WO2022231242A1 - Composé indazole ayant une activité inhibitrice de lrrk2 - Google Patents

Composé indazole ayant une activité inhibitrice de lrrk2 Download PDF

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WO2022231242A1
WO2022231242A1 PCT/KR2022/005878 KR2022005878W WO2022231242A1 WO 2022231242 A1 WO2022231242 A1 WO 2022231242A1 KR 2022005878 W KR2022005878 W KR 2022005878W WO 2022231242 A1 WO2022231242 A1 WO 2022231242A1
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alkyl
mmol
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residue
mixture
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김승찬
김주연
강은지
김현진
조대현
송상옥
고은
이재영
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주식회사 스탠다임
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Priority to KR1020237025049A priority Critical patent/KR102588242B1/ko
Publication of WO2022231242A1 publication Critical patent/WO2022231242A1/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
    • 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
    • C07D401/14—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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a 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.
  • the compound represented by Formula 1 may be a compound represented by Formula 1A.
  • the compounds of Formulas 1 and 1A may include derivatives of indazole or 3-(pyrimidin-2-yl)indazole.
  • the indazole may be 1H-indazole or 2H-indazole.
  • one of Z 1 and Z 2 is N, the other is NR a , and R a is H, halogen, CN, OH, NO 2 , NH 2 , NH(C 1-6 alkyl), N (C 1-6 alkyl) 2 , halo-C 1-6 alkyl, SO 2 , C 1-6 alkyl, C 2-6 alkenyl, and C 1-6 alkoxy.
  • Z 1 can be N and Z 2 can be NR a
  • Z 1 can be NR a and Z 2 can be N .
  • R a can be H or C 1-6 alkyl, H or C 1-4 alkyl, H, methyl or ethyl.
  • R 1 may be bonded to the 5th or 6th position of the indazole group including Z 1 and Z 2 .
  • the position of the substituent substituted on the indazole ring is according to the following numbering.
  • Z 1 is N
  • Z 2 is NR a
  • n is 1
  • R 1 may be bonded to the 5th position of a 1H-indazole group comprising Z 1 and Z 2 .
  • R 1 is H, halogen, CN, NO 2 , halo-C 1-6 alkyl, SO 2 , C 1-6 alkyl, C 2-6 alkenyl, OR 1a , 1 to 4 hetero selected from C 3-8 cycloalkyl, C 3-8 cycloalkenyl, C 6-12 aryl (eg phenyl, benzyl, naphthalenyl, etc.), NR 1b R 1c , N, O and S saturated or partially unsaturated 4 to 8 membered heterocyclyl containing atoms (eg, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydro 1 selected from furanyl, tetrahydropyranyl, dihydrofuranyl, dihydropyranyl, morpholinyl, thiomorpholiny
  • pyrrolyl pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, furanyl, pyranyl, oxazolyl, isoxazolyl, oxadiazolyl, thi Openyl, thiazolyl or thiadiazolyl, indolyl, [1,2,4]triazolo[1,5-a]pyridinyl, 1H-1,2,3-triazolo[4,5-b]pyridine yl, etc.), and -NH-CO-tetrazolo[1,5-a]pyrimidine which may optionally be substituted with C 1-6 alkyl.
  • the cycloalkyl ring, cycloalkenyl ring, aryl ring, heterocyclyl ring or heteroaryl ring in R 1 is halogen, oxo, CN, OH, NO 2 , -NH 2 , -NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , halo-C 1-6 alkyl, C 1-6 alkyl, C 3-8 cycloalkyl (eg cyclobutanyl), C 1-6 alkoxy, C 1-6 alkoxy -C 1-6 alkyl, hydroxy-C 1-6 alkyl, -CONR 11 R 12 , SO 2 , SO 2 NR 13 R 14 , and 4 to 8 membered heterocyclyl containing 1 to 2 heteroatoms selected from N, O and S (eg, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, p Rollidinyl, piperidinyl
  • R 1a is H, C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 3-8 cycloalkyl, and 1 selected from N, O and S 3- to 8-membered heterocyclyl containing two heteroatoms (eg, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrothiophenyl, etc.) may be selected from the group consisting of, and R 1a may be further optionally substituted with C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, or hydroxy-C 1-6 alkyl.
  • R 11 and R 12 may each independently be H, C 1-6 alkyl, hydroxy-C 1-6 alkyl, or C 1-6 alkoxy-C 1-6 alkyl.
  • R 13 and R 14 are each independently H, C 1-6 alkyl, hydroxy-C 1-6 alkyl, or C 1-6 alkoxy-C 1-6 alkyl, or 4 to 8 members together with N to which they are bonded
  • One heterocyclyl eg, azetidinyl, pyrrolidinyl, piperidinyl
  • azetidinyl e.g., azetidinyl, pyrrolidinyl, piperidinyl
  • n may be an integer of 0, 1, or 2. In one embodiment, n can be 1.
  • said R 1 is halogen, CN, NO 2 , C 1-6 alkyl, C 3-8 cycloalkyl halo-C 1-6 alkyl, OR 1a , NR 1b R 1c , a quaternary comprising N to 8-membered heterocyclyl and C 1-4 alkyl substituted with 4- to 8-membered heterocyclyl containing N.
  • R 1 is CN, halo-C 1-4 alkyl (eg, trifluoromethyl, etc.), OR 1a , C 3-6 cycloalkyl (eg, cyclopropyl, etc.), NR 1b R 1c , a 4- to 8-membered heterocyclyl containing N (eg, piperidinyl, etc.) and a 4- to 8-membered heterocyclyl containing N (eg, a piperidinyl group, etc.) It may be selected from the group consisting of C 1-4 alkyl substituted with (eg, methyl, etc.).
  • the piperidinyl may be piperidin-4-yl.
  • the piperidinyl group may be piperidin-1-yl.
  • the nitrogen atom may be bonded to the C 1-4 alkyl.
  • R 1a comprises H, C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 3-8 cycloalkyl, and O 3 to 7 membered heterocyclyl.
  • R 1a is C 1-6 alkyl (eg, methyl, ethyl, isopropyl, etc.), C 1-4 alkoxy-C 1-6 alkyl (eg, 2-methoxy-ethyl, etc.) ), a 3- to 7-membered heterocyclyl containing O (eg, tetrahydrofuranyl, oxetanyl, etc.) may be selected from the group consisting of.
  • the tetrahydrofuranyl may be tetrahydrofuran-3-yl.
  • the oxetanyl may be oxetan-3-yl.
  • R 1b and R 1c are each independently H, C 1-6 alkyl or 4 to 8 membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O and S, R 1b is H, and R 1c can be C 1-6 alkyl (eg, methyl, isopropyl, etc.) or 4-7 membered heterocyclyl containing O (eg, oxetanyl, etc.) have.
  • the oxetanyl may be oxetan-3-yl.
  • the heterocyclyl ring in R 1 is C 1-6 alkyl (eg, isopropyl, neopentyl, etc.), C 3-8 cycloalkyl (eg, cyclobutyl, etc.), halo 3-7 membered hetero including -C 1-6 alkyl (eg 2-fluoroethyl, etc.), C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl and O It may be optionally substituted with at least one substituent selected from the group consisting of cyclyl (eg, tetrahydrofuranyl group, etc.). The tetrahydrofuranyl group may be tetrahydrofuran-3-yl. When the heterocyclyl contains a nitrogen atom, the substituent may be substituted for the nitrogen atom.
  • cyclyl eg, tetrahydrofuranyl group, etc.
  • the tetrahydrofuranyl group may be te
  • R 1 is 5 or 6 membered including halogen, CN, C 3-6 cycloalkyl, C 1-6 alkyl, halo-C 1-6 alkyl, OR 1a , NR 1b R 1c , N heterocyclyl and C 1-4 alkyl substituted with 5- or 6-membered heterocyclyl containing N.
  • said 5 or 6 membered heterocyclyl ring is C 1-6 alkyl, C 3-6 cycloalkyl, halo-C 1-6 alkyl, C 1-4 alkoxy-C 1-4 alkyl or 4 membered including O may be optionally substituted with to 7 membered heterocyclyl.
  • the 4-membered to 7-membered heterocyclyl containing O may be a 5-membered or 6-membered heterocyclyl containing O (eg, tetrahydrofuranyl, tetrahydropyranyl, etc.).
  • R 1a may be selected from C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, or 3-7 membered heterocyclyl including O.
  • the 3- to 7-membered heterocyclyl containing O is a 4- to 6-membered heterocyclyl containing O (eg, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, etc.) can be
  • R 1b and R 1c may each independently be selected from H, C 1-6 alkyl or 4-6 membered heterocyclyl comprising O.
  • the 4-membered to 6-membered heterocyclyl containing O may be a 4-membered to 5-membered heterocyclyl containing O (eg, oxetanyl, tetrahydrofuranyl, etc.).
  • the R 1 The heterocyclyl ring in C 1-4 alkyl substituted with 5 or 6 membered heterocyclyl containing N is C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy-C 1-6 alkyl or C 1 -6 alkoxy-C 1-6 alkyl may be optionally substituted.
  • the heterocyclyl ring in C 1-4 alkyl substituted with 5 or 6 membered heterocyclyl containing N is halo-C 1-4 alkyl (eg difluoromethyl, etc.) or C 1-4 alkoxy-C 1-4 alkyl (eg, methoxymethyl, etc.).
