WO2020138398A1 - Nouveau composé inhibiteur de l'enzyme 1 déméthylase spécifique de la lysine, son procédé de production et son utilisation - Google Patents

Nouveau composé inhibiteur de l'enzyme 1 déméthylase spécifique de la lysine, son procédé de production et son utilisation Download PDF

Info

Publication number
WO2020138398A1
WO2020138398A1 PCT/JP2019/051371 JP2019051371W WO2020138398A1 WO 2020138398 A1 WO2020138398 A1 WO 2020138398A1 JP 2019051371 W JP2019051371 W JP 2019051371W WO 2020138398 A1 WO2020138398 A1 WO 2020138398A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
formula
hydrogen
alkyl
Prior art date
Application number
PCT/JP2019/051371
Other languages
English (en)
Japanese (ja)
Inventor
祟史 梅原
心 佐藤
山本　博文
泰子 甲田
近藤　豊
恵子 新城
Original Assignee
国立研究開発法人理化学研究所
国立大学法人東海国立大学機構
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 国立研究開発法人理化学研究所, 国立大学法人東海国立大学機構 filed Critical 国立研究開発法人理化学研究所
Priority to JP2020562479A priority Critical patent/JPWO2020138398A1/ja
Publication of WO2020138398A1 publication Critical patent/WO2020138398A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • 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
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • 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
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • 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
    • 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
    • A61K31/435—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
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4465—Non condensed piperidines, e.g. piperocaine only substituted in position 4
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—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
    • 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
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • the present invention relates to a novel compound having a lysine-specific demethylase 1 inhibitory activity, a method for producing the same, and its use.
  • chromatin activity is regulated by its post-translational modification.
  • lysine residues are known to undergo post-translational modifications such as methylation or acetylation.
  • post-translational modifications such as methylation or acetylation.
  • LSD1/KDM1A is a protein conserved among eukaryotic species above fission yeast.
  • LSD1/KDM1A is also referred to as the amine oxidase flavin-containing domain 2 (AOF2) or BRAF-histone deacetylase complex 110 (BRHC-histone deacetylase complex 110, BHC110) as another name.
  • OAF2 amine oxidase flavin-containing domain 2
  • BHC-histone deacetylase complex 110 BHC110
  • LSD1 is a kind of oxidase having flavin adenine dinucleotide (hereinafter, also referred to as “FAD”) as a coenzyme. LSD1 demethylates the side chain amines of lysine residues of histone H3 proteins that are monomethylated or dimethylated.
  • FAD flavin adenine dinucleotide
  • Non-Patent Document 1 The main residue targeted for demethylation is the lysine residue (K4) at the 4th position from the N-terminus of histone H3 protein (Non-Patent Document 1).
  • the major protein that is demethylated by LSD1 is histone H3, but other non-histone proteins in the nucleus such as p53, Dnmt1, E2F1 and MYPT1 are also reported to be demethylated by LSD1.
  • LSD2 is also an oxidase having FAD as a coenzyme and can demethylate K4 of histone H3.
  • the LSD1 enzyme active site forms a structure that can be inhibited by low-molecular compounds. Therefore, many chemical probes that target LSD1 as an inhibitor have been developed.
  • Non-Patent Documents 2 and 3 describe that 2-phenylcyclopropylamine (2-PCPA) showed inhibitory activity against LSD1 by inactivating FAD which is a coenzyme of LSD1. To do.
  • Non-Patent Document 4 describes that a compound S2101 having LSD1 selective inhibitory activity was obtained by molecular design based on the crystal structure analysis of LSD1.
  • Compound S2101 has a structure in which the phenyl ring of 2-PCPA is chemically modified.
  • Patent Document 1 describes a compound represented by the formula I, which is a 2-PCPA analog. The document describes that this compound has LSD1 inhibitory activity. The document describes that N-alkylation of 2-PCPA can improve the inhibitory activity against LSD1.
  • Patent Documents 2, 3 and 4 describe compounds represented by the formula (I) having a cyclopropan-1-ylamine skeleton having an aryl or heteroaryl ring at the 2-position. The document describes that these compounds have LSD1 inhibitory activity.
  • LSD1 is highly expressed or functions in disease-related cells such as stem cells of acute myelogenous leukemia and stem cells of glioblastoma. Therefore, inhibitors against LSD1 are expected to exert therapeutic effects on diseases such as acute myelogenous leukemia, primary brain tumors such as glioblastoma, small cell lung cancer, myelodysplastic syndrome and non-Hodgkin's lymphoma. (Non-patent documents 5 to 9).
  • an inhibitor against LSD1 will exert a therapeutic effect in cancer immunotherapy by using it in combination with an inhibitor against PD-1 (Non-patent document 10).
  • 2-PCPA described in Non-Patent Document 2 is a compound originally developed as an inhibitor against monoamine oxidase (hereinafter, also referred to as “MAO”) and inhibits MAO more strongly than LSD1. Therefore, 2-PCPA has low selectivity for LSD1 inhibition.
  • MAO monoamine oxidase
  • LSD1 inhibitors are expected to exert therapeutic effects on various diseases. However, it is difficult to predict what disease the compound having an inhibitory activity against LSD1 has a therapeutic effect based on the LSD1 inhibitory activity.
  • an object of the present invention is to provide a novel compound having a high LSD1 inhibitory activity, a high selectivity for LSD1 inhibition, and/or a useful therapeutic effect on various diseases.
  • the present inventors examined various means for solving the above problems.
  • the present inventors have found that, in a group of compounds having a skeleton similar to 2-phenylcyclopropan-1-ylamine skeleton, a novel compound having a specific structure has high inhibitory activity against LSD1.
  • the present inventors have also found that some novel compounds having the above characteristics have high selectivity for LSD1 inhibition.
  • the present inventors have completed the present invention based on the above findings.
  • the gist of the present invention includes the following aspects and embodiments.
  • Ar 1 is not phenyl and L is a single bond, substituted or unsubstituted C 1 to C 6 alkylene, substituted or unsubstituted C 2 to C 6 alkenylene, substituted or unsubstituted C 2 to C 6 alkynylene, substituted or unsubstituted C 1 to C 6 alkylene-CO-, substituted or unsubstituted C 2 -C 6 alkenylene-CO-, or substituted or unsubstituted C 2 -C 6 alkynylene-CO-, provided that any of the last 3 groups L is bonded to A at the -CO- carbon atom), A is -CHR 1 R 2 , -NR 3 R 4 , or -CHR 3 R 4 , R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 to C 3 alkyl, substituted or unsubstituted 5 to 10 membered aryl, or substituted or unsubstituted 5
  • R 1 and R 2 together with the carbon atom to which they are attached form a substituted or unsubstituted C 4 -C 7 cycloalkyl
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 to C 6 alkoxy-C 1 to C 6 alkyl, substituted or unsubstituted C 3 to C 7 cycloalkyl, or substituted or non-substituted.
  • L is a substituted or unsubstituted C 1 -C 6 alkylene-CO-, a stereoisomer thereof, a salt thereof, or a solvate thereof.
  • X 2 is CR 22
  • X 3 is CR 23
  • X 4 is CR 24
  • R 22 is hydrogen
  • R 23 is hydrogen or fluorine
  • R 24 is hydrogen, fluorine or chlorine
  • R 25 is hydrogen or fluorine
  • Ar 1 is 5- to 10-membered aryl which is unsubstituted or substituted with one or more halogens, or 5- to 9-membered heteroaryl which is unsubstituted or substituted with one or more halogens.
  • Ar 1 is phenyl which is unsubstituted or substituted with one or more halogen, or pyridinyl or pyrazolyl which is unsubstituted or substituted with one or more halogen Of the above, its stereoisomers or salts thereof, or solvates thereof.
  • Ar 1 is pyridinyl unsubstituted or substituted with one or more halogen, and n is 1.
  • Ar 1 is 2-fluoro-pyridin-3-yl, n is 1, and X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 is hydrogen, R 23 is hydrogen or fluorine, R 24 is hydrogen, fluorine or chlorine, and R 25 is hydrogen or fluorine,
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 to C 3 alkyl, substituted or unsubstituted 5 to 10 membered aryl, or substituted or unsubstituted 5 to 9 Membered heteroaryl, or R 1 and R 2 together with the carbon atom to which they are attached have 1 or 2 R 5 and 1 or more R 6 C 4 -C 7 Forming a cycloalkyl, R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 to C 6 alkoxy-C 1 to C 6 alkyl, substituted or unsubstituted C 3 to C 7 cycloalkyl, or 1 or 2 A straight or branched C 1 -C 7 alkyl having one R 8 and one or more R 9 or R 3 and R 4 together with the carbon or nitrogen atom to which they are attached.
  • R 7 is hydrogen, halogen, substituted or unsubstituted C 6 to C 15 aryl, substituted or unsubstituted 5 or 6 membered heteroaryl, and substituted or unsubstituted C 1 to C 6 alkyl
  • R 8 is hydrogen, halogen, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkoxy-C 1 -C 6 alkyl, -COR 13 , -COOR 13 , -CONR 12 R 13 , -NR 12 R 13 , -NR 12 COR 13 , -NR 12 CO 2 R 13 , -NR 14 CONR 12 R 13 , -NR 12 SO 2 R 13 , and substituted or unsubstituted C 1 to C
  • a monovalent group independently selected from the group consisting of 6 alkyl, or R 8 together with 1 or 2 atoms selected from the carbon atom and the nitrogen atom to which they are attached are non- C 3 -C 7 cycloalkyl substituted or substituted with one or more R 10 , one or more heteroatoms selected from N, S and O as a ring atom, and unsubstituted or one or more Forming
  • R 9 is hydrogen, halogen, substituted or unsubstituted 4 to 7 membered heterocycloalkyl, substituted or unsubstituted C 6 to C 15 aryl, substituted or unsubstituted C 6 to C 15 aryl-C 1 to C
  • R 10 is a monovalent group or a divalent group independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 to C 6 alkyl, —CONR 12 R 13 and oxo ( ⁇ O), Alternatively, R 10 is one or more selected from substituted or unsubstituted C 3 to C 7 cycloalkyl, N, S and O together with 1 or 2 carbon atoms or nitrogen atoms to which they are attached.
  • R 11 is a monovalent group independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1 to C 6 alkoxy, and substituted or unsubstituted C 1 to C 6 alkyl
  • R 12 and R 13 are monovalent groups independently selected from the group consisting of hydrogen, substituted or unsubstituted C 6 -C 15 aryl, and substituted or unsubstituted C 1 -C 6 alkyl
  • R 12 and R 13 together with the carbon atom or nitrogen atom to which they are attached form a substituted or unsubstituted C 4 to C 7 cycloalkyl or a substituted or unsubstituted 4 to 7 membered heterocycloalkyl.
  • R 14 is a monovalent group independently selected from the group consisting of hydrogen and substituted or unsubstituted C 1 -C 6 alkyl, The compound according to any one of the embodiments (1) to (11), a stereoisomer thereof, a salt thereof, or a solvate thereof.
  • R 6 is hydrogen, halogen, substituted or unsubstituted C 6 -C 15 aryl, substituted or unsubstituted 5- or 6-membered heteroaryl, and unsubstituted or one or more halogen, substituted or unsubstituted C A monovalent group independently selected from the group consisting of 6 to C 15 aryl or C 1 to C 6 alkyl substituted with 5 or 6 membered heteroaryl, said aryl or heteroaryl being substituted In this
  • R 9 is hydrogen, halogen, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted phenyl, substituted Or independently selected from the group consisting of unsubstituted benzyl, substituted or unsubstituted benzimidazolyl, pyridinyl, pyrazinyl, and C 1 -C 6 alkyl unsubstituted or substituted with one or more oxetanyl, tetrahydrofuranyl, or phenyl.
  • R 10 is a monovalent group independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, —CONR 12 R 13 and oxo, or R 10 is one or two to which they are attached. Together with a carbon atom of to form a substituted or unsubstituted C 3 -C 7 cycloalkyl, or a substituted or unsubstituted C 5 -C 6 aryl, R 11 is hydrogen, halogen, C 1 ⁇ C 6 alkoxy, and unsubstituted or one or more halogen, hydroxyl, dimethylamino, N- morpholino, N- pyrrolidino or C 1 ⁇ C 6 alkyl substituted with carboxyl
  • a monovalent group independently selected from the group consisting of R 12 and R 13 are hydrogen, C 6 -C 15 aryl, and unsubstituted or one or more halogen, piperazin-1-yl, 4-methylpiperazin-1-yl,
  • R 12 and R 13 taken together with the carbon or nitrogen atom to which they are attached form an unsubstituted C 4 -C 7 cycloalkyl or a 4-7 membered substituted or unsubstituted heterocycloalkyl
  • R 14 is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C 1 -C 6 alkyl
  • a method for producing a solvate comprising: Formula (II): [In the formula, Ar 1 , n, X 2 , X 3 , X 4 and R 25 have the same meaning as defined in any one of the embodiments (1) and (6) to (10), PG N1 is hydrogen or a protecting group.
  • R L1 -L-OR L2 (III)
  • L has the same meaning as defined in any one of the above embodiments (1) and (6) to (13)
  • R L1 is halogen
  • R L2 is hydrogen, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 2 -C 5 alkenyl, or substituted or unsubstituted C 2 -C 5 alkynyl.
  • a method for producing a solvate comprising: Formula (II'): [In the formula, Ar 1 'is a substituted or unsubstituted 5-10 membered aryl, or a substituted or unsubstituted 5-9 membered heteroaryl (wherein, Ar 1' is is, Ar 1 and not the same), n, X 2 , X 3 , X 4 , and R 25 have the same meaning as defined in any one of the embodiments (1) and (6) to (13), PG N1 is hydrogen or a protecting group.
  • R L1 -L-OR L2 (III)
  • L has the same meaning as defined in any one of the above embodiments (1) and (6) to (13)
  • R L1 is halogen
  • R L2 is hydrogen, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 2 -C 5 alkenyl, or substituted or unsubstituted C 2 -C 5 alkynyl.
  • R A1 -A (V) [In the formula, A has the same meaning as defined in any one of the above embodiments (1) and (6) to (13), R A1 is hydrogen.
  • a step of obtaining a compound represented by A compound represented by the formula (I′) is reacted under hydrogenation conditions to give a compound represented by the formula (XI): [In the formula, X 2 , X 3 , X 4 , R 25 , L and A are as defined above. ]
  • the above method comprising the step of reacting with a compound represented by the formula (1) to obtain a compound represented by the formula (I).
  • a compound represented by the formula (I) (wherein L is a single bond) according to any one of the embodiments (1) and (6) to (13), a stereoisomer thereof, or A method for producing a salt thereof or a solvate thereof, comprising: Formula (II): [In the formula, Ar 1 , n, X 2 , X 3 , X 4 and R 25 have the same meaning as defined in any one of the embodiments (1) and (6) to (13), PG N1 is hydrogen or a protecting group.
  • a step of obtaining a compound represented by A compound represented by the formula (I′) is reacted under hydrogenation conditions to give a compound represented by the formula (XI): [In the formula, X 2 , X 3 , X 4 , R 25 , L and A are as defined above. ]
  • the above method comprising the step of reacting with a compound represented by the formula (1) to obtain a compound represented by the formula (I).
  • A has the same meaning as defined in any one of the above embodiments (1) and (6) to (13), L'is a substituted or unsubstituted C 1 -C 6 alkylene, a substituted or unsubstituted C 2 -C 6 alkenylene, or a substituted or unsubstituted C 2 -C 6 alkynylene (where L'is more than L The chain has one less carbon), R L3 is -CHO.
  • the above method comprising the step of reacting with a compound represented by the formula (1) to obtain a compound represented by the formula (I).
  • R L3 -L'-A (VII) [In the formula, A has the same meaning as defined in any one of the above embodiments (1) and (6) to (13), L'is a substituted or unsubstituted C 1 -C 6 alkylene, a substituted or unsubstituted C 2 -C 6 alkenylene, or a substituted or unsubstituted C 2 -C 6 alkynylene (where L'is more than L The chain has one less carbon), R L3 is -CHO.
  • Ar 1 has the same meaning as defined in any one of the embodiments (1) and (6) to (13)
  • n has the same meaning as above
  • R L11 is halogen.
  • the above method comprising the step of reacting with a compound represented by the formula (1) to obtain a compound represented by the formula (I).
  • the compound according to any one of the embodiments (1) to (13), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is used as an active ingredient.
  • the compound according to any one of the embodiments (1) to (13), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof is used as an active ingredient.
  • Pharmaceuticals including. The pharmaceutical agent according to the above embodiment (21), which is used for preventing or treating one or more symptoms, diseases and/or disorders selected from the group consisting of primary brain tumors.
  • (23) A compound according to any one of the embodiments (1) to (13), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one kind.
  • a pharmaceutical composition comprising the above pharmaceutically acceptable carrier.
  • a method for preventing or treating the above-mentioned symptoms, diseases and/or disorders which comprises administering an upper acceptable salt or a pharmaceutically acceptable solvate thereof.
  • the present invention makes it possible to provide a novel compound having high LSD1 inhibitory activity and/or high selectivity for LSD1 inhibition.
  • alkyl means a straight or branched chain saturated aliphatic hydrocarbon group containing the specified number of carbon atoms.
  • C 1 -C 6 alkyl means a straight or branched chain saturated aliphatic hydrocarbon group containing at least 1 and at most 6 carbon atoms.
  • Suitable alkyls include, but are not limited to, linear or branched such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. Mention may be made of branched chain C 1 -C 6 alkyls.
  • alkenyl means a group in which one or more CC single bonds of the alkyl are substituted with a double bond.
  • Suitable alkenyls include, but are not limited to, vinyl, 1-propenyl, allyl, 1-methylethenyl (isopropenyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2 -Methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 3-methylbut-2-en-1-yl, 1-pentenyl and 1-hexenyl straight-chain or branched chains C 2 -C 6 alkenyl can be mentioned.
  • alkynyl means a group in which one or more CC single bonds of the alkyl are substituted with triple bonds.
  • Suitable alkynyls include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl and 1-hexynyl. And straight-chain or branched C 2 -C 6 alkynyl.
  • cycloalkyl means a cycloaliphatic alkyl containing the specified number of carbon atoms.
  • C 3 -C 7 cycloalkyl means a cyclic hydrocarbon group containing at least 3 and at most 7 carbon atoms.
  • Suitable cycloalkyls include, but are not limited to, C 3 -C 7 cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • cycloalkenyl means a group in which one or more CC single bonds of the cycloalkyl are substituted with double bonds.
  • Suitable cycloalkenyls include, but are not limited to, C 4 -C 6 cycloalkenyls such as cyclobutenyl, cyclopentenyl and cyclohexenyl.
  • cycloalkynyl means a group in which one or more CC single bonds of the cycloalkyl are substituted with triple bonds.
  • Suitable cycloalkynyls include, but are not limited to, C 4 -C 6 cycloalkynyls such as cyclobutynyl, cyclopentynyl and cyclohexynyl.
  • heterocycloalkyl means that one or more carbon atoms of the cycloalkyl, cycloalkenyl or cycloalkynyl are each independently selected from nitrogen (N), sulfur (S) and oxygen (O). Is a group substituted with one or more heteroatoms.
  • substitution by N or S includes substitution of N-oxide or S by oxide or dioxide, respectively.
  • Suitable heterocycloalkyl include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl, etc. 3 to 6-membered heterocycloalkyl can be mentioned.
  • Suitable heterocycloalkenyls include, but are not limited to, 5- or 6-membered heterocycloalkenyls such as dihydropyrrole and tetrahydropyridine.
  • cycloalkylalkyl means a group in which one of the alkyl, alkenyl or alkynyl hydrogen atoms is substituted with the above cycloalkyl, cycloalkenyl or cycloalkynyl.
  • Suitable cycloalkylalkyls include, but are not limited to, C 7 -C 11 cycloalkylalkyls such as cyclohexylmethyl and cyclohexenylmethyl.
  • heterocycloalkylalkyl means a group in which one of the alkyl, alkenyl or alkynyl hydrogen atoms is substituted with the above heterocycloalkyl.
  • Suitable heterocycloalkylalkyls include, but are not limited to, 3-6 membered heterocycloalkyl-C 1 -C 6 alkyl.
  • alkoxy means a group in which a hydrogen atom of hydroxyl is substituted with the above alkyl, alkenyl or alkynyl.
  • Suitable alkoxys include, but are not limited to, C 1 -C 6 alkoxy such as methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
  • cycloalkoxy means a group in which a hydrogen atom of hydroxyl is substituted with the above cycloalkyl, cycloalkenyl or cycloalkynyl.
  • Suitable cycloalkoxys include, but are not limited to, C 3 -C 6 cycloalkoxys such as cyclopropoxy, cyclobutoxy, cyclopentoxy and cyclohexoxy.
  • heterocycloalkoxy means a group in which a hydrogen atom of hydroxyl is substituted with the above heterocycloalkyl.
  • Suitable cycloalkoxys include, but are not limited to, 3-6 membered heterocycloalkoxy.
  • aryl means an aromatic ring group. Suitable aryls include, but are not limited to, C 6 -C 18 aryl such as phenyl, biphenyl, terphenyl, naphthyl and anthracenyl.
  • arylalkyl means a group in which one of the alkyl, alkenyl or alkynyl hydrogen atoms is substituted with the above aryl.
  • Suitable arylalkyls include, but are not limited to, C 7 -C 20 arylalkyls such as benzyl, 1-phenethyl, 2-phenethyl, biphenylmethyl, terphenylmethyl and styryl.
  • heteroaryl means a group in which one or more carbon atoms of the aryl are independently substituted with one or more heteroatoms selected from N, S and O.
  • substitution by N or S includes substitution of N-oxide or S by oxide or dioxide, respectively.
  • Suitable heteroaryls include, but are not limited to, furanyl, thienyl (thiophenyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, Mention may be made of 5- to 15-membered heteroaryls such as pyrimidinyl, quinolinyl, isoquinolinyl and indolyl.
  • heteroarylalkyl means a group in which one of the alkyl, alkenyl or alkynyl hydrogen atoms is substituted with the above heteroaryl.
  • Suitable heteroarylalkyls include, but are not limited to, 5-15 membered heteroaryl-C 1 -C 6 alkyl such as pyridylmethyl.
  • aryloxy means a group in which a hydrogen atom of hydroxyl is substituted with the above aryl.
  • Suitable aryloxys include, but are not limited to, C 6 -C 15 aryloxy such as, for example, phenoxy, biphenyloxy, naphthyloxy and anthryloxy (anthracenyloxy).
  • arylalkyloxy means a group in which a hydrogen atom of hydroxyl is substituted with the above arylalkyl.
  • Suitable arylalkyloxys include, but are not limited to, C 7 -C 20 arylalkyloxys such as benzyloxy, 1-phenethyloxy, 2-phenethyloxy and styryloxy.
  • heteroaryloxy means a group in which a hydrogen atom of hydroxyl is substituted with the above heteroaryl.
  • Suitable heteroaryloxys include, but are not limited to, furanyloxy, thienyloxy (thiophenyloxy), pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy, tetrazolyloxy, thiazolyloxy, oxazolyloxy, iso 5-15 such as oxazolyloxy, oxadiazolyloxy, thiadiazolyloxy, isothiazolyloxy, pyridyloxy, pyridazinyloxy, pyrazinyloxy, pyrimidinyloxy, quinolinyloxy, isoquinolinyloxy and indolyloxy Member heteroaryloxy may be mentioned.
  • heteroarylalkyloxy means a group in which a hydrogen atom of hydroxyl is substituted with the above heteroarylalkyl.
  • Suitable heteroarylalkyloxys include, but are not limited to, 5-15 membered heteroaryl-C 1 -C 5 alkyloxy.
  • acyl means a group in which a monovalent group selected from the groups explained above and a carbonyl are linked. Suitable acyl may include, but are not limited to, such as formyl, acetyl and C 1 ⁇ C 5 aliphatic acyl, and C 1 ⁇ C 20 acyl includes C 7 ⁇ C 120 aromatic acyl of benzoyl propionyl, etc. Can be mentioned.
  • the groups described above may each independently be unsubstituted or may be further substituted by one or more monovalent groups described above.
  • halogen or “halo” means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • the present invention relates to a compound represented by, its stereoisomer or a salt thereof, or a solvate thereof.
  • the present inventors have discovered that, in a group of compounds having a skeleton similar to 2-phenylcyclopropan-1-ylamine skeleton, a novel compound having a specific structure has high inhibitory activity against LSD1.
  • the present inventors have also found that some novel compounds having the above characteristics have high selectivity for LSD1 inhibition.
  • the compound represented by the formula (I) of this embodiment has an alkyloxy having an aromatic ring or a heteroaromatic ring at the 2-position on a phenyl ring or a heteroaromatic ring in which a carbon atom of the phenyl ring is substituted with a nitrogen source. , And the amino group is substituted with a specific group.
  • the compound represented by the formula (I) of the present embodiment has a high LSD1 inhibitory activity, a high selectivity for LSD1 inhibition, and/or a useful therapeutic effect for various diseases. Can have
  • Ar 1 is substituted or unsubstituted 5 to 10 membered aryl, or substituted or unsubstituted 5 to 9 membered heteroaryl.
  • n is 1
  • X 2 is CR 22
  • X 3 is CR 23
  • X 4 is CR 24
  • R 22 and R 24 are hydrogen
  • R 23 and R 25 are fluorine.
  • Ar 1 is not phenyl.
  • Ar 1 is preferably a 5- to 10-membered aryl unsubstituted or substituted with one or more halogens, or 5- to 9-membered heteroaryl unsubstituted or substituted with one or more halogens.
  • n 1, X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 and R 24 are hydrogen, and R 23 and R 25 are When fluorine, Ar 1 is not phenyl; more preferably phenyl unsubstituted or substituted with one or more halogens, or pyridinyl or pyrazolyl unsubstituted or substituted with one or more halogens.
  • n 1, X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 and R 24 are hydrogen, and R 23 and R 25 are When fluorine, Ar 1 is not phenyl; phenyl, 3-methoxy-1-phenyl, 1-fluoro-4-phenyl, 3-fluoro-1-phenyl, 2-fluoro-pyridin-3-yl, 2- More preferably fluoro-pyridin-4-yl, 2-fluoro-pyridin-5-yl, 1H-pyrazol-3-yl, or 1H-pyrazol-4-yl, provided that n is 1 and X When 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 and R 24 are hydrogen, and R 23 and R 25 are fluorine, Ar 1 is phenyl.
  • the compound represented by the formula (I) of the present embodiment has particularly high inhibitory activity against LSD1, particularly high selectivity against LSD1 inhibition, and/or is particularly useful for a specific disease. Can have various therapeutic effects.
  • n is 1, X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 and R 24 are hydrogen, and R 23 and R
  • Ar 1 is preferably substituted phenyl, substituted or unsubstituted 5- and 7-10 membered aryl, or substituted or unsubstituted 5-9 membered heteroaryl; one or more Phenyl substituted with 1 halogen, 5 or 7-10 membered aryl unsubstituted or substituted with 1 or more halogens, or 5-9 membered unsubstituted or substituted with 1 or more halogens More preferably heteroaryl; phenyl substituted with one or more halogen, more preferably pyridinyl or pyrazolyl unsubstituted or substituted with one or more halogen; 1-fluoro-4 -Phenyl, 2-fluoro-pyridin-3-yl, 2-fluoro-
  • the compound represented by the formula (I) of the present embodiment has particularly high inhibitory activity against LSD1, particularly high selectivity against LSD1 inhibition, and/or is particularly useful for a specific disease. Can have various therapeutic effects.
  • n is 1 or 2. n is preferably 1.
  • the compound represented by the formula (I) of the present embodiment has particularly high inhibitory activity against LSD1, particularly high selectivity against LSD1 inhibition, and/or is particularly useful against a specific disease. Can have a therapeutic effect.
  • X 2 is CR 22 or N.
  • X 2 is preferably CR 22 ; more preferably CH or CF.
  • the compound represented by the formula (I) of the present embodiment has particularly high inhibitory activity against LSD1, particularly high selectivity against LSD1 inhibition, and/or is particularly useful against a specific disease. Can have various therapeutic effects.
  • X 3 is CR 23 or N.
  • X 3 is preferably CR 23 ; more preferably CH, CF, CBr, C-methyl or C-methoxy.
  • the compound represented by the formula (I) of the present embodiment has particularly high inhibitory activity against LSD1, particularly high selectivity against LSD1 inhibition, and/or is particularly useful against a specific disease. Can have various therapeutic effects.
  • X 4 is CR 24 or N.
  • X 4 is preferably CR 24 ; more preferably CH, CF or CCl.
  • the compound represented by the formula (I) of the present embodiment has particularly high inhibitory activity against LSD1, particularly high selectivity against LSD1 inhibition, and/or is particularly useful for a specific disease. Can have various therapeutic effects.
  • R 22 , R 23 , R 24 and R 25 are each independently hydrogen, halogen, substituted or unsubstituted C 1 to C 6 alkyl or substituted or unsubstituted C 1 to C 6 It is an alkoxy.
  • R 22 , R 23 , R 24 and R 25 are each independently preferably hydrogen, fluorine, chlorine, bromine, methyl, methoxy or ethoxy;
  • R 22 is hydrogen and R 23 is hydrogen.
  • R 24 is hydrogen, fluorine or chlorine
  • R 25 is hydrogen, fluorine or substituted or unsubstituted C 1 -C 6 alkoxy (eg, methoxy or ethoxy).
  • R 22 is hydrogen
  • R 23 is hydrogen or fluorine
  • R 24 is hydrogen, fluorine or chlorine
  • R 25 is hydrogen or fluorine.
  • R 22 and R 24 are both preferably hydrogen.
  • the compound represented by the formula (I) of the present embodiment has a particularly high inhibitory activity against LSD1, a particularly high selectivity against LSD1 inhibition, and/or a specific disease. Can have a particularly useful therapeutic effect on.
  • R 23 is preferably hydrogen, halogen, substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted C 1 -C 6 alkoxy; hydrogen, fluorine, bromine, methyl or More preferably it is methoxy.
