro; C 1-6 alkyl; C 1-6 alkoxy; formyl; C 1-6 alkylcarbonyl; mono- or di-C 1-6 alkylamino; formylamino; C 1-6 alkylcarbonylamino; mono- or di-C 1-6 alkylaminocarbonyl; formyloxy; and C 1-6 alkylcarbonyloxy.
  • said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl, mono- or di-C 1-6 alkylamino, C 1-6 alkylcarbonylamino, mono- or di- C 1-6 alkylaminocarbonyl, and C 1-6 alkylcarbonyloxy may be optionally substituted with halogen, OH, CN, amino or nitro.
  • n may be an integer of 0 to 3.
  • R 2 Is halogen; OH; CN; amino; nitro; C 1-6 alkyl; C 1-6 alkoxy; C 1-6 alkylcarbonyl; and mono- or di-C 1-6 alkylamino, said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl, and mono- or di-C 1-6 Alkylamino may be optionally substituted with halogen, OH, CN, amino or nitro.
  • n may be an integer of 0 to 2, preferably 0 or 1.
  • rings A and B are each independently a 3- to 10-membered heterocycle containing one additional heteroatom optionally selected from N, O and S together with N bonded to a phenyl ring or a pyrimidine ring reel, provided that at least one of Rings A and B may be a spiro, fused or bridged heteropolycyclyl. In one embodiment, both rings A and B may be spiro, fused or bridged heteropolycyclyl. In one embodiment, either ring A or B can be a spiro, fused or bridged heteropolycyclyl.
  • At least one of rings A and B, together with N bonded to a phenyl ring or a pyrimidine ring, is a spiro of 5 to 10 members, optionally comprising one additional heteroatom selected from N, O and S; spiro), fused or bridged heteropolycyclyl.
  • the heteropolycyclyl contains, as a heteroatom, only N bonded to a phenyl ring or pyrimidine ring, or together with N bonded to a phenyl ring or pyrimidine ring, adding 1 N or O atom can be included as
  • the heteropolycyclyl includes as a heteroatom only N bonded to the phenyl ring or pyrimidine ring of Formula 1, or together with N bonded to the phenyl ring or pyrimidine ring, 1 O atom may additionally include.
  • the 5- to 10-membered spiro, fused or bridged heteropolycyclyl is, for example, 5 to 10 membered, 5 to 9 membered, 6 to 8 membered, 7 membered or 8-membered heteropolycyclyl.
  • the heteropolycyclyl may be spiro or bridged heteropolycyclyl.
  • Said heteropolycyclyl may be bicyclic heterocyclyl, or tricyclic heterocyclyl if the number of ring atoms permits.
  • the heteropolycyclyl is bicyclic spiro-heterocyclyl, bicyclic fusion-heterocyclyl, bicyclic bridge-heterocyclyl, tricyclic spiro-heterocyclyl, tricyclic fusion- heterocyclyl, tricyclic bridge-heterocyclyl.
  • the 5- to 10-membered spiro, fused or bridged heteropolycyclyl is azabicyclo[3.1.0]hexanyl, azabicyclo[2.2.0]hexanyl , azabicyclo[4.1.0]heptanyl, azabicyclo[3.2.0]heptanyl, azabicyclo[5.1.0]octanyl, azabicyclo[4.2.0]octanyl, azabicyclo[3.3 .0]octanyl, oxaazabicyclo[3.1.0]hexanyl, oxaazabicyclo[2.2.0]hexanyl, oxaazabicyclo[4.1.0]heptanyl, oxaazabicyclo[3.2.0 ]heptanyl, oxaazabicyclo[5.1.0]octanyl, oxaazabicyclo[4.2.0]octanyl, oxaazabicyclo[3.3.0]octanyl,
  • heteropolycyclyl is 2-oxa-5-azabicyclo[2.1.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 5-azaspiro[2.4]heptanyl or 2-azaspiro[3.3]heptanyl.
  • the remaining non-heteropolycyclyl rings of Rings A and B, together with N attached to the phenyl ring or pyrimidine ring optionally contain 1 additional heteroatom selected from N, O and S from 3 to 8-membered heteromonocyclyl.
  • the 3-8 membered heteromonocyclyl is a heteroatom containing only N bonded to a phenyl ring or a pyrimidine ring, or together with N bonded to a phenyl ring or a pyrimidine ring, one It may further contain N, O or S atoms.