  • R 1 is CN, methoxy, ethoxy, isopropoxy, trifluoromethyl, cyclopropyl, tetrahydrofuran-3-yloxy, oxetan-3-yloxy, 2-methoxy to Toxy, methylamino, isopropylamino, oxetan-3-ylamino, 1-neopentylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-(2-fluoroethyl)p Peridin-4-yl, 1-isopropylpiperidin-4-yl, 1-cyclobutylpiperidin-4-yl, 1-(tetrahydrofuran-3-yl)piperidin-4-yl, (4-difluoromethylpiperidin-1-yl)methyl and (3-methoxymethylpiperidin-1-yl)methyl.
  • R 1 can be selected from halogen, CN, C 3-6 cycloalkyl, C 1-6 alkyl, halo-C 1-6 alkyl, OR 1a and NR 1b R 1c .
  • R 1a is C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl or 3-7 membered heterocyclyl including O (eg, oxetane yl, tetrahydrofuranyl, tetrahydropyranyl, etc.).
  • Each of R 1b and R 1c may be independently selected from H, C 1-6 alkyl, or 4 to 6 membered heterocyclyl containing O (eg, oxetanyl, tetrahydrofuranyl, etc.) .
  • R 2 is H, halogen, CN, OH, NO 2 , NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , halo-C 1-6 alkyl, SO 2 , C 1-6 alkyl, C 2-6 alkenyl, and C 1-6 alkoxy.
  • R 2 can be H, halogen, CN, OH, halo-C 1-6 alkyl, C 1-6 alkyl, C 2-6 alkenyl or C 1-6 alkoxy.
  • R 2 can be H, OH, halogen, CN, C 1-6 alkyl, C 1-6 alkoxy or halo-C 1-6 alkyl.
  • R 2 can be H, OH, C 1-6 alkyl or C 1-6 alkoxy. In one embodiment, R 2 can be H, C 1-4 alkyl or C 1-4 alkoxy. In one embodiment, R 2 can be H, methyl or methoxy.
  • R 2 may be bonded to the 5th or 6th position of the pyrimidine group.
  • R 3 is C 1-6 alkyl; NH 2 ; NH(C 1-6 alkyl); N(C 1-6 alkyl) 2 ; oxo; or 3-7 membered saturated or partially unsaturated heterocyclyl containing 1 to 3 heteroatoms selected from NR 31 R 32 , N, O and S optionally substituted with at least one substituent selected from carbamoyl (eg For example, azetidinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, imidazolinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, etc.), C 6-12 aryl or N, O and 5 to 10 membered heteroaryl containing 1 to 3 heteroatoms selected from S (eg, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridaziny
  • R 31 and R 32 may each independently be H or C 1-6 alkyl, or H or C 1-4 alkyl. In one embodiment, R 31 and R 32 may be the same as or different from each other.
  • R 31 and R 32 of NR 31 R 32 each is at least one selected from C 1-6 alkyl, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , oxo or carbamoyl may be optionally substituted with a substituent of
  • R 31 or R 32 when R 31 or R 32 is C 1-6 alkyl, the carbon atom adjacent to N in NR 31 R 32 may be substituted with oxo.
  • NR 31 R 32 may be alkanoylamino.
  • the alkyl included in the alkanoylamino may be optionally substituted with at least one substituent selected from NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , oxo or carbamoyl.
  • the aryl ring, heterocyclyl ring and heteroaryl ring in R 3 are each H, halogen, oxo, CN, OH, COOR 3a , NO 2 , NR 3b R 3c , halo-C 1-6 alkyl, cyano-C 1-6 alkyl, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy -C 1-6 alkoxy-C 1-6 alkyl, carboxy-C 1-6 alkyl, amino-C 1-6 alkyl, carbamoyl, N-mono-C 1-6 alkylcarbamoyl, N,N-di- C 1-6 Alkylcarbamoyl, Carbamoyl-C 1-6 Alkyl, N-Mono-C 1-6 Alkylcarbamoyl-C 1-6 Alkyl, N,
  • said cyano-C 1-6 alkyl, halo-C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkoxy C 1-6 alkyl of —C 1-6 alkyl, carboxy-C 1-6 alkyl, amino-C 1-6 alkyl and ureido-C 1-6 alkyl can be straight-chain or branched alkyl, cyano , halogen, hydroxy, alkoxy, carboxy, amino, carbamoyl, N-mono-C 1-6 alkylcarbamoyl, N,N-di-C 1-6 alkylcarbamoyl and ureido represent the terminus or chain of said alkyl may be substituted in the middle.
  • R 3a is H, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-8 cycloalkyl-C 1-6 alkyl, C 3-8 cycloalkyl, or 5 members comprising 1 heteroatom selected from N, O and S or 6 membered heterocyclyl or heteroaryl (eg, tetrahydrofuranyl, furanyl, pyrrolyl, pyrrolidinyl, pyridinyl, piperidinyl, thiophenyl, tetrahydrothiophenyl, etc.).
  • heterocyclyl or heteroaryl eg, tetrahydrofuranyl, furanyl, pyrrolyl, pyrrolidinyl, pyridinyl, piperidinyl, thiopheny
  • R 3b and R 3c may each independently be H, C 1-6 alkyl, hydroxy-C 1-6 alkyl, or amino-C 1-6 alkyl.
  • R 3b may be H and R 3c may be aminopropyl (eg, 2-aminopropyl).
  • R 3d is H, C 1-6 alkyl, C 2-6 alkenyl, hydroxy-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 3-8 cycloalkyl-C 1- 6 alkyl, C 3-8 cycloalkyl, or 5 or 6 membered heterocyclyl or heteroaryl comprising 1 heteroatom selected from N, O and S.
  • R 3e and R 3f are each independently C 3-8 cycloalkyl, C 6-12 aryl, or 4 to 8 membered heterocyclyl containing 1 to 3 heteroatoms selected from N, O and S; Heteroaryl (e.g., tetrahydrothiophenyl, oxadiazolyl, triazolyl, thiadiazolyl, triazolyl, pyrimidinyl, pyrazolyl, imidazolyl, pyridinyl, morpholinyl, tetrahydrofuranyl, furanyl , pyrazinyl, etc.).
  • Heteroaryl e.g., tetrahydrothiophenyl, oxadiazolyl, triazolyl, thiadiazolyl, triazolyl, pyrimidinyl, pyrazolyl, imidazolyl, pyridinyl, morpholinyl, tetrahydrofuranyl, furanyl
  • R 3e and R 3f are further optionally substituted with halogen, oxo, CN, OH, NO 2 , NH 2 , C 1-6 alkyl, C 1-6 alkoxy or C 3-8 cycloalkyl.
  • R 3g may be absent, C 1-6 alkyl, or C 3-8 cycloalkyl.
  • Each of o, p and q may independently be an integer of 0, 1, 2, or 3. In one embodiment, o, p and q can be 0 or 1.
  • R 3 is C 1-4 alkyl; NH 2 ; NH(C 1-6 alkyl); N(C 1-6 alkyl) 2 ; oxo; or NR 31 R 32 , optionally substituted with at least one substituent selected from carbamoyl, 3-7 membered saturated or partially unsaturated heterocyclyl comprising N, C 6-12 aryl or the group consisting of N, O and S It may be a 5- to 8-membered heteroaryl containing 1 to 3 heteroatoms selected from.
  • the aryl ring, heterocyclyl ring and heteroaryl ring in R 3 are halogen, oxo, CN, NO 2 , OH, COOR 3a , NR 3b R 3c , cyano-C 1-6 alkyl, C 1-6 alkyl, hydroxy-C 1-6 alkyl, carboxy-C 1-6 alkyl, amino-C 1-6 alkyl, carbamoyl, N-mono-C 1-6 alkylcarbamoyl, N,N-di -C 1-6 alkylcarbamoyl, carbamoyl-C 1-6 alkyl, N-mono-C 1-6 alkylcarbamoyl-C 1-6 alkyl, N,N-di-C 1-6 alkylcarbamoyl- It may be substituted with 1 to 3 substituents selected from the group consisting of C 1-6 alkyl, ureido and ureido-C 1-6 alkyl
  • the o may be an integer of 0 to 3.
  • R 3a is H, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 or C 1-6 alkyl, and R 3b and R 3c are each independently H, C 1-6 alkyl or amino-C 1-6 alkyl.
  • R 3 is C 1-4 alkyl; NH 2 ; NH(C 1-6 alkyl); N(C 1-6 alkyl) 2 ; oxo; or C 1-6 alkanoylamino, azetidinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, furanyl, thiophenyl optionally substituted with at least one substituent selected from carbamoyl , may be selected from the group consisting of imidazolinyl, oxodihydroimidazolyl and pyridinyl.
  • the imidazolinyl may be 2-imidazolinyl, 3-imidazolinyl or 4-imidazolinyl.
  • R 3 is and It can be selected from the group consisting of.
  • R 3 is halogen, CN, C 1-6 alkyl, OH, cyano-C 1-6 alkyl, hydroxy-C 1-6 alkyl, COOR 3a , carboxy-C 1-6 alkyl, amino- C 1-6 alkyl, carbamoyl, N-mono-C 1-6 alkylcarbamoyl, N,N-di-C 1-6 alkylcarbamoyl, carbamoyl-C 1-6 alkyl, N-mono-C 1 consisting of -6 alkylcarbamoyl-C 1-6 alkyl, N,N-di-C 1-6 alkylcarbamoyl-C 1-6 alkyl, NR 3b R 3c , ureido and ureido-C 1-6 alkyl It may be substituted with 1 to 3 substituents selected from the group.
  • the o may be an integer of
  • R 3 is C 1-6 alkanoylamino substituted with carbamoyl or methyl, or phenyl or azetidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, furanyl, thi It may be a heterocyclyl or heteroaryl selected from the group consisting of offenyl, imidazolinyl, oxodihydroimidazolyl and pyridinyl.