  • R 23 is the group exemplified above, the compound represented by the formula (I) of the present embodiment has particularly high inhibitory activity against LSD1, particularly high selectivity against LSD1 inhibition, and/or is particularly useful for a specific disease. Can have various therapeutic effects.
  • R 25 is preferably hydrogen, halogen or substituted or unsubstituted C 1 -C 6 alkoxy; more preferably hydrogen, fluorine or ethoxy.
  • R 25 is the group exemplified above, the compound represented by the formula (I) of the present embodiment has particularly high inhibitory activity against LSD1, particularly high selectivity against LSD1 inhibition, and/or is particularly useful for a specific disease. Can have various therapeutic effects.
  • L is a single bond, substituted or unsubstituted C 1 -C 6 alkylene, substituted or unsubstituted C 2 -C 6 alkenylene, substituted or unsubstituted C 2 -C 6 alkynylene, substituted or Unsubstituted C 1 -C 6 alkylene-CO-, substituted or unsubstituted C 2 -C 6 alkenylene-CO-, or substituted or unsubstituted C 2 -C 6 alkynylene-CO-.
  • L is preferably a single bond, a substituted or unsubstituted C 1 to C 6 alkylene, or a substituted or unsubstituted C 1 to C 6 alkylene-CO—; a single bond, a substituted or unsubstituted C 1 to More preferably, it is C 2 alkylene, or substituted or unsubstituted C 1 -C 2 alkylene-CO-; still more preferably a single bond, methylene, ethylene or methylene-CO-.
  • the compound represented by the formula (I) of the present embodiment has particularly high inhibitory activity against LSD1, particularly high selectivity against LSD1 inhibition, and/or is particularly useful for a specific disease. Can have a therapeutic effect.
  • A is —CHR 1 R 2 , —NR 3 R 4 , or —CHR 3 R 4 .
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 to C 3 alkyl, substituted or unsubstituted 5 to 10 membered aryl, or substituted or unsubstituted 5 to 9 membered hetero.
  • Aryl, or R 1 and R 2 taken together with the carbon atom to which they are attached, form a substituted or unsubstituted C 4 -C 7 cycloalkyl.
  • R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 to C 3 alkyl, substituted or unsubstituted 5 to 10 membered aryl, or substituted or unsubstituted 5 to 9 membered hetero.
  • Aryl, or R 1 and R 2 , together with the carbon atom to which they are attached, are C 4 -C 7 cycloalkyl having 1 or 2 R 5 and 1 or more R 6.
  • they are each independently hydrogen, substituted or unsubstituted C 1 to C 3 alkyl, or substituted or unsubstituted 5 to 9 membered heteroaryl, or a carbon atom to which they are attached. More preferably taken together to form C 5 -C 6 cycloalkyl having 1 or 2 R 5 and 1 or more R 6 ; each independently hydrogen, methyl, or pyridyl or indolyl. Or more preferably together with the carbon atom to which they are attached form cyclopentyl or cyclohexyl having 1 or 2 R 5 and 1 or more R 6 .
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 to C 6 alkoxy-C 1 to C 6 alkyl, substituted or unsubstituted C 3 to C 7 cycloalkyl, or substituted or non-substituted.
  • a substituted straight or branched chain C 1 -C 7 alkyl, or R 3 and R 4 , together with the carbon or nitrogen atom to which they are attached, is selected from N, S and O To form a substituted or unsubstituted 4 to 7 membered heterocycloalkyl or heterocycloalkenyl containing one or more heteroatoms as ring atoms.
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 to C 6 alkoxy-C 1 to C 6 alkyl, substituted or unsubstituted C 3 to C 7 cycloalkyl, or 1 or 2
  • a straight or branched C 1 -C 7 alkyl having one R 8 and one or more R 9 , or R 3 and R 4 are the same as the carbon atom or nitrogen atom to which they are attached.
  • alkyl or heterocycloalkenyl each independently hydrogen, substituted or unsubstituted C 1 -C 3 alkoxy-C 1 -C 3 alkyl, substituted or unsubstituted C 3 -C 5 cycloalkyl Or a straight or branched C 1 -C 5 alkyl having 1 or 2 R 8 and 1 or more R 9 or together with the carbon or nitrogen atom to which they are attached.
  • a 5- to 6-membered heterocycloalkyl having one or more heteroatoms selected from N, S and O as a ring atom, and having 1 or 2 R 8 and 1 or a plurality of R 9.
  • heterocycloalkenyl each independently hydrogen, 2-methoxyethyl, cyclopropyl, or methyl, ethyl, 2- having 1 or 2 R 8 and 1 or more R 9.
  • Methylpropyl or tert-butyl, or together with the carbon atom or nitrogen atom to which they are attached, has 1 or 2 R 8 and 1 or more R 9 piperazinyl, piperidinyl, pyrrolidinyl, tetrahydro It is further preferred to form pyranyl or 1,2,3,6-tetrahydropyridyl.
  • R 5 is hydrogen, -NR 12 R 13 , R 12 R 13 NC 1 -C 3 alkyl, -NR 12 COR 13 , -NR 12 SO 2 R 13 , -NR 12 COOR 13 , -NR 12 SO.
  • R 5 is C 3 -C 7 cycloalkyl, unsubstituted or substituted with one or more R 7 , together with the 1 or 2 carbon atoms to which they are attached, N, S and O.
  • a 3- to 7-membered heterocycloalkyl which contains one or more heteroatoms selected from as ring atoms and is unsubstituted or substituted with one or more R 7 , unsubstituted C 5 -C 6 aryl, or It forms a 5-9 membered heteroaryl which contains one or more heteroatoms selected from N, S and O as ring atoms and is unsubstituted or substituted with one or more R 7 .
  • R 5 is C 3 -C 7 cycloalkyl, unsubstituted or substituted with one or more R 7 , together with the 1 or 2 carbon atoms to which they are attached, N, S and A 3- to 7-membered heterocycloalkyl, which contains one or more heteroatoms selected from O as a ring atom, and is unsubstituted or substituted with one or more R 7 , unsubstituted C 5 -C 6 aryl, Or, forming a 5- or 6-membered heteroaryl which contains one or more heteroatoms selected from N, S and O as a ring atom and is unsubstituted or substituted with one or more R 7 's.
  • C 3 -C 7 cycloalkyl unsubstituted or substituted with one or more R 7 together with the 1 or 2 carbon atoms to which they are attached, N, S and O It is possible to form a 4- to 6-membered heterocycloalkyl which contains one or more heteroatoms as ring atoms and is unsubstituted or substituted by one or more R 7 or unsubstituted C 5 -C 6 aryl.
  • R 6 is hydrogen, halogen, substituted or unsubstituted C 6 to C 15 aryl, substituted or unsubstituted 5 or 6 membered heteroaryl, and substituted or unsubstituted C 1 to C 6 alkyl Independently selected.
  • R 6 is hydrogen, halogen, substituted or unsubstituted C 6 -C 15 aryl, substituted or unsubstituted 5- or 6-membered heteroaryl, and unsubstituted or one or more halogen, substituted or unsubstituted C It is preferably independently selected from the group consisting of C 1 -C 6 alkyl substituted with 6 to C 15 aryl or 5 or 6 membered heteroaryl; hydrogen, substituted or unsubstituted C 6 to C 15 Aryl, substituted or unsubstituted 5- or 6-membered heteroaryl, and substituted with unsubstituted or one or more halogen, substituted or unsubstituted C 6 -C 15 aryl or 5- or 6-membered heteroaryl More preferably, it is independently selected from the group consisting of C 1 -C 6 alkyl; hydrogen, phenyl, pyridinyl, 3-methyl-1,2,4-oxadiazol-5-yl or methyl
  • the substituent is C 1 -C 6 alkyl which is unsubstituted or substituted with one or more halogen, C 1 -C 6 alkoxy, halogen, cyano.
  • it is one or more groups independently selected from the group consisting of, OH, carboxyl, C 1 -C 6 alkyloxycarbonyl and carbamoyl.
  • R 7 is preferably a monovalent group or a divalent group independently selected from the group consisting of hydrogen and oxo ( ⁇ O).
  • R 8 is hydrogen, halogen, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkoxy-C 1 -C 6 alkyl, -COR 13 , -COOR 13 , -CONR 12 R 13 , -NR 12 R 13 , -NR 12 COR 13 , -NR 12 CO 2 R 13 , -NR 14 CONR 12 R 13 , -NR 12 SO 2 R 13 , and substituted or unsubstituted C 1 to C A monovalent group independently selected from the group consisting of 6 alkyl.
  • R 8 is hydrogen, halogen, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, unsubstituted or substituted with one or more hydroxyl, —COR 13 , COOR 13 , -CONR 12 R 13 , -NR 12 R 13 , -NR 12 COR 13 , -NR 12 CO 2 R 13 , -NR 14 CONR 12 R 13 , -NR 12 SO 2 R 13 , as well as unsubstituted or 1 Be a monovalent group independently selected from the group consisting of one or more halogen, hydroxyl, phenyl, substituted amino, cyclic amino, C 1 to C 6 alkyl substituted with -COOR 12 or -CONR 12 R 13.
  • hydrogen, halogen, C 4 ⁇ C 6 cycloalkyl, unsubstituted or one or more C 1 is substituted with a hydroxyl ⁇ C 3 alkoxy -C 1 ⁇ C 3 alkyl, -COR 13, -COOR 13, - CONR 12 R 13 , -NR 12 R 13 , -NR 12 COR 13 , -NR 12 CO 2 R 13 , -NR 14 CONR 12 R 13 , -NR 12 SO 2 R 13 , as well as unsubstituted or one or more halogens.
  • R 8 is C 3 -C 7 unsubstituted or substituted with one or more R 10 together with 1 or 2 atoms selected from the carbon and nitrogen atoms to which they are attached.
  • 3-7 membered heterocycloalkyl which contains one or more heteroatoms selected from cycloalkyl, N, S and O as a ring atom, and is unsubstituted or substituted with one or more R 10 It forms a C 5 -C 6 aryl or a 5-9 membered heteroaryl which is unsubstituted or substituted with one or more R 11 .
  • R 8 is C 3 -C unsubstituted or substituted with one or more R 10 together with 1 or 2 atoms selected from the carbon and nitrogen atoms to which they are attached. 7 cycloalkyl, 3 to 7 membered heterocycloalkyl containing at least one heteroatom selected from N, S and O as a ring atom and unsubstituted or substituted with one or more R 10.
  • a substituted C 5 -C 6 aryl or a 5-9 membered heteroaryl which is unsubstituted or substituted by one or more R 11 ; selected from the carbon and nitrogen atoms to which they are attached
  • One or more heteroatoms selected from C 4 -C 6 cycloalkyl, which is unsubstituted or substituted with 1 or more R 10 , together with 1 or 2 atoms, 4 to 6-membered heterocycloalkyl, which is contained as a ring atom and is unsubstituted or substituted with one or more R 10 , unsubstituted C 5 to C 6 aryl, or unsubstituted or one or more R 11 .
  • R 9 is hydrogen, halogen, substituted or unsubstituted 4 to 7 membered heterocycloalkyl, substituted or unsubstituted C 6 to C 15 aryl, substituted or unsubstituted C 6 to C 15 aryl-C 1 to C A monovalent group independently selected from the group consisting of 3 alkyl, substituted or unsubstituted 5 to 9 membered heteroaryl, and substituted or unsubstituted C 1 to C 6 alkyl.
  • R 9 is hydrogen, halogen (eg, fluorine, chlorine, bromine or iodine), oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted Of piperazinyl, substituted or unsubstituted aryl, substituted or unsubstituted C 6 -C 15 aryl-C 1 -C 3 alkyl, substituted or unsubstituted 5-9 membered heteroaryl, and unsubstituted or one or more
  • it is a monovalent group independently selected from the group consisting of C 1 -C 6 alkyl substituted with oxetanyl, tetrahydrofuranyl, aryl, or 5-9 membered heteroaryl; hydrogen,
  • a monovalent group selected; hydrogen, halogen (eg, fluorine, chlorine, bromine or iodine), oxetane-3-yl, morpholin-4-yl, azetidin-3-yl, piperidin-2- -Yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 3-methoxyphenyl, 4-chlorophenyl, 4-carboxyphenyl, 1H-benzo[d]imidazol-1-yl, 2-hydroxy-1H-benzo [d] More preferably, it is a monovalent group independently selected from the group consisting of imidazol-1-yl, pyridin-2-yl, pyrazin-2-yl, methyl, and benzyl.
  • halogen eg, fluorine, chlorine, bromine or iodine
  • oxetane-3-yl morpholin-4-yl
  • azetidin-3-yl piperidin
  • R 10 is a monovalent or divalent group independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, —CONR 12 R 13 and oxo ( ⁇ O).
  • R 10 is preferably a monovalent group independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, —CONR 12 R 13 and oxo; consisting of hydrogen, oxo and methyl More preferably, it is a monovalent group independently selected from the group.
  • R 10 is one or more selected from substituted or unsubstituted C 3 -C 7 cycloalkyl, N, S and O together with 1 or 2 carbon atoms or nitrogen atoms to which they are attached.
  • R 10 taken together with the 1 or 2 carbon atoms to which they are attached form a substituted or unsubstituted C 3 -C 7 cycloalkyl, or a substituted or unsubstituted C 5 -C 6 aryl. Is more preferred; it is more preferred that they are taken together with the 1 or 2 carbon atoms to which they are attached to form phenyl.
  • R 11 is a monovalent group independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1 to C 6 alkoxy, and substituted or unsubstituted C 1 to C 6 alkyl.
  • R 11 is hydrogen, halogen, C 1 ⁇ C 6 alkoxy, and unsubstituted or one or more halogen or hydroxyl, dimethylamino, N- morpholino, from C 1 ⁇ C 6 alkyl substituted with N- pyrrolidino or carboxyl
  • It is preferably a monovalent group independently selected from the group consisting of hydrogen, methyl, ethyl, hydroxymethyl, trifluoromethyl, carboxymethyl, 2-(dimethylamino)ethyl and 2-(N-pyrrolidino)ethyl. More preferably, it is a monovalent group independently selected from the group consisting of, 2-(N-morpholino)ethyl, 2-(carboxy)ethyl,
  • R 12 and R 13 are monovalent groups independently selected from the group consisting of hydrogen, substituted or unsubstituted C 6 -C 15 aryl, and substituted or unsubstituted C 1 -C 6 alkyl.
  • R 12 and R 13 are hydrogen, C 6 -C 15 aryl, and unsubstituted or one or more halogen, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-(methylaminoethyl)-piperazine
  • R 12 and R 13 are, together with the carbon atom or nitrogen atom to which they are attached, a substituted or unsubstituted C 4 -C 7 cycloalkyl or a substituted or unsubstituted 4-7 membered heterocycloalkyl To form.
  • R 12 and R 13 are preferably taken together with the carbon or nitrogen atom to which they are attached to form an unsubstituted C 4 -C 7 cycloalkyl or a 4-7 membered substituted or unsubstituted heterocycloalkyl.
  • R 14 is a monovalent group independently selected from the group consisting of hydrogen and substituted or unsubstituted C 1 -C 6 alkyl.
  • R 14 is preferably a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C 1 -C 6 alkyl; more preferably hydrogen.
  • substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted.
  • Alkyl substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted Or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, Substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted ary
  • halogen fluorine, chlorine, bromine or iodine
  • cyano nitro, hydroxyl
  • substituted or unsubstituted C 1 to C 5 alkyl substituted or unsubstituted C 2 to C 5 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 cycloalkenyl, substituted or unsubstituted C 3 -C 6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C 7 to C 11 cycloalkylalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C 1 to C 5 alkyl, substituted or unsubstituted C 6 -C 15 ary
  • the compound represented by the formula (I) includes Ar 1 , n, X 2 , X 3 , X 4 , R 22 , R 23 , R 24 , R 25 , L, A, R 1 and R exemplified above. 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9, R 10, R 11, the inclusion of R 12, R 13 and compounds defined by any combination of R 14 You can
  • the compound represented by formula (I) is Ar 1 is 5- to 10-membered aryl which is unsubstituted or substituted with one or more halogens, or 5- to 9-membered heteroaryl which is unsubstituted or substituted with one or more halogens, provided that n is 1, X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 and R 24 are hydrogen, and R 23 and R 25 are fluorine.
  • Ar 1 is not phenyl, n is 1 or 2, X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 , R 23 , R 24 and R 25 are each independently hydrogen, halogen, substituted or unsubstituted C 1 to C 6 alkyl or substituted or unsubstituted C 1 to C 6 alkoxy, L is a single bond, substituted or unsubstituted C 1 -C 6 alkylene, or substituted or unsubstituted C 1 -C 6 alkylene-CO-, A is -CHR 1 R 2 , -NR 3 R 4 , or -CHR 3 R 4 , R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 to C 3 alkyl, substituted or unsubstituted 5 to 10 membered aryl, or substituted or unsubstituted 5 to 9 membered hetero.
  • Aryl, or R 1 and R 2 together with the carbon atom to which they are attached, is a C 4 -C 7 cycloalkyl having 1 or 2 R 5 and 1 or more R 6.
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 to C 6 alkoxy-C 1 to C 6 alkyl, substituted or unsubstituted C 3 to C 7 cycloalkyl, or 1 or 2
  • R 8 is hydrogen, halogen, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkoxy-C 1 -C 6 alkyl, -COR 13 , -COOR 13 , -CONR 12 R 13 , -NR 12 R 13 , -NR 12 COR 13 , -NR 12 CO 2 R 13 , -NR 14 CONR 12 R 13 , -NR 12 SO 2 R 13 , and substituted or unsubstituted C 1 to C
  • a monovalent group independently selected from the group consisting of 6 alkyl, or R 8 together with 1 or 2 atoms selected from the carbon atom and the nitrogen atom to which they are attached are non- C 3 -C 7 cycloalkyl substituted or substituted with one or more R 10 , one or more heteroatoms selected from N, S and O as a ring atom, and unsubstituted or one or more Forming
  • R 9 is hydrogen, halogen, substituted or unsubstituted 4 to 7 membered heterocycloalkyl, substituted or unsubstituted C 6 to C 15 aryl, substituted or unsubstituted C 6 to C 15 aryl-C 1 to C
  • R 10 is a monovalent group or a divalent group independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 to C 6 alkyl, —CONR 12 R 13 and oxo ( ⁇ O), Alternatively, R 10 is, together with one or two carbon atoms or nitrogen atoms to which they are attached, one or more selected from substituted or unsubstituted C 3 -C 7 cycloalkyl, N, S and O.
  • R 11 is a monovalent group independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1 to C 6 alkoxy, and substituted or unsubstituted C 1 to C 6 alkyl
  • R 12 and R 13 are monovalent groups independently selected from the group consisting of hydrogen, substituted or unsubstituted C 6 -C 15 aryl, and substituted or unsubstituted C 1 -C 6 alkyl
  • R 12 and R 13 together with a carbon atom or a nitrogen atom to which they are bonded are substituted or unsubstituted C 4 to C 7 cycloalkyl or substituted or unsubstituted 4 to 7 membered heterocycloalkyl.
  • R 14 is a monovalent group independently selected from the group consisting of hydrogen and substituted or unsubstituted C 1 -C 6 alkyl, When the above groups are substituted, unless otherwise stated, the substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 2 -C 5 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkenyl, substituted or unsubstituted C 3 to C 6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C 7 to C 11 cycl
  • the compound represented by formula (I) is Ar 1 is phenyl unsubstituted or substituted with one or more halogen, or pyridinyl or pyrazolyl unsubstituted or substituted with one or more halogen, provided that n is 1 and X 2 is
  • CR 22 is, X 3 is CR 23 , X 4 is CR 24 , R 22 and R 24 are hydrogen, and R 23 and R 25 are fluorine, then Ar 1 is not phenyl and n is 1 or 2, X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 , R 23 , R 24 and R 25 are each independently hydrogen, halogen, substituted or unsubstituted C 1 to C 6 alkyl or substituted or unsubstituted C 1 to C 6 alkoxy, L is a single bond, substituted or unsubstituted C 1 -C 6 alkylene, or substituted or unsubstistit
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 to C 3 alkoxy-C 1 to C 3 alkyl, substituted or unsubstituted C 3 to C 5 cycloalkyl, or 1 or 2 A straight or branched C 1 -C 5 alkyl having one R 8 and one or more R 9 or R 3 and R 4 together with the carbon atom or nitrogen atom to which they are attached.
  • R 5 is hydrogen, -NR 12 R 13 , R 12 R 13 NC 1 to C 3 alkyl, -NR 12 COR 13 , -NR 12 SO 2 R 13 , -NR 12 COOR 13 , -NR 12 SO 2 NR 13 R 14 , —OH, HO—C 1 -C 3 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkoxy, —CONR 12 R 13 , oxo ( ⁇ O), —COR 12 , —COOR 12 , Substituted or unsubstituted morpholin-4-yl, substituted or unsubstituted pyrrolidinyl, and unsubstituted or one or more -NR 12 R 13 , -NR 12 COR 13 , -NR 12 SO 2 R 13 , -NR 12 COOR 13 , -NR 12 SO 2 NR 13 R 14 , -OH,
  • R 6 is hydrogen, halogen, substituted or unsubstituted C 6 -C 15 aryl, substituted or unsubstituted 5- or 6-membered heteroaryl, and unsubstituted or one or more halogen, substituted or unsubstituted C A monovalent group independently selected from the group consisting of 6 to C 15 aryl or C 1 to C 6 alkyl substituted with 5 or 6 membered heteroaryl, said aryl or heteroaryl being substituted In this case, the substituent is C 1 -C
  • R 11 is hydrogen, halogen, C 1 ⁇ C 6 alkoxy, and unsubstituted or one or more halogen, hydroxyl, dimethylamino, N- morpholino, N- pyrrolidino or C 1 ⁇ C 6 alkyl substituted with carboxyl
  • a monovalent group independently selected from the group consisting of R 12 and R 13 are hydrogen, C 6 -C 15 aryl, and unsubstituted or one or more halogen, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-(methylaminoethyl)-piperazine Is it a monovalent group independently selected from the group consisting of C 1 -C 6 alkyl substituted with 1-yl, 2,8-diazaspiro[4.5]decan
  • R 14 is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C 1 -C 6 alkyl,
  • the substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 2 -C 5 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkenyl, substituted or un
  • the compound represented by formula (I) is Ar 1 is phenyl unsubstituted or substituted with one or more halogen, or pyridinyl or pyrazolyl unsubstituted or substituted with one or more halogen, provided that n is 1 and X 2 is
  • CR 22 is, X 3 is CR 23 , X 4 is CR 24 , R 22 and R 24 are hydrogen, and R 23 and R 25 are fluorine
  • Ar 1 is not phenyl and n is 1 or 2
  • X 2 is CR 22
  • X 3 is CR 23
  • X 4 is CR 24
  • R 22 , R 23 , R 24 and R 25 are each independently hydrogen, fluorine, chlorine, bromine, methyl, methoxy or ethoxy
  • L is a single bond, substituted or unsubstituted C 1 -C 6 alkylene, or substituted or unsubstituted C 1 -C 6 alkylene-CO-
  • A
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 to C 3 alkoxy-C 1 to C 3 alkyl, substituted or unsubstituted C 3 to C 5 cycloalkyl, or 1 or 2 A straight or branched C 1 -C 5 alkyl having one R 8 and one or more R 9 or R 3 and R 4 together with the carbon atom or nitrogen atom to which they are attached.
  • R 5 is hydrogen, -NR 12 R 13 , R 12 R 13 NC 1 to C 3 alkyl, HO-C 1 to C 3 alkyl, C 3 to C 7 cycloalkoxy, substituted or unsubstituted morpholin-4-yl And a monovalent group independently selected from the group consisting of unsubstituted or one or more —NR 12 R 13 , or C 1 -C 6 alkyl substituted with —OH, or R 5 is One selected from C 3 -C 7 cycloalkyl, which is unsubstituted or substituted by one or more R 7 together with 1 or 2 carbon atoms to which they are attached, N, S and O Forming a 4- to 6-membered heterocycloalkyl, which is unsubstituted or substituted with one or more R 7 or an unsubstituted C 5 -C 6 aryl, containing the above hetero atom as a ring atom, R
  • R 7 is a monovalent group or a divalent group independently selected from the group consisting of hydrogen and oxo ( ⁇ O)
  • R 8 is hydrogen, halogen, C 4 -C 6 cycloalkyl, C 1 -C 3 alkoxy-C 1 -C 3 alkyl unsubstituted or substituted with one or more hydroxyl, —COR 13 , —COOR 13 , -CONR 12 R 13 , -NR 12 R 13 , -NR 12 COR 13 , -NR 12 CO 2 R 13 , -NR 14 CONR 12 R 13 , -NR 12 SO 2 R 13 , as well as unsubstituted or one or more One independently selected from the group consisting of halogen, hydroxyl, phenyl, methylamino, dimethylamino, N-pyrrolidino, N-morpholino, C 1 -C 3 alkyl substituted with —COOR 12 or —CONR 12 R 13.
  • a valent group, or R 8 is unsubstituted or substituted with one or more R 10 together with one or two atoms selected from the carbon and nitrogen atoms to which they are attached.
  • 4- to 6 -membered hetero containing as ring atoms one or more heteroatoms selected from C 4 to C 6 cycloalkyl, N, S and O, and unsubstituted or substituted with one or more R 10.
  • R 9 is hydrogen, halogen (eg, fluorine, chlorine, bromine or iodine), oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzimidazolyl, pyridinyl, pyrazinyl, and unsubstituted or one or more oxetanyl, tetrahydrofuranyl, or C 1 ⁇ substituted by phenyl
  • R 10 is a monovalent group independently selected from the group consisting of hydrogen
  • R 11 is hydrogen, methyl, ethyl, hydroxymethyl, trifluoromethyl, carboxymethyl, 2-(dimethylamino)ethyl, 2-(N-pyrrolidino)ethyl, 2-(N-morpholino)ethyl, 2-(carboxy ) Ethyl, and a monovalent group independently selected from the group consisting of 2,3-dihydroxypropyl
  • R 12 and R 13 are hydrogen, phenyl, methyl, ethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-(methylaminoethyl)-piperazin-1-ylmethyl, (2,8-diazaspiro [4.5] decan-8-yl)-methyl, and a monovalent group independently selected from the group consisting of morpholin-4-yl-methyl, or R 12 and R 13 are carbons to which they are attached.
  • R 14 is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C 1 -C 6 alkyl, When the above groups are substituted, unless otherwise stated, the substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 2 -C 5 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkenyl, substituted
  • the compound of formula (I) is Ar 1 is phenyl, 3-methoxy-1-phenyl, 1-fluoro-4-phenyl, 3-fluoro-1-phenyl, 2-fluoro-pyridin-3-yl, 2-fluoro-pyridin-4-yl, 2-fluoro-pyridin-5-yl, 1H-pyrazol-3-yl, or 1H-pyrazol-4-yl, provided that n is 1, X 2 is CH, X 3 is CF , X 4 is CH and R 25 is fluorine, Ar 1 is not phenyl and n is 1 or 2, X 2 is CH or CF, X 3 is CH, CF, CBr, C-methyl or C-methoxy, X 4 is CH, CF or CCl, R 25 is hydrogen, fluorine or ethoxy, L is a single bond, methylene, ethylene or methylene-CO-, A is -CHR 1 R 2 , -NR
  • R 3 and R 4 together with the carbon or nitrogen atom to which they are attached have 1 or 2 R 8 and 1 or more R 9 morpholinyl, piperazinyl, Forms piperidinyl, pyrrolidinyl, tetrahydropyranyl or 1,2,3,6-tetrahydropyridinyl
  • R 5 is a monovalent group independently selected from the group consisting of hydrogen, NH 2 , cyclohexyloxy, morpholin-4-yl, methyl, aminomethyl and hydroxymethyl, or R 5 taken together with the 1 or 2 carbon atoms to which they are attached form cyclopentyl, azetidinyl, pyrrolidinyl, 2-pyrrolidonyl, imidazolidine-2,4-dionyl, piperidinyl or phenyl
  • R 6 is hydrogen, phenyl, pyridinyl, 3-methyl-1,2,4-oxadiazol-5-yl or methyl
  • R 9 is hydrogen, halogen (for example, fluorine, chlorine, bromine or iodine), oxetane-3-yl, morpholin-4-yl, azetidin-3-yl, piperidin-2-yl, piperidin-4-yl, 1 -Methylpiperidin-4-yl, 3-methoxyphenyl, 4-chlorophenyl, 4-carboxyphenyl, 1H-benzo[d]imidazol-1-yl, 2-hydroxy-1H-benzo[d]imidazol
  • the compound of formula (I) is Ar 1 is 2-fluoro-pyridin-3-yl, n is 1, and X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 is hydrogen, R 23 is hydrogen or fluorine, R 24 is hydrogen, fluorine or chlorine, R 25 is hydrogen or fluorine, L is a single bond, methylene, ethylene, or methylene-CO-, A is -CHR 1 R 2 , -NR 3 R 4 , or -CHR 3 R 4 , R 1 and R 2 are each independently hydrogen, methyl, or pyridyl or indolyl, or R 1 and R 2 are taken together with the carbon atom to which they are attached, 1 or 2 R Forming cyclopentyl or cyclohexyl having 5 and 1 or a plurality of R 6 ; R 3 and R 4 are each independently hydrogen, 2-methoxyethyl, cyclopropyl, or 1
  • R 3 and R 4 together with the carbon or nitrogen atom to which they are attached have 1 or 2 R 8 and 1 or more R 9 morpholinyl, piperazinyl, Forms piperidinyl, pyrrolidinyl, tetrahydropyranyl or 1,2,3,6-tetrahydropyridinyl
  • R 5 is a monovalent group independently selected from the group consisting of hydrogen, NH 2 , cyclohexyloxy, morpholin-4-yl, methyl, aminomethyl and hydroxymethyl, or R 5 taken together with the 1 or 2 carbon atoms to which they are attached form cyclopentyl, azetidinyl, pyrrolidinyl, 2-pyrrolidonyl, imidazolidine-2,4-dionyl, piperidinyl or phenyl
  • R 6 is hydrogen, phenyl, pyridinyl, 3-methyl-1,2,4-oxadiazol-5-yl or methyl
  • R 9 is hydrogen, halogen (for example, fluorine, chlorine, bromine or iodine), oxetane-3-yl, morpholin-4-yl, azetidin-3-yl, piperidin-2-yl, piperidin-4-yl, 1 -Methylpiperidin-4-yl, 3-methoxyphenyl, 4-chlorophenyl, 4-carboxyphenyl, 1H-benzo[d]imidazol-1-yl, 2-hydroxy-1H-benzo[d]imidazol
  • the compound of formula (I) is selected from the group consisting of:
  • the compound represented by the formula (I) of this embodiment having the characteristics described above has a particularly high inhibitory activity against LSD1, a particularly high selectivity against LSD1 inhibition, and/or a particularly useful therapeutic effect against a specific disease. be able to.
  • the compound of formula (I) has the formula (Ia): It is preferable that it is a compound represented by, its stereoisomer, a salt thereof, or a solvate thereof.
  • a a is —CHR 1 R 2 or —CHR 3 R 4 .
  • Ar 1 , n, X 2 , X 3 , X 4 , R 22 , R 23 , R 24 , R 25 , R 1 , R 2 , R 3 and R 4 are as defined above. ..
  • a a is a substituted or unsubstituted 5-9 membered heteroaryl C 1 -C 6 alkyl, a substituted or unsubstituted C 4 -C 11 cycloalkyl, or a substituted or unsubstituted 4 to 15-membered heterocycloalkyl is preferred; substituted or unsubstituted 5-9 membered heteroaryl C 1 -C 6 alkyl, substituted or unsubstituted C 4 -C 11 cycloalkyl, or substituted or unsubstituted More preferably 4-11 membered heterocycloalkyl; substituted or unsubstituted 5-9 membered heteroaryl C 1 -C 3 alkyl, substituted or unsubstituted C 5 -C 11 cycloalkyl, or substituted or More preferably, it is an unsubstituted 5-11 membered heterocycloalkyl; substituted or unsubstituted quinu
  • each of the substituents is independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or non-substituted Substituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted
  • halogen fluorine, chlorine, bromine or iodine
  • cyano nitro, hydroxyl
  • substituted or unsubstituted C 1 to C 5 alkyl substituted or unsubstituted C 2 to C 5 alkenyl, substituted or unsubstituted C 2 To C 5 alkynyl, substituted or unsubstituted C 3 to C 6 cycloalkyl, substituted or unsubstituted C 3 to C 6 cycloalkenyl, substituted or unsubstituted C 3 to C 6 cycloalkynyl, substituted or unsubstituted 3 To 6-membered heterocycloalkyl, substituted or unsubstituted C 7 to C 11 cycloalkylalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C 1 to C 5 alkyl, substituted or unsubstituted C 6 ⁇ C 15 aryl, substituted
  • each group of A a exemplified above is substituted with one or more groups
  • the substituent, together with the carbon atom to which they are attached is a substituted or unsubstituted C 4 -C 7 cycloalkyl group.
  • a 4- to 7-membered heteroaryl containing one or more selected heteroatoms as ring atoms may be formed.
  • a a is preferably a substituted or unsubstituted polycyclic ring such as a bridged ring, a condensed ring or a spiro ring.