  • the 3 to 8 membered heteromonocyclyl is 3 to 7 membered, 3 to 6 membered, 4 to 8 membered, 4 to 7 membered, 4 to 6 membered, 5 to 7 membered or 5 to 5 membered. 6 membered heteromonocyclyl.
  • the 3- to 8-membered heteromonocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl and thiazepanyl.
  • the 3- to 8-membered heteromonocyclyl may be selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl and diazepanyl.
  • the 3- to 8-membered heteromonocyclyl may be pyrrolidinyl or piperidinyl.
  • rings A and B is 2-oxa-5-azabicyclo[2.1.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 5-azaspiro[ 2.4]heptanyl or 2-azaspiro[3.3]heptanyl, and the remaining ring may be pyrrolidinyl or piperidinyl.
  • either ring A or B can be 2-oxa-5-azabicyclo[2.1.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 5-azaspiro[2.4 ]heptanyl or 2-azaspiro[3.3]heptanyl, and the other may be pyrrolidinyl or piperidinyl.
  • ring A is piperidinyl and ring B is 2-oxa-5-azabicyclo[2.1.1]heptanyl, 5-azaspiro[2.4]heptanyl or 2-azaspiro[ 3.3]heptanyl.
  • ring A is 2-oxa-5-azabicyclo[2.1.1]heptanyl or 2-oxa-6-azaspiro[3.3]heptanyl
  • ring B is pyrrolidinyl or piperidinylyl can
  • rings A and B are each independently halogen; OH; CN; oxo; amino; nitro; C 1-6 alkyl; C 1-6 alkoxy; mono- or di-C 1-6 alkylamino; and 3 to 8 membered heteromonocyclyl containing 1 to 3 heteroatoms selected from N, O and S may be optionally substituted with 1 to 3 substituents selected from the group consisting of.
  • the C 1-6 alkyl, C 1-6 alkoxy, mono- or di-C 1-6 alkylamino may be optionally substituted with halogen, OH, CN, oxo, amino or nitro
  • the 3-membered to The 8 membered heteromonocyclyl may be optionally substituted with halogen, OH, CN, oxo, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, mono- or di-C 1-6 alkylamino.
  • rings A and B are each independently halogen; OH; CN; oxo; amino; C 1-6 alkyl; C 1-6 alkoxy; and 1 or 2 substituents selected from the group consisting of mono- or di-C 1-6 alkylamino.
  • said C 1-6 alkyl, C 1-6 alkoxy, mono- or di-C 1-6 alkylamino may be optionally substituted with halogen, OH, CN, oxo, amino or nitro.
  • rings A and B are each independently halogen; OH; oxo; And it may be optionally substituted with 1 to 3 substituents selected from the group consisting of amino.
  • rings A and B are each independently halogen (eg, F, Cl, Br or I); OH; oxo; And it may be optionally substituted with 1-2 substituents selected from the group consisting of amino.
  • alkyl refers to a fully saturated branched or unbranched (or straight-chain or linear) hydrocarbon.
  • the alkyl may be a substituted or unsubstituted alkyl group.
  • the C 1-6 alkyl may be a C 1 to C 5 , C 1 to C 4 , C 1 to C 3 , or C 1 to C 2 alkyl group.
  • Non-limiting examples of the alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, iso-amyl, or n-hexyl. have.
  • halogen refers to an atom belonging to group 17 of the periodic table. Halogen atoms include fluorine, chlorine, bromine, and iodine.
  • hydroxy refers to a -OH functional group (hydroxyl group).
  • alkoxy refers to an alkyl bound to an oxygen atom.
  • the C 1 to C 6 alkoxy group may be, for example, a C 1 to C 5 , C 1 to C 4 , C 1 to C 3 , or C 1 to C 2 alkoxy group.
  • the alkoxy group may be methoxy, ethoxy, or propoxy.
  • amino refers to —NH 2 .
  • nitro refers to —NO 2 .
  • cyano refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom as -CN.
  • alkylamino refers to a functional group in which one or two hydrogen atoms of an amino (—NH 2 ) group are substituted with any one or two of the aforementioned alkyl groups, and includes both mono-alkylamino groups and di-alkylamino groups; , the two alkyl groups in the di-alkylamino group may be the same or different.
  • mono-C 1-6 alkylamino one hydrogen atom of an amino (-NH 2 ) group is substituted with C 1-6 alkyl
  • di-C 1-6 alkylamino is an amino (-NH 2 ) group of Two hydrogen atoms may be substituted with the same or different C 1-6 alkyl.
  • mono-C 1-6 alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino, etc.