  • the carbamoyl or methyl substituted C 1-6 alkanoylamino is carbamoyl-C 1-6 alkanoylamino or N1-C 1-6 alkyl-carbamoyl-C 1-6 alkanoylamino can be
  • R 3 is 3-carbamoyl-N1-methylpropanoylamino, or phenyl, 1H-pyrrol-1-yl, 1H-pyrrol-3-yl, 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-imidazol-1-yl, 1H-imidazol-4-yl, 1H-triazol-1-yl, thiazol-4- yl, furan-2-yl, thiophen-2-yl, thiophen-3-yl, pyridin-3-yl, 4-imidazolin-1-yl, azetidin-3-yl or 2-oxo-2 ,3-dihydro-1H-imidazol-1-yl.
  • the position number in the ring of heterocyclyl, aryl and heteroaryl of R 3 may be defined such that the number of positions bonded to pyridinyl of the
  • the phenyl ring, heterocyclyl ring and heteroaryl ring in R 3 are F, Cl, cyano, oxo, methyl, isobutyl, hydroxy, 2-cyanoethyl, hydroxymethyl, 1- Hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxyisobutyl, 3-hydroxybutyl , 1-hydroxybutan-2-yl, carboxy, 1-carboxyethyl, 2-carboxyethyl, methoxycarbonyl, 3-aminopropyl, 3-aminoisobutyl, 2-aminopropylamino, carbamoyl, 1- It may be substituted with at least one substituent selected from the group consisting of carbamoylethyl, 2-carbamoylethyl and ureidomethyl.
  • the substituent when R 3 is heterocyclyl or heteroaryl including secondary amino (—NH—), the substituent may be substituted at the nitrogen atom of the secondary amino.
  • the substituent may be a nitrogen atom included in the amino group of the C 1-6 alkanoylamino group (R—CO—NH—) or pyrrolyl, pyrazolyl, pyrazolyl, imidazolyl, azetidinyl and 2- It may be substituted for the nitrogen atom of -NH- contained in the ring of oxo-2,3-dihydroimidazolyl.
  • R 3 is a C 1-6 alkanoylamino group
  • the substituent may be substituted at the middle or terminal of the alkanoyl group or at the nitrogen atom of the amino group.
  • R 3 when R 3 is phenyl, the substituent may be substituted at the 2nd, 3rd or 4th position of phenyl, and two substituents may be substituted at the 2nd and 4th or 3rd and 4th positions, respectively. It might be
  • R 3 is 1H-pyrrol-1-yl
  • the substituent may be substituted in the 3rd or 4th position of 1H-pyrrol-1-yl, and the two substituents are in the 3rd and 4th positions, respectively. may be substituted for
  • R 3 is 1H-pyrrol-3-yl
  • the substituent may be substituted at the 1st or 5th position of 1H-pyrrol-3-yl, and the two substituents are at the 1st and 5th positions, respectively. may be substituted for
  • R 3 is 1H-pyrazol-1-yl
  • the substituent may be substituted at the 3rd or 4th position of 1H-pyrazol-1-yl, and the two substituents are 3 and 4, respectively. It may be substituted at the n position.
  • R 3 when R 3 is 1H-pyrazol-3-yl, the substituent may be substituted at the 1st or 5th position of 1H-pyrazol-3-yl, and the two substituents are 1 and 5, respectively. It may be substituted at the n position.
  • R 3 is 1H-pyrazol-4-yl
  • the substituent may be substituted at positions 1, 3, or 5 of 1H-pyrazol-4-yl, and two substituents are each 3 It may be substituted at the positions No. and No. 5.
  • R 3 is 1H-imidazol-1-yl
  • the substituent may be substituted at the 4th position of 1H-imidazol-1-yl.
  • R 3 is 1H-imidazol-4-yl
  • the substituent may be substituted at the 1-position of 1H-imidazol-4-yl.
  • R 3 is 1H-triazol-1-yl
  • the substituent may be substituted at the 4th position of 1H-triazol-1-yl.
  • R 3 when R 3 is thiazol-4-yl, the substituent may be substituted at the 2-position of thiazol-4-yl.
  • R 3 is furan-2-yl
  • the substituent may be substituted at the 5-position of furan-2-yl.
  • R 3 is thiophen-2-yl
  • the substituent may be substituted at the 5th position of thiophen-2-yl.
  • R 3 is thiophen-3-yl
  • the substituent may be substituted at the 5-position of thiophen-3-yl.
  • R 3 when R 3 is pyridin-3-yl, the substituent may be substituted at the 5th or 6th position of pyridin-3-yl, and two substituents may be substituted at the 5th and 6th positions, respectively. have.
  • R 3 when R 3 is azetidin-3-yl, the substituent may be substituted at the 1-position of azetidin-3-yl.
  • R 3 is 2-oxo-2,3-dihydro-1H-imidazol-1-yl
  • the substituent is 2-oxo-2,3-dihydro-1H-imidazol-1-yl may be substituted at the 3-position of
  • alkyl refers to a fully saturated branched or unbranched (or straight-chain or linear) hydrocarbon.
  • the alkyl may be a substituted or unsubstituted alkyl.
  • the C 1-6 alkyl may be C 1 to C 5 , C 1 to C 4 , C 1 to C 3 , or C 1 to C 2 alkyl.
  • 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.
  • alkenyl includes straight-chain or branched alkenyl having 2 to 6 carbon atoms, 2 to 5 carbon atoms, and 2 to 4 carbon atoms having one or more double bonds at any position.
  • vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, etc. can be heard
  • alkoxy refers to an alkyl bound to an oxygen atom.
  • the C 1 to C 6 alkoxy may be, for example, C 1 to C 5 , C 1 to C 4 , C 1 to C 3 , or C 1 to C 2 alkoxy.
  • the alkoxy may be methoxy, ethoxy, or propoxy.
  • cycloalkyl includes mono- or polycyclic saturated carbocycles having 3 to 8 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. are mentioned.
  • cycloalkenyl includes non-aromatic single or polycyclic rings of 3 to 8 carbon atoms containing at least one carbon-carbon double bond.
  • cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc. are mentioned.
  • halogen refers to an atom belonging to group 17 of the periodic table. Halogen atoms include fluorine, chlorine, bromine, and iodine.
  • haloalkyl refers to an alkyl substituted with one or more halogen atoms.
  • hydroxy refers to an OH functional group (hydroxyl group).
  • cyano refers to a functional group consisting of a triple bond between a carbon atom and a nitrogen atom as CN.
  • nitro refers to NO 2 .
  • amino refers to —NH 2 .
  • alkylamino refers to a functional group in which one or two hydrogen atoms of the amino (—NH 2 ) group are substituted with any one or two of the aforementioned alkyls, and includes both mono-alkylamino and di-alkylamino and , the two alkyls in di-alkylamino may be the same or different. Specifically, in mono-C 1-6 alkylamino, one hydrogen atom of an amino (-NH 2 ) group is substituted with C 1-6 alkyl, and 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 (—NH(C 1-6 alkyl)) is methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert. -Butylamino, pentylamino, hexylamino and the like may be included.
  • di-C 1-6 alkylamino(—N(C 1-6 alkyl) 2 ) is, for example, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropylamino, methylisopropylamino, methylbutylamino , methylisobutylamino, ethylpropylamino, ethylisopropylamino, ethylisobutylamino, isopropylisobutylamino, methylhexylamino, ethylhexylamino, and the like.
  • N-mono-C 1-6 alkylcarbamoyl and “N,N-di-C 1-6 alkylcarbamoyl” refer to one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl (-CONH 2 ). It means that the hydrogen atom of is substituted with C 1-6 alkyl. In N,N-di-C 1-6 alkylcarbamoyl, the two C 1-6 alkyls may be the same as or different from each other.
  • ureido refers to -NHCONH 2 .
  • alkanoyl methanyl formyl: -COH
  • ethanoyl acetyl: -COCH 3
  • propanoyl -COCH 2 CH 3
  • butanoyl -CO(CH 2 ) 2 CH 3
  • alkanoylamino refers to amino (ie, —NH(C ⁇ O)-alkyl) substituted with an alkanoyl group.
  • the nitrogen atom of the alkanoylamino may have further substituents such as, for example, alkyl groups.
  • alkanoylamino is formylamino (-NHCOH), acetylamino (-NHCOCH 3 ), propanoylamino (-NHCOCH 2 CH 3 ), butanoylamino (-NHCO(CH 2 ) 2 CH 3 ) etc.
  • N1-C 1-6 alkyl-carbamoyl-C 1-6 alkanoylamino refers to a substituent in which C 1-6 alkyl is substituted for the nitrogen atom of alkanoylamino and carbamoyl is substituted for alkanoyl.
  • Hal-indazole refers to indazole in which nitrogen 2 is bonded to hydrogen.
  • cyano-C 1-6 alkyl is cyano, halogen, hydroxy, alkoxy, carboxy, amino, carbamoyl at the end or in the middle of C 1-6 alkyl.
  • N-mono-C 1-6 alkylcarbamoyl, N,N-di-C 1-6 alkylcarbamoyl, and “ureido-C 1-6 alkyl” is cyano, halogen, hydroxy, alkoxy, carboxy, amino, carbamoyl at the end or in the middle of C 1-6 alkyl.
  • N-mono-C 1-6 alkylcarbamoyl, N,N-di-C 1-6 alkylcarbamoyl, N,N-di-C 1-6 alkylcarbamoyl-C 1-6 alkylcarbamoyl-C 1-6 alkyl is cyano, halogen, hydroxy, alkoxy, carboxy, amino, carbamoyl at the end
  • heterocyclyl refers to a saturated or partially unsaturated cyclic hydrocarbon containing at least one heteroatom.