  • the substituent is preferably selected from the substituents of A a exemplified above.
  • the compound represented by formula (Ia) is Ar 1 is 5- to 10-membered aryl which is unsubstituted or substituted with one or more halogens, or 5- to 9-membered heteroaryl which is unsubstituted or substituted with one or more halogens, provided that n is 1, X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 and R 24 are hydrogen, and R 23 and R 25 are fluorine.
  • Ar 1 is not phenyl, n is 1 or 2, X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 , R 23 , R 24 and R 25 are each independently hydrogen, halogen, substituted or unsubstituted C 1 to C 6 alkyl or substituted or unsubstituted C 1 to C 6 alkoxy, A a is -CHR 1 R 2 or -CHR 3 R 4 , R 1 and R 2 are each independently hydrogen, substituted or unsubstituted C 1 to C 3 alkyl, substituted or unsubstituted 5 to 10 membered aryl, or substituted or unsubstituted 5 to 9 membered hetero.
  • Aryl, or R 1 and R 2 together with the carbon atom to which they are attached, is a C 4 -C 7 cycloalkyl having 1 or 2 R 5 and 1 or more R 6.
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 to C 6 alkoxy-C 1 to C 6 alkyl, substituted or unsubstituted C 3 to C 7 cycloalkyl, or 1 or 2
  • R 7 is hydrogen, halogen, substituted or unsubstituted C 6 to C 15 aryl, substituted or unsubstituted 5 or 6 membered heteroaryl, and substituted or unsubstituted C 1 to C 6 alkyl
  • R 8 is hydrogen, halogen, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkoxy-C 1 -C 6 alkyl, -COR 13 , -COOR 13 , -CONR 12 R 13 , -NR 12 R 13 , -NR 12 COR 13 , -NR 12 CO 2 R 13 , -NR 14 CONR 12 R 13 , -NR 12 SO 2 R 13 , and substituted or unsubstituted C 1 to C
  • a monovalent group independently selected from the group consisting of 6 alkyl, or R 8 together with one or two atoms selected from the carbon atom and the nitrogen atom to which they are attached are non- C 3 -C 7 cycloalkyl substituted or substituted with one or more R 10 , one or more heteroatoms selected from N, S and O as a ring atom, and unsubstituted or one or more Forming
  • R 9 is hydrogen, halogen, substituted or unsubstituted 4 to 7 membered heterocycloalkyl, substituted or unsubstituted C 6 to C 15 aryl, substituted or unsubstituted C 6 to C 15 aryl-C 1 to C
  • R 10 is a monovalent group or a divalent group independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 to C 6 alkyl, —CONR 12 R 13 and oxo ( ⁇ O),
  • R 10 is, together with one or two carbon atoms or nitrogen atoms to which they are attached, one or more selected from substituted or unsubstituted C 3 -C 7 cycloalkyl, N, S and O.
  • R 11 is a monovalent group independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1 to C 6 alkoxy, and substituted or unsubstituted C 1 to C 6 alkyl
  • R 12 and R 13 are monovalent groups independently selected from the group consisting of hydrogen, substituted or unsubstituted C 6 -C 15 aryl, and substituted or unsubstituted C 1 -C 6 alkyl
  • R 12 and R 13 together with a carbon atom or a nitrogen atom to which they are bonded are substituted or unsubstituted C 4 to C 7 cycloalkyl or substituted or unsubstituted 4 to 7 membered heterocycloalkyl.
  • R 14 is a monovalent group independently selected from the group consisting of hydrogen and substituted or unsubstituted C 1 -C 6 alkyl, When the above groups are substituted, unless otherwise stated, the substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 2 -C 5 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkenyl, substituted or unsubstituted C 3 to C 6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C 7 to C 11 cycl
  • the compound represented by formula (Ia) is Ar 1 is phenyl unsubstituted or substituted with one or more halogen, or pyridinyl or pyrazolyl unsubstituted or substituted with one or more halogen, provided that n is 1 and X 2 is
  • CR 22 is, X 3 is CR 23 , X 4 is CR 24 , R 22 and R 24 are hydrogen, and R 23 and R 25 are fluorine, then Ar 1 is not phenyl and n is 1 or 2, X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 , R 23 , R 24 and R 25 are each independently hydrogen, halogen, substituted or unsubstituted C 1 to C 6 alkyl or substituted or unsubstituted C 1 to C 6 alkoxy, A a is -CHR 1 R 2 or -CHR 3 R 4 , R 1 and R 2 are each independently hydrogen, substituted or
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 to C 3 alkoxy-C 1 to C 3 alkyl, substituted or unsubstituted C 3 to C 5 cycloalkyl, or 1 or 2 A straight or branched C 1 -C 5 alkyl having one R 8 and one or more R 9 or R 3 and R 4 together with the carbon atom or nitrogen atom to which they are attached.
  • R 5 is hydrogen, -NR 12 R 13 , R 12 R 13 NC 1 to C 3 alkyl, -NR 12 COR 13 , -NR 12 SO 2 R 13 , -NR 12 COOR 13 , -NR 12 SO 2 NR 13 R 14 , —OH, HO—C 1 -C 3 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkoxy, —CONR 12 R 13 , oxo ( ⁇ O), —COR 12 , —COOR 12 , Substituted or unsubstituted morpholin-4-yl, substituted or unsubstituted pyrrolidinyl, and unsubstituted or one or more -NR 12 R 13 , -NR 12 COR 13 , -NR 12 SO 2 R 13 , -NR 12 COOR 13 , -NR 12 SO 2 NR 13 R 14 , -OH, -CONR 12 R 13 ,
  • R 6 is hydrogen, halogen, substituted or unsubstituted C 6 -C 15 aryl, substituted or unsubstituted 5- or 6-membered heteroaryl, and unsubstituted or one or more halogen, substituted or unsubstituted C A monovalent group independently selected from the group consisting of 6 to C 15 aryl or C 1 to C 6 alkyl substituted with 5 or 6 membered heteroaryl, said aryl or heteroaryl being substituted In this case, the substituent is C 1 -C
  • R 11 is hydrogen, halogen, C 1 ⁇ C 6 alkoxy, and unsubstituted or one or more halogen or hydroxyl substituted with a C 1 ⁇ C 6 monovalent radical independently selected from the group consisting of alkyl Yes
  • R 12 and R 13 are hydrogen, C 6 -C 15 aryl, and unsubstituted or one or more halogen, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-(methylaminoethyl)-piperazine Is it a monovalent group independently selected from the group consisting of C 1 -C 6 alkyl substituted with 1-yl, 2,8-diazaspiro[4.5]decan-8-yl or morpholin-4-yl?
  • R 14 is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C 1 -C 6 alkyl,
  • the substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 2 -C 5 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkenyl, substituted or un
  • the compound represented by formula (Ia) is Ar 1 is phenyl unsubstituted or substituted with one or more halogen, or pyridinyl or pyrazolyl unsubstituted or substituted with one or more halogen, provided that n is 1 and X 2 is
  • CR 22 is, X 3 is CR 23 , X 4 is CR 24 , R 22 and R 24 are hydrogen, and R 23 and R 25 are fluorine
  • Ar 1 is not phenyl and n is 1 or 2
  • X 2 is CR 22
  • X 3 is CR 23
  • X 4 is CR 24
  • R 22 , R 23 , R 24 and R 25 are each independently hydrogen, fluorine, chlorine, bromine, methyl, methoxy or ethoxy
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 to C 3 alkoxy-C 1 to C 3 alkyl, substituted or unsubstituted C 3 to C 5 cycloalkyl, or 1 or 2 A straight or branched C 1 -C 5 alkyl having one R 8 and one or more R 9 or R 3 and R 4 together with the carbon atom or nitrogen atom to which they are attached.
  • R 5 is hydrogen, -NR 12 R 13 , R 12 R 13 NC 1 to C 3 alkyl, HO-C 1 to C 3 alkyl, C 3 to C 7 cycloalkoxy, substituted or unsubstituted morpholin-4-yl And a monovalent group independently selected from the group consisting of C 1 -C 6 alkyl which is unsubstituted or substituted with one or more —NR 12 R 13 , —OH, or R 5 is One selected from C 3 -C 7 cycloalkyl, which is unsubstituted or substituted by one or more R 7 together with 1 or 2 carbon atoms to which they are attached, N, S and O Forming a 4- to 6-membered heterocycloalkyl, which is unsubstituted or substituted with one or more R 7 or an unsubstituted C 5 -C 6 aryl, containing the above hetero atom as a ring atom, R 6 is hydrogen, substituted or
  • R 7 is a monovalent group or a divalent group independently selected from the group consisting of hydrogen and oxo ( ⁇ O)
  • R 8 is hydrogen, halogen, C 4 -C 6 cycloalkyl, C 1 -C 3 alkoxy-C 1 -C 3 alkyl unsubstituted or substituted with one or more hydroxyl, —COR 13 , —COOR 13 , -CONR 12 R 13 , -NR 12 R 13 , -NR 12 COR 13 , -NR 12 CO 2 R 13 , -NR 14 CONR 12 R 13 , -NR 12 SO 2 R 13 , as well as unsubstituted or 1 or more
  • a monovalent radical independently selected from the group consisting of C 1 -C 3 alkyl substituted with halogen, hydroxyl, phenyl, methylamino, dimethylamino, —COOR 12 or —CONR 12 R 13 , or R 8 is C 4 -C
  • R 11 is a monovalent group independently selected from the group consisting of hydrogen, methyl, ethyl, hydroxymethyl, and trifluoromethyl
  • R 12 and R 13 are hydrogen, phenyl, methyl, ethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-(methylaminoethyl)-piperazin-1-ylmethyl, (2,8-diazaspiro [4.5] decan-8-yl)-methyl, and a monovalent group independently selected from the group consisting of morpholin-4-yl-methyl, or R 12 and R 13 are carbons to which they are attached.
  • R 14 is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C 1 -C 6 alkyl, When the above groups are substituted, unless otherwise stated, the substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 2 -C 5 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkenyl, substituted
  • the compound represented by formula (Ia) is Ar 1 is phenyl, 3-methoxy-1-phenyl, 1-fluoro-4-phenyl, 3-fluoro-1-phenyl, 2-fluoro-pyridin-3-yl, 2-fluoro-pyridin-4-yl, 2-fluoro-pyridin-5-yl, 1H-pyrazol-3-yl, or 1H-pyrazol-4-yl, provided that n is 1, X 2 is CH, X 3 is CF , X 4 is CH and R 25 is fluorine, Ar 1 is not phenyl and n is 1 or 2, X 2 is CH or CF, X 3 is CH, CF, CBr, C-methyl or C-methoxy, X 4 is CH, CF or CCl, R 25 is hydrogen, fluorine or ethoxy, A a is -CHR 1 R 2 or -CHR 3 R 4 , R 1 and R 2 are each independently hydrogen, methyl
  • R 3 and R 4 together with the carbon or nitrogen atom to which they are attached have 1 or 2 R 8 and 1 or more R 9 piperazinyl, piperidinyl, Forming pyrrolidinyl or tetrahydropyranyl
  • R 5 is a monovalent group independently selected from the group consisting of hydrogen, NH 2 , cyclohexyloxy, morpholin-4-yl, methyl, aminomethyl and hydroxymethyl, or R 5 taken together with the 1 or 2 carbon atoms to which they are attached form cyclopentyl, azetidinyl, pyrrolidinyl, 2-pyrrolidonyl, imidazolidine-2,4-dionyl, piperidinyl or phenyl
  • R 6 is hydrogen, phenyl, pyridinyl, 3-methyl-1,2,4-oxadiazol-5-yl or methyl
  • R 7 is a monovalent group or a divalent group independently selected from the group consisting of
  • R 9 is hydrogen, halogen (for example, fluorine, chlorine, bromine or iodine), oxetane-3-yl, morpholin-4-yl, azetidin-3-yl, piperidin-2-yl, piperidin-4-yl, 1 -Methylpiperidin-4-yl, 3-methoxyphenyl, 4-chlorophenyl, 4-carboxyphenyl, 1H-benzo[d]imidazol-1-yl, 2-hydroxy-1H-benzo[d]imidazol-1-yl, It is a monovalent group independently
  • the compound of formula (Ia) is Ar 1 is 2-fluoro-pyridin-3-yl, n is 1, and X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 is hydrogen, R 23 is hydrogen or fluorine, R 24 is hydrogen, fluorine or chlorine, R 25 is hydrogen or fluorine, A a is -CHR 1 R 2 or -CHR 3 R 4 , R 1 and R 2 are each independently hydrogen, methyl, or pyridyl or indolyl, or R 1 and R 2 are taken together with the carbon atom to which they are attached, 1 or 2 R Forming cyclopentyl or cyclohexyl having 5 and 1 or a plurality of R 6 ; R 3 and R 4 are each independently hydrogen, 2-methoxyethyl, cyclopropyl, or 1 or 2 R 8 and methyl having 1 or more R 9 , ethyl, 2-methylpropyl or ter
  • R 3 and R 4 together with the carbon or nitrogen atom to which they are attached have 1 or 2 R 8 and 1 or more R 9 morpholinyl, piperazinyl, Forms piperidinyl, pyrrolidinyl, tetrahydropyranyl or 1,2,3,6-tetrahydropyridinyl
  • R 5 is a monovalent group independently selected from the group consisting of hydrogen, NH 2 , cyclohexyloxy, morpholin-4-yl, methyl, aminomethyl and hydroxymethyl, or R 5 taken together with the 1 or 2 carbon atoms to which they are attached form cyclopentyl, azetidinyl, pyrrolidinyl, 2-pyrrolidonyl, imidazolidine-2,4-dionyl, piperidinyl or phenyl
  • R 6 is hydrogen, phenyl, pyridinyl, 3-methyl-1,2,4-oxadiazol-5-yl or methyl
  • R 9 is hydrogen, halogen (for example, fluorine, chlorine, bromine or iodine), oxetane-3-yl, morpholin-4-yl, azetidin-3-yl, piperidin-2-yl, piperidin-4-yl, 1 -Methylpiperidin-4-yl, 3-methoxyphenyl, 4-chlorophenyl, 4-carboxyphenyl, 1H-benzo[d]imidazol-1-yl, 2-hydroxy-1H-benzo[d]imidazol
  • the compounds represented by formula (Ia) are synthetic compounds 20 to 23, 25 to 44, 46, 49, 53, 54, 59, 61, 63, 65, 66, 68 and 69, especially selected from synthetic compounds 21, 46, 49 and 69.
  • the compound represented by the formula (Ia) of the present embodiment having the above characteristics is used to prevent primary brain tumors (eg glioblastoma) or T-progenitor-derived acute lymphocytic leukemia (T-ALL) described below.
  • primary brain tumors eg glioblastoma
  • T-ALL T-progenitor-derived acute lymphocytic leukemia
  • the compound represented by the formula (Ia) of the present embodiment through the LSD1 inhibitory activity, a disease or condition such as a primary brain tumor (eg glioblastoma) or T-ALL. Can be prevented or treated particularly effectively.
  • the compound of formula (I) has the formula (Ib): It is preferable that it is a compound represented by, its stereoisomer, a salt thereof, or a solvate thereof.
  • a b is —CHR 3 R 4 or —NR 3 R 4 .
  • Ar 1 , n, X 2 , X 3 , X 4 , R 22 , R 23 , R 24 , R 25 , R 3 and R 4 have the same meanings as described above.
  • a b is a substituted or unsubstituted C 4 to C 11 cycloalkyl, a substituted or unsubstituted C 1 to C 6 alkylamino, a substituted or unsubstituted C 3 to C 11 cycloalkylamino, Or substituted or unsubstituted 4 to 15 membered heterocycloalkyl or heterocycloalkenyl; substituted or unsubstituted C 4 to C 7 cycloalkyl, substituted or unsubstituted C 1 to C 4 alkylamino, More preferably substituted or unsubstituted C 3 -C 7 cycloalkylamino, or substituted or unsubstituted 4 to 7 membered heterocycloalkyl or heterocycloalkenyl; substituted or unsubstituted C 5 -C 6 cyclo Alkyl, substituted or unsubstituted C 1 to C 4 alkylamino, substituted or
  • each of the substituents is independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or non-substituted Substituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted
  • halogen fluorine, chlorine, bromine or iodine
  • cyano nitro, hydroxyl
  • substituted or unsubstituted C 1 to C 5 alkyl substituted or unsubstituted C 2 to C 5 alkenyl, substituted or unsubstituted C 2 To C 5 alkynyl, substituted or unsubstituted C 3 to C 6 cycloalkyl, substituted or unsubstituted C 3 to C 6 cycloalkenyl, substituted or unsubstituted C 3 to C 6 cycloalkynyl, substituted or unsubstituted 3 To 6-membered heterocycloalkyl, substituted or unsubstituted C 7 to C 11 cycloalkylalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C 1 to C 5 alkyl, substituted or unsubstituted C 6 ⁇ C 15 aryl, substituted
  • each group of A b exemplified above is substituted with one or more groups
  • the substituent, together with the carbon atom to which they are attached is a substituted or unsubstituted C 4 -C 7 cycloalkyl group.
  • a 4- to 7-membered heteroaryl containing one or more heteroatoms selected from S and O as ring atoms may be formed.
  • a b is preferably a substituted or unsubstituted bridged ring, condensed ring or polycycle of spiro ring.
  • the substituent is preferably selected from the substituents of A b exemplified above.
  • the compound represented by formula (Ib) is Ar 1 is 5- to 10-membered aryl which is unsubstituted or substituted with one or more halogens, or 5- to 9-membered heteroaryl which is unsubstituted or substituted with one or more halogens, provided that n is 1, X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 and R 24 are hydrogen, and R 23 and R 25 are fluorine.
  • Ar 1 is not phenyl, n is 1 or 2, X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 , R 23 , R 24 and R 25 are each independently hydrogen, halogen, substituted or unsubstituted C 1 to C 6 alkyl or substituted or unsubstituted C 1 to C 6 alkoxy, A b is -CHR 3 R 4 , or -NR 3 R 4 , R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 to C 6 alkoxy-C 1 to C 6 alkyl, substituted or unsubstituted C 3 to C 7 cycloalkyl, or 1 or 2 A straight or branched C 1 -C 7 alkyl having one R 8 and one or more R 9 or R 3 and R 4 together with the carbon or nitrogen atom to which they are attached.
  • R 8 is hydrogen, halogen, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkoxy-C 1 -C 6 alkyl, -COR 13 , -COOR 13 , -CONR 12 R 13 , -NR 12 R 13 , -NR 12 COR 13 , -NR 12 CO 2 R 13 , -NR 14 CONR 12 R 13 , -NR 12 SO 2 R 13 , and substituted or unsubstituted C 1 to C A monovalent group independently selected from the group consisting of 6 alkyl, or R 8 together with 1 or 2 atoms selected from the carbon atom and the nitrogen atom to which they are
  • R 9 is hydrogen, halogen, substituted or unsubstituted 4 to 7 membered heterocycloalkyl, substituted or unsubstituted C 6 to C 15 aryl, substituted or unsubstituted C 6 to C 15 aryl-C 1 to C
  • R 10 is a monovalent group or a divalent group independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 to C 6 alkyl, —CONR 12 R 13 and oxo ( ⁇ O), Alternatively, R 10 is, together with one or two carbon atoms or nitrogen atoms to which they are attached, one or more selected from substituted or unsubstituted C 3 -C 7 cycloalkyl, N, S and O.
  • R 11 is a monovalent group independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1 to C 6 alkoxy, and substituted or unsubstituted C 1 to C 6 alkyl
  • R 12 and R 13 are monovalent groups independently selected from the group consisting of hydrogen, substituted or unsubstituted C 6 -C 15 aryl, and substituted or unsubstituted C 1 -C 6 alkyl
  • R 12 and R 13 together with a carbon atom or a nitrogen atom to which they are bonded are substituted or unsubstituted C 4 to C 7 cycloalkyl or substituted or unsubstituted 4 to 7 membered heterocycloalkyl.
  • R 14 is a monovalent group independently selected from the group consisting of hydrogen and substituted or unsubstituted C 1 -C 6 alkyl, When the above groups are substituted, unless otherwise stated, the substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 2 -C 5 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkenyl, substituted or unsubstituted C 3 to C 6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C 7 to C 11 cycl
  • the compound represented by formula (Ib) is Ar 1 is phenyl unsubstituted or substituted with one or more halogen, or pyridinyl or pyrazolyl unsubstituted or substituted with one or more halogen, provided that n is 1 and X 2 is
  • CR 22 is, X 3 is CR 23 , X 4 is CR 24 , R 22 and R 24 are hydrogen, and R 23 and R 25 are fluorine
  • Ar 1 is not phenyl and n is 1 or 2
  • X 2 is CR 22
  • X 3 is CR 23
  • X 4 is CR 24
  • R 22 , R 23 , R 24 and R 25 are each independently hydrogen, halogen, substituted or unsubstituted C 1 to C 6 alkyl or substituted or unsubstituted C 1 to C 6 alkoxy
  • a b is -CHR 3 R 4 , or -NR 3 R 4 , R 3 and R 4 are each independently hydrogen
  • R 8 is hydrogen, halogen, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl unsubstituted or substituted with one or more hydroxyl, -COR 13 , -COOR 13 , -CONR 12 R 13 , -NR 12 R 13 , -NR 12 COR 13 , -NR 12 CO 2 R 13 , -NR 14 CONR 12 R 13 , -NR 12 SO 2 R 13 , as well as unsubstituted or one or more Is a monovalent group independently selected from the group consisting of halogen, hydroxyl, phenyl, substituted amino, cyclic amino, C 1 -C 6 alkyl
  • R 11 is hydrogen, halogen, C 1 ⁇ C 6 alkoxy, and unsubstituted or one or more halogen, hydroxyl, dimethylamino, N- morpholino, N- pyrrolidino or C 1 ⁇ C 6 alkyl substituted with carboxyl
  • a monovalent group independently selected from the group consisting of R 12 and R 13 are hydrogen, C 6 -C 15 aryl, and unsubstituted or one or more halogen, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-(methylaminoethyl)-piperazine Is it a monovalent group independently selected from the group consisting of C 1 -C 6 alkyl substituted with 1-yl, 2,8-diazaspiro[4.5]decan
  • R 14 is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C 1 -C 6 alkyl,
  • the substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 2 -C 5 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkenyl, substituted or un
  • the compound represented by formula (Ib) is Ar 1 is phenyl unsubstituted or substituted with one or more halogen, or pyridinyl or pyrazolyl unsubstituted or substituted with one or more halogen, provided that n is 1 and X 2 is
  • CR 22 is, X 3 is CR 23 , X 4 is CR 24 , R 22 and R 24 are hydrogen, and R 23 and R 25 are fluorine
  • Ar 1 is not phenyl and n is 1 or 2
  • X 2 is CR 22
  • X 3 is CR 23
  • X 4 is CR 24
  • R 22 , R 23 , R 24 and R 25 are each independently hydrogen, fluorine, chlorine, bromine, methyl, methoxy or ethoxy
  • a b is -CHR 3 R 4 , or -NR 3 R 4 , R 3 and R 4 are each independently hydrogen, substituted or unsubstituted C 1 to C 3 alkoxy-
  • R 8 is hydrogen, halogen, C 4 -C 6 cycloalkyl, C 1 -C 3 alkoxy-C 1 -C 3 alkyl unsubstituted or substituted with one or more hydroxyl, —COR 13 , —COOR 13 , -CONR 12 R 13 , -NR 12 R 13 , -NR 12 COR 13 , -NR 12 CO 2 R 13 , -NR 14 CONR 12 R 13 , -NR 12 SO 2 R 13 , as well as unsubstituted or one or more One independently selected from the group consisting of halogen, hydroxyl, phenyl, methylamino, dimethylamino, N-pyrrolidino, N-morpholin
  • a valent group, or R 8 is unsubstituted or substituted with one or more R 10 together with one or two atoms selected from the carbon and nitrogen atoms to which they are attached.
  • 4- to 6 -membered hetero containing as ring atoms one or more heteroatoms selected from C 4 to C 6 cycloalkyl, N, S and O, and unsubstituted or substituted with one or more R 10.
  • R 9 is hydrogen, halogen (eg, fluorine, chlorine, bromine or iodine), oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted Of piperazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzimidazolyl, pyridinyl, pyrazinyl, and C 1 -C substituted or unsubstituted with one or more oxetanyl, tetrahydrofuranyl or phenyl
  • R 10 is a monovalent group independently selected from the group consisting of hydrogen
  • R 11 is hydrogen, methyl, ethyl, hydroxymethyl, trifluoromethyl, carboxymethyl, 2-(dimethylamino)ethyl, 2-(N-pyrrolidino)ethyl, 2-(N-morpholino)ethyl, 2-(carboxy ) Ethyl, and a monovalent group independently selected from the group consisting of 2,3-dihydroxypropyl
  • R 12 and R 13 are hydrogen, phenyl, methyl, ethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-(methylaminoethyl)-piperazin-1-ylmethyl, (2,8-diazaspiro [4.5] decan-8-yl)-methyl, and a monovalent group independently selected from the group consisting of morpholin-4-yl-methyl, or R 12 and R 13 are carbons to which they are attached.
  • R 14 is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C 1 -C 6 alkyl, When the above groups are substituted, unless otherwise stated, the substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 2 -C 5 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkenyl, substituted
  • the compound represented by formula (Ib) is Ar 1 is phenyl, 3-methoxy-1-phenyl, 1-fluoro-4-phenyl, 3-fluoro-1-phenyl, 2-fluoro-pyridin-3-yl, 2-fluoro-pyridin-4-yl, 2-fluoro-pyridin-5-yl, 1H-pyrazol-3-yl, or 1H-pyrazol-4-yl, provided that n is 1, X 2 is CH, X 3 is CF , X 4 is CH and R 25 is fluorine, Ar 1 is not phenyl and n is 1 or 2, X 2 is CH or CF, X 3 is CH, CF, CBr, C-methyl or C-methoxy, X 4 is CH, CF or CCl, R 25 is hydrogen, fluorine or ethoxy, A b is -CHR 3 R 4 , or -NR 3 R 4 , R 3 and R 4 are each independently hydrogen, 2-
  • R 8 is hydrogen, cyclohexyl, cyclopropyl, -COCH 3, -COC 6 H 5 , -COOCH 2 CH 3, -CONH 2, -CONHCH 3, -NH 2, -NHCH 3, -N (CH 3) 2 , -NHCOCH 3 , -NHCOOCH 3 , -NHCONHCH 3 , -NHSO 2 CH 3 , 4-methylpiperazin-1-ylacetyl, piperazin-1-ylacetyl, 4-(methylaminoethyl)-piperazin-1-ylacetyl, (2 ,8-Diazaspiro[4.5]decan-8-yl)
  • R 9 is hydrogen, halogen (for example, fluorine, chlorine, bromine or iodine), oxetane-3-yl, morpholin-4-yl, azetidin-3-yl, piperidin-2-yl, piperidin-4-yl, 1 -Methylpiperidin-4-yl, 3-methoxyphenyl, 4-chlorophenyl, 4-carboxyphenyl, 1H-benzo[d]imidazol-1-yl, 2-hydroxy-1H-benzo[d]imidazol-1
  • the compound represented by the formula (I-b) is selected from the synthetic compounds 1 to 19, 45, 47 and 48 exemplified above.
  • the compound represented by the formula (Ib) of the present embodiment having the above characteristics is used for the prevention of primary brain tumors (eg glioblastoma) or T-progenitor-derived acute lymphocytic leukemia (T-ALL) described below.
  • primary brain tumors eg glioblastoma
  • T-ALL T-progenitor-derived acute lymphocytic leukemia
  • the compound represented by the formula (Ib) of the present embodiment through the LSD1 inhibitory activity, a disease or condition such as primary brain tumor (eg glioblastoma) or T-ALL. Can be prevented or treated particularly effectively.
  • the compound of formula (I) has the formula (Ic): It is preferable that it is a compound represented by, its stereoisomer, a salt thereof, or a solvate thereof.
  • m is an integer in the range of 1 to 4. m is preferably 1 or 2.
  • the compound represented by the formula (Ic) of the present embodiment has particularly high inhibitory activity against LSD1, particularly high selectivity against LSD1 inhibition, and/or is particularly useful for a specific disease. Can have various therapeutic effects.
  • a c is —CHR 1 R 2 or —CHR 3 R 4 .
  • Ar 1 , n, X 2 , X 3 , X 4 , R 22 , R 23 , R 24 , R 25 , R 1 , R 2 , R 3 and R 4 are as defined above. ..
  • a c is preferably a substituted or unsubstituted C 4 to C 11 cycloalkyl or a substituted or unsubstituted 4 to 15 membered heterocycloalkyl; a substituted or unsubstituted C 4 To C 7 cycloalkyl, or substituted or unsubstituted 4 to 7 membered heterocycloalkyl is more preferable; substituted or unsubstituted C 5 to C 6 cycloalkyl, or substituted or unsubstituted 5 to 6 membered Is more preferably heterocycloalkyl; substituted or unsubstituted cyclopentyl, cyclohexyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl is particularly preferable; piperidin-4-yl, 1-(piperazin-1-ylacetyl )-Piperidin-4-yl, 1-(4-methylpiperazin-1-y
  • each of the substituents is independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or non-substituted Substituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted
  • halogen fluorine, chlorine, bromine or iodine
  • cyano nitro, hydroxyl
  • substituted or unsubstituted C 1 to C 5 alkyl substituted or unsubstituted C 2 to C 5 alkenyl, substituted or unsubstituted C 2 To C 5 alkynyl, substituted or unsubstituted C 3 to C 6 cycloalkyl, substituted or unsubstituted C 3 to C 6 cycloalkenyl, substituted or unsubstituted C 3 to C 6 cycloalkynyl, substituted or unsubstituted 3 To 6-membered heterocycloalkyl, substituted or unsubstituted C 7 to C 11 cycloalkylalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl-C 1 to C 5 alkyl, substituted or unsubstituted C 6 ⁇ C 15 aryl, substituted
  • the substituent is, together with the carbon atom to which they are attached, substituted or unsubstituted C 4 -C 7 cyclo 4- to 7-membered heterocycloalkyl containing at least one heteroatom selected from alkyl, substituted or unsubstituted C 4 -C 7 aryl, N, S and O as a ring atom, or from N, S and O
  • a 4- to 7-membered heteroaryl containing one or more selected heteroatoms as ring atoms may be formed.
  • a c is preferably a substituted or unsubstituted bridged ring, condensed ring or polycycle of spiro ring.
  • the substituent is preferably selected from the substituents of A c exemplified above.
  • the compound represented by formula (Ic) is Ar 1 is 5- to 10-membered aryl which is unsubstituted or substituted with one or more halogens, or 5- to 9-membered heteroaryl which is unsubstituted or substituted with one or more halogens, provided that n is 1, X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 and R 24 are hydrogen, and R 23 and R 25 are fluorine.
  • Ar 1 is not phenyl, n is 1 or 2, X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 , R 23 , R 24 and R 25 are each independently hydrogen, halogen, substituted or unsubstituted C 1 to C 6 alkyl or substituted or unsubstituted C 1 to C 6 alkoxy, m is an integer in the range of 1 to 4, A c is -CHR 1 R 2 , or -CHR 3 R 4 , R 1 and R 2 taken together with the carbon atom to which they are attached form C 4 -C 7 cycloalkyl having 1 or 2 R 5 and 1 or more R 6 .
  • R 3 and R 4 together with the carbon or nitrogen atom to which they are attached, contain as ring atoms one or more heteroatoms selected from N, S and O, and 1 or 2 R Forming a 4- to 7-membered heterocycloalkyl having 8 and 1 or a plurality of R 9 s
  • heteroatoms selected from C 3 -C 7 cycloalkyl, N, S and O which is unsubstituted or substituted with one or more R 7 as a ring atom.
  • 3-7 membered heterocycloalkyl which is unsubstituted or substituted with one or more R 7 s , unsubstituted C 5 -C 6 aryl, or one or more hetero selected from N, S and O Forming a 5- or 6-membered heteroaryl which contains an atom as a ring atom, and is unsubstituted or substituted with one or more R 7 .
  • R 6 is hydrogen, halogen, substituted or unsubstituted C 6 to C 15 aryl, substituted or unsubstituted 5 or 6 membered heteroaryl, and substituted or unsubstituted C 1 to C 6 alkyl
  • R 8 is hydrogen, halogen, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted C 1 -C 6 alkoxy-C 1 -C 6 alkyl, -COR 13 , -COOR 13 , -CONR 12 R 13 , -NR 12 R 13 , -NR 12 COR 13 , -NR 12 CO 2 R 13 , -NR 14 CONR 12 R 13 , -NR 12 SO 2 R 13 , and substituted or unsubstituted C 1 to C
  • a monovalent group independently selected from the group consisting of 6 alkyl, or R 8 together with one or two atoms selected from the carbon atom and the nitrogen atom to which they are attached are non- C 3 -C 7 cycloalkyl substituted or substituted with one or more R 10 , one or more heteroatoms selected from N, S and O as a ring atom, and unsubstituted or one or more Forming
  • R 9 is hydrogen, substituted or unsubstituted 4 to 7 membered heterocycloalkyl, substituted or unsubstituted C 6 to C 15 aryl, substituted or unsubstituted 5 to 9 membered heteroaryl, and substituted or unsubstituted
  • R 10 is a monovalent group or a divalent group independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1 to C 6 alkyl, —CONR 12 R 13 and oxo ( ⁇ O)
  • R 10 is, together with one or two carbon atoms or nitrogen atoms to which they are attached, one or more selected from substituted or unsubstituted C 3 -C 7 cycloalkyl, N, S and O.
  • R 11 is a monovalent group independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1 to C 6 alkoxy, and substituted or unsubstituted C 1 to C 6 alkyl