  • a di-C 1-6 alkylamino group is, for example, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropylamino, methylisopropylamino, methylbutylamino, methylisobutylamino, ethylpropylamino, ethyliso propylamino, ethylisobutylamino, isopropylisobutylamino, methylhexylamino, ethylhexylamino, and the like.
  • alkylcarbonyl refers to an alkyl group linked to the remainder of the molecule through a carbonyl (CO) group, wherein “alkyl” has the meaning defined above.
  • C 1-6 alkylcarbonyl includes acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, and the like.
  • alkylcarbonylamino refers to the group alkyl-C(O)-NH-, which is acetylamino, propionylamino, butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino , hexanoylamino, heptanoylamino, and the like.
  • alkylaminocarbonyl means an alkyl-NHC(O)- group, eg, C 1-6 alkylaminocarbonyl is acetamido, propylaminocarbonyl, butylaminocarbonyl, isobutylaminocarbonyl, pentylaminocarbonyl, hexylaminocarbonyl, and the like.
  • alkylcarbonyloxy refers to the group alkyl-C(O)-O-, eg, C 1-6 alkylcarbonyloxy is acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryl oxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, heptanoyloxy and the like.
  • Formyl refers to the group HC(O)—
  • the term “formyloxy” refers to the group HC(O)—O—
  • the term “formylamino” refers to the group HC(O)—NH— .
  • heterocyclyl refers to a saturated or partially unsaturated cyclic hydrocarbon containing at least one heteroatom.
  • Heterocyclyl may be monocyclic or polycyclic, monocyclic heterocyclyl referred to herein as “heteromonocyclyl” and polycyclic heterocyclyl referred to herein as “heteropolycyclyl” do.
  • heteropolycyclyl refers to a saturated or partially unsaturated polycyclic hydrocarbon group containing at least one heteroatom.
  • Heteropolycyclyl may be one in which two or more rings are bonded in a spiro, bridged or fused form.
  • Heteropolycyclyl may include heterobicyclyl containing two rings, heterotricyclyl containing three rings, and the like.
  • Heteropolycyclyl is 5 to 12, 5 to 10, 4 to 9, 4 to 8, 5 to 15, 5 to 12, 5 to 9, 5 to 8, 6 to 15, 6 to 12, 6 to 9 or 6 to 8 ring atoms.
  • the heteroatom may be any one or more selected from the group consisting of N, O and S.
  • the heteroatom may be 1 to 3 heteroatoms selected from the group consisting of N, O, and S.
  • the heteroatom may be one or two heteroatoms selected from N and O.
  • Non-limiting examples of spiro heterocyclyl include azaspiro[2.3]hexanyl, azaspiro[2.4]heptanyl, azaspiro[3.3]heptanyl, azaspiro[2.5]octanyl, azaspiro[3.4]octanyl, Oxazaspiro[2.3]hexanyl, oxaazaspiro[2.4]heptanyl, oxaazaspiro[3.3]heptanyl, oxaazaspiro[2.5]octanyl, oxaazaspiro[3.4]octanyl, diazaspiro[2.3] ]hexanyl, diazaspiro[2.4]heptanyl, diazaspiro[3.3]heptanyl, diazaspiro[2.5]octanyl, diazaspiro[3.4]octanyl, and the like.
  • bridged heterocyclyls include azabicyclo[2.1.1]hexanyl, azabicyclo[3.1.1]heptanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[4.1.1 ]octanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.2]octanyl, oxaazabicyclo[2.1.1]hexanyl, oxaazabicyclo[3.1.1]heptanyl, Oxaazabicyclo[2.2.1]heptanyl, oxaazabicyclo[4.1.1]octanyl, oxaazabicyclo[3.2.1]octanyl, oxaazabicyclo[2.2.2]octanyl, diazabi Cyclo[2.1.1]hexanyl, diazabicyclo[3.1.1]heptanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[4.1.1]oct
  • Non-limiting examples of fused heterocyclyls include azabicyclo[3.1.0]hexanyl, azabicyclo[2.2.0]hexanyl, azabicyclo[4.1.0]heptanyl, azabicyclo[3.2.0 ]heptanyl, azabicyclo[5.1.0]octanyl, azabicyclo[4.2.0]octanyl, azabicyclo[3.3.0]octanyl, oxaazabicyclo[3.1.0]hexanyl, oxa Azabicyclo[2.2.0]hexanyl, oxaazabicyclo[4.1.0]heptanyl, oxaazabicyclo[3.2.0]heptanyl, oxaazabicyclo[5.1.0]octanyl, oxaazabi Cyclo[4.2.0]octanyl, oxaazabicyclo[3.3.0]octanyl, diazabicyclo[3.1.0]hexanyl,
  • heteromonocyclyl refers to a saturated or partially unsaturated monocyclic hydrocarbon group containing at least one heteroatom. Heteromonocyclyl groups are 3 to 20, 3 to 10, 3 to 8, 3 to 7, 3 to 6, 4 to 9, 4 to 8, 4 to 7 , 4 to 6 ring atoms.