  • the heterocyclyl ring group may be monocyclic or bicyclic.
  • the bicyclic heterocyclyl may be a spiro, bridged and fused ring group.
  • Heterocyclyl is 3 to 20, 3 to 10, 3 to 8, 3 to 7, 3 to 6, 4 to 9, 4 to 8, 4 to 7, It may contain 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, 1 or 2 heteroatoms selected from the group consisting of N, O, and S.
  • heterocyclyl examples include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dihydropyridinyl, tetrahydropyridinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyran yl, dihydrofuranyl, dihydropyranyl, tetrahydrothiophenyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, and the like.
  • heteroaryl refers to a monocyclic or bicyclic aromatic compound containing one or more heteroatoms selected from the group consisting of N, O, and S, and the remaining ring atoms are carbon.
  • the heteroaryl group may contain, for example, 1 to 4, 1 to 3 or 1 or 2 heteroatoms.
  • the heteroaryl group may contain 5 to 10, 5 to 7, or 5 or 6 ring elements.
  • the heteroaryl may be a 5-6 membered heteroaryl containing 1 or 2 N, O or S.
  • the heteroaryl group may be a single ring group, two ring groups, or three ring groups.
  • the two ring groups may be a spiro-ring group, a bridged-ring group, and a fused-ring group.
  • heteroaryl examples include pyrrolyl, imidazolyl, pyrazolyl, pyridazinyl, furanyl, pyranyl, thienyl, thiophenyl, 1,2,3-oxadiazolyl, 1, 2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl group, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1 , 2,5-thiadiazolyl, 1,3,4-thiadiazolyl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2-yl, Oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, 1,2,4-triazol-3-yl , 1,2,4-tri
  • 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 .
  • Substituents are, for example, halogen, oxo, CN, OH, NO 2 , NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , halo-C 1-6 alkyl, C 1 - 6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkenyl, amide group, sulfone group , a sulfonamide group, and a 4 to 8 membered heterocyclyl or heteroaryl including 1 to 2 heteroatoms selected from N, O and S.
  • the reaction for preparing the compound of the present invention can be carried out in a suitable solvent which can be appropriately selected by a person skilled in the art of organic synthesis.
  • suitable solvents are those that are substantially unreactive with the starting materials (reactants), intermediates or objects at the temperature at which the reaction occurs.
  • a person skilled in the art will be able to properly select a suitable solvent for a particular reaction step.
  • each reaction can be monitored by an appropriate method known in the art.
  • the synthesis of the target compound may be monitored by spectroscopic means, such as NMR (eg, 1 H or 13 C), mass spectroscopy, or chromatography (HPLC or TLC).
  • the compound of the present invention can be synthesized according to the synthesis procedure described in the following examples, and based on this, reactants and reaction conditions (eg, reaction solvent, reaction temperature, reaction time, reaction catalyst, etc.) according to the structure of the target compound, etc. With appropriate modifications, the target compound may be prepared.
  • reactants and reaction conditions eg, reaction solvent, reaction temperature, reaction time, reaction catalyst, etc.
  • a tetrahydropyran (THP) protecting group may be introduced into the indazole compound by reacting a suitable indazole compound with 3,4-dihydro-2H-pyran under appropriate reaction conditions depending on the compound to be prepared.
  • the reaction may be performed in a suitable solvent (eg, THP) in the presence of p-toluenesulfonic acid (p-TSA).
  • p-TSA p-toluenesulfonic acid
  • the reaction may be carried out at a temperature of about 50° C. to about 100° C., about 60° C. to about 90° C., or about 70° C. to about 80° C. for about tens of minutes to about overnight, about several hours, or about 1 hour to about 4 can be done over time.
  • Indazole compounds suitable as starting materials include, for example, introduction of a THP protecting group into halogenated or hydroxylated indazole, substitution of R 1 on the phenyl ring of indazole through reaction with an appropriate boronic acid compound or halogenated compound, and indazole. It can be prepared by performing a deprotection reaction and an iodination reaction of the sol, but is not limited thereto.
  • step 2 the indazole compound introduced with a THP protecting group and 4-chloro-2-(tributylstannyl)pyrimidine are reacted in a suitable solvent (eg, DMF) in the presence of CuI, Pd(PPh 3 ) 4 and the like. can do it
  • a suitable solvent eg, DMF
  • the reaction may be carried out at a temperature of about 50° C. to about 150° C., about 80° C. to about 120° C., or about 100° C. for about 12 hours to overnight, or about 18 hours to overnight.
  • step 3 the intermediate obtained in step 2 and a precursor of the R 3 substituent (eg, R 3 -H) may be reacted in an appropriate solvent (eg, DMF) in the presence of Cs 2 CO 3 or the like.
  • the reaction may be performed at a temperature of about 50°C to about 150°C, about 80°C to about 120°C, or about 100°C for about tens of minutes to several hours, about tens of minutes to about 5 hours, about 1 hour to about 3 hours, or about 1 can be done over time.
  • steps for protection and deprotection reactions, esterification and de-esterification reactions, oxidation and reduction reactions, etc. may be appropriately added.
  • step 4 above a few drops (eg, 4-5 drops) of concentrated hydrochloric acid is added to the compound obtained in step 3, or a solution of HCl (eg, 5M HCl solution) in a suitable solvent (eg, IPA) is added to form a THP protecting group can be deprotected, and the target compound can be obtained in the form of a hydrochloride salt.
  • the reaction is performed at a temperature of about 50° C. to about 150° C., about 60° C. to about 120° C., or about 70° C. to about 100° C. for about several tens of minutes to several hours, about tens of minutes to about 5 hours, about 1 hour to about 3 hours. , or for about 1 hour.
  • step 4 acetic acid, tetrafluoroacetic acid, or p-toluenesulfonic acid (TsOH) may be used instead of hydrochloric acid (concentrated hydrochloric acid), and as the solvent, methanol, dioxane, dichloromethane, and combinations thereof, etc. in addition to IPA are used.
  • hydrochloric acid concentrated hydrochloric acid
  • solvent methanol, dioxane, dichloromethane, and combinations thereof, etc. in addition to IPA are used.
  • step 1 2,4-dichloropyrimidine or a derivative thereof is used as a precursor of the R 3 substituent (eg, R 3 -H, R 3 -BPin (pinacol boronic acid) or R 3 -B(OH) 2 ) and under appropriate reaction conditions, 2-chloropyrimidine in which the 4th position of the ring is substituted with R 3 can be synthesized.
  • the reaction may be performed in a suitable solvent (eg, acetonitrile) in the presence of Cs 2 CO 3 or the like.
  • the reaction may be carried out at about 20 °C to about 150 °C, for example, at 20 °C to 40 °C, 40 °C to 60 °C, 60 °C to 80 °C, 80 °C to 120 °C or 120 °C to 150 °C can be performed.
  • the reaction may be carried out for about several minutes to 24 hours, for example, from about several tens of minutes to about 12 hours, from about 1 hour to about 6 hours, or from about 1 hour to 3 hours.
  • K 2 CO 3 , K 3 PO 4 , DIEA, NaH, KOAc, Pd(Ph 3 ) 2 Cl 2 and the like may be used for the reaction, and as a solvent, water, dioxane, in addition to the acetonitrile , dichloromethane, DMF, and combinations thereof may be used.
  • step 2 the compound obtained in step 1 may be reacted with a THP-protected 4-BPin-1H-indazole derivative to synthesize a THP-protected 4-pyrimidin-2-yl-1H-indazole derivative.
  • the reaction may be carried out in the presence of Pd(dppf)Cl 2 , K 2 CO 3 , or the like in a suitable solvent (eg, dioxane) under a nitrogen atmosphere.
  • the reaction may be performed at about 60 °C to about 150 °C, for example, 60 °C to 80 °C, 80 °C to 100 °C, 100 °C to 120 °C or 120 °C to 150 °C.
  • the reaction may be carried out for about several hours to 24 hours, for example, about 1 hour to about 12 hours, about 1 hour to about 6 hours, or about 1 hour to 3 hours.
  • the solvent a mixed solvent of dioxane and water may be used, and DMF, THF, etc. may be used.
  • K 2 CO 3 , K 3 PO 4 may be used.
  • step 3 a few drops (eg 4-5 drops) of concentrated hydrochloric acid is added to the compound obtained in step 2, or a solution of HCl (eg 5M HCl solution) in a suitable solvent (eg IPA) is added to form a THP protecting group can be deprotected.
  • the reaction may be performed at a temperature of about 20°C to about 150°C, about 20°C to about 100°C, or about 20°C to about 60°C for about tens of minutes to several hours, about tens of minutes to about 5 hours, about 1 hour to about 3 hours. , or for about 1 hour.
  • step 3 acetic acid, tetrafluoroacetic acid, or p-toluenesulfonic acid (TsOH) may be used instead of hydrochloric acid, and as the solvent, methanol, dioxane, dichloromethane, and combinations thereof may be used in addition to IPA.
  • TsOH p-toluenesulfonic acid
  • step 1 and step 2 between step 2 and step 3 or after step 3, depending on the type of R 1 and R 3 , for example, protection and deprotection reactions, esterification and de-esterification Steps for oxidation reactions, oxidation and reduction reactions, and the like may be appropriately added.
  • 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 the present invention is in the form of a hydrochloride 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, DAR13ARIN, 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.
