[go: up one dir, main page]

US20160355511A1 - Novel 1-substituted indazole derivative - Google Patents

Novel 1-substituted indazole derivative Download PDF

Info

Publication number
US20160355511A1
US20160355511A1 US15/060,902 US201615060902A US2016355511A1 US 20160355511 A1 US20160355511 A1 US 20160355511A1 US 201615060902 A US201615060902 A US 201615060902A US 2016355511 A1 US2016355511 A1 US 2016355511A1
Authority
US
United States
Prior art keywords
optionally substituted
group
alkoxy
independently selected
substituents independently
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US15/060,902
Inventor
Shinya Usui
Hiroki Yamaguchi
Yoko Nakai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sumitomo Pharma Co Ltd
Original Assignee
Sumitomo Dainippon Pharma Co Ltd
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 Sumitomo Dainippon Pharma Co Ltd filed Critical Sumitomo Dainippon Pharma Co Ltd
Priority to US15/060,902 priority Critical patent/US20160355511A1/en
Assigned to DAINIPPON SUMITOMO PHARMA CO., LTD. reassignment DAINIPPON SUMITOMO PHARMA CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NAKAI, YOKO, YAMAGUCHI, HIROKI, USUI, Shinya
Assigned to SUMITOMO DAINIPPON PHARMA CO., LTD. reassignment SUMITOMO DAINIPPON PHARMA CO., LTD. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: DAINIPPON SUMITOMO PHARMA CO., LTD.
Publication of US20160355511A1 publication Critical patent/US20160355511A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • C07D471/04—Ortho-condensed 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D405/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor

Definitions

  • the present invention relates to a novel indazole derivative which is a modulator of ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR).
  • ⁇ 7 nAChR nicotinic acetylcholine receptor
  • the present compound can be useful for treating, for example, diseases related to cholinergic properties in the central nervous system (CNS) and/or peripheral nervous system (PNS), diseases associated with smooth muscle contraction, endocrine disorders, neurodegenerative disorders, diseases such as inflammation and pain, and diseases associated with withdrawal symptoms caused by addictive drug abuse.
  • ⁇ 7 nicotinic acetylcholine receptor is typically a suitable molecular-target for neuroprotection.
  • the neuroprotection may be accomplished by developing an active agonist/positive modulator (i.e. positive allosteric modulator: PAM) of the receptor.
  • PAM positive allosteric modulator
  • ⁇ 7 nicotinic acetylcholine receptor agonist has already been identified, and is expected to provide a possible clue to the development of neuroprotective drugs.
  • ⁇ 7 nicotinic acetylcholine receptor is also involved in inflammation.
  • the development of a novel modulator of the receptor is expected to lead to a novel treatment for nervous system diseases, psychiatric diseases and inflammatory diseases.
  • a problem to be solved by the present invention is to provide a novel compound which has potent modulatory-effects on the activity of ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR), and can be useful as a novel medicament for treating and/or preventing nervous system diseases, psychiatric diseases and inflammatory diseases.
  • ⁇ 7 nAChR nicotinic acetylcholine receptor
  • WO 2012/133509 and WO 2012/176763 are applications related to the present application, which have already been published.
  • the compounds therein have similar but different structures from that of the present compound.
  • the priority date of the present application is earlier than the published dates of the related applications, and thus they are not prior art documents for the present application.
  • the present inventors have extensively studied to solve the above problem and then have found that a novel compound of the following Formula (I) exhibits potent modulatory-effects on the activity of ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR).
  • ⁇ 7 nAChR nicotinic acetylcholine receptor
  • the present invention provides a 1-substituted indazole derivative of the following Formula (I) or a pharmaceutically acceptable salt thereof (hereinafter, optionally referred to as “the present compound”).
  • the present invention is as follows:
  • A is CR 1E or a nitrogen atom
  • X—Y—Z is N—CO—NR 3A R 3B , N—CO—R 4 , CR 2E —CO—NR 3A R 3B , CR 2E —NR 5 —COR 4 or CR 2E —NR 5 —CONR 3A R 3B ,
  • R 1A is a C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkoxy, a C 3-6 cycloalkyl, —NR 6 R 7 , —CONR 6 R 7 and —NR 6 COR 7 ; a C 3-10 cycloalkyl or a 4- to 10-membered saturated heterocycle (wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkyl, a C 1-6 alkoxy and —NR 6 R 7 ); a C 1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkoxy, —NR 6 R 7 , —CONR 6 R
  • R 1B to R 1E are each independently a C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkoxy, a C 3-6 cycloalkyl, —NR 6′ R 7′ , —CONR 6′ R 7′ and —NR 6′ COR 7′ ; a C 3-10 cycloalkyl or a 4- to 10-membered saturated heterocycle (wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkyl, a C 1-6 alkoxy, —NR 6′ R 7′ , —CONR 6′ R 7′ and —NR 6′ COR 7′ ); a C 1-6 alkoxy or a C 3-10 cycloalkoxy (wherein the alkoxy and the
  • R 2A to R 2E are each independently a C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C 1-6 alkoxy and —NR 8 R 9 ; a hydrogen atom; a halogen; a hydroxy group; or a C 1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, or when two of R 2A to R 2E are a C 1-6 alkyl, they may be taken together to form a 4- to 10-membered saturated carbocyclic ring (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkyl, a C 1-6 alkoxy and —NR 8 R 9 ),
  • R 3A , R 3B and R 4 are each independently a C 1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a phenyl group, a monocyclic heteroaryl, a 4- to 10-membered saturated heterocycle, a C 3-10 cycloalkyl, a fluorine atom, a hydroxy group, a C 1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, and —NR 10 R 11 ; a C 3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; a phenyl group; a monocyclic heteroaryl; or a hydrogen atom, wherein the cycloalkyl, the saturated heterocycle, the phenyl and the monocyclic heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of an aryl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a
  • R 5 to R 11 , R 6′ and R 7′ are the same or different (each symbol is also the same or different when each symbol exists plurally) and are a hydrogen atom or a C 1-6 alkyl optionally substituted with 1 to 5 fluorine atoms, provided that in each combination of R 6 -R 7 , R 6′ -R 7′ , R 8 -R 9 , and R 10 -R 11 , (1) when one is a hydrogen atom, the other one is not a hydrogen atom, and (2) each combination may be taken together to form a 4- to 10-membered saturated heterocycle (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkyl, a C 1-6 alkoxy and —NR 6 R 7 ), and
  • A is CR 1E or a nitrogen atom
  • X—Y—Z is N—CO—NR 3A R 3B , N—CO—R 4 , CR 2E —CO—NR 3A R 3B , CR 2E —NR 5 —COR 4 or CR 2E —NR 5 —CO—NR 3A R 3B ,
  • R 1A is a C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkoxy, a C 3-6 cycloalkyl, —NR 6 R 7 , —CONR 6 R 7 , and —NR 6 COR 7 ; a C 3-10 cycloalkyl or a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkyl, a C 1-6 alkoxy and —NR 6 R 7 ; a C 1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkoxy, —NR 6 R 7 , —CONR 6 R 7 , and —NR 6 COR 7 ; a
  • R 1B to R 1E are each independently a C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkoxy, a C 3-6 cycloalkyl, —NR 6 R 7 , —CONR 6 R 7 and —NR 6 COR 7 ; a C 3-10 cycloalkyl or a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkyl, a C 1-6 alkoxy, —NR 6 R 7 , —CONR 6 R 7 and —NR 6 COR 7 ; a C 1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkoxy, —CONR 6 R 7 and
  • R 2A to R 2E are each independently a C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C 1-6 alkoxy and —NR 8 R 9 ; a hydrogen atom; a halogen; a hydroxy group; or a C 1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, or when two of R 2A to R 2E are a C 1-6 alkyl, they may be taken together to form a 4- to 10-membered saturated carbocyclic ring (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkyl, a C 1-6 alkoxy and —NR 6 R 7 ),
  • R 3A , R 3B and R 4 are each independently a C 1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a phenyl group, a monocyclic heteroaryl, a 4- to 10-membered saturated heterocycle, a C 3-10 cycloalkyl, a fluorine atom, a hydroxy group, a C 1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms and —NR 10 R 11 ; a C 3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; a phenyl group; a monocyclic heteroaryl; or a hydrogen atom, wherein the cycloalkyl, the saturated heterocycle, the phenyl and the monocyclic heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkyl (which may be optionally substituted
  • R 5 to R 11 are the same or different (each symbol is also the same or different when each symbol exists plurally) and a hydrogen atom or a C 1-6 alkyl optionally substituted with 1 to 5 fluorine atoms, provided that in each combination of R 6 -R 7 , R 8 -R 9 , and R 10 -R 11 , (1) when one is a hydrogen atom, the other one is not a hydrogen atom, and (2) each combination may be taken together to form a 4- to 10-membered saturated heterocycle (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkyl, a C 1-6 alkoxy and —NR 6 R 7 ), and
  • n 1 or 2.
  • Term 3 The compound of Term 1 or 2 or a pharmaceutically acceptable salt thereof wherein X—Y—Z is N—CO—NR 3A R 3B , N—CO—R 4 or CR 2E —NR 5 —COR 4 .
  • Term 4 The compound of any one of Terms 1 to 3 or a pharmaceutically acceptable salt thereof wherein n is 1.
  • Term 5 The compound of any one of Terms 1 to 4 or a pharmaceutically acceptable salt thereof wherein either R 3A or R 3B is a hydrogen atom.
  • Term 6 The compound of any one of Terms 1 to 4 or a pharmaceutically acceptable salt thereof wherein either R 3A or R 3B is a hydrogen atom.
  • R 2A to R 2E are each independently a C 1-6 alkyl optionally substituted with 1 to 5 fluorine atoms; a C 1-6 alkoxy; a hydrogen atom; or a fluorine atom.
  • R 3A , R 3E and R 4 are each independently a C 1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a 4- to 10-membered saturated heterocycle, a C 3-10 cycloalkyl, a fluorine atom, a hydroxy group, a C 1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms and —NR 10 R 11 ; a C 3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; a nitrogen-containing monocyclic heteroaryl; or a hydrogen atom, wherein the cycloalkyl, the saturated heterocycle and the nitrogen-containing monocyclic heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkyl (which may be optionally substituted with 1 to 5 substituent
  • R 1A to R 1E are each independently a C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 3-6 cycloalkyl, a hydroxy group and a C 1-6 alkoxy; a C 3-8 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkyl and a C 1-6 alkoxy; a C 1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group and a C 1-6 alkoxy; a hydrogen atom; a halogen; or a 4- to 10-membered saturated heterocycle optionally substituted with a C 1-6 alkyl.
  • Term 9 The compound of any one of Terms 1 to 8 or a pharmaceutically acceptable salt thereof wherein X—Y—Z is N—CO—NR 3A R 3B or CR 2E —NR 5 —COR 4 .
  • Term 10 The compound of any one of Terms 1 to 9 or a pharmaceutically acceptable salt thereof wherein A is CR 1E .
  • Term 11 The compound of any one of Terms 1 to 9 or a pharmaceutically acceptable salt thereof wherein A is CR 1E .
  • R 3A , R 3B and R 4 are each independently a C 1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C 1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms; a C 3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; or a hydrogen atom, wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 1-6 alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C 1-6 alkoxy) and a C 1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, provided that (1) both R 3A and R 3B are not a hydrogen
  • R 1A to R 1E are each independently a C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C 1-6 alkoxy; a C 3-8 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 1-6 alkyl and a C 1-6 alkoxy; a C 1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C 1-6 alkoxy; a hydrogen atom; or a halogen.
  • Term 13 The compound of any one of Terms 1 to 12 or a pharmaceutically acceptable salt thereof wherein X—Y—Z is N—CO—NR 3A R 3B .
  • Term 14 The compound of Term 1 selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the present compound is useful as a novel medicament for treating and/or preventing nervous system diseases, psychiatric diseases, and inflammatory diseases such as dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder and cerebrovascular disorder. Furthermore, the present compound in combination with a drug classified as atypical antipsychotic drugs is useful for treating and/or preventing nervous system diseases and psychiatric diseases such as schizophrenia.
  • the present compound may exist in a form of hydrates and/or solvates, and thus such hydrates and/or solvates are also included in the present compound.
  • the compound of Formula (I) may contain one or more asymmetric carbon atoms, or may have a geometrical isomerism or an axial chirality; thus the compound may exist as several stereoisomers. Such stereoisomers, mixtures thereof, and racemates are also included in the present compound of Formula (I).
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof can be obtained in a form of crystal which may show polymorphism, thus such crystalline polymorphism is also included in the present invention.
  • alkyl refers to a straight or branched saturated hydrocarbon group.
  • C 1-4 alkyl refers to an alkyl with 1 to 4, 1 to 6 and 1 to 10 carbon atoms, respectively.
  • C 1-4 alkyl includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • C 1-6 alkyl includes, for example, pentyl, isopentyl, neopentyl, and hexyl.
  • C 1-10 alkyl includes, for example, heptyl and octyl.
  • cycloalkyl refers to a monocyclic or polycyclic saturated hydrocarbon including those which have a partially-cross-linked structure or form a fused ring with an aryl or heteroaryl.
  • C 3-10 cycloalkyl refers to a cyclic alkyl with 3 to 10 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl.
  • alkoxy refers to a straight or branched saturated hydrocarbon group attached to the parent molecular moiety through an oxygen atom.
  • C 1-6 alkoxy refers to an alkoxy with 1 to 6 carbon atoms and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butyloxy, pentyloxy, isopentyloxy, neopentyloxy, and hexyloxy.
  • cycloalkoxy refers to the above-defined “cycloalkyl” which is attached to the parent molecular moiety through an oxygen atom.
  • C 1-6 alkylcarbonyl as used herein includes, for example, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, and t-butylcarbonyl; preferably “C 1-3 alkylcarbonyl”; and more preferably acetyl.
  • halogen refers to a fluorine, chlorine, bromine or iodine atom; and preferably a fluorine or chlorine atom.
  • aryl as used herein includes, for example, phenyl, 1-naphthyl, 2-naphthyl, and anthracenyl; and preferably phenyl.
  • heteroaryl as used herein includes a 5- to 7-membered monocyclic aromatic heterocyclic group, a 8- to 11-membered bicyclic aromatic heterocyclic group, and a 12- to 16-membered tricyclic aromatic heterocyclic group which comprise 1 to 4 atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms.
  • the heteroaryl includes, for example, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, indazolyl, chromenyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, thioxanthenyl, and 6,11-dihydrodibenzo[B,E]
  • the term “monocyclic heteroaryl” as used herein includes a 5- to 7-membered monocyclic aromatic heterocyclic group which comprises 1 to 4 atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms.
  • the monocyclic heteroaryl includes, for example, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl, triazolyl, and tetrazolyl; preferably a nitrogen-containing monocyclic heteroaryl, for example, pyridyl and pyrimidinyl.
  • 4- to 10-membered saturated heterocycle refers to a monocyclic or bicyclic saturated heterocycle comprising 4 to 10 ring atoms which include 1 to 2 atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms.
  • the 4- to 10-membered saturated heterocycle also includes those which have a partially-cross-linked structure, those which are partially spirocyclized, those which are partially unsaturated, and those which form a fused ring with an aryl or heteroaryl.
  • the 4- to 10-membered saturated heterocycle includes, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, tetrahydrofuran, tetrahydropyran, and 3,6-dihydro-2H-pyran.
  • R 1A to R 1E , R 2A to R 2E , R 3A , R 3B , R 4 to R 11 , R 6′ , R 7′ and n are preferably those shown below, but the technical scope of the present invention should not be limited to the following compounds.
  • R 4 to R 11 means R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 , and other similar phrases mean likewise.
  • A is preferably CR 1E or a nitrogen atom, and more preferably CR 1E .
  • X—Y—Z is preferably N—CO—NR 3A R 3B , N—CO—R 4 , CR 2E —CO—NR 3A R 3B or CR 2E —NR 5 —COR 4 , more preferably N—CO—NR 3A R 3B or CR 2E NR 5 —COR 4 , and even more preferably N—CO—NR 3A R 3B .
  • R 1A to R 1E are preferably a C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group and a C 1-6 alkoxy; a C 3-8 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkyl and a C 1-6 alkoxy; a C 1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group and a C 1-6 alkoxy; a hydrogen atom; a halogen; or a 4- to 10-membered saturated heterocycle optionally substituted with a C 1-6 alkyl.
  • R 1A to R 1E are more preferably a C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C 1-6 alkoxy; a C 3-8 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 1-6 alkyl and a C 1-6 alkoxy; a C 1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms; a hydrogen atom; or a halogen.
  • R 1A to R 1E are even more preferably a C 1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C 1-6 alkoxy; a C 1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms; a hydrogen atom; or a halogen.
  • R 1A to R 1E are the most preferably a C 1-6 alkyl optionally substituted with 1 to 5 fluorine atoms; a C 1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms; or a hydrogen atom.
  • R 2A to R 2E are preferably a C 1-6 alkyl optionally substituted with 1 to 5 fluorine atoms; a C 1-6 alkoxy; a hydrogen atom; or a fluorine atom.
  • R 2A to R 2E are more preferably a C 1-6 alkyl, a hydrogen atom or a fluorine atom, even more preferably a C 1-6 alkyl or a hydrogen atom, and the most preferably a hydrogen atom.
  • R 3A , R 3B and R 4 are preferably a C 1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a 4- to 10-membered saturated heterocycle, a C 3-10 cycloalkyl, a fluorine atom, a hydroxy group, a C 1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, and —NR 10 R 11 ; a C 3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; a nitrogen-containing monocyclic heteroaryl; or a hydrogen atom, wherein the cycloalkyl, the saturated heterocycle and the nitrogen-containing monocyclic heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C 1-6 alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom,
  • R 3A , R 3B and R 4 are more preferably, a C 1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C 1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms; a C 3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; or a hydrogen atom, wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C 1-6 alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C 1-6 alkoxy) and a C 1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms.
  • R 3A , R 3B and R 4 are even more preferably a C 1-10 alkyl; a C 3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; or a hydrogen atom, wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of a fluorine atom, a C 1-6 alkyl and a C 1-6 alkoxy.
  • R 3A , R 3B and R 4 are the most preferably a C 3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; or a hydrogen atom, wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of a C 1-6 alkyl and a C 1-6 alkoxy.
  • R 3A or R 3B is a hydrogen atom.
  • R 5 to R 11 , R 6′ and R 7′ are the same or different (each symbol is also the same or different when each symbol exists plurally) and are preferably a hydrogen atom or a C 1-6 alkyl optionally substituted with 1 to 5 fluorine atoms, more preferably a hydrogen atom or a C 1-6 alkyl, and even more preferably a C 1-6 alkyl, provided that in each combination of R 6 -R 7 , R 6′ -R 7′ , R 8 -R 9 , and R 10 -R 11 , (1) when one is a hydrogen atom, the other one is not a hydrogen atom, and (2) each combination may be taken together to form a 4- to 10-membered saturated heterocycle.
  • n 1 or 2, and preferably 1.
  • a pharmaceutically acceptable salt of the compound of Formula (I) means that the structure of Formula (I) has a group which can form an acid or base addition salt, thereby forming a pharmaceutically acceptable acid or base addition salt of the compound of Formula (I).
  • the acid addition salt of the present compound includes, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, and phosphate; organic acid salts such as oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate; and amino-acid salts such as glutamate and aspartate.
  • inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, and phosphate
  • organic acid salts such as oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesul
  • Such pharmaceutically acceptable salts include, for example, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium salts, and ammonium salts.
  • These salts can be prepared by mixing the present compound of Formula (I) with the above-mentioned acid or base and then isolating it according to conventional methods such as recrystallization.
  • DMSO dimethylsulfoxide
  • PAM positive allosteric modulator
  • HEPES N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
  • BSA bovine serum albumin
  • Boc tert-butoxycarbonyl c-Hex: cyclohexyl c-Pen: cyclopentyl iPr: isopropyl c-Pr: cyclopropyl n-Pr: normalpropyl EDCI HCl: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride HOBt: 1-hydroxybenzotriazole DIEA: diisopropylethylamine TEA: triethylamine Ms: methanesulfonyl
  • the present compound of Formula (I) can be prepared by, for example, the following Processes A 1 , A 2 , B, C 1 , C 2 and D.
  • Compound A1 can be prepared by, for example, the following process:
  • R 1B to R 1D , R 2A to R 2D , R 3A , R 3B and n are as defined in Term 1,
  • R 1A′ is the same as R 1A defined in Term 1 except that alkoxy and a hydrogen atom are excluded,
  • X 1 is a halogen
  • L is a leaving group
  • P is a protecting group for the amino group
  • R a1 is a hydrogen atom or a C 1-6 alkyl.
  • Compound a1 wherein A is CR 1E can be synthesized by methods disclosed in publications such as Bioorganic & Medicinal Chemistry Letters 2002, 12 (20), 2925-2930, European Journal of Organic Chemistry 2010, 24, 4662-4670 and WO 2009/001132, or be commercially available.
  • Compound a1 wherein A is a nitrogen atom can be synthesized by methods disclosed in publications such as WO 2008/157404 and WO 2009/088103, or be commercially available.
  • Compound a1 is reacted with, for example, sodium nitrite and sodium tetrafluoroborate in the presence of any acid in a suitable solvent to give Compound a2.
  • the acid used herein includes mineral acids such as hydrochloric acid, nitric acid, and sulfuric acid, and preferably hydrochloric acid.
  • the solvent used herein may be selected from those exemplified later, and preferably water.
  • the reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically ⁇ 50° C. to 150° C., preferably ⁇ 30° C. to 100° C., and more preferably ⁇ 10° C. to 60° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • Compound a2 prepared in Step A-1 is cyclized, for example, in the presence or absence of organic or inorganic salts and crown ethers to give Compound a3.
  • the organic or inorganic salts used herein include, for example, potassium acetate, sodium acetate, sodium bicarbonate and potassium tert-butoxide, and preferably potassium acetate.
  • the solvent used herein may be selected from those exemplified later, and preferably chloroform or dichloromethane. Similar reactions of the step herein are disclosed in, for example, Tetrahedron Lett. 2002, 43, 2695-2697 and Tetrahedron 2006, 62, 7772-7775, and such reactions can also be used to prepare the product herein.
  • the reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically ⁇ 50° C. to 100° C., preferably ⁇ 30° C. to 50° C., and more preferably ⁇ 10° C. to 30° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • Step A-2 Compound a3 prepared in Step A-2 is halogenated to give Compound a4.
  • the reaction can be carried out with iodine in the presence of any base in a suitable solvent.
  • the base used herein may be selected from those exemplified later, and preferably sodium hydroxide or potassium hydroxide.
  • the solvent used herein may be selected from those exemplified later, and preferably dimethylformamide or chloroform.
  • the reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically ⁇ 30° C. to 200° C., preferably ⁇ 10° C. to 100° C., and more preferably 0° C. to 80° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • Compound a4 prepared in Step A-3 is coupled with borane acid and the like in the presence of a catalyst and base to give Compound a5.
  • the catalyst used herein includes those wherein a transition metal (e.g. palladium), a salt, complex or polymer thereof, or the like is supported on a carrier.
  • the base used herein may be selected from those exemplified later, and preferably sodium carbonate, potassium carbonate or the like.
  • the solvent used herein may be selected from those exemplified later, and preferably a mixed solvent of dioxane and water. Similar reactions of the step herein are disclosed in, for example, WO 2005/073219 and such reactions can also be used to prepare the product herein.
  • the reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically 0° C. to 200° C., preferably 30° C. to 150° C., and more preferably 50° C. to 120° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • Compound a5 prepared in Step A-4 is reacted with Compound a8 in the presence of a base to give Compound a6.
  • the base used herein may be selected from those exemplified later, and preferably sodium hydride, potassium t-butoxide or the like.
  • the reductant used herein may be hydrogen, formates such as ammonium formate, or hydrazine.
  • the solvent used herein may be selected from those exemplified later, and preferably DMF or THF.
  • Compound a8 can also be synthesized by methods disclosed in publications such as WO 2012/068106, WO 2007/030366 and Tetrahedron Lett. 2012, 53, 948-951, or be commercially available.
  • the reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically 0° C. to 200° C., preferably 30° C. to 150° C., and more preferably 50° C. to 120° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • the protecting group for the amino group of Compound a6 prepared in Step A-5 (defined as “P”) is deprotected to give Compound a7.
  • the step herein can be carried out according to methods disclosed in, for example, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • the reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically ⁇ 30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 80° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • Step A-6 Compound a7 prepared in Step A-6 is reacted with Compound a9 or a10 in the presence of any base in a suitable solvent to give compound A1.
  • the base used herein may be selected from those exemplified later, and preferably diisopropylethylamine or triethylamine.
  • the solvent used herein may be selected from those exemplified later, and preferably tetrahydrofuran or dimethylformamide.
  • Compound a9 or a10 can be commercially available or prepared according to conventional methods.
  • the reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically ⁇ 50° C. to 200° C., preferably ⁇ 20° C. to 150° C., and more preferably 0° C. to 100° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • R 1B to R 1D , R 2A to R 2D , R 3A , R 3B and n are as defined in Term 1,
  • R 1A′′ is an optionally-substituted C 1-6 alkyl
  • P is a protecting group for the amino group.
  • 2-Aminobenzoate derivative (Compound a11) can be synthesized by methods disclosed in publications such as Chemistry Letters, 2009, 38 (3), 200-201 and Organic Process Research & Development, 2009, 13 (4), 698-705, or be commercially available.
  • Compound a11 is reacted with sodium nitrite and then sodium thiosulfate in the presence of any acid in a suitable solvent to give Compound a12.
  • the acid used herein is selected from mineral acids such as hydrochloric acid, nitric acid and sulfuric acid, and preferably hydrochloric acid.
  • the solvent used herein may be selected from those exemplified later, and preferably water.
  • the reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically ⁇ 50° C. to 150° C., preferably ⁇ 30° C. to 100° C., and more preferably ⁇ 10° C. to 60° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • the hydrogen atom at 1-position of the indazole in Compound a12 prepared in Step A-8 is replaced with a protecting group for the amino group (defined as “P”) to give Compound a13.
  • the step herein can be carried out according to methods disclosed in, for example, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • the reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically ⁇ 30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 60° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • Compound a13 prepared in Step A-9 is reacted with any alkylating agent in the presence of any base in a suitable solvent to give Compound a14.
  • the electrophile used herein may be, for example, 1-methyl-1-nitrosourea, ethyl iodide, or isopropyl iodide.
  • the base used herein may be selected from those exemplified later, and preferably potassium carbonate, cesium carbonate, silver carbonate or the like.
  • the solvent used herein is preferably acetonitrile or diethyl ether.
  • the reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically ⁇ 30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 100° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • the protecting group for the amino group of Compound a14 prepared in Step A-10 (defined as “P”) is deprotected to give Compound a15.
  • the step herein can be carried out according to methods disclosed in, for example, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • the reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically ⁇ 30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 60° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • Step A-11 Compound a15 prepared in Step A-11 is converted to Compound a16 according to the conditions in Step A-5.
  • Step A-12 Compound a16 prepared in Step A-12 is converted to Compound a17 according to the conditions in Step A-6.
  • Step A-13 Compound a17 prepared in Step A-13 is converted to compound A2 according to the conditions in Step A-7.
  • Compound B1 Among the compounds of Formula (I), those wherein X—Y—Z is N—CO—NR 4 as shown by Formula B1 (i.e. Compound B1) can be prepared by, for example, the following process:
  • R 1A to R 1D , R 2A to R 2D , R 4 and n are as defined in Term 1.
  • Step A-6 or A-13 Compound a7 or a17 prepared in Step A-6 or A-13 respectively is reacted with Compound b1 or b2 in the presence of any condensing agent or base in a suitable solvent to give compound B1.
  • the condensing agent used herein includes various types used in conventional methods, and preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride thereof).
  • the base used herein may be selected from those exemplified later and preferably diisopropylethylamine or triethylamine.
  • the solvent used herein may be selected from those exemplified later, and preferably dimethylformamide or tetrahydrofuran.
  • the reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically ⁇ 30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 80° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • R 1A to R 1D , R 2A to R 2E , R 4 , R 5 and n are as defined in Term 1,
  • X 2 is a leaving group such as a halogen
  • P is a protecting group for the amino group.
  • Compound a3, a5 or a15 is reacted with Cyclohexylalcohol c3 by Mitsunobu reaction in the presence of an azo compound analog and an organophosphorus compound to give Compound c1.
  • the azo compound analog used herein includes, for example, diethylazodicarboxylate and diisopropylazodicarboxylate.
  • the organophosphorus compound used herein is preferably triphenylphosphine or the like.
  • the solvent used herein may be selected from those exemplified later, and preferably tetrahydrofuran.
  • reaction temperature depends on factors such as the types of starting compound and reagents, and it is typically ⁇ 30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 100° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • the protecting group for the amino group of Compound c1 prepared in Step C-1 (defined as “P”) is deprotected to give Compound c2.
  • the step herein can be carried out according to methods disclosed in, for example, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • the reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically ⁇ 30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 60° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • Step C-2 Compound c2 prepared in Step C-2 is converted to Compound C1 according to the conditions in Step B-1.
  • Step C-3 Compound C1 prepared in Step C-3 is reacted with Compound c4 in the presence of any base in a suitable solvent to give Compound C2.
  • the base used herein may be selected from those exemplified later, and preferably sodium hydride or diisopropylamine.
  • the solvent used herein may be selected from those exemplified later, and preferably dimethylformamide or tetrahydrofuran.
  • the reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically ⁇ 30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 80° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • R 1A to R 1D , R 2A to R 2E , R 3A , R 3B , R 5 and n are as defined in Term 1,
  • X 2 is a leaving group such as a halogen
  • P is a protecting group for the amino group.
  • Step C-2 Compound c2 prepared in Step C-2 is converted to Compound C3 according to the conditions in Step A-14.
  • Step C-5 Compound C3 prepared in Step C-5 is converted to Compound C4 according to the conditions in Step C-4.
  • Compound D1 Among the compounds of Formula (I), those wherein X—Y—Z is CR 2E —CO—NR 3A R 3B as shown by Formula D1 (i.e. Compound D1) can be prepared by, for example, the following process:
  • R 1A to R 1D , R 2A to R 2E , R 3A , R 3B and n are as defined in Term 1, and
  • Rx is a protecting group for the carboxyl group.
  • Step C-1 Compound a3, a5 or a15 is converted to Compound d1 according to the conditions in Step C-1.
  • the ester Compound d1 prepared in Step D-1 is converted to a corresponding carboxylic Compound d2.
  • the step herein can be carried out according to methods disclosed in, for example, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999).
  • the reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically ⁇ 30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 60° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • Step D-2 Compound d2 prepared in Step D-2 is reacted with Compound d3 in the presence of any condensing agent in a suitable solvent to give compound D1.
  • the condensing agent used herein includes various types used in conventional methods, and preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride thereof).
  • the solvent used herein may be selected from those exemplified later.
  • the reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically ⁇ 30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 80° C.
  • the reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • the base used in each step in each of the above-shown processes can be selected depending on various factors such as the type of reaction and starting compound; and includes, for example, alkaline bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkaline carbonates such as sodium carbonate and potassium carbonate, metal hydrides such as sodium hydride and potassium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as sodium methoxide and sodium t-butoxide, organometallic bases such as butyllithium and lithium diisopropylamide, and organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU).
  • alkaline bicarbonates such as sodium bicarbonate and potassium bicarbonate
  • alkaline carbonates such as sodium carbonate and potassium carbonate
  • the solvent used in each step in the above-shown processes can be optionally selected depending on various factors such as the type of reaction and starting compound; and includes, for example, alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ketone, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran (THF) and dioxane, aromatic hydrocarbons such as toluene and benzene, aliphatic hydrocarbons such as hexane and heptane, esters such as ethyl acetate and propyl acetate, amides such as N,N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone, sulfoxides such as dimethylsulfoxide (DMSO), and nitriles such as acetonitrile.
  • solvents can be used alone or in combination with two or more.
  • organic bases may
  • the present compound of Formula (I) or an intermediate thereof can be isolated and purified by well-known methods such as extraction, partition, reprecipitation, column chromatography (e.g. silica gel column chromatography, ion exchange column chromatography and preparative liquid chromatography) and recrystallization.
  • column chromatography e.g. silica gel column chromatography, ion exchange column chromatography and preparative liquid chromatography
  • the recrystallization solvent used herein includes, for example, alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, ketone solvents such as acetone, halogen solvents such as dichloromethane and chloroform, hydrocarbon solvents such as hexane, aprotic solvents such as dimethylformamide and acetonitrile, water, and a mixed solvent selected from two or more of the above-listed solvents.
  • Other purification methods for example, those disclosed in Experimental Chemistry Textbook Vol. 1 (the Chemical Society of Japan, ed., Maruzen) can also be used herein.
  • the present compound of Formula (I) or a pharmaceutically acceptable salt thereof may exhibit chirality or contain a substituent with an asymmetric carbon, which can exist as optical isomers.
  • the present compound includes a mixture of each of the isomers and an isolated single isomer, which can be prepared according to a conventional process, for example, using a starting material with an asymmetric center or introducing chirality during the process.
  • an optical isomer it can be prepared by using optically active compounds as a starting material or optically resolving the mixture at an appropriate stage during the process.
  • the optical resolution method used herein includes, for example, an isolation technique via diastereomeric salt formed as follows.
  • such diastereomeric salt can be formed with optically active acids such as monocarboxylic acids (e.g. mandelic acid, N-benzyloxyalanine, and lactic acid), dicarboxylic acids (e.g. tartaric acid, o-diisopropylidene tartaric acid, and malic acid) and sulfonic acids (e.g. camphor sulfonic acid and bromocamphor sulfonic acid) in an inert solvent such as alcohol solvents (e.g. methanol, ethanol, and 2-propanol), ether solvents (e.g. diethyl ether), ester solvents (e.g.
  • monocarboxylic acids e.g. mandelic acid, N-benzyloxyalanine, and lactic acid
  • dicarboxylic acids e.g. tartaric acid, o-diisopropylidene tartaric acid, and malic acid
  • sulfonic acids
  • ethyl acetate ethyl acetate
  • hydrocarbon solvents e.g. toluene
  • aprotic solvents e.g. acetonitrile
  • a mixed solvent selected from two or more of the above-listed solvents.
  • optically active amines such as organic amines (e.g. 1-phenylethylamine, kinin, quinidine, cinchonidine, cinchonine and strychnine).
  • organic amines e.g. 1-phenylethylamine, kinin, quinidine, cinchonidine, cinchonine and strychnine.
  • the present compound can be a novel medicament for treating and/or preventing a disease due to an abnormality of the intracellular signaling mediated by acetylcholine, and in particular, nervous system diseases, psychiatric diseases, and inflammatory diseases [e.g. dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder, and cerebral angiopathy].
  • the administration route of the present compound may be any of oral, parenteral and rectal ones; and the daily dosage thereof may vary depending on the type of compound, administration method, symptom/age of the patient, and other factors.
  • the present compound in case of oral administration, can be administered to human beings or mammals at typically about 0.01 mg to 1000 mg and preferably about 0.1 mg to 500 mg per kg of body weight as a single or multiple doses.
  • parenteral administration such as intravenous injection, the present compound can be administered to human beings or mammals at typically about 0.01 mg to 300 mg and preferably about 1 mg to 100 mg per kg of body weight.
  • the dosage forms of the present compound include, for example, tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, embrocations, adhesive skin patches, and inhalants.
  • These formulations can be prepared according to conventional methods.
  • liquid formulations may be in a form wherein the present compound is dissolved or suspended in water, appropriate aqueous solutions, or other appropriate vehicles at the time of use. Tablets and granules may be coated according to known methods.
  • the formulations may comprise additional ingredients which are useful for the treatment.
  • the present compound can be used in combination with a drug classified as atypical antipsychotic drugs.
  • the atypical antipsychotic drugs include, for example, olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, aripiprazole, asenapine, iloperidone, clozapine, sertindole, blonanserin and lurasidone.
  • the temperature for forming the salt is in the range of room temperature to boiling point of a solvent as used. In order to improve the optical purity, it is desirable that the temperature is once raised to around the boiling point of the solvent.
  • the precipitated salt is collected on a filter; and if necessary, the filtration may be carried out under cooled conditions to improve the yield.
  • the appropriate amount of an optically active acid or amine used herein is about 0.5 to about 2.0 equivalents, preferably about 1 equivalent per the reactant.
  • the crystal can be recrystallized from an inert solvent such as alcohol solvents (e.g. methanol, ethanol and 2-propanol), ether solvents (e.g. diethyl ether), ester solvents (e.g.
  • optically active salt in high purity.
  • hydrocarbon solvents e.g. toluene
  • aprotic solvents e.g. acetonitrile
  • a mixed solvent selected from two or more of the above-listed solvents to give the optically active salt in high purity.
  • Solution A 0.05% TFA/H 2 O
  • Solution B 0.05% TFA/MeOH
  • HPLC LCMS-2010EV manufactured by Shimadzu
  • Solvent Solution A: 0.05% HCOOH/H 2 O, Solution B: CH 3 CN
  • Example 1 To a solution of Reference Example 1 (600 mg) in DMF (5 mL) were added trans-phenyl-4-methoxycyclohexane carbamate (564 mg) and diisopropylethylamine (1.24 mL), and the mixture was stirred with heating at 70° C. for 16 hours. Then, the mixture was partitioned between ethyl acetate and water, the organic layer was dried over Na 2 SO 4 , and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate as the eluting solvent) to give Example 1 (564 mg).
  • Example 2 To a solution of the above-obtained Reference Example 2 (136 mg) in DMF (3 mL) were added phenyl-4-pyran carbamate (97 mg) and diisopropylethylamine (307 ⁇ L), and the mixture was stirred with heating at 70° C. for 16 hours. Then, the mixture was partitioned between ethyl acetate and water, the organic layer was washed with brine and dried over Na 2 SO 4 , and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate as the eluting solvent) to give Example 2 (71 mg).
  • Example 5 To a solution of the above-obtained Reference Example 4 (131 mg) in DMF (3 mL) were added phenyl 4,4-difluorocyclohexane carbamate (119 mg) and diisopropylethylamine (328 ⁇ L), and the mixture was stirred with heating at 70° C. for 16 hours. Then, the mixture was partitioned between ethyl acetate and water, the organic layer was washed with brine and dried over Na 2 SO 4 , and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate as the eluting solvent) to give Example 5 (24 mg).
  • Human ⁇ 7 nAChR stably expressing cells were generated and cultured.
  • GH4C1 cells derived from rat pituitary catalog #1, 32, 33, 34, 35, 36, 39, 40, 41, 42, 43, 44, 45, 46, 47, 46, 47, 46, 47, 46, 47, 46, 47, 46, 47, 46, 47, 46, 47, 46, 47, 49, 50, 51, 52, 53, 52, 52, 52, 52, 52, 52, 52, 52, 52, 52, 52, 52, 52, 52, 52, 52, 52, 52, 52, 52, 52, 52, 52, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44, 44,
  • the aequorins and human ⁇ 7 nAChR stably expressing cells were screened with Zeocin (cat#R25001, invitrogen, Carlsbad, Calif., USA) and Geneticin (cat#10131-027, invitrogen, Carlsbad, Calif., USA) respectively.
  • the cells were cultured in F-10 Nutrient Mixture (Ham) medium (cat#11550-043, invitrogen, Carlsbad, Calif., USA) containing 2.5% fetal bovine serum (cat#2917354, ICN Biomedicals, Inc, USA), 15% inactivated horse serum (cat#26050-088, invitrogen, Carlsbad, Calif., USA), 1 ⁇ g/mL Geneticin, and 5 ⁇ g/mL Puromycin (cat#14861-84, invitrogen, Carlsbad, Calif., USA), in a Collagen Type 1-coated dish (cat#4030-010, iwaki, Tokyo, Japan).
  • Am Nutrient Mixture
  • the medium was replaced with fresh medium in every 2 to 3 days, and the cells were treated with TrypLE Express (cat#45604-021, invitrogen, Carlsbad, Calif., USA) to collect them in every 7 days. Thus, the cells were subcultured.
  • the cells were treated with TrypLE Express to collect them when they were about 80% confluent.
  • the cells were suspended in a reaction medium containing Hanks (cat#14065-056, invitrogen, Carlsbad, Calif., USA)/20 mmol/L Hepes (cat#15630-080, invitrogen, Carlsbad, Calif., USA), Buffer (pH 7.4), F-10 Nutrient Mixture (Ham), and 0.1 mg/mL Geneticin, and the suspension was seeded in a 384-well plate (cat#781090, Greiner, Germany) at 20000 cells/25 ⁇ L per well.
  • Viviren (cat#E649X, Promega, Madison, Wis., USA) was added to the medium so that the final concentration could be 4 ⁇ mol/L (15 ⁇ L/well). The plates were centrifuged and then placed in the dark for 4 hours at room temperature.
  • test compounds were dissolved in DMSO to prepare each test sample at a concentration of 1000-fold the final concentration.
  • To the solution was added Hanks/20 mM HEPES/0.2% BSA (cat#A3803, Sigma, St. Louis, Mo., USA), and the concentration was adjusted to 6-fold the final concentration.
  • FDSS7000 (Hamamatsu Photonics) was used to detect the luminescence signal evoked by ⁇ 7 nAChR stimulation.
  • the cells and a luminescent substrate were put on a plate, and the test sample was added thereto. After 150 seconds, ACh whose concentration shows 20% (EC 20 ) of the maximal signal was added thereto. After the addition of ACh, the luminescence signal (the central wavelength: 465 nm) was measured for 138 seconds to calculate RLU (Max ⁇ Min).
  • the ratio of the RLU (Max ⁇ Min) of the test-compound-containing wells to that of the control wells was defined as PAM activity.
  • Table 8 shows ⁇ 7 PAM activity data of the representative compounds in the present invention.
  • Table 8 demonstrates that the present compounds have PAM activity for ⁇ 7 nAChR according to the evaluation test of PAM activity.
  • the compounds of Examples 4, 8, 13, 17, 18, 20, 23, 40, 41, 119 and 220 show a stronger PAM activity than others.
  • the hERG (human ether-a-go-go) potassium current in CHO cells which stably express hERG gene was recorded by whole-cell patch clamping technique using an automated patch clamp system, QPatch HT (Sophion Bioscience A/S).
  • QPatch HT Sophion Bioscience A/S
  • the membrane potential was held at ⁇ 80 mV in voltage clamp mode, and then depolarized to ⁇ 50 mV for 20 msec and then +20 mV for 5 sec. Then, the membrane potential was repolarized to ⁇ 50 mV for 5 sec and the tail current amplitude was measured.
  • the stimulation was given at a frequency of every 15 seconds, and the experiment was carried out at room temperature (22 ⁇ 2° C.).
  • the compound was cumulatively administered to each cell in 4 concentrations, wherein the administration was done over 5 minutes in each concentration.
  • the inhibition percentage of the inhibited current was calculated by comparing the current intensities before and after the compound was given in each concentration. According to Hill equation, each 50% inhibitory concentration was calculated (IC 50 [ ⁇ mol/L]).
  • the test solutions used herein were as follows:
  • extracellular solution (mmol/L): 2 CaCl 2 , 1 MgCl 2 , 10 HEPES, 4 KCl, 145 NaCl, 10 glucose, intracellular solution (mmol/L): 5.4 CaCl 2 , 1.8 MgCl 2 , 10 HEPES, 31 KOH, 10 EGTA, 120 KCl, 4 ATP
  • metabolites generated in liver microsomes from the present compound those which react with dansyl glutathione (dGSH) were detected and quantified.
  • concentration of the binding compound of metabolite and dansyl glutathione was measured with a UPLC fluorescence detection system (UPLC manufactured by Waters Corporation).
  • Test Example 3 reactive metabolites test
  • the present compound was administered intravenously in saline solution or orally in methylcellulose solution to 7 weeks old rats, and their blood was collected according to the following schedule:
  • the collected blood was centrifuged at 3000 rpm for 10 minutes in a refrigerated centrifuge set at 4° C.
  • the obtained plasma was measured with a HPLC to give a time curve of plasma level, thereby calculating the pharmacokinetic parameters.
  • the test herein demonstrated that the present compounds have excellent pharmacokinetics.
  • the compounds in Examples 1, 163 and 227 have a bioavailability of 41%, 41% and 69% respectively.
  • the protein-binding ratio of the present compounds in serum was measured by an equilibrium dialysis method using 96-well Equilibrium Dialyzer MW10K (HARVARD APPARATUS).
  • the human serum used herein was frozen human serum pools (Cosmo Bio, No. 12181201), and the buffer used herein was PBS pH 7.4 (GIBCO, No. 10010-0231).
  • Example 1 The test herein demonstrated that the present compounds have a low protein-binding ratio.
  • the compound in Example 1 had a protein binding ratio of 84.7% in the plasma, and that of 91.9% in the brain.
  • the plasma and brain homogenates were deproteinized with methanol and then centrifuged. The supernatant was filtered, and the obtained sample was quantified with LC-MS/MS to calculate the concentration of the plasma and brain.
  • the concentration ratio of the brain to the plasma was 1.27, 2.01, 1.92 and 1.55 in the compounds of Examples 1, 163, 227 and 258 respectively.
  • Slc ddY mice (25 g to 30 g, male, Japan SLC) can be used in the novel object recognition test wherein the interval between the 1 st trial (training) and the 2 nd trial (test) correlates with the memory loss for the objects used in the 1 st trial, and a significant memory-loss is observed when the 2 nd trial is performed 24 hours after the 1 st trial. According to the test mechanism, the present compounds were administered prior to the 1 st trial, and the enhancement effect on memory in the 2 nd trial was evaluated.
  • the test herein demonstrated that the present compounds can exhibit effects of improving cognitive function even with an extremely low dose in a continuous manner.
  • the compound in Example 1 had a minimum effective dose of 0.1 mg/kg, and the efficacy did not decrease at a dose of 0.3 mg/kg, 1.0 mg/Kg or 3 mg/kg.
  • the compound in Example 74 had a minimum effective dose of 0.1 mg/kg, and the efficacy did not decrease at a dose of 0.3 mg/kg, 1.0 mg/kg or 3 mg/kg.
  • the compounds in Example 63 and 66 showed the efficacy at doses of 3 mg/Kg and 1 mg/Kg respectively.
  • scopolamine HBr (cat#S0929, Sigma Aldrich, Japan) can be subcutaneously administered to Slc: Wistar rats (280 g to 300 g, male, Japan SLC) to cause cognitive impairment and decrease the percentage of alternation behavior.
  • Slc Wistar rats (280 g to 300 g, male, Japan SLC)
  • the present compounds were treated prior to the administration of scopolamine, and the improvement effect on cognitive impairment was evaluated.
  • Example 1 significantly improved cognitive function from a dose of 0.3 mg/kg.
  • Example 74 significantly improved cognitive function from a dose of 0.3 mg/kg.
  • the compound in Example 63 showed a tendency to improve cognitive function from a dose of 0.3 mg/kg.
  • the compound of Formula (I) or a pharmaceutically acceptable salt thereof has potent modulatory-effects on the activity of ⁇ 7 nicotinic acetylcholine receptor ( ⁇ 7 nAChR), and is thus useful for treating, for example, diseases associated with cholinergic properties in the central nervous system (CNS) and/or peripheral nervous system (PNS), diseases associated with smooth muscle contraction, endocrine disorders, neurodegenerative disorders, diseases such as inflammation and pain, and diseases associated with withdrawal symptoms caused by addictive drug abuse.
  • CNS central nervous system
  • PNS peripheral nervous system