  • the heteroatom may be any one or more selected from the group consisting of N, O and S.
  • the heteroatom may be 1 to 3 heteroatoms selected from the group consisting of N, O, and S.
  • the heteroatom may be one or two heteroatoms selected from N and O.
  • heteromonocyclyl examples include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl, thia A plate making date, etc. are mentioned.
  • substituted of “substituted or unsubstituted” refers to introduced instead of a hydrogen atom when a derivative is formed by substituting one or more hydrogen atoms in an organic compound with another atomic group, and “substituent” refers to an introduced atomic group .
  • a substituent may be, for example, halogen, OH, CN, oxo, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy or mono- or di-(C 1-6 alkyl)amino, said substituent being which may be further substituted with halogen, OH, CN, oxo, amino, nitro, C 1-6 alkyl, C 1-6 alkoxy, mono- or di-(C 1-6 alkyl)amino.
  • the compound of Formula 1 may be prepared according to Scheme A below.
  • step 1 the amine compound containing ring A and the 4-fluoro-nitrobenzene compound substituted with R 2 are mixed in a suitable organic solvent, such as N,N-diisopropylethylamine (abbreviated as DIPEA or DIEA),
  • DIPEA N,N-diisopropylethylamine
  • the reaction can be carried out in acetonitrile (ACN), dichloromethane (DCM).
  • the reaction is at about 10 °C to about 120 °C, about 20 °C to about 100 °C, or about 50 °C to about 80 °C from about several hours to overnight, from about 12 hours to about 18 hours, about This can be done for 16 hours.
  • the —NO 2 group of the product obtained in step 1 may be reduced to an NH 2 group in an appropriate reduction reaction condition, for example, in a hydrogen atmosphere in the presence of a Pd/C catalyst.
  • the reduction reaction is carried out at about 10°C to about 50°C, about 20°C to about 40°C or room temperature in an alcoholic solvent such as EtOH, from about tens of minutes to several hours, from about 30 minutes to about 5 hours, about 1 hour. to about 4 hours.
  • step 3 the aniline compound and dichloropyrimidine compound obtained in step 2 are optionally mixed with a suitable organic solvent such as dichloroethane (DCE), t-butanol (tBuOH) and the like with a suitable catalyst such as ZnCl 2 , triethylammonium (TEA) It can be reacted by mixing in the presence of such.
  • a suitable organic solvent such as dichloroethane (DCE), t-butanol (tBuOH) and the like
  • a suitable catalyst such as ZnCl 2 , triethylammonium (TEA) It can be reacted by mixing in the presence of such.
  • the reaction may be carried out at about -10 °C to about 25 °C, about -5 °C to about 10 °C, or about 0 °C for about 1 to 5 hours, or about 2 to 3 hours.
  • step 4 the compound obtained in step 3 is mixed with an amine compound containing ring B in a suitable organic solvent such as DIPEA, ACN at about 10° C. to about 80° C., about 20° C. to about 60° C. or at room temperature for 1 hour to overnight or from 2 hours to 18 hours.
  • a suitable organic solvent such as DIPEA, ACN
  • the compound of Formula 1 is prepared by separately reacting a dichloropyrimidine compound with an amine compound containing ring B as shown in Scheme A-1 below to prepare a product obtained in the above step It can be prepared by reacting with the product of 2.
  • steps 3-1 and 4-1 may be performed by appropriately modifying steps 3 and 4 of Scheme A.
  • step 3-1 may be performed in a suitable solvent such as DIPEA, DMF, DCM, NMP (N-methylpyrrolidone) by adding an appropriate reagent such as K 2 CO 3 as needed to about -80°C to about 50°C, The reaction may be carried out at about -70°C to about 30°C or at about room temperature for several tens of minutes to overnight, from about 20 minutes to about 18 hours, or from about 30 minutes to about 12 hours.
  • step 4-1 is performed by adding an appropriate reagent such as concentrated hydrochloric acid as needed in an appropriate solvent such as DIPEA, n-BuOH, and the like, from about room temperature to about 150°C, from about 50°C to about 100°C, or from about 80°C to about
  • an appropriate reagent such as concentrated hydrochloric acid as needed in an appropriate solvent such as DIPEA, n-BuOH, and the like
  • the reaction may be carried out at 100° C. for several tens of minutes to several tens of hours, about 30 minutes to about 18 hours, or about 1 hour to about 12 hours.
  • the method for preparing the compound of Formula 1 described above is exemplary, and may be modified by selecting an appropriate solvent, catalyst, reaction conditions, etc. depending on the type of starting material for obtaining the final compound, and these solvents, catalysts, and reaction conditions etc. are well known to those skilled in the art.
  • the compound of Formula 1 may be selected from the group consisting of the following compounds:
  • isomer of the term “stereoisomer” refers to a compound that has the same molecular formula but does not have the same spatial arrangement or connection mode of constituent atoms in the molecule.
  • Isomers include, for example, structural isomers, and stereoisomers.
  • the stereoisomer may be a diastereomer or an enantiomer.
  • Enantiomers refer to isomers that do not overlap their mirror images, such as the relationship between the left and right hands, and are also called optical isomers. Enantiomers are divided into R (Rectus: clockwise) and S (Sinister: counterclockwise) when 4 or more substituents differ from each other at the chiral central carbon.
  • Diastereomers refer to stereoisomers that are not in a mirror image relationship, and are isomers caused by different spatial arrangement of atoms.
  • the diastereomers may be divided into cis-trans isomers and conformational isomers or conformers.
  • solvate refers to a compound solvated in an organic or inorganic solvent.
  • the solvate is, for example, a hydrate.
  • salt refers to inorganic and organic acid addition salts of compounds.
  • the pharmaceutically acceptable salt may be a salt that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound.
  • the inorganic acid salt may be hydrochloride, bromate, phosphate, sulfate, or disulfate.
  • the organic acid salt is formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camsylate, edicyl salt, trichloroacetic acid, trifluoroacetate , benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, embonate, glutamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspartate It may be an acid.
  • the metal salt may be a calcium salt, a sodium salt, a magnesium salt, a strontium salt, or a potassium salt.
  • the compound of Formula 1 may be a Leucine-rich repeat kinase 2 (LRRK2) inhibitor.
  • the LRRK2 may be a protein belonging to a leucine-rich repeat kinase family.
  • the LRRK2 may also be referred to as AURA17, DARDARIN, PARK8, RIPK7, or ROCO2.
  • the LRRK2 is Uniprot No. It may be a protein comprising the amino acid sequence of Q5S007.
  • the LRRK2 may include a Gly2019Ser mutation.
  • Another aspect of the present invention is a pharmaceutical for preventing or treating a disease or disorder mediated by or related to LRRK2, comprising the compound of Formula 1, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof according to an aspect Provides an enemy composition.
  • the disease or condition mediated by or associated with LRRK2 may be a neurodegenerative disease.
  • neurodegenerative disease refers to any disease associated with degenerative changes in the nervous system, and specifically may refer to degenerative brain diseases associated with degenerative changes in the brain.
  • the degenerative brain disease is Parkinson's disease, Alzheimer's disease, Huntington's disease, mild cognitive impairment, amyloidosis, multiple system atrophy, multiple Multiple sclerosis, tauopathies, Pick's disease, senile dementia, amyotrophic lateral sclerosis, Spinocerebellar Atrophy, Tourette's Syndrome, Friedrich's Syndrome, Friedrich's Ataxia, Machado-Joseph's disease, Lewy Body Dementia, Dystonia, Progressive Supranuclear Palsy and Frontotemporal Dementia It can be selected from the group consisting of.
  • the disease or disorder mediated by or related to LRRK2 may be a disease selected from the group consisting of dyskinesia, central nervous system disorder, cancer, rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, Inflammatory Bowel Disease, and tuberculosis.
  • the pharmaceutical composition may further include a known active ingredient having degenerative brain disease prevention, treatment, or amelioration activity.
  • active ingredients having degenerative brain disease prevention, treatment, or amelioration activity include, for example, decarboxylase inhibitors such as carbidopa, levodopa, catechol-O-methyltransferase (Catechol-) O-methyltransferase (COMT) inhibitors, dopamine agonists, monoamine oxidase B (MAO-B) inhibitors, amantadine, anticholinergics, acetylcholinesterase inhibitors, or N-Methyl-D-aspartate receptor antagonists can be COMT inhibitors may be opicapone, entacapone and tolcapone.
  • Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, and apomorphine. and lisuride.
  • MAO-B inhibitors are safinamide, selegiline, and rasagiline.
  • the acetylcholinesterase inhibitor may be tacrine, rivastigmine, galantamine and donepezil.
  • the NMDA receptor antagonist may be memantine.
  • the compound represented by Formula 1, a derivative, stereoisomer, solvate, or pharmaceutically acceptable salt thereof and the known active ingredient may be a single or separate composition for simultaneous or sequential administration.
  • prevention refers to any action of inhibiting the onset of or delaying the onset of a disease or disorder mediated by or related to LRRK2 by administration of the pharmaceutical composition.
  • treatment refers to any action in which the symptoms of a disease or disorder mediated by or related to LRRK2 are ameliorated or beneficially altered by administration of the pharmaceutical composition.
  • the pharmaceutical composition may include a pharmaceutically acceptable carrier.
  • the carrier is used in the sense of including excipients, diluents or adjuvants.
  • the carrier may be, for example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pi It may be selected from the group consisting of rolidone, water, physiological saline, buffers such as PBS, methyl hydroxy benzoate, propyl hydroxy benzoate, talc, magnesium stearate, and mineral oil.
  • the composition may include a filler, an anti-agglomeration agent, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, a preservative, or a combination thereof
  • the pharmaceutical composition may be prepared in any formulation according to a conventional method.
  • the composition may be formulated, for example, as an oral dosage form (eg, a powder, tablet, capsule, syrup, pill, or granule), or a parenteral dosage form (eg, an injection).
  • the composition may be prepared as a systemic formulation, or as a topical formulation.
  • the solid preparation for oral administration may be a tablet, pill, powder, granule, or capsule.
  • the solid formulation may further include an excipient.
  • the excipient may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin.
  • the solid formulation may further include a lubricant such as magnesium stearate or talc.
  • the oral liquid formulation may be a suspension, an internal solution, an emulsion, or a syrup.
  • the liquid formulation may contain water or liquid paraffin.
  • the liquid formulation may contain excipients, for example, wetting agents, sweetening agents, perfuming agents, or preservatives.
  • the preparation for parenteral administration may be a sterile aqueous solution, non-aqueous solution, suspension, emulsion, freeze-dried or suppository.
  • Non-aqueous solvents or suspending agents may include vegetable oils or esters.
  • the vegetable oil may be, for example, propylene glycol, polyethylene glycol, or olive oil.
  • the ester may be, for example, ethyl oleate.
  • the base of the suppository may be witepsol, macrogol, tween 61, cacao butter, laurin, or glycerogelatin.
  • the pharmaceutical composition includes the compound according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof as an active ingredient of the pharmaceutical composition.
  • Active ingredient refers to a physiologically active substance used to achieve pharmacological activity (eg, treatment of degenerative brain disease).
  • the pharmaceutical composition may include the compound according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof in an effective amount.
  • effective amount refers to an amount sufficient to exhibit the effect of preventing or treating a disease when administered to a subject in need thereof.
  • the effective amount can be appropriately selected by those skilled in the art depending on the cell or individual to be selected.
  • the preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the subject, the degree of disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art.
  • the compound, stereoisomer, solvate, or pharmaceutically acceptable salt thereof may be, for example, in an amount from about 0.0001 mg/kg to about 100 mg/kg, or from about 0.001 mg/kg to about 100 mg/kg. may be administered in divided doses 1 to 24 times a day, 1 to 7 times per 2 days to 1 week, or 1 to 24 times in 1 month to 12 months.
  • the compound, stereoisomer, solvate, or pharmaceutically acceptable salt thereof is present in an amount of from about 0.0001% to about 10% by weight, or from about 0.001% to about 1% by weight, based on the total weight of the composition. may be included.
  • the administration method may be oral or parenteral administration.
  • the method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal routes.
  • the composition may be administered systemically or locally, alone or in combination with other pharmaceutically active compounds.
  • Another aspect of the present invention is to prevent or treat a disease mediated by or related to LRRK2, comprising administering to an individual a compound of Formula 1, a stereoisomer, solvate, or pharmaceutically acceptable salt thereof according to an aspect provides a way to
  • the compounds of Formula 1, stereoisomers, solvates, pharmaceutically acceptable salts, diseases or disorders mediated by or related to LRRK2, prevention, and treatment are as described above.
  • the subject may be a mammal, such as a human, mouse, rat, cow, horse, pig, dog, monkey, sheep, goat, ape, or cat.
  • the subject may be suffering from, or likely to suffer from, a condition associated with a disease or condition mediated by or associated with LRRK2.
  • the method may further comprise administering to the subject a known active ingredient having an effect of preventing or treating a disease or disorder mediated by or related to LRRK2.
  • the known active ingredient may be administered to the subject simultaneously, separately, or sequentially with the compound according to an aspect, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.
  • the administration method may be oral or parenteral administration.
  • the method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal, or intradermal routes.
  • the pharmaceutical composition may be administered systemically or locally, alone or in combination with other pharmaceutically active compounds.
  • the preferred dosage of the pharmaceutical composition varies depending on the condition and weight of the patient, the degree of disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art.
  • the dosage is, for example, in the range of about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 10 mg/kg, or about 0.1 mg/kg to about 1 mg/kg, on an adult basis.
  • the administration may be administered once a day, multiple times a day, or once a week, once every two weeks, once every three weeks, or once every four weeks to once a year.
  • Another aspect of the present invention is the use of a compound of Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof according to one aspect, for use in the prevention or treatment of a disease or condition mediated by or related to LRRK2. to provide.
  • Another aspect of the present invention is a compound of Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable compound according to one aspect, for preparing a medicament for preventing or treating a disease or condition mediated by or related to LRRK2. Uses of salts are provided.
  • the disease or disorder mediated by or related to LRRK2, prevention, treatment, compound of Formula 1, stereoisomer, solvate, and pharmaceutically acceptable salt are as described above.
  • the compound of Formula 1 according to the present invention has excellent LRRK2 inhibitory activity, and thus a pharmaceutical composition for preventing or treating a disease or disease mediated by or related to LRRK2 (eg, Parkinson's disease), and treatment and prevention of a disease or disorder using the same method can be used effectively.
  • LRRK2 eg, Parkinson's disease
  • Step 3 of N-4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl)-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine synthesis
  • Example 1 was carried out in the same manner as in Example 1, except that (R)-pyrrolidin-3-ol was used instead of (3S,5R)-piperidine-3,5-diol in step 4 of Example 1
  • the compound of 2 was obtained as a white powder.
  • Example 1 was carried out in the same manner as in Example 1, except that (S)-pyrrolidin-3-ol was used instead of (3S,5R)-piperidine-3,5-diol in step 4 of Example 1 Compound 3 was obtained as a white powder.
  • Step 1 tert-Butyl (1- ⁇ 2-[(4- ⁇ 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl ⁇ phenyl)amino]-5-(trifluoromethyl) Synthesis of pyrimidin-4-yl ⁇ -3-hydroxypiperidin-4-yl)carbamate
  • Example 1 Step 4 except that tert-butyl (3-hydroxypiperidin-4-yl)carbamate was used instead of (3S,5R)-piperidin-3,5-diol
  • tert-butyl (1- ⁇ 2-[(4- ⁇ 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl ⁇ phenyl)amino]-5-(trifluoro Rhomethyl)pyrimidin-4-yl ⁇ -3-hydroxypiperidin-4-yl)carbamate was obtained.
  • Step 2 4-amino-1- ⁇ 2-[(4- ⁇ 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl ⁇ phenyl)amino]-5-(trifluoromethyl) Synthesis of pyrimidin-4-yl ⁇ piperidin-3-ol
  • step 1 of Example 4 tert-butyl (5-hydroxypiperidin-3-yl)carbamate was used instead of tert-butyl (3-hydroxypiperidin-4-yl)carbamate. Except for that, the compound of Example 5 was obtained as a yellow solid in the same manner as in Example 4.
  • step 1 of Example 1 (3S,5R)-piperidine-3,5-diol was used instead of 2-oxa-azabicyclo[2.2.1]heptane, and in step 4 of Example 1 (
  • the compound of Example 6 was prepared in the same manner as in Example 1, except that 2-oxa-azabicyclo[2.2.1]heptane was used in place of 3S,5R)-piperidine-3,5-diol. It was obtained as a solid (32.6 mg, 0.75 mmol, 55% yield).
  • step 1 of Example 1 Using (3R,4R)-4-fluoropiperidin-3-ol in step 1 of Example 1 instead of 2-oxa-5-azabicyclo[2.2.1]heptane, the step of Example 1 In 4, the compound of Example 7 was obtained as a white powder in the same manner as in Example 1, except that 5-azaspiro[2.4]heptane was used instead of (3S,5R)-piperidine-3,5-diol. did.
  • step 1 The compound obtained in step 1 (90 mg, 0.32 mmol, 1.00 equiv) and 1-(4-aminophenyl)piperidin-3-ol (74 mg, 0.39 mmol, 1.20 equiv) were mixed with n-BuOH (2 mL) ), and HCl (1 drop) was added. The resulting mixture was stirred under a nitrogen atmosphere at 80° C. for 6 hours, and the mixture was cooled to room temperature. The mixture was purified by silica gel column chromatography, eluting with DCM/MeOH (10:1) to give the crude product.
  • the crude product was purified by Prep-HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 30 ⁇ 150 mm, mobile phase, water (10 mmol/L NH 4 HCO 3 + 0.1% NH 3 .H 2 O) and ACN (42% Phase B, up to 72% in 7 minutes). Detector, UV 254/220 nm.
  • the collected fractions were lyophilized to 1-[4-[(4-[2-azaspiro[3.3]heptan-2-yl]-5-(trifluoromethyl)pyrimidin-2-yl)amino]phenyl] Piperidin-3-ol (compound of Example 8; 8.6 mg, 6.1%) was obtained as a white solid.
  • Example 9 The compound of Example 9 was prepared in the same manner as in Example 8, except that 2-azaspiro[3.3]heptan-5-one was used instead of 2-azaspiro[3.3]heptane hydrochloride in Step 1 of Example 8. It was obtained as a solid (8.2 mg, 4.4%).
  • step 1 The compound obtained in step 1 (500 mg, 2.27 mmol, 1.00 equiv) was stirred mixed in THF (8 mL) and EtOH (8 mL), NH 4 Cl (242 mg, 4.54 mmol) in H 2 O (2 mL) , 2 eq) was added. To the mixture was added Fe (634 mg, 11.35 mmol, 5.00 equiv), followed by stirring at 80° C. under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 ⁇ 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • the compound of preparation 1 (79 mg, 0.31 mmol, 1 equiv) was stirred mixed in tBuOH (3 mL) and DCE (3 mL) and ZnCl 2 in ether (0.32 mL, 0.64 mmol, 2.03 equiv, 1 mol/L) ) was added dropwise at 0°C. The resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 1 hour. To the mixture, the compound obtained in step 2 (60 mg, 0.31 mmol, 1.00 equiv) was added dropwise at 0°C. The resulting mixture was further stirred at 0° C. under a nitrogen atmosphere for 0.5 h.
  • LRRK2 enzyme inhibitory activity was determined by Nat Biotechnol. 2011 Oct 30;29(11):1039-45.
  • LRRK2 G2019S enzyme Invitrogen, PR8764C
  • LRRKtide SynignalChem, L10-58
  • reaction buffer 20 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.01% (v/v) Brij35, 0.02 mg/mL BSA) , 0.1 mM Na 3 VO 4 , 2 mM DTT, and 1% (w/v) DMSO
  • LRRKtide 20 ⁇ M LRRKtide was added to fresh reaction buffer, 30 nM LRRK2 (G2019S) enzyme was added, and then gently mixed.
  • the prepared compound (in 100% DMSO) was added to the LRRK2 (G2019S) mixture using Acoustic technology (Echo550; nano level).
  • 33 P-ATP was added to the reaction mixture to initiate the reaction, followed by incubation at room temperature for 2 hours.
  • the IC 50 for LRRK2 (G2019S) was calculated by the P81 filter-binding method, and the results were evaluated based on the criteria in Table 1 below, and are shown in Table 2.

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Abstract

La présente invention concerne : un nouveau inhibiteur de kinase 2 à répétition riche en leucine (LRRK2) de formule chimique 1 ; une composition pharmaceutique le contenant pour prévenir ou traiter des maladies ou des troubles médiés par LRRK2 ou liés à LRRK2 ; et une méthode de traitement et de prévention de maladies ou de troubles à l'aide de celui-ci. Le composé selon la présente invention a une excellente activité inhibitrice de LRRK2, et peut donc être utilisé de manière efficace pour prévenir ou traiter des maladies ou des troubles induits ou associés à LRRK2 (par exemple, la maladie de Parkinson).
PCT/KR2022/005074 2021-04-08 2022-04-07 Nouvel inhibiteur de lrrk2 WO2022216097A1 (fr)

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KR102585193B1 (ko) 2023-10-06
WO2022216098A1 (fr) 2022-10-13
KR20230119013A (ko) 2023-08-14
KR20230117460A (ko) 2023-08-08

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