  • known active ingredients having degenerative brain disease prevention, treatment, or amelioration activity include, for example, decaR11 oxylase inhibitors such as carbidopa (caR11idopa), levodopa, catechol-O-methyltransferase ( Catechol-O-methyltransferase (COMT) inhibitors, dopamine agonists, monoamine oxidase B (MAO-B) inhibitors, amantadine, anticholinergics, acetylcholinesterase inhibitors, or NMDA receptor antagonists (N-methyl-D-aspartate) receptor antagonist).
  • decaR11 oxylase inhibitors such as carbidopa (caR11idopa), levodopa, catechol-O-methyltransferase ( Catechol-O-methyltransferase (COMT) inhibitors, dopamine agonists
  • 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 (calcium caR11onate), 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 a disease or disorder mediated by or related to LRRK2, comprising administering to an individual a compound of Formula 1, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof according to an aspect or a method of treatment.
  • 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 relates to 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 a method for treating and preventing a disease using the same can be used effectively.
  • LRRK2 eg, Parkinson's disease
  • LDA lithium diisopropylamide
  • THF tetrahydrofuran
  • SnBu 3 H 9.4 ml, 34.9 mmol
  • 2,4-dichloropyrimidine 4 g, 26.9 mmol
  • the cooling bath was removed and the reaction was slowly warmed to 0° C. within 30 minutes.
  • the mixture was poured into 10% NH 4 Cl at 0° C. and the aqueous layer was extracted with Et 2 O.
  • the desired compound was obtained in the same manner as in Preparation Example 1, except that 2,4-dichloro-5-methylpyrimidine was used instead of 2,4-dichloropyrimidine in Preparation Example 1.
  • step 1 The compound obtained in step 1 above (818 mg, 2.93 mmol), cyclopropyl boronic acid (500 mg, 5.82 mmol), K 3 PO 4 ( 1.85 g, 8.73 mmol) and To a suspension of tricyclohexylphosphine (81.6 mg, 0.29 mmol) was added Pd(OAc) 2 (32.8 mg, 0.15 mmol) at room temperature under N 2 . The resulting mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was filtered through celite, diluted with EtOAc, washed with water, then the combined organic layers were dried over anhydrous MgSO 4 .
  • Step 5 Synthesis of 5-cyclopropyl-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
  • step 4 To a solution of the compound obtained in step 4 above (2.61 g, 9.20 mmol) and p-toluenesulfonic acid (317 mg, 1.84 mmol) in THF, 3,4-dihydro-2H-pyran (DHP) (1.55 g, 18.4) mmol) was added at room temperature. The mixture was stirred at 80° C. for 4 h. After completion of the reaction, water was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO 4 , and the residue was concentrated under reduced pressure.
  • DHP 3,4-dihydro-2H-pyran
  • Step 6 Synthesis of 3-(4-chloropyrimidin-2-yl)-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
  • Step 4 Synthesis of 3-(4-chloropyrimidin-2-yl)-5-isopropoxy-1-tetrahydropyran-2-yl-indazole
  • Step 3 Synthesis of 3-(4-chloropyrimidin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-5-(trifluoromethyl)-1H-indazole
  • step 2 The compound obtained in step 2 (267 mg, 0.68 mmol), 4-chloro-2-(tributylstannyl)pyrimidine (357 mg, 0.88 mmol) and CuI (12.9 mg, 0.07 mmol) were mixed with anhydrous under N 2 . dissolved in DMF. The reaction mixture was degassed for 15 min and Pd(PPh 3 ) 4 (78 mg, 0.07 mmol) was added. The mixture was degassed for an additional 15 minutes. The reaction mixture was heated to 100° C. and stirred overnight. After completion of the reaction, water was poured into the reaction mixture and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous MgSO 4 .
  • Step 3 5-isopropoxy-1-tetrahydropyran-2-yl-3-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) synthesis of sol
  • Step 1 Methyl 2-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]acetate and Synthesis of methyl 2-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]acetate
  • Step 2 2-[4-(2-Chloropyrimidin-4-yl)-3-methyl-pyrazol-1-yl]acetic acid and 2-[4-(2-chloropyrimidin-4-yl)- Synthesis of 5-methyl-pyrazol-1-yl]acetic acid
  • Step 3 2-[4-[2-(5-Isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-3-methyl-pyrazole- 1-yl]acetic acid and 2-[4-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-5-methyl- Synthesis of pyrazol-1-yl]acetic acid
  • step 2 The compound obtained in step 2 (240 mg, 949.91 ⁇ mol), the compound of Preparation 6 (733.88 mg, 1.90 mmol), Pd(dppf)Cl 2 in dioxane (7 mL) and H 2 O (1 mL) After degassing a solution of CH 2 Cl 2 (77.57 mg, 94.99 ⁇ mol) and Na 2 CO 3 (201.36 mg, 1.90 mmol) and purging with N 2 3 times, the mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. did. The reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (30 mL ⁇ 2) and the organic layers were discarded.
  • Step 1 Synthesis of 2-chloro-4- (1-tetrahydropyran-2-ylpyrazol-4-yl) pyrimidine
  • Triisopropyl-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrol-1-yl]silane 1.64 g, 4.70 mmol
  • 2,4-dichloropyrimidine 700 mg, 4.70 mmol
  • Pd(dppf)Cl 2 .CH 2 Cl 2 (191.86 mg, 234.93 ⁇ mol)
  • K 3 PO 4 (1.50 g) , 7.05 mmol
  • Step 2 Synthesis of 5-isopropoxy-3-[4-(1H-pyrrol-3-yl)pyrimidin-2-yl]-1-tetrahydropyran-2-yl-indazole
  • Step 2 Synthesis of tert-butyl-dimethyl-(1-tetrahydropyran-2-ylindazol-5-yl)oxy-silane
  • step 2 To a solution of the compound obtained in step 1 above (3 g, 13.75 mmol) in DCM (50 mL) was added tert-butyldimethylsilyl chloride (4.14 g, 27.49 mmol, 3.37 mL) and imidazole (1.87 g, 27.49 mmol) did. The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was partitioned between 50 mL of dichloromethane and 50 mL of water. The organic phase was separated, washed with water (50 mL * 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was used directly in the next step without further purification.
  • Step 3 tert-Butyl-dimethyl-[1-tetrahydropyran-2-yl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Synthesis of indazol-5-yl]oxy-silane
  • Step 4 2-[1-[2-[5-[tert-Butyl(dimethyl)silyl]oxy-1-tetrahydropyran-2-yl-indazol-3-yl]pyrimidin-4-yl]pyra Synthesis of zol-4-yl]ethanol
  • Step 5 tert-Butyl-dimethyl-[1-tetrahydropyran-2-yl-3-[4-[4-(2-tetrahydropyran-2-yloxyethyl)pyrazol-1-yl]pyrimidine Synthesis of -2-yl]indazol-5-yl]oxy-silane
  • tert-butyl-dimethyl-[1-tetrahydropyran-2-yl-3-[4-[4-(2-tetrahydropyran-2-yloxyethyl)pyrazol-1-yl]pyrimidine Obtained -2-yl]indazol-5-yl]oxy-silane (1.9 g, 3.14 mmol, 86% yield) as a yellow oil.
  • Step 4 5-Nitro-1-(tetrahydro-2H-pyran-2-yl)-3-(4-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl) Synthesis of -1H-pyrazol-1-yl)pyrimidin-2-yl)-1H-indazole
  • the crude product was purified by reverse phase HPLC (column: Phenomenex luna C18 250*50mm*10 um; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 60 min) to 5-nitro-1- Tetrahydropyran-2-yl-3-[4-[4-(2-tetrahydropyran-2-yloxyethyl)pyrazol-1-yl]pyrimidin-2-yl]indazole (550 mg, 1.06 mmol, 62.01% yield) as a white solid.
  • Step 5 1-(Tetrahydro-2H-pyran-2-yl)-3-(4-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyra Synthesis of zol-1-yl)pyrimidin-2-yl)-1H-indazol-5-amine
  • Step 2 Synthesis of tert-butyl 4-(1-tetrahydropyran-2-ylindazol-5-yl)-3,6-dihydro-2H-pyridine-1-carboxylate
  • the residue was diluted with 100 mL of water and extracted with ethyl acetate (2 ⁇ 100 mL). The mixed organic layers were washed with brine (2 x 100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 100 g SepaFlash® Silica Flash column, eluent: 0-10% ethyl acetate/petroleum ether, gradient @60 mL/min).
  • Step 3 Synthesis of tert-butyl 4-(1-tetrahydropyran-2-ylindazol-5-yl)piperidine-1-carboxylate
  • Step 4 tert-Butyl 4-[1-tetrahydropyran-2-yl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Synthesis of zol-5-yl]piperidine-1-carboxylate
  • Step 5 tert-Butyl 4-[3-[4-[4-(2-hydroxyethyl)pyrazol-1-yl]pyrimidin-2-yl]-1-tetrahydropyran-2-yl-inda Synthesis of zol-5-yl]piperidine-1-carboxylate
  • the mixed organic layers were washed with brine (2 x 50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 50 g SepaFlash® Silica Flash column, eluent: 0-75% ethyl acetate/petroleum ether, gradient @ 60 mL/min).
  • Step 6 2-[1-[2-[5-(4-piperidyl)-1-tetrahydropyran-2-yl-indazol-3-yl]pyrimidin-4-yl]pyrazole-4 -synthesis of yl]ethanol
  • Step 1 Ethyl 1-(2-(5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-4-yl)-1H-pyra Synthesis of sol-4-carboxylate
  • Step 3 Synthesis of 1-(2-(5-cyclopropyl-1H-indazol-3-yl)pyrimidin-4-yl)-1H-pyrazole-4-carboxylic acid hydrochloride
  • Step 1 5-Cyclopropyl-3-(4-(4-isobutyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-1-(tetrahydro-2H-pyran-2-yl) Synthesis of -1H-indazole
  • Step 2 Synthesis of 5-cyclopropyl-3-(4-(4-isobutyl-1H-pyrazol-1-yl)pyrimidin-2-yl)-1H-indazole hydrochloride
  • Example 3 The compound of Example 3 was prepared as a brown powder in the same manner as in Example 2, except that 1H-pyrrole-3-carboxylate was used instead of 4-isobutyl-1H-pyrazole in Step 1 of Example 2 obtained.
  • 1 H NMR 400 MHz, DMSO-d 6 ); ⁇ 9.01 (brs, 1H), 8.58 (brs, 1H), 8.22 (brs, 1H), 7.99 (s, 1H), 7.91 (brs, 1H), 7.58-7.57 (brs, 1H), 7.25 (brs, 1H) ), 6.80 (s, 1H), 3.81 (s, 3H), 2.12-2.08 (m, 1H), 1.02 (m, 2H), 0.75 (m, 2H); MS m/z: 360 [M+H] + .
  • Step 1 Synthesis of 3-(4-chloro-5-methylpyrimidin-2-yl)-5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole
  • the desired compound was obtained in the same manner as in Preparation Example 3, except that the compound of Preparation Example 2 was used instead of the compound of Preparation Example 1 in step 6 of Preparation Example 3.
  • Step 2 2-(1-(2-(5-cyclopropyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-5-methylpyrimidin-4- Synthesis of yl)-1H-pyrazol-4-yl)ethan-1-ol
  • Example 1 the compound of Example 3 was obtained as a yellow solid in the same manner as in Example 1, except that the compound of Preparation Example 5 was used instead of the compound of Preparation Example 3.
  • Step 2 of Example 4 the compound of Example 6 was whitened in the same manner as in Steps 2 and 3 of Example 4, except that the compound of Preparation 5 was used instead of the compound obtained in Step 1 of Example 4 It was obtained as a powder.
  • Example 7 The compound of Example 7 was obtained as a yellow solid in the same manner as in Example 1, except that the compound of Preparation Example 4 was used instead of the compound of Preparation Example 3 in Example 1.
  • Example 8 The compound of Example 8 was obtained as a pale yellow powder in the same manner as in Example 2, except that the compound of Preparation Example 4 was used instead of the compound of Preparation Example 3 in step 1 of Example 2.
  • Step 1 2-[1-[2-(5-Isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]pyrazol-4-yl]ethanol synthesis of
  • Step 1 Synthesis of methyl 1-(2-chloropyrimidin-4-yl)pyrrole-3-carboxylate
  • Step 2 Synthesis of methyl 1-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]pyrrole-3-carboxylate
  • step 1 The compound obtained in step 1 (100 mg, 0.42 mmol), the compound of Preparation 6 (195.06 mg, 504.96 ⁇ mol), Pd(dppf)Cl 2 ( A solution of 30.79 mg, 42.08 ⁇ mol) and K 3 PO 4 (178.64 mg, 841.60 ⁇ mol) was degassed and heated to 80 °C under N 2 for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 10 mL of water and extracted with ethyl acetate (2 x 10 mL). The mixed organic layers were washed with brine (2 x 10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue.
  • Step 3 Synthesis of methyl 1-[2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]pyrrole-3-carboxylate
  • Examples 11 and 12 2-(3-methyl-4- ⁇ 2-[5-(propan-2-yloxy)-1H-indazol-3-yl]pyrimidin-4-yl ⁇ -1H-pyra zol-1-yl)ethan-1-ol (compound of Example 11) and 2-(5-methyl-4- ⁇ 2-[5-(propan-2-yloxy)-1H-indazol-3- yl]pyrimidin-4-yl ⁇ -1H-pyrazol-1-yl)ethan-1-ol (compound of Example 12)
  • Step 1 2-[4-[2-(5-Isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-3-methyl-pyrazole- 1-yl]ethanol and 2-[4-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-5-methyl- Synthesis of pyrazol-1-yl]ethanol
  • Step 2 Methyl 2-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]acetate and Synthesis of methyl 2-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]acetate
  • Examples 13 and 14 2-(3-methyl-4- ⁇ 2-[5-(propan-2-yloxy)-1H-indazol-3-yl]pyrimidin-4-yl ⁇ -1H-pyrazol-1-yl) propan-1-ol and 2-(5-methyl-4- ⁇ 2-[5-(propan-2-yloxy)-1H-indazol-3-yl]pyrimidin-4-yl ⁇ -1H-pyrazol-1-yl) propan-1-ol
  • Step 1 2-[4-[2-(5-Isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-3-methyl-pyrazole- 1-yl]propionic acid and 2-[4-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-5-methyl- Synthesis of pyrazol-1-yl]propionic acid
  • Step 2 Methyl 2-[4-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-3-methyl-pyrazole -1-yl]propionate and 2-[4-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-5 Synthesis of -methyl-pyrazol-1-yl]propionate
  • Steps 3 and 4 2-[4-[2-(5-Isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-3-methyl-pyra zol-1-yl]propan-1-ol and 2-[4-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl Synthesis of ]-5-methyl-pyrazol-1-yl]propan-1-ol
  • Example 11 and 12 the compound of Example 13 (19.90 mg, 50.49 ⁇ mol, 66.05%) was used in the same manner as in Examples 11 and 12, except that the compound obtained in Step 2 was used instead of the mixture of Preparation Example 9. yield) as a pink solid, and the compound of Example 14 (11.42 mg, 28.25 ⁇ mol, 36.96% yield) was obtained as a yellow solid.
  • the mixed organic layers were washed with brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue.
  • Step 3 1-[4-[2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-3-methyl-pyrazol-1-yl]propan-2- synthesis of on
  • the reaction mixture was concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Phenomenex C18 75*30mm*3um; mobile phase: [water(FA)-ACN];B%: 28%-58%, 7min) to obtain the desired compound as a yellow solid, SFC (Column: DAICEL CHIRALPAK IE (250mm*30mm, 10um); Mobile phase: [Neu-IPA];B%: 60%-60%, 4.5min).
  • Step 4 1-[4-[2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-3-methyl-pyrazol-1-yl]propan-2- synthesis of ol
  • Step 1 Synthesis of methyl 2-(4-bromo-3-cyano-1H-pyrazol-1-yl)propionate
  • Step 3 Synthesis of methyl 2-(4-(2-chloropyrimidin-4-yl)-3-cyano-1H-pyrazol-1-yl)propionate
  • Example 17 3-(3- ⁇ 2-[5-(propan-2-yloxy)-1H-indazol-3-yl]pyrimidin-4-yl ⁇ azetidin-1-yl)propan-1 -amine
  • Step 1 Synthesis of tert-butyl 3-(2-chloropyrimidin-4-yl)azetidine-1-carboxylate
  • Step 3 Synthesis of tert-butyl N-[3-[3-(2-chloropyrimidin-4-yl)azetidin-1-yl]propyl]carbamate
  • Step 4 tert-Butyl N-[3-[3-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]azetidine Synthesis of -1-yl]propyl]carbamate
  • Step 5 Synthesis of 3-[3-[2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]azetidin-1-yl]propan-1-amine
  • Step 1 Synthesis of tert-butyl 3-[3-(2-chloropyrimidin-4-yl)azetidin-1-yl]propionate
  • Step 3 Synthesis of 3-[3-[2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]azetidin-1-yl]propionic acid
  • Step 3 1-[1-[2-(5-Isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]imidazol-4-yl]ethanol synthesis of
  • step 3 of Example 19 using the compound obtained in Step 2 of Example 19 as a starting material
  • EtMgBr 3 M, 308.30 ⁇ L
  • MeMgBr 3 M, 308.30 ⁇ L
  • Step 1 Synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)ethanone
  • reaction mixture was quenched to 20 °C by addition of water (50 mL), diluted with EtOAc (20 mL) and extracted with EtOAc (20 mL * 2).
  • the mixed organic layers were washed with brine (30 mL * 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to 1-[4-(4,4,5,5-tetramethyl-1,3,2). Obtained -dioxaborolan-2-yl)-2-thienyl]ethanone (2 g, 7.93 mmol, 81.33% yield) as a brown oil.
  • Step 2 (5-(2-(5-isopropoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-4-yl)thiophene- 2-yl) synthesis of methanol
  • step 1 The compound obtained in step 1 (70 mg, 308.80 ⁇ mol), the compound of Preparation 6 (119.29 mg, 308.80 ⁇ mol), K 2 CO 3 (85.36 mg, 617.60 ⁇ mol), Pd (dppf) in dioxane (1 mL) )Cl 2 CH 2 Cl 2 (25.22 mg, 30.88 ⁇ mol) and a mixture of H 2 O (0.2 mL) were degassed and purged 3 times with N 2 , after which the mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. did.
  • Step 1 Synthesis of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate
  • Step 2 Synthesis of methyl 5-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]thiophene-2-carboxylate
  • Step 3 Synthesis of methyl 5-[2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]thiophene-2-carboxylate
  • Step 2 Synthesis of methyl 2-(3-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)butanoate
  • step 2 The compound obtained in step 2 (300 mg, 1.07 mmol), the compound of Preparation 6 (412.84 mg, 1.07 mmol), K 3 PO 4 (453.71 mg, 2.14 mmol), Pd (dppf) in dioxane (6 mL) After degassing a mixture of )Cl 2 (78.20 mg, 106.87 ⁇ mol) and H 2 O (1 mL) and purging with N 2 three times, the mixture was stirred at 90 °C for 12 h under a nitrogen atmosphere. The reaction mixture was quenched to 20 °C by addition of water (30 mL), diluted with EtOAc (20 mL) and extracted with EtOAc (20 mL * 2).
  • Step 5 of 2-(3-(2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-1-ol synthesis
  • Step 2 2-methyl-3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]propanamide synthesis
  • step 3 The compound obtained in step 3 (180 mg, 0.68 mmol), the compound of Preparation 6 (183.19 mg, 474.22 ⁇ mol), Pd(dppf)Cl 2 , in dioxane (4 mL) and H 2 O (1 mL)
  • a solution of CH 2 Cl 2 (55.32 mg, 67.75 ⁇ mol) and K 2 CO 3 (187.26 mg, 1.35 mmol) was degassed and heated to 80 °C under a nitrogen atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent.
  • Step 6 2-[1-[2-[5-(4-piperidyl)-1-tetrahydropyran-2-yl-indazol-3-yl]pyrimidin-4-yl]pyrazole-4 -synthesis of yl]ethanol
  • Step 7 3-[3-[2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]pyrazol-1-yl]-2-methyl-propan-1- Synthesis of amines
  • Step 4 Synthesis of 3-[3-[2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]pyrazol-1-yl]propan-1-ol
  • a crude product was obtained in the same manner as in Step 3 of Example 23, except that the compound obtained in Step 3 was used instead of the compound obtained in Step 2 of Example 23 in Step 3 of Example 23.
  • the crude product was concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water(FA)-ACN];B%: 30%-60%, 10 min). This gave the compound of Example 26 (102.24 mg, 270.17 ⁇ mol, 73.85% yield) as a white solid.
  • Step 1 Synthesis of ethyl 4-cyano-1H-pyrrole-3-carboxylate
  • Step 4 4-Cyano-1-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]pyrrole-3-carbox Synthesis of amides
  • Step 2 Synthesis of 3-(3-(2-chloropyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)propenenitrile
  • the crude product was purified by reverse phase HPLC (column: Phenomenex luna C18 150*40mm*15um; mobile phase: [water (FA)-ACN]; B%: 10%-40%, 10 min) to 3-[3-(2) -Chloropyrimidin-4-yl)-2-oxo-imidazol-1-yl]propenenitrile (300 mg, 1.20 mmol, 18.17% yield) was obtained as a yellow oil.
  • Step 3 3-(3-(2-(5-isopropoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-4-yl)- Synthesis of 2-oxo-2,3-dihydro-1H-imidazol-1-yl)propenenitrile
  • step 2 The compound obtained in step 2 (150 mg, 600.83 ⁇ mol), the compound of Preparation 6 (301.72 mg, 781.07 ⁇ mol), Pd(dppf)Cl 2 ( After degassing a mixture of 43.96 mg, 60.08 ⁇ mol) and K 3 PO 4 (191.30 mg, 901.24 ⁇ mol) and purging with N 2 three times, the mixture was stirred at 90 °C for 5 h under a nitrogen atmosphere. The reaction mixture was quenched to 20 °C by the addition of water (30 mL), diluted with EtOAc (20 mL) and extracted with EtOAc (20 mL * 2).
  • Step 4 3-(3-(2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl)-2-oxo-2,3-dihydro-1H-imidazole Synthesis of -1-yl) propenenitrile
  • Step 1 Synthesis of methyl 2-[4-(2-chloropyrimidin-4-yl)pyrazol-1-yl]propionate
  • step 1 The compound obtained in step 1 above (310 mg, 1.16 mmol), the compound of Preparation 6 (673.55 mg, 1.74 mmol), K 3 PO 4 (740.25 mg) in dioxane (8 mL) and H 2 O (2 mL) , 3.49 mmol), Pd(dppf)Cl 2 (85.06 mg, 116.24 ⁇ mol) was degassed and purged 3 times with N 2 , after which the mixture was stirred at 80 °C for 12 h under a nitrogen atmosphere. The residue was diluted with 10 mL of water and extracted with DCM (3 ⁇ 10 mL).
  • the mixed organic layers were washed with water (2 x 5 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 10 g SepaFlash® Silica Flash column, eluent: 0-70% ethyl acetate/petroleum ether, gradient @ 60 mL/min).
  • Step 4 Synthesis of 2-[4-[2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]pyrazol-1-yl]propan-1-ol
  • Step 1 Synthesis of methyl 2-[4-(2-chloropyrimidin-4-yl)pyrazol-1-yl]acetate
  • step 1 The compound obtained in step 1 (200 mg, 0.79 mmol), the compound of Preparation 6 (458.68 mg, 1.19 mmol), Pd(dppf)Cl 2 ( After degassing a mixture of 57.92 mg, 79.16 ⁇ mol) and K 3 PO 4 (504.09 mg, 2.37 mmol) and purging with N 2 three times, the mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent.
  • Step 3 1-[4-[2-(5-Isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]pyrazol-1-yl]propane Synthesis of -2-ones
  • Step 5 1-[4-[2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]pyrazol-1-yl]-2-methyl-propan-2- synthesis of ol
  • step 1 The compound obtained in step 1 above (100 mg, 0.42 mmol), the compound of Preparation 6 (194.22 mg, 502.78 ⁇ mol), K 3 PO 4 (266.81 mg) in dioxane (4 mL) and H 2 O (1 mL) , 1.26 mmol) and Pd(dppf)Cl 2 (30.66 mg, 41.90 ⁇ mol) was degassed and purged 3 times with N 2 , after which the mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent.
  • Step 3 Synthesis of 1-[4-[2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]pyrazol-1-yl]propan-2-ol
  • Step 1 Synthesis of ethyl 2-(4-iodoimidazol-1-yl)propionate
  • Step 2 Synthesis of ethyl 2-[4-(2-chloropyrimidin-4-yl)imidazol-1-yl]propionate
  • Step 3 2-[4-[2-(5-Isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]imidazol-1-yl]propionic acid synthesis of
  • Step 1 2-[3-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]pyrrol-1-yl]ethanol synthesis
  • Step 3 5-Isopropoxy-1-tetrahydropyran-2-yl-3-[4-[1-(3-tetrahydropyran-2-yloxybutyl)pyrrol-3-yl]pyrimidine-2 -synthesis of general]indazole
  • Step 4 Synthesis of 4-[3-[2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]pyrrol-1-yl]butan-2-ol
  • the mixed organic layers were washed with brine (30 mL * 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue.
  • the residue was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash column, eluent: 8-15% ethyl acetate/petroleum ether, gradient 20 mL/min) to 2-chloro-4-(1-ethoxyvinyl) Pyrimidine (5 g, 27.08 mmol, 81% yield) was obtained as a yellow solid.
  • step 4 The compound obtained in step 4 (50 mg, 211.26 ⁇ mol), the compound of Preparation 6 (97.93 mg, 253.51 ⁇ mol) in dioxane (1.5 mL), Pd(dppf)Cl 2 .CH 2 Cl 2 (17.25 mg, After degassing a mixture of 21.13 ⁇ mol), K 3 PO 4 (112.11 mg, 528.14 ⁇ mol) and H 2 O (0.3 mL) and purging 3 times with N 2 , the mixture is stirred at 90 °C for 12 h under a nitrogen atmosphere. did. To the mixed reaction mixture was added water (10 mL), and extracted with EtOAc (20 mL *3).
  • step 5 After degassing a mixture of the compound obtained in step 5 (40 mg, 86.85 ⁇ mol) in HCl (12 M, 7.24 ⁇ L) and purging with N 2 three times, the mixture was stirred at 20 °C for 1 h under a nitrogen atmosphere. did. To the reaction mixture was added water (10 mL), adjusted to pH 7-8, and extracted with EtOAc (10 mL *3). The mixed organic layers were washed with brine (40 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue.
  • Step 1 Synthesis of methyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate
  • Step 2 Synthesis of methyl 4-(2-chloropyrimidin-4-yl)-1-methyl-1H-pyrrole-2-carboxylate
  • Step 3 4-(2-(5-Isopropoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-4-yl)-1-methyl Synthesis of -1H-pyrrole-2-carboxylic acid
  • Step 4 Synthesis of 4-(2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl)-1-methyl-1H-pyrrole-2-carboxylic acid
  • Step 1 Synthesis of tert-butyl (1-((4-bromo-2-methylphenyl)amino)-1-oxopropan-2-yl)carbamate
  • Step 2 Synthesis of tert-butyl (1-((4-bromo-2-methylphenyl)amino)propan-2-yl)carbamate
  • Step 3 tert-Butyl (1-((2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)propane Synthesis of -2-yl) carbamate
  • Step 4 Synthesis of tert-butyl (1-((4-(2-chloropyrimidin-4-yl)-2-methylphenyl)amino)propan-2-yl)carbamate
  • Step 5 tert-Butyl (1-((4-(2-(5-isopropoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidine- Synthesis of 4-yl)-2-methylphenyl)amino)propan-2-yl)carbamate
  • Step 6 Synthesis of N1-(4-(2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl)-2-methylphenyl)propane-1,2-diamine
  • step 1 400 mg, 2.79 mmol
  • the compound of Preparation 6 (1.61 g, 4.18 mmol)
  • Pd(dppf)Cl 2 in dioxane (10 mL) and H 2 O (2 mL)
  • the mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. did.
  • To the mixture was added water (10 mL) and extracted with ethyl acetate (10 mL ⁇ 3).
  • Step 3 4-[[2-(5-Isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-methyl-amino]-4-oxo- synthesis of butanoic acid
  • Step 4 N′-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-N′-methyl-butanediamide synthesis
  • Step 1 Synthesis of tert-butyl (4-(2-chloropyrimidin-4-yl)benzyl)carbamate
  • Step 2 tert-Butyl (4-(2-(5-isopropoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-4-yl) Synthesis of benzyl) carbamate
  • Step 4 1-(4-(2-(5-isopropoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-4-yl)benzyl ) synthesis of urea
  • Step 1 Synthesis of methyl 2-[3-(2-chloropyrimidin-4-yl)-5-methyl-pyrazol-1-yl]acetate
  • step 2 The compound obtained in step 2 (80 mg, 0.34 mmol), the compound of Preparation 6 (142.43 mg, 368.71 ⁇ mol), Pd(dppf)Cl 2 ( A solution of 24.53 mg, 33.52 ⁇ mol) and K 2 CO 3 (92.65 mg, 670.37 ⁇ mol) was degassed and then heated to 80 °C under a nitrogen atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 10 mL of water and extracted with ethyl acetate (2 ⁇ 10 mL). The mixed organic layers were washed with brine (2 x 10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue.
  • Step 1 Synthesis of methyl 2-[3-(2-chloropyrimidin-4-yl)-5-methyl-pyrazol-1-yl]propionate
  • step 1 The compound obtained in step 1 (0.2 g, 0.71 mmol), the compound of Preparation 6 (302.75 mg, 783.73 ⁇ mol), Pd(dppf)Cl 2 ( A solution of 52.13 mg, 71.25 ⁇ mol) and K 3 PO 4 (302.48 mg, 1.42 mmol) was degassed and heated to 80 °C under a nitrogen atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 10 mL of water and extracted with ethyl acetate (2 x 10 mL). The mixed organic layers were washed with brine (2 x 10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue.
  • Step 3 2-[3-[2-(5-Isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-5-methyl-pyrazole- 1-yl] propionic acid synthesis
  • Step 4 Synthesis of 2-[3-[2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-5-methyl-pyrazol-1-yl]propionic acid
  • Step 2 1-tert-Butyl 2-methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrole-1,2-dicarboxyl synthesis of rates
  • step 1 400 mg, 1.32 mmol
  • BPD 667.96 mg, 2.63 mmol
  • dioxane 8 mL
  • KOAc 322.68 mg, 3.29 mmol
  • Pd(dppf)Cl 2 19.25 mg, 26.30 ⁇ mol
  • Pd(PPh 3 ) 2 Cl 2 18.46 mg, 26.30 ⁇ mol
  • Step 4 of methyl 4-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-1H-pyrrole-2-carboxylate synthesis
  • step 3 The compound obtained in step 3 (80 mg, 0.34 mmol), the compound of Preparation 6 (195.06 mg, 504.96 ⁇ mol), Pd(dppf)Cl 2 ( After degassing a mixture of 24.63 mg, 33.66 ⁇ mol) and K 2 CO 3 (139.58 mg, 1.01 mmol) and purging with N 2 three times, the mixture was stirred at 90 °C for 12 h under a nitrogen atmosphere. The residue was diluted with 10 mL of water and extracted with DCM (3 ⁇ 15 mL). The mixed organic layers were washed with water (2 x 15 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue.
  • Step 5 Synthesis of 4-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-1H-pyrrole-2-carboxylic acid
  • step 2 To a solution of the compound obtained in step 1 above (700 mg, 3.03 mmol) in THF (10 mL) and H 2 O (10 mL), sodium;acetate (1.24 g, 15.15 mmol) and 4-methylbenzenesulfonohydrazide (1.97 g, 10.60 mmol) was added. The mixture was stirred at 80 °C for 18 h. The reaction mixture was diluted with 10 mL of water and extracted with 20 mL of ethyl acetate (10 mL * 2).
  • Step 4 Synthesis of methyl 1-[(4-methoxyphenyl)methyl]-2-oxo-3H-imidazo[4,5-c]pyridine-6-carboxylate
  • Step 5 Methyl 3-[5-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-2-furyl]propio synthesis of nate
  • Step 6 3-[5-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-2-furyl]propanamide synthesis
  • Step 7 3-[5-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]-2-furyl]propanamide synthesis
  • But-3-yn-1-ol 3 g, 42.80 mmol, 3.24 mL) and azido(trimethyl)silane (7.40) in DMF (27 mL) and MeOH (0.75 mL) g, 64.20 mmol, 8.44 mL) was added CuI (407.59 mg, 2.14 mmol). The mixture was stirred at 95 °C for 12 h. The mixture was concentrated under reduced pressure to give a residue. The residue was used without further purification. This gave 2-(1H-thiazol-4-yl)ethanol (4 g, 35.36 mmol, 82.62% yield) as a yellow oil.
  • Step 3 2-[1-[2-(5-Isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]thiazol-4-yl]ethanol synthesis of
  • step 2 The compound obtained in step 2 (140 mg, 620.47 ⁇ mol), the compound of Preparation 6 (287.62 mg, 744.57 ⁇ mol), Pd(dppf)Cl 2 ( After degassing a mixture of 45.40 mg, 62.05 ⁇ mol) and Na 2 CO 3 (131.53 mg, 1.24 mmol) and purging with N 2 three times, the mixture was stirred at 90 °C for 3 h under a nitrogen atmosphere. The reaction mixture was washed with water (30 mL) and then extracted with ethyl acetate (30 mL ⁇ 2).
  • Step 5 1-[4-Chloro-1-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]pyrazole-3 -synthesis of yl]ethanol
  • step 4 The compound obtained in step 4 above (300 mg, 1.16 mmol) in dioxane (4 mL) and water (0.6 mL), the compound of Preparation 6 (581 mg, 1.51 mmol), [1,1'-bis(di After degassing a mixture of phenylphosphino)ferrocene]dichloropalladium (II) and a complex of dichloromethane (94 mg, 0.11 mmol) and K 2 CO 3 (480 mg, 3.47 mmol) and purging with N 2 3 times, the mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. To the mixture was added water (5 mL) and extracted with ethyl acetate (5 mL ⁇ 3).
  • Step 1 Synthesis of methyl 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
  • Step 3 Synthesis of methyl 3-hydroxy-4-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]benzoate
  • Step 4 Synthesis of 5-(hydroxymethyl)-2-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]phenol
  • Step 5 Synthesis of 3-hydroxy-4-[2-(5-isopropoxy-1-tetrahydropyran-2-yl-indazol-3-yl)pyrimidin-4-yl]benzaldehyde
  • step 4 To a solution of the compound obtained in step 4 above (260 mg, 564.57 ⁇ mol) in DCM (10 mL) was added DMP (478.92 mg, 1.13 mmol, 349.58 ⁇ L) at 0°C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue.
  • Step 8 Synthesis of 5-(1-hydroxyethyl)-2-[2-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]phenol

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Abstract

La présente invention concerne : un nouveau inhibiteur de kinase 2 à répétition riche en leucine (LRRK2) de formule 1 ; une composition pharmaceutique pour prévenir ou traiter des maladies ou des troubles médiés par LRRK2 ou associés à LRRK2, la composition pharmaceutique comprenant l'inhibiteur de LRRK2 ; et une méthode de traitement et de prévention de maladies l'utilisant. Le composé selon la présente invention a une excellente activité inhibitrice de LRRK2, et peut donc être utilisé de manière efficace dans la prévention ou le traitement de maladies ou de troubles (par exemple, la maladie de Parkinson) médiés par ou associés à LRRK2.
PCT/KR2022/005878 2021-04-26 2022-04-25 Composé indazole ayant une activité inhibitrice de lrrk2 WO2022231242A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007065010A2 (fr) * 2005-12-02 2007-06-07 Hif Bio, Inc. Composes anti-angiogenese
WO2012078777A1 (fr) * 2010-12-09 2012-06-14 Amgen Inc. Composés bicycliques en tant qu'inhibiteurs de pim
KR20150028999A (ko) * 2012-06-27 2015-03-17 에프. 호프만-라 로슈 아게 5-아자인다졸 화합물 및 이의 사용 방법
WO2017157991A1 (fr) * 2016-03-18 2017-09-21 Bayer Pharma Aktiengesellschaft 1-alkyl-pyrazoles et 1-alkyl-indazoles utilisés en tant qu'inhibiteurs de bub1 pour le traitement de maladies hyperprolifératives
WO2018234354A1 (fr) * 2017-06-20 2018-12-27 Grünenthal GmbH Nouveaux composés 3-indole et 3-indazole substitués utilisées en tant qu'inhibiteurs de phosphodiestérase

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018033082A1 (fr) * 2016-08-16 2018-02-22 Sunshine Lake Pharma Co., Ltd. Inhibiteurs de réplication du virus de la grippe, procédés d'application et utilisations associées

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007065010A2 (fr) * 2005-12-02 2007-06-07 Hif Bio, Inc. Composes anti-angiogenese
WO2012078777A1 (fr) * 2010-12-09 2012-06-14 Amgen Inc. Composés bicycliques en tant qu'inhibiteurs de pim
KR20150028999A (ko) * 2012-06-27 2015-03-17 에프. 호프만-라 로슈 아게 5-아자인다졸 화합물 및 이의 사용 방법
WO2017157991A1 (fr) * 2016-03-18 2017-09-21 Bayer Pharma Aktiengesellschaft 1-alkyl-pyrazoles et 1-alkyl-indazoles utilisés en tant qu'inhibiteurs de bub1 pour le traitement de maladies hyperprolifératives
WO2018234354A1 (fr) * 2017-06-20 2018-12-27 Grünenthal GmbH Nouveaux composés 3-indole et 3-indazole substitués utilisées en tant qu'inhibiteurs de phosphodiestérase

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