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Psychiatry (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Plant Pathology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

A medicament for treating diseases associated with cholinergic properties in the central nervous system (CNS) and/or peripheral nervous system (PNS), diseases associated with smooth muscle contraction, endocrine disorders, neurodegenerative disorders and the like, which comprises a compound of Formula (I):
Figure US20160355511A1-20161208-C00001
wherein A is CR1E or a nitrogen atom, X—Y—Z is N—CO—NR3AR3B and the like, R1A to R1E are each independently a hydrogen atom and the like, R2A to R2D are each independently a hydrogen atom and the like, R3A and R3B are each independently an optionally-substituted C3-10 cycloalkyl and the like, and n is 1 or 2
or a pharmaceutically acceptable salt thereof, which exhibits potent modulatory-effects on the activity of α7 nicotinic acetylcholine receptor (α7 nAChR).

Description

    TECHNICAL FIELD
  • The present invention relates to a novel indazole derivative which is a modulator of α7 nicotinic acetylcholine receptor (α7 nAChR). On the basis of such pharmacological properties, the present compound can be useful for treating, for example, diseases related to cholinergic properties in the central nervous system (CNS) and/or peripheral nervous system (PNS), diseases associated with smooth muscle contraction, endocrine disorders, neurodegenerative disorders, diseases such as inflammation and pain, and diseases associated with withdrawal symptoms caused by addictive drug abuse.
    • BACKGROUND OF THE INVENTION
  • Recently, potential neuroprotective-effects of nicotine have been shown, and meanwhile various neurodegenerative-models in animals and cultured cells suffering from excitotoxic injury, athrepsia, ischemia, injury, neuronal cell death induced by amyloid beta (Aβ) or neurodegeneration induced by protein aggregation have been proposed. In many cases where nicotine shows neuroprotective effects, it has been found that nicotinic acetylcholine receptors containing alpha7 subtype are activated. These findings suggest that nicotine is useful in providing neuroprotective effects, and indicate that receptors containing α7-subtype are directly related with the effects. These data suggest that α7 nicotinic acetylcholine receptor is typically a suitable molecular-target for neuroprotection. In other words, the neuroprotection may be accomplished by developing an active agonist/positive modulator (i.e. positive allosteric modulator: PAM) of the receptor. In fact, α7 nicotinic acetylcholine receptor agonist has already been identified, and is expected to provide a possible clue to the development of neuroprotective drugs. In addition, it has recently been reported that α7 nicotinic acetylcholine receptor is also involved in inflammation. Thus, the development of a novel modulator of the receptor is expected to lead to a novel treatment for nervous system diseases, psychiatric diseases and inflammatory diseases.
  • In the past, there were some disclosures about modulators of α7 nicotinic acetylcholine receptor (α7 nAChR), but the chemical structures thereof are different from that of the present compound (see, Patent Reference 1 and Patent Reference 2).
    • PRIOR ART DOCUMENTS Patent References
  • [Patent Reference 1] WO 2003/093250
  • [Patent Reference 2] WO 2006/138510
    • SUMMARY OF THE INVENTION Technical Problem
  • A problem to be solved by the present invention is to provide a novel compound which has potent modulatory-effects on the activity of α7 nicotinic acetylcholine receptor (α7 nAChR), and can be useful as a novel medicament for treating and/or preventing nervous system diseases, psychiatric diseases and inflammatory diseases.
  • In addition, WO 2012/133509 and WO 2012/176763 are applications related to the present application, which have already been published. The compounds therein have similar but different structures from that of the present compound. However, the priority date of the present application is earlier than the published dates of the related applications, and thus they are not prior art documents for the present application.
    • Solution to Problem
  • The present inventors have extensively studied to solve the above problem and then have found that a novel compound of the following Formula (I) exhibits potent modulatory-effects on the activity of α7 nicotinic acetylcholine receptor (α7 nAChR). On the basis of the new findings, the present invention has been completed. The present invention provides a 1-substituted indazole derivative of the following Formula (I) or a pharmaceutically acceptable salt thereof (hereinafter, optionally referred to as “the present compound”). In specific, the present invention is as follows:
  • Term 1. A compound of Formula (I):
  • Figure US20160355511A1-20161208-C00002
  • or a pharmaceutically acceptable salt thereof
    wherein
  • A is CR1E or a nitrogen atom,
  • X—Y—Z is N—CO—NR3AR3B, N—CO—R4, CR2E—CO—NR3AR3B, CR2E—NR5—COR4 or CR2E—NR5—CONR3AR3B,
  • R1A is a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, a C3-6 cycloalkyl, —NR6R7, —CONR6R7 and —NR6COR7; a C3-10 cycloalkyl or a 4- to 10-membered saturated heterocycle (wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR6R7); a C1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, —NR6R7, —CONR6R7 and —NR6COR7; a hydrogen atom; a halogen; —NR6R7; a cyano group; —CONR6R7; —NR6COR7; or —SO2R6, provided that both R6 and R7 are not a hydrogen atom,
  • R1B to R1E are each independently a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, a C3-6 cycloalkyl, —NR6′R7′, —CONR6′R7′ and —NR6′COR7′; a C3-10 cycloalkyl or a 4- to 10-membered saturated heterocycle (wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy, —NR6′R7′, —CONR6′R7′ and —NR6′COR7′); a C1-6 alkoxy or a C3-10 cycloalkoxy (wherein the alkoxy and the cycloalkoxy may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, —CONR6′R7′ and —NR6′COR7′); a hydrogen atom; a hydroxy group; a halogen; an aryl or a heteroaryl (wherein the aryl and the heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C1-6 alkyl optionally substituted with 1 to 5 fluorine atoms, a C1-6 alkoxy, —NR6′R7′, —CONR6′R7′ and —NR6′COR7′); —NR6′R7′; a cyano group; —CONR6′R7′; —NR6′COR7′; or —SO2R6′, provided that both R6′ and R7′ are not a hydrogen atom,
  • R2A to R2E are each independently a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C1-6 alkoxy and —NR8R9; a hydrogen atom; a halogen; a hydroxy group; or a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, or when two of R2A to R2E are a C1-6 alkyl, they may be taken together to form a 4- to 10-membered saturated carbocyclic ring (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR8R9),
  • R3A, R3B and R4 are each independently a C1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a phenyl group, a monocyclic heteroaryl, a 4- to 10-membered saturated heterocycle, a C3-10 cycloalkyl, a fluorine atom, a hydroxy group, a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, and —NR10R11; a C3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; a phenyl group; a monocyclic heteroaryl; or a hydrogen atom, wherein the cycloalkyl, the saturated heterocycle, the phenyl and the monocyclic heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of an aryl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkoxy and —NR10R11), a halogen, a hydroxy group, a C1-6 alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6, alkoxy and —NR10R11), a C1-6 alkoxy (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a C3-6 cycloalkyl, a C3-6 cycloalkyl-C1-6 alkyl, a C1-6 alkoxy and a fluorine atom), a C1-6 alkylcarbonyl and —NR10R11, provided that (1) R3A and R3B may be taken together to form a 4- to 10-membered saturated heterocycle (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR10R11), (2) both R3A and R3B are not a hydrogen atom, and (3) R4 is not a hydrogen atom,
  • R5 to R11, R6′ and R7′ are the same or different (each symbol is also the same or different when each symbol exists plurally) and are a hydrogen atom or a C1-6 alkyl optionally substituted with 1 to 5 fluorine atoms, provided that in each combination of R6-R7, R6′-R7′, R8-R9, and R10-R11, (1) when one is a hydrogen atom, the other one is not a hydrogen atom, and (2) each combination may be taken together to form a 4- to 10-membered saturated heterocycle (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR6R7), and
      • n is 1 or 2.
        Term 2. A compound of Formula (I):
  • Figure US20160355511A1-20161208-C00003
  • or a pharmaceutically acceptable salt thereof
    wherein
  • A is CR1E or a nitrogen atom,
  • X—Y—Z is N—CO—NR3AR3B, N—CO—R4, CR2E—CO—NR3AR3B, CR2E—NR5—COR4 or CR2E—NR5—CO—NR3AR3B,
  • R1A is a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, a C3-6 cycloalkyl, —NR6R7, —CONR6R7, and —NR6COR7; a C3-10 cycloalkyl or a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR6R7; a C1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, —NR6R7, —CONR6R7, and —NR6COR7; a hydrogen atom; a halogen; —NR6R7; a cyano group; —CONR6R7; —NR6COR7; or —SO2R6, provided that both R6 and R7 are not a hydrogen atom,
  • R1B to R1E are each independently a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, a C3-6 cycloalkyl, —NR6R7, —CONR6R7 and —NR6COR7; a C3-10 cycloalkyl or a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy, —NR6R7, —CONR6R7 and —NR6COR7; a C1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, —CONR6R7 and —NR6COR7; a hydrogen atom; a hydroxy group; a halogen; an aryl or heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C1-6 alkyl optionally substituted with 1 to 5 fluorine atoms, a C1-6 alkoxy, —NR6R7, —CONR6R7 and —NR6COR7; —NR6R7; a cyano group; —CONR6R7; —NR6COR7; or —SO2R6 provided that both R6 and R7 are not a hydrogen atom,
  • R2A to R2E are each independently a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C1-6 alkoxy and —NR8R9; a hydrogen atom; a halogen; a hydroxy group; or a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, or when two of R2A to R2E are a C1-6 alkyl, they may be taken together to form a 4- to 10-membered saturated carbocyclic ring (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR6R7),
  • R3A, R3B and R4 are each independently a C1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a phenyl group, a monocyclic heteroaryl, a 4- to 10-membered saturated heterocycle, a C3-10 cycloalkyl, a fluorine atom, a hydroxy group, a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms and —NR10R11; a C3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; a phenyl group; a monocyclic heteroaryl; or a hydrogen atom, wherein the cycloalkyl, the saturated heterocycle, the phenyl and the monocyclic heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkoxy and —NR10R11), a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms and C3-6 cycloalkyl or with 1 to 5 fluorine atoms, a C1-6 alkylcarbonyl and —NR10R11, provided that (1) R3A and R3B may be taken together to form a 4- to 10-membered saturated heterocycle (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR6R7), (2) both R3A and R3B are not a hydrogen atom, and (3) R4 is not a hydrogen atom,
  • R5 to R11 are the same or different (each symbol is also the same or different when each symbol exists plurally) and a hydrogen atom or a C1-6 alkyl optionally substituted with 1 to 5 fluorine atoms, provided that in each combination of R6-R7, R8-R9, and R10-R11, (1) when one is a hydrogen atom, the other one is not a hydrogen atom, and (2) each combination may be taken together to form a 4- to 10-membered saturated heterocycle (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR6R7), and
  • n is 1 or 2.
  • Term 3. The compound of Term 1 or 2 or a pharmaceutically acceptable salt thereof wherein X—Y—Z is N—CO—NR3AR3B, N—CO—R4 or CR2E—NR5—COR4.
    Term 4. The compound of any one of Terms 1 to 3 or a pharmaceutically acceptable salt thereof wherein n is 1.
    Term 5. The compound of any one of Terms 1 to 4 or a pharmaceutically acceptable salt thereof wherein either R3A or R3B is a hydrogen atom.
    Term 6. The compound of any one of Terms 1 to 5 or a pharmaceutically acceptable salt thereof wherein R2A to R2E are each independently a C1-6 alkyl optionally substituted with 1 to 5 fluorine atoms; a C1-6 alkoxy; a hydrogen atom; or a fluorine atom.
    Term 7. The compound of any one of Terms 1 to 6 or a pharmaceutically acceptable salt thereof wherein R3A, R3E and R4 are each independently a C1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a 4- to 10-membered saturated heterocycle, a C3-10 cycloalkyl, a fluorine atom, a hydroxy group, a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms and —NR10R11; a C3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; a nitrogen-containing monocyclic heteroaryl; or a hydrogen atom, wherein the cycloalkyl, the saturated heterocycle and the nitrogen-containing monocyclic heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkoxy and —NR10R11), a C1-6 alkoxy optionally substituted with a C3-6 cycloalkyl or 1 to 5 fluorine atoms, and —NR10R11, provided that (1) R3A and R3B may be taken together to form a 4- to 10-membered nitrogen-containing saturated heterocycle (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR10R11), (2) both R3A and R3B are not a hydrogen atom, and (3) R4 is not a hydrogen atom.
    Term 8. The compound of any one of Terms 1 to 7 or a pharmaceutically acceptable salt thereof wherein R1A to R1E are each independently a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C3-6 cycloalkyl, a hydroxy group and a C1-6 alkoxy; a C3-8 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl and a C1-6 alkoxy; a C1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group and a C1-6 alkoxy; a hydrogen atom; a halogen; or a 4- to 10-membered saturated heterocycle optionally substituted with a C1-6 alkyl.
    Term 9. The compound of any one of Terms 1 to 8 or a pharmaceutically acceptable salt thereof wherein X—Y—Z is N—CO—NR3AR3B or CR2E—NR5—COR4.
    Term 10. The compound of any one of Terms 1 to 9 or a pharmaceutically acceptable salt thereof wherein A is CR1E.
    Term 11. The compound of any one of Terms 1 to 10 or a pharmaceutically acceptable salt thereof wherein R3A, R3B and R4 are each independently a C1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms; a C3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; or a hydrogen atom, wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C1-6 alkoxy) and a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, provided that (1) both R3A and R3B are not a hydrogen atom, and (2) R4 is not a hydrogen atom.
    Term 12. The compound of any one of Terms 1 to 11 or a pharmaceutically acceptable salt thereof wherein R1A to R1E are each independently a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C1-6 alkoxy; a C3-8 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkyl and a C1-6 alkoxy; a C1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C1-6 alkoxy; a hydrogen atom; or a halogen.
    Term 13. The compound of any one of Terms 1 to 12 or a pharmaceutically acceptable salt thereof wherein X—Y—Z is N—CO—NR3AR3B.
    Term 14. The compound of Term 1 selected from the following compounds or a pharmaceutically acceptable salt thereof:
    • N-(trans-4-methoxycyclohexyl)-4-(5-methyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 1),
    • 4-(3-ethoxy-5-ethyl-1H-indazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-carboxamide (Example 2),
    • (4,4-difluorocyclohexyl) (4-(5-ethoxy-1H-indazol-1-yl)piperidin-1-yl)methanone (Example 3),
    • N-(cis-4-(5-ethyl-1H-indazol-1-yl)cyclohexyl)-4,4-difluorocyclohexanecarboxamide (Example 4),
    • 1-(4,4-difluorocyclohexyl)-3-(cis-4-(5-ethyl-1H-indazol-1-yl)cyclohexyl)urea (Example 5),
    • cis-N-(4,4-difluorocyclohexyl)-4-(5-ethyl-1H-indazol-1-yl)cyclohexanecarboxamide (Example 6),
    • N-cyclohexyl-4-(5-methyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 8),
    • N-(4,4-difluorocyclohexyl)-4-(5-methyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 13),
    • 4-(5-propyl-1H-indazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-carboxamide (Example 15),
    • 4-(5-ethyl-1H-indazol-1-yl)-N-(trans-4-methoxycyclohexyl)piperidine-1-carboxamide (Example 16),
    • N-cyclohexyl-4-(5-ethoxy-1H-indazol-1-yl)piperidine-1-carboxamide (Example 18),
    • 4-(5-ethyl-1H-indazol-1-yl)-N-(tetrahydro-2H-pyran-3-yl)piperidine-1-carboxamide (Example 22),
    • N-(4,4-difluorocyclohexyl)-4-(5-ethoxy-1H-indazol-1-yl)piperidine-1-carboxamide (Example 27),
    • N-(4,4-difluorocyclohexyl)-4-(5-fluoro-1H-indazol-1-yl)piperidine-1-carboxamide (Example 28),
    • 4-(5-chloro-1H-indazol-1-yl)-N-cyclopentylpiperidine-1-carboxamide (Example 33),
    • 4-(5-chloro-1H-indazol-1-yl)-N-(4,4-difluorocyclohexyl)piperidine-1-carboxamide (Example 34),
    • N-(4,4-difluorocyclohexyl)-4-(3-(methoxymethyl)-5-methyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 36),
    • N-(4,4-difluorocyclohexyl)-4-(5-methoxy-1H-indazol-1-yl)piperidine-1-carboxamide (Example 41),
    • N-(4,4-difluorocyclohexyl)-4-(3-ethyl-5-methyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 42),
    • N-(4,4-difluorocyclohexyl)-4-(3,5-dimethyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 45),
    • N-(4,4-difluorocyclohexyl)-4-(5-isopropoxy-1H-indazol-1-yl)piperidine-1-carboxamide (Example 46),
    • N-cyclohexyl-4-(5-isopropoxy-1H-indazol-1-yl)piperidine-1-carboxamide (Example 48),
    • N-(4,4-difluorocyclohexyl)-4-(5-methyl-3-(tetrahydro-2H-pyran-4-yl)-1H-indazol-1-yl)piperidine-1-carboxamide (Example 52),
    • 4-(5-ethyl-3-isopropoxy-1H-indazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-carboxamide (Example 63),
    • N-(4,4-difluorocyclohexyl)-4-(4-ethyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 64),
    • 4-(4-ethyl-1H-indazol-1-yl)-N-(trans-4-methoxycyclohexyl)piperidine-1-carboxamide (Example 66),
    • N-(4,4-difluorocyclohexyl)-4-(5-(4-fluorophenyl)-1H-indazol-1-yl)piperidine-1-carboxamide (Example 70),
    • 4-(5-cyclopropyl-1H-indazol-1-yl)-N-(trans-4-methoxycyclohexyl)piperidine-1-carboxamide (Example 74),
    • (R)—N-(2,2-difluorocyclohexyl)-4-(5-methyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 78),
    • (S)—N-(2,2-difluorocyclohexyl)-4-(5-methyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 79),
    • (S)—N-(2,2-difluorocyclopentyl)-4-(5-methyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 80),
    • (R)—N-(2,2-difluorocyclopentyl)-4-(5-methyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 81),
    • N-(trans-4-ethoxycyclohexyl)-4-(5-methyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 90), and
    • (4-(5-isobutyl-1H-indazol-1-yl)piperidin-1-yl) (tetrahydro-2H-pyran-4-yl)methanone (Example 103).
      Term 15. The compound of Term 1 selected from the following compounds or a pharmaceutically acceptable salt thereof:
    • N-(trans-4-methoxycyclohexyl)-4-(5-methyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 1),
    • (4,4-difluorocyclohexyl) (4-(5-ethoxy-1H-indazol-1-yl)piperidin-1-yl)methanone (Example 3),
    • N-(4,4-difluorocyclohexyl)-4-(5-methyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 13),
    • 4-(5-ethyl-1H-indazol-1-yl)-N-(trans-4-methoxycyclohexyl)piperidine-1-carboxamide (Example 16),
    • 4-(5-ethyl-3-isopropoxy-1H-indazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-carboxamide (Example 63),
    • 4-(4-ethyl-1H-indazol-1-yl)-N-(trans-4-methoxycyclohexyl)piperidine-1-carboxamide (Example 66),
    • 4-(5-cyclopropyl-1H-indazol-1-yl)-N-(trans-4-methoxycyclohexyl)piperidine-1-carboxamide (Example 74), and
    • N-(trans-4-ethoxycyclohexyl)-4-(5-methyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 90).
      Term 16. The compound of Term 1 selected from the following compounds or a pharmaceutically acceptable salt thereof:
    • N-(trans-4-methoxycyclohexyl)-4-[5-(2H3)methyl-1H-indazol-1-yl]piperidine-1-carboxamide (Example 144),
    • 4-(4-ethoxy-5-methyl-1H-indazol-1-yl)-N-(trans-4-methoxycyclohexyl)piperidine-1-carboxamide (Example 145),
    • N-(trans-4-methoxycyclohexyl)-4-[5-(trifluoromethyl)-1H-indazol-1-yl]piperidine-1-carboxamide (Example 163),
    • N-{trans-4-[(2H3)methoxy]cyclohexyl}-4-[5-(trifluoromethyl)-1H-indazol-1-yl]piperidine-1-carboxamide (Example 178),
    • N-(trans-4-methoxycyclohexyl)-4-[5-(trifluoromethoxy)-1H-indazol-1-yl]piperidine-1-carboxamide (Example 219),
    • N-{trans-4-[(2H3)methoxy]cyclohexyl}-4-[5-(trifluoromethoxy)-1H-indazol-1-yl]piperidine-1-carboxamide (Example 226),
    • N-(tetrahydro-2H-pyran-4-yl)-4-[5-(trifluoromethoxy)-1H-indazol-1-yl]piperidine-1-carboxamide (Example 227),
    • 4-[5-(cyclopropoxy)-1H-indazol-1-yl]-N-(trans-4-methoxycyclohexyl)piperidine-1-carboxamide (Example 230),
    • 4-[5-(cyclopropoxy)-1H-indazol-1-yl]-N-(4,4-difluorocyclohexyl)piperidine-1-carboxamide (Example 249),
    • 4-(5-ethyl-4-methoxy-1H-indazol-1-yl)-N-(trans-4-methoxycyclohexyl)piperidine-1-carboxamide (Example 255),
    • 4-(5-cyclopropyl-4-methyl-1H-indazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-carboxamide (Example 283),
    • 4-(5-methyl-1H-indazol-1-yl)-N-{trans-4-[(2H3)methoxy]cyclohexyl}piperidine-1-carboxamide (Example 295),
    • 4-(5-cyclopropyl-1H-indazol-1-yl)-N-{trans-4-[(2H3)methoxy]cyclohexyl}piperidine-1-carboxamide (Example 296),
    • N-(tetrahydro-2H-pyran-3-yl)-4-[5-(trifluoromethoxy)-1H-indazol-1-yl]piperidine-1-carboxamide (Example 300),
    • 4-(5-cyclopropyl-1H-indazol-1-yl)-N-[(1S,3S)-3-methoxycyclohexyl]piperidine-1-carboxamide (Example 211),
    • 4-(5-cyclopropyl-4-methoxy-1H-indazol-1-yl)-N-(trans-4-methoxycyclohexyl)piperidine-1-carboxamide (Example 263),
    • 4-(4-ethoxy-5-ethyl-1H-indazol-1-yl)-N-(trans-4-methoxycyclohexyl)piperidine-1-carboxamide (Example 272),
    • 4-(5-ethyl-4-methoxy-1H-indazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-carboxamide (Example 275),
    • 4-(5-cyclopropyl-4-methyl-1H-indazol-1-yl)-N-(trans-4-methoxycyclohexyl)piperidine-1-carboxamide (Example 277),
    • 4-[5-(difluoromethoxy)-1H-indazol-1-yl]-N-(trans-4-methoxycyclohexyl)piperidine-1-carboxamide (Example 291), and
    • N-cyclobutyl-4-[5-(trifluoromethyl)-1H-indazol-1-yl]piperidine-1-carboxamide (Example 298).
      Term 17. The compound of Term 1 selected from the following compounds or a pharmaceutically acceptable salt thereof:
    • N-(trans-4-methoxycyclohexyl)-4-(5-methyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 1),
    • 4-(5-ethyl-3-isopropoxy-1H-indazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-carboxamide (Example 63),
    • 4-(5-cyclopropyl-1H-indazol-1-yl)-N-(trans-4-methoxycyclohexyl)piperidine-1-carboxamide (Example 74),
    • N-(trans-4-methoxycyclohexyl)-4-[5-(2H3)methyl-1H-indazol-1-yl]piperidine-1-carboxamide (Example 144),
    • 4-(4-ethoxy-5-methyl-1H-indazol-1-yl)-N-(trans-4-methoxycyclohexyl)piperidine-1-carboxamide (Example 145),
    • N-(trans-4-methoxycyclohexyl)-4-[5-(trifluoromethyl)-1H-indazol-1-yl]piperidine-1-carboxamide (Example 163),
    • N-{trans-4-[(2H3)methoxy]cyclohexyl}-4-[5-(trifluoromethyl)-1H-indazol-1-yl]piperidine-1-carboxamide (Example 178),
    • N-{trans-4-[(2H3)methoxy]cyclohexyl}-4-[5-(trifluoromethoxy)-1H-indazol-1-yl]piperidine-1-carboxamide (Example 226),
    • N-(tetrahydro-2H-pyran-4-yl)-4-[5-(trifluoromethoxy)-1H-indazol-1-yl]piperidine-1-carboxamide (Example 227),
    • 4-(5-methyl-1H-indazol-1-yl)-N-{trans-4-[(2H3)methoxy]cyclohexyl}piperidine-1-carboxamide (Example 295),
    • 4-(5-cyclopropyl-1H-indazol-1-yl)-N-{trans-4-[(2H3)methoxy]cyclohexyl}piperidine-1-carboxamide (Example 296), and
    • N-(tetrahydro-2H-pyran-3-yl)-4-[5-(trifluoromethoxy)-1H-indazol-1-yl]piperidine-1-carboxamide (Example 300).
      Term 18. The compound of Term 1 which is N-(trans-4-methoxycyclohexyl)-4-(5-methyl-1H-indazol-1-yl)piperidine-1-carboxamide (Example 1), or a pharmaceutically acceptable salt thereof.
      Term 19. The compound of Term 1 which is 4-(5-ethyl-3-isopropoxy-1H-indazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-carboxamide (Example 63), or a pharmaceutically acceptable salt thereof.
      Term 20. The compound of Term 1 which is N-(trans-4-methoxycyclohexyl)-4-[5-(2H3)methyl-1H-indazol-1-yl]piperidine-1-carboxamide (Example 144), or a pharmaceutically acceptable salt thereof.
      Term 21. The compound of Term 1 which is N-(tetrahydro-2H-pyran-4-yl)-4-[5-(trifluoromethoxy)-1H-indazol-1-yl]piperidine-1-carboxamide (Example 227), or a pharmaceutically acceptable salt thereof.
      Term 22. The compound of Term 1 which is 4-(5-methyl-1H-indazol-1-yl)-N-{trans-4-[(2H3)methoxy]cyclohexyl}piperidine-1-carboxamide (Example 295), or a pharmaceutically acceptable salt thereof.
      Term 23. A pharmaceutical composition comprising the compound of any one of Terms 1 to 22 or a pharmaceutically acceptable salt thereof.
      Term 24. A medicament for treating a disease related to acetylcholine comprising the compound of any one of Terms 1 to 22 or a pharmaceutically acceptable salt thereof as an active ingredient.
      Term 25. The medicament of Term 24 wherein the disease related to acetylcholine is a nervous system disease, psychiatric disease or inflammatory disease.
      Term 26. The medicament of Term 25 wherein the nervous system disease, the psychiatric disease or the inflammatory disease is dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder or cerebral angiopathy.
      Term 27. A method for treating or preventing a nervous system disease, psychiatric disease or inflammatory disease which comprises administering a therapeutically effective amount of the compound of any one of Terms 1 to 22 or a pharmaceutically acceptable salt thereof to a patient in need thereof.
      Term 28. A combination drug comprising the compound of any one of Terms 1 to 22 or a pharmaceutically acceptable salt thereof, and at least one drug selected from drugs classified as atypical antipsychotic drugs.
      Term 29. A method for treating a disease due to an abnormality of the intracellular signaling mediated by acetylcholine which comprises administering a therapeutically effective amount of the compound of any one of Terms 1 to 22 or a pharmaceutically acceptable salt thereof to a patient in need thereof.
      Term 30. The compound of any one of Terms 1 to 22 or a pharmaceutically acceptable salt thereof for use in the treatment of a disease due to an abnormality of the intracellular signaling mediated by acetylcholine.
      Term 31. A pharmaceutical composition comprising the compound of any one of Terms 1 to 22 or a pharmaceutically acceptable salt thereof for use in the treatment of a disease due to an abnormality of the intracellular signaling mediated by acetylcholine.
      Term 32. Use of the compound of any one of Terms 1 to 22 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament to treat a disease due to an abnormality of the intracellular signaling mediated by acetylcholine.
    Effects of Invention
  • The present compound is useful as a novel medicament for treating and/or preventing nervous system diseases, psychiatric diseases, and inflammatory diseases such as dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder and cerebrovascular disorder. Furthermore, the present compound in combination with a drug classified as atypical antipsychotic drugs is useful for treating and/or preventing nervous system diseases and psychiatric diseases such as schizophrenia.
    • DESCRIPTION OF EMBODIMENTS
  • The present compound may exist in a form of hydrates and/or solvates, and thus such hydrates and/or solvates are also included in the present compound.
  • The compound of Formula (I) may contain one or more asymmetric carbon atoms, or may have a geometrical isomerism or an axial chirality; thus the compound may exist as several stereoisomers. Such stereoisomers, mixtures thereof, and racemates are also included in the present compound of Formula (I).
  • The compound of Formula (I) wherein one or more of 1H are substituted with 2H(D) (i.e. deuterated form) is also included in the present compound of Formula (I).
  • The compound of Formula (I) or a pharmaceutically acceptable salt thereof can be obtained in a form of crystal which may show polymorphism, thus such crystalline polymorphism is also included in the present invention.
  • The terms used herein are explained hereinafter.
  • The term “alkyl” as used herein refers to a straight or branched saturated hydrocarbon group. For example, the terms “C1-4 alkyl”, “C1-6 alkyl” and “C1-10 alkyl” refer to an alkyl with 1 to 4, 1 to 6 and 1 to 10 carbon atoms, respectively. In specific, “C1-4 alkyl” includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. In addition to said groups, “C1-6 alkyl” includes, for example, pentyl, isopentyl, neopentyl, and hexyl. In addition to said groups, “C1-10 alkyl” includes, for example, heptyl and octyl.
  • The term “cycloalkyl” as used herein refers to a monocyclic or polycyclic saturated hydrocarbon including those which have a partially-cross-linked structure or form a fused ring with an aryl or heteroaryl. For example, “C3-10 cycloalkyl” refers to a cyclic alkyl with 3 to 10 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl.
  • The term “alkoxy” as used herein refers to a straight or branched saturated hydrocarbon group attached to the parent molecular moiety through an oxygen atom. For example, “C1-6 alkoxy” refers to an alkoxy with 1 to 6 carbon atoms and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butyloxy, pentyloxy, isopentyloxy, neopentyloxy, and hexyloxy.
  • The term “cycloalkoxy” as used herein refers to the above-defined “cycloalkyl” which is attached to the parent molecular moiety through an oxygen atom.
  • The term “C1-6 alkylcarbonyl” as used herein includes, for example, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, and t-butylcarbonyl; preferably “C1-3 alkylcarbonyl”; and more preferably acetyl.
  • The term “halogen” as used herein refers to a fluorine, chlorine, bromine or iodine atom; and preferably a fluorine or chlorine atom.
  • The term “aryl” as used herein includes, for example, phenyl, 1-naphthyl, 2-naphthyl, and anthracenyl; and preferably phenyl.
  • The term “heteroaryl” as used herein includes a 5- to 7-membered monocyclic aromatic heterocyclic group, a 8- to 11-membered bicyclic aromatic heterocyclic group, and a 12- to 16-membered tricyclic aromatic heterocyclic group which comprise 1 to 4 atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms. The heteroaryl includes, for example, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, indazolyl, chromenyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, thioxanthenyl, and 6,11-dihydrodibenzo[B,E]thiepinyl; and preferably pyridyl, pyrimidinyl, quinolyl, and isoquinolyl.
  • The term “monocyclic heteroaryl” as used herein includes a 5- to 7-membered monocyclic aromatic heterocyclic group which comprises 1 to 4 atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms. The monocyclic heteroaryl includes, for example, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl, triazolyl, and tetrazolyl; preferably a nitrogen-containing monocyclic heteroaryl, for example, pyridyl and pyrimidinyl.
  • The term “4- to 10-membered saturated heterocycle” as used herein refers to a monocyclic or bicyclic saturated heterocycle comprising 4 to 10 ring atoms which include 1 to 2 atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms. The 4- to 10-membered saturated heterocycle also includes those which have a partially-cross-linked structure, those which are partially spirocyclized, those which are partially unsaturated, and those which form a fused ring with an aryl or heteroaryl. The 4- to 10-membered saturated heterocycle includes, for example, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, tetrahydrofuran, tetrahydropyran, and 3,6-dihydro-2H-pyran.
  • Among the present compounds represented by Formula (I), A, X—Y—Z, R1A to R1E, R2A to R2E, R3A, R3B, R4 to R11, R6′, R7′ and n are preferably those shown below, but the technical scope of the present invention should not be limited to the following compounds. In addition, the phrase “R4 to R11” means R4, R5, R6, R7, R8, R9, R10 and R11, and other similar phrases mean likewise.
  • A is preferably CR1E or a nitrogen atom, and more preferably CR1E.
  • X—Y—Z is preferably N—CO—NR3AR3B, N—CO—R4, CR2E—CO—NR3AR3B or CR2E—NR5—COR4, more preferably N—CO—NR3AR3B or CR2E NR5—COR4, and even more preferably N—CO—NR3AR3B.
  • R1A to R1E are preferably a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group and a C1-6 alkoxy; a C3-8 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl and a C1-6 alkoxy; a C1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group and a C1-6 alkoxy; a hydrogen atom; a halogen; or a 4- to 10-membered saturated heterocycle optionally substituted with a C1-6 alkyl. R1A to R1E are more preferably a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C1-6 alkoxy; a C3-8 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkyl and a C1-6 alkoxy; a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms; a hydrogen atom; or a halogen. R1A to R1E are even more preferably a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C1-6 alkoxy; a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms; a hydrogen atom; or a halogen. R1A to R1E are the most preferably a C1-6 alkyl optionally substituted with 1 to 5 fluorine atoms; a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms; or a hydrogen atom.
  • R2A to R2E are preferably a C1-6 alkyl optionally substituted with 1 to 5 fluorine atoms; a C1-6 alkoxy; a hydrogen atom; or a fluorine atom. R2A to R2E are more preferably a C1-6 alkyl, a hydrogen atom or a fluorine atom, even more preferably a C1-6 alkyl or a hydrogen atom, and the most preferably a hydrogen atom.
  • R3A, R3B and R4 are preferably a C1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a 4- to 10-membered saturated heterocycle, a C3-10 cycloalkyl, a fluorine atom, a hydroxy group, a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, and —NR10R11; a C3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; a nitrogen-containing monocyclic heteroaryl; or a hydrogen atom, wherein the cycloalkyl, the saturated heterocycle and the nitrogen-containing monocyclic heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkoxy and —NR10R11), a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms and —NR10R11, provided that (1) R3A and R3B may be taken together to form a 4- to 10-membered nitrogen-containing saturated heterocycle (which may be optionally substituted with the substituents of the above-mentioned saturated heterocycle), (2) both R3A and R3B are not a hydrogen atom, and (3) R4 is not a hydrogen atom.
  • R3A, R3B and R4 are more preferably, a C1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms; a C3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; or a hydrogen atom, wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C1-6 alkoxy) and a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms.
  • R3A, R3B and R4 are even more preferably a C1-10 alkyl; a C3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; or a hydrogen atom, wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkyl and a C1-6 alkoxy.
  • R3A, R3B and R4 are the most preferably a C3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; or a hydrogen atom, wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of a C1-6 alkyl and a C1-6 alkoxy.
  • Furthermore, in another embodiment, either R3A or R3B is a hydrogen atom.
  • R5 to R11, R6′ and R7′ are the same or different (each symbol is also the same or different when each symbol exists plurally) and are preferably a hydrogen atom or a C1-6 alkyl optionally substituted with 1 to 5 fluorine atoms, more preferably a hydrogen atom or a C1-6 alkyl, and even more preferably a C1-6 alkyl, provided that in each combination of R6-R7, R6′-R7′, R8-R9, and R10-R11, (1) when one is a hydrogen atom, the other one is not a hydrogen atom, and (2) each combination may be taken together to form a 4- to 10-membered saturated heterocycle.
  • n is 1 or 2, and preferably 1.
  • A pharmaceutically acceptable salt of the compound of Formula (I) means that the structure of Formula (I) has a group which can form an acid or base addition salt, thereby forming a pharmaceutically acceptable acid or base addition salt of the compound of Formula (I).
  • When the present compound has basic groups such as an amino group, it may form various acid salts. The acid addition salt of the present compound includes, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, and phosphate; organic acid salts such as oxalate, malonate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate; and amino-acid salts such as glutamate and aspartate.
  • When the present compound has acid groups such as a carboxyl group, it may form salts with various bases. Such pharmaceutically acceptable salts include, for example, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium salts, and ammonium salts.
  • These salts can be prepared by mixing the present compound of Formula (I) with the above-mentioned acid or base and then isolating it according to conventional methods such as recrystallization.
  • For the purpose of simplifying expressions, the following abbreviations may be optionally used herein.
  • o-: ortho-
    m-: meta-
    p-: para-
    t-: tert-
    s-: sec-
    CHCl3: chloroform
    CH2Cl2: dichloromethane
    THF: tetrahydrofuran
    • DMF: N,N-dimethylformamide
  • DMSO: dimethylsulfoxide
    PAM: positive allosteric modulator
    HEPES: N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
    BSA: bovine serum albumin
    • FDSS: Functional Drug Screening System
  • Boc: tert-butoxycarbonyl
    c-Hex: cyclohexyl
    c-Pen: cyclopentyl
    iPr: isopropyl
    c-Pr: cyclopropyl
    n-Pr: normalpropyl
    EDCI HCl: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride
    HOBt: 1-hydroxybenzotriazole
    DIEA: diisopropylethylamine
    TEA: triethylamine
    Ms: methanesulfonyl
  • Hereinafter, processes of the present compound are explained. The present compound of Formula (I) can be prepared by, for example, the following Processes A1, A2, B, C1, C2 and D.
    • Process A1
  • Among the compounds of Formula (I), those wherein X—Y—Z is N—CO—NR3AR3B and R1A is neither alkoxy nor hydrogen atom as shown by Formula A1 (i.e. Compound A1) can be prepared by, for example, the following process:
  • Figure US20160355511A1-20161208-C00004
    Figure US20160355511A1-20161208-C00005
  • wherein
  • A, R1B to R1D, R2A to R2D, R3A, R3B and n are as defined in Term 1,
  • R1A′ is the same as R1A defined in Term 1 except that alkoxy and a hydrogen atom are excluded,
  • An is a counter anion,
  • X1 is a halogen,
  • L is a leaving group,
  • P is a protecting group for the amino group, and
  • Ra1 is a hydrogen atom or a C1-6 alkyl.
  • Compound a1 wherein A is CR1E (i.e. 2-methylaniline) can be synthesized by methods disclosed in publications such as Bioorganic & Medicinal Chemistry Letters 2002, 12 (20), 2925-2930, European Journal of Organic Chemistry 2010, 24, 4662-4670 and WO 2009/001132, or be commercially available.
  • Compound a1 wherein A is a nitrogen atom (i.e. 2-methyl-3-aminopyridine) can be synthesized by methods disclosed in publications such as WO 2008/157404 and WO 2009/088103, or be commercially available.
    • (Step A-1)
  • In this step, Compound a1 is reacted with, for example, sodium nitrite and sodium tetrafluoroborate in the presence of any acid in a suitable solvent to give Compound a2. The acid used herein includes mineral acids such as hydrochloric acid, nitric acid, and sulfuric acid, and preferably hydrochloric acid. The solvent used herein may be selected from those exemplified later, and preferably water. The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically −50° C. to 150° C., preferably −30° C. to 100° C., and more preferably −10° C. to 60° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
    • (Step A-2)
  • In this step, Compound a2 prepared in Step A-1 is cyclized, for example, in the presence or absence of organic or inorganic salts and crown ethers to give Compound a3. The organic or inorganic salts used herein include, for example, potassium acetate, sodium acetate, sodium bicarbonate and potassium tert-butoxide, and preferably potassium acetate. The solvent used herein may be selected from those exemplified later, and preferably chloroform or dichloromethane. Similar reactions of the step herein are disclosed in, for example, Tetrahedron Lett. 2002, 43, 2695-2697 and Tetrahedron 2006, 62, 7772-7775, and such reactions can also be used to prepare the product herein. The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically −50° C. to 100° C., preferably −30° C. to 50° C., and more preferably −10° C. to 30° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
    • (Step A-3)
  • In this step, Compound a3 prepared in Step A-2 is halogenated to give Compound a4. For example, in case of iodination, the reaction can be carried out with iodine in the presence of any base in a suitable solvent. The base used herein may be selected from those exemplified later, and preferably sodium hydroxide or potassium hydroxide. The solvent used herein may be selected from those exemplified later, and preferably dimethylformamide or chloroform. The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically −30° C. to 200° C., preferably −10° C. to 100° C., and more preferably 0° C. to 80° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
    • (Step A-4)
  • In this step, Compound a4 prepared in Step A-3 is coupled with borane acid and the like in the presence of a catalyst and base to give Compound a5. The catalyst used herein includes those wherein a transition metal (e.g. palladium), a salt, complex or polymer thereof, or the like is supported on a carrier. The base used herein may be selected from those exemplified later, and preferably sodium carbonate, potassium carbonate or the like. The solvent used herein may be selected from those exemplified later, and preferably a mixed solvent of dioxane and water. Similar reactions of the step herein are disclosed in, for example, WO 2005/073219 and such reactions can also be used to prepare the product herein. The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically 0° C. to 200° C., preferably 30° C. to 150° C., and more preferably 50° C. to 120° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
    • (Step A-5)
  • In this step, Compound a5 prepared in Step A-4 is reacted with Compound a8 in the presence of a base to give Compound a6. The base used herein may be selected from those exemplified later, and preferably sodium hydride, potassium t-butoxide or the like. The reductant used herein may be hydrogen, formates such as ammonium formate, or hydrazine. The solvent used herein may be selected from those exemplified later, and preferably DMF or THF. In addition, Compound a8 can also be synthesized by methods disclosed in publications such as WO 2012/068106, WO 2007/030366 and Tetrahedron Lett. 2012, 53, 948-951, or be commercially available. The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically 0° C. to 200° C., preferably 30° C. to 150° C., and more preferably 50° C. to 120° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
    • (Step A-6)
  • In this step, the protecting group for the amino group of Compound a6 prepared in Step A-5 (defined as “P”) is deprotected to give Compound a7. The step herein can be carried out according to methods disclosed in, for example, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999). The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically −30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 80° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
    • (Step A-7)
  • In this step, Compound a7 prepared in Step A-6 is reacted with Compound a9 or a10 in the presence of any base in a suitable solvent to give compound A1. The base used herein may be selected from those exemplified later, and preferably diisopropylethylamine or triethylamine. The solvent used herein may be selected from those exemplified later, and preferably tetrahydrofuran or dimethylformamide. In addition, Compound a9 or a10 can be commercially available or prepared according to conventional methods. The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically −50° C. to 200° C., preferably −20° C. to 150° C., and more preferably 0° C. to 100° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
    • Process A2
  • Among the compounds of Formula (I), those wherein X—Y—Z is N—CO—NR3AR3B and R1A is an optionally-substituted alkoxy as shown by Formula A2 (i.e. Compound A2) can be prepared by, for example, the following process:
  • Figure US20160355511A1-20161208-C00006
    Figure US20160355511A1-20161208-C00007
  • wherein
  • A, R1B to R1D, R2A to R2D, R3A, R3B and n are as defined in Term 1,
  • R1A″ is an optionally-substituted C1-6 alkyl, and
  • P is a protecting group for the amino group.
  • 2-Aminobenzoate derivative (Compound a11) can be synthesized by methods disclosed in publications such as Chemistry Letters, 2009, 38 (3), 200-201 and Organic Process Research & Development, 2009, 13 (4), 698-705, or be commercially available.
    • (Step A-8)
  • In this step, Compound a11 is reacted with sodium nitrite and then sodium thiosulfate in the presence of any acid in a suitable solvent to give Compound a12. The acid used herein is selected from mineral acids such as hydrochloric acid, nitric acid and sulfuric acid, and preferably hydrochloric acid. The solvent used herein may be selected from those exemplified later, and preferably water. The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically −50° C. to 150° C., preferably −30° C. to 100° C., and more preferably −10° C. to 60° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
    • (Step A-9)
  • In this step, the hydrogen atom at 1-position of the indazole in Compound a12 prepared in Step A-8 is replaced with a protecting group for the amino group (defined as “P”) to give Compound a13. The step herein can be carried out according to methods disclosed in, for example, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999). The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically −30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 60° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
    • (Step A-10)
  • In this step, Compound a13 prepared in Step A-9 is reacted with any alkylating agent in the presence of any base in a suitable solvent to give Compound a14. The electrophile used herein may be, for example, 1-methyl-1-nitrosourea, ethyl iodide, or isopropyl iodide. The base used herein may be selected from those exemplified later, and preferably potassium carbonate, cesium carbonate, silver carbonate or the like. The solvent used herein is preferably acetonitrile or diethyl ether. The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically −30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 100° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
    • (Step A-11)
  • In this step, the protecting group for the amino group of Compound a14 prepared in Step A-10 (defined as “P”) is deprotected to give Compound a15. The step herein can be carried out according to methods disclosed in, for example, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999). The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically −30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 60° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
    • (Step A-12)
  • In this step, Compound a15 prepared in Step A-11 is converted to Compound a16 according to the conditions in Step A-5.
    • (Step A-13)
  • In this step, Compound a16 prepared in Step A-12 is converted to Compound a17 according to the conditions in Step A-6.
    • (Step A-14)
  • In this step, Compound a17 prepared in Step A-13 is converted to compound A2 according to the conditions in Step A-7.
    • Process B
  • Among the compounds of Formula (I), those wherein X—Y—Z is N—CO—NR4 as shown by Formula B1 (i.e. Compound B1) can be prepared by, for example, the following process:
  • Figure US20160355511A1-20161208-C00008
  • wherein A, R1A to R1D, R2A to R2D, R4 and n are as defined in Term 1.
    • (Step B-1)
  • In this step, Compound a7 or a17 prepared in Step A-6 or A-13 respectively is reacted with Compound b1 or b2 in the presence of any condensing agent or base in a suitable solvent to give compound B1. The condensing agent used herein includes various types used in conventional methods, and preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride thereof). The base used herein may be selected from those exemplified later and preferably diisopropylethylamine or triethylamine. The solvent used herein may be selected from those exemplified later, and preferably dimethylformamide or tetrahydrofuran. The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically −30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 80° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
    • Process C1
  • Among the compounds of Formula (I), those wherein X—Y—Z is CR2E—NR5—COR4 as shown by Formulae C1 and C2 (i.e. Compounds C1 and C2) can be prepared by, for example, the following process:
  • Figure US20160355511A1-20161208-C00009
    Figure US20160355511A1-20161208-C00010
  • wherein
  • A, R1A to R1D, R2A to R2E, R4, R5 and n are as defined in Term 1,
  • X2 is a leaving group such as a halogen, and
  • P is a protecting group for the amino group.
    • (Step C-1)
  • In this step, Compound a3, a5 or a15 is reacted with Cyclohexylalcohol c3 by Mitsunobu reaction in the presence of an azo compound analog and an organophosphorus compound to give Compound c1. The azo compound analog used herein includes, for example, diethylazodicarboxylate and diisopropylazodicarboxylate. The organophosphorus compound used herein is preferably triphenylphosphine or the like. The solvent used herein may be selected from those exemplified later, and preferably tetrahydrofuran. Similar reactions of the step herein are disclosed in, for example, Synlett, 2009, 16, 2673-2675 and Bioorganic & Medicinal Chemistry Letters, 2007, 17 (7), 2036-2042. In addition, Compound c3 can be synthesized by methods disclosed in publications such as WO 2011/035159 and WO 2010/032009, or be commercially available. The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically −30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 100° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
    • (Step C-2)
  • In this step, the protecting group for the amino group of Compound c1 prepared in Step C-1 (defined as “P”) is deprotected to give Compound c2. The step herein can be carried out according to methods disclosed in, for example, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999). The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically −30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 60° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
    • (Step C-3)
  • In this step, Compound c2 prepared in Step C-2 is converted to Compound C1 according to the conditions in Step B-1.
    • (Step C-4)
  • In this step, Compound C1 prepared in Step C-3 is reacted with Compound c4 in the presence of any base in a suitable solvent to give Compound C2. The base used herein may be selected from those exemplified later, and preferably sodium hydride or diisopropylamine. The solvent used herein may be selected from those exemplified later, and preferably dimethylformamide or tetrahydrofuran. The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically −30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 80° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
    • Process C2
  • Among the compounds of Formula (I), those wherein X—Y—Z is CR2E—NR5—CONR3AR3B as shown by Formulae C3 and C4 (i.e. Compounds C3 and C4) can be prepared by, for example, the following process:
  • Figure US20160355511A1-20161208-C00011
  • wherein
  • A, R1A to R1D, R2A to R2E, R3A, R3B, R5 and n are as defined in Term 1,
  • X2 is a leaving group such as a halogen, and
  • P is a protecting group for the amino group.
    • (Step C-5)
  • In this step, Compound c2 prepared in Step C-2 is converted to Compound C3 according to the conditions in Step A-14.
    • (Step C-6)
  • In this step, Compound C3 prepared in Step C-5 is converted to Compound C4 according to the conditions in Step C-4.
    • Process D
  • Among the compounds of Formula (I), those wherein X—Y—Z is CR2E—CO—NR3AR3B as shown by Formula D1 (i.e. Compound D1) can be prepared by, for example, the following process:
  • Figure US20160355511A1-20161208-C00012
  • wherein
  • A, R1A to R1D, R2A to R2E, R3A, R3B and n are as defined in Term 1, and
  • Rx is a protecting group for the carboxyl group.
    • (Step D-1)
  • In this step, Compound a3, a5 or a15 is converted to Compound d1 according to the conditions in Step C-1.
    • (Step D-2)
  • In this step, the ester Compound d1 prepared in Step D-1 is converted to a corresponding carboxylic Compound d2. The step herein can be carried out according to methods disclosed in, for example, Protective Groups in Organic Synthesis (Theodora W. Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., 1999). The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically −30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 60° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
    • (Step D-3)
  • In this step, Compound d2 prepared in Step D-2 is reacted with Compound d3 in the presence of any condensing agent in a suitable solvent to give compound D1. The condensing agent used herein includes various types used in conventional methods, and preferably 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (including hydrochloride thereof). The solvent used herein may be selected from those exemplified later. The reaction temperature herein depends on factors such as the types of starting compound and reagents, and it is typically −30° C. to 200° C., preferably 0° C. to 150° C., and more preferably 0° C. to 80° C. The reaction time herein is typically about 1 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 16 hours.
  • The base used in each step in each of the above-shown processes can be selected depending on various factors such as the type of reaction and starting compound; and includes, for example, alkaline bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkaline carbonates such as sodium carbonate and potassium carbonate, metal hydrides such as sodium hydride and potassium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as sodium methoxide and sodium t-butoxide, organometallic bases such as butyllithium and lithium diisopropylamide, and organic bases such as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU).
  • The solvent used in each step in the above-shown processes can be optionally selected depending on various factors such as the type of reaction and starting compound; and includes, for example, alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ketone, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran (THF) and dioxane, aromatic hydrocarbons such as toluene and benzene, aliphatic hydrocarbons such as hexane and heptane, esters such as ethyl acetate and propyl acetate, amides such as N,N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone, sulfoxides such as dimethylsulfoxide (DMSO), and nitriles such as acetonitrile. These solvents can be used alone or in combination with two or more. In addition, organic bases may also be used as the solvent, depending on the type of reaction.
  • The present compound of Formula (I) or an intermediate thereof can be isolated and purified by well-known methods such as extraction, partition, reprecipitation, column chromatography (e.g. silica gel column chromatography, ion exchange column chromatography and preparative liquid chromatography) and recrystallization. The recrystallization solvent used herein includes, for example, alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, ketone solvents such as acetone, halogen solvents such as dichloromethane and chloroform, hydrocarbon solvents such as hexane, aprotic solvents such as dimethylformamide and acetonitrile, water, and a mixed solvent selected from two or more of the above-listed solvents. Other purification methods, for example, those disclosed in Experimental Chemistry Textbook Vol. 1 (the Chemical Society of Japan, ed., Maruzen) can also be used herein.
  • The present compound of Formula (I) or a pharmaceutically acceptable salt thereof may exhibit chirality or contain a substituent with an asymmetric carbon, which can exist as optical isomers. The present compound includes a mixture of each of the isomers and an isolated single isomer, which can be prepared according to a conventional process, for example, using a starting material with an asymmetric center or introducing chirality during the process. In detail, in order to obtain an optical isomer, it can be prepared by using optically active compounds as a starting material or optically resolving the mixture at an appropriate stage during the process. The optical resolution method used herein includes, for example, an isolation technique via diastereomeric salt formed as follows. When the compound of Formula (I) or an intermediate thereof has a basic group, such diastereomeric salt can be formed with optically active acids such as monocarboxylic acids (e.g. mandelic acid, N-benzyloxyalanine, and lactic acid), dicarboxylic acids (e.g. tartaric acid, o-diisopropylidene tartaric acid, and malic acid) and sulfonic acids (e.g. camphor sulfonic acid and bromocamphor sulfonic acid) in an inert solvent such as alcohol solvents (e.g. methanol, ethanol, and 2-propanol), ether solvents (e.g. diethyl ether), ester solvents (e.g. ethyl acetate), hydrocarbon solvents (e.g. toluene), aprotic solvents (e.g. acetonitrile), and a mixed solvent selected from two or more of the above-listed solvents. When the present compound of Formula (I) or an intermediate thereof has an acidic group such as a carboxyl group, such diastereomeric salt can be formed with optically active amines such as organic amines (e.g. 1-phenylethylamine, kinin, quinidine, cinchonidine, cinchonine and strychnine). Thus, it is possible to resolve a mixture of optical isomers via the resolution of such diastereomeric salt.
  • The present compound can be a novel medicament for treating and/or preventing a disease due to an abnormality of the intracellular signaling mediated by acetylcholine, and in particular, nervous system diseases, psychiatric diseases, and inflammatory diseases [e.g. dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder, and cerebral angiopathy]. The administration route of the present compound may be any of oral, parenteral and rectal ones; and the daily dosage thereof may vary depending on the type of compound, administration method, symptom/age of the patient, and other factors. For example, in case of oral administration, the present compound can be administered to human beings or mammals at typically about 0.01 mg to 1000 mg and preferably about 0.1 mg to 500 mg per kg of body weight as a single or multiple doses. In case of parenteral administration such as intravenous injection, the present compound can be administered to human beings or mammals at typically about 0.01 mg to 300 mg and preferably about 1 mg to 100 mg per kg of body weight.
  • The dosage forms of the present compound include, for example, tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, embrocations, adhesive skin patches, and inhalants. These formulations can be prepared according to conventional methods. In addition, liquid formulations may be in a form wherein the present compound is dissolved or suspended in water, appropriate aqueous solutions, or other appropriate vehicles at the time of use. Tablets and granules may be coated according to known methods. Furthermore, the formulations may comprise additional ingredients which are useful for the treatment.
  • The present compound can be used in combination with a drug classified as atypical antipsychotic drugs. The atypical antipsychotic drugs include, for example, olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, aripiprazole, asenapine, iloperidone, clozapine, sertindole, blonanserin and lurasidone.
  • The temperature for forming the salt is in the range of room temperature to boiling point of a solvent as used. In order to improve the optical purity, it is desirable that the temperature is once raised to around the boiling point of the solvent. The precipitated salt is collected on a filter; and if necessary, the filtration may be carried out under cooled conditions to improve the yield. The appropriate amount of an optically active acid or amine used herein is about 0.5 to about 2.0 equivalents, preferably about 1 equivalent per the reactant. If necessary, the crystal can be recrystallized from an inert solvent such as alcohol solvents (e.g. methanol, ethanol and 2-propanol), ether solvents (e.g. diethyl ether), ester solvents (e.g. ethyl acetate), hydrocarbon solvents (e.g. toluene), aprotic solvents (e.g. acetonitrile), and a mixed solvent selected from two or more of the above-listed solvents to give the optically active salt in high purity. In addition, if necessary, it is also possible to treat the optically-resolved salt with an acid or base by a conventional method to give a free form thereof.
    • Example
  • Hereinafter, the present invention is further explained in detail in Reference Examples, Examples and Test Examples, but the present invention should not be limited thereto. In addition, the compounds were identified by, for example, elementary analysis, mass spectra, high performance liquid chromatograph-mass spectrometer, LCMS, IR spectra, NMR spectra, and high performance liquid chromatography (HPLC).
  • For the purpose of simplifying expressions, the following abbreviations may be optionally used in Reference Examples, Examples and the tables thereof. When referring to substituents, Me and Ph are abbreviations of methyl and phenyl respectively. TFA is an abbreviation of trifluoroacetic acid. The following abbreviations are used in NMR data.
  • s: singlet
    d: doublet
    dd: doublet of doublet
    t: triplet
    td: triplet of doublet
    q: quartet
    m: multiplet
    br: broad
    brs: broad singlet
    brs: broad multiplet
    J: coupling constant
  • The measurement conditions of LCMS by high performance liquid chromatograph-mass spectrometer are shown below. The observed value of mass spectrometry [MS(m/z)] is shown as MH+, and the retention time is shown as Rt (min). In addition, the conditions used in measuring each of the observed value are shown as A to F:
    • Measurement Condition A
  • Detector: Agilent 1100 series for API series manufactured by Applied Biosystems
    HPLC: API 150EX LC/MS system manufactured by Applied Biosystems
    • Column: YMC CombiScreen Hydrosphere C18 (S-5 μM, 12 nm, 4.6×50 mm) Solvent: Solution A: 0.05% TFA/H2O, Solution B: 0.05% TFA/MeOH Gradient Condition:
  • 0.0-6.0 min; A/B=75:25-1:99 (linear gradient)
  • Flow rate: 3.5 mL/min
    • UV: 254 nm Measurement Condition B
  • Detector: HPLC: LCMS-2010EV manufactured by Shimadzu
    Column: Xtimate (3 μM, 2.1×30 mm) manufactured by Welch Materials
    • Solvent: Solution A: 0.019% TFA/H2O, Solution B: 0.038% TFA/MeOH Gradient Condition:
  • 0.0-1.35 min; A/B=90:10-20:80 (linear gradient)
  • 1.35-2.25 min; A/B=20:80
  • Flow rate: 0.8 mL/min
    • UV: 220 nm
  • Column temperature: 50° C.
    • Measurement Condition C Detector: Perkin-Elmer Sciex API 150EX Massspectrometer (40 eV) HPLC: Shimadzu LC 10ATVP
  • Column: Shiseido CAPCELL PAK C18 ACR (S-5 μm, 4.6 mm×50 mm)
    Solvent: Solution A: 0.035% TFA/CH3CN, Solution B: 0.05% TFA/H2O
    • Gradient Condition:
  • 0.0-0.5 min; A/B=1:99
  • 0.5-4.8 min; A/B=10:90-99:1 (linear gradient)
  • 4.8-5.0 min; A/B=99:1
  • Flow rate: 3.5 mL/min
    • UV: 220 nm
  • Column temperature: 40° C.
    • Measurement Condition D Detector: Waters ACQUITY UltraPerfomanc LC-PDA-ELSD-SQD
  • Column: Waters UPLC BEH C18 1.7 m, 2.1×30 mm (Part. No. 186002349)
    Solvent: Solution A: 0.05% HCOOH/H2O, Solution B: CH3CN
    • Gradient Condition:
  • 0.0 min; A/B=90:10
  • 0.0-1.3 min; A/B=90:10-5:95 (linear gradient)
  • Flow rate: 0.80 mL/min
    • UV: 220, 254 nm
  • Column temperature: 40° C.
    • Measurement Condition E Detector: Shimadzu LCMS-2020
  • Column: Phenomenex Kinetex (1.7 μm C18, 50 mm×2.10 mm)
    • Solvent: Solution A: MeOH, Solution B: 0.05% TFA/H2O Gradient Condition:
  • 0.0 min; A/B=30:70
  • 0.0-1.9 min; A/B=99:1
  • 1.9-3.0 min; A/B=30:70
  • Flow rate: 0.5 mL/min
    • UV: 220 nm
  • Column temperature: 40° C.
    • Measurement Condition F Detector: Waters ACQUITY UPLC Column: Waters ACQUITY UPLC BEH Phenyl 1.7 μm 2.1×50 mm
  • Solvent: Solution A: 0.05% HCOOH/H2O, Solution B: CH3CN
    • Gradient Condition:
  • 0.0-1.3 min; A/B=90:10-1:99 (linear gradient)
  • 1.3-1.5 min; A/B=1:99
  • 1.5-2.0 min; A/B=90:10
  • Flow rate: 0.75 mL/min
    • UV: 220, 254 nm
  • Column temperature: 50° C.
    • Reference Example 1 5-methyl-1-(4-piperidyl)-1H-indazole hydrochloride
  • Figure US20160355511A1-20161208-C00013
    • a) Preparation of tert-butyl 4-(5-methyl-1H-indazol-1-yl)piperidine-1-carboxylate (Compound Q1)
  • To a solution of 5-methylindazole (901 mg) in DMF (10 mL) was added sodium hydride (327 mg) at 0° C., and the mixture was stirred with heating at 40° C. for 30 minutes. To the reaction solution was added tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (2.28 g), and the mixture was stirred with heating at 90° C. for 19 hours. Then, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine and dried over Na2SO4. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:5 as the eluting solvent) to give Compound Q1 (1.04 g).
  • 1H-NMR (400 MHz, CDCl3): 1.47 (9H, s), 2.00 (2H, m), 2.21 (2H, m), 2.43 (3H, s), 2.93 (2H, br), 4.28 (2H, br), 4.50 (1H, m), 7.19 (1H, d, J=8.0 Hz), 7.32 (1H, d, J=8.0 Hz), 7.48 (1H, s), 7.89 (1H, s).
    • b) Preparation of 5-methyl-1-(4-piperidyl)-1H-indazole hydrochloride (Reference Example 1)
  • To a solution of Compound Q1 (1.04 g) in chloroform (20 mL) was added 4 mol/L HCl-dioxane (3.3 mL), and the mixture was stirred at room temperature for 7 hours. Then, the solvent was evaporated under reduced pressure to give Reference Example 1 (720 mg).
    • Reference Example 2 3-ethoxy-5-ethyl-1-(piperidin-4-yl)-1H-indazole hydrochloride
  • Figure US20160355511A1-20161208-C00014
    Figure US20160355511A1-20161208-C00015
    • a) Preparation of 5-bromo-1H-indazol-3-ol (Compound Q2)
  • To a solution of 2-amino-5-bromobenzoic acid (50 g) in water (200 mL) was added HCl (46 mL). To the mixture was added aqueous NaNO2 solution (17.7 g/37 mL) at 0° C., and the mixture was stirred at 0° C. for 30 minutes. To the reaction solution was added dropwise aqueous Na2SO3 solution (79.3 g/200 mL) at 0° C., and the mixture was stirred at room temperature for 2 hours. To the mixture was added HCl (70 mL), and the mixture was stirred at room temperature for 18 hours and then at 80° C. for 4 hours. The precipitated solid was dissolved by basifying the reaction solution, and then the solution was acidified to precipitate a solid. The solid was collected by filtration and dried under reduced pressure to give Compound Q2 (36 g).
  • 1H-NMR (400 MHz, d-DMSO): 7.28 (1H, d, J=8.0 Hz), 7.39 (1H, d, J=8.0 Hz), 7.82 (1H, s), 10.67 (1H, s), 11.75 (1H, s).
    • b) Preparation of tert-butyl 5-bromo-3-hydroxy-1H-indazole-1-carboxylate (Compound Q3)
  • To a solution of Compound Q2 (5.00 g) in acetonitrile (50 mL) were added under nitrogen atmosphere triethylamine (3.60 g) and 4-N,N-dimethylaminopyridine (144 mg), and the mixture was stirred at room temperature for 10 minutes. To the mixture was added di-tert-butyl dicarbonate (5.14 g), and the mixture was stirred for 10 hours at room temperature. The solvent was removed out, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated under reduced pressure to give Compound Q3 (4.5 g).
  • 1H-NMR (400 MHz, d-DMSO): 1.61 (9H, s), 7.73 (1H, dd, J=8.0 Hz, 1.6 Hz), 7.94 (2H, m).
    • c) Preparation of tert-butyl 5-bromo-3-ethoxy-1H-indazole-1-carboxylate (Compound Q4)
  • A solution of Compound Q3 (15.0 g), ethyl iodide (7.5 g) and cesium carbonate (31.3 g) in acetonitrile (250 mL) was stirred with heating at 80° C. for 16 hours. The solvent was removed out, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine and dried over Na2SO4. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=30:1 as the eluting solvent) to give Compound Q4 (9.00 g).
  • 1H-NMR (400 MHz, CDCl3): 1.50 (3H, t, J=7.2 Hz), 1.72 (9H, s), 4.56 (2H, q, J=7.2 Hz), 7.60 (1H, dd, J=8.0 Hz, 1.6 Hz), 7.85 (2H, m)
    • d) Preparation of 5-bromo-3-ethoxy-1H-indazole (Compound
  • Q5) To a solution of Compound Q4 (7.60 g) in ethyl acetate (50 mL) was added 4 mol/L HCl-ethyl acetate (50 mL), and the mixture was stirred at room temperature for 8 hours. Then, the solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate, collected by filtration and dried under reduced pressure to give Compound Q5 (6.20 g).
  • 1H-NMR (400 MHz, CD3OD): 1.48 (3H, t, J=7.2 Hz), 4.44 (2H, q, J=7.2 Hz), 7.31 (1H, d, J=9.2 Hz), 7.49 (1H, d, J=9.2 Hz), 7.80 (1H, s).
    • e) Preparation of tert-butyl 4-(5-bromo-3-ethoxy-1H-indazol-1-yl)piperidine-1-carboxylate (Compound Q6)
  • To a solution of the above-obtained Compound Q5 (2.03 g) in dehydrated DMF (120 mL) was added under nitrogen atmosphere sodium hydride (1.17 g), and the mixture was stirred at 0° C. for 30 minutes. To the reaction solution was added tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (4.08 g), and the mixture was stirred with heating at 90° C. for 16 hours. Then, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine and dried over Na2SO4. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:30 as the eluting solvent) to give Compound Q6 (3.10 g).
  • 1H-NMR (400 MHz, CDCl3): 1.41 (3H, t, J=7.2 Hz), 1.45 (3H, s), 1.90 (2H, m), 2.15 (2H, m), 2.93 (2H, m), 4.28 (3H, m), 4.40 (2H, q, J=7.2 Hz), 7.14 (1H, d, J=9.2 Hz), 7.39 (1H, dd, J=9.2 Hz, 1.6 Hz), 7.79 (1H, d, J=1.6 Hz).
    • f) Preparation of tert-butyl 4-(3-ethoxy-5-vinyl-1H-indazol-1-yl)piperidine-1-carboxylate (Compound Q7)
  • A solution of the above-obtained Compound Q6 (2.40 g), 2,4,6-trivinylcyclotriboroxan (1.09 g), cesium carbonate (5.51 g), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (0.83 g) in dioxane (50 mL)-water (5 mL) was stirred under nitrogen atmosphere at 90° C. for 16 hours. Then, the solvent was removed out, the mixture was partitioned between dichloromethane and water, and the organic layer was washed with brine and dried over Na2SO4. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:40 as the eluting solvent) to give Compound Q7 (2.00 g).
  • 1H-NMR (400 MHz, CDCl3): 1.49 (12H, m), 1.90 (2H, m), 2.19 (2H, m), 2.93 (2H, m), 4.28 (3H, m), 4.43 (2H, q, J=7.2 Hz), 5.16 (1H, d, J=11.0 Hz), 5.69 (1H, d, J=17.2 Hz), 6.80 (1H, dd, J=17.2 Hz, 11.0 Hz), 7.20 (1H, d, J=8.8 Hz), 7.49 (1H, dd, J=8.8 Hz, 1.6 Hz), 7.63 (1H, d, 1.6 Hz).
    • g) Preparation of tert-butyl 4-(3-ethoxy-5-ethyl-1H-indazol-1-yl)piperidine-1-carboxylate (Compound Q8)
  • A solution of the above-obtained Compound Q7 (1.62 g) and palladium (II) hydroxide/carbon (162 mg) in ethanol (180 mL) was stirred under hydrogen atmosphere at room temperature for 16 hours. Then, the mixture was filtered through Celite and the solvent was removed out to give Compound Q8 (1.60 g).
  • 1H-NMR (400 MHz, CDCl3): 1.27 (3H, t, J=7.2 Hz), 1.49 (3H, t, J=7.2 Hz), 1.51 (9H, s), 1.93 (2H, m), 2.16 (2H, m), 2.74 (2H, q, J=7.2 Hz), 2.97 (2H, m), 4.28 (3H, m), 4.43 (2H, q, J=7.2 Hz), 7.27 (2H, m), 7.63 (1H, s).
    • h) Preparation of 3-ethoxy-5-ethyl-1-(piperidin-4-yl)-1H-indazole (Reference Example 2)
  • To a solution of the above-obtained Compound Q8 (1.45 g) in ethyl acetate (15 mL) was added 4 mol/L HCl-ethyl acetate (15 mL), and the mixture was stirred at room temperature for 8 hours. Then, the solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate, collected by filtration and dried under reduced pressure to give Reference Example 2 (1.20 g).
  • 1H-NMR (400 MHz, CDCl3): 1.28 (3H, t, J=7.2 Hz), 1.49 (3H, t, J=7.2 Hz), 2.40 (2H, br), 2.50 (2H, br), 2.74 (2H, q, J=7.2 Hz), 3.28 (2H, br), 3.75 (2H, br), 4.44 (2H, q, J=7.2 Hz), 4.58 (1H, m), 7.24 (2H, m), 7.49 (1H, s).
    • Reference Example 3 5-ethoxy-1-(piperidin-4-yl)-1H-indazole hydrochloride
  • Figure US20160355511A1-20161208-C00016
    • a) Preparation of 5-ethoxy-1H-indazole (Compound Q9)
  • To a solution of 5-hydroxyindazole (2.68 g) in DMF (50 mL) were added ethyl iodide (3.28 g) and potassium carbonate (4.16 g), and the mixture was stirred at room temperature for 1 day. Then, the mixture was partitioned between ethyl acetate and water, the organic layer was washed with brine and dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate as the eluting solvent) to give Compound Q9 (1.95 g).
  • 1H-NMR (400 MHz, CDCl3): 1.43 (3H, t, J=7.0 Hz), 4.05 (2H, q, J=7.0 Hz), 7.07 (2H, m), 7.39 (1H, m), 7.98 (1H, s).
    • b) Preparation of tert-butyl 4-(5-ethoxy-1H-indazol-1-yl)piperidine-1-carboxylate (Compound Q10)
  • To a solution of the above-obtained Compound Q9 (810 mg) in anhydrous DMF (10 mL) was added sodium hydride (220 mg) at 0° C., and the mixture was stirred with heating at 40° C. for 30 minutes. To the reaction solution was added tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (1.54 g), and the mixture was stirred with heating at 90° C. for 16 hours. Then, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine and dried over Na2SO4. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 as the eluting solvent) to give Compound Q10 (521 mg).
  • 1H-NMR (400 MHz, CDCl3): 1.43 (3H, t, J=7.0 Hz), 1.46 (9H, s), 1.99 (2H, m), 2.17 (2H, m), 2.91 (2H, m), 4.04 (2H, q, J=7.0 Hz), 4.28 (2H, br), 4.50 (1H, m), 7.04 (2H, m), 7.33 (1H, m), 7.87 (1H, s).
    • c) Preparation of 5-ethoxy-1-(piperidin-4-yl)-1H-indazole hydrochloride (Reference Example 3)
  • To a solution of the above-obtained Compound Q10 (637 mg) in chloroform (10 mL) was added 4 mol/L HCl-ethyl acetate (1.38 mL), and the mixture was stirred at room temperature for 16 hours. Then, the solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate, collected by filtration and dried under reduced pressure to give Reference Example 3 (484 mg).
    • Reference Example 4 cis-4-(5-ethyl-1H-indazol-1-yl)cyclohexylamine hydrochloride
  • Figure US20160355511A1-20161208-C00017
    • a) Preparation of tert-butyl cis-4-(5-bromo-1H-indazol-1-yl)cyclohexylcarbamate (Compound Q11)
  • A solution of 5-bromoindazole (15 g), tert-butyl trans-4-hydroxycyclohexylcarbamate (50 g) and triphenylphosphine (50 g) in THF was stirred at 0° C. for 15 minutes. To the reaction solution was added dropwise diisopropylazodicarboxylate (38.5 g) under nitrogen atmosphere at 0° C., and the mixture was stirred at 50° C. for 1 day. Then, the solvent was removed out, ethyl acetate (300 mL) and petroleum ether (90 mL) were added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:80-1:15 as the eluting solvent) to give Compound Q11 (8.00 g).
  • 1H-NMR (400 MHz, CDCl3): 1.48 (9H, s), 1.80 (2H, m), 1.94-2.10 (4H, m), 2.18 (2H, m), 3.93 (1H, br), 4.45 (1H, m), 4.90 (1H, br), 7.31 (1H, d, J=9.2 Hz), 7.46 (1H, dd, J=9.2 Hz, 0.8 Hz), 7.89 (1H, d, J=0.8 Hz), 7.96 (1H, s).
    • b) Preparation of tert-butyl cis-4-(5-vinyl-1H-indazol-1-yl)cyclohexylcarbamate (Compound Q12)
  • A solution of the above-obtained Compound Q11 (5.00 g), 2,4,6-trivinylcyclotriboroxan (4.57 g), cesium carbonate (12.40 g), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (0.75 g) in dioxane (150 mL)-water (25 mL) was stirred under nitrogen atmosphere at 90° C. for 15 hours. Then, the solvent was removed out, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine and dried over Na2SO4. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:30-1:10 as the eluting solvent) to give Compound Q12 (4.00 g).
  • 1H-NMR (400 MHz, CDCl3): 1.49 (9H, s), 1.82 (2H, m), 1.96-2.12 (4H, m), 2.20 (2H, m), 3.94 (1H, br), 4.47 (1H, m), 4.92 (1H, br), 5.24 (1H, d, J=10.8 Hz), 5.75 (1H, d, J=17.6 Hz), 6.85 (1H, dd, J=17.6 Hz, 10.8 Hz), 7.40 (1H, d, J=8.8 Hz), 7.56 (1H, d, J=8.8 Hz), 7.71 (1H, s), 8.00 (1H, s).
    • c) Preparation of tert-butyl cis-4-(5-ethyl-1H-indazol-1-yl)cyclohexylcarbamate (Compound Q13)
  • A solution of the above-obtained Compound Q12 (4.00 g) and palladium (II) hydroxide/carbon (20%, 400 mg) in ethanol (100 mL) was stirred under hydrogen atmosphere at room temperature for 16 hours. Then, the mixture was filtered through Celite and the solvent was removed out to give Compound Q13 (3.50 g).
  • 1H-NMR (400 MHz, CDCl3): 1.28 (3H, t, J=7.6 Hz), 1.48 (9H, s), 1.79 (2H, m), 1.95-2.10 (4H, m), 2.26 (2H, m), 2.77 (2H, q, J=7.6 Hz), 3.93 (1H, br), 4.46 (1H, m), 4.98 (1H, br), 7.26 (1H, d, J=8.8 Hz), 7.36 (1H, d, J=8.8 Hz), 7.54 (1H, s), 7.95 (1H, s).
    • d) Preparation of cis-4-(5-ethyl-1H-indazol-1-yl)cyclohexylamine hydrochloride (Reference Example 4)
  • To a solution of the above-obtained Compound Q13 (2.50 g) in ethyl acetate (15 mL) was added 4 mol/L HCl-ethyl acetate (15 mL), and the mixture was stirred at room temperature for 8 hours. Then, the solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate, collected by filtration and dried under reduced pressure to give Reference Example 4 (2.0 g).
  • 1H-NMR (400 MHz, dDMSO): 1.22 (3H, t, J=7.6 Hz), 1.87-2.02 (6H, m), 2.21 (2H, m), 2.71 (2H, q, J=7.6 Hz), 3.35 (1H, m), 4.73 (1H, m), 7.25 (1H, d, J=8.8 Hz), 7.54 (1H, s), 7.64 (1H, d, J=8.8 Hz), 7.98 (1H, s).
    • Reference Example 5 cis-4-(5-ethyl-1H-indazol-1-yl)cyclohexanecarboxylic acid (Reference Example 5)
  • Figure US20160355511A1-20161208-C00018
    • a) Preparation of ethyl cis-4-(5-bromo-1H-indazol-1-yl)cyclohexanecarboxylate (Compound Q14)
  • A solution of 5-bromoindazole (5.00 g), ethyl trans-4-hydroxycyclohexanecarboxylate (8.73 g), triphenylphosphine (13.3 g) in THF (150 mL) was stirred at 0° C. for 15 minutes. To the reaction solution was added dropwise diethylazodicarboxylate (9.03 g) under nitrogen atmosphere at 0° C., and the mixture was stirred at 50° C. for 13 hours. Then, the solvent was removed out, and ethyl acetate (100 mL) and petroleum ether (30 mL) were added thereto. The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:80-1:15 as the eluting solvent) to give Compound Q14 (3.50 g).
  • 1H-NMR (400 MHz, CDCl3): 1.28 (3H, t, J=7.6 Hz), 1.76 (2H, m), 1.95 (2H, m), 2.27 (2H, m), 2.35 (2H, m), 2.70 (1H, m), 4.20 (1H, q, J=7.6 Hz), 4.45 (1H, m), 7.35 (1H, d, J=8.8 Hz), 7.43 (1H, d, J=8.8H), 7.85 (1H, s), 7.91 (1H, s).
    • b) Preparation of ethyl cis-4-(5-vinyl-1H-indazol-1-yl)cyclohexanecarboxylate (Compound Q15)
  • A solution of the above-obtained Compound Q14 (3.80 g), 2,4,6-trivinylcyclotriboroxan (3.90 g), cesium carbonate (10.5 g), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (0.38 g) in dioxane (80 mL)-water (8 mL) was stirred under nitrogen atmosphere at 90° C. for 18 hours. Then, the solvent was removed out, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine and dried over Na2SO4. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:30-1:10 as the eluting solvent) to give Compound Q15 (2.10 g).
  • 1H-NMR (400 MHz, CDCl3): 1.28 (3H, t, J=7.6 Hz), 1.75 (2H, m), 1.98 (2H, m), 2.25 (2H, m), 2.40 (2H, m), 2.70 (1H, m), 4.22 (1H, q, J=7.6 Hz), 4.47 (1H, m), 5.20 (1H, d, J=10.8 Hz), 5.72 (1H, d, J=17.6 Hz), 6.82 (1H, dd, J=17.6 Hz, 10.8 Hz), 7.49 (1H, d, J=8.8 Hz), 7.52 (1H, d, J=8.8H), 7.67 (1H, s), 7.95 (1H, s).
    • c) Preparation of ethyl cis-4-(5-ethyl-1H-indazol-1-yl)cyclohexanecarboxylate (Compound Q16)
  • A solution of the above-obtained Compound Q15 (3.00 g), palladium (II) hydroxide/carbon (20%, 300 mg) in ethanol (80 mL) was stirred under hydrogen atmosphere at room temperature for 16 hours. Then, the mixture was filtered through Celite and the solvent was removed out to give Compound Q16 (2.80 g).
  • 1H-NMR (400 MHz, CDCl3): 1.29 (7H, m), 1.76 (2H, m), 2.00 (2H, m), 2.27 (2H, m), 2.41 (2H, m), 2.70-2.80 (3H, m), 4.25 (1H, q, J=7.6 Hz), 4.48 (1H, m), 7.23 (1H, d, J=8.8 Hz), 7.38 (1H, d, J=8.8 Hz), 7.53 (1H, s), 7.92 (1H, s).
    • d) Preparation of cis-4-(5-ethyl-1H-indazol-1-yl)cyclohexanecarboxylic acid (Reference Example 5)
  • To a solution of the above-obtained Compound Q16 (2.00 g) and lithium hydroxide (32 mg) in methanol (5 mL) were added water (5 mL) and THF (5 mL), and the mixture was stirred at room temperature for 7 hours. The solvent was removed out, water (30 mL) was added thereto, and the mixture was adjusted to pH 5 to 6 with 10% aqueous HCl solution and then extracted with ethyl acetate. The solvent was removed out to give Reference Example 5.
  • 1H-NMR (400 MHz, CDCl3): 1.25 (3H, t, J=7.6 Hz), 1.76 (2H, m), 1.75 (2H, m), 1.98 (2H, m), 2.25-2.50 (4H, m), 2.70-2.83 (3H, m), 4.45 (1H, m), 7.23 (1H, d, J=8.8 Hz), 7.37 (1H, d, J=8.8 Hz), 7.51 (1H, s), 7.95 (1H, s).
    • Reference Example 6 5-(2H3)methyl-1-(piperidin-4-yl)-1H-indazole hydrochloride
  • Figure US20160355511A1-20161208-C00019
    • a) Preparation of tert-butyl 4-(5-bromo-1H-indazol-1-yl)piperidine-1-carboxylate (Compound Q17)
  • To a suspension of potassium tert-butoxide (37.25 g) in tetrahydrofuran (1000 mL) was added 5-bromoindazole (54.52 g), and the mixture was stirred at room temperature for 15 minutes. To the reaction solution was added tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (98.74 g), and the reaction solution was heated at reflux for 1 day. Then, the mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine and dried over Na2SO4. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 as the eluting solvent) to give Compound Q17 (45.68 g).
  • 1H-NMR (400 MHz, CDCl3): 1.49 (9H, s), 2.00 (2H, m), 2.21 (2H, m), 2.96 (2H, m), 4.31 (2H, m), 4.52 (1H, m), 7.34 (1H, d, J=8.8 Hz), 7.45 (1H, d, J=1.7 Hz, 8.8 Hz), 7.88 (1H, d, J=1.7 Hz), 7.94 (1H, s).
    • b) Preparation of tert-butyl 4-[5-(2H3)methyl-1H-indazol-1-yl]piperidine-1-carboxylate (Compound Q18)
  • To a solution of Compound Q17 (5.70 g) in anhydrous tetrahydrofuran (60 mL) was added dropwise at −78° C. n-butyllithium (2.6 mol/L in n-hexane, 7.61 mL). The reaction solution was stirred at −78° C. for 3 hours, and deuterated methyl iodide (4.35 g) was added thereto at −78° C. The mixture was stirred at room temperature for 16 hours, and saturated aqueous NH4Cl solution was added thereto at ice temperature. The mixture was partioned between ethyl acetate and water, and the organic layer was washed with brine and dried over Na2SO4. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:2 as the eluting solvent) to give Compound Q18 (3.64 g).
  • 1H-NMR (400 MHz, CDCl3): 1.49 (9H, s), 2.02 (2H, t, J=10.5 Hz), 2.22 (2H, m), 2.96 (2H, m), 4.31 (2H, s), 4.54 (1H, m), 7.21 (1H, m), 7.34 (1H, d, J=8.5 Hz), 7.50 (1H, m), 7.90 (1H, s).
    • c) Preparation of 5-(2H3)methyl-1-(piperidin-4-yl)-1H-indazole hydrochloride (Reference Example 6)
  • To a solution of Compound Q18 (225 mg) in dioxane (3 mL) was added at room temperature 4 mol/L HCl-dioxane (3.3 mL), and the mixture was stirred at 55° C. for 2 hours. Then, the solvent was evaporated under reduced pressure to give Reference Example 6 (225 mg).
    • Reference Example 7 Preparation of 4-(4-ethoxy-5-methyl-1H-indazol-1-yl)piperidine hydrochloride
  • Figure US20160355511A1-20161208-C00020
    Figure US20160355511A1-20161208-C00021
    • a) Preparation of 2-(benzyloxy)-3-bromo-6-fluorobenzaldehyde (Compound Q20)
  • To a solution of 2-bromo-5-fluorophenol (10 g) in acetone (100 mL) were added potassium carbonate (8.68 g) and benzyl bromide (7.51 mL), and the mixture was heated at reflux for 18 hours. The reaction solution was cooled to room temperature and the insoluble matter was removed by filtration to give Compound Q19 as a crude product.
  • A solution of diisopropylamine (2.88 mL) in anhydrous tetrahydrofuran (40 mL) was cooled to −78° C. To the mixture was added dropwise n-butyllithium (2.6 mol/L in n-hexane, 6.19 mL), and the mixture was stirred at −78° C. for 10 minutes. To the mixture was added dropwise a solution of Compound Q19 (4.10 g) in anhydrous tetrahydrofuran (10 mL) over 15 minutes. The reaction solution was stirred at −78° C. for 1 hour, dimethylformamide (1.25 mL) was added thereto, and the mixture was stirred at the same temperature for 5 minutes. The reaction solution was warmed to room temperature, saturated aqueous NH4Cl solution (100 mL) was added to the solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solution of ethyl acetate/hexane to give Compound Q20 (3.08 g).
  • 1H-NMR (400 MHz, CDCl3) δ: 5.03 (2H, s), 6.78-6.90 (1H, m), 7.22-7.51 (5H, m), 7.64-7.78 (1H, m), 10.14 (1H, s).
    • b) Preparation of 4-(benzyloxy)-5-bromo-1H-indazole (Compound Q21)
  • To a solution of Compound Q20 (3.0 g) in 1,2-dimethoxyethane (15 mL) were added potassium carbonate (1.47 g) and O-methylhydroxyamine hydrochloride (810 mg), and the mixture was stirred at room temperature for 5 hours. The insoluble matter was removed by filtration and the solvent was evaporated under reduced pressure. To the residue were added 1,2-dimethoxyethane (15 mL) and hydrazine hydrate (15 mL), and the mixture was heated at reflux for 21 hours. The reaction solution was cooled to room temperature, the 1,2-dimethoxyethane layer was washed with brine, the mixture was dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-40:60 as the eluting solvent) to give Compound Q21 (1.37 g).
  • 1H-NMR (300 MHz, CDCl3) δ: 5.40 (2H, s), 7.06-7.16 (1H, m), 7.30-7.62 (6H, m), 8.06 (1H, s), 10.58 (1H, br s).
    • c) Preparation of tert-butyl 4-[4-(benzyloxy)-5-bromo-1H-indazol-1-yl]piperidine-1-carboxylate (Compound Q22)
  • To a suspension of sodium hydride (271 mg) in anhydrous dimethylformamide (20 mL) was added Compound Q21 (1.37 g), and the mixture was stirred at room temperature for 5 minutes. To the reaction solution was added tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (1.89 g), and the mixture was stirred at 80° C. for 2 hours. The reaction solution was cooled to room temperature, water (100 mL) was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-50:50 as the eluting solvent) to give Compound Q22 (1.26 g).
  • 1H-NMR (300 MHz, CDCl3) δ: 1.49 (9H, s), 1.92-2.08 (2H, m), 2.09-2.29 (2H, m), 2.84-3.06 (2H, m), 4.19-4.39 (2H, m), 4.41-4.58 (1H, m), 5.39 (2H, s), 7.00-7.08 (1H, m), 7.28-7.60 (6H, m), 7.99 (1H, s).
    • d) Preparation of tert-butyl 4-[4-(benzyloxy)-5-methyl-1H-indazol-1-yl]piperidine-1-carboxylate (Compound Q23)
  • To a solution of Compound Q22 (1.2 g) and bis(tri-tert-butylphosphine)palladium (63 mg) in anhydrous tetrahydrofuran (12 mL) was added dropwise under nitrogen atmosphere chloromethylzinc (0.5 mol/L in tetrahydrofuran, 1.24 mL), and the mixture was stirred at room temperature for 24 hours. To the reaction solution was added water (50 mL), and the insoluble matter was removed by filtration. The filtrate was extracted with ethyl acetate, the organic layer was dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-50:50 as the eluting solvent) to give Compound Q23 (981 mg).
  • 1H-NMR (300 MHz, CDCl3) δ: 1.92-2.09 (2H, m), 2.11-2.41 (2H, m), 2.32 (3H, s), 2.83-3.10 (2H, m), 4.19-4.61 (3H, m), 5.33 (2H, s), 7.01-7.09 (1H, m), 7.14-7.23 (1H, m), 7.32-7.55 (5H, m), 8.02 (1H, s).
    • e) Preparation of tert-butyl 4-(4-ethoxy-5-methyl-1H-indazol-1-yl)piperidine-1-carboxylate (Compound Q25)
  • To a solution of Compound Q23 (981 mg) in ethanol/ethyl acetate (3/1, 20 mL) was added palladium hydroxide on carbon (100 mg), and the mixture was stirred under hydrogen atmosphere for 16 hours. The reaction solution was filtered through Celite and the filtrate was evaporated under reduced pressure to give Compound Q24 as a crude product. To acetone (10 mL) were added the obtained Compound Q24, potassium carbonate (817 mg) and ethyl iodide (0.284 mL), and the mixture was heated at reflux for 24 hours. The reaction solution was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-20:80 as the eluting solvent) to give Compound Q25 (611 mg).
  • 1H-NMR (300 MHz, CDCl3) δ: 1.46 (3H, t, J=7.1 Hz), 1.94-2.07 (2H, m), 2.13-2.27 (2H, m), 2.32 (3H, s), 2.85-3.04 (2H, m), 4.21-4.43 (2H, m), 4.37 (2H, q, J=7.1 Hz), 4.43-4.55 (1H, m), 6.98-7.04 (1H, m), 7.15-7.20 (1H, m), 8.02 (1H, s).
    • f) Preparation of 4-ethoxy-5-methyl-1-(piperidin-4-yl)-1H-indazole hydrochloride (Reference Example 7)
  • To a solution of Compound Q25 (611 mg) in ethyl acetate (15 mL) was added 4 mol/L HCl-dioxane (1.8 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, the residue was washed with ethyl acetate, and the precipitated crystal was collected by filtration to give Reference Example 7 (420 mg).
  • 1H-NMR (300 MHz, DMSO-D6) δ: 1.36 (3H, t, J=7.0 Hz), 1.98-2.14 (2H, m), 2.17-2.41 (2H, m), 2.23 (3H, s), 2.99-3.22 (2H, m), 3.32-3.50 (2H, m), 4.34 (2H, q, J=7.0 Hz), 4.81-4.98 (1H, m), 7.16-7.29 (2H, m), 8.17 (1H, s), 8.79-9.03 (1H, m), 9.06-9.29 (1H, m).
    • Example 1 N-(trans-4-methoxycyclohexyl)-4-(5-methyl-1H-indazol-1-yl)piperidine-1-carboxamide
  • Figure US20160355511A1-20161208-C00022
  • To a solution of Reference Example 1 (600 mg) in DMF (5 mL) were added trans-phenyl-4-methoxycyclohexane carbamate (564 mg) and diisopropylethylamine (1.24 mL), and the mixture was stirred with heating at 70° C. for 16 hours. Then, the mixture was partitioned between ethyl acetate and water, the organic layer was dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate as the eluting solvent) to give Example 1 (564 mg).
  • 1H-NMR (400 MHz, CDCl3): 1.16 (2H, m), 1.36 (2H, m), 2.06 (6H, m), 2.25 (2H, m), 2.46 (3H, s), 2.93-3.21 (3H, m), 3.35 (3H, s), 3.68 (1H, m), 4.10 (2H, m), 4.28 (1H, m), 4.55 (2H, m), 7.21 (1H, d, J=8.8 Hz), 7.34 (1H, d, J=8.8 Hz), 7.50 (1H, s), 7.90 (1H, s).
    • Example 2 4-(3-ethoxy-5-ethyl-1H-indazol-1-yl)-N-(tetrahydro-2H-pyran-4-yl)piperidine-1-carboxamide
  • Figure US20160355511A1-20161208-C00023
  • To a solution of the above-obtained Reference Example 2 (136 mg) in DMF (3 mL) were added phenyl-4-pyran carbamate (97 mg) and diisopropylethylamine (307 μL), and the mixture was stirred with heating at 70° C. for 16 hours. Then, the mixture was partitioned between ethyl acetate and water, the organic layer was washed with brine and dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate as the eluting solvent) to give Example 2 (71 mg).
  • 1H-NMR (400 MHz, CDCl3): 1.28 (3H, t, J=7.2 Hz), 1.48 (7H, m), 1.99 (2H, m), 2.21 (2H, m), 2.74 (2H, q, J=7.2 Hz), 3.03 (2H, m), 3.51 (2H, m), 3.98 (3H, m), 4.12 (2H, m), 4.30-4.50 (3H, m), 4.58 (1H, m), 7.23 (2H, m), 7.48 (1H, s).
    • Example 3 (4,4-difluorocyclohexyl) (4-(5-ethoxy-1H-indazol-1-yl)piperidin-1-yl)methanone
  • Figure US20160355511A1-20161208-C00024
  • To a solution of the above-obtained Reference Example 3 (25 mg), EDCI-HCl (25 mg), HOBt (17 mg) and diisopropylethylamine (62 μL) in DMF (1.0 mL) was added 4,4-difluorocyclohexanecarboxylic acid (14 mg), and the mixture was stirred at room temperature for 1 day. Then, the mixture was partitioned between dichloromethane and water, the organic layer was washed with brine, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1 as the eluting solvent) to give Example 3 (18 mg).
  • 1H-NMR (400 MHz, CDCl3): 1.38 (3H, t, J=7.0 Hz), 1.87-1.66 (6H, m), 2.16-2.02 (6H, m), 2.56 (1H, s), 2.77 (1H, s), 3.23 (1H, s), 3.99 (3H, q, J=7.0 Hz), 4.53 (1H, m), 4.70 (1H, m), 7.00 (2H, m), 7.26 (1H, m), 7.82 (1H, s).
    • Example 4 N-(cis-4-(5-ethyl-1H-indazol-1-yl)cyclohexyl)-4,4-difluorocyclohexanecarboxamide
  • Figure US20160355511A1-20161208-C00025
  • To a solution of the above-obtained Reference Example 4 (94 mg), EDCI.HCl (95 mg), HOBt (66 mg), and diisopropylethylamine (236 μL) in DMF (2.0 mL) was added 4,4-difluorocyclohexanecarboxylic acid (55 mg), and the mixture was stirred at room temperature for 1 day. Then, the mixture was partitioned between dichloromethane and water, the organic layer was washed with brine, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1 as the eluting solvent) to give Example 4 (72 mg).
  • 1H-NMR (400 MHz, CDCl3): 1.30 (3H, t, J=7.6 Hz), 1.65-2.08 (12H, m), 2.10-2.30 (5H, m), 2.78 (2H, q, J=7.6 Hz), 4.25 (1H, m), 4.51 (1H, m), 5.81 (1H, m), 7.26 (1H, d, J=8.8 Hz), 7.54 (1H, d, J=8.4 Hz), 7.55 (1H, s), 7.96 (1H, s).
    • Example 5 1-(4,4-difluorocyclohexyl)-3-(cis-4-(5-ethyl-1H-indazol-1-yl)cyclohexyl)urea
  • Figure US20160355511A1-20161208-C00026
  • To a solution of the above-obtained Reference Example 4 (131 mg) in DMF (3 mL) were added phenyl 4,4-difluorocyclohexane carbamate (119 mg) and diisopropylethylamine (328 μL), and the mixture was stirred with heating at 70° C. for 16 hours. Then, the mixture was partitioned between ethyl acetate and water, the organic layer was washed with brine and dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate as the eluting solvent) to give Example 5 (24 mg).
  • 1H-NMR (400 MHz, CDCl3): 1.25 (3H, t, J=7.6 Hz), 1.50 (2H, m), 1.70-2.25 (13H, m), 2.75 (2H, q, J=7.6 Hz), 3.65 (1H, m), 4.08 (1H, m), 4.45 (1H, m), 4.55 (1H, m), 5.00 (1H, m), 7.25 (1H, d, J=8.8 Hz), 7.45 (1H, d, J=8.4 Hz), 7.51 (1H, s), 7.93 (1H, s).
    • Example 6 cis-N-(4,4-difluorocyclohexyl)-4-(5-ethyl-1H-indazol-1-yl)cyclohexanecarboxamide
  • Figure US20160355511A1-20161208-C00027
  • To a solution of the above-obtained Reference Example 5 (155 mg), EDCI HCl (107 mg), HOBt (74 mg), and diisopropylethylamine (399 μL) in DMF (3.0 mL) was added 4,4-difluorocyclohexylamine (77 mg), and the mixture was stirred at room temperature for 1 day. Then, the mixture was partitioned between dichloromethane and water, the organic layer was washed with brine, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1 as the eluting solvent) to give Example 6 (127 mg).
  • 1H-NMR (400 MHz, CDCl3): 1.26 (3H, t, J=7.2 Hz), 1.50 (2H, m), 1.70-2.22 (12H, m), 2.30-2.48 (3H, m), 2.72 (2H, q, J=7.2 Hz), 3.92 (1H, m), 4.52 (1H, m), 5.45 (1H, m), 7.21 (1H, d, J=8.8 Hz), 7.37 (1H, d, J=8.8 Hz), 7.49 (1H, s), 7.87 (1H, s).
    • Examples 7 to 101
  • The compounds in Table 1 were prepared in the same manner as Examples 1 to 2 except that the corresponding starting compounds were used.
  • TABLE 1
    Figure US20160355511A1-20161208-C00028
    (LC-MS:
    [M + H]+/Rt LC-MS
    Ex. R1A R1B R1C R1D R3A R3B A n (min)) Method
    7 H H Me H H c-Pen CH 1 327.5/3.71 C
    8 H H Me H H c-Hex CH 1 341.4/3.87 C
    9 H H Me H H
    Figure US20160355511A1-20161208-C00029
         		CH 1 343.4/3.27 C
    10 H H Me H
    Figure US20160355511A1-20161208-C00030
         		CH 1 363.5/3.91 C
    11 H H Me H
    Figure US20160355511A1-20161208-C00031
         		CH 1 357.4/3.56 C
    12 H H Me H H
    Figure US20160355511A1-20161208-C00032
         		CH 1 371.5/3.40 C
    13 H H Me H H
    Figure US20160355511A1-20161208-C00033
         		CH 1 377.6/3.79 C
    14 H H iPr H H
    Figure US20160355511A1-20161208-C00034
         		CH 1 371.5/4.63 A
    15 H H n-Pr H H
    Figure US20160355511A1-20161208-C00035
         		CH 1 371.4/4.63 A
    16 H H Et H H
    Figure US20160355511A1-20161208-C00036
         		CH 1 385.6/4.66 A
    17 H H OEt H H c-Pen CH 1 357.3/0.901 D
    18 H H OEt H H c-Hex CH 1 371.4/0.955 D
    19 H H OEt H H
    Figure US20160355511A1-20161208-C00037
         		CH 1 373.3/0.738 D
    20 H H Et H H c-Pen CH 1 341.3/0.987 D
    21 H H Et H H
    Figure US20160355511A1-20161208-C00038
         		CH 1 385.4/0.899 D
    22 H H Et H H
    Figure US20160355511A1-20161208-C00039
         		CH 1 357.3/0.857 D
    23 H H Et H H
    Figure US20160355511A1-20161208-C00040
         		CH 1 391.3/1.004 D
    24 H H Et H H
    Figure US20160355511A1-20161208-C00041
         		CH 1 357.3/0.828 D
    25 H H
    Figure US20160355511A1-20161208-C00042
         		H H
    Figure US20160355511A1-20161208-C00043
         		CH 1 386.2/4.24 A
    26 H H
    Figure US20160355511A1-20161208-C00044
         		H H
    Figure US20160355511A1-20161208-C00045
         		CH 1 435.6/4.63 A
    27 H H EtO H H
    Figure US20160355511A1-20161208-C00046
         		N 1 407.5/4.54 A
    28 H H F H H
    Figure US20160355511A1-20161208-C00047
         		CH 1 381.3/3.64 C
    29 H H F H H
    Figure US20160355511A1-20161208-C00048
         		CH 1 375.3/3.26 C
    30 H H EtO H H
    Figure US20160355511A1-20161208-C00049
         		CH 1 401.4/3.38 C
    31 H H
    Figure US20160355511A1-20161208-C00050
         		H H c-Pen CH 1 385.4/3.63 C
    32 H H
    Figure US20160355511A1-20161208-C00051
         		H H
    Figure US20160355511A1-20161208-C00052
         		CH 1 429.4/3.38 C
    33 H H Cl H H c-Pen CH 1 347.3/3.79 C
    34 H H Cl H H
    Figure US20160355511A1-20161208-C00053
         		CH 1 397.2/3.87 C
    35 H H Cl H H
    Figure US20160355511A1-20161208-C00054
         		CH 1 391.1/3.52 C
    36
    Figure US20160355511A1-20161208-C00055
         		H Me H H
    Figure US20160355511A1-20161208-C00056
         		CH 1 421.5/4.60 A
    37 H c-Pr H H H
    Figure US20160355511A1-20161208-C00057
         		CH 1 397.0/4.63 A
    38 H H H H H
    Figure US20160355511A1-20161208-C00058
         		CH 1 363.2/3.67 A
    39 H H H H H c-Hex CH 1 327.0/4.19 A
    40 H H OMe H H c-Hex CH 1 356.8/4.21 A
    41 H H OMe H H
    Figure US20160355511A1-20161208-C00059
         		CH 1 393.0/3.68 A
    42 Et H Me H H
    Figure US20160355511A1-20161208-C00060
         		CH 1 405.4/4.86 A
    43 Et H Me H H
    Figure US20160355511A1-20161208-C00061
         		CH 1 371.0/4.57 A
    44 H c-Pr H H H
    Figure US20160355511A1-20161208-C00062
         		CH 1 411.1/4.71 A
    45 Me H Me H H
    Figure US20160355511A1-20161208-C00063
         		CH 1 371.0/4.51 A
    46 H H OiPr H H
    Figure US20160355511A1-20161208-C00064
         		CH 1 421.0/4.63 A
    47 H H OiPr H H
    Figure US20160355511A1-20161208-C00065
         		CH 1 415.5/4.45 A
    48 H H OiPr H H c-Hex CH 1 385.0/4.68 A
    49 H H OiPr H H c-Pen CH 1 371.0/4.54 A
    50 H H H H H
    Figure US20160355511A1-20161208-C00066
         		C—Et 1 391.0/4.47 A
    51 H H H H Et
    Figure US20160355511A1-20161208-C00067
         		CH 1 385.4/4.50 A
    52
    Figure US20160355511A1-20161208-C00068
         		H Me H H
    Figure US20160355511A1-20161208-C00069
         		CH 1 461.4/3.90 C
    53 Et H H H H
    Figure US20160355511A1-20161208-C00070
         		CH 1 391.2/3.91 C
    54 H H
    Figure US20160355511A1-20161208-C00071
         		H H
    Figure US20160355511A1-20161208-C00072
         		CH 1 407.2/3.45 C
    55
    Figure US20160355511A1-20161208-C00073
         		H Me H H
    Figure US20160355511A1-20161208-C00074
         		CH 1 455.5/3.58 C
    56 OEt H Et H H c-Pen CH 1 385.2/2.47 B
    57 OEt H Et H H
    Figure US20160355511A1-20161208-C00075
         		CH 1 429.2/2.29 B
    58 OiPr H Et H H c-Pen CH 1 399.2/1.95 B
    59 OiPr H Et H H
    Figure US20160355511A1-20161208-C00076
         		CH 1 443.2/1.81 B
    60 OEt H Et H H c-Hex CH 1 399.2/2.06 B
    61 OEt H Et H H
    Figure US20160355511A1-20161208-C00077
         		CH 1 435.2/1.99 B
    62 OiPr H Et H H
    Figure US20160355511A1-20161208-C00078
         		CH 1 449.2/2.29 B
    63 OiPr H Et H H
    Figure US20160355511A1-20161208-C00079
         		CH 1 415.2/2.07 B
    64 H Et H H H
    Figure US20160355511A1-20161208-C00080
         		CH 1 391.0/4.65 A
    65 H H Br H H
    Figure US20160355511A1-20161208-C00081
         		CH 1 408.1/4.26 A
    66 H Et H H H
    Figure US20160355511A1-20161208-C00082
         		CH 1 385.5/4.30 A
    67
    Figure US20160355511A1-20161208-C00083
         		H Me H H c-Pen CH 1 371.2/4.57 A
    68
    Figure US20160355511A1-20161208-C00084
         		H Me H H c-Hex CH 1 385.5/4.74 A
    69
    Figure US20160355511A1-20161208-C00085
         		H Me H H
    Figure US20160355511A1-20161208-C00086
         		CH 1 415.5/4.40 A
    70 H H
    Figure US20160355511A1-20161208-C00087
         		H H
    Figure US20160355511A1-20161208-C00088
         		CH 1 457.8/4.96 A
    71 H H Br H H
    Figure US20160355511A1-20161208-C00089
         		CH 1 436.4/4.45 A
    72 H H Et H H
    Figure US20160355511A1-20161208-C00090
         		CH 1 343.5/4.25 A
    73 H H Et H H
    Figure US20160355511A1-20161208-C00091
         		CH 2 405.4/4.89 A
    74 H H c-Pr H H
    Figure US20160355511A1-20161208-C00092
         		CH 1 397.0/4.63 A
    75 H H c-Pr H H
    Figure US20160355511A1-20161208-C00093
         		CH 1 368.9/4.46 A
    76 H H n-Pr H H
    Figure US20160355511A1-20161208-C00094
         		CH 1 399.4/4.85 A
    77 H H c-Pr H H
    Figure US20160355511A1-20161208-C00095
         		CH 1 403.2/4.78 A
    78 H H Me H H
    Figure US20160355511A1-20161208-C00096
         		CH 1 377.5/4.53 A
    79 H H Me H H
    Figure US20160355511A1-20161208-C00097
         		CH 1 377.2/4.51 A
    80 H H Me H H
    Figure US20160355511A1-20161208-C00098
         		CH 1 363.6/4.44 A
    81 H H Me H H
    Figure US20160355511A1-20161208-C00099
         		CH 1 363.3/4.44 A
    82 H H Me H H
    Figure US20160355511A1-20161208-C00100
         		CH 1 377.4/4.57 A
    83 H H Me H H
    Figure US20160355511A1-20161208-C00101
         		CH 1 439.1/4.68 A
    84 H H Et H H
    Figure US20160355511A1-20161208-C00102
         		CH 2 399.0/4.71 A
    85 H H MeO H H
    Figure US20160355511A1-20161208-C00103
         		CH 1 392.8/4.28 A
    86 H H MeO H H
    Figure US20160355511A1-20161208-C00104
         		CH 1 392.8/4.30 A
    87 H H MeO H H
    Figure US20160355511A1-20161208-C00105
         		CH 1 379.0/4.16 A
    88 H H MeO H H
    Figure US20160355511A1-20161208-C00106
         		CH 1 379.0/4.15 A
    89 Me H Me H H
    Figure US20160355511A1-20161208-C00107
         		CH 1 385.4/4.59 A
    90 H H Me H H
    Figure US20160355511A1-20161208-C00108
         		CH 1 385.0/4.57 A
    91 H H Me H H
    Figure US20160355511A1-20161208-C00109
         		CH 1 371.0/4.46 A
    92 H H Et H H
    Figure US20160355511A1-20161208-C00110
         		CH 1 385.4/4.67 A
    93 H Me H H H
    Figure US20160355511A1-20161208-C00111
         		CH 1 377.3/4.54 A
    94 H Me H H H
    Figure US20160355511A1-20161208-C00112
         		CH 1 371.0/4.38 A
    95 H Me H H H
    Figure US20160355511A1-20161208-C00113
         		CH 1 371.0/4.41 A
    96 H Me H H H
    Figure US20160355511A1-20161208-C00114
         		CH 1 385.4/4.51 A
    97 H Me H H H
    Figure US20160355511A1-20161208-C00115
         		CH 1 407.2/4.54 A
    98 H Br H H H
    Figure US20160355511A1-20161208-C00116
         		CH 1 435.1/4.63 A
    99 H H Et H H
    Figure US20160355511A1-20161208-C00117
         		N 1 392.0/4.49 A
    100 H H Et H H
    Figure US20160355511A1-20161208-C00118
         		N 1 386.2/4.31 A
    101 H H Et H H
    Figure US20160355511A1-20161208-C00119
         		N 1 358.0/4.09 A
    • Examples 102 to 118
  • The compounds in Table 2 were prepared in the same manner as Example 3 except that the corresponding starting compounds were used.
  • TABLE 2
    Figure US20160355511A1-20161208-C00120
    (LC-MS:
    [M + LC-MS
    H]+/Rt Meth-
    Ex. R1C R4 (min)) od
    102 Br
    Figure US20160355511A1-20161208-C00121
         		394.0/4.01 A
    103
    Figure US20160355511A1-20161208-C00122
    Figure US20160355511A1-20161208-C00123
         		370.3/4.70 A
    104 F
    Figure US20160355511A1-20161208-C00124
         		332.4/3.89 A
    105 Me c-Hex 326.5/4.08 C
    106 Me c-Pen 312.3/3.93 C
    107 iPr
    Figure US20160355511A1-20161208-C00125
         		356.2/4.66 A
    108 n-Pr
    Figure US20160355511A1-20161208-C00126
         		356.3/4.65 A
    109 OEt c-Hex 356.3/1.01 C
    110 OEt c-Pen 342.3/0.959 C
    111 Et
    Figure US20160355511A1-20161208-C00127
         		342.3/0.868 C
    112 OEt
    Figure US20160355511A1-20161208-C00128
         		368.1/3.79 C
    113 Et
    Figure US20160355511A1-20161208-C00129
         		376.4/4.57 A
    114 OEt
    Figure US20160355511A1-20161208-C00130
         		369.2/4.28 A
    115 OiPr
    Figure US20160355511A1-20161208-C00131
         		383.0/4.39 A
    116 OiPr
    Figure US20160355511A1-20161208-C00132
         		406.3/4.55 A
    117 Et
    Figure US20160355511A1-20161208-C00133
         		370.2/3.86 C
    118 Et
    Figure US20160355511A1-20161208-C00134
         		353.3/3.74 C
    • Examples 119 to 126
  • The compounds in Table 3 were prepared in the same manner as Examples 4 and 5 except that the corresponding starting compounds were used.
  • TABLE 3
    Figure US20160355511A1-20161208-C00135
    (LC-MS:
    [M + H]+/Rt LC-MS
    Ex. R1A R1C R4 (min)) Method
    119 H Et c-Hex 354.1/2.18 B
    120 H Et
    Figure US20160355511A1-20161208-C00136
         		356.1/1.88 B
    121 H Et
    Figure US20160355511A1-20161208-C00137
         		328.1/2.11 B
    122 H Et
    Figure US20160355511A1-20161208-C00138
         		384.1/2.00 B
    123 H Et
    Figure US20160355511A1-20161208-C00139
         		340.1/2.11 B
    124 H Et
    Figure US20160355511A1-20161208-C00140
         		384.1/2.04 B
    125
    Figure US20160355511A1-20161208-C00141
         		Me
    Figure US20160355511A1-20161208-C00142
         		414.4/4.86 A
    126
    Figure US20160355511A1-20161208-C00143
         		Me
    Figure US20160355511A1-20161208-C00144
         		420.1/4.92 A
    • Examples 127 to 131
  • The compounds in Table 4 were prepared in the same manner as Example 6 except that the corresponding starting compounds were used.
  • TABLE 4
    Figure US20160355511A1-20161208-C00145
    (LC-MS:
    [M + H]+/Rt LC-MS
    Ex. R1C R3A R3B (min)) Method
    127 Et H c-Hex 354.2/2.32 B
    128 Et H c-Pen 340.1/2.10 B
    129 Et H
    Figure US20160355511A1-20161208-C00146
         		356.2/2.04 B
    130 Et H
    Figure US20160355511A1-20161208-C00147
         		384.2/1.85 B
    131 Et H
    Figure US20160355511A1-20161208-C00148
         		327.2/2.31 B
    • Examples 132 to 141
  • The compounds in Table 5 were prepared in the same manner as Example 3 except that the corresponding starting compounds were used.
  • TABLE 5
    Figure US20160355511A1-20161208-C00149
    (LC-MS:
    [M + H]+/Rt LC-MS
    Ex. R1A R1B R1C R4 (min)) Method
    132 H H OEt
    Figure US20160355511A1-20161208-C00150
         		418.8/4.63 A
    133 H H Me
    Figure US20160355511A1-20161208-C00151
         		362.1/4.48 A
    134 H H F
    Figure US20160355511A1-20161208-C00152
         		366.0/4.32 A
    135
    Figure US20160355511A1-20161208-C00153
         		H Me
    Figure US20160355511A1-20161208-C00154
         		406.7/4.48 A
    136
    Figure US20160355511A1-20161208-C00155
         		H Et
    Figure US20160355511A1-20161208-C00156
         		420.0/4.69 A
    137 H H H
    Figure US20160355511A1-20161208-C00157
         		348.1/4.27 A
    138 H H Me
    Figure US20160355511A1-20161208-C00158
         		362.0/4.56 A
    139 H Et H
    Figure US20160355511A1-20161208-C00159
         		376.1/4.66 A
    140 H H c-Pr
    Figure US20160355511A1-20161208-C00160
         		354.4/4.42 A
    141 H H c-Pr
    Figure US20160355511A1-20161208-C00161
         		382.5/4.63 A
    • Examples 142 and 143
  • The compounds in Table 6 were prepared in the same manner as Examples 1 and 2 except that the corresponding starting compounds were used.
  • TABLE 6
    Figure US20160355511A1-20161208-C00162
    (LC-MS:
    [M + H]+/Rt LC-MS
    Ex. R1C R4 (min)) Method
    142 Et
    Figure US20160355511A1-20161208-C00163
         		383.1/1.93 B
    143 Et
    Figure US20160355511A1-20161208-C00164
         		417.2/1.83 B
    • Example 144 N-(trans-4-methoxycyclohexyl)-4-[5-(2H3)methyl-1H-indazol-1-yl]piperidine-1-carboxamide
  • Figure US20160355511A1-20161208-C00165
  • To a solution of Reference Example 6 (225 mg) in acetonitrile (5 mL) were added trans-phenyl-4-methoxycyclohexane carbamate (176 mg) and diisopropylethylamine (0.62 mL), and the mixture was stirred with heating at 80° C. for 16 hours. Then, the mixture was partitioned between ethyl acetate and water, the organic layer was dried over Na2SO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate as the eluting solvent) to give Example 144 (127 mg).
  • 1H-NMR (400 MHz, CDCl3): 1.16 (2H, m), 1.36 (2H, m), 2.07 (6H, m), 2.25 (2H, m), 2.46 (3H, s), 2.97-3.07 (2H, m), 3.13 (1H, m), 3.35 (3H, s), 3.68 (1H, m), 4.11 (2H, m), 4.31 (1H, m), 4.55 (2H, m), 7.21 (1H, dd, J=1.7 Hz, 8.6 Hz), 7.34 (1H, d, J=8.8 Hz), 7.50 (1H, m), 7.90 (1H, s). LC-MS: [M+H]+/Rt (min)=374.4/4.63 (Method A)
    • Example 145 4-(4-ethoxy-5-methyl-1H-indazol-1-yl)-N-(trans-4-methoxycyclohexyl)piperidine-1-carboxamide
  • Figure US20160355511A1-20161208-C00166
  • To a solution of Reference Example 7 (89 mg) and diisopropylethylamine (0.156 mL) in acetonitrile (4 mL) was added trans-phenyl-4-methoxycyclohexane carbamate (75 mg), and the mixture was stirred at 80° C. for 17 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=40:60-1:100 as the eluting solvent) and then recrystallized (ethyl acetate:hexane) to give Example 145 (61 mg).
  • 1H-NMR (300 MHz, CDCl3) δ: 1.04-1.56 (4H, m), 1.46 (3H, t, J=7.0 Hz), 1.94-2.41 (8H, m), 2.32 (3H, s), 2.92-3.21 (3H, m), 3.35 (3H, s), 3.59-3.77 (1H, m), 4.02-4.18 (2H, m), 4.29 (1H, d, J=7.2 Hz), 4.37 (2H, q, J=7.0 Hz), 4.43-4.60 (1H, m), 6.96-7.04 (1H, m), 7.13-7.21 (1H, m), 8.01 (1H, s).
    • Examples 146 to 303
  • The compounds in Table 7 were prepared in the same manner as Examples 1, 2, 144 and 145 except that the corresponding starting compounds were used.
  • TABLE 7
    Figure US20160355511A1-20161208-C00167
    (LC-MS:
    [M +
    H]+/Rt LC-MS
    Ex. R1A R1B R1C R1D R3A R3B (min)) Method
    146 OMe H Me H H
    Figure US20160355511A1-20161208-C00168
         		357.2/1.61 B
    147 OMe H Me H H
    Figure US20160355511A1-20161208-C00169
         		401.2/1.47 B
    148 OMe H Me H H
    Figure US20160355511A1-20161208-C00170
         		373.2/1.15 B
    149 OMe H Et H H
    Figure US20160355511A1-20161208-C00171
         		421.0/2.41 B
    150 OMe H Et H H
    Figure US20160355511A1-20161208-C00172
         		387.1/2.14 B
    151 OMe H Et H H c-Hex 385.1/1.83 B
    152 OMe H Et OMe H c-Pen 371.1/1.70 B
    153 OiPr H Et H H c-Hex 413.1/2.37 B
    154 H H Me H H
    Figure US20160355511A1-20161208-C00173
         		407/1.030 F
    155 H H
    Figure US20160355511A1-20161208-C00174
         		H H
    Figure US20160355511A1-20161208-C00175
         		451/1.084 F
    156 H H
    Figure US20160355511A1-20161208-C00176
         		H H
    Figure US20160355511A1-20161208-C00177
         		469/1.170 F
    157
    Figure US20160355511A1-20161208-C00178
         		H Et H H
    Figure US20160355511A1-20161208-C00179
         		435/1.116 F
    158 H Et H H H
    Figure US20160355511A1-20161208-C00180
         		385.4/4.65 A
    159 H Et H H H
    Figure US20160355511A1-20161208-C00181
         		421.1/4.70 A
    160 H c-Pr H H H
    Figure US20160355511A1-20161208-C00182
         		397.0/4.68 A
    161 H c-Pr H H H
    Figure US20160355511A1-20161208-C00183
         		403.4/4.84 A
    162 H H Me H H
    Figure US20160355511A1-20161208-C00184
         		411/1.057 F
    163 H H CF3 H H
    Figure US20160355511A1-20161208-C00185
         		424.5/4.59 A
    164 H H CF3 H H
    Figure US20160355511A1-20161208-C00186
         		431.4/471 A
    165 H
    Figure US20160355511A1-20161208-C00187
         		H H H c-Hex 371.1/1.99 B
    166 H
    Figure US20160355511A1-20161208-C00188
         		H H H
    Figure US20160355511A1-20161208-C00189
         		407.1/1.93 B
    167 H
    Figure US20160355511A1-20161208-C00190
         		H H H c-Hex 385.2/2.10 B
    168 H
    Figure US20160355511A1-20161208-C00191
         		Et H H
    Figure US20160355511A1-20161208-C00192
         		421.1/2.04 B
    169 H CF3 H H H
    Figure US20160355511A1-20161208-C00193
         		431.1/1.84 B
    170 H H Me H H
    Figure US20160355511A1-20161208-C00194
         		385/1.045 F
    171 H H c-Pr H H c-Pen 353/1.101 F
    172 H H c-Pr H H t-Bu 341/1.123 F
    173 H H c-Pr H
    Figure US20160355511A1-20161208-C00195
         		353/1.215 D
    174 H H c-Pr H
    Figure US20160355511A1-20161208-C00196
         		355/0.962 F
    175 H H c-Pr H H
    Figure US20160355511A1-20161208-C00197
         		381/1.183 F
    176 H H c-Pr H H c-Pr 325/0.929 F
    177 H H c-Pr H H
    Figure US20160355511A1-20161208-C00198
         		369/0.940 F
    178 H H CF3 H H
    Figure US20160355511A1-20161208-C00199
         		428/1.93 E
    179 H H c-Pr H H
    Figure US20160355511A1-20161208-C00200
         		411/1.131 F
    180 H OiPr H H H c-Hex 385.2/2.46 B
    181 H OMe H H H c-Hex 357.1/2.21 B
    182 H OMe H H H
    Figure US20160355511A1-20161208-C00201
         		393.1/2.15 B
    183 H OiPr H H H
    Figure US20160355511A1-20161208-C00202
         		421.1/2.39 B
    184 H OEt H H H
    Figure US20160355511A1-20161208-C00203
         		401.2/1.95 B
    185 H H c-Pr H H c-Bu 339/1.107 F
    186 H H c-Pr H H
    Figure US20160355511A1-20161208-C00204
         		411/1.014 F
    187 H H c-Pr H H
    Figure US20160355511A1-20161208-C00205
         		430/1.127 F
    188 H H c-Pr H
    Figure US20160355511A1-20161208-C00206
         		389/1.175 D
    189 H H c-Pr H H
    Figure US20160355511A1-20161208-C00207
         		397.4/4.61 A
    190 H F H H H
    Figure US20160355511A1-20161208-C00208
         		381.1/1.58 B
    191 H OEt H H H c-Hex 371.1/2.35 B
    192 H OEt H H H
    Figure US20160355511A1-20161208-C00209
         		407.2/2.28 B
    193 H H c-Pr H H
    Figure US20160355511A1-20161208-C00210
         		405/1.091 F
    194 H H c-Pr H H
    Figure US20160355511A1-20161208-C00211
         		375/1.105 F
    195 H H c-Pr H H
    Figure US20160355511A1-20161208-C00212
         		443/1.221 F
    196 H H
    Figure US20160355511A1-20161208-C00213
         		H H
    Figure US20160355511A1-20161208-C00214
         		440/0.714 F
    197 H H H c-Pr H
    Figure US20160355511A1-20161208-C00215
         		397.3/4.55 A
    198 H H CN H H
    Figure US20160355511A1-20161208-C00216
         		388.3/4.16 A
    199 H H c-Pr H H c-Hex 367/1.219 F
    200 H H c-Pr H H
    Figure US20160355511A1-20161208-C00217
         		339/0.981 F
    201 H OCHF2 H H H
    Figure US20160355511A1-20161208-C00218
         		429.2/2.06 B
    202 H OCHF2 H H H
    Figure US20160355511A1-20161208-C00219
         		423.2/1.93 B
    203 H H c-Pr H H
    Figure US20160355511A1-20161208-C00220
         		410/0.857 F
    204 H H c-Pr H H
    Figure US20160355511A1-20161208-C00221
         		397/1.022 F
    205 H H c-Pr H H
    Figure US20160355511A1-20161208-C00222
         		433/1.127 F
    206 H H c-Pr H H
    Figure US20160355511A1-20161208-C00223
         		431/1.102 F
    207 H H
    Figure US20160355511A1-20161208-C00224
         		H H
    Figure US20160355511A1-20161208-C00225
         		421.3/4.34 A
    208 OiPr H Me H H
    Figure US20160355511A1-20161208-C00226
         		401/1.742 E
    209 OCHF2 H Et H H
    Figure US20160355511A1-20161208-C00227
         		423/1.694 E
    210 H H c-Pr H H
    Figure US20160355511A1-20161208-C00228
         		397/0.970 F
    211 H H c-Pr H H
    Figure US20160355511A1-20161208-C00229
         		397/1.019 F
    212 H H Me H H
    Figure US20160355511A1-20161208-C00230
         		371/0.950 F
    213 H
    Figure US20160355511A1-20161208-C00231
         		Me H H
    Figure US20160355511A1-20161208-C00232
         		421/0.962 F
    214 H
    Figure US20160355511A1-20161208-C00233
         		Me H H
    Figure US20160355511A1-20161208-C00234
         		415/0.871 F
    215 H
    Figure US20160355511A1-20161208-C00235
         		c-Pr H H
    Figure US20160355511A1-20161208-C00236
         		447/1.046 F
    216 H
    Figure US20160355511A1-20161208-C00237
         		c-Pr H H
    Figure US20160355511A1-20161208-C00238
         		441/0.957 F
    217 H H c-Pr H H
    Figure US20160355511A1-20161208-C00239
         		375/1.015 F
    218 H H Me H H
    Figure US20160355511A1-20161208-C00240
         		349/0.949 F
    219 H H OCF3 H H
    Figure US20160355511A1-20161208-C00241
         		441/1.62 E
    220 H H Me H H
    Figure US20160355511A1-20161208-C00242
         		385.5/4.59 A
    221 H H c-Pr H H
    Figure US20160355511A1-20161208-C00243
         		411.5/4.75 A
    222 H F Me H H
    Figure US20160355511A1-20161208-C00244
         		395/1.051 F
    223 H F Me H H
    Figure US20160355511A1-20161208-C00245
         		389/0.961 F
    224 H H
    Figure US20160355511A1-20161208-C00246
         		H H
    Figure US20160355511A1-20161208-C00247
         		432/1.52 E
    225 H Me Me H H
    Figure US20160355511A1-20161208-C00248
         		385/0.963 F
    226 H H OCF3 H H
    Figure US20160355511A1-20161208-C00249
         		444/1.96 E
    227 H H OCF3 H H
    Figure US20160355511A1-20161208-C00250
         		413/1.51 E
    228 H H OCF3 H H
    Figure US20160355511A1-20161208-C00251
         		455/1.71 E
    229 H H OCF3 H H c-Pen 397/1.75 E
    230 H H
    Figure US20160355511A1-20161208-C00252
         		H H
    Figure US20160355511A1-20161208-C00253
         		413/0.941 F
    231 H
    Figure US20160355511A1-20161208-C00254
         		H H H
    Figure US20160355511A1-20161208-C00255
         		421/0.980 F
    232 H
    Figure US20160355511A1-20161208-C00256
         		Me H H
    Figure US20160355511A1-20161208-C00257
         		435/1.035 F
    233 H
    Figure US20160355511A1-20161208-C00258
         		Me H H
    Figure US20160355511A1-20161208-C00259
         		429/0.944 F
    234 H H OEt H H
    Figure US20160355511A1-20161208-C00260
         		415/1.90 E
    235 H H OiPr H H
    Figure US20160355511A1-20161208-C00261
         		429/1.95 E
    236 H H F H H
    Figure US20160355511A1-20161208-C00262
         		389/1.80 E
    237 H H Cl H H
    Figure US20160355511A1-20161208-C00263
         		405/2.00 E
    238 H H Br H H
    Figure US20160355511A1-20161208-C00264
         		450/2.00 E
    239 H H
    Figure US20160355511A1-20161208-C00265
         		H H
    Figure US20160355511A1-20161208-C00266
         		421/1.80 E
    240 Et H OMe H H
    Figure US20160355511A1-20161208-C00267
         		415/1.872 E
    241 Et H OMe H H
    Figure US20160355511A1-20161208-C00268
         		421/1.960 E
    242 Me H OMe H H
    Figure US20160355511A1-20161208-C00269
         		401/1.761 E
    243 Me H OMe H H
    Figure US20160355511A1-20161208-C00270
         		407/1.863 E
    244 Et H OMe H H
    Figure US20160355511A1-20161208-C00271
         		387.0/0.879 F
    245 H H
    Figure US20160355511A1-20161208-C00272
         		H H
    Figure US20160355511A1-20161208-C00273
         		415.3/4.52 A
    246 H H
    Figure US20160355511A1-20161208-C00274
         		H H
    Figure US20160355511A1-20161208-C00275
         		427/1.75 E
    247 H H
    Figure US20160355511A1-20161208-C00276
         		H H
    Figure US20160355511A1-20161208-C00277
         		429/1.73 E
    248 H H
    Figure US20160355511A1-20161208-C00278
         		H H
    Figure US20160355511A1-20161208-C00279
         		433/1.78 E
    249 H H
    Figure US20160355511A1-20161208-C00280
         		H H
    Figure US20160355511A1-20161208-C00281
         		419/1.094 F
    250 H
    Figure US20160355511A1-20161208-C00282
         		H H H
    Figure US20160355511A1-20161208-C00283
         		419/1.075 F
    251 H H
    Figure US20160355511A1-20161208-C00284
         		H H
    Figure US20160355511A1-20161208-C00285
         		435/1.83 E
    252 H H
    Figure US20160355511A1-20161208-C00286
         		H H
    Figure US20160355511A1-20161208-C00287
         		435/1.86 E
    253 H OMe Me H H
    Figure US20160355511A1-20161208-C00288
         		401/1.802 E
    254 H OMe Me H H
    Figure US20160355511A1-20161208-C00289
         		405/1.871 E
    255 H OMe Et H H
    Figure US20160355511A1-20161208-C00290
         		415/1.913 E
    256 H OMe Et H H
    Figure US20160355511A1-20161208-C00291
         		421/1.986 E
    257 c-Pr H OMe H H
    Figure US20160355511A1-20161208-C00292
         		427/0.901 F
    258 OMe H Me H H c-Hex 371.1/1.75 B
    259
    Figure US20160355511A1-20161208-C00293
         		H OMe H H
    Figure US20160355511A1-20161208-C00294
         		475/0.920 F
    260
    Figure US20160355511A1-20161208-C00295
         		H OMe H H
    Figure US20160355511A1-20161208-C00296
         		469/0.849 F
    261
    Figure US20160355511A1-20161208-C00297
         		H OMe H H
    Figure US20160355511A1-20161208-C00298
         		477/1.001 F
    262
    Figure US20160355511A1-20161208-C00299
         		H OMe H H
    Figure US20160355511A1-20161208-C00300
         		471/0.946 F
    263 H OMe c-Pr H H
    Figure US20160355511A1-20161208-C00301
         		427/0.907 F
    264 OMe H OCF3 H H
    Figure US20160355511A1-20161208-C00302
         		443/2.05 E
    265 OEt H OCF3 H H
    Figure US20160355511A1-20161208-C00303
         		457/2.13 E
    266 OMe H CF3 H H
    Figure US20160355511A1-20161208-C00304
         		427/2.00 E
    267 OEt H CF3 H H
    Figure US20160355511A1-20161208-C00305
         		441/2.11 E
    268 H OMe Me H H
    Figure US20160355511A1-20161208-C00306
         		373/0.880 F
    269 H OEt Me H H
    Figure US20160355511A1-20161208-C00307
         		421/1.090 F
    270 OMe H Me H H
    Figure US20160355511A1-20161208-C00308
         		407.2/1.67 B
    271 H OEt Et H H
    Figure US20160355511A1-20161208-C00309
         		435/1.259 F
    272 H OEt Et H H
    Figure US20160355511A1-20161208-C00310
         		429/1.101 F
    273 H OEt Me H H
    Figure US20160355511A1-20161208-C00311
         		387/0.970 F
    274 H OEt Et H H
    Figure US20160355511A1-20161208-C00312
         		401/1.017 F
    275 H OMe Et H H
    Figure US20160355511A1-20161208-C00313
         		387/0.917 F
    276 H Me c-Pr H H
    Figure US20160355511A1-20161208-C00314
         		417/1.148 F
    277 H Me c-Pr H H
    Figure US20160355511A1-20161208-C00315
         		411/1.094 F
    278 H Me OMe H H
    Figure US20160355511A1-20161208-C00316
         		407/1.066 F
    279 H Me OMe H H
    Figure US20160355511A1-20161208-C00317
         		401/0.935 F
    280 H c-Pr OMe H H
    Figure US20160355511A1-20161208-C00318
         		433/1.106 F
    281 H Me OEt H H
    Figure US20160355511A1-20161208-C00319
         		421/1.082 F
    282 H Me OEt H H
    Figure US20160355511A1-20161208-C00320
         		415/1.010 F
    283 H Me c-Pr H H
    Figure US20160355511A1-20161208-C00321
         		383/0.975 F
    284 H OMe Br H H
    Figure US20160355511A1-20161208-C00322
         		472/1056 F
    285 H OMe Br H H
    Figure US20160355511A1-20161208-C00323
         		466/0.976 F
    286 H Me Br H H
    Figure US20160355511A1-20161208-C00324
         		456/1.131 F
    287 H Et OMe H H
    Figure US20160355511A1-20161208-C00325
         		421/1.117 F
    288 H Et OMe H H
    Figure US20160355511A1-20161208-C00326
         		415/0.965 F
    289 H Et OMe H H
    Figure US20160355511A1-20161208-C00327
         		387/0.912 F
    290 H H OCHF2 H H
    Figure US20160355511A1-20161208-C00328
         		429/1000 F
    291 H H OCHF2 H H
    Figure US20160355511A1-20161208-C00329
         		423/0.936 F
    292 H H OCHF2 H H
    Figure US20160355511A1-20161208-C00330
         		395/0.848 F
    293 H Me OCHF2 H H
    Figure US20160355511A1-20161208-C00331
         		437/0.967 F
    294 H Me OCHF2 H H
    Figure US20160355511A1-20161208-C00332
         		409/0.894 F
    295 H H Me H H
    Figure US20160355511A1-20161208-C00333
         		374/1.84 E
    296 H H c-Pr H H
    Figure US20160355511A1-20161208-C00334
         		400/1.98 E
    297 H H CF3 H H
    Figure US20160355511A1-20161208-C00335
         		397.2/4.62 A
    298 H H CF3 H H
    Figure US20160355511A1-20161208-C00336
         		367.2/4.82 A
    299 H H OCF3 H H
    Figure US20160355511A1-20161208-C00337
         		383.0/4.91 A
    300 H H OCF3 H H
    Figure US20160355511A1-20161208-C00338
         		413.7/4.79 A
    301 H H OCF3 H H
    Figure US20160355511A1-20161208-C00339
         		399.7/4.67 A
    302 H H H H H
    Figure US20160355511A1-20161208-C00340
         		399.7/4.69 A
    303 H OMe c-Pr H H
    Figure US20160355511A1-20161208-C00341
         		399/0.951 F
    304 H OCF3 H H H
    Figure US20160355511A1-20161208-C00342
         		413.0/0.971 F
    305 H OMe OMe H H
    Figure US20160355511A1-20161208-C00343
         		423/0.971 F
    306 H OMe OMe H H
    Figure US20160355511A1-20161208-C00344
         		417/0.781 F
    307 H Et H H H
    Figure US20160355511A1-20161208-C00345
         		388/1.925 E
    308 H H CD3 H H
    Figure US20160355511A1-20161208-C00346
         		377/1.808 E
    309 OCD3 H CF3 H H
    Figure US20160355511A1-20161208-C00347
         		430/1.992 E
    310 OCD3 H CF3 H H
    Figure US20160355511A1-20161208-C00348
         		464/2.150 E
    311 H H CD3 H H
    Figure US20160355511A1-20161208-C00349
         		380/1.850 E
    312 H H CD3 H H
    Figure US20160355511A1-20161208-C00350
         		380/1.815 E
    313 H H CD3 H H
    Figure US20160355511A1-20161208-C00351
         		380/1.850 E
    314 H H CD3 H H
    Figure US20160355511A1-20161208-C00352
         		388/1.867 E
    315 H H CD3 H H c-Pen 330/1.858 E
    316
    Figure US20160355511A1-20161208-C00353
         		H Me H H
    Figure US20160355511A1-20161208-C00354
         		458/1.942 E
    317 H OMe CF3 H H
    Figure US20160355511A1-20161208-C00355
         		455/0.867 F
    318 H OMe Et H H
    Figure US20160355511A1-20161208-C00356
         		418/1.942 E
    319 H H OCD3 H H
    Figure US20160355511A1-20161208-C00357
         		396/0.988 F
    320 H H OCD3 H H
    Figure US20160355511A1-20161208-C00358
         		396/0.960 F
    321 H H OCD3 H H
    Figure US20160355511A1-20161208-C00359
         		396/0.948 F
    322 H H Oc-Pr H H
    Figure US20160355511A1-20161208-C00360
         		416/0.948 F
    323 H OCD3 c-Pr H H
    Figure US20160355511A1-20161208-C00361
         		402/0.943 F
    324 H H OCD3 H H c-Hex 360/0.976 F
    325 H H Et H H
    Figure US20160355511A1-20161208-C00362
         		388/1.942 E
    326 H H OCHF2 H H
    Figure US20160355511A1-20161208-C00363
         		426/1.692 E
    • Test Example
  • Hereinafter, pharmacological test results of the representative compounds of the present invention are demonstrated and pharmacological actions of such compounds are explained, but the present invention should not be limited thereto.
    • Test Example 1 Evaluation of PAM Activity with Human 07 nACh Receptor Stably Expressing Cells
  • (1) Human α7 nAChR Stably Expressing Cells
  • Human α7 nAChR stably expressing cells were generated and cultured. In detail, GH4C1 cells derived from rat pituitary (cat#CCL-82.2, ATCC, USA) were used as a host cell. PcDNA3.1Zeo vector containing a nucleotide sequence encoding a protein GenBank BAC81731 and pcDNA3.1 vector containing human α7 nAChR gene (cat#V790-20, invitrogen, Carlsbad, Calif., USA) were transfected to the cells to give aequorins and human α7 nAChR stably expressing cells respectively. The aequorins and human α7 nAChR stably expressing cells were screened with Zeocin (cat#R25001, invitrogen, Carlsbad, Calif., USA) and Geneticin (cat#10131-027, invitrogen, Carlsbad, Calif., USA) respectively.
  • The cells were cultured in F-10 Nutrient Mixture (Ham) medium (cat#11550-043, invitrogen, Carlsbad, Calif., USA) containing 2.5% fetal bovine serum (cat#2917354, ICN Biomedicals, Inc, USA), 15% inactivated horse serum (cat#26050-088, invitrogen, Carlsbad, Calif., USA), 1 μg/mL Geneticin, and 5 μg/mL Puromycin (cat#14861-84, invitrogen, Carlsbad, Calif., USA), in a Collagen Type 1-coated dish (cat#4030-010, iwaki, Tokyo, Japan). During the culture, the medium was replaced with fresh medium in every 2 to 3 days, and the cells were treated with TrypLE Express (cat#45604-021, invitrogen, Carlsbad, Calif., USA) to collect them in every 7 days. Thus, the cells were subcultured.
  • 7 Days after subculturing, the cells were treated with TrypLE Express to collect them when they were about 80% confluent. The cells were suspended in a reaction medium containing Hanks (cat#14065-056, invitrogen, Carlsbad, Calif., USA)/20 mmol/L Hepes (cat#15630-080, invitrogen, Carlsbad, Calif., USA), Buffer (pH 7.4), F-10 Nutrient Mixture (Ham), and 0.1 mg/mL Geneticin, and the suspension was seeded in a 384-well plate (cat#781090, Greiner, Germany) at 20000 cells/25 μL per well.
  • On the next day after seeding, Viviren (cat#E649X, Promega, Madison, Wis., USA) was added to the medium so that the final concentration could be 4 μmol/L (15 μL/well). The plates were centrifuged and then placed in the dark for 4 hours at room temperature.
    • (2) Preparation of the Test Samples
  • Each of the test compounds was dissolved in DMSO to prepare each test sample at a concentration of 1000-fold the final concentration. To the solution was added Hanks/20 mM HEPES/0.2% BSA (cat#A3803, Sigma, St. Louis, Mo., USA), and the concentration was adjusted to 6-fold the final concentration.
    • (3) Evaluation of PAM Activity
  • FDSS7000 (Hamamatsu Photonics) was used to detect the luminescence signal evoked by α7 nAChR stimulation. The cells and a luminescent substrate were put on a plate, and the test sample was added thereto. After 150 seconds, ACh whose concentration shows 20% (EC20) of the maximal signal was added thereto. After the addition of ACh, the luminescence signal (the central wavelength: 465 nm) was measured for 138 seconds to calculate RLU (Max−Min). The ratio of the RLU (Max−Min) of the test-compound-containing wells to that of the control wells was defined as PAM activity. Table 8 shows α7 PAM activity data of the representative compounds in the present invention.
  • TABLE 8
    α7PAM
    (%)
    @ 10
    Ex. μmol/L
    1 1209
    2 625
    3 512
    4 2344
    5 1368
    6 285
    7 1044
    8 3053
    9 332
    10 355
    11 221
    12 231
    13 3399
    14 728
    15 1025
    16 1764
    17 2469
    18 6779
    19 306
    20 2215
    21 523
    22 1425
    23 6196
    24 745
    25 253
    26 521
    27 1673
    28 340
    29 206
    30 908
    31 1191
    32 430
    33 430
    34 445
    35 411
    36 897
    37 481
    38 1101
    39 1892
    40 3205
    41 3749
    42 241
    43 528
    44 322
    45 1576
    46 544
    47 375
    48 1202
    49 429
    50 219
    51 295
    52 366
    53 309
    54 657
    55 603
    56 676
    57 382
    58 577
    59 433
    60 846
    61 1092
    62 653
    63 358
    64 1133
    65 385
    66 466
    67 436
    68 430
    69 242
    70 719
    71 763
    72 158
    73 453
    74 1226
    75 621
    76 420
    77 1780
    78 987
    79 1064
    80 1033
    81 819
    82 888
    83 420
    84 179
    85 1081
    86 1481
    87 514
    88 1063
    89 1506
    90 1467
    91 217
    92 356
    93 934
    94 154
    95 133
    96 143
    97 117
    98 89
    99 755
    100 198
    101 338
    102 228
    103 281
    104 190
    105 338
    106 164
    107 159
    108 207
    109 267
    110 291
    111 410
    112 265
    113 654
    114 189
    115 182
    116 279
    117 209
    118 188
    119 2154
    120 654
    121 1601
    122 410
    123 1445
    124 1230
    125 119
    126 118
    127 806
    128 429
    129 325
    130 252
    131 107
    132 361
    133 568
    134 237
    135 310
    136 327
    137 328
    138 642
    139 1018
    140 265
    141 448
    142 238
    143 574
    144 637
    145 804
    146 513
    147 181
    148 412
    149 1053
    150 643
    151 746
    152 707
    153 386
    154 811
    155 210
    156 358
    157 366
    158 292
    159 187
    160 207
    161 567
    162 1874
    163 318
    164 979
    165 442
    166 711
    167 434
    168 737
    169 359
    170 1413
    171 1382
    172 541
    173 263
    174 186
    175 223
    176 187
    177 712
    178 524
    179 788
    180 274
    181 538
    182 742
    183 342
    184 200
    185 494
    186 389
    187 220
    188 231
    189 257
    190 256
    191 493
    192 699
    193 889
    194 278
    195 232
    196 229
    197 184
    198 268
    199 1497
    200 471
    201 370
    202 195
    203 271
    204 193
    205 1187
    206 196
    207 335
    208 328
    209 266
    210 209
    211 1034
    212 1184
    213 800
    214 207
    215 851
    216 271
    217 517
    218 648
    219 238
    220 2160
    221 1942
    222 638
    223 257
    224 286
    225 480
    226 594
    227 768
    228 276
    229 689
    230 621
    231 647
    232 860
    233 307
    234 824
    235 611
    236 331
    237 832
    238 1031
    239 485
    240 833
    241 358
    242 901
    243 842
    244 324
    245 182
    246 364
    247 353
    248 851
    249 1463
    250 1215
    251 868
    252 364
    253 563
    254 1238
    255 1096
    256 1668
    257 801
    258 941
    259 309
    260 428
    261 924
    262 348
    263 749
    264 263
    265 181
    266 448
    267 292
    268 361
    269 835
    270 364
    271 931
    272 442
    273 341
    274 618
    275 1093
    276 1351
    277 729
    278 861
    279 185
    280 299
    281 197
    282 215
    283 845
    284 1109
    285 293
    286 825
    287 645
    288 218
    289 255
    290 1173
    291 1433
    292 413
    293 525
    294 523
    295 1143
    296 1268
    297 340
    298 315
    299 302
    300 376
    301 246
    302 389
    303 1058
    304 380
    305 729
    306 147
    307 464
    308 1021
    309 406
    310 134
    311 1393
    312 1220
    313 1433
    314 949
    315 825
    316 807
    317 360
    318 1084
    319 1337
    320 1315
    321 994
    322 639
    323 886
    324 1352
    325 997
    326 1251
  • Table 8 demonstrates that the present compounds have PAM activity for α7 nAChR according to the evaluation test of PAM activity. In particular, the compounds of Examples 4, 8, 13, 17, 18, 20, 23, 40, 41, 119 and 220 show a stronger PAM activity than others.
    • Test Example 2 hERG Inhibition Test
  • The hERG (human ether-a-go-go) potassium current in CHO cells which stably express hERG gene was recorded by whole-cell patch clamping technique using an automated patch clamp system, QPatch HT (Sophion Bioscience A/S). Inducing the hERG current, the membrane potential was held at −80 mV in voltage clamp mode, and then depolarized to −50 mV for 20 msec and then +20 mV for 5 sec. Then, the membrane potential was repolarized to −50 mV for 5 sec and the tail current amplitude was measured. The stimulation was given at a frequency of every 15 seconds, and the experiment was carried out at room temperature (22±2° C.). The compound was cumulatively administered to each cell in 4 concentrations, wherein the administration was done over 5 minutes in each concentration. The inhibition percentage of the inhibited current was calculated by comparing the current intensities before and after the compound was given in each concentration. According to Hill equation, each 50% inhibitory concentration was calculated (IC50 [μmol/L]). The test solutions used herein were as follows:
  • extracellular solution (mmol/L): 2 CaCl2, 1 MgCl2, 10 HEPES, 4 KCl, 145 NaCl, 10 glucose,
    intracellular solution (mmol/L): 5.4 CaCl2, 1.8 MgCl2, 10 HEPES, 31 KOH, 10 EGTA, 120 KCl, 4 ATP
  • The compounds in the Examples were tested according to Test Example 2 (hERG inhibition test), and the test results thereof are shown below.
  • TABLE 9
    IC50 IC50 IC50 IC50
    Ex. (μM) Ex. (μM) Ex. (μM) Ex. (μM)
    1 84.3 63 >10 74 13.2 258 47.3
    • Test Example 3 Reactive Metabolites Test
  • Among metabolites generated in liver microsomes from the present compound, those which react with dansyl glutathione (dGSH) were detected and quantified. The concentration of the binding compound of metabolite and dansyl glutathione was measured with a UPLC fluorescence detection system (UPLC manufactured by Waters Corporation).
  • The compounds of the Examples were tested according to Test Example 3 (reactive metabolites test), and the test results thereof are shown below.
  • TABLE 10
    IC50 IC50 IC50 IC50
    Ex. (μM) Ex. (μM) Ex. (μM) Ex. (μM)
    1 n.d. 63 n.d. 74 n.d. 163 n.d.
    227 n.d. 258 n.d.
    n.d. = no detection of reactive metabolites
    • Test Example 4 Rat PK Test
  • The present compound was administered intravenously in saline solution or orally in methylcellulose solution to 7 weeks old rats, and their blood was collected according to the following schedule:
  • (intravenous administration) 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after the administration
    (oral administration) 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after the administration
  • The collected blood was centrifuged at 3000 rpm for 10 minutes in a refrigerated centrifuge set at 4° C. The obtained plasma was measured with a HPLC to give a time curve of plasma level, thereby calculating the pharmacokinetic parameters.
  • The test herein demonstrated that the present compounds have excellent pharmacokinetics. For example, the compounds in Examples 1, 163 and 227 have a bioavailability of 41%, 41% and 69% respectively.
    • Test Example 5 Measurement of Protein Binding Ratio
  • The protein-binding ratio of the present compounds in serum was measured by an equilibrium dialysis method using 96-well Equilibrium Dialyzer MW10K (HARVARD APPARATUS). The human serum used herein was frozen human serum pools (Cosmo Bio, No. 12181201), and the buffer used herein was PBS pH 7.4 (GIBCO, No. 10010-0231).
  • The test herein demonstrated that the present compounds have a low protein-binding ratio. For example, the compound in Example 1 had a protein binding ratio of 84.7% in the plasma, and that of 91.9% in the brain.
    • Test Example 6 Measurement of Brain Penetration
  • The plasma and brain homogenates were deproteinized with methanol and then centrifuged. The supernatant was filtered, and the obtained sample was quantified with LC-MS/MS to calculate the concentration of the plasma and brain.
  • The test herein demonstrated that the present compounds have an excellent brain-penetration. For example, the concentration ratio of the brain to the plasma was 1.27, 2.01, 1.92 and 1.55 in the compounds of Examples 1, 163, 227 and 258 respectively.
    • Test Example 7 Evaluation of Cognitive Function with Mice in Novel Object Recognition Test (Hereinafter, Referred to as “mORT”)
  • Slc: ddY mice (25 g to 30 g, male, Japan SLC) can be used in the novel object recognition test wherein the interval between the 1st trial (training) and the 2nd trial (test) correlates with the memory loss for the objects used in the 1st trial, and a significant memory-loss is observed when the 2nd trial is performed 24 hours after the 1st trial. According to the test mechanism, the present compounds were administered prior to the 1st trial, and the enhancement effect on memory in the 2nd trial was evaluated.
  • The test herein demonstrated that the present compounds can exhibit effects of improving cognitive function even with an extremely low dose in a continuous manner. For example, the compound in Example 1 had a minimum effective dose of 0.1 mg/kg, and the efficacy did not decrease at a dose of 0.3 mg/kg, 1.0 mg/Kg or 3 mg/kg. The compound in Example 74 had a minimum effective dose of 0.1 mg/kg, and the efficacy did not decrease at a dose of 0.3 mg/kg, 1.0 mg/kg or 3 mg/kg. Furthermore, the compounds in Example 63 and 66 showed the efficacy at doses of 3 mg/Kg and 1 mg/Kg respectively.
    • Test Example 8 Evaluation on Improvement Against Cognitive Impairment with Rats in Y-Shaped Maze Test (Hereinafter, Referred to as “Y-Maze Test”)
  • In Y-maze test, 0.6 mg/kg scopolamine HBr (cat#S0929, Sigma Aldrich, Japan) can be subcutaneously administered to Slc: Wistar rats (280 g to 300 g, male, Japan SLC) to cause cognitive impairment and decrease the percentage of alternation behavior. According to the test mechanism, the present compounds were treated prior to the administration of scopolamine, and the improvement effect on cognitive impairment was evaluated.
  • The test herein demonstrated that the present compounds can exhibit effects of improving cognitive function even with an extremely low dose in a continuous manner. For example, the compound in Example 1 significantly improved cognitive function from a dose of 0.3 mg/kg. The compound in Example 74 significantly improved cognitive function from a dose of 0.3 mg/kg. The compound in Example 63 showed a tendency to improve cognitive function from a dose of 0.3 mg/kg.
    • INDUSTRIAL APPLICABILITY
  • As explained above, the compound of Formula (I) or a pharmaceutically acceptable salt thereof has potent modulatory-effects on the activity of α7 nicotinic acetylcholine receptor (α7 nAChR), and is thus useful for treating, for example, diseases associated with cholinergic properties in the central nervous system (CNS) and/or peripheral nervous system (PNS), diseases associated with smooth muscle contraction, endocrine disorders, neurodegenerative disorders, diseases such as inflammation and pain, and diseases associated with withdrawal symptoms caused by addictive drug abuse.

Claims (27)

1. A compound of Formula (I):
Figure US20160355511A1-20161208-C00364
or a pharmaceutically acceptable salt thereof
wherein
A is CR1E or a nitrogen atom,
X—Y—Z is N—CO—NR3AR3B, N—CO—R4, CR2E—CO—NR3AR3B, CR2E—NR5—COR4 or CR2E—NR5—CONR3AR3B,
R1A is a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, a C3-6 cycloalkyl, —NR6R7, —CONR6R7 and —NR6COR7; a C3-10 cycloalkyl or a 4- to 10-membered saturated heterocycle (wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR6R7); a C1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, —NR6R7, —CONR6R7 and —NR6COR7; a hydrogen atom; a halogen; —NR6R7; a cyano group; —CONR6R7; —NR6COR7; or —SO2R6, provided that both R6 and R7 are not a hydrogen atom,
R1B to R1E are each independently a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, a C3-6 cycloalkyl, —NR6′R7′, —CONR6′R7′ and —NR6′COR7′; a C3-10 cycloalkyl or a 4- to 10-membered saturated heterocycle (wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy, —NR6′R7′, —CONR6′R7′ and —NR6′COR7′); a C1-6 alkoxy or a C3-10 cycloalkoxy (wherein the alkoxy and the cycloalkoxy may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, —CONR6′R7′ and —NR6′COR7′); a hydrogen atom; a hydroxy group; a halogen; an aryl or a heteroaryl (wherein the aryl and the heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C1-6 alkyl optionally substituted with 1 to 5 fluorine atoms, a C1-6 alkoxy, —NR6′R7′, —CONR6′R7′ and —NR6′COR7′); —NR6′R7′; a cyano group; —CONR6′R7′; —NR6′COR7′; or —SO2R6′, provided that both R6′ and R7′ are not a hydrogen atom,
R2A to R2E are each independently a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C1-6 alkoxy and —NR8R9; a hydrogen atom; a halogen; a hydroxy group; or a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, or when two of R2A to R2E are a C1-6 alkyl, they may be taken together to form a 4- to 10-membered saturated carbocyclic ring (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR8R9),
R3A, R3B and R4 are each independently a C1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of phenyl, a monocyclic heteroaryl, a 4- to 10-membered saturated heterocycle, a C3-10 cycloalkyl, a fluorine atom, a hydroxy group, a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, and —NR10R11; a C3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; phenyl; a monocyclic heteroaryl; or a hydrogen atom, wherein the cycloalkyl, the saturated heterocycle, the phenyl and the monocyclic heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of an aryl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkoxy and —NR10R11), a halogen, a hydroxy group, a C1-6 alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkoxy and —NR10R11), a C1-6 alkoxy (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a C3-6 cycloalkyl, a C3-6 cycloalkyl-C1-6 alkyl, a C1-6 alkoxy and a fluorine atom), a C1-6 alkylcarbonyl and —NR10R11, provided that (1) R3A and R3B may be taken together to form a 4- to 10-membered saturated heterocycle (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR10R11), (2) only one of R3A and R3B can be a hydrogen atom, and (3) R4 is not a hydrogen atom,
R5 to R11, R6′ and R7′ are the same or different (each symbol is also the same or different when each symbol exists plurally) and are a hydrogen atom or a C1-6 alkyl optionally substituted with 1 to 5 fluorine atoms, provided that in each combination of R6-R7, R6′-R7′, R8-R9, and R10-R11, (1) when one is a hydrogen atom, the other one is not a hydrogen atom, and (2) each combination may be taken together to form a 4- to 10-membered saturated heterocycle (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR6R7), and
n is 1 or 2.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein X—Y—Z is N—CO—NR3AR3B, N—CO—R4 or CR2E—NR5—COR4.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein n is 1.
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein either R3A or R3B is a hydrogen atom.
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R2A to R2E are each independently a C1-6 alkyl optionally substituted with 1 to 5 fluorine atoms; a C1-6 alkoxy; a hydrogen atom; or a fluorine atom.
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R3A, R3B and R4 are each independently a C1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a 4- to 10-membered saturated heterocycle, a C3-10 cycloalkyl, a fluorine atom, a hydroxy group, a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms and —NR10R11; a C3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; a nitrogen-containing monocyclic heteroaryl; or a hydrogen atom, wherein the cycloalkyl, the saturated heterocycle and the nitrogen-containing monocyclic heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkoxy and —NR10R11), a C1-6 alkoxy optionally substituted with a C3-6 cycloalkyl or 1 to 5 fluorine atoms and —NR10R11, provided that (1) R3A and R3B may be taken together to form a 4- to 10-membered nitrogen-containing saturated heterocycle (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR10R11), (2) only one of R3A and R3B can be a hydrogen atom, and (3) R4 is not a hydrogen atom.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R1A to R1E are each independently a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C3-6 cycloalkyl, a hydroxy group and a C1-6 alkoxy; a C3-8 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl and a C1-6 alkoxy; a C1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group and a C1-6 alkoxy; a hydrogen atom; a halogen; or a 4- to 10-membered saturated heterocycle optionally substituted with a C1-6 alkyl.
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein X—Y—Z is N—CO—NR3AR3B or CR2E—NR5—COR4.
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein A is CR1E.
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R3A, R3B and R4 are each independently a C1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms; a C3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; or a hydrogen atom, wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C1-6 alkoxy) and a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, provided that (1) only one of R3A and R3B can be a hydrogen atom, and (2) R4 is not a hydrogen atom.
11. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein R1A to R1E are each independently a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C1-6 alkoxy; a C3-8 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkyl and a C1-6 alkoxy; a C1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C1-6 alkoxy; a hydrogen atom; or a halogen.
12. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein X—Y—Z is N—CO—NR3AR3B.
13. The compound of claim 1 selected from the following compounds or a pharmaceutically acceptable salt thereof:
N-(cis-4-(5-ethyl-1H-indazol-1-yl)cyclohexyl)-4,4-difluorocyclohexanecarboxamide,
1-(4,4-difluorocyclohexyl)-3-(cis-4-(5-ethyl-1H-indazol-1-yl)cyclohexyl)urea, and
cis-N-(4,4-difluorocyclohexyl)-4-(5-ethyl-1H-indazol-1-yl)cyclohexanecarboxamide.
14. (canceled)
15. A compound of Formula (I′):
Figure US20160355511A1-20161208-C00365
or a pharmaceutically acceptable salt thereof
wherein
A is CR1E;
X—Y—Z is N—CO—NR3AR3B;
R1A to R1E are each independently a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C1-6 alkoxy; a C3-8 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkyl and a C1-6 alkoxy; a C1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C1-6 alkoxy; a hydrogen atom; or a halogen;
R2A to R2E are each independently a C1-6 alkyl optionally substituted with 1 to 5 fluorine atoms; a C1-6 alkoxy; a hydrogen atom; or a fluorine atom;
R3A and R3B are each independently a C1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms; a C3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; or a hydrogen atom, wherein the cycloalkyl and the saturated heterocycle may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkyl (which may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom and a C1-6 alkoxy) and a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, provided that either R3A or R3B is a hydrogen atom; and
n is 1.
16. A pharmaceutical composition comprising the compound of either claim 1 or 15 or a pharmaceutically acceptable salt thereof.
17. (canceled)
18. (canceled)
19. A method for treating or preventing a nervous system disease, psychiatric disease or inflammatory disease which comprises administering a therapeutically effective amount of the compound of either claim 1 or 15 or a pharmaceutically acceptable salt thereof to a patient in need thereof.
20. A combination drug comprising the compound of either claim 1 or 15 or a pharmaceutically acceptable salt thereof, and at least one drug selected from drugs classified as atypical antipsychotic drugs.
21. A method for treating a disease due to an abnormality of the intracellular signaling mediated by acetylcholine which comprises administering a therapeutically effective amount of the compound of either claim 1 or 15 or a pharmaceutically acceptable salt thereof to a patient in need thereof.
22. (canceled)
23. (canceled)
24. A method for treating or preventing a nervous system disease, psychiatric disease or inflammatory disease which comprises administering a therapeutically effective amount of the compound of Formula (I″):
Figure US20160355511A1-20161208-C00366
or a pharmaceutically acceptable salt thereof
wherein
A is CR1E,
X—Y—Z is N—CO—NR3AR3B or N—CO—R4,
R1A is a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, a C3-6 cycloalkyl, —NR6R7, —CONR6R7 and —NR6COR7; a C3-10 cycloalkyl or a 4- to 10-membered saturated heterocycle, wherein the cycloalkyl and the saturated heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR6R7; a C1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, —NR6R7, —CONR6R7 and —NR6COR7; a hydrogen atom; a halogen; —NR6R7; a cyano group; —CONR6R7; —NR6COR7; or —SO2R6, provided that both R6 and R7 are not a hydrogen atom,
R1B to R1E are each independently a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, a C3-6 cycloalkyl, —NR6′R7′, —CONR6′R7′ and —NR6′COR7′; a C3-10 cycloalkyl or a 4- to 10-membered saturated heterocycle, wherein the cycloalkyl and the saturated heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy, —NR6′R7′, —CONR6′R7′ and —NR6′COR7′; a C1-6 alkoxy or a C3-10 cycloalkoxy, wherein the alkoxy and the cycloalkoxy are optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, —CONR6′R7′ and —NR6′COR7′; a hydrogen atom; a hydroxy group; a halogen; an aryl or a heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C1-6 alkyl optionally substituted with 1 to 5 fluorine atoms, a C1-6 alkoxy, —NR6′R7′, —CONR6′R7′ and —NR6′COR7′; —NR6′R7′; a cyano group; —CONR6′R7′; —NR6′COR7′; or —SO2R6′, provided that both R6′ and R7′ are not a hydrogen atom,
R2A to R2D are each independently a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C1-6 alkoxy and —NR8R9; a hydrogen atom; a halogen; a hydroxy group; or a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, or when two of R2A to R2D are a C1-6 alkyl, they may be taken together to form a 4- to 10-membered saturated carbocyclic ring optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR8R9,
R3A, R3B and R4 are each independently a C1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of phenyl, a monocyclic heteroaryl, a 4- to 10-membered saturated heterocycle, a C3-10 cycloalkyl, a fluorine atom, a hydroxy group, a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, and —NR10R11; a C3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; phenyl; a monocyclic heteroaryl; or a hydrogen atom, wherein the cycloalkyl, the saturated heterocycle, the phenyl and the monocyclic heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of an aryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkoxy and —NR10R11, a halogen, a hydroxy group, a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkoxy and —NR10R11, a C1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a C3-6 cycloalkyl, a C3-6 cycloalkyl-C1-6 alkyl, a C1-6 alkoxy and a fluorine atom, a C1-6 alkylcarbonyl, and —NR10R11, provided that (1) R3A and R3B may be taken together to form a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR10R11, (2) only one of R3A and R3B can be a hydrogen atom, and (3) R4 is not a hydrogen atom,
R6 to R11, R6′ and R7′ are the same or different and are a hydrogen atom or a C1-6 alkyl optionally substituted with 1 to 5 fluorine atoms, provided that in each combination of R6-R7, R6′-R7′, R8-R9, and R10-R11, (1) when one is a hydrogen atom, the other one is not a hydrogen atom, and (2) each combination may be taken together to form a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR6R7, and
n is 1.
25. The method of claim 24 wherein the nervous system disease, the psychiatric disease or the inflammatory disease is dementia, schizophrenia, Alzheimer's disease, Down's syndrome, attention deficit disorder or cerebral angiopathy.
26. A method for treating a disease due to an abnormality of the intracellular signaling mediated by acetylcholine which comprises administering a therapeutically effective amount of the compound of Formula (I″):
Figure US20160355511A1-20161208-C00367
or a pharmaceutically acceptable salt thereof
wherein
A is CR1E,
X—Y—Z is N—CO—NR3AR3B or N—CO—R4,
R1A is a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, a C3-6 cycloalkyl, —NR6R7, —CONR6R7 and —NR6COR7; a C3-10 cycloalkyl or a 4- to 10-membered saturated heterocycle, wherein the cycloalkyl and the saturated heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR6R7; a C1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, —NR6R7, —CONR6R7 and —NR6COR7; a hydrogen atom; a halogen; —NR6R7; a cyano group; —CONR6R7; —NR6COR7; or —SO2R6, provided that both R6 and R7 are not a hydrogen atom,
R1B to R1E are each independently a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, a C3-6 cycloalkyl, —NR6′R7′, —CONR6′R7′ and —NR6′COR7′; a C3-10 cycloalkyl or a 4- to 10-membered saturated heterocycle, wherein the cycloalkyl and the saturated heterocycle are optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy, —NR6′R7′, —CONR6′R7′ and —NR6′COR7′; a C1-6 alkoxy or a C3-10 cycloalkoxy, wherein the alkoxy and the cycloalkoxy are optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkoxy, —CONR6′R7′ and —NR6′COR7′; a hydrogen atom; a hydroxy group; a halogen; an aryl or a heteroaryl, wherein the aryl and the heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C1-6 alkyl optionally substituted with 1 to 5 fluorine atoms, a C1-6 alkoxy, —NR6′R7′, —CONR6′R7′ and —NR6′COR7′; —NR6′R7′; a cyano group; —CONR6′R7′; —NR6′COR7′; or —SO2R6′, provided that both R6′ and R7′ are not a hydrogen atom,
R2A to R2D are each independently a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen, a hydroxy group, a C1-6 alkoxy and —NR8R9; a hydrogen atom; a halogen; a hydroxy group; or a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, or when two of R2A to R2D are a C1-6 alkyl, they may be taken together to form a 4- to 10-membered saturated carbocyclic ring optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR8R9,
R3A, R3B and R4 are each independently a C1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of phenyl, a monocyclic heteroaryl, a 4- to 10-membered saturated heterocycle, a C3-10 cycloalkyl, a fluorine atom, a hydroxy group, a C1-6 alkoxy optionally substituted with 1 to 5 fluorine atoms, and —NR10R11; a C3-10 cycloalkyl; a 4- to 10-membered saturated heterocycle; phenyl; a monocyclic heteroaryl; or a hydrogen atom, wherein the cycloalkyl, the saturated heterocycle, the phenyl and the monocyclic heteroaryl may be optionally substituted with 1 to 5 substituents independently selected from the group consisting of an aryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkoxy and —NR10R11, a halogen, a hydroxy group, a C1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a C1-6 alkoxy and —NR10R11, a C1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of a C3-6 cycloalkyl, a C3-6 cycloalkyl-C1-6 alkyl, a C1-6 alkoxy and a fluorine atom, a C1-6 alkylcarbonyl, and —NR10R11, provided that (1) R3A and R3B may be taken together to form a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR10R11, (2) only one of R3A and R3B can be a hydrogen atom, and (3) R4 is not a hydrogen atom,
R6 to R11, R6′ and R7′ are the same or different and are a hydrogen atom or a C1-6 alkyl optionally substituted with 1 to 5 fluorine atoms, provided that in each combination of R6-R7, R6′-R7′, R8-R9, and R10-R11, (1) when one is a hydrogen atom, the other one is not a hydrogen atom, and (2) each combination may be taken together to form a 4- to 10-membered saturated heterocycle optionally substituted with 1 to 5 substituents independently selected from the group consisting of a fluorine atom, a hydroxy group, a C1-6 alkyl, a C1-6 alkoxy and —NR6R7, and
n is 1.
27. The method of claim 19 wherein the nervous system disease, the psychiatric disease or the inflammatory disease is dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder or cerebral angiopathy.
US15/060,902 2012-04-10 2016-03-04 Novel 1-substituted indazole derivative Abandoned US20160355511A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US15/060,902 US20160355511A1 (en) 2012-04-10 2016-03-04 Novel 1-substituted indazole derivative

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
JP2012089057 2012-04-10
JP2012-089057 2012-04-10
PCT/JP2013/060744 WO2013154109A1 (en) 2012-04-10 2013-04-09 Novel 1-substituted indazole derivative
US14/128,516 US9309221B2 (en) 2012-04-10 2013-04-09 1-substituted indazole derivative
US15/060,902 US20160355511A1 (en) 2012-04-10 2016-03-04 Novel 1-substituted indazole derivative

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/JP2013/060744 Division WO2013154109A1 (en) 2012-04-10 2013-04-09 Novel 1-substituted indazole derivative
US14/128,516 Division US9309221B2 (en) 2012-04-10 2013-04-09 1-substituted indazole derivative

Publications (1)

Publication Number Publication Date
US20160355511A1 true US20160355511A1 (en) 2016-12-08

Family

ID=49327671

Family Applications (4)

Application Number Title Priority Date Filing Date
US14/128,516 Active US9309221B2 (en) 2012-04-10 2013-04-09 1-substituted indazole derivative
US14/137,904 Active US9051295B2 (en) 2012-04-10 2013-12-20 1-substituted indazole derivative
US14/137,895 Active US8765786B2 (en) 2012-04-10 2013-12-20 1-substituted indazole derivative
US15/060,902 Abandoned US20160355511A1 (en) 2012-04-10 2016-03-04 Novel 1-substituted indazole derivative

Family Applications Before (3)

Application Number Title Priority Date Filing Date
US14/128,516 Active US9309221B2 (en) 2012-04-10 2013-04-09 1-substituted indazole derivative
US14/137,904 Active US9051295B2 (en) 2012-04-10 2013-12-20 1-substituted indazole derivative
US14/137,895 Active US8765786B2 (en) 2012-04-10 2013-12-20 1-substituted indazole derivative

Country Status (13)

Country Link
US (4) US9309221B2 (en)
EP (1) EP2837623A4 (en)
JP (1) JP6088491B2 (en)
KR (1) KR20150000900A (en)
CN (1) CN104395292B (en)
AU (1) AU2013247697B2 (en)
BR (1) BR112014025201A2 (en)
CA (1) CA2869143A1 (en)
HK (1) HK1202860A1 (en)
MX (1) MX2014012236A (en)
RU (1) RU2014144951A (en)
TW (1) TWI606043B (en)
WO (1) WO2013154109A1 (en)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2014012236A (en) 2012-04-10 2014-11-25 Sumitomo Dainippon Pharma Co Ltd Novel 1-substituted indazole derivative.
JP2015214492A (en) * 2012-09-07 2015-12-03 大日本住友製薬株式会社 3-(4-piperidyl)-imidazole derivative
AU2013325615A1 (en) * 2012-10-02 2015-04-09 Sumitomo Dainippon Pharma Co., Ltd. Imidazole derivative
JP6088476B2 (en) * 2013-10-08 2017-03-01 大日本住友製薬株式会社 A pharmaceutical comprising a novel 1-substituted indazole derivative
CN107619392B (en) * 2016-07-15 2021-01-01 西华大学 1H-indazole-4-ether compounds and use thereof as IDO inhibitors
WO2021207302A1 (en) * 2020-04-09 2021-10-14 Disarm Therapeutics, Inc. Indazole derivatives as inhibitors of sarm1
CN114790174B (en) * 2022-04-14 2023-09-29 淮阴工学院 A method for continuously synthesizing 1H-indazole compounds
EP4581018A1 (en) * 2022-08-29 2025-07-09 Mindset Pharma Inc. Indazole derivatives as serotonergic agents useful for the treatment of disorders related thereto

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9511989D0 (en) * 1995-06-13 1995-08-09 Glaxo Group Ltd Chemical compounds
CN100341862C (en) * 2001-09-14 2007-10-10 三菱制药株式会社 Thiazolidine derivative and medicinal use thereof
US20030236287A1 (en) 2002-05-03 2003-12-25 Piotrowski David W. Positive allosteric modulators of the nicotinic acetylcholine receptor
SG149830A1 (en) * 2003-12-22 2009-02-27 Memory Pharm Corp Indoles, 1h-indazoles, 1,2-benzisoxazoles, and 1,2- benzisothiazoles, and preparation and uses thereof
GB0402140D0 (en) 2004-01-30 2004-03-03 Smithkline Beecham Corp Novel compounds
US7820663B2 (en) 2005-06-17 2010-10-26 The Regents Of The University Of California Substituted enaminones, their derivatives and uses thereof
ES2338590T3 (en) 2005-09-06 2010-05-10 Glaxosmithkline Llc REGIONAL ELEMENT PROCEDURE FOR THE PREPARATION OF BENZOIMIDAZOLTIOFENOS.
WO2007102883A2 (en) 2005-10-25 2007-09-13 Smithkline Beecham Corporation Chemical compounds
US8367684B2 (en) 2007-06-13 2013-02-05 Valeant Pharmaceuticals International Derivatives of 4-(N-azacycloalkyl) anilides as potassium channel modulators
SG182958A1 (en) 2007-06-27 2012-08-30 Astrazeneca Ab Pyrazinone derivatives and their use in the treatment of lung diseases
US8114891B2 (en) 2007-10-01 2012-02-14 Comentis, Inc. 4-substituted quinuclidine derivatives, methods of production, pharmaceutical uses thereof
JP2009185020A (en) 2008-01-11 2009-08-20 Ishihara Sangyo Kaisha Ltd Pyridylamidine derivative or salt thereof, and agricultural or horticultural fungicide containing the same as active ingredient
GB0817207D0 (en) 2008-09-19 2008-10-29 Pimco 2664 Ltd therapeutic apsac compounds and their use
WO2010101246A1 (en) * 2009-03-05 2010-09-10 塩野義製薬株式会社 Piperidine and pyrrolidine derivatives having npy y5 receptor antagonism
CN102762534A (en) 2009-09-18 2012-10-31 扎里卡斯药品有限公司 Arylsulfone derivatives as calcium channel blockers
TWI513695B (en) 2009-10-27 2015-12-21 Merck Sharp & Dohme (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl derivatives
WO2012068106A2 (en) 2010-11-15 2012-05-24 Exelixis, Inc. Benzoxazepines as inhibitors of pi3k/mtor and methods of their use and manufacture
ES2951688T3 (en) * 2011-02-28 2023-10-24 Epizyme Inc 6,5-Substituted Fused Bicyclic Heteroaryl Compounds
JP2014114212A (en) * 2011-03-29 2014-06-26 Dainippon Sumitomo Pharma Co Ltd New benzimidazole derivative
JP2014166961A (en) * 2011-06-20 2014-09-11 Dainippon Sumitomo Pharma Co Ltd Novel indazole derivative
WO2013085954A1 (en) 2011-12-06 2013-06-13 Janssen Pharmaceutica Nv Substituted piperidinyl-carboxamide derivatives useful as scd 1 inhibitors
MX2014012236A (en) 2012-04-10 2014-11-25 Sumitomo Dainippon Pharma Co Ltd Novel 1-substituted indazole derivative.

Also Published As

Publication number Publication date
CN104395292B (en) 2017-03-01
US9051295B2 (en) 2015-06-09
US8765786B2 (en) 2014-07-01
EP2837623A1 (en) 2015-02-18
JP6088491B2 (en) 2017-03-01
MX2014012236A (en) 2014-11-25
CA2869143A1 (en) 2013-10-17
TW201345904A (en) 2013-11-16
AU2013247697A1 (en) 2014-10-23
KR20150000900A (en) 2015-01-05
BR112014025201A2 (en) 2017-07-11
US20140121243A1 (en) 2014-05-01
US9309221B2 (en) 2016-04-12
CN104395292A (en) 2015-03-04
US20140121244A1 (en) 2014-05-01
TWI606043B (en) 2017-11-21
HK1202860A1 (en) 2015-10-09
US20150031681A1 (en) 2015-01-29
RU2014144951A (en) 2016-06-10
WO2013154109A1 (en) 2013-10-17
AU2013247697B2 (en) 2017-03-02
JPWO2013154109A1 (en) 2015-12-17
EP2837623A4 (en) 2015-12-16

Similar Documents

Publication Publication Date Title
US8765786B2 (en) 1-substituted indazole derivative
WO2012176763A1 (en) Novel indazