WO2024111560A1 - Ｄｄｒ１キナーゼ阻害剤としての化合物および医薬 - Google Patents

Ｄｄｒ１キナーゼ阻害剤としての化合物および医薬 Download PDF

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WO2024111560A1
WO2024111560A1 PCT/JP2023/041679 JP2023041679W WO2024111560A1 WO 2024111560 A1 WO2024111560 A1 WO 2024111560A1 JP 2023041679 W JP2023041679 W JP 2023041679W WO 2024111560 A1 WO2024111560 A1 WO 2024111560A1
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carbonyl
indazol
azetidin
ethan
trifluoromethyl
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French (fr)
Japanese (ja)
Inventor
公佑 橋本
純司 浅田
明 菅野又
洋平 本田
洋太 都築
圭司 古杉
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Nippon Shinyaku Co Ltd
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Nippon Shinyaku Co Ltd
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Priority to CN202380091730.4A priority Critical patent/CN120569374A/zh
Priority to PE2025001026A priority patent/PE20251709A1/es
Priority to EP23894566.1A priority patent/EP4624465A1/en
Priority to KR1020257020743A priority patent/KR20250109234A/ko
Priority to AU2023386923A priority patent/AU2023386923A1/en
Priority to JP2024560149A priority patent/JP7823226B2/ja
Application filed by Nippon Shinyaku Co Ltd filed Critical Nippon Shinyaku Co Ltd
Publication of WO2024111560A1 publication Critical patent/WO2024111560A1/ja
Priority to IL320735A priority patent/IL320735A/en
Priority to MX2025005556A priority patent/MX2025005556A/es
Anticipated expiration legal-status Critical
Priority to CONC2025/0006877A priority patent/CO2025006877A2/es
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    • C07—ORGANIC CHEMISTRY
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines 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
    • A61K31/495—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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
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    • A61P35/00—Antineoplastic agents
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
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    • 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
    • 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
    • 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
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • 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
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to substituted bicyclic heterocyclic compounds useful as DDR1 kinase inhibitors and pharmaceuticals containing said compounds.
  • DDR1 Discoidin Domain Receptor 1
  • DDR1 Discoidin Domain Receptor 1
  • DDR1 is a tyrosine kinase receptor that belongs to the discoidin domain receptor family and is known to be involved in cell proliferation and differentiation as well as migration, invasion, and adhesion. It is mainly expressed in epithelial cells of the lungs, kidneys, mammary glands, and digestive tract.
  • DDR1 transmits collagen signals into cells by binding to the ligand collagen through its discoidin domain.
  • DDR1 is characterized by its ability to recognize basement membrane collagens such as type IV collagen as well as fibrous collagens such as type I as ligands.
  • basement membrane collagens such as type IV collagen
  • fibrous collagens such as type I as ligands.
  • DDR1 activation is involved in various kidney diseases. DDR1 activation is involved in the pathology of various kidney diseases, including Alport syndrome (Non-Patent Documents 1 and 2), which is caused by mutations in the type IV collagen gene, IgA nephropathy (Non-Patent Document 3), Goodpasture syndrome (Non-Patent Document 4), lupus nephritis (Non-Patent Document 4), ANCA (anti-neutrophil cytoplasmic antibody)-associated nephritis (Non-Patent Document 5), and diabetic nephropathy (Non-Patent Document 6).
  • Alport syndrome Non-Patent Documents 1 and 2
  • IgA nephropathy Non-Patent Document 3
  • Goodpasture syndrome Non-Patent Document 4
  • lupus nephritis Non-Patent Document 4
  • ANCA anti-neutrophil cytoplasmic antibody-associated nephritis
  • Non-Patent Document 7 pulmonary fibrosis
  • Non-Patent Document 8 liver cirrhosis
  • Th17 cells which are involved in autoimmune diseases and allergies.
  • Th17 cells are involved in the pathogenesis of diseases such as rheumatoid arthritis, multiple sclerosis, ulcerative colitis, and Crohn's disease.
  • Non-Patent Document 10 acute myeloid leukemia
  • Non-Patent Document 11 acute lymphocytic leukemia
  • Non-Patent Document 12 chronic lymphocytic leukemia
  • Hodgkin's lymphoma Non-Patent Document 13
  • glioma Non-Patent Document 14
  • non-small cell lung cancer Non-Patent Document 15
  • breast cancer Non-Patent Document 16
  • ovarian cancer Non-Patent Document 17
  • prostate cancer Non-Patent Document 18
  • colon cancer Non-Patent Document 19
  • DDR1 has also been reported to be involved in pathological conditions such as systemic lupus erythematosus (Non-Patent Document 5), osteoarthritis (Non-Patent Document 20), heparin-induced thrombocytopenia (Non-Patent Document 21), atherosclerosis (Non-Patent Document 22), and vitiligo vulgaris (Non-Patent Document 23).
  • pathological conditions such as systemic lupus erythematosus (Non-Patent Document 5), osteoarthritis (Non-Patent Document 20), heparin-induced thrombocytopenia (Non-Patent Document 21), atherosclerosis (Non-Patent Document 22), and vitiligo vulgaris (Non-Patent Document 23).
  • DDR1 inhibitors could provide a new treatment for these DDR1-related diseases.
  • the object of the present invention is to provide a compound having DDR1 kinase inhibitory activity, or a pharma- ceutically acceptable salt thereof, or a solvate thereof.
  • the present invention includes the following aspects (Item 1) to (Item 22).
  • (Item 1) Formula (I) [Wherein, A is, (Wherein, Y 1 , Y 2 , Y 3 and Y 4 are each independently N or C-R 5 and Here, the Y 1 , Y 2 , Y 3 and Y 4 Of these, a maximum of two are N, and the rest are C-R. 5 and R 5 is hydrogen, halogen, cyano, alkoxy, or optionally substituted C 1 -C 6 is alkyl, The dashed lines indicate the attachment points.
  • R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g and R 6h Each independently is hydrogen, halogen, cyano or optionally substituted C 1 -C 6 is alkyl,
  • the dashed lines indicate the attachment points.
  • X is N or C-R 7 where R 7 is hydrogen, halogen, cyano or optionally substituted C 1 -C 6 is alkyl, R 1 are each independently hydrogen, halogen, cyano, oxo, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkoxy, hydroxy, carboxy, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C 3 -C 10 Cycloalkyl, C 3 -C 6 selected from the group consisting of cycloalkenyl, heterocycloalkyl, aryl, and heteroaryl, each of which is optionally substituted; R 2 and R 3 Each independently represents hydrogen, halogen or optionally substituted C 1 -C 6
  • the compound of formula (I) is represented by the formula (III) [Wherein, B, R 1 , R 2 , R 3 , R 4 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , Het, X, m and n are as defined in formula (I).
  • Item 2 The compound according to item 1, or a pharma- ceutically acceptable salt thereof, or a solvate thereof, which is represented by the following formula: (Item 3)
  • the compound of formula (I) is represented by the formula (III) [Wherein, B, R 1 , R 2 , R 3 , R 4 , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R
  • R 1 each independently represents hydrogen, halogen, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C 3 -C 10
  • R 1 each independently represents hydrogen, halogen, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C 3 -C 10
  • the compound is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted, or a pharma- ceutically acceptable salt or solvate thereof.
  • R 8 and R 9 each independently represents hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 10 Cycloalkyl, C 3 -C 6 is selected from the group consisting of cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, each of which is optionally substituted;
  • R 8 and R 9 together with the atoms to which they are attached form an optionally substituted 5- to 10-membered mono- or bicyclic saturated heterocycle or a 5- to 10-membered mono- or bicyclic unsaturated heterocycle; Item 5.
  • X is C-R 7 where R 7 is hydrogen, halogen, cyano or optionally substituted C 1 -C 6 Item 7.
  • R is alkyl, or a pharma- ceutically acceptable salt thereof, or a solvate thereof.
  • a DDR1 kinase inhibitor comprising the compound according to any one of Items 1 to 15, or a pharma- ceutically acceptable salt thereof, or a solvate thereof, as an active ingredient.
  • Item 18 Item 16.
  • a method for inhibiting DDR1 kinase comprising administering to a subject in need thereof the compound according to any one of Items 1 to 15, or a pharma- ceutically acceptable salt thereof, or a solvate thereof.
  • Item 19 Item 16.
  • a preventive or therapeutic agent for a disease involving DDR1 kinase comprising the compound according to any one of Items 1 to 15, or a pharma- ceutically acceptable salt thereof, or a solvate thereof.
  • Item 20 Item 16.
  • a therapeutic agent for Alport syndrome IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpura nephritis, focal segmental glomerulosclerosis, chronic renal failure, minimal change nephrotic syndrome, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, hepatic fibrosis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioma, non-small cell lung
  • a method for preventing or treating a disease involving DDR1 kinase comprising administering the compound according to any one of Items 1 to 15, or a pharma- ceutically acceptable salt thereof, or a solvate thereof to a subject in need thereof.
  • (Item 23) Item 16.
  • (Item 24) Item 12.
  • halogen refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • a fluorine atom or a chlorine atom is preferred.
  • alkyl may, for example, be a straight or branched alkyl having 1 to 8 carbon atoms (C 1 -C 8 ), preferably 1 to 6 carbon atoms (C 1 -C 6 ). Specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, isoamyl, -CH(CH 2 CH 3 ) 2 , hexyl, isohexyl, -CH 2 CH 2 C(CH 3 ) 3 , -CH 2 CH(CH 2 CH 3 ) 2 , heptyl, isoheptyl, octyl, isooctyl, and the like.
  • alkenyl includes, for example, straight-chain or branched-chain alkenyl having 2 to 8 carbon atoms (C 2 -C 8 ) and one or two double bonds. Specific examples include ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, etc. Alkenyl having 2 to 6 carbon atoms is preferred, and alkenyl having 2 to 4 carbon atoms is more preferred.
  • alkynyl includes, for example, straight-chain or branched-chain alkynyl having 2 to 8 carbon atoms (C 2 -C 8 ) and one or two triple bonds. Specific examples include ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, etc. Alkynyl having 2 to 6 carbon atoms is preferred, and alkynyl having 2 to 4 carbon atoms is more preferred.
  • alkyl portion of "alkylcarbonyl,” “monoalkylamino,” “dialkylamino,” and “aminoalkyl” used in this specification can be the same as the “alkyl” described above.
  • Haloalkyl as used herein includes, for example, groups in which one to three hydrogen atoms of the above “alkyl” are replaced by the above "halogen". Specific examples include fluoromethyl, chloromethyl, fluoroethyl, difluoromethyl, dichloromethyl, difluoroethyl (e.g., 2,2-difluoroethyl), trifluoromethyl, trichloromethyl, trifluoroethyl (e.g., 2,2,2-trifluoroethyl), etc.
  • alkoxy includes, for example, straight or branched chain alkoxy having 1 to 8 carbon atoms (C 1 -C 8 ), preferably 1 to 6 carbon atoms (C 1 -C 6 ). Specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, n-octyloxy, and the like.
  • Haloalkoxy as used herein includes, for example, the above “alkoxy” groups in which one to three hydrogen atoms have been replaced with the above "halogen". Specific examples include fluoromethoxy, chloromethoxy, fluoroethoxy, difluoromethoxy, dichloromethoxy, difluoroethoxy (e.g., 2,2-difluoroethoxy), trifluoromethoxy, trichloromethoxy, trifluoroethoxy (e.g., 2,2,2-trifluoroethoxy), etc.
  • cycloalkyl may, for example, be a monocyclic, bicyclic or tricyclic saturated hydrocarbon group having 3 to 10 carbon atoms (C 3 -C 10 ). Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, adamantyl (also called tricyclo[3.3.1.1 3,7 ]decanyl), and the like.
  • halocycloalkyl refers to, for example, the above-mentioned “cycloalkyl” in which one to three hydrogen atoms have been replaced with the above-mentioned "halogen".
  • Specific examples include 2-fluorocyclopropyl, 3,3-difluorocyclobutyl, 2,2-difluorocyclopentyl, and 4,4-difluorocyclohexyl.
  • cycloalkenyl refers to, for example, a monocyclic, bicyclic or tricyclic unsaturated hydrocarbon group having 3 to 10 carbon atoms (C 3 -C 10 ) and one or two double bonds in the molecule. Specific examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, etc.
  • heterocycloalkyl refers to a monocyclic or bicyclic saturated heterocyclic ring having 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms in the ring and 4 to 10 ring atoms.
  • Specific examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxolanyl, and tetrahydrothiophenyl.
  • aryl refers to, for example, a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group having 6 to 14 carbon atoms. Specific examples include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, and 10-phenanthryl. Phenyl is particularly preferred.
  • Heteroaryl as used herein includes, for example, monocyclic or bicyclic aromatic heterocyclic groups having 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms in the ring and 5 to 10 ring atoms.
  • Specific examples include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-5-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-2
  • oxazolyl for example, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl
  • isoxazolyl for example, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl
  • oxadiazolyl for example, 1,3,4-oxadiazol-2-yl
  • thiazolyl for example, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl
  • thiadiazolyl isoxazolyl, isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl)
  • pyridyl e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyridazinyl e.g., 3-pyridazinyl, 4-pyridazinyl
  • pyrimidinyl e.g., 2-pyrimidinyl, 4-
  • furyl e.g., 2-furyl, 3-furyl
  • imidazolyl e.g., 2-imidazolyl, 4-imidazolyl
  • thiazolyl e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl
  • pyridyl e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyridazinyl e.g., 3-pyridazinyl, 4-pyridazinyl
  • pyrimidinyl e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl
  • Carbocycle means a ring structure composed of carbon atoms, and includes the above-mentioned “cycloalkyl”, “cycloalkenyl”, and “aryl”.
  • Heterocycle means a ring structure composed of carbon atoms and one or more heteroatoms selected from, for example, nitrogen atoms, sulfur atoms, and oxygen atoms, and “heterocycle” includes the above-mentioned “heterocycloalkyl” and “heteroaryl”.
  • 3- to 8-membered saturated or unsaturated monocyclic nitrogen-containing heterocycle refers to, for example, a saturated or unsaturated monocyclic heterocycle having 1 to 4 nitrogen atoms in the ring and 3 to 8 ring atoms.
  • pyrrolyl e.g., 2-pyrrolyl, 3-pyrrolyl
  • imidazolyl e.g., 2-imidazolyl, 4-imidazolyl
  • pyrazolyl e.g., 3-pyrazolyl, 4-pyrazolyl
  • triazolyl e.g., 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2, 3-triazol-4-yl
  • tetrazolyl e.g., 5-tetrazolyl
  • pyridyl e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl
  • 1,2,3,6-tetrahydropyridyl pyridazinyl (e.g., 3-pyrid
  • the term "5- to 10-membered monocyclic or bicyclic saturated heterocycle” refers to a monocyclic or bicyclic saturated heterocycle having 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms in the ring and consisting of 5 to 10 ring atoms.
  • Specific examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxolanyl, and tetrahydrothiophenyl.
  • 5- to 10-membered monocyclic or bicyclic unsaturated heterocycle refers to a monocyclic or bicyclic aromatic heterocycle or non-aromatic unsaturated heterocycle that has 1 to 4 heteroatoms selected from, for example, nitrogen atoms, sulfur atoms, and oxygen atoms in the ring and is composed of 5 to 10 constituent atoms.
  • furyl e.g., 2-furyl, 3-furyl
  • thienyl e.g., 2-thienyl, 3-thienyl
  • pyrrolyl e.g., 2-pyrrolyl, 3-pyrrolyl
  • imidazolyl e.g., 2-imidazolyl, 4-imidazolyl
  • pyrazolyl e.g., 3-pyrazolyl, 4-pyrazolyl
  • triazolyl e.g., 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3-triazol-4-yl
  • tetrazolyl e.g., 5-tetrazolyl
  • oxazolyl e.g., 2-oxazolyl, 4-oxazolyl
  • aryl 5-oxazolyl
  • isoxazolyl e.g., 3-isoxazolyl, 4-isoxazolyl, 5-is
  • the aryl group is furyl (e.g., 2-furyl, 3-furyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), benzimidazolyl (e.g., 2-benzimidazolyl, 4-benzimidazo
  • Cyano refers to the group represented by -CN.
  • Hydrox refers to the group represented by -OH.
  • Optionally substituted means that the specified group may or may not be substituted, i.e., substituted or unsubstituted.
  • optionally substituted alkyl refers to both unsubstituted and substituted alkyl.
  • substituents substituting the specified group include alkyl, haloalkyl, alkoxy, cycloalkyl, halocycloalkyl, heterocycloalkyl, halogen, cyano, oxo, hydroxy, amino, aryl, or heteroaryl, as defined above, and combinations thereof (e.g., alkyl, alkoxy, cycloalkyl, heterocycloalkyl, amino, aryl, or heteroaryl, substituted with at least one substituent selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, halogen, cyano, oxo, hydroxy, amino, aryl, and heteroaryl).
  • the number of substituents substituting a specified group is, for example, 1 to 3, preferably 1 or 2, and more preferably 1.
  • A is preferably (Wherein, Y 1 , Y 2 , Y 3 and Y 4 are each independently N or C—R 5 ; wherein at most one of Y 1 , Y 2 , Y 3 and Y 4 is N, and the rest are C—R 5 ; R 5 is hydrogen, halogen (e.g., fluorine atom, chlorine atom), alkoxy (e.g., methoxy), or optionally substituted C 1 -C 6 alkyl (e.g., methyl);
  • the dashed lines indicate the attachment points.
  • R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g and R 6h are each independently hydrogen, halogen (e.g., fluorine atom), or optionally substituted C 1 -C 6 alkyl (e.g., methyl);
  • the dashed lines indicate the attachment points. It is.
  • A is more preferably (Wherein, Y 1 , Y 2 , Y 3 and Y 4 are C-R 5 ; R5 is hydrogen; The dashed lines indicate the attachment points. It is.
  • B is preferably an optionally substituted 4-6 membered saturated or unsaturated monocyclic nitrogen-containing heterocycle, more preferably azetidinyl, piperidinyl or 1,2,3,6-tetrahydropyridyl, optionally substituted with C 1 -C 6 alkyl (e.g., methyl), particularly preferably azetidinyl.
  • X is preferably N or C—R 7 , where said R 7 is preferably hydrogen, more preferably N.
  • R 1 is preferably independently selected from the group consisting of hydrogen, halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C 3 -C 10 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted.
  • R 1 is more preferably independently selected from the group consisting of hydrogen, halogen (e.g., fluorine atom, chlorine atom), oxo, C 1 -C 6 alkyl (e.g., methyl), amino or monoalkylamino (e.g., methylamino, ethylamino), where amino may be substituted by cycloalkyl (e.g., cyclopropyl, cyclobutyl, 1-methylcyclopropyl) or heterocycloalkyl (e.g., oxetanyl, tetrahydropyranyl), and C 1 -C 6 alkyl may be substituted by 1 to 3 halogen (e.g., fluorine atom). More preferably, each R 1 is independently hydrogen, halogen (eg, a fluorine atom) or amino.
  • halogen e.g., fluorine atom, chlorine atom
  • oxo C 1 -C 6 alky
  • R2 and R3 are preferably each independently hydrogen or halogen (eg, a fluorine atom).
  • R4 is preferably selected from the group consisting of hydrogen, halogen, cyano, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C1 - C6 alkoxy, hydroxy, carboxy, alkylcarbonyloxy, amino, monoalkylamino, dialkylamino, aminoalkyl, alkylcarbonylamino, C3 - C10 cycloalkyl, C3 - C6 cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted.
  • R 4 is more preferably selected from the group consisting of C 2 -C 6 alkynyl (e.g.
  • ethynyl carboxy, monocyclic or bicyclic saturated carbocycles (e.g. cyclohexyl), monocyclic or bicyclic unsaturated carbocycles (e.g. phenyl, 2,3-dihydro-1H-indenyl), monocyclic or bicyclic saturated heterocycles (e.g. azetidinyl) and monocyclic or bicyclic unsaturated heterocycles (e.g.
  • C2 - C6 alkynyl is optionally substituted with C3 - C10 cycloalkyl (e.g., cyclopropyl) or aryl (e.g., phenyl);
  • carboxy is optionally substituted with C 1 -C 6 alkyl (e.g., tert-butyl);
  • the monocyclic or bicyclic saturated carbocyclic ring may be substituted with a halogen (e.g., a fluorine atom);
  • the monocyclic or bicyclic unsaturated carbocyclic ring is optionally substituted with haloalkyl (e.g., trifluoromethyl);
  • the monocyclic or bicyclic saturated heterocycles may be substituted with aryl (e.g., phenyl) or haloalkyl (e
  • R 4 is preferably -CONR 8 R 9 ; wherein each of R 8 and R 9 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, each of which may be optionally substituted; or R 8 and R 9 together with the atoms to which they are attached form an optionally substituted 5-10 membered mono- or bicyclic saturated heterocycle or a 5-10 membered mono- or bicyclic unsaturated heterocycle; It is something.
  • each of R 8 and R 9 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocycloalkyl, and heteroaryl, each of which is optionally substituted;
  • C 1 -C 6 alkyl is, for example, methyl, ethyl, isopropyl, tert-butyl, and may be substituted with substituents selected from the following group: (i) halogen (e.g., fluorine atom); (ii) C 1 -C 6 alkoxy (e.g., methoxy); (iii) haloalkoxy (e.g., trifluoromethoxy), (iv) heterocycloalkyl (e.g., tetrahydropyranyl, morpholinyl).
  • halogen e.g., fluorine atom
  • C 1 -C 6 alkoxy e.g., methoxy
  • halocycloalkyl e.g., 3,3-difluorocyclobutyl
  • aryl e.g., phenyl
  • C3 - C6 cycloalkyl is in particular cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted by halogen (e.g., fluorine atom), cyano
  • Heterocycloalkyl is, for example, oxetanyl, tetrahydropyranyl, which may be substituted with
  • Heteroaryl is, for example, pyrazolyl, which may be substituted with a halogen (for example, a fluorine atom).
  • R 8 and R 9 preferably together with the atom to which they are attached form an optionally substituted 5- to 10-membered monocyclic or bicyclic saturated heterocycle or a 5- to 10-membered monocyclic or bicyclic unsaturated heterocycle;
  • the 5- to 10-membered monocyclic or bicyclic saturated heterocycle is, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azabicyclo[3.1.0]hexanyl, azaspiro[3.4]octanyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, azabicyclo[3.2.1]octanyl, optionally substituted with a substituent selected from the group consisting of: (i) Halogen (e.g., fluorine atom, bromine atom) (ii) C 1 -C 6 alkyl (e.g., methyl, ethyl, isoprop
  • Halogen e
  • R4 is -CONR8R9 , where R8 and R9 together with the atoms to which they are attached form a 5-membered monocyclic saturated heterocycle (e.g., pyrrolidinyl) substituted with haloalkyl (e.g., trifluoromethyl).
  • a 5-membered monocyclic saturated heterocycle e.g., pyrrolidinyl
  • haloalkyl e.g., trifluoromethyl
  • n is preferably an integer from 0 to 2, and more preferably an integer of 2.
  • n is preferably an integer from 0 to 1, and more preferably an integer of 1.
  • Het is preferably a 5- to 10-membered monocyclic or bicyclic unsaturated heterocycle, more preferably pyridyl, pyrimidinyl, 1,3-thiazolyl, pyridazinyl, 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrrolo[2,3-b]pyridyl, 1,3-thiazolyl, imidazo[1,2-a]pyridyl, pyrazolo[3,2-b][1,3]thiazolyl, 1,3-oxazolyl, 1H-indazolyl, pyrazolyl, or 1H-1,2,3-benzotriazolyl, and even more preferably pyridyl.
  • the compounds of the present invention can be produced using known compounds or intermediates that can be easily synthesized from known compounds, for example, according to the methods described below, the Examples described below, or known methods.
  • the compounds of the present invention if the raw materials have substituents that affect the reaction, it is common to first protect the raw materials with an appropriate protecting group by a known method before carrying out the reaction.
  • the protecting group can be deprotected by a known method after the reaction.
  • TFA trifluoroacetic acid AZADOL®: 2-azaadamantane-N-hydroxyl Pd-C: palladium-on-carbon PdCl 2 (PPh 3 ) 2 : bis(triphenylphosphine)palladium(II) dichloride Pd(OAc) 2 : palladium(II) acetate Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 : [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct
  • Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
  • BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Boc: tert-butoxycarbonyl
  • Step 1 This step is a step of reacting a commercially available compound A-1 or a compound synthesized by a known method with a commercially available compound B-1 or a compound synthesized by a known method in the presence of lithium diisopropylamide (LDA) in a solvent such as THF or diethyl ether at ⁇ 78° C. to 0° C., preferably ⁇ 78° C. to ⁇ 60° C., more preferably ⁇ 78° C., for 30 minutes to 12 hours, preferably 30 minutes to 6 hours, more preferably 30 minutes to 3 hours, to obtain a compound C-1.
  • LDA may be commercially available or may be prepared from diisopropylamine and n-butyllithium (n-BuLi).
  • Step 2 This step is a reaction for oxidizing the hydroxyl group of compound C-1 to obtain D-1.
  • 2-azaadamantane-N-oxyl AZADOL registered trademark
  • 2,2,6,6-tetramethylpiperidine-1-oxyl radical TEMPO
  • Dess-Martin reagent or the like
  • the reaction is carried out in a solvent such as dichloromethane or dichloroethane at 0° C. to room temperature for 30 minutes to 24 hours, preferably 30 minutes to 6 hours, and more preferably 30 minutes to 3 hours, to synthesize D-1.
  • iodobenzene diacetate, sodium hypochlorite (NaOCl), or the like is usually used as a co-oxidant.
  • Step 3 is a step of reacting compound D-1 with hydrazine monohydrate in a solvent such as dioxane or THF at room temperature to reflux temperature, preferably dioxane, at 100° C. for 1 to 48 hours, preferably 8 to 24 hours, to obtain compound Ea-1.
  • a solvent such as dioxane or THF
  • Step 4 is a step of alkylating compound Ea-1 with alkylating agent F-1 in the presence of a base to obtain compound G-1, which can be carried out in accordance with a method known as an alkylation reaction.
  • the reaction can be carried out by reacting compound Ea-1 with alkylating agent F-1 in the presence of a base such as sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, etc. in a solvent such as dimethylformamide or tetrahydrofuran at 0°C to 120°C, preferably room temperature to 120°C, for 1 hour to 48 hours, preferably 1 hour to 12 hours.
  • a base such as sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, etc.
  • a solvent such as dimethylformamide or tetrahydrofuran
  • C-1 and D-1 can also be produced by the following method.
  • Y1 , Y2 , Y3 , Y4 , B and PG1 are the same as defined above.
  • X2 represents Br or I.
  • This step is a step of reacting a commercially available compound A-2 or a compound synthesized by a known method with B-1 in the presence of butyllithium (n-BuLi) in a solvent such as THF or diethyl ether at ⁇ 78° C. to 0° C., preferably ⁇ 78° C. to ⁇ 60° C., more preferably ⁇ 78° C., for 30 minutes to 12 hours, preferably 30 minutes to 6 hours, more preferably 30 minutes to 3 hours, to obtain a compound C-1.
  • a solvent such as THF or diethyl ether
  • This step is a step of reacting a commercially available compound A-1 or a compound synthesized by a known method with a commercially available compound B-2 or a compound synthesized by a known method in the presence of butyllithium (n-BuLi) in a solvent such as THF or diethyl ether at ⁇ 78° C. to 0° C., preferably ⁇ 78° C. to 60° C., more preferably ⁇ 78° C., for 30 minutes to 12 hours, preferably 30 minutes to 6 hours, more preferably 30 minutes to 3 hours, to obtain a compound D-1.
  • a solvent such as THF or diethyl ether
  • Step 1 This step is a step in which compound H-1, which is commercially available or has been synthesized by a known method, is halogenated to obtain J-1.
  • the halogenation can be carried out by a reaction usually used for halogenating aromatic rings.
  • Compound H-1 can be reacted with chlorine, bromine, iodine, N-chlorosuccinimide (NCS), or N-bromosuccinimide (NBS) in a solvent such as dichloromethane, dichloroethane, carbon tetrachloride, or DMF at 0° C. to room temperature for 30 minutes to 48 hours, preferably 1 hour to 12 hours, to obtain compound J-1.
  • NCS N-chlorosuccinimide
  • N-bromosuccinimide N-bromosuccinimide
  • Step 2 This step is a step in which compound J-1 is alkylated using alkylating agent F-1 in the presence of a base to obtain compound K-1.
  • K-1 can be obtained by carrying out the reaction under the same conditions as in Step 4 in the synthesis of compound (G-1) above.
  • Step 3 This step is a step of obtaining compound G-2 by Negishi coupling reaction between compound K-1 and L-1.
  • a palladium catalyst such as tetrakistriphenylphosphine palladium (hereinafter referred to as "Pd(PPh 3 ) 4 "), palladium(II) acetate (hereinafter referred to as “Pd(OAc) 2 "), bis(triphenylphosphine)palladium(II) dichloride (hereinafter referred to as “Pd(PPh 3 ) 2 Cl 2 " ), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)-dichloromethane adduct (hereinafter referred to as "Pd(dppf) 2 Cl 2 "), and L-1, which is commercially available or synthesized by a known method, are added to compound K-1 in a solvent such as dioxane, tolu
  • Step 1 This step is a step of deprotecting the protecting group of compound G-2 to obtain M-1, and can be introduced with reference to Wuts and Greene, “Greene's Protective Groups in Organic Synthesis", 4th Edition, John Wiley & Sons Inc., 2006, or P. J. Kocienski, "Protecting Groups", 3rd Edition, Thiemes, 2005.
  • Step 2 is a step of obtaining compound (I) by condensing compound M-1 with compound N-1 or a reactive compound N-1 thereof in the presence of a condensing agent.
  • a solvent such as compound M-1, compound N-1, an organic base such as TEA, DIPEA, N,N-dimethylaniline, or DBU, toluene, xylene, 1,4-dioxane, THF, DME, DMF, DMA, dichloromethane, or dichloroethane, 1,1'-carbonyldiimidazole (hereinafter referred to as "CDI”), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (hereinafter referred to as "EDCI”), diisopropylcarbodiimide (hereinafter referred to as "DIC”), diethyl cyanophosphonate, O-(benzotriazol-1-yl)-N,N,
  • examples of the reactive compound for compound N-1 include those typically used in amide condensation reactions, such as acid halides (e.g., acid chlorides, acid bromides), mixed acid anhydrides, imidazolides, and activated amides.
  • acid halides e.g., acid chlorides, acid bromides
  • mixed acid anhydrides e.g., imidazolides
  • activated amides e.g., activated amides.
  • additives such as 1-hydroxybenzotriazole (hereinafter referred to as "HOBt”), N-hydroxysuccinimide, and 1-hydroxy-7-azabenzotriazole (hereinafter referred to as "HOAt”) can be added as necessary.
  • Step 1 This step is a step of deprotecting the protecting group of compound G-2 to obtain M-2, and the synthesis can be performed with reference to "Greene's Protective Groups in Organic Synthesis” by Wuts and Greene, 4th Edition, John Wiley & Sons Inc., 2006, or "Protecting Groups” by P. J. Kocienski, 3rd Edition, Thiemes, 2005.
  • Step 2 This step is a step of obtaining compound O-2 by condensing compound M-2 with compound N-1 or a reactive compound thereof in the presence of a condensing agent, and can be synthesized by a method similar to that of Step 2 in the synthesis of compound (I) described above.
  • Step 3 This step is a step of deprotecting the protecting group (PG 2 ) of compound O-2 to obtain P-2, and the compound can be synthesized with reference to "Greene's Protective Groups in Organic Synthesis” by Wuts and Greene, 4th Edition, John Wiley & Sons Inc., 2006, or "Protecting Groups” by P. J. Kocienski, 3rd Edition, Thiemes, 2005.
  • Step 4 is a step of obtaining compound I-2 by condensing compound Q-1 with compound P-2 or a reactive compound thereof in the presence of a condensing agent, and can be synthesized by the same method as in Step 2 in the synthesis of compound (I) above.
  • compound I-2 can also be obtained by switching the order of Step 1-Step 2 and Step 3-Step 4. That is, the carboxylic acid obtained by deprotecting (hydrolyzing) R A of G-2 is condensed with Q-1. Then, the amine obtained by deprotecting PG1 is condensed with N-1 to synthesize I-2.
  • the compounds of the present invention can be used as they are as medicines, but can also be used in the form of pharma- ceutically acceptable salts, solvates, or solvates of salts by known methods.
  • pharma-ceutically acceptable salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; salts of organic acids such as acetic acid, malic acid, lactic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid; and salts of organic bases such as salts of alkali metals such as lithium, potassium, and sodium; salts of alkaline earth metals such as magnesium and calcium; and ammonium salts. These salts can be formed by conventional methods.
  • the free base of the compound of the present invention can be obtained by dissolving it in hydrochloric acid, an alcoholic solution of hydrogen chloride, an ethyl acetate solution of hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, a cyclopentyl methyl ether solution of hydrogen chloride, or a diethyl ether solution of hydrogen chloride.
  • the compounds of the present invention may become solvates by incorporating solvent molecules when left in the air or by recrystallization, and such solvates are also included in the compounds of the present invention.
  • solvates include solvates with solvent molecules such as methanol solvates, ethanol solvates, isopropyl alcohol solvates, butanol solvates, dimethyl sulfoxide solvates, and acetonitrile solvates, as well as monohydrates and dihydrates.
  • Stereoisomers can be produced, for example, by optically resolving a racemate using an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) by known methods, taking advantage of its basicity, or by using a pre-prepared optically active compound as a raw material.
  • stereoisomers can also be produced by optical resolution using a chiral column or asymmetric synthesis.
  • the compound of the present invention has DDR1 kinase inhibitory activity, as shown in the test examples described below.
  • one embodiment of the present invention provides a DDR1 kinase inhibitor containing the compound of the present invention.
  • a method for inhibiting DDR1 kinase comprising administering a compound of the present invention to a subject in need thereof.
  • the compound of the present invention is provided for use in inhibiting DDR1 kinase.
  • one embodiment of the present invention provides the use of a compound of the present invention in the manufacture of a DDR1 kinase inhibitor.
  • a preventive or therapeutic agent for a disease involving DDR1 kinase is provided, which contains the compound of the present invention.
  • a method for preventing or treating a disease involving DDR1 kinase comprising administering the compound of the present invention to a subject in need thereof.
  • the compound of the present invention is provided for use in the prevention or treatment of a disease involving DDR1 kinase.
  • one embodiment of the present invention provides the use of the compound of the present invention in the manufacture of a preventive or therapeutic agent for a disease involving DDR1 kinase.
  • Diseases to which the compound of the present invention can be applied include, for example, Alport syndrome, IgA nephropathy, Goodpasture syndrome, anti-glomerular basement membrane nephritis, lupus nephritis, ANCA-associated nephritis, diabetic nephropathy, purpura nephritis, focal segmental glomerulosclerosis, chronic renal failure, minimal change nephrotic syndrome, mesangial proliferative glomerulonephritis, membranous proliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, pulmonary fibrosis, myelofibrosis, hepatic fibrosis, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymph
  • one embodiment of the present invention provides a preventive or therapeutic agent for the above-mentioned diseases, which contains the compound of the present invention.
  • the compound of the present invention is provided for use in the prevention or treatment of the above diseases.
  • one embodiment of the present invention provides the use of the compound of the present invention in the manufacture of a preventive or therapeutic agent for the above-mentioned diseases.
  • Subject refers to a human or non-human animal having or suspected of having a disease in which DDR1 is involved or a disease in which DDR1 is involved. In one embodiment of the invention, the subject is a mammal. In one embodiment of the invention, the subject is a human.
  • the compound of the present invention can be used as it is or mixed with a pharmacologically acceptable carrier or the like to prepare a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%, and can be used as a therapeutic agent for the above-mentioned various diseases in mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, and monkeys.
  • the carrier may be one or more conventional solid, semi-solid, or liquid diluents, fillers, and other formulation auxiliaries that are pharma- ceutical acceptable.
  • the pharmaceutical composition of the present invention is preferably administered in a dosage unit form.
  • the pharmaceutical composition may be administered intra-tissue, orally, intravenously, topically (transdermally, ophthalmically, intraperitoneally, intrathoracically, etc.), or rectally.
  • the pharmaceutical composition of the present invention is administered in a dosage form suitable for these administration methods.
  • the dosage as a medicine should be adjusted taking into consideration the patient's condition such as age, body weight, type and severity of disease, route of administration, type of compound of the present invention, whether it is a salt, type of salt, etc., but normally, the amount of active ingredient of the compound of the present invention or a pharma- ceutical acceptable salt thereof for an adult is within the range of 0.01 mg to 5 g per adult, preferably 1 mg to 500 mg per adult, when administered orally. In some cases, a lower dose may be sufficient, or conversely, a higher dose may be required. Usually, it is administered once a day or in several divided doses, or when administered intravenously, it can be administered rapidly or continuously within 24 hours.
  • the compounds of the present invention may be used alone or in combination with additional therapeutic agents, such as angiotensin converting enzyme inhibitors (ACE inhibitors) or angiotensin II A T1 receptor blockers (ARBs).
  • ACE inhibitors include candesartan, losartan, valsartan, olmesartan, azilsartan, irbesartan, and telmisartan.
  • ARBs include candesartan, losartan, valsartan, olmesartan, azilsartan, irbesartan, and telmisartan.
  • ACE inhibitors include ramipril, lisinopril, enalapril, imidapril, and trandolapril.
  • One or more hydrogen, carbon and/or other atoms of the compounds of the present invention may be replaced with isotopes of hydrogen, carbon and/or other atoms, respectively.
  • isotopes include 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, 123I and 36Cl, i.e., hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, respectively.
  • Compounds substituted with such isotopes are also useful as pharmaceuticals, and include all radiolabeled forms of the compounds of the present invention.
  • the compounds of the present invention can be produced from known compounds themselves or from intermediates that can be easily prepared from known compounds, for example, by the methods described below, the examples described below, or known methods.
  • the solvents, reagents, and raw materials used in each step in the manufacturing methods described below are commercially available, the commercially available products can be used as they are.
  • the compounds obtained in each step in the manufacturing methods described below and the raw materials used may form salts, and can be converted into other types of salts or free forms by known methods.
  • the compounds obtained in each step in the manufacturing methods described below and the raw materials used are in free forms, they can be converted into the desired salt by known methods. Examples of such salts include the same salts as those used in the compounds of the present invention described above.
  • a protecting group may be introduced to the substituent in advance by a known method, and the target compound can be obtained by removing the protecting group after the reaction as necessary.
  • protecting groups include those shown in Wuts and Greene, “Greene's Protective Groups in Organic Synthesis", 4th Edition, John Wiley & Sons Inc., 2006, or P.J. Kocienski, "Protecting Groups", 3rd Edition, Thieme, 2005, and the like, which may be appropriately selected depending on the reaction conditions.
  • the compounds obtained in each step of the manufacturing methods below can be isolated or purified in the usual manner using methods such as solvent extraction, concentration, distillation, sublimation, recrystallization, reprecipitation, and chromatography, or can be used in the next step in the form of a reaction mixture or crude product.
  • MS was measured by LCMS.
  • ESI was used as the ionization method.
  • the observed mass spectrometry values are expressed as m/z.
  • an Initiator 60 (Biotage) was used. It can achieve temperatures of 40-250°C and pressures of up to 20 bar.
  • the conditions for measuring the optical rotation are as follows.
  • Analytical equipment Automatic polarimeter SEPA-500 (manufactured by Horiba, Ltd.)
  • the r and s (lower case) in the compound names indicate the stereochemistry of the pseudo-asymmetric carbon atom according to IUPAC rules.
  • Step 2 Preparation of intermediate RE-1B To a mixture of intermediate RE-1A (3.23 g) and dichloromethane (48 mL), iodobenzene diacetate (3.74 g) and AZADOL (registered trademark) (74 mg) were added in that order, and the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (3.09 g). MS (m/z): 332.5 [M+H] +
  • Step 4 Preparation of intermediate RE-1D To a mixture of intermediate RE-1C (1.47 g) and DMF (23 mL), cesium carbonate (1.76 g) and ethyl 2-bromoacetate (0.600 mL) were added in this order under ice bath, and the mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.76 g). MS (m/z): 412.3 [M+H] +
  • Step 5 Preparation of intermediate RE-1E To a mixture of intermediate RE-1D (1.75 g), methanol (8.5 mL), and THF (8.5 mL), 2M aqueous sodium hydroxide solution (10.6 mL) was added at room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, diluted with water, and acidified with 2M hydrochloric acid in an ice bath. The precipitate was collected by filtration to obtain the title compound (1.56 g). MS (m/z): 382.4 [M-H] -
  • Step 2 Preparation of intermediate RE-2B
  • the title compound (9.49 g) was obtained by a method similar to that in Step 2 of Reference Example 1, except that Intermediate RE-2A (9.74 g) was used instead of Intermediate RE-1A.
  • Step 3 Preparation of intermediate RE-2C
  • the title compound (8.25 g) was obtained by a method similar to that of Step 3 of Reference Example 1, except that intermediate RE-2B (9.49 g) was used instead of intermediate RE-1B.
  • Step 4 Preparation of intermediate RE-2D
  • the title compound (6.2 g) was obtained by a method similar to that of Step 4 of Reference Example 1, except that intermediate RE-2C (5.0 g) was used instead of intermediate RE-1C.
  • Step 5 Preparation of intermediate RE-2E The title compound (1.89 g) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-2D (2.23 g) was used instead of intermediate RE-1D. MS (m/z): 366.4 [M ⁇ H] ⁇
  • Step 6 Preparation of intermediate RE-2F
  • the title compound (1.32 g) was obtained by a method similar to that of Step 6 of Reference Example 1, using Intermediate RE-2E (1.04 g) instead of Intermediate RE-1E and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (596 mg) instead of 2,2,2-trifluoroethanamine hydrochloride.
  • Step 7 Preparation of Compound RE-2
  • the title compound (117 mg) was obtained by a method similar to Step 7 of Reference Example 1, except that intermediate RE-2F (125 mg) was used instead of intermediate RE-1F.
  • Step 2 Preparation of intermediate RE-4B A reaction vessel containing zinc (3.62 g) was heated under reduced pressure using a heat gun for 3 minutes and argon was substituted. After returning to room temperature, DMA (40 mL) was added, and after degassing with argon, 1,2-dibromoethane (0.341 mL) and chloro(trimethyl)silane (0.602 mL) were added and stirred at room temperature for 15 minutes. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (11.2 g) in DMA (40 mL) was added dropwise using a dropping funnel.
  • Step 3 Preparation of intermediate RE-4C
  • the title compound (4.99 g) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-4B (5.08 g) was used instead of intermediate RE-1D.
  • Step 4 Preparation of intermediate RE-4D HBTU (206 mg) was added to a mixture of intermediate RE-4C (150 mg), DMF (1.5 mL), DIPEA (0.235 mL), and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (95 mg), and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (200 mg). MS (m/z): 353.1 [M-Boc+2H] +
  • Step 2 Preparation of intermediate RE-5B A mixture of intermediate RE-5A (1.21 g), 1,4-dioxane (39 mL), and hydrazine monohydrate (0.940 mL) was stirred at 100° C. for 2 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (635 mg). MS (m/z): 208.0 [M-Boc+2H] +
  • Step 3 Preparation of intermediate RE-5C
  • the title compound (246 mg) was obtained by a method similar to that of Step 1 of Reference Example 4, using intermediate RE-5B (200 mg) instead of 3-iodo-2H-indazole.
  • Step 4 Preparation of intermediate RE-5D
  • the title compound (184 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-5C (246 mg) was used instead of intermediate RE-1D.
  • Step 5 Preparation of intermediate RE-5E To a mixture of intermediate RE-5D (100 mg), acetonitrile (2 mL), 1-hydroxybenzotriazole monohydrate (50 mg), NMM (0.090 mL), and 2,2,2-trifluoro-N-methylethanamine hydrochloride (49 mg), EDCI.HCl (63 mg) was added and stirred at room temperature for 2 hours. Saturated sodium bicarbonate water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (123 mg). MS (m/z): 483.2 [M+Na] +
  • Step 2 Preparation of intermediate RE-6B A reaction vessel containing zinc (481 mg) was heated under reduced pressure using a heat gun for 5 minutes and argon was substituted. After returning to room temperature, DMA (5.25 mL) was added, and after degassing with argon, 1,2-dibromoethane (0.045 mL) and chloro(trimethyl)silane (0.080 mL) were added and stirred at room temperature for 15 minutes. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (1.49 g) in DMA (5.25 mL) was added dropwise to this mixture using a dropping funnel.
  • Step 4 Preparation of intermediate RE-6D EDCI.HCl (231 mg) was added to a mixture of intermediate RE-6C (350 mg), acetonitrile (3 mL), 1-hydroxybenzotriazole monohydrate (184 mg), NMM (0.330 mL), and 2,2,2-trifluoro-N-methylethanamine hydrochloride (180 mg), and the mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the product was purified by silica gel column chromatography to obtain the title compound (318 mg). MS (m/z): 467.3 [M+Na] +
  • Step 2 Preparation of intermediate RE-7B A mixture of intermediate RE-7A (620 mg), DMA (7 mL), hydrazine monohydrate (1.03 mL), and potassium carbonate (438 mg) was reacted in a microwave reaction apparatus at 150° C. for 3 hours. After cooling, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
  • Step 3 Preparation of intermediate RE-7C
  • the title compound (466 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-7B (629 mg) was used instead of intermediate RE-1D.
  • Step 4 Preparation of intermediate RE-7D To a mixture of intermediate RE-7C (100 mg), DMF (1.0 mL), DIPEA (0.150 mL), and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (61 mg), HBTU (132 mg) was added and stirred overnight at room temperature. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The reaction solution was purified by silica gel column chromatography to obtain the title compound (108 mg). MS (m/z): 489.4 [M+Na] +
  • Reference Example 8 2-[3-(azetidin-3-yl)-1H-indazol-1-yl]-1-(3,3-dimethylmorpholin-4-yl)ethan-1-one trifluoroacetate (compound RE-8) [Step 1] Preparation of intermediate RE-8A The title compound (100 mg) was obtained by a method similar to that of Step 4 of Reference Example 7, using intermediate RE-4C (100 mg) instead of intermediate RE-7C and 3,3-dimethylmorpholine (45 mg) instead of (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride. MS (m/z): 329.2 [M-Boc+2H] +
  • Step 2 Preparation of intermediate RE-10B
  • the title compound (3.48 g) was obtained by a method similar to that in Step 2 of Reference Example 1, except that Intermediate RE-10A (3.98 g) was used instead of Intermediate RE-1A.
  • Step 3 Preparation of intermediate RE-10C
  • the title compound (3.31 g) was obtained by a method similar to that of Step 3 of Reference Example 1, except that intermediate RE-10B (3.48 g) was used instead of intermediate RE-1B.
  • Step 4 Preparation of intermediate RE-10D To a mixture of intermediate RE-10C (50 mg) and acetonitrile (0.5 mL), cesium carbonate (77 mg) and 2-(bromomethyl)-5-(trifluoromethyl)pyridine (56 mg) were added in that order, and the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (34 mg). MS (m/z): 379.1 [M-Boc+2H] +
  • Step 2 Preparation of intermediate RE-11B 10% Pd-C (21 mg) was added to intermediate RE-11A (500 mg), methanol (53 mL), and ammonium formate (1.30 g), and the mixture was stirred at 80° C. overnight. Insoluble matter was filtered off using Celite (registered trademark), and the residue was concentrated under reduced pressure to obtain the title compound (400 mg). MS (m/z): 219.2 [M-Boc+2H] +
  • Step 3 Preparation of intermediate RE-11C
  • the title compound (450 mg) was obtained by a method similar to that of Step 4 of Reference Example 1, using intermediate RE-11B (480 mg) instead of intermediate RE-1C.
  • Step 4 Preparation of intermediate RE-11D
  • the title compound (350 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-11C (450 mg) was used instead of intermediate RE-1D.
  • Step 5 Preparation of intermediate RE-11E A mixture of intermediate RE-11D (100 mg), DMF (0.5 mL), DIPEA (0.138 mL), and HATU (121 mg) was stirred at room temperature for 15 minutes. (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (56 mg) was added thereto and stirred at room temperature for 1 hour. The reaction solution was purified by silica gel column chromatography to obtain the title compound (120 mg). MS (m/z): 398.2 [M-Boc+2H] +
  • Step 6 Preparation of Compound RE-11 The title compound (85 mg) was obtained by a method similar to that of Step 7 of Reference Example 1, except that intermediate RE-11E (120 mg) was used instead of intermediate RE-1F. MS (m/z): 398.2 [M+H] +
  • Step 2 Preparation of intermediate RE-12B To a mixture of intermediate RE-12A (920 mg) and dichloromethane (6.4 mL), triethylsilane (3.82 mL) was added in an ice bath, and then trifluoroacetic acid (0.811 mL) was slowly added, followed by stirring for 10 minutes in an ice bath. Saturated aqueous sodium bicarbonate was added to the reaction solution, which was extracted with dichloromethane and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by silica gel column chromatography to obtain the title compound (370 mg). MS (m/z): 271.4 [M-H] -
  • Step 3 Preparation of intermediate RE-12C
  • the title compound (400 mg) was obtained by a method similar to that of Step 4 of Reference Example 1, except that intermediate RE-12B (370 mg) was used instead of intermediate RE-1C.
  • Step 4 Preparation of intermediate RE-12D To a mixture of intermediate RE-12C (400 mg), methanol (10 mL), and THF (10 mL), 2M aqueous sodium hydroxide solution (2.79 mL) was added at room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water, and acidified with 2M hydrochloric acid in an ice bath. The solvent was removed under reduced pressure, and the product was purified by silica gel column chromatography to obtain the title compound (350 mg). MS (m/z): 329.1 [M-H] -
  • Step 5 Preparation of compound RE-12
  • the title compound (50 mg) was obtained by a method similar to that of Step 5 of Reference Example 11, except that intermediate RE-12D (50 mg) was used instead of intermediate RE-11D.
  • Step 2 Preparation of intermediate RE-13B To a mixture of intermediate RE-13A (608 mg) and dichloromethane (10 mL), iodobenzene diacetate (793 mg) and AZADOL (registered trademark) (16 mg) were added in that order, and the mixture was stirred at room temperature for 2 hours. AZADOL (registered trademark) (16 mg) was added, and the mixture was further stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (542 mg). MS (m/z): 295.1 [M+H] +
  • Step 4 Preparation of intermediate RE-13D The title compound (359 mg) was obtained by a method similar to that of Step 4 of Reference Example 1, except that intermediate RE-13C (290 mg) was used instead of intermediate RE-1C. MS (m/z): 375.1 [M+H] +
  • Step 5 Preparation of intermediate RE-13E The title compound (187 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-13D (359 mg) was used instead of intermediate RE-1D. MS (m/z): 347.1 [M+H] +
  • Step 6 Preparation of compound RE-13 The title compound (100 mg) was obtained by a method similar to that of Step 5 of Reference Example 11, except that intermediate RE-13E (90 mg) was used instead of intermediate RE-11D. MS (m/z): 468.3 [M+H] +
  • Step 2 Preparation of intermediate RE-14B
  • the title compound (1.47 g) was obtained by a method similar to that in Step 2 of Reference Example 1, except that Intermediate RE-14A (1.62 g) was used instead of Intermediate RE-1A.
  • Step 3 Preparation of intermediate RE-14C A mixture of intermediate RE-14B (1.37 g), 1,4-dioxane (28 mL), and hydrazine monohydrate (0.65 mL) was stirred at 100° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.79 g). MS (m/z): 309.1 [M+H] +
  • Step 4 Preparation of intermediate RE-14D
  • the title compound (1.04 g) was obtained by a method similar to that of Step 4 of Reference Example 1, except that intermediate RE-14C (0.79 g) was used instead of intermediate RE-1C.
  • Step 5 Preparation of intermediate RE-14E 5% Pd-C (100 mg) was added to intermediate RE-14D (300 mg), ethyl acetate (7.6 mL), and triethylamine (0.21 mL), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere (0.1 MPa). Insoluble matter was removed by filtration through Celite (registered trademark), and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound (249 mg). MS (m/z): 361.2 [M+H] +
  • Step 7 Preparation of intermediate RE-14G The title compound (92 mg) was obtained by a method similar to that of Step 5 of Reference Example 11, except that intermediate RE-14F (100 mg) was used instead of intermediate RE-11D. MS (m/z): 454.3 [M+H] +
  • Step 8 Preparation of Compound RE-14 A brown oil was obtained by a method similar to Reference Example 3, using intermediate RE-14G (92 mg) instead of intermediate RE-2F. 39 mg of the oil was purified by silica gel column chromatography to obtain the title compound (30 mg). MS (m/z): 354.1 [M+H] +
  • Step 2 Preparation of intermediate RE-15B
  • the title compound (4.64 g) was obtained by a method similar to that in Step 2 of Reference Example 1, except that Intermediate RE-15A (4.86 g) was used instead of Intermediate RE-1A.
  • Step 4 Preparation of intermediate RE-15D
  • the title compound (1.22 g) was obtained by a method similar to that of Step 4 of Reference Example 10, using Intermediate RE-15C (1.0 g) instead of Intermediate RE-10C, and 2-chloroacetonitrile (0.323 mL) instead of 2-(bromomethyl)-5-(trifluoromethyl)pyridine.
  • Step 5 Preparation of intermediate RE-15E Hydroxylamine hydrochloride (0.48 g) and a solution of intermediate RE-15D (1.22 g) in ethanol (11.4 mL) were added to a solution of potassium carbonate (0.95 g) in water (3.1 mL), and the mixture was stirred at room temperature for 3 hours. After the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue to suspend it, and the mixture was filtered through Celite (registered trademark) to remove insoluble matter. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.72 g). MS (m/z): 365.1 [M+H] +
  • Step 6 Preparation of intermediate RE-15F HATU (41 mg) was added to a mixture of intermediate RE-15E (39 mg), 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (15 mg), DIPEA (0.019 mL), and DMF (0.3 mL), and the mixture was stirred at room temperature overnight. Then, the mixture was stirred at 120° C. for 2 hours. After cooling, the reaction solution was purified by silica gel column chromatography to obtain the title compound (27 mg). MS (m/z): 483.2 [M+H] +
  • Step 2 Preparation of intermediate RE-16B The title compound (241 mg) was obtained by a method similar to that of Step 2 of Reference Example 1, except that intermediate RE-16A (0.57 g) was used instead of intermediate RE-1A. MS (m/z): 195.0 [M-Boc+2H] +
  • Step 3 Preparation of intermediate RE-16C
  • the title compound (148 mg) was obtained by a method similar to that of Step 3 of Reference Example 1, except that intermediate RE-16B (241 mg) was used instead of intermediate RE-1B.
  • Step 4 Preparation of intermediate RE-16D The title compound (166 mg) was obtained by a method similar to that of Step 4 of Reference Example 1, except that intermediate RE-16C (148 mg) was used instead of intermediate RE-1C. MS (m/z): 375.1 [M+H] +
  • Step 5 Preparation of intermediate RE-16E The title compound (139 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, using intermediate RE-16D (166 mg) instead of intermediate RE-1D. MS (m/z): 347.1 [M+H] +
  • Step 2 Preparation of intermediate RE-17B A mixture of intermediate RE-17A (5.15 g), NMP (50 mL), and hydrazine monohydrate (8.99 mL) was stirred at 150° C. for 2 days. After cooling, water was added to the reaction solution, and the mixture was extracted with ethyl acetate/n-hexane (1/1). The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (4.39 g). MS (m/z): 274.1 [M+H] +
  • Step 2 Preparation of intermediate RE-18B The title compound (2.39 g) was obtained by a method similar to that of Step 2 of Reference Example 1, except that intermediate RE-18A (2.72 g) was used instead of intermediate RE-1A. MS (m/z): 298.0 [M+H] +
  • Step 3 Preparation of intermediate RE-18C
  • the title compound (2.15 g) was obtained by a method similar to that of Step 3 of Reference Example 1, except that intermediate RE-18B (2.39 g) was used instead of intermediate RE-1B.
  • Step 4 Preparation of intermediate RE-18D Potassium carbonate (726 mg) and propargyl bromide (0.332 mL) were added in sequence to a mixture of intermediate RE-18C (1.02 g) and DMF (12 mL), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.01 g). MS (m/z): 230.1 [M-Boc+2H] +
  • Step 5 Preparation of Compound RE-18 Sodium azide (84.7 mg) was added to a mixture of (3,3-difluorocyclobutyl)methyl 4-methylbenzenesulfonate (for example, synthesized according to the method described in WO2014205234) (300 mg) and DMF (3 mL), and the mixture was stirred overnight at 120° C. to prepare a DMF solution of 3-(azidomethyl)-1,1-difluorocyclobutane (about 0.36 mol/L).
  • Step 2 Preparation of intermediate RE-20B The title compound (476 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-20A (638 mg) was used instead of intermediate RE-1D. MS (m/z): 348.4 [M ⁇ H] ⁇
  • Step 3 Preparation of intermediate RE-20C
  • the title compound (81 mg) was obtained by a method similar to that of Step 5 of Reference Example 5, except that intermediate RE-20B (64 mg) was used instead of intermediate RE-5D.
  • Step 2 Preparation of intermediate RE-21B
  • the title compound (0.39 g) was obtained by a method similar to that of Step 2 of Reference Example 4, except that the intermediate RE-21A (2.14 g) obtained in Step 1 of Reference Example 21 was used instead of the intermediate RE-4A.
  • Step 3 Preparation of intermediate RE-21C
  • the title compound (34 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-21B (0.39 g) was used instead of intermediate RE-1D.
  • Step 4 Preparation of intermediate RE-21D
  • the title compound (16 mg) was obtained by a method similar to that of Step 5 of Reference Example 11, except that intermediate RE-21C (34 mg) was used instead of intermediate RE-11D.
  • Step 2 Preparation of intermediate RE-22B Hydrazine monohydrate (0.487 mL) was added dropwise to a mixture of intermediate RE-22A (1.35 g) and methanol (8.3 mL), and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.65 g). MS (m/z): 159.1 [M+H] +
  • Step 3 Preparation of intermediate RE-22C Potassium hydroxide (0.92 g) and iodine (2.1 g) were added in this order to a mixture of intermediate RE-22B (0.65 g) and DMF (8.2 mL) in an ice bath, and the mixture was stirred overnight at room temperature. A saturated aqueous solution of sodium thiosulfate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (468 mg). MS (m/z): 284.8 [M+H] +
  • Step 4 Preparation of intermediate RE-22D The procedure of Step 1 of Reference Example 4 was repeated, except that intermediate RE-22C (468 mg) was used instead of 3-iodo-2H-indazole, to give the title compound and a mixture (582 mg) of about 24% regioisomers. MS (m/z): 356.8 [M+H] +
  • Step 5 Preparation of intermediate RE-22E The title compound (360 mg) was obtained by a method similar to that of Step 2 of Reference Example 4, using intermediate RE-22D (582 mg) instead of intermediate RE-4A. MS (m/z): 408.3 [M+Na] +
  • Step 6 Preparation of intermediate RE-22F The title compound (103 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-22E (360 mg) was used instead of intermediate RE-1D. MS (m/z): 370.2 [M ⁇ H] ⁇
  • Step 7 Preparation of intermediate RE-22G The title compound (60 mg) was obtained by a method similar to that of Step 5 of Reference Example 11, except that intermediate RE-22F (50 mg) was used instead of intermediate RE-11D. MS (m/z): 515.3 [M+Na] +
  • Step 2 Preparation of Compound RE-23 Potassium hydroxide (970 mg) was added to a mixture of intermediate RE-23A (550 mg), ethanol (2 mL), and water (2 mL), and the mixture was stirred at 80° C. overnight. The solvent was removed under reduced pressure, and 2M hydrochloric acid was added to the residue to adjust the pH to 7-8. The precipitate was collected by filtration to obtain the title compound (313 mg). MS (m/z): 179.1 [M+H] +
  • Step 2 Preparation of intermediate RE-25B The title compound (4.02 g) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-25A (4.07 g) was used instead of intermediate RE-1D. MS (m/z): 273.0 [M+H] +
  • Step 3 Preparation of Compound RE-25 A mixture of intermediate RE-25B (1.64 g) and trifluoroacetic acid (20 mL) was stirred at 70° C. overnight. The mixture was concentrated under reduced pressure, and the residue was slurry washed with ethyl acetate to obtain the title compound (1.25 g). MS (m/z): 153.0 [M+H] +
  • Step 2 Preparation of intermediate RE-26B
  • a solution of sodium periodate (3.41 g) in water (24 mL) and potassium permanganate (252 mg) were added at room temperature. Thereafter, potassium permanganate (252 mg) was added three times every two hours, and the mixture was stirred for another two hours.
  • Saturated sodium bicarbonate water was added to the reaction solution, which was then diluted with ethyl acetate and filtered through Celite (registered trademark) to remove insoluble matter.
  • the mother liquor was extracted with ethyl acetate.
  • the organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain the title compound (400 mg).
  • Step 3 Preparation of Compound RE-26
  • the title compound (140 mg) was obtained by a method similar to that of Step 5 of Reference Example 1, except that intermediate RE-26B (400 mg) was used instead of intermediate RE-1D.
  • Step 2 Preparation of Compound RE-28 Potassium hydroxide (0.2 g) was added to a mixture of intermediate RE-28A (110 mg), ethanol (2 mL), and water (2 mL), and the mixture was allowed to react overnight at 80° C. The solvent was removed under reduced pressure, and the residue was adjusted to pH 7-8 with 2M hydrochloric acid. The resulting precipitate was collected by filtration and washed with water. The mixture was dried to obtain the title compound (63 mg).
  • 1 H-NMR 400 MHz, DMSO-d6) ⁇ 8.12 (d, 1H), 7.10 (s, 1H), 7.03 (s, 1H), 6.92 (dd, 1H), 1.32 (s, 3H), 0.65 (d, 4H)
  • Step 1 Preparation of intermediate RE-30A The title compound was obtained by a method similar to that of Step 1 of Reference Example 1, except that 1-chloro-3-fluorobenzene was used instead of 2-chloro-1,4-difluorobenzene. MS (m/z): 316.1 [M+H] +
  • Step 2 Preparation of intermediate RE-30B To a mixture of intermediate RE-30A (600 mg) and dichloromethane (19 mL), sodium hydrogen carbonate (479 mg) and 1,1-triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3-(1H)-one (1.21 g) were added under ice-cooling, and the mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
  • Step 3 Preparation of intermediate RE-30 Compound RE-30 was synthesized starting from intermediate RE-30B according to a procedure similar to that described in steps 3 to 7 of Reference Example 1 for the preparation of compound RE-1. MS (m/z): 347.0 [M+H] +
  • Step 1 Preparation of intermediate RE-31A A mixture of intermediate RE-1B (1.34 g), ethanol (10 mL), and hydrazine monohydrate (3.94 mL) was reacted in a microwave reaction apparatus at 140° C. for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (218 mg). MS (m/z): 310.5 [M+H] +
  • Step 2 Preparation of intermediate RE-31B To a mixture of intermediate RE-31A (218 mg) and DMF (3.5 mL), cesium carbonate (276 mg) and propyl 2-bromoacetate (153 mg) were added in this order under ice bath, and the mixture was stirred at room temperature. A saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (238 mg).
  • Step 3 Preparation of Compound RE-31
  • Compound RE-31 was synthesized starting from intermediate RE-31A according to a procedure similar to that described in Steps 5 to 7 of Reference Example 1 for the preparation of compound RE-1.
  • Step 1 Preparation of intermediate RE-32A The title compound was obtained by a method similar to that of Step 1 of Reference Example 1, except that 2-bromo-1,3-difluorobenzene was used instead of 2-chloro-1,4-difluorobenzene.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ 7.12-7.02 (m, 2H), 5.38 (t, 1H), 4.19-4.10 (m, 1H), 4.06-3.98 (m, 1H), 3.87-3.80 (m, 1H), 3.65-3.60 (m, 1H), 3.30-3.18 (m, 1H), 2.59-2.51 (m, 1H), 1.44 (s, 9H).
  • Step 2 Preparation of intermediate RE-32B
  • the title compound was obtained by a method similar to that of Step 2 of Reference Example 30, using Intermediate RE-32A instead of Intermediate RE-30A.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ 7.22-7.16 (m, 1H), 7.14-7.09 (m, 1H), 4.37-4.30 (m, 2H), 4.10 (t, 2H), 3.97-3.88 (m, 1H), 1.45 (s, 9H).
  • Step 3 Preparation of intermediate RE-32C
  • Intermediate RE-32C was synthesized starting from intermediate RE-32B following a procedure similar to that described in steps 1 to 2 of Reference Example 31 for the preparation of intermediate RE-31B.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ 7.22-7.16 (m, 2H), 5.10 (s, 2H), 4.37-4.30 (m, 4H), 4.15-4.11 (m, 3H), 1.70-1.61 (m, 2H), 1.45 (s, 9H), 0.89 (t, 3H).
  • Step 4 Preparation of Compound RE-32
  • Compound RE-32 was synthesized starting from intermediate RE-32C according to the procedure similar to that described in Steps 5 to 7 of Reference Example 1 for the preparation of compound RE-1.
  • Step 2 Preparation of Compound RE-33 To a mixture of intermediate RE-33A (98 mg), methanol (1 mL), and THF (1 mL), 2M aqueous sodium hydroxide solution (1 mL) was added at room temperature, and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure, diluted with water, and then 2M hydrochloric acid was added under ice bath to make the mixture acidic. Saturated sodium bicarbonate water was added to make the mixture neutral, and the solvent was concentrated.
  • Step 1 Preparation of intermediate RE-34A To a mixture of 3-fluoropyridine (674 mg) and THF (9 mL), lithium diisopropylamide (1.08 M n-hexane/tetrahydrofuran solution, 6.4 mL) was added dropwise at ⁇ 78° C. After stirring at ⁇ 78° C. for 1 hour, a solution of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (1.13 g) (for example, synthesized according to the method described in WO20129649) in THF (9 mL) was added dropwise, and the mixture was stirred at ⁇ 78° C. for 2 hours.
  • tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate (1.13 g) (for example, synthesized according to the method described in WO20129649) in THF (9 mL) was added drop
  • Step 2 Preparation of intermediate RE-34B The title compound was obtained by a method similar to that of Step 1 of Reference Example 31, except that Intermediate RE-34A was used instead of Intermediate RE-1B. MS (m/z): 275.1 [M+H] +
  • Step 3 Preparation of Compound RE-34
  • Compound RE-34 was synthesized starting from intermediate RE-34B according to a procedure similar to that described in Steps 1 to 2 of Reference Example 33 for the preparation of compound RE-33.
  • Step 1 Preparation of intermediate RE-35A The title compound was obtained by a method similar to that of Step 1 of Reference Example 34, except that 2-chloro-5-fluoropyridine was used instead of 3-fluoropyridine.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ 8.43 (d, 1H), 7.76 (d, 1H), 4.22-4.15 (m, 4H), 4.08-3.95 (m, 1H), 1.44 (s, 9H).
  • Step 2 Preparation of intermediate RE-35B The title compound was obtained by a method similar to that of Step 1 of Reference Example 31, except that Intermediate RE-35A was used instead of Intermediate RE-1B. MS (m/z): 309.1 [M+H] +
  • Step 2 Preparation of intermediate RE-36B
  • Intermediate RE-36B was synthesized starting from intermediate RE-36A according to a procedure similar to that described in steps 4 to 5 of Reference Example 1 for the preparation of intermediate RE-1E.
  • Step 1 Preparation of intermediate RE-37A The title compound was obtained by a method similar to that of Step 1 of Reference Example 5, except that 2-bromo-1-fluoro-4-methylbenzene was used instead of 2-bromo-4-chloro-1-fluorobenzene. MS (m/z): 294.0 [M+H] +
  • Step 2 Preparation of intermediate RE-37B A mixture of intermediate RE-37A (1.87 g), 1,4-dioxane (64 mL), and hydrazine monohydrate (1.55 mL) was stirred at 100° C. for 3 days. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain tert-butyl 3-(5-methyl-1H-indazol-3-yl)azetidine-1-carboxylate.
  • tert-butyl 3-[1-(2-ethoxy-2-oxoethyl)-5-methyl-1H-indazol-3-yl]azetidine-1-carboxylate To a mixture of the obtained tert-butyl 3-[1-(2-ethoxy-2-oxoethyl)-5-methyl-1H-indazol-3-yl]azetidine-1-carboxylate (467 mg), methanol (2 mL), and THF (2 mL), 2M aqueous sodium hydroxide solution (1.9 mL) was added at room temperature and stirred overnight.
  • Step 3 Preparation of intermediate RE-37C
  • the title compound was obtained by a method similar to that of Step 4 of Reference Example 4, except that intermediate RE-37B was used instead of intermediate RE-4C.
  • Step 4 Preparation of Compound RE-37 Trifluoroacetic acid (1 mL) was added to a mixture of intermediate RE-37C (171 mg) and dichloromethane (4 mL) and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and toluene was added to the residue and removed under reduced pressure. Then, ethyl acetate and hexane were added, and the solvent was removed under reduced pressure to obtain the title compound (145 mg). MS (m/z): 367.2 [M+H] +
  • Step 1 Preparation of intermediate RE-38A The title compound was obtained by a method similar to that of Step 1 of Reference Example 5, except that 1,4-difluoro-2-iodobenzene was used instead of 2-bromo-4-chloro-1-fluorobenzene. MS (m/z): 298.1 [M+H] +
  • Step 2 Preparation of intermediate RE-38B The title compound was obtained by a method similar to that of Step 3 of Reference Example 1, except that Intermediate RE-38A was used instead of Intermediate RE-1B. MS (m/z): 290.1 [M ⁇ H] ⁇
  • Step 3 Preparation of intermediate RE-38C
  • cesium carbonate (236 mg) and methyl bromoacetate (111 mg) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour.
  • Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (183 mg).
  • Step 4 Preparation of intermediate RE-38D
  • the title compound was obtained by a method similar to that of Step 5 of Reference Example 1, except that Intermediate RE-38C was used instead of Intermediate RE-1D.
  • Step 5 Preparation of intermediate RE-38E The title compound was obtained by a method similar to that of Step 6 of Reference Example 1, using Intermediate RE-38D instead of Intermediate RE-1E and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride instead of 2,2,2-trifluoroethanamine hydrochloride. MS (m/z): 471.3 [M+H] +
  • Step 1 Preparation of intermediate RE-39A A mixture of 1-benzyloxycarbonylazetidine-3-carboxylic acid (120 mg), di(pyridin-2-yl)carbonate (100 mg), DMAP (6 mg), and dichloromethane (1.2 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (94 mg). MS (m/z): 313.1 [M+H] +
  • Step 2 Preparation of intermediate RE-39B A mixture of intermediate RE-39A (630 mg), (2-fluorophenyl)boronic acid (560 mg), triphenylphosphine (160 mg), and 1,4-dioxane (6.7 mL) was degassed, and then Pd(OAc) 2 (45 mg) was added and the mixture was stirred overnight at 50° C. under an argon atmosphere. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (207 mg). MS (m/z): 314.0 [M+H] +
  • Step 4 Preparation of intermediate RE-39D To a mixture of intermediate RE-39C (1.00 g) and DMF (11 mL), cesium carbonate (1.27 g) and tert-butyl 2-bromoacetate (762 mg) were added under ice cooling, and the mixture was stirred for 30 minutes. Then, the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (875 mg). MS (m/z): 444.2 [M+Na] +
  • Step 5 Preparation of Compound RE-39 To a mixture of intermediate RE-39D (875 mg) and methanol (21 mL), 5% Pd—C (440 mg) was added and the mixture was stirred overnight at room temperature under a hydrogen atmosphere (0.1 MPa). Insoluble matter was removed by filtration through Celite (registered trademark), and the filtrate was concentrated under reduced pressure to obtain the title compound (473 mg). MS (m/z): 288.2 [M+H] +
  • Step 1 Preparation of intermediate RE-40A To a mixture of 3-bromo-1H-indazole (2 g) and DMF (34 mL), cesium carbonate (1.27 g) and methyl bromoacetate (1.86 g) were added under ice cooling, and the mixture was stirred for 30 minutes. Then, the mixture was stirred at room temperature for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
  • Step 2 Preparation of intermediate RE-40B A mixture of intermediate RE-40A (200 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (345 mg), sodium carbonate (236 mg), Pd(dppf)Cl 2 ⁇ CH 2 Cl 2 (91 mg), 1,4-dioxane (1.5 mL), and water (0.5 mL) was degassed and then stirred overnight at 95°C under an argon atmosphere. Insoluble matter was removed by filtration through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (255 mg). MS (m/z): 356.3 [M-H] -
  • Step 3 Preparation of Compound RE-40 HBTU (162 mg) was added to a mixture of intermediate RE-40B (127 mg), DMF (1.2 mL), DIPEA (0.184 mL), and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (75 mg), and the mixture was stirred at room temperature for 4 hours.
  • the reaction solution was purified by silica gel column chromatography to obtain the title compound (105 mg). MS (m/z): 479.3 [M+H] +
  • Step 1 Preparation of intermediate RE-42A The title compound was obtained by a method similar to that of Step 6 of Reference Example 1, using Intermediate RE-38D instead of Intermediate RE-1E and 2,2,2-trifluoro-N-methylethanamine hydrochloride instead of 2,2,2-trifluoro-N-methylethanamine hydrochloride. MS (m/z): 467.2 [M+Na] +
  • Step 1 Preparation of intermediate RE-43A To a mixture of 5,6-difluoro-1H-indazole (513 mg), potassium hydroxide (374 mg), and DMF (1.3 mL), iodine (1.01 g) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium thiosulfate was added to the reaction solution, and the resulting precipitate was collected by filtration and washed with water. The mixture was dried to obtain the title compound (899 mg). MS (m/z): 281.0 [M+H] +
  • Step 2 Preparation of intermediate RE-43B
  • Intermediate RE-43B was synthesized starting from intermediate RE-43A according to a procedure similar to that described in steps 1 to 3 of Reference Example 6 for the preparation of compound RE-6C.
  • Step 3 Preparation of intermediate RE-43C
  • the title compound was obtained by a method similar to that of Step 6 of Reference Example 1, using Intermediate RE-43B instead of Intermediate RE-1E and 2,2,2-trifluoro-N-methylethanamine hydrochloride instead of 2,2,2-trifluoroethanamine hydrochloride.
  • Step 4 Preparation of Compound RE-43
  • the title compound was obtained by a method similar to that of Step 4 of Reference Example 37, except that Intermediate RE-43C was used instead of Intermediate RE-37C.
  • Step 1 Preparation of intermediate RE-45A To a mixture of 1-(tert-butyl) 3-methyl 3-hydroxyazetidine-1,3-dicarboxylate (1.0 g) and DMF (14 mL), 60% sodium hydride (260 mg) was added under ice cooling and stirred for 50 minutes. Then, benzyl bromide (1.10 g) was added and stirred at room temperature for 5 hours. Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
  • Step 2 Preparation of intermediate RE-45B To a mixture of intermediate RE-45A (1.07 g), methanol (8 mL), and THF (8 mL), 2M aqueous sodium hydroxide solution was added and stirred at room temperature. The solvent was evaporated under reduced pressure, neutralized with 2M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with hexane and dried to obtain the title compound (866 mg). MS (m/z): 306.1 [M-H] -
  • Step 4 Preparation of intermediate RE-45D
  • the title compound was obtained by a method similar to that of Step 1 of Reference Example 5, except that 1-fluoro-2-iodobenzene was used instead of 2-bromo-4-chloro-1-fluorobenzene and intermediate RE-45C was used instead of tert-butyl 3-[methoxy(methyl)carbamoyl]azetidine-1-carboxylate.
  • Step 5 Preparation of intermediate RE-45E A mixture of intermediate RE-45D (785 mg), hydrazine monohydrate (0.99 mL), potassium carbonate (844 mg), and DMA (15 mL) was reacted in a microwave reaction apparatus at 100° C. for 1 hour. Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate.
  • Step 6 Preparation of intermediate RE-45F To a mixture of intermediate RE-45E (709 mg) and THF (20 mL), 5% Pd-C (600 mg) was added and the mixture was stirred under a hydrogen atmosphere (0.3 MPa) at 40° C. for 6 hours. After stirring at 50° C. for 11 hours, insoluble matter was removed by filtration through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (425 mg). MS (m/z): 384.2 [M+Na] +
  • Step 7 Preparation of intermediate RE-45G The title compound was obtained by a method similar to that of Step 5 of Reference Example 1, except that Intermediate RE-45F was used instead of Intermediate RE-1D. MS (m/z): 346.1 [M ⁇ H] ⁇
  • Step 8 Preparation of intermediate RE-45H EDCI.HCl (132 mg) was added to a mixture of intermediate RE-45G (159 mg), (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (121 mg), HOBt (93 mg), DIPEA (0.24 mL), and DMF (0.3 mL), and the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (193 mg). MS (m/z): 491.3 [M+Na] +
  • Step 9 Preparation of Compound RE-45
  • the title compound was obtained by a method similar to that of Step 4 of Reference Example 37, except that intermediate RE-45H was used instead of intermediate RE-37C.
  • Step 1 Preparation of intermediate RE-47A The title compound was obtained by a method similar to that of Step 6 of Reference Example 1, using Intermediate RE-37B instead of Intermediate RE-1E and 2,2,2-trifluoro-N-methylethanamine hydrochloride instead of 2,2,2-trifluoroethanamine hydrochloride. MS (m/z): 463.3 [M+Na] +
  • Step 1 Preparation of intermediate RE-48A
  • Intermediate RE-48A was synthesized starting from 3-iodo-5-methoxy-1H-indazole according to a procedure similar to that described in steps 1 to 3 of Reference Example 6 for the preparation of intermediate RE-6C.
  • Step 2 Preparation of Compound RE-48 The title compound was obtained by a method similar to Step 6 of Reference Example 1, using Intermediate RE-48A instead of Intermediate RE-1E and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride instead of 2,2,2-trifluoroethanamine hydrochloride.
  • Step 1 Preparation of intermediate RE-49A
  • Intermediate RE-49A was synthesized starting from 3-iodo-5,5-dimethyl-1,4,6,7-tetrahydroindazole (for example, synthesized according to the method described in Journal of Medicinal Chemistry 2013, 56(4), 1677-1692) according to a procedure similar to that described in steps 1 to 3 of Reference Example 6 for the preparation of intermediate RE-6C.
  • Step 2 Preparation of intermediate RE-49B The title compound was obtained by a method similar to that of Step 6 of Reference Example 1, using Intermediate RE-49A instead of Intermediate RE-1E and (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride instead of 2,2,2-trifluoroethanamine hydrochloride. MS (m/z): 485.4 [M+H] +
  • Step 3 Preparation of Compound RE-49 The title compound was obtained by a method similar to that of Step 4 of Reference Example 37, except that Intermediate RE-49B was used instead of Intermediate RE-37C. MS (m/z): 385.4 [M+H] +
  • Reference Example 50 2-[3-(azetidin-3-yl)-4-chloro-5-fluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (compound RE-50)
  • compound RE-50 2-[3-(azetidin-3-yl)-4-chloro-5-fluoro-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one trifluoroacetate (compound RE-50)
  • DIPEA 0.3 mL
  • reaction solution was purified by silica gel column chromatography to obtain tert-butyl 3-(4-chloro-5-fluoro-1- ⁇ 2-oxo-2-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl ⁇ -1H-indazol-3-yl)azetidine-1-carboxylate (250 mg).
  • Step 1 Preparation of intermediate RE-51A The title compound was obtained by a method similar to that of Step 6 of Reference Example 1, except that 2,2,2-trifluoro-N-methylethanamine hydrochloride was used instead of 2,2,2-trifluoroethanamine hydrochloride. MS (m/z): 501.2 [M+Na] +
  • Step 2 Preparation of Compound RE-51
  • the title compound was obtained by a method similar to that of Step 4 of Reference Example 37, except that Intermediate RE-51A was used instead of Intermediate RE-37C.
  • Step 1 Preparation of intermediate RE-58A A mixture of intermediate RE-2C (300 mg), benzyl 3-(p-toluenesulfonyloxymethyl)azetidine-1-carboxylate (437 mg), cesium carbonate (474 mg), and DMF (3.9 mL) was stirred at room temperature for 4 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous sodium sulfate.
  • Step 2 Preparation of Compound RE-58 A mixture of intermediate RE-58A (30 mg), bromobenzene (15 mg), Pd(OAc) 2 (2 mg), Xantphos (9 mg), cesium carbonate (52 mg), and 1,4-dioxane (0.3 mL) was stirred at 90° C. for 3 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (6 mg). MS (m/z): 455.3 [M+H] +
  • Step 1 Preparation of intermediate RE-61A To a mixture of intermediate RE-2E (100 mg), DMF (0.9 mL), DIPEA (0.14 mL), and (2R)-2-(trifluoromethyl)morpholine hydrochloride (63 mg), HBTU (124 mg) was added and stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (131 mg). MS (m/z): 405.1 [M-Boc+2H] +
  • Step 2 Preparation of Compound RE-61
  • the title compound was obtained by a method similar to that of Step 4 of Reference Example 37, except that Intermediate RE-61A was used instead of Intermediate RE-37C.
  • Reference Example 64 2-[3-(azetidin-3-yl)-1H-indazol-1-yl]-N,N-bis(propan-2-yl)acetamide trifluoroacetate (compound RE-64)
  • Compound RE-64 was synthesized starting from intermediate RE-4C, following a procedure similar to that described in steps 1 to 2 of Reference Example 51 for the preparation of compound RE-51, using diisopropylamine instead of 2,2,2-trifluoro-N-methylethanamine hydrochloride.
  • Reference Example 65 2-[3-(azetidin-3-yl)-1H-indazol-1-yl]-N-tert-butyl-N-methylacetamide trifluoroacetate (compound RE-65)
  • Compound RE-65 was synthesized starting from intermediate RE-4C, following a procedure similar to that described in steps 1 to 2 of Reference Example 51 for the preparation of compound RE-51, using N,2-dimethylpropan-2-amine instead of 2,2,2-trifluoro-N-methylethanamine hydrochloride.
  • Step 1 Preparation of intermediate RE-66A EDCI.HCl (243 mg) was added to a mixture of intermediate RE-4C (350 mg), 2,2,2-trifluoro-N-methylethanamine hydrochloride (190 mg), 1-hydroxybenzotriazole monohydrate (194 mg), NMM (0.35 mL), and acetonitrile (3 mL), and the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (280 mg). MS (m/z): 449.3 [M+Na] +
  • Step 2 Preparation of Compound RE-66
  • the title compound was obtained by a method similar to that of Step 4 of Reference Example 37, except that Intermediate RE-66A was used instead of Intermediate RE-37C.
  • Step 1 Preparation of intermediate RE-71A
  • Compound RE-71A was synthesized starting from intermediate RE-10C according to a procedure similar to that described in steps 4 to 5 of Reference Example 2 for the preparation of intermediate RE-2E.
  • Step 2 Preparation of Compound RE-71 A mixture of intermediate RE-71A (800 mg), HATU (967 mg), DIPEA (1.1 mL), and DMF (4.2 mL) was stirred at room temperature for 15 minutes. (2S)-2-(trifluoromethyl)pyrrolidine hydrochloride (447 mg) was added, and the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate.
  • Step 2 Preparation of Compound RE-78 The title compound was obtained by a method similar to that of Step 7 of Reference Example 1, except that Intermediate RE-78A was used instead of Intermediate RE-1F. MS (m/z): 384.2 [M+H] +
  • Step 1 Preparation of intermediate RE-79A DIPEA (0.08 mL) was added to a mixture of intermediate RE-13D (52 mg), DMF (1.0 mL), HBTU (74 mg), and 3,3-dimethylmorpholine (22 mg), and the mixture was stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography to obtain the title compound (50 mg). MS (m/z): 444.3 [M+H] +
  • Step 2 Preparation of Compound RE-79 The title compound was obtained by a method similar to Step 7 of Reference Example 1, except that Intermediate RE-79A was used instead of Intermediate RE-1F. MS (m/z): 344.2 [M+H] +
  • Step 1 Preparation of intermediate RE-80A
  • Intermediate RE-80A was synthesized starting from intermediate RE-15C according to a procedure similar to that described in steps 4 to 5 of Reference Example 1 for the preparation of intermediate RE-1E.
  • Step 2 Preparation of Compound RE-80
  • the title compound was obtained by a method similar to that of Step 6 of Reference Example 1, using Intermediate RE-80A instead of Intermediate RE-1E and (2R)-2-(trifluoromethyl)morpholine hydrochloride instead of 2,2,2-trifluoroethanamine hydrochloride.
  • Step 1 Preparation of intermediate RE-87A DIPEA (0.2 mL) was added to a mixture of intermediate RE-80A (80 mg), DMF (0.8 mL), HBTU (130 mg), and (2S)-2-(trifluoromethoxymethyl)pyrrolidine hydrochloride (56 mg), and the mixture was stirred at room temperature overnight.
  • the reaction solution was purified by silica gel column chromatography to obtain the title compound (60 mg). MS (m/z): 502.3 [M+H] +
  • Step 2 Preparation of Compound RE-87 The title compound was obtained by a method similar to that of Step 7 of Reference Example 1, except that Intermediate RE-87A was used instead of Intermediate RE-1F. MS (m/z): 402.2 [M+H] +
  • Step 1 Preparation of intermediate RE-88A Compound RE-88A was synthesized starting from intermediate RE-17B following a procedure similar to that described in steps 4 to 5 of Reference Example 15 for the preparation of intermediate RE-15E. MS (m/z): 346.2 [M+H] +
  • Step 1 Preparation of intermediate RE-98A Intermediate RE-98A was synthesized starting from intermediate RE-18C following a procedure similar to that described in steps 4 to 5 of Reference Example 15 for the preparation of intermediate RE-15E. MS (m/z): 364.2 [M+H] +
  • Step 2 Preparation of Compound RE-98 A mixture of intermediate RE-98A (51 mg), 4-fluorobenzoic acid (18 mg), DIPEA (0.02 mL), HATU (54 mg), and DMF (0.4 mL) was stirred at room temperature overnight. Then, the mixture was stirred at 120° C. for 2 hours. After cooling, the reaction solution was purified by silica gel column chromatography to obtain the title compound (13 mg). MS (m/z): 368.1 [M-Boc+2H] +
  • Step 1 Preparation of intermediate RE-116A A mixture of intermediate RE-2D (280 mg), ethanol (2 mL), and hydrogen chloride (2M ethanol solution, 1.8 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure, and a mixture of the residue, ethanol (2 mL), and hydrogen chloride (2M ethanol solution, 1.8 mL) was stirred at room temperature overnight, and then the solvent was removed under reduced pressure, and the resulting residue (220 mg) was dissolved in DMF (2 mL).
  • Step 2 Preparation of Compound RE-116 To a mixture of intermediate RE-116A (343 mg) and methanol (4.1 mL), 2M aqueous sodium hydroxide solution (0.5 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. 2M hydrochloric acid was added for neutralization, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (183 mg). MS (m/z): 388.1 [M+H] +
  • Step 1 Preparation of intermediate RE-117A DIPEA (0.85 mL) was added to a mixture of compound RE-39 (473 mg), compound RE-24 (349 mg), HOBt (289 mg), EDCI.HCl (410 mg), and DMF (5.5 mL), and the mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (409 mg). MS (m/z): 426.2 [M+H] +
  • Step 2 Preparation of Compound RE-117 Trifluoroacetic acid (0.5 mL) was added to a mixture of intermediate RE-117A (389 mg) and dichloromethane (2 mL), and the mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature overnight. Toluene was added to the residue obtained by distilling off the solvent under reduced pressure, and the mixture was distilled off under reduced pressure. Then, ethyl acetate and hexane were added, and the solvent was distilled off under reduced pressure. The residue was washed with diethyl ether and then dried to obtain the title compound (396 mg). MS (m/z): 370.2 [M+H] +
  • Step 1 Preparation of intermediate RE-118A A mixture of intermediate RE-20A (300 mg) and hydrogen chloride (2M ethanol solution, 2 mL) was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the resulting residue (232 mg) was dissolved in a small amount of DMF. In a separate vessel, a mixture of 2-aminopyridine-4-carboxylic acid (80 mg), DMF (5.8 mL), DIPEA (0.8 mL), and HBTU (286 mg) was stirred at room temperature for 2 hours, and then a separately prepared DMF solution of the residue was added and stirred at room temperature overnight.
  • 2-aminopyridine-4-carboxylic acid 80 mg
  • DMF 5.8 mL
  • DIPEA 0.8 mL
  • HBTU HBTU
  • Step 2 Preparation of Compound RE-118 To a mixture of intermediate RE-118A (83 mg) and methanol (2 mL), 2M aqueous sodium hydroxide solution (0.1 mL) was added under ice cooling, and the mixture was stirred at room temperature overnight. 2M hydrochloric acid was added for neutralization, and the solvent was distilled off under reduced pressure to obtain the title compound (77 mg). MS (m/z): 370.0 [M+H] +
  • Reference Example 120 2- ⁇ 3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl ⁇ acetic acid (compound RE-120)
  • Compound RE-120 was synthesized starting from intermediate RE-2D, following a procedure similar to that described in steps 1 to 2 of Reference Example 116 for the preparation of compound RE-116, using compound RE-24 instead of 2-aminopyridine-4-carboxylic acid.
  • Reference Example 122 4- ⁇ 3-[4-fluoro-1-(prop-2-yn-1-yl)-1H-indazol-3-yl]azetidine-1-carbonyl ⁇ pyridin-2-amine (Compound RE-122)
  • a mixture of intermediate RE-18D (100 mg) and hydrogen chloride (4M 1,4-dioxane solution, 2 mL) was stirred at room temperature for 3 hours.
  • the solvent was removed under reduced pressure, and the resulting residue (80 mg) was dissolved in a small amount of DMF.
  • Example 4 2- ⁇ 3-[1-(2-aminopyrimidine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl ⁇ -N-methyl-N-(2,2,2-trifluoroethyl)acetamide (Compound E-4)
  • the title compound (24 mg) was obtained by a method similar to that of Example 3, using compound RE-5 (43 mg) obtained in step 6 of Reference Example 5 instead of compound RE-4, and 2-aminopyrimidine-4-carboxylic acid (15 mg) instead of compound RE-24.
  • Example 5 2- ⁇ 3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-6-fluoro-1H-indazol-1-yl ⁇ -N-methyl-N-(2,2,2-trifluoroethyl)acetamide (Compound E-5)
  • the title compound (32 mg) was obtained by a method similar to that of Example 3, using the compound RE-6 (40 mg) obtained in Step 5 of Reference Example 6 instead of the compound RE-4.
  • Example 6 2- ⁇ 3-[1-(2-aminopyridine-4-carbonyl)-3-methylazetidin-3-yl]-1H-indazol-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-6)
  • the title compound (7 mg) was obtained by a method similar to that of Step 1 of Example 2, except that Compound RE-7 (55 mg) obtained in Step 5 of Reference Example 7 was used instead of Compound RE-2.
  • Example 7 2- ⁇ 3-[1-(2-amino-4-methyl-1,3-thiazole-5-carbonyl)azetidin-3-yl]-1H-indazol-1-yl ⁇ -1-(3,3-dimethylmorpholin-4-yl)ethan-1-one (Compound E-7)
  • the title compound (12 mg) was obtained by a method similar to that of Example 3, using compound RE-8 (15 mg) obtained in step 2 of Reference Example 8 instead of compound RE-4, and 2-amino-4-methyl-1,3-thiazole-5-carboxylic acid (5.9 mg) instead of compound RE-24.
  • Example 8 2- ⁇ 3-[1-(2-amino-3-methylpyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl ⁇ -1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (Compound E-8)
  • the title compound (15 mg) was obtained by a method similar to that of Step 1 of Example 2, using Compound RE-9 (20 mg) obtained in Step 2 of Reference Example 9 instead of Compound RE-2, and Compound RE-25 (14 mg) obtained in Step 3 of Reference Example 25 instead of 2-aminopyridine-4-carboxylic acid.
  • Example 9 4-[4-(4-fluoro-1- ⁇ [5-(trifluoromethyl)pyridin-2-yl]methyl ⁇ -1H-indazol-3-yl)piperidine-1-carbonyl]pyridin-2-amine (Compound E-9)
  • the title compound (25 mg) was obtained by a method similar to that of Step 1 of Example 2, using Compound RE-10 (35 mg) obtained in Step 5 of Reference Example 10 instead of Compound RE-2.
  • Example 10 2- ⁇ 3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidin-4-yl]-4-fluoro-1H-indol-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-10)
  • the title compound (17 mg) was obtained by a method similar to that of Example 3, using the compound RE-11 (46 mg) obtained in Step 6 of Reference Example 11 instead of the compound RE-4.
  • Example 11 2- ⁇ 3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indol-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-11)
  • hydrogen chloride 4 M ethyl acetate solution, 0.14 mL
  • Example 12 2- ⁇ 3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-5-methyl-1H-pyrazolo[4,3-b]pyridin-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-12)
  • hydrogen chloride (2M methanol solution, 0.53 mL) was added and stirred at room temperature overnight.
  • Hydrogen chloride (2M methanol solution, 0.53 mL) was added due to the remaining raw material, and the mixture was stirred at room temperature for 7 hours.
  • Example 13 2- ⁇ 3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-pyrazolo[4,3-c]pyridin-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (Compound E-13) [Step 1] Preparation of 2- ⁇ 3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-pyrazolo[4,3-c]pyridin-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (compound E-13A) The title compound (22 mg) was obtained by a method similar to that in Step 1 of Example 2, except that compound RE-14 (30 mg) obtained in Step 8 of Reference Example 14 was used instead of compound RE-2.
  • Step 2 Preparation of Compound E-13 The title compound (18 mg) was obtained by a method similar to Step 2 of Example 2, except that Compound E-13A (22 mg) was used instead of Compound E-2A. MS (m/z): 474.2 [M+H] +
  • Example 14 4- ⁇ 3-[4-fluoro-1-( ⁇ 5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl ⁇ methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl]azetidine-1-carbonyl ⁇ pyridin-2-amine (Compound E-14)
  • the title compound (22.3 mg) was obtained by a method similar to that of Step 1 of Example 2, using Compound RE-15 (27.5 mg) obtained in Step 7 of Reference Example 15 instead of Compound RE-2.
  • Example 15 2- ⁇ 3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-methyl-1H-pyrazolo[3,4-b]pyridin-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-15)
  • the title compound (27 mg) was obtained by a method similar to that of Step 1 of Example 2, except that Compound RE-16 (43 mg) obtained in Step 7 of Reference Example 16 was used instead of Compound RE-2.
  • Example 16 2- ⁇ 3-[1-(6-aminopyridazine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-16)
  • the title compound (5 mg) was obtained by a method similar to that of Step 1 of Example 2, using Compound RE-3 (20 mg) obtained in Reference Example 3 instead of Compound RE-2, and using 6-aminopyridazine-4-carboxylic acid (8.3 mg) instead of 2-aminopyridine-4-carboxylic acid.
  • Example 17 2-[4,6-difluoro-3-(1- ⁇ 1H-pyrazolo[3,4-b]pyridine-4-carbonyl ⁇ azetidin-3-yl)-1H-indazol-1-yl]-1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-17) DIPEA (0.021 mL) was added to a mixture of 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (7.8 mg), EDCI.HCl (9.2 mg), HOBt (6.5 mg), and DMF (0.5 mL), and the mixture was stirred at room temperature for 10 minutes.
  • Example 18 5-fluoro-4-[3-(1- ⁇ [3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl ⁇ -1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (Compound E-18)
  • the title compound (12 mg) was obtained by a method similar to that of Step 1 of Example 2, using Compound RE-17 (49 mg) obtained in Step 4 of Reference Example 17 instead of Compound RE-2, and Compound RE-24 (32 mg) obtained in Reference Example 24 instead of 2-aminopyridine-4-carboxylic acid.
  • Example 19 4- ⁇ 3-[1-( ⁇ 1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl ⁇ methyl)-4-fluoro-1H-indazol-3-yl]azetidine-1-carbonyl ⁇ pyridin-2-amine hydrochloride (Compound E-19) [Step 1] Preparation of 4- ⁇ 3-[1-( ⁇ 1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl ⁇ methyl)-4-fluoro-1H-indazol-3-yl]azetidine-1-carbonyl ⁇ pyridin-2-amine (compound E-19A) According to a method similar to Step 7 of Reference Example 1, 3-(azetidin-3-yl)-1-( ⁇ 1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl ⁇ methyl)-4-
  • Step 2 Preparation of compound E-19 The title compound (5.4 mg) was obtained by a method similar to that of Step 2 of Example 2, except that compound E-19A (14 mg) was used instead of compound E-2A. MS (m/z): 497.1 [M+H] +
  • Example 20 4-[3-(4-fluoro-1- ⁇ [5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl ⁇ -1H-indazol-3-yl)azetidine-1-carbonyl]pyridin-2-amine (Compound E-20)
  • the title compound (53 mg) was obtained by a method similar to that of Step 1 of Example 2, except that Compound RE-19 (67 mg) obtained in Step 2 of Reference Example 19 was used instead of Compound RE-2.
  • Example 21 2- ⁇ 3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl]-5-chloro-1H-indazol-1-yl ⁇ -N-methyl-N-(2,2,2-trifluoroethyl)acetamide (Compound E-21)
  • the title compound (6 mg) was obtained by a method similar to that of Example 3, using compound RE-5 (43 mg) obtained in step 6 of Reference Example 5 instead of compound RE-4, and compound RE-26 (17 mg) obtained in step 3 of Reference Example 26 instead of compound RE-24.
  • Example 22 2- ⁇ 3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-22)
  • the title compound (22 mg) was obtained by a method similar to that of Example 3, using the compound RE-26 (16 mg) obtained in Step 3 of Reference Example 26 instead of the compound RE-24.
  • Example 23 2- ⁇ 3-[1-(2-amino-5-fluoropyrimidine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl ⁇ -N-methyl-N-(2,2,2-trifluoroethyl)acetamide (Compound E-23)
  • the title compound (19 mg) was obtained by a method similar to that of Example 3, using compound RE-20 (41 mg) obtained in step 4 of Reference Example 20 instead of compound RE-4, and compound RE-26 (17 mg) obtained in step 3 of Reference Example 26 instead of compound RE-24.
  • Example 24 2- ⁇ 3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,5,6,7-tetrahydro-1H-indazol-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-24)
  • the title compound (9 mg) was obtained by a method similar to that of Example 3, using the compound RE-21 (16 mg) obtained in Step 6 of Reference Example 21 instead of the compound RE-4.
  • Example 25 2- ⁇ 3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-5,5-difluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-25)
  • the title compound (40 mg) was obtained by a method similar to that of Example 3, using the compound RE-22 (62 mg) obtained in Step 8 of Reference Example 22 instead of the compound RE-4.
  • Example 27 2- ⁇ 3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one methanesulfonate (Compound E-27)
  • Compound E-2A (1.80 g) was dissolved in THF (36 mL) by heating, methanesulfonic acid (344 mg) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in acetonitrile by heating.
  • Example 28 2- ⁇ 3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (Compound E-28)
  • the title compound was obtained by a method similar to that of Step 2 of Example 2, except that Compound E-3 was used instead of Compound E-2A.
  • Example 29 2- ⁇ 3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one methanesulfonate (Compound E-29)
  • Compound E-3 50 mg was dissolved in THF (2 mL), methanesulfonic acid (11 mg) was added, and the mixture was stirred at room temperature for 30 minutes.
  • Example 31 2-(3- ⁇ 1-[6-(cyclopropylamino)pyrimidine-4-carbonyl]azetidin-3-yl ⁇ -4,6-difluoro-1H-indazol-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (Compound E-31) [Step 1] Preparation of 6-(cyclopropylamino)pyrimidine-4-carboxylic acid trifluoroacetate A mixture of compound RE-27 (46 mg), dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (56 mg).
  • Step 2 Preparation of Compound E-33
  • the title compound was obtained by a method similar to Step 2 of Example 2, except that Compound E-33A was used instead of Compound E-2A.
  • Step 2 Preparation of Compound E-35 A mixture of compound E-35A (141 mg), hydrogen chloride (4 M 1,4-dioxane solution, 2 mL), and 1,4-dioxane (2 mL) was stirred at room temperature overnight. After adding 4 M hydrochloric acid (3 mL) and stirring, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (64 mg). MS (m/z): 483.2 [M+H] +
  • Example 36 2- ⁇ 3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl ⁇ -1-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-36) DMTMM (21 mg) was added to a mixture of compound RE-116 (20 mg), D-prolinol (8 mg), DIPEA (0.03 mL), and methanol (0.5 mL), and the mixture was stirred at room temperature overnight. The reaction solution was purified by silica gel column chromatography to obtain the title compound (5 mg). MS (m/z): 471.2 [M+H] +
  • Example 38 4- ⁇ 3-[4-fluoro-1-( ⁇ 1-[(oxetan-3-yl)methyl]-1H-1,2,3-triazol-4-yl ⁇ methyl)-1H-indazol-3-yl]azetidine-1-carbonyl ⁇ pyridin-2-amine (compound E-38)
  • the title compound was obtained by a method similar to that of Step 1 of Example 37, except that 3-(azidomethyl)oxetane was used instead of azidomethylcyclopropane.
  • Example 39 4- ⁇ 4-[1-( ⁇ 1-[(3,3-difluorocyclobutyl)methyl]-1H-1,2,3-triazol-4-yl ⁇ methyl)-4-fluoro-1H-indazol-3-yl]piperidine-1-carbonyl ⁇ pyridin-2-amine (Compound E-39)
  • the title compound was obtained by a method similar to that of Step 1 of Example 37, using Compound RE-115 instead of Compound RE-122 and 3-(azidomethyl)-1,1-difluorocyclobutane instead of azidomethylcyclopropane.
  • Example 40 2- ⁇ 3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (compound E-40)
  • the title compound was obtained by a method similar to that of Step 1 of Example 2, except that Compound RE-4 was used instead of Compound RE-2.
  • Example 41 2- ⁇ 3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one hydrochloride (Compound E-41)
  • Compound E-40 (3.2 g) was dissolved in methanol (23 mL), 2M hydrochloric acid (3.6 mL) was added, and the mixture was stirred at room temperature for 10 minutes. The solvent was removed under reduced pressure, the residue was dissolved in 2-propanol, hexane was added, and the precipitated solid was collected by filtration. The mixture was dried under reduced pressure to obtain the title compound (3.47 g).
  • Example 42 2- ⁇ 3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl ⁇ -1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one (Compound E-42)
  • the title compound was obtained by a method similar to that of Example 3, using compound RE-61 instead of compound RE-4.
  • Example 43 2- ⁇ 3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl ⁇ -1-[(2R)-2-(trifluoromethyl)morpholin-4-yl]ethan-1-one p-toluenesulfonate (Compound E-43)
  • Compound E-42 32 mg was dissolved in THF (2 mL), p-toluenesulfonic acid monohydrate (13 mg) was added, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (36 mg).
  • Example 46 2- ⁇ 3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl ⁇ -N-methyl-N-(2,2,2-trifluoroethyl)acetamide p-toluenesulfonate (Compound E-46)
  • Compound E-45 50 mg was dissolved in THF (1.1 mL), p-toluenesulfonic acid monohydrate (23 mg) was added, and the mixture was stirred at room temperature for 10 minutes. The solvent was removed under reduced pressure, the residue was dissolved in methanol, and diethyl ether was added to the precipitated solid, which was then filtered.
  • Example 47 2- ⁇ 3-[1-(2-amino-5-fluoropyridine-4-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indazol-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-47)
  • a mixture of compound RE-40 (105 mg), dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was stirred at room temperature. Toluene was added to the residue obtained by distilling off the solvent under reduced pressure, and the mixture was distilled off under reduced pressure.
  • Example 49 2- ⁇ 3-[1-(2-amino-5-fluoropyridine-4-carbonyl)piperidin-4-yl]-1H-indazol-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-49)
  • the title compound was obtained by a method similar to that of Step 2 of Example 48, except that compound E-47 was used instead of compound E-48A.
  • Example 50 2- ⁇ 3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl ⁇ -1-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-50)
  • the reaction solution was purified by silica gel column chromatography to obtain the title compound (21 mg). MS (m/z): 509.1 [M+H] +
  • Example 53 2- ⁇ 3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4-methyl-1H-pyrazolo[4,3-c]pyridin-1-yl ⁇ -1-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-53)
  • a mixture of compound RE-33 (97 mg), dichloromethane (2 mL), and trifluoroacetic acid (0.2 mL) was stirred at room temperature for 8 hours. Toluene was added to the residue obtained by distilling off the solvent under reduced pressure, and the mixture was distilled off under reduced pressure.
  • Example 55 4- ⁇ 3-[4-fluoro-1-( ⁇ 3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl ⁇ methyl)-1H-indazol-3-yl]azetidine-1-carbonyl ⁇ pyridin-2-amine (Compound E-55)
  • Compound RE-109 45 mg was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, and the resulting residue was dissolved in DMF.
  • Example 56 2- ⁇ 3-[1-(2-aminopyridine-4-carbonyl)azetidin-3-yl]-4,6-difluoro-1H-indazol-1-yl ⁇ -1-[(2S)-2-[(trifluoromethoxy)methyl]pyrrolidin-1-yl]ethan-1-one (Compound E-56) DIPEA (0.1 mL) was added to a mixture of compound RE-116 (30 mg), HBTU (38 mg), and DMF (0.5 mL), and the mixture was stirred at room temperature for 5 minutes. (2S)-2-(trifluoromethoxymethyl)pyrrolidine hydrochloride (19 mg) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (19 mg). MS (m/z): 539.2 [M+H] +
  • Example 57 4-(3- ⁇ 1-[(4,4-difluorocyclohexyl)methyl]-4,6-difluoro-1H-indazol-3-yl ⁇ azetidine-1-carbonyl)pyridin-2-amine (Compound E-57)
  • Compound RE-55 80 mg was dissolved in methanol (0.7 mL), hydrogen chloride (4M in ethyl acetate, 0.03 mL) was added, and the mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, and the resulting residue was dissolved in DMF (0.5 mL).
  • Example 59 2- ⁇ 3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-4-fluoro-1H-indazol-1-yl ⁇ -N-methyl-N-(2,2,2-trifluoroethyl)acetamide (Compound E-59)
  • a mixture of intermediate RE-20C (81 mg), dichloromethane (2 mL), and trifluoroacetic acid (0.7 mL) was stirred at room temperature for 2.5 hours. The solvent was removed under reduced pressure, and toluene was added to the resulting residue, which was then removed under reduced pressure. Then, ethyl acetate and hexane were added, and the solvent was removed under reduced pressure.
  • Example 60 2- ⁇ 3-[1-(2-amino-5-fluoropyridine-4-carbonyl)azetidin-3-yl]-1H-indazol-1-yl ⁇ -1-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]ethan-1-one (Compound E-60)
  • a mixture of compound RE-117 (50 mg), (2R)-2-(trifluoromethyl)pyrrolidine hydrochloride (24 mg), HOBt (18 mg), DIPEA (0.07 mL), DMF (0.5 mL), and EDCI.HCl (26 mg) was stirred at room temperature overnight.
  • the reaction solution was purified by silica gel column chromatography to obtain the title compound (20 mg). MS (m/z): 491.0 [M+H] +
  • Tables 49 to 72 below show the numbers and chemical names of the example compounds.
  • the chemical names indicate the names of the compounds that correspond to the compound numbers.
  • Test substances were prepared at 10 mM with dimethyl sulfoxide (DMSO, Nacalai Tesque, 13445-74), and six concentrations were selected for each compound, which were then diluted with DMSO to final concentrations of 1000, 100, 10, 1, 0.1, 0.01, and 0.001 ⁇ M.
  • DMSO dimethyl sulfoxide
  • this solution was diluted with a buffer containing 50 mM HEPES (Fujifilm Wako Pure Chemical Industries, 340-01371), 1 mM EGTA (DOJINDO, G002), 10 mM magnesium chloride hexahydrate (Nacalai Tesque, 20908-65), 2 mM dithiothreitol (Nacalai Tesque, 14112-52), and 0.01% Tween 20 (Tokyo Chemical Industry, T0543) to six concentrations selected for each compound, so as to obtain test substance solutions of 330,000, 33,000, 330, 33, 3, 0.3, and 0.03 nM. 2.
  • HEPES Flujifilm Wako Pure Chemical Industries, 340-01371
  • 1 mM EGTA DOJINDO, G002
  • 10 mM magnesium chloride hexahydrate Nacalai Tesque, 20908-65
  • 2 mM dithiothreitol Nacalai Tesque, 14112-
  • DDR1 kinase activity Six concentrations were selected for each compound, and the prepared test substance solutions were added to a 384-well plate (Corning, 4512) at 3 ⁇ L/well so that the final concentrations were 10000, 1000, 100, 10, 1, 0.1, and 0.01 nM, respectively. DDR1 protein (Carna Biosciences, 08-113) was added at 2 ⁇ L/well so that the final concentration was 0.5 nM.
  • LANCE Ultra ULight TM -poly GAT PerkinElmer, TRF0101
  • ATP Sigma-Aldrich, A6559
  • 10 ⁇ L/well of LANCE Detection Buffer PerkinElmer, CR97-100
  • 10 mM EDTA DOJINDO, K001
  • 1 nM Europium PerkinElmer, AD0068
  • the fluorescence intensity at 615 nm and 665 nm was measured using Envision (PerkinElmer) or SpectraMax iD5 (Molecular Devices). The test was performed in duplicate. 3. Analysis of the measurement results The fluorescence intensity at 665 nM was divided by the fluorescence intensity at 615 nM to calculate the inhibition rate of the test substance, with the maximum inhibition rate for each test substance being 100% and the minimum inhibition rate being 0%. The IC50 value (50% inhibition concentration) of the test substance was calculated by logistic regression analysis. The results for each example compound are shown in Tables 73 to 78 below.
  • Test substances were prepared to 10 mM with DMSO and diluted with DMSO to final concentrations of 1000, 100, 10, 1, and 0.1 ⁇ M. This solution was further diluted with E-MEM medium (Fujifilm Wako Pure Chemical Industries, 051-07615) containing 10% fetal bovine serum (FBS, Gibco, 10270106) to 60,000, 6,000, 60, 6, and 0.6 nM to prepare test substance solutions. 2.
  • E-MEM medium Flujifilm Wako Pure Chemical Industries, 051-07615
  • FBS fetal bovine serum
  • DDR1 kinase inhibitory effect in DDR1-expressing U2OS cells DDR1-expressing U2OS cells (DiscoverX, 93-0894C3) suspended in 10% FBS + E-MEM medium at 2.5 x 10 ⁇ 5 cells/mL were seeded in 384-well plates (DiscoverX, 92-0013) in 20 ⁇ L portions and cultured overnight at 37°C and 5% CO2 . The next day, the prepared test substance solutions were added at 5 ⁇ L/well to give final concentrations of 10,000, 1,000, 100, 10, 1, and 0.1 nM.
  • type I collagen (Nitta Gelatin, 631-00771) was added at 5 ⁇ L/well to give a final concentration of 50 ⁇ g/mL, and the cells were cultured at 37°C and 5% CO2 overnight. The next day, the plate was left at room temperature for 1 hour, and then detection solution was added at 5 ⁇ L/well according to the instruction manual for PathHunter (registered trademark) Detection Kit (DiscoverX, 93-0001). After incubation at room temperature for 2 hours, the luminescence intensity was measured using Envision (PerkinElmer). The test was performed in duplicate. 3.
  • PathHunter registered trademark
  • Detection Kit DiscoverX, 93-0001
  • the inhibition rate of the test substance was calculated by taking the blank (only type I collagen stimulation) as 100% and the negative control group (no type I collagen stimulation) as 0%.
  • the IC50 value (50% inhibitory concentration) of the test substance was calculated by logistic regression analysis. The results of each example compound are shown in Tables 79 to 81 below.
  • Example 3 Examination of in vivo efficacy using anti-glomerular basement membrane antibody-induced nephritis model> 1. Preparation of Test Substances The test substance was weighed and suspended in 0.5% methylcellulose (Shin-Etsu Chemical Co., Ltd.) + 99.5% Otsuka distilled water (Otsuka Pharmaceutical Factory) to prepare a test substance administration solution. 2.
  • the albumin concentration in urine was quantified using a JCA-BM6050 automatic analyzer (JEOL).
  • the amount of albumin in urine was calculated by correcting for the measured urine weight. 4.
  • the amount of albumin in urine in the test substance-administered group was calculated based on the amount of albumin in urine in the anti-glomerular basement membrane antibody-unadministered group and the vehicle-administered group, which were set at 0% and 100%, respectively.
  • the experimental results are shown in Table X.

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PCT/JP2023/041679 2022-11-21 2023-11-20 Ｄｄｒ１キナーゼ阻害剤としての化合物および医薬 Ceased WO2024111560A1 (ja)

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PE2025001026A PE20251709A1 (es) 2022-11-21 2023-11-20 Compuesto que sirve como inhibidor de cinasa del receptor 1 del dominio de discoidina (ddr1) y medicamento
EP23894566.1A EP4624465A1 (en) 2022-11-21 2023-11-20 Compound serving as ddr1 kinase inhibitor, and medicine
KR1020257020743A KR20250109234A (ko) 2022-11-21 2023-11-20 Ddr1 키나아제 저해제로서의 화합물 및 의약
AU2023386923A AU2023386923A1 (en) 2022-11-21 2023-11-20 Compound serving as ddr1 kinase inhibitor, and medicine
JP2024560149A JP7823226B2 (ja) 2022-11-21 2023-11-20 Ｄｄｒ１キナーゼ阻害剤としての化合物および医薬
CN202380091730.4A CN120569374A (zh) 2022-11-21 2023-11-20 作为ddr1激酶抑制剂的化合物和药物
IL320735A IL320735A (en) 2022-11-21 2025-05-06 A compound used as a DDR1 kinase inhibitor, and a drug
MX2025005556A MX2025005556A (es) 2022-11-21 2025-05-13 Compuesto que sirve como inhibidor de cinasa del receptor 1 del dominio de discoidina (ddr1) y medicamento
CONC2025/0006877A CO2025006877A2 (es) 2022-11-21 2025-05-26 Compuesto que sirve como inhibidor de cinasa del receptor 1 del dominio de discoidina (ddr1) y medicamento

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