  • R 12 and R 13 are monovalent groups independently selected from the group consisting of hydrogen, substituted or unsubstituted C 6 -C 15 aryl, and substituted or unsubstituted C 1 -C 6 alkyl
  • R 12 and R 13 together with a carbon atom or a nitrogen atom to which they are bonded are substituted or unsubstituted C 4 to C 7 cycloalkyl or substituted or unsubstituted 4 to 7 membered heterocycloalkyl.
  • R 14 is a monovalent group independently selected from the group consisting of hydrogen and substituted or unsubstituted C 1 -C 6 alkyl, When the above groups are substituted, unless otherwise stated, the substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 2 -C 5 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkenyl, substituted or unsubstituted C 3 to C 6 cycloalkynyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted C 7 to C 11 cycl
  • the compound represented by formula (Ic) is Ar 1 is phenyl unsubstituted or substituted with one or more halogen, or pyridinyl or pyrazolyl unsubstituted or substituted with one or more halogen, provided that n is 1 and X 2 is
  • CR 22 is, X 3 is CR 23 , X 4 is CR 24 , R 22 and R 24 are hydrogen, and R 23 and R 25 are fluorine, then Ar 1 is not phenyl and n is 1 or 2
  • X 2 is CR 22
  • X 3 is CR 23
  • X 4 is CR 24
  • R 22 , R 23 , R 24 and R 25 are each independently hydrogen, halogen, substituted or unsubstituted C 1 to C 6 alkyl or substituted or unsubstituted C 1 to C 6 alkoxy
  • m is an integer in the range of 1 to 4,
  • a c is -CHR 1 R 2 , or -C
  • R 3 and R 4 together with the carbon or nitrogen atom to which they are attached, contain as ring atoms one or more heteroatoms selected from N, S and O, and 1 or 2 R Forming a 4- to 7-membered heterocycloalkyl having 8 and 1 or a plurality of R 9 s
  • R 6 is hydrogen, halogen, substituted or unsubstituted C 6 -C 15 aryl, substituted or unsubstituted 5- or 6-membered heteroaryl, and unsubstituted or one or more halogen, substituted or unsubstituted C
  • R 11 is hydrogen, halogen, C 1 ⁇ C 6 alkoxy, and unsubstituted or one or more halogen or hydroxyl substituted with a C 1 ⁇ C 6 monovalent radical independently selected from the group consisting of alkyl Yes
  • R 12 and R 13 are hydrogen, C 6 -C 15 aryl, and unsubstituted or one or more halogen, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-(methylaminoethyl)-piperazine Is it a monovalent group independently selected from the group consisting of C 1 -C 6 alkyl substituted with 1-yl, 2,8-diazaspiro[4.5]decan-8-yl or morpholin-4-yl?
  • R 14 is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C 1 -C 6 alkyl,
  • the substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 2 -C 5 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkenyl, substituted or un
  • the compound represented by formula (Ic) is Ar 1 is phenyl unsubstituted or substituted with one or more halogen, or pyridinyl or pyrazolyl unsubstituted or substituted with one or more halogen, provided that n is 1 and X 2 is
  • CR 22 is, X 3 is CR 23 , X 4 is CR 24 , R 22 and R 24 are hydrogen, and R 23 and R 25 are fluorine
  • Ar 1 is not phenyl and n is 1 or 2
  • X 2 is CR 22
  • X 3 is CR 23
  • X 4 is CR 24
  • R 22 , R 23 , R 24 and R 25 are each independently hydrogen, fluorine, chlorine, bromine, methyl, methoxy or ethoxy
  • m is 1 or 2
  • a c is -CHR 1 R 2 , or -CHR 3 R 4 , R 1 and R 2 taken together with the carbon atom to which they are attached form C
  • R 3 and R 4 together with the carbon or nitrogen atom to which they are attached, contain as ring atoms one or more heteroatoms selected from N, S and O, and 1 or 2 R Forming a 5 to 6 membered heterocycloalkyl having 8 and 1 or a plurality of R 9 s ,
  • R 5 is hydrogen, -NR 12 R 13 , C 3 -C 7 cycloalkoxy, substituted or unsubstituted morpholin-4-yl, and unsubstituted or substituted with one or more -NR 12 R 13 or -OH
  • R 7 is a monovalent group or a divalent group independently selected from the group consisting of hydrogen and oxo ( ⁇ O)
  • R 8 is hydrogen, halogen, C 4 -C 6 cycloalkyl, C 1 -C 3 alkoxy-C 1 -C 3 alkyl unsubstituted or substituted with one or more hydroxyl, —COR 13 , —COOR 13 , -CONR 12 R 13 , -NR 12 R 13 , -NR 12 COR 13 , -NR 12 CO 2 R 13 , -NR 14 CONR 12 R 13 , -NR 12 SO 2 R 13 , as well as unsubstituted or 1 or more
  • a monovalent radical independently selected from the group consisting of C 1 -C 3 alkyl substituted with halogen, hydroxyl, phenyl, methylamino, dimethylamino, —COOR 12 or —CONR 12 R 13 , or R 8 is C 4 -C
  • R 11 is a monovalent group independently selected from the group consisting of hydrogen, methyl, ethyl, hydroxymethyl, and trifluoromethyl
  • R 12 and R 13 are hydrogen, phenyl, methyl, ethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-(methylaminoethyl)-piperazin-1-ylmethyl, (2,8-diazaspiro [4.5] decan-8-yl)-methyl, and a monovalent group independently selected from the group consisting of morpholin-4-yl-methyl, or R 12 and R 13 are carbons to which they are attached.
  • R 14 is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C 1 -C 6 alkyl, When the above groups are substituted, unless otherwise stated, the substituents are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C 1 -C 5 alkyl, substituted or unsubstituted C 2 -C 5 alkenyl, substituted or unsubstituted C 2 -C 5 alkynyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 Cycloalkenyl, substituted
  • the compound represented by formula (Ic) is Ar 1 is phenyl, 3-methoxy-1-phenyl, 1-fluoro-4-phenyl, 3-fluoro-1-phenyl, 2-fluoro-pyridin-3-yl, 2-fluoro-pyridin-4-yl, 2-fluoro-pyridin-5-yl, 1H-pyrazol-3-yl, or 1H-pyrazol-4-yl, provided that n is 1, X 2 is CH, X 3 is CF , X 4 is CH and R 25 is fluorine, Ar 1 is not phenyl and n is 1 or 2, X 2 is CH or CF, X 3 is CH, CF, CBr, C-methyl or C-methoxy, X 4 is CH, CF or CCl, R 25 is hydrogen, fluorine or ethoxy, m is 1 or 2, A c is -CHR 1 R 2 , or -CHR 3 R 4 , R 1 and R
  • R 3 and R 4 together with the carbon or nitrogen atom to which they are attached form piperazinyl, piperidinyl or pyrrolidinyl having 1 or 2 R 8 and 1 or more R 9 .
  • R 5 is a monovalent group independently selected from the group consisting of hydrogen, NH 2 , cyclohexyloxy, morpholin-4-yl, methyl, aminomethyl and hydroxymethyl, or R 5 is a group to which they are attached.
  • R 6 is hydrogen, phenyl, pyridinyl, 3-methyl-1,2,4-oxadiazol-5-yl or methyl
  • R 8 is hydrogen, cyclohexyl, cyclopropyl, -COCH 3, -COC 6 H 5 , -COOCH 2 CH 3, -CONH 2, -CONHCH 3, -NH 2, -NHCH 3, -N (CH 3) 2 , -NHCOCH 3 , -NHCOOCH 3 , -NHCONHCH 3 , -NHSO 2 CH 3 , 4-methylpiperazin-1-ylacetyl, piperazin-1-ylacetyl, 4-(methylaminoethyl)-piperazin-1-ylacetyl, (2 ,8-Diazaspiro[4.5]decan-8-y
  • R 9 is hydrogen, oxetane-3-yl, azetidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 3-methoxyphenyl, 4-chlorophenyl, 4-carboxyphenyl, 1H-benzo independently selected from the group consisting of [d]imidazol-1-yl, 2-hydroxy-1H-benzo[d]imidazol-1-yl, pyridin-2-yl, pyrazin-2-yl, methyl, and benzyl. It is a monovalent group.
  • the compound represented by formula (Ic) is Ar 1 is 2-fluoro-pyridin-3-yl, n is 1, and X 2 is CR 22 , X 3 is CR 23 , X 4 is CR 24 , R 22 is hydrogen, R 23 is hydrogen or fluorine, R 24 is hydrogen, fluorine or chlorine, R 25 is hydrogen, fluorine or ethoxy, m is 1 or 2,
  • a c is -CHR 1 R 2 , or -CHR 3 R 4 , R 1 and R 2 are each independently hydrogen, methyl, or pyridyl or indolyl, or R 1 and R 2 are taken together with the carbon atom to which they are attached, 1 or 2 R Forming cyclopentyl or cyclohexyl having 5 and 1 or a plurality of R 6 ; R 3 and R 4 are each independently hydrogen, 2-methoxyethyl, cyclopropyl, or 1 or 2 R 8 and methyl having 1 or more R 9 ,
  • R 3 and R 4 together with the carbon or nitrogen atom to which they are attached have 1 or 2 R 8 and 1 or more R 9 morpholinyl, piperazinyl, Forms piperidinyl, pyrrolidinyl, tetrahydropyranyl or 1,2,3,6-tetrahydropyridinyl
  • R 5 is a monovalent group independently selected from the group consisting of hydrogen, NH 2 , cyclohexyloxy, morpholin-4-yl, methyl, aminomethyl and hydroxymethyl, or R 5 taken together with the 1 or 2 carbon atoms to which they are attached form cyclopentyl, azetidinyl, pyrrolidinyl, 2-pyrrolidonyl, imidazolidine-2,4-dionyl, piperidinyl or phenyl
  • R 6 is hydrogen, phenyl, pyridinyl, 3-methyl-1,2,4-oxadiazol-5-yl or methyl
  • R 9 is hydrogen, halogen (for example, fluorine, chlorine, bromine or iodine), oxetane-3-yl, morpholin-4-yl, azetidin-3-yl, piperidin-2-yl, piperidin-4-yl, 1 -Methylpiperidin-4-yl, 3-methoxyphenyl, 4-chlorophenyl, 4-carboxyphenyl, 1H-benzo[d]imidazol-1-yl, 2-hydroxy-1H-benzo[d]imidazol
  • the compounds represented by formula (Ic) are synthetic compounds 24, 50 to 52, 55 to 58, 60, 62, 64, 67 and 70 to 73, particularly synthetic compounds 24 and 50, as exemplified above. , 64, 70, 71 and 72.
  • the compound represented by the formula (Ic) of the present embodiment having the above characteristics is used to prevent primary brain tumors (eg glioblastoma) or T-progenitor-derived acute lymphocytic leukemia (T-ALL) described below.
  • primary brain tumors eg glioblastoma
  • T-ALL T-progenitor-derived acute lymphocytic leukemia
  • the compound represented by the formula (Ic) of the present embodiment through the LSD1 inhibitory activity, a disease or condition such as a primary brain tumor (eg glioblastoma) or T-ALL. Can be prevented or treated particularly effectively.
  • the compounds represented by the formulas (I), (Ia), (Ib) and (Ic) and the formulas (II) to (XII) described below are not limited to the compounds themselves.
  • Its salts are also included.
  • the salt of the compound include, but are not limited to, a salt with a cation such as sodium ion, potassium ion, calcium ion, magnesium ion, or a substituted or unsubstituted ammonium ion, or hydrochloric acid, hydrogen bromide.
  • Acid inorganic acid such as sulfuric acid, nitric acid, carbonic acid or phosphoric acid, or formic acid, acetic acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, lactic acid, succinic acid, bismethylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, Propionic acid, tartaric acid, malic acid, salicylic acid, citric acid, gluconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, cyclohexylsulfamic acid, methanesulfonic acid , Salts with organic acid anions such as ethanesulfonic acid, isethionic acid, p-toluenesulfonic acid or naphthalenesulfonic acid are preferred.
  • the compounds represented by the formulas (I), (Ia), (Ib) and (Ic) and the formulas (II) to (XII) described below are not limited to the above-mentioned compounds themselves.
  • solvates of the compounds or salts thereof includes, but is not limited to, for example, water, or a lower alcohol (for example, methanol, ethanol or 2-propanol (isopropyl alcohol)).
  • Organic solvents such as ethyl are preferred.
  • the compounds represented by the formulas (I), (Ia), (Ib) and (Ic), and the formulas (II) to (XII) described below, or salts thereof are solvates with the above solvents. When in the form, the compound can be used without substantially reducing the LSD1 inhibitory activity.
  • the compounds represented by the formulas (I), (Ia), (Ib) and (Ic) and the formulas (II) to (XII) described below are not limited to the above-mentioned compounds themselves.
  • their protected forms are also included.
  • the “protected form” means a form in which a protecting group is introduced into one or more functional groups (eg, hydroxyl group or amino group).
  • the protected form of the compound may be referred to as a protected derivative of the compound.
  • the “protecting group” is a group introduced into a specific functional group in order to prevent the progress of an undesired reaction, and is quantitatively removed under specific reaction conditions, and Under the reaction conditions other than, it means a group which is substantially stable, that is, reaction inactive.
  • the protecting group capable of forming a protected form of the compound is not limited, but for example, in the case of a hydroxyl protecting group, silyl (for example, t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS)) Or tert-butyldiphenylsilyl (TBDPS)), or when alkoxy (eg, methoxymethoxy (MOM) or methoxy (Me)) is a protecting group for amino group, t-butoxycarbonyl (Boc), 2-bromobenzyloxy Carbonyl (BrZ) or 9-fluorenylmethoxycarbonyl (Fmoc) are respectively preferred.
  • silyl for example, t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS)) Or tert-butyldiphenylsilyl (TBDPS)
  • alkoxy eg, methoxymeth
  • the protection and deprotection with the above protecting group can be appropriately carried out by those skilled in the art based on known reaction conditions. Even when the compounds represented by the formulas (I), (Ia), (Ib) and (Ic) and the formulas (II) to (XII) described below are in a protected form by the above protecting group. In some cases, the compound can be used without substantially reducing the LSD1 inhibitory activity.
  • one or more compounds represented by the formulas (I), (Ia), (Ib) and (Ic) and the formulas (II) to (XII) described below are used.
  • the stereoisomers of the compound including the individual enantiomers and diastereomers of the compound, as well as mixtures thereof, such as the racemates.
  • the compounds represented by the formulas (I), (Ia), (Ib) and (Ic) have a particularly high inhibitory activity against LSD1, a particularly high selectivity against LSD1 inhibition, and/or a specific compound. It may have a particularly useful therapeutic effect on the disease.
  • Another aspect of the present invention relates to a method for producing the compounds represented by formulas (I), (Ia), (Ib) and (Ic) according to the aspect of the present invention.
  • the production method of this embodiment can be carried out based on various known compound synthesis methods.
  • the functional group can be protected and deprotected, if necessary.
  • the protection and deprotection of functional groups is not limited, but known, for example, by the methods described in Greene and Wuts, “Protective Groups in organic Synthesis”, 4th edition. Can be carried out by applying the protection and deprotection methods of.
  • the compounds represented by the formulas (I), (Ia), (Ib) and (Ic) of one aspect of the present invention are the same as or similar to the production methods 1 to 6 exemplified below. It can be manufactured by the method.
  • the compound obtained in each step described below can be used in the reaction of the next step as the reaction mixture after completion of the reaction or in the state of a crude product.
  • the compound obtained in each step is used in the reaction of the next step in the state of being isolated or purified from the reaction mixture based on isolation or purification means of organic compounds usually used in the art, or It can also be obtained as the final product.
  • the means for isolating or purifying the compound that can be used is not limited, and examples thereof include concentration, extraction, filtration, centrifugation, adsorption, recrystallization, distillation, and various chromatography. it can.
  • the compound obtained in each step described below when the compound obtained in each step described below is in the form of a mixture of stereoisomers, the compound can be used as it is for the reaction in the next step.
  • these compounds may be used in the reaction of the next step as stereoisomers optically resolved by a known means such as chiral column chromatography, optical separation or diastereomer derivatization.
  • the compound obtained in each step described below when the compound obtained in each step described below is in a protected form having a protecting group, the compound can be used as it is for the reaction in the next step.
  • the compound in protected form is deprotected in the form of the compound itself by applying a known deprotection method, such as the method described in the above-mentioned document, in the following step. It can be used in the reaction or obtained as the final product.
  • the production method of this aspect can be carried out by a method including steps 1-11 and 1-12 illustrated below (hereinafter, also referred to as “production method 1”).
  • production method 1 the compound represented by the formula (I) (wherein L is a substituted or unsubstituted C 1 to C 6 alkylene-CO—, a substituted or unsubstituted C 2 to C 6 alkenylene-CO—, Or a substituted or unsubstituted C 2 -C 6 alkynylene-CO—), especially a compound of formula (Ib).
  • the manufacturing method 1 of the present embodiment is Formula (II): And a compound of formula (III): R L1 -L-OR L2 (III)
  • the compound represented by the formula (Ib) when the compound represented by the formula (Ib) is produced, in the compound represented by the formula (III), L is methylene-CO—.
  • the compound represented by the formula (III) has the formula (III′): R L1 -CH 2 -CO-OR L2 (III') The compound represented by is preferable.
  • the compound represented by the formula (Ib) when the compound represented by the formula (Ib) is produced, the compound represented by the formula (V) has the formula (V′): R A1 -A b (V') The compound represented by is preferable.
  • PGN1 is hydrogen or a protecting group.
  • the protecting group is preferably the amino protecting group exemplified above.
  • Ar 1 , n, X 2 , X 3 , X 4 , R 22 , R 23 , R 24 , R 25 , L , A and Ab are as defined above.
  • R L1 is halogen.
  • R L1 is preferably F, Cl, Br or I, and more preferably Cl or Br.
  • R L2 is hydrogen, substituted or unsubstituted C 1 to C 5 alkyl, substituted or unsubstituted C 2 to C 5 alkenyl, or substituted or unsubstituted C 2 -C 5 alkynyl.
  • R L2 is preferably methyl, ethyl or propyl.
  • R A1 is hydrogen
  • Steps 1-11 can be carried out by reacting the compound represented by the formula (II) with the compound represented by the formula (III) in the presence of a base.
  • the compound represented by the formula (II) may be prepared by, for example, purchasing the compound prepared in advance, and known compounds (Mimasu, S et al., Biochemistry, 49(30) ), p. 6494-6503; 2010).
  • a compound represented by the formula (II) (wherein AR 1 is phenyl, n is 1 and PGN 1 is tert-butoxycarbonyl) should be prepared based on the reaction scheme shown below. You can The compound represented by the formula (II-1) shown in the reaction scheme is included in the compound represented by the formula (II).
  • Step 1-1 is a step of producing the compound (2) by reacting the compound (1) with trimethylsulfoxonium iodide in the presence of a base.
  • step 1-1 the amount of trimethylsulfoxonium iodide used is usually in the range of 1 to 10 molar equivalents relative to compound (1). This reaction is usually performed in an inert solvent.
  • examples of the base include potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hexamethyldisilazane, sodium hexamethyldisilazane, sodium hydride and the like. You can The base is preferably potassium tert-butoxide or sodium hydride. The amount of the base used in this step is usually 1 molar equivalent or more relative to compound (1).
  • examples of the inert solvent include tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, and the like.
  • the inert solvent two or more kinds of the above solvents may be mixed and used at an arbitrary ratio.
  • the reaction temperature is usually in the range of 0 to 100°C.
  • the reaction time is not particularly limited, but is usually in the range of 0.1 to 100 hours, preferably in the range of 0.5 to 24 hours.
  • Step 1-2 is a step of producing compound (3) by subjecting compound (2) to a reduction reaction.
  • step 1-2 this reaction is usually carried out in a water-containing solvent in the presence of a metal reagent.
  • examples of the metal reagent include iron, zinc, nickel, tin, tin (II) chloride, and the like.
  • the amount of the metal reagent used is usually 1 to 1000 molar equivalents relative to compound (2).
  • step 1-2 the progress of this reaction can be accelerated by adding additives such as calcium chloride, ammonium chloride, sodium acetate, acetic acid, hydrochloric acid or hydrazine to the reaction system.
  • additives such as calcium chloride, ammonium chloride, sodium acetate, acetic acid, hydrochloric acid or hydrazine
  • the salt of the product can be converted into a free form by carrying out an appropriate treatment if desired. Examples of the treatment include basic water or washing with water.
  • examples of the water-containing solvent include tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethoxyethane, methanol, ethanol and isopropanol.
  • the water-containing solvent two or more kinds of the above solvents may be mixed and used at an arbitrary ratio.
  • the reaction temperature is usually in the range of 0 to 150°C.
  • the reaction time is not particularly limited, but is usually in the range of 0.1 to 100 hours, preferably in the range of 0.5 to 72 hours.
  • Steps 1-3 are steps of producing compound (II-1) by reacting compound (3) with di-tert-butyl dicarbonate under basic conditions.
  • step 1-3 the amount of di-tert-butyl dicarbonate used is usually in the range of 1 to 10 molar equivalents relative to compound (3).
  • step 1-3 this reaction is usually performed in the presence of a base in an inert solvent.
  • examples of the base include triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium hydroxide. And potassium hydroxide and the like.
  • the base is preferably triethylamine, diisopropylethylamine or sodium hydroxide.
  • the amount of the base used is usually 1 molar equivalent or more with respect to the compound (3).
  • examples of the inert solvent include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dimethoxyethane, acetone, methylene chloride and water.
  • the inert solvent two or more kinds of the above solvents may be mixed and used at an arbitrary ratio.
  • reaction temperature is usually in the range of 0 to 100°C.
  • the reaction time is not particularly limited, but is usually in the range of 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Steps 1-4 are steps for producing the compound (5) by reacting the compound (4) with trimethylsulfoxonium iodide in the presence of a base.
  • step 1-4 this reaction can be carried out under the same conditions as in step 1-1 described above.
  • Steps 1-5 are steps for producing the compound (6) by subjecting the compound (5) to hydrolysis.
  • step 1-5 this reaction is usually performed in water or a water-containing solvent in the presence of a base.
  • examples of the base include sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide, sodium ethoxide, sodium methoxide, and the like.
  • the amount of base used is usually in the range of 1 to 1000 molar equivalents relative to compound (5).
  • examples of the water-containing solvent include tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethoxyethane, methanol, ethanol, isopropanol, acetone, N,N-dimethylformamide and N,N-dimethylacetamide. be able to.
  • the water-containing solvent two or more kinds of the above solvents may be mixed and used at an arbitrary ratio.
  • the reaction temperature is usually in the range of 0 to 100°C.
  • the reaction time is not particularly limited, but is usually in the range of 0.1 to 100 hours, preferably in the range of 0.5 to 72 hours.
  • Steps 1-6 are steps for producing the compound (II-1) by reacting the compound (6) with diphenylphosphoryl azide and tert-butyl alcohol.
  • step 1-6 this reaction is usually performed in the presence of a base, in an inert water solvent or in an excess amount of tert-butyl alcohol.
  • examples of the base include triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5. 4. 0]undecane-7-ene, potassium carbonate, cesium carbonate and potassium tert-butoxide. it can.
  • the base is preferably triethylamine or diisopropylethylamine.
  • the amount of the base used is usually in the range of 1 to 10 molar equivalents relative to compound (6).
  • examples of the inert solvent include toluene, benzene, xylene, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile and the like.
  • the inert solvent two or more kinds of the above solvents may be mixed and used at an arbitrary ratio.
  • reaction temperature is usually in the range of 0 to 100°C.
  • the reaction time is not particularly limited, but is usually in the range of 0.1 to 100 hours, preferably in the range of 0.5 to 72 hours.
  • step 1-11 the compound represented by the formula (III) may be prepared by purchasing the compound prepared in advance.
  • step 1-11 the compound represented by the formula (III) is usually used in an amount within the range of 1 to 10 molar equivalents relative to the compound represented by the formula (II).
  • the base used is not limited, but examples thereof include triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, cesium carbonate, and potassium carbonate.
  • examples thereof include tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hexamethyldisilazane, sodium hexamethyldisilazane and NaH.
  • the base used in this step is preferably lithium hexamethyldisilazane or NaH.
  • step 1-11 the base is usually used in an amount of 1 molar equivalent or more with respect to the compound represented by the formula (II).
  • this reaction is usually performed in an inert solvent.
  • the solvent used is not limited, and examples thereof include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide. .. These solvents may be used as a mixture of two or more kinds of the above solvents at an arbitrary ratio.
  • the reaction temperature of this reaction is usually in the range of 0 to 100°C.
  • the reaction time of this reaction is not particularly limited, but is usually in the range of 0.1 to 100 hours, and preferably in the range of 0.5 to 24 hours.
  • step 1-11 it is preferable to hydrolyze the reaction product under basic conditions after the completion of the reaction. Hydrolysis is usually carried out by mixing the reaction product with a basic aqueous solution in a water-soluble solvent. Thereby, the compound represented by the formula (IV) in which R L2 is hydrogen can be obtained.
  • the basic aqueous solution used is not limited, but examples thereof include sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, lithium hydroxide aqueous solution, and barium hydroxide aqueous solution.
  • the base used for hydrolysis is usually used in an amount of 1 molar equivalent or more with respect to the compound represented by the formula (II).
  • the water-soluble solvent used in the hydrolysis includes, but is not limited to, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, dimethoxyethane and the like.
  • the reaction temperature for hydrolysis is usually in the range of 0 to 100°C.
  • the reaction time of hydrolysis is not particularly limited, but is usually in the range of 0.1 to 100 hours, and preferably in the range of 0.5 to 24 hours.
  • Steps 1-12 can be carried out by reacting the compound represented by formula (IV) with the compound represented by formula (V) in the presence of a condensing agent.
  • the compound represented by the formula (V) may be prepared by purchasing the compound prepared in advance, or the like, and known literatures (Bonnet, PA et al., Journal of of Chemical Research, Synopses, Volume 2, p.28; 1984).
  • step 1-12 the compound represented by the formula (V) is usually used in an amount within the range of 1 to 10 molar equivalents relative to the compound represented by the formula (IV).
  • the condensing agent used is not limited, and examples thereof include 1-ethyl-1-(3-methylaminopropyl)carbodiimide hydrochloride, 1,3-dicyclohexylcarbodiimide, diethyl cyanophosphate.
  • a condensing agent bound to the porous resin such as PS-carbodiimide resin (manufactured by Biotage), can be used.
  • the condensing agent is usually used in an amount within the range of 1 to 10 molar equivalents with respect to the compound represented by the formula (V).
  • condensation accelerators in addition to the condensing agent, if desired, one or more condensation accelerators may be used.
  • the condensation accelerator include, but are not limited to, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N,N-dimethyl-4-aminopyridine, and the like.
  • a condensation accelerator bound to the porous resin such as PS-HOBt resin (manufactured by Biotage), can be used.
  • the condensation accelerator is usually used in an amount within the range of 0.1 to 10 molar equivalents with respect to the compound represented by the formula (IV).
  • this reaction is preferably carried out in the presence of a base such as triethylamine, diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene.
  • a base such as triethylamine, diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene.
  • the base is usually used in an amount within the range of 0.1 to 10 molar equivalents relative to the compound represented by the formula (V).
  • this reaction is usually performed in an inert solvent.
  • the solvent used is not limited, but examples thereof include dichloromethane, dichloroethane, chloroform, tetrahydrofuran, 1,4-dioxane, N,N-dimethylacetamide, acetonitrile and the like. Two or more kinds of these solvents may be mixed and used at an arbitrary ratio.
  • the reaction temperature of this reaction is usually in the range of 0 to 150°C.
  • the reaction time of this reaction is not particularly limited, but is usually in the range of 0.1 to 100 hours, and preferably in the range of 0.5 to 72 hours.
  • the production method 1 further includes Step 1-13 of deprotecting PGN 1 from the reaction product of Step 1-12.
  • step 1-13 the conditions of the reaction for deprotecting the PG N1, based on the type of protective group used, a person skilled in the art can appropriately set.
  • the deprotection reaction can usually be carried out in the presence of acid, in an inert solvent, or in excess of acid.
  • the acid used is not limited, but examples thereof include hydrochloric acid, trifluoroacetic acid, hydrobromic acid, sulfuric acid, hydrofluoric acid, and the like.
  • the acid used is preferably hydrochloric acid or trifluoroacetic acid.
  • the compound represented by formula (I) obtained by the production method 1 of the present embodiment may be obtained in the form of their hydrochloride. it can.
  • the compound represented by the formula (I) obtained by the production method 1 of the present embodiment, particularly the compound represented by the formula (Ib) is used in the form of their trifluoroacetate.
  • the compound in the form of such a salt can be converted into the educt form by a means such as amino silica gel chromatography, treatment with an ion exchange resin, or washing treatment with a basic aqueous solution.
  • the acid is usually used in an amount in the range of 1 to 1000 molar equivalents relative to the reaction product of step 1-12.
  • the compound represented by the formula (I) (wherein L is a substituted or unsubstituted C 1 to C 6 alkylene-CO—, a substituted or unsubstituted C 2 to C 6 alkenylene-CO—, Or a substituted or unsubstituted C 2 -C 6 alkynylene-CO—), especially a compound of formula (Ib).
  • the production method of this aspect can be carried out by a method including Step 2-1 to Step 2-4 exemplified below (hereinafter, also referred to as “Production Method 2”). To).
  • Step 2-1 to Step 2-4 exemplified below
  • formula (I) (wherein L is a substituted or unsubstituted C 1 to C 6 alkylene-CO-, a substituted or unsubstituted C 2 to C 6 alkenylene-CO-, Or a substituted or unsubstituted C 2 -C 6 alkynylene-CO—), especially a compound of formula (Ib).
  • the compound represented by the formula (Ib) when the compound represented by the formula (Ib) is produced, in the compound represented by the formula (III), L is methylene-CO—.
  • the compound represented by the formula (III) has the formula (III′): R L1 -CH 2 -CO-OR L2 (III') The compound represented by is preferable.
  • the compound represented by the formula (Ib) when the compound represented by the formula (Ib) is produced, the compound represented by the formula (V) has the formula (V′): R A1 -A b (V') The compound represented by is preferable.
  • Ar 1′ is a substituted or unsubstituted 5 to 10 membered aryl, or a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • Ar 1′ is preferably selected from the groups included in Ar 1 exemplified above, provided that Ar 1′ is not the same as Ar 1 in the formulas (I) and (XII).
  • PGN1 is hydrogen or a protecting group.
  • the protecting group is preferably the amino protecting group exemplified above.
  • R L1 is halogen.
  • R L1 is preferably F, Cl, Br or I, and more preferably Cl or Br.
  • R L2 is hydrogen, substituted or unsubstituted C 1 to C 5 alkyl, substituted or unsubstituted C 2 to C 5 alkenyl, or substituted or non-substituted. Substituted C 2 -C 5 alkynyl. R L2 is preferably methyl, ethyl or propyl.
  • R A1 is hydrogen
  • R L11 is halogen.
  • R L11 is preferably F, Cl, Br or I, and more preferably Cl or Br.
  • the production method 2 can be carried out based on the reaction scheme shown below.
  • the compound represented by the formula (I-2-1) shown in the reaction scheme is included in the compound represented by the formula (I).
  • Step 2-1 includes, for example, a compound represented by the formula (II′) (for example, the compound (II-1) in the above reaction scheme) and a compound represented by the formula (III) (for example, in the above reaction scheme). It can be carried out by reacting with ethyl bromoacetate or ethyl chloroacetate in the presence of a base. This step is optionally carried out by hydrolyzing the reaction product represented by the formula (IV′) compound under basic conditions to obtain the free acid form of the formula (IV′). It may include a step of obtaining a compound (for example, the compound (7) in the above reaction scheme).
  • a compound represented by the formula (II′) for example, the compound (II-1) in the above reaction scheme
  • a compound represented by the formula (III) for example, in the above reaction scheme
  • the amount of the compound represented by the formula (III) is the amount of the compound represented by the formula (IV′) in the form of a free acid.
  • it is usually in the range of 1 to 10 molar equivalents.
  • step 2-1 this reaction is usually performed in an inert solvent.
  • step 2-1 as the base, for example, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium hydroxide, hydroxide Examples thereof include potassium, lithium hexamethyldisilazane, sodium hexamethyldisilazane and NaH.
  • the base is preferably lithium hexamethyldisilazane or NaH.
  • the amount of the base used in this step is usually 1 molar equivalent or more with respect to the compound represented by the formula (IV′) in the form of a free acid (for example, the compound (7) in the reaction scheme). ..
  • examples of the inert solvent include tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and the like.
  • the inert solvent two or more kinds of the above solvents may be mixed and used at an arbitrary ratio.
  • the reaction temperature is usually in the range of 0 to 100°C.
  • the reaction time is not particularly limited, but is usually in the range of 0.1 to 100 hours, preferably in the range of 0.5 to 24 hours.
  • this reaction can be carried out using a basic aqueous solution and a water-soluble solvent.
  • the basic aqueous solution include sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, lithium hydroxide aqueous solution, and barium hydroxide aqueous solution.
  • the amount of the base used in this reaction is usually 1 molar equivalent or more relative to the compound represented by the formula (IV′) in the form of free acid (for example, the compound (7) in the above reaction scheme).
  • examples of the water-soluble solvent include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, dimethoxyethane and the like.
  • the reaction temperature is usually in the range of 0 to 100°C.
  • the reaction time is not particularly limited, but is usually in the range of 0.1 to 100 hours, preferably in the range of 0.5 to 24 hours.
  • Step 2-2 includes, for example, a compound represented by the formula (IV′) (for example, the compound (7) in the above reaction scheme) and a compound represented by the formula (V) (for example, the compound (in the above reaction scheme, It can be carried out by reacting with 8)) in the presence of a condensing agent.
  • the compound represented by the formula (I′) for example, the compound (9) in the above reaction scheme
  • the compound represented by the formula (I′) for example, the compound (9) in the above reaction scheme
  • the compound represented by the formula (V) (for example, the compound (8) in the above reaction scheme) may be prepared by purchasing the compound prepared in advance, or the like, and the known literature (Bonnet ,, PA et al., Journal of Chemical Research, Synopses, Vol. 2, p. 28; 1984)).
  • step 2-2 this reaction is usually performed in an inert solvent.
  • examples of the inert solvent include dichloromethane, dichloroethane, chloroform, tetrahydrofuran, 1,4-dioxane, N,N-dimethylacetamide, acetonitrile and the like.
  • the inert solvent two or more kinds of the above solvents may be mixed and used at an arbitrary ratio.
  • Step 2-2 as the condensing agent, for example, 1-ethyl-1-(3-methylaminopropyl)carbodiimide hydrochloride, 1,3-dicyclohexylcarbodiimide, diethyl cyanophosphate, diphenylphosphoryl azide, 1, 1′ -Carbonyldiimidazole, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, o-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluoroline Examples thereof include acid salts and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate.
  • a condensing agent bound to the porous resin such as PS-carbodiimide resin (manufact
  • step 2-2 the amount of the condensing agent used is usually in the range of 1 to 10 molar equivalents relative to the compound represented by the formula (IV′) (for example, compound (7) in the above reaction scheme). is there.
  • one or more condensation accelerators may be used, if desired, in addition to the condensing agent.
  • the condensation accelerator include, but are not limited to, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N,N-dimethyl-4-aminopyridine, and the like.
  • a condensation accelerator bound to the porous resin such as PS-HOBt resin (manufactured by Biotage), can be used.
  • step 2-2 when a condensation accelerator is used, the condensation accelerator is usually 0.1 to the compound represented by the formula (IV′) (for example, the compound (7) in the above reaction scheme). Used in amounts ranging from to 10 molar equivalents.
  • step 2-2 this reaction is preferably carried out in the presence of a base such as triethylamine, diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene.
  • a base such as triethylamine, diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene.
  • the base is usually used in an amount within the range of 0.1 to 10 molar equivalents relative to the compound represented by the formula (IV′) (for example, compound (7) in the above reaction scheme).
  • the reaction temperature is usually in the range of 0 to 150°C.
  • the reaction time is not particularly limited, but is usually in the range of 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Step 2-3 is performed, for example, by reacting a compound represented by the formula (I′) (for example, compound (9) in the above reaction scheme) with hydrogen in the presence of a metal catalyst in an inert solvent. can do.
  • a compound represented by the formula (XI) for example, the compound (10) in the above reaction scheme
  • examples of the inert solvent include methanol, ethanol, propanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene and 1,2-dimethoxyethane.
  • the inert solvent two or more kinds of the above solvents may be mixed and used at an arbitrary ratio.
  • examples of the metal catalyst include palladium/carbon, and Raney nickel W2 or W4.
  • the amount of the metal catalyst used is usually in the range of 0.01 to 10 molar equivalents with respect to the compound represented by the formula (I′) (for example, the compound (9) in the above reaction scheme).
  • the reaction temperature is usually in the range of 0 to 150°C.
  • step 2-3 hydrogen is usually reacted under atmospheric pressure.
  • the reaction time is not particularly limited, but is usually in the range of 0.1 to 100 hours, and preferably in the range of 0.5 to 72 hours.
  • Step 2-4 includes, for example, a compound represented by the formula (XI) (for example, the compound (10) in the reaction scheme) and a compound represented by the formula (XII) (for example, the compound (11 in the reaction scheme, )) can be carried out in the presence of a base.
  • a compound represented by the formula (I) in protected form for example, the compound (12) in the above reaction scheme
  • the compound represented by the formula (XII) (for example, the compound (11) in the above reaction scheme) may be prepared by purchasing the compound prepared in advance. May be prepared based on the method described in 2013/073875A1).
  • step 2-4 this reaction is usually performed in the presence of a base in an inert solvent.
  • examples of the base include potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hexamethyldisilazane, sodium hexamethyldisilazane and NaH. ..
  • examples of the inert solvent include dichloromethane, dichloroethane, chloroform, tetrahydrofuran, 1,4-dioxane, diethyl ether, dimethoxyethane, N,N-dimethylacetamide, methanol and ethanol. ..
  • the inert solvent two or more kinds of the above solvents may be mixed and used at an arbitrary ratio.
  • reaction temperature is usually in the range of 0 to 150°C.
  • the reaction time is not particularly limited, but is usually in the range of 0.1 to 100 hours, preferably in the range of 0.5 to 72 hours.
  • the production method 2 includes deprotecting the compound represented by the formula (I) in a protected form (for example, the compound (12) in the above reaction scheme) to give the compound represented by the formula ( It is preferable to further include a step (step 2-5) of obtaining a compound represented by I) (for example, compound (I-2-1) in the above reaction scheme).
  • the conditions for the reaction for deprotecting PGN1 can be appropriately set by those skilled in the art based on the type of protecting group used.
  • the deprotection reaction can usually be carried out in the presence of acid, in an inert solvent, or in excess of acid.
  • the acid used is not limited, but examples thereof include hydrochloric acid, trifluoroacetic acid, hydrobromic acid, sulfuric acid, hydrofluoric acid, and the like.
  • the acid used is preferably hydrochloric acid or trifluoroacetic acid.
  • a compound represented by the formula (I) obtained by the production method 2 of the present embodiment for example, the compound (I-2-1) in the above reaction scheme
  • the compound represented by the formula (Ib) can be obtained in the form of their hydrochloride salts.
  • the compound represented by the formula (I) obtained by the production method 2 of the present embodiment for example, the compound (I-2-1) in the above reaction scheme
  • the compound represented by the formula (Ib) can be obtained in the form of their trifluoroacetates.
  • the compound in the form of such a salt can be converted into the educt form by a means such as amino silica gel chromatography, treatment with an ion exchange resin, or washing treatment with a basic aqueous solution.
  • the amount of the acid used is based on the compound represented by the formula (I) in a protected form (for example, the compound (12) in the above reaction scheme). Usually in the range of 1 to 1000 molar equivalents.
  • step 2-5 when carrying out the deprotection reaction by acid treatment, examples of the inert solvent include dichloromethane, dichloroethane, chloroform, tetrahydrofuran, 1,4-dioxane, diethyl ether, dimethoxyethane, N,N-dimethyl. Acetamide, methanol, ethanol, etc. can be mentioned. As the inert solvent, two or more kinds of the above solvents may be mixed and used at an arbitrary ratio.
  • step 2-5 when the deprotection reaction is carried out by acid treatment, the reaction temperature is usually in the range of 0 to 150°C.
  • the reaction time is not particularly limited, but is usually in the range of 0.1 to 100 hours, preferably in the range of 0.5 to 72 hours.
  • formula (I) (wherein L is a substituted or unsubstituted C 1 to C 6 alkylene-CO-, a substituted or unsubstituted C 2 to C 6 alkenylene-CO-, Or a substituted or unsubstituted C 2 -C 6 alkynylene-CO—), especially a compound of formula (Ib).
  • the production method of this aspect can be carried out by a method including Step 3-11 exemplified below (hereinafter, also referred to as “production method 3”).
  • the production method 3 of the present embodiment can produce a compound represented by the formula (I) (wherein L is a single bond), particularly a compound represented by the formula (Ia).
  • Ar 1 , n, X 2 , X 3 , X 4 , R 22 , R 23 , R 24 , R 25 and PGN 1 have the same meanings as described above.
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • the production method 3 can be carried out based on the reaction scheme shown below.
  • the compound represented by the formula (I-3-1) shown in the reaction scheme is included in the compound represented by the formula (I).
  • Step 3-1 is carried out, for example, by reacting a compound represented by the formula (II′) (for example, compound (II-1) in the above reaction scheme) with hydrogen in the presence of a metal catalyst in an inert solvent. , Can be implemented. Through this step, a compound in which the group containing Ar 1′ is removed from the compound represented by the formula (II′) (for example, the compound (13) in the above reaction scheme) can be obtained.
  • a compound represented by the formula (II′) for example, compound (II-1) in the above reaction scheme
  • step 3-1 this reaction can be carried out under the same conditions as in step 2-3 described above.
  • Step 3-2 includes, for example, a compound represented by the formula (II′) in which the group containing Ar 1′ is removed (for example, the compound (13) in the above reaction scheme) and a compound represented by the formula (XII). It can be carried out by reacting the compound (for example, compound (14) in the above reaction scheme) in the presence of a base. Through this step, a compound represented by the formula (II) in protected form (for example, the compound (15) in the above reaction scheme) can be obtained.
  • step 3-2 this reaction can be carried out under the same conditions as in step 2-4 described above.
  • the production method 3 comprises deprotecting the protected form of the compound represented by formula (II) (for example, compound (15) in the above reaction scheme) to deprotect it. It is preferable to further include a step (Step 3-3) of obtaining the compound represented by the formula (II) in the form (for example, the compound (16) in the above reaction scheme).
  • step 3-3 this reaction can be carried out under the same conditions as in step 2-5 described above.
  • Step 3-11 includes, for example, a compound represented by the formula (II) in a deprotected form (for example, the compound (16) in the above reaction scheme) and a compound represented by the formula (VI) (for example, the above reaction scheme). It can be carried out by reacting the compound (17) or (18) in the above in the presence of a reducing agent. By this step, the compound represented by the formula (I) (for example, the compound (I-3-1) in the above reaction scheme) can be obtained.
  • a compound represented by the formula (II) in a deprotected form for example, the compound (16) in the above reaction scheme
  • a compound represented by the formula (VI) for example, the above reaction scheme
  • the compound represented by the formula (VI) (for example, the compound (17) or (18) in the above reaction scheme) may be prepared by purchasing the compound prepared in advance, You may prepare based on the method described in a well-known literature (for example, CN105330648A).
  • step 3-11 the amount of the compound represented by the formula (VI) (for example, the compound (17) or (18) in the above reaction scheme) is the deprotected form of the compound represented by the formula (II) (for example, it is usually in the range of 0.5 to 3 molar equivalents relative to compound (16) in the above reaction scheme.
  • step 3-11 this reaction is usually performed in the presence of a reducing agent in an inert solvent.
  • examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, and 2-picolineborane complex.
  • a condensing agent bound to the porous resin such as MP-BH4 resin, MP-(OAc)3BH resin and MP-CNBH3 resin (manufactured by Biotage), can be used.
  • the amount of the reducing agent used is usually 1 to 50 molar equivalents relative to the compound of formula (II) in deprotected form (eg, compound (16) in the above reaction scheme). Is the range.
  • Step 3-11 as the inert solvent, for example, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, 1,4-dioxane, diethyl ether, dimethoxyethane, N,N-dimethylacetamide, methanol, ethanol, isopropanol, acetic acid and water. Etc. can be mentioned.
  • the inert solvent two or more kinds of the above solvents may be mixed and used at an arbitrary ratio.
  • the reaction temperature is usually in the range of 0 to 150°C.
  • the reaction time is not particularly limited, but is usually in the range of 0.1 to 100 hours, preferably in the range of 0.5 to 72 hours.
  • each compound has, for example, an amino group, a carboxyl group, a hydroxyl group or a carbonyl group
  • each compound in a protected form in which a protecting group is introduced into the group is used in each step of this embodiment. You may.
  • a compound represented by the formula (II) in a deprotected form for example, the compound (16) in the above reaction scheme
  • a compound represented by the formula (VI) for example, the above reaction scheme
  • the protecting group is deprotected to give a compound (I)
  • the deprotection step can be performed, for example, under the same conditions as in Steps 2-5 described above.
  • a compound represented by the formula (I) (wherein L is a single bond), particularly a compound represented by the formula (I-a) can be produced.
  • the production method of this aspect can be carried out by a method including Step 4-1 to Step 4-3 exemplified below (hereinafter, also referred to as “Production Method 4”). To).
  • the production method 4 of the present embodiment can produce a compound represented by the formula (I) (wherein L is a single bond), particularly a compound represented by the formula (Ia).
  • Ar 1′ , n, X 2 , X 3 , X 4 , R 22 , R 23 , R 24 , R 25 and PGN 1 have the same meanings as described above.
  • A′ has the same meaning as above.
  • Ar 1 , Ar 1′ , n, X 2 , X 3 , X 4 , R 22 , R 23 , R 24 , R 25 , L and A are It is synonymous with the above.
  • step 4-1 this reaction can be carried out under the same conditions as in step 3-11 explained above.
  • step 4-2 this reaction can be carried out under the same conditions as in step 2-3 described above.
  • step 4-3 this reaction can be carried out under the same conditions as in step 2-4 described above.
  • a compound represented by the formula (I) (wherein L is a single bond), particularly a compound represented by the formula (I-a) can be produced.
  • the production method of this aspect can be carried out by a method including Step 5-1 exemplified below (hereinafter, also referred to as “production method 5”).
  • production method 5 a method including Step 5-1 exemplified below
  • formula (I) (wherein L is a substituted or unsubstituted C 1 to C 6 alkylene, a substituted or unsubstituted C 2 to C 6 alkenylene, or a substituted or unsubstituted C 2 -C 6 alkynylene) can be prepared, in particular the compound of formula (Ic).
  • the compound represented by the formula (Ic) when the compound represented by the formula (Ic) is produced, in the compound represented by the formula (VII), L′ is —(CH 2 ) m-1 — (m is as defined above. There is).
  • the compound represented by the formula (VII) has the formula (VII′): R L3 -(CH 2 ) m-1 -A c (VII') The compound represented by is preferable.
  • Ar 1 , n, X 2 , X 3 , X 4 , R 22 , R 23 , R 24 , R 25 and PGN 1 have the same meanings as described above.
  • a and A c are as defined above.
  • L′ is a substituted or unsubstituted C 1 to C 6 alkylene, a substituted or unsubstituted C 2 to C 6 alkenylene, or a substituted or unsubstituted C 2 to C 6 alkynylene.
  • L' has one less carbon atom in the main chain than L.
  • L′ is preferably selected from the groups included in L exemplified above, provided that L′ has one less carbon atom in the main chain than L.
  • m has the same meaning as above.
  • -(CH 2 ) m-1- means a single bond.
  • R L3 is —CHO.
  • the production method 5 can be carried out based on the reaction scheme shown below.
  • the compound represented by the formula (I-3-1) shown in the reaction scheme is included in the compound represented by the formula (I).
  • Step 5-1 includes, for example, a compound represented by the formula (II) (for example, the compound (16) in the reaction scheme) and a compound represented by the formula (VII) (for example, the compound (19 in the reaction scheme, ) Or (20)) in the presence of a reducing agent.
  • a compound represented by the formula (II) for example, the compound (16) in the reaction scheme
  • a compound represented by the formula (VII) for example, the compound (19 in the reaction scheme, ) Or (20)
  • the compound represented by the formula (VII) may be prepared by purchasing the compound prepared in advance, It may be prepared based on the method described in a known document (for example, WO2017/089849A1 and Itani, Hiromichi et al., Bioorganic & Medicinal Chemistry Letters, Volume 12(5), p.
  • step 5-1 this reaction can be performed under the same conditions as in step 3-11 explained above.
  • each compound in a protected form in which a protecting group is introduced into the group is used in each step of this embodiment.
  • a compound represented by the formula (II) for example, the compound (16) in the above reaction scheme
  • a compound represented by the formula (VII) for example, the compound (19 in the above reaction scheme ) Or (20)
  • the protecting group is deprotected to give a compound represented by the formula (I) (for example, the above-mentioned reaction).
  • the deprotection step can be performed, for example, under the same conditions as in Steps 2-5 described above.
  • formula (I) (wherein L is a substituted or unsubstituted C 1 to C 6 alkylene, a substituted or unsubstituted C 2 to C 6 alkenylene, or a substituted or unsubstituted C 2 -C 6 alkynylene) can be prepared, in particular the compound of formula (Ic).
  • the production method of this aspect can be carried out by a method including Step 6-1 to Step 6-3 exemplified below (hereinafter, also referred to as “Production Method 6”).
  • Step 6-1 to Step 6-3 exemplified below
  • the compound represented by the formula (I) (wherein L is a substituted or unsubstituted C 1 to C 6 alkylene, a substituted or unsubstituted C 2 to C 6 alkenylene, or a substituted or unsubstituted C 2 -C 6 alkynylene), in particular compounds of formula (Ic) can be prepared.
  • the compound represented by the formula (Ic) when the compound represented by the formula (Ic) is produced, in the compound represented by the formula (VII), L′ is —(CH 2 ) m-1 — (m is as defined above. There is).
  • the compound represented by the formula (VII) has the formula (VII′): R L3 -(CH 2 ) m-1 -A c (VII') The compound represented by is preferable.
  • Ar 1′ , n, X 2 , X 3 , X 4 , R 22 , R 23 , R 24 , R 25 , L, A and PG N1 are , Is synonymous with the above.
  • m has the same meaning as above.
  • -(CH 2 ) m-1- means a single bond.
  • Ar 1 , n and R L11 are as defined above.
  • step 6-1 this reaction can be carried out under the same conditions as in step 5-1 described above.
  • step 6-2 this reaction can be carried out under the same conditions as in step 4-2 described above.
  • step 6-3 this reaction can be carried out under the same conditions as in step 4-3 described above.
  • the compound represented by the formula (I) (wherein L is a substituted or unsubstituted C 1 to C 6 alkylene, a substituted or unsubstituted C 2 to C 6 alkenylene, or a substituted or unsubstituted C 2 -C 6 alkynylene), in particular compounds of formula (Ic) can be prepared.
  • the production methods 1 to 6 of one embodiment of the present aspect are the compounds represented by the formulas (I), (Ia), (Ib) and (Ic) of the aspect of the present invention, and the formulas (II) to (XII).
  • the compound represented by, and any compound selected from the group consisting of their reaction intermediates, is subjected to a reaction of introducing or converting a functional group known per se to give a compound of formula (I), (Ia), (Ib ) And (Ic) may be further included to introduce or convert a functional group to obtain a new compound.
  • the conversion reaction of the functional group is not limited, but for example, substitution of primary or secondary amine, reduction of nitro group to amine, amine to amide, sulfone Conversion to amides, sulfamides, carbamates or ureas, palladium-catalyzed cross-coupling of amines with aryl halides, conversion of esters to carboxy groups by hydrolysis, conversion of carboxyl groups to carbamoyl groups by amidation, conversion of carboxyl groups Conversion to hydroxymethyl group by reduction, conversion of carbonyl group to alcohol by reduction or alkylation, reductive amination of carbonyl group, oximation of carbonyl group, conversion of cyano group to carboxyl group by hydrolysis, cyano Examples thereof include conversion to an aminomethyl group by reduction of a group, conversion to an amine by alkylation of a cyano group, and conversion to a carbamoyl group by addition of water.
  • the production methods 1 to 6 of one embodiment of the present aspect are the compounds represented by the formulas (I), (Ia), (Ib) and (Ic) of the aspect of the present invention, and the formulas (II) to (XII).
  • a step of obtaining the compound in an optically pure form is carried out at a desired stage.
  • the step may be performed, for example, by a method of performing diastereomeric pair formation by salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base, or separation by chiral preparative chromatography. It can be carried out using various methods known in the technical field.
  • the compounds represented by formulas (I), (Ia), (Ib) and (Ic) according to one embodiment of the present invention have high inhibitory activity against LSD1. Therefore, another aspect of the present invention is a compound represented by the formula (I), (Ia), (Ib) or (Ic) of the aspect of the present invention, a stereoisomer thereof or a pharmaceutically acceptable thereof. And a pharmaceutically acceptable solvate thereof as an active ingredient. Further, when the compound represented by the formula (I), (Ia), (Ib) or (Ic) of one embodiment of the present invention is administered to a subject, the specific disease of the subject is mediated by LSD1 inhibitory activity. , Can prevent or treat symptoms or disorders.
  • another aspect of the present invention is a compound represented by the formula (I), (Ia), (Ib) or (Ic) of the aspect of the present invention, a stereoisomer thereof or a pharmaceutically acceptable thereof. Or a pharmaceutically acceptable solvate thereof as an active ingredient.
  • epigenetics means a mechanism of gene expression control through chemical and/or structural modification of chromatin composed of genomic DNA, histone proteins and the like.
  • the N-terminal region of core histones may undergo various modifications such as acetylation, methylation, phosphorylation and ubiquitination.
  • the chromatin structure changes, affecting gene expression.
  • chemical and/or structural modifications involved in epigenetic regulation are diverse in terms of the site of chromatin and the position of the lysine residue undergoing modification. Therefore, epigenetic control has the characteristic of being highly plastic and capable of changing spatiotemporally.
  • LSD is an enzyme involved in epigenetic regulation in eukaryotes.
  • LSD1 and LSD2 isozymes are known (Karytinos, A, et al., The Journal of of biological chemistry, vol. 284, p. 17775-82, 2009).
  • LSD1 demethylates the mono- or dimethyl group added to the 4th lysine residue (H3K4) or 9th lysine residue (H3K9) of histone H3 (Shi Y, et al., Cell 119). Vol., 941-53, 2004).
  • H3K4 4th lysine residue
  • H3K9 9th lysine residue
  • LSD1 may be involved in both transcriptional activation and transcriptional repression.
  • the compounds represented by formulas (I), (Ia), (Ib) and (Ic) preferably have specific inhibitory activity against LSD1, and the compound is administered. It is more preferable to have a specific inhibitory activity against LSD1 derived from a subject, and a human or non-human mammal (for example, pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey) It is more preferable to have a specific inhibitory activity against LSD1 derived from warm-blooded animals such as baboons, baboons, or chimpanzees), and it is particularly preferable to have a specific inhibitory activity against LSD1 derived from humans.
  • a human or non-human mammal for example, pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey
  • a specific inhibitory activity against LSD1 derived from warm-blooded animals such as baboons, baboon
  • a compound represented by formula (I), (Ia), (Ib) or (Ic), or a drug or the like containing the compound as an active ingredient By administering to the subject a compound represented by formula (I), (Ia), (Ib) or (Ic), or a drug or the like containing the compound as an active ingredient, a specific disease that the subject has , Symptoms or disorders can be prevented or treated.
  • the LSD1 inhibitory activity of the compound represented by formula (I), (Ia), (Ib) or (Ic) used as an active ingredient is not limited, but for example, histone
  • the synthetic peptide of 20 residues (H3K4me2 peptide), which is the dimethylated 4th lysine residue (K4) of H3, as a substrate the demethylation reaction by LSD1 is performed in the presence of the target compound, and it is produced as a by-product. It can be evaluated by quantitatively measuring hydrogen peroxide by a known peroxidase assay. LSD1 releases hydrogen peroxide as a reaction by-product with the demethylation reaction.
  • peroxidase uses this hydrogen peroxide as a substrate, 4-aminoantipyrine (4-AA), which is a coupling agent, and N-ethyl-N-(2-, a water-soluble aniline derivative of a hydrogen donor. Oxidative condensation with hydroxy-3-sulfopropyl)-3-methoxyaniline (new Trinder reagent). In this reaction, a purple color having an absorption maximum wavelength of 555 nm is exhibited in a dose-dependent manner. Hydrogen peroxide can be quantified by measuring the violet color development at an absorbance of 562 nm.
  • LSD1 is an enzyme protein prepared from cells of a human or non-human mammal (for example, a warm-blooded animal such as pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, baboon, or chimpanzee). Or a recombinant enzyme protein prepared from cultured cells in which LSD1 of the human or non-human mammal is highly expressed.
  • a human or non-human mammal for example, a warm-blooded animal such as pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, baboon, or chimpanzee.
  • a recombinant enzyme protein prepared from cultured cells in which LSD1 of the human or non-human mammal is highly expressed.
  • the selectivity of the compound represented by the formula (I), (Ia), (Ib) or (Ic) used as an active ingredient for LSD1 inhibition compares the LSD1 inhibitory activity of the compound with the monoamine oxidase inhibitory activity. By that, it can be determined.
  • Monoamine oxidase A hereinafter also referred to as “MAO-A”
  • monoamine oxidase B hereinafter also referred to as “MAO-B” are known as enzymes having similar catalytic reaction mechanisms to LSD1.
  • Both MAO-A and MAO-B have an activity to oxidize low molecular weight amines in vivo such as dopamine and serotonin by using flavin adenine dinucleotide (FAD) as a coenzyme. Due to the similarity to the reaction in which FAD is used as a coenzyme to oxidize an amine, a compound having LSD1 inhibitory activity may inhibit MAO-A and/or MAO-B depending on its structure.
  • FAD flavin adenine dinucleotide
  • 2-PCPA which is one of the known LSD1 inhibitors, was originally known as an inhibitor against MAO-A and MAO-B, but it was later reported that LSD1 can also be inhibited (Lee et al., Chemistry & Biology Volume 13, p.563, 2006). Therefore, in a compound having an inhibitory activity against LSD1, by comparing the inhibitory activity against LSD1 with the inhibitory activity against MAO-A and/or MAO-B, the selectivity for LSD1 can be evaluated (Mimasu et al., Biochemistry). Volume 49, p. 6494, 2010; Mohammad et al., Cancer Cell vol. 28, p. 57, 2015).
  • expression used as an active ingredient (I), (Ia), a compound represented by (Ib) or (Ic) is, IC 50 values of LSD1 inhibitory activity was determined by the procedure, Usually less than 10 ⁇ M, typically less than 3 ⁇ M, especially less than 1 ⁇ M.
  • the compound represented by the formula (I), (Ia), (Ib) or (Ic) used as an active ingredient usually has a selectivity value for LSD1 inhibition determined by the above procedure of more than 1. The value is typically 1.2 or more, particularly 10 or more.
  • the compound represented by the formula (I), (Ia), (Ib) or (Ic) used as an active ingredient when it has an IC 50 value and/or a selectivity value in the above range is a specific compound possessed by the subject.
  • the disease, symptom or disorder of can be prevented or treated particularly effectively.
  • prodrug means a compound that is converted in vivo to the parent drug.
  • the prodrug form of the compound is not limited, but for example, when a hydroxyl group is present, an ester of the hydroxyl group with an arbitrary carboxylic acid, an amide of the hydroxyl group with an arbitrary amine, and the like can be used. Can be mentioned. For example, when an amino group is present, an amide of the amino group and any carboxylic acid can be mentioned.
  • the compounds represented by the formulas (I), (Ia), (Ib) and (Ic) according to one embodiment of the present invention are applied to pharmaceutical use, the compounds may be used alone, and one or more kinds thereof may be used. It may be used in combination with a pharmaceutically acceptable ingredient.
  • the medicament of this aspect can be formulated into various dosage forms usually used in the art depending on the desired administration method. Therefore, the medicament of this aspect also includes a compound represented by the formula (I), (Ia), (Ib) or (Ic) of one aspect of the present invention, a stereoisomer thereof or a pharmaceutically acceptable thereof. It can also be provided in the form of a pharmaceutical composition comprising a salt, or a pharmaceutically acceptable solvate thereof, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition according to this embodiment includes one or more pharmaceutically acceptable vehicles (for example, a solvent such as sterile water or a solution such as saline), an excipient, a binder, Vehicles, solubilizers, preservatives, stabilizers, swelling agents, lubricants, surfactants, emulsifiers, oily liquids (eg vegetable oils), suspending agents, buffers, soothing agents, antioxidants, sweeteners and A flavoring agent or the like may be included.
  • a pharmaceutically acceptable vehicles for example, a solvent such as sterile water or a solution such as saline
  • an excipient for example, a solvent such as sterile water or a solution such as saline
  • Vehicles solubilizers, preservatives, stabilizers, swelling agents, lubricants, surfactants, emulsifiers, oily liquids (eg vegetable oils), suspending agents, buffers, soothing agents, antioxidants, sweeteners and A flavoring agent or the like
  • the pharmaceutical dosage form of the present embodiment containing a solvate as an active ingredient is not particularly limited, and may be a preparation for parenteral administration or a preparation for oral administration. .. Further, the dosage form of the medicament of the present aspect may be a unit dosage form preparation or a multiple dosage form preparation.
  • Formulations for use in parenteral administration include, for example, injections such as sterile solutions or suspensions with water or other pharmaceutically acceptable media, lotions, ointments, eye drops and suppositories. Can be mentioned.
  • the components that can be mixed with the injection include, but are not limited to, physiological saline, glucose or other adjuvants (for example, D-sorbitol, D-mannitol, D-mannose or sodium chloride).
  • Vehicles such as isotonic solutions, solubilizing agents such as alcohols (eg ethanol or benzyl alcohol), polyalcohols (eg propylene glycol or polyethylene glycol) or esters (eg benzyl benzoate), Polysorbate 80TM or poly Non-ionic surfactants such as oxyethylene hydrogenated castor oil, oily liquids such as sesame oil or soybean oil, buffers such as phosphate buffer or sodium acetate buffer, benzalkonium chloride or procaine hydrochloride. Examples thereof include soothing agents, stabilizers such as human serum albumin or polyethylene glycol, preservatives, and antioxidants.
  • the prepared injection is usually filled in an appropriate vial (for example, an ampoule) and stored in an appropriate environment until use.
  • formulations for oral administration include tablets, pills, powders, granules, powders, capsules, microcapsules, elixirs, solutions, syrups, slurries and suspensions.
  • the tablet may be formulated as a sugar-coated tablet, a sugar-coated tablet coated with a soluble coating, a gelatin-coated tablet, an enteric-coated tablet or a film-coated tablet, if desired, or as a double- or multi-layer tablet. It may be formulated.
  • components that can be mixed with tablets or capsules and the like include, but are not limited to, water, ethanol, propanol, simple syrup, glucose solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, Binders such as gelatin, corn starch, tragacanth or gum arabic; excipients such as crystalline cellulose, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin or silicic acid; dry starch, sodium alginate.
  • the medicine of this aspect can also be formulated as a depot preparation.
  • the drug of the present embodiment in the form of a depot preparation can be administered, for example, subcutaneously or intramuscularly, or by intramuscular injection.
  • the pharmacological activity of the compounds represented by formulas (I), (Ia), (Ib) and (Ic) of one aspect of the present invention can be exerted for a long period of time. It can be expressed continuously.
  • the pharmaceutical agent of the present embodiment containing a solvate as an active ingredient can also be used in combination with one or more other pharmaceutical agents useful as a pharmaceutical agent.
  • other agents used in combination with the compound represented by formula (I), (Ia), (Ib) or (Ic) of one aspect of the present invention are not limited, Examples thereof include anticancer agents, steroidal anti-inflammatory agents, thalidomide, lenalidomide, and the like.
  • anticancer agents for example, alkylating agents such as cyclophosphamide and melphalan, anticancer agents such as cytarabine and L-asparaginase, bortezomib, carfilzomib and ixazomib and other proteasome inhibitors, vorinostat, panobinostat, romidepsin, rocilino.
  • anticancer agents include HDAC inhibitors such as stat, phenylbutyric acid, Tubastatin A, and Tubacin.
  • the steroidal anti-inflammatory agent include cortisol, prednisolone, triamcinolone, dexamethasone and betamethasone.
  • the medicament of this aspect is a compound represented by the formula (I), (Ia), (Ib) or (Ic) of one aspect of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof. Or a pharmaceutically acceptable solvate thereof, and one or more other drugs as described above in the form of a combination drug.
  • the concomitant drug is a compound represented by the formula (I), (Ia), (Ib) or (Ic) of one embodiment of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof, or a compound thereof.
  • composition comprising a combination of a pharmaceutically acceptable solvate and one or more of the above-mentioned other drugs, and one of the formula (I), (Ia), ( A compound represented by Ib) or (Ic), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and used in combination with one or more other drugs as described above.
  • the pharmaceutical composition may be in the form of a pharmaceutical composition.
  • a compound represented by the formula (I), (Ia), (Ib) or (Ic) of one aspect of the present invention, its stereoisomer or It may be provided in the form of a single preparation containing a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate thereof and one or more other drugs, and one or more other drugs. May be provided in the form of a pharmaceutical combination or kit containing a plurality of formulations separately formulated. When in the form of a pharmaceutical combination or kit, the respective formulations may be administered simultaneously or separately (eg sequentially).
  • glioblastoma Among primary brain tumors, glioblastoma has the highest malignancy and is extremely difficult to be cured.
  • One of the causes of refractory glioblastoma lies in the cell population called brain tumor stem cells that are present in the tumor tissue. Brain tumor stem cells are important for tumor progression, treatment resistance and recurrence. Therefore, development of a therapeutic method targeting brain tumor stem cells is desired. So far, it has been revealed that regulation of gene expression by epigenome mechanism plays an important role in the maintenance of brain tumor stem cells.
  • LSD1 is overexpressed in many cancer types including glioblastoma and has been reported to be involved in cancer malignancy (Zhang X et al., Cell Report, Vol. 5, p. 445-457, 2013; SuvaML et al., Cell, Volume 157, p.580-594, 2014).
  • ALL Acute lymphoblastic leukemia
  • T-ALL T progenitor cells
  • B-ALL ALL derived from B cells
  • JALSG Japan-Leukemia Study Group
  • CNS central nervous system
  • the medicament of the present embodiment containing a solvate as an active ingredient can similarly prevent or treat various diseases, symptoms and/or disorders involving LSD1.
  • diseases, symptoms and/or disorders involving LSD1 include, but are not limited to, primary brain tumors (eg glioblastoma), T-ALL (eg T-ALL with CNS lesions), small cell lung cancer, myeloma. It may include plastic syndrome, non-Hodgkin's lymphoma and malignant tumors.
  • malignant tumors include hematopoietic tumors, epithelial cell-derived cancers, and non-epithelial cell-derived sarcomas.
  • Hematopoietic tumors can include, but are not limited to, leukemias, malignant lymphomas, and multiple myeloma.
  • the cancer includes, but is not limited to, lung cancer, breast cancer, gastric cancer, liver cancer, pancreatic cancer, colon cancer, uterine cancer, ovarian cancer, prostate cancer, kidney cancer, esophageal cancer, laryngeal cancer, pharyngeal cancer and tongue. Cancer can be mentioned.
  • Sarcomas include, but are not limited to, osteosarcoma and soft tissue sarcoma.
  • the disease, condition and/or disorder is preferably one or more disease, condition or disorder selected from the group consisting of primary brain tumor (eg glioblastoma) and T-ALL.
  • primary brain tumor eg glioblastoma
  • T-ALL T-ALL
  • the medicament of the present embodiment containing a solvate as an active ingredient can be applied to various subjects in need of prevention or treatment of the above-mentioned symptoms, diseases and/or disorders involving LSD1.
  • the subject is a human or non-human mammal (for example, a warm-blooded animal such as pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, baboon, or chimpanzee), or a patient. It is preferable to have.
  • the disease, condition and/or disorder associated with LSD1 in the subject can be prevented or treated.
  • prevention means substantially preventing the occurrence (occurrence or manifestation) of a symptom, disease and/or disorder.
  • treatment means suppressing (eg, suppressing progression), ameliorating, repairing and/or healing a symptom, disease and/or disorder that has occurred (occurred or developed).
  • the compounds represented by the formulas (I), (Ia), (Ib) and (Ic) according to one embodiment of the present invention can be used for the symptoms, diseases and/or disorders (eg, primary brain tumor (eg, glioblastoma)) described above.
  • diseases and/or disorders eg, primary brain tumor (eg, glioblastoma)
  • the medicament of this embodiment is preferably a medicament for use in the prevention or treatment of the symptoms, diseases and/or disorders described above, including primary brain tumor (eg glioblastoma) and T-ALL ( More preferably, it is a medicament for use in the prevention or treatment of one or more diseases, symptoms or disorders selected from the group consisting of, for example, T-ALL having CNS lesions.
  • the compounds represented by the formulas (I), (Ia), (Ib) and (Ic) according to one embodiment of the present invention can be used for the symptoms, diseases and/or disorders (eg, primary brain tumor (eg, glioblastoma)) described above.
  • diseases and/or disorders eg, primary brain tumor (eg, glioblastoma)
  • T-ALL eg, T-ALL with CNS lesions
  • small cell lung cancer myelodysplastic syndrome, non-Hodgkin's lymphoma or malignant tumor
  • prevention or treatment of said symptoms, diseases and/or disorders Can be used for Therefore, another aspect of the present invention provides a subject in need of prophylaxis or treatment of the symptoms, diseases and/or disorders described above, in an effective amount of formula (I), (Ia ), (Ib) or (Ic), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, which is administered, It is a method for preventing or treating symptoms.
  • the symptom, disease and/or disorder is one or more disease, symptom or disorder selected from the group consisting of primary brain tumor (eg glioblastoma) and T-ALL (eg T-ALL with CNS lesions). It is preferable to have.
  • the symptom, disease and/or disorder can be prevented or treated via LSD1 inhibitory activity.
  • Another aspect of the present invention is the above-described symptoms, diseases and/or disorders (eg, primary brain tumor (eg, glioblastoma), T-ALL (eg, T-ALL with CNS lesions), small cell lung cancer. , Myelodysplastic syndrome, non-Hodgkin's lymphoma or malignant tumor) for use in the prevention or treatment of the compound of formula (I), (Ia), (Ib) or (Ic) of one embodiment of the present invention , A stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.
  • primary brain tumor eg, glioblastoma
  • T-ALL eg, T-ALL with CNS lesions
  • small cell lung cancer small cell lung cancer.
  • Myelodysplastic syndrome non-Hodgkin's lymphoma or malignant tumor
  • a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof for use in the prevention or treatment of the
  • Another aspect of the present invention is the above-described symptoms, diseases and/or disorders (eg, primary brain tumor (eg, glioblastoma), T-ALL (eg, T-ALL with CNS lesions), small cell lung cancer. , Myelodysplastic syndrome, non-Hodgkin's lymphoma or malignant tumor) for the manufacture of a medicament for use in the prevention or treatment of formula (I), (Ia), (Ib) or (Ic) of one embodiment of the present invention.
  • the symptom, disease and/or disorder is one or more disease, symptom or disorder selected from the group consisting of primary brain tumor (eg glioblastoma) and T-ALL (eg T-ALL with CNS lesions). It is preferable to have.
  • the symptom, disease and/or disorder can be prevented or treated via LSD1 inhibitory activity.
  • a drug containing a solvate as an active ingredient is administered to a subject, particularly a human patient
  • the exact dose and usage for example, dose, frequency of administration and/or route of administration
  • the attending physician will decide the therapeutically effective dose, the frequency of administration and the route of administration. The final decision should be taken into consideration.
  • the compound represented by formula (I), (Ia), (Ib) or (Ic) which is the active ingredient is administered to a subject in a therapeutically effective amount and frequency. ..
  • the dose of the compound represented by formula (I), (Ia), (Ib) or (Ic), which is the active ingredient is usually once.
  • the range is from 0.001 to 100 mg/kg body weight, and the typical range is from 0.01 to 10 mg/kg body weight per dose, and in particular, the range is 0.1 to 10 mg/kg body weight per dose. Is the range.
  • the administration frequency of the medicine of the present embodiment can be, for example, once a day or a plurality of times (for example, 2 or 3 times) or once every several days.
  • the administration route of the pharmaceutical agent of this embodiment is not particularly limited, and may be administered orally, parenterally (for example, rectal, mucous membrane, intestine, intramuscular, subcutaneous, intramedullary, intrathecal). , Intraventricularly, intravenously, intravitreally, intraperitoneally, intranasally or intraocularly), and may be administered once or multiple times.
  • the stereochemical configuration refers to the respective compound, even if the depicted structure may represent a more specific configuration. Is defined by the chemical name shown.
  • the relative configuration of adjacent substituents attached to the cyclopropyl ring is "trans", a mixture of absolute configurations of both (1R, 2S) and (1S, 2R). Is. This is because the starting material or synthetic intermediate phenylcyclopropanecarboxylic acid or nitrocyclopropylbenzene is a racemic mixture of which the configuration is “trans”. Starting materials in the "cis" configuration, and individual diastereomers/enantiomers, can also be prepared by similar procedures, if available by purchasing or synthesizing their starting materials.
  • the production method of one embodiment of the present invention produces a mixture of stereoisomers
  • individual isomerism of the compound represented by the formula (I), (Ia), (Ib) or (Ic) of one embodiment of the present invention The bodies are obtained as a mixture of stereoisomers by well known methods such as formation of diastereomeric pairs by salt formation with an optically active acid, followed by fractional crystallization and regeneration of the free base or by chiral preparative chromatography. It can be obtained by separating from the compound. Alternatively, optically pure or enantiomerically enriched synthetic intermediates can be obtained. These synthetic intermediates can then be used as such in subsequent steps, at various stages of the synthetic procedure described above using any known method of chiral fractionation.
  • chiral separation is performed on a compound represented by formula (I), (II) or (IV) of one aspect of the present invention in a trans-configuration (ie, trans-cyclopropylamine).
  • the separation can also be carried out, for example on the synthetic compounds (64) or (112) shown below, at other stages of the procedure.
  • a suitable method for obtaining the enantiomer of a compound of formula (I), (II) or (IV) of one aspect of the invention in trans-configuration is to combine the compound with a chiral recrystallization agent in a solvent. (Especially under conditions that are sufficient for the crystallization of the salt of the chiral recrystallization agent and the compound); and the crystallization salt of the chiral recrystallization agent and the compound are isolated thereby Preparing the enantiomer of the compound.
  • Suitable chiral recrystallization agents include, for example, S(+)-mandelic acid, D(-)-tartaric acid, L(+)-tartaric acid, L(-)-di-p-toluoyl tartaric acid, D(+) Mention may be made of -10-camphor-sulphonic acid and R(-)-mandelic acid.
  • Suitable solvents include, for example, tetrahydrofuran, ethanol and acetone, and mixtures thereof with water.
  • chiral chromatography examples include CHIRALPACK AD-H, CHIRALPACK OD-H, CHIRALPACK OZ-H, and CHIRALPACK IC.
  • elution solvents in these chiral chromatography include methanol, ethanol, isopropyl alcohol, acetonitrile and normal hexane, and mixed solvents thereof.
  • each aspect of the present invention relates to all stereoisomers of the compounds described and defined herein. That is, each aspect of the present invention includes not only the compounds described in the examples as defined by their chemical names, but also all stereoisomers arising from the depicted structure.
  • room temperature usually indicates a temperature in the range of 10 to 35°C.
  • value in% means the value in weight%.
  • MS mass spectrum
  • LC/MS liquid chromatograph mass spectrometer
  • the retention time of liquid chromatography usually indicates the retention time of a compound observed when measured under the following conditions.
  • Synthetic compound 112 (33 mg) was suspended in dichloromethane (4 mL), tert-butyl 4-formylpiperidine-1-carboxylate (21.5 mg, 18.7 ⁇ L) and sodium acetate (18.4 mg) were added, and the mixture was stirred at room temperature. Stir for 15 minutes. Sodium triacetoxyborohydride (45.2 mg) was added, the mixture was stirred at room temperature for 15 min, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform/methanol), the obtained compound was dissolved in methanol (0.5 mL), and 4 N hydrochloric acid/1,4-dioxane solution (1 mL) was added.
  • Synthetic compound 112 (31 mg) was suspended in dichloromethane (3 mL), 1-acetylpiperidin-4-one (17.8 mg, 15.5 ⁇ L) and sodium acetate (17.3 mg) were added, and the mixture was stirred at room temperature for 40 minutes. .. Sodium triacetoxyborohydride (42.3 mg) was added, the mixture was stirred at room temperature for 60 min, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform/methanol), the obtained compound was dissolved in methanol (0.5 mL), and 4 N hydrochloric acid/1,4-dioxane solution (1 mL) was added. It was The solvent was distilled off under reduced pressure to obtain 37.2 mg of the title compound.
  • Synthetic compound 113 (17 mg), isonicotinic aldehyde (8.36 mg, 7.3 ⁇ L), sodium acetate (8.7 mg) and sodium triacetoxyborohydride (42.3 mg) were suspended in ethanol and heated at 100° C. under microwave irradiation. It was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by a preparative thin layer plate (developing solvent: dichloromethane-methanol). The obtained compound was dissolved in methanol (0.5 mL), and 4 N hydrochloric acid/1,4-dioxane solution (1 mL) was added. The solvent was distilled off under reduced pressure to obtain the title compound (18.2 mg).
  • a saturated aqueous sodium hydrogen carbonate solution was added to the mixture to stop the reaction, and the organic layer was separated.
  • the solvent was evaporated, and the obtained compound was dissolved in acetonitrile (6 mL).
  • Di-tert-butyl dicarbonate (50.5 mg) and 1N aqueous sodium hydroxide solution (0.23 mL) were added to the solution, and the mixture was stirred at 5°C overnight.
  • the mixture was added to a mixed solvent of water and ethyl acetate, and the aqueous layer was separated.
  • the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate.
  • Synthetic compound 143 was suspended in dichloromethane (4 mL) and acetic acid (0.3 mL), tert-butyl 4-(formylmethyl)piperidine-1-carboxylate (26.8 mg) was added, and the mixture was stirred at room temperature for 15 min.
  • Sodium triacetoxyborohydride (75 mg) was added, the mixture was stirred at room temperature for 15 min, and concentrated under reduced pressure.
  • the residue was purified by preparative thin layer chromatography (chloroform/methanol), and the obtained compound was dissolved in dichloromethane (0.5 mL). 4 N hydrochloric acid/1,4-dioxane solution (1 mL) was added to the solution.
  • peroxidase uses this hydrogen peroxide as a substrate, 4-aminoantipyrine (4-AA), which is a coupling agent, and N-ethyl-N-(2-, a water-soluble aniline derivative of a hydrogen donor. Oxidative condensation with hydroxy-3-sulfopropyl)-3-methoxyaniline (new Trinder reagent). In this reaction, a purple color having an absorption maximum wavelength of 555 nm is exhibited in a dose-dependent manner. Hydrogen peroxide can be quantified by measuring the violet color development at an absorbance of 562 nm.
  • the absorbance of the reaction solution at a wavelength of 562 nm was measured. Based on the absorbance 30 minutes after the start of measurement, the percentage of the absorbance of the reaction solution of the test compound to the absorbance of the reaction solution of the control (DMSO) (residual activity) was calculated, and the inhibition rate (%) of the test compound at each concentration was calculated. Was calculated. Based on the calculated inhibition rate of each test compound at each concentration, Prism6 (GraphPad Software, San Diego, Calif., USA) was used to draw a dose-response curve for each test compound to test for 50% inhibition of LSD1 activity. The concentration of the compound (IC 50 value) was calculated.
  • Comparative compound A is the compound (N1-((trans)-2-phenylcyclopropyl)cyclohexane-1,4-diamine) described in Example 1 of WO 2013/057322 (Patent Document 3).
  • Comparative compound B is the compound (4-((4-((((1R,2S)-2-phenylcyclopropyl)amino) described in Example 29 of WO 2012/135113 (Patent Document 4)). Methyl)piperidin-1-yl)methyl)benzoic acid).
  • Comparative compound C is the compound (2-((trans)-2-(4-(benzoyloxy)phenyl)cyclopropylamino)- described in Example 26 of WO 2010/043721 (Patent Document 1). 1-(4-methylpiperazin-1-yl)ethanone).
  • Comparative compound D is the compound (4′-((trans)-2-aminocyclopropyl)biphenyl-3-ol) described in Example 4 of WO 2012/013727 (Patent Document 2).
  • Comparative compound E is compound S2101 described in Mimasu S et al., Biochemistry, 49(30), p. 6494-6503, 2010 (Non-patent document 4).
  • Comparative compound F is the compound ((2-((trans)-2-(5′-fluoro-2′-trifluoromethyl)) described in Example 57 of WO 2010/043721 (Patent Document 1). Biphenyl-4-yl)cyclopropylamino)-1-(4-methylpiperazin-1-yl)ethanone).
  • Comparative compound G is the compound (1-((S)-3-aminopyrrolidin-1-yl)-2-((trans)) described in Example 16 of WO 2010/043721 (Patent Document 1). -2-phenylcyclopropylamino)ethanone).
  • Comparative compound H is the compound (1-(4-methylpiperazin-1-yl)-2-((trans)-2-phenyl) described in Example 22 of WO 2010/043721 (Patent Document 1). Cyclopropylamino)ethanone).
  • tyramine was added to the reaction solution at a final concentration of 50 ⁇ M for the MAO-A reaction solution and 150 ⁇ M for the MAO-B reaction solution to start the reaction.
  • the absorbance of the reaction solution at a wavelength of 562 nm was measured. Based on the absorbance 30 minutes after the start of measurement, the percentage of the absorbance of the reaction solution of the test compound to the absorbance of the reaction solution of the control (DMSO) (residual activity) was calculated, and the inhibition rate (%) of the test compound at each concentration was calculated.
  • DMSO control
  • the synthetic compounds tested among which the synthetic compounds 50 and 64 are equivalent to or have been known as comparative compounds A, B, E and H having LSD1 inhibitory activity. It showed a remarkable antitumor effect exceeding that of the compound.
  • the present invention is not limited to the above-mentioned embodiments, but includes various modifications.
  • the above-described embodiments have been described in detail in order to explain the present invention in an easy-to-understand manner, and are not necessarily limited to those having all the configurations described. Further, it is possible to add, delete, and/or replace another configuration with respect to a part of the configuration of each embodiment.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

La présente invention aborde le problème de la fourniture d'un nouveau composé ayant une activité inhibitrice de LSD1 élevée, une haute sélectivité pour l'inhibition de LSD1, et/ou ayant un effet thérapeutique utile pour diverses maladies. Selon un mode de réalisation, l'invention concerne un composé représenté par la formule (I) [dans la formule, Ar1, n, X2, X3, X4, R25, L et A sont tels que définis dans la description et les revendications], un stéréoisomère de celui-ci ou des sels, ou des solvates de celui-ci. Selon un autre mode de réalisation, l'invention concerne : des procédés de production d'un composé représenté par la formule (I), un stéréoisomère de celui-ci ou des sels, ou des solvates de celui-ci ; et un inhibiteur de LSD1, un agent pharmaceutique ou une composition pharmaceutique qui comprennent, en tant que composant efficace, ledit composé, un stéréoisomère de celui-ci ou des sels pharmaceutiquement acceptables de celui-ci, ou des solvates pharmaceutiquement acceptables de celui-ci.
PCT/JP2019/051371 2018-12-28 2019-12-27 Nouveau composé inhibiteur de l'enzyme 1 déméthylase spécifique de la lysine, son procédé de production et son utilisation WO2020138398A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2020562479A JPWO2020138398A1 (ja) 2018-12-28 2019-12-27 リジン特異的脱メチル化酵素１を阻害する新規化合物、その製造方法及びその用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2018-247742 2018-12-28
JP2018247742 2018-12-28

Publications (1)

Publication Number Publication Date
WO2020138398A1 true WO2020138398A1 (fr) 2020-07-02

Family

ID=71128775

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2019/051371 WO2020138398A1 (fr) 2018-12-28 2019-12-27 Nouveau composé inhibiteur de l'enzyme 1 déméthylase spécifique de la lysine, son procédé de production et son utilisation

Country Status (2)

Country Link
JP (1) JPWO2020138398A1 (fr)
WO (1) WO2020138398A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022214303A1 (fr) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 pour le traitement de cancers myéloïdes
WO2023217784A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement de tumeurs mutantes nf1 à l'aide d'inhibiteurs de lsd1
WO2023217758A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement d'une tumeur maligne des gaines des nerfs périphériques (tmgnp) à l'aide d'inhibiteurs de lsd1
WO2024110649A1 (fr) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 et d'inhibiteurs de ménine pour le traitement du cancer

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010043721A1 (fr) * 2008-10-17 2010-04-22 Oryzon Genomics, S.A. Inhibiteurs d’oxydases et leur utilisation
JP2014515013A (ja) * 2011-03-25 2014-06-26 グラクソスミスクライン、インテレクチュアル、プロパティー、ナンバー２、リミテッド Ｌｓｄ１阻害剤としてのシクロプロピルアミン
JP2014532619A (ja) * 2011-10-20 2014-12-08 オリゾン・ジェノミックス・ソシエダッド・アノニマＯｒｙｚｏｎ Ｇｅｎｏｍｉｃｓ Ｓ．Ａ． Ｌｓｄ１阻害剤としての（ヘテロ）アリールシクロプロピルアミン化合物
WO2019009412A1 (fr) * 2017-07-07 2019-01-10 国立研究開発法人理化学研究所 Nouveau composé ayant une activité inhibitrice de l'enzyme 1 déméthylase spécifique de la lysine, son procédé de production et son utilisation
JP2019014683A (ja) * 2017-07-07 2019-01-31 学校法人自治医科大学 多能性幹細胞からのテラトーマ形成抑制剤及びその用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010043721A1 (fr) * 2008-10-17 2010-04-22 Oryzon Genomics, S.A. Inhibiteurs d’oxydases et leur utilisation
JP2014515013A (ja) * 2011-03-25 2014-06-26 グラクソスミスクライン、インテレクチュアル、プロパティー、ナンバー２、リミテッド Ｌｓｄ１阻害剤としてのシクロプロピルアミン
JP2014532619A (ja) * 2011-10-20 2014-12-08 オリゾン・ジェノミックス・ソシエダッド・アノニマＯｒｙｚｏｎ Ｇｅｎｏｍｉｃｓ Ｓ．Ａ． Ｌｓｄ１阻害剤としての（ヘテロ）アリールシクロプロピルアミン化合物
WO2019009412A1 (fr) * 2017-07-07 2019-01-10 国立研究開発法人理化学研究所 Nouveau composé ayant une activité inhibitrice de l'enzyme 1 déméthylase spécifique de la lysine, son procédé de production et son utilisation
JP2019014683A (ja) * 2017-07-07 2019-01-31 学校法人自治医科大学 多能性幹細胞からのテラトーマ形成抑制剤及びその用途

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022214303A1 (fr) 2021-04-08 2022-10-13 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 pour le traitement de cancers myéloïdes
WO2023217784A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement de tumeurs mutantes nf1 à l'aide d'inhibiteurs de lsd1
WO2023217758A1 (fr) 2022-05-09 2023-11-16 Oryzon Genomics, S.A. Méthodes de traitement d'une tumeur maligne des gaines des nerfs périphériques (tmgnp) à l'aide d'inhibiteurs de lsd1
WO2024110649A1 (fr) 2022-11-24 2024-05-30 Oryzon Genomics, S.A. Combinaisons d'inhibiteurs de lsd1 et d'inhibiteurs de ménine pour le traitement du cancer

Also Published As

Publication number Publication date
JPWO2020138398A1 (ja) 2021-11-04

Similar Documents

Publication Publication Date Title
US11155532B2 (en) Cyclopropylamines as LSD1 inhibitors
WO2020138398A1 (fr) Nouveau composé inhibiteur de l'enzyme 1 déméthylase spécifique de la lysine, son procédé de production et son utilisation
US20210040089A1 (en) Kras mutant protein inhibitors
US10183952B2 (en) Thienopyrroles as histone demethylase inhibitors
US10562870B2 (en) Prodrugs of riluzole and their method of use
EP3675848B1 (fr) Composés spirocycliques et leurs procédés de préparation et d'utilisation
US10961255B2 (en) Imidazoles as histone demethylase inhibitors
US20220041576A1 (en) Isoindoline compound, preparation method, pharmaceutical composition and use thereof
JP2020152641A (ja) リジン特異的脱メチル化酵素１阻害活性を有する新規化合物、その製造方法及びその用途
CA2787248C (fr) Compose de piperazine ayant un effet inhibiteur des prostaglandines
EP3392244A1 (fr) Cyclopropylamines en tant qu'inhibiteurs de lsd1
US11325889B2 (en) Substituted 3-((3-aminophenyl)amino)piperidine-2,6-dione compounds, compositions thereof, and methods of treatment therewith
JP2016510033A (ja) 強力なｒｏｃｋ１およびｒｏｃｋ２阻害剤としてのフェニルピラゾール誘導体
EP3686196A1 (fr) Composé polycyclique agissant en tant qu'inhibiteur de l'ido et/ou en tant qu'inhibiteur double de l'ido-hdac
EA016108B1 (ru) [2,6]нафтиридины, применимые в качестве ингибиторов протеинкиназы
TWI843372B (zh) 用於降解突變kras蛋白之化合物及其應用
EP4329877A1 (fr) Composés macrocycliques d'amide substitués ayant une activité agoniste du récepteur de l'orexine 2
WO2021097240A1 (fr) Composés et leurs utilisations
WO2013192610A2 (fr) Promédicaments du riluzole et leur procédé d'utilisation pour le traitement d'une sclérose latérale amyotrophique
JP2022520930A (ja) 化合物及びその使用
US20240182491A1 (en) Substituted fused bicyclic macrocyclic compounds and related methods of treatment
US20240174689A1 (en) Substituted carbamate macrocyclic compounds and related methods of treatment
EP1646622B1 (fr) Derives de tacrine utilises en tant qu'inhibiteurs de l'acetylcholinesterase
CA3228299A1 (fr) Antagonistes de lpar1 et leurs utilisations
JP2019014683A (ja) 多能性幹細胞からのテラトーマ形成抑制剤及びその用途

Legal Events

Date Code Title Description
ENP Entry into the national phase

Ref document number: 2020562479

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19905344

Country of ref document: EP

Kind code of ref document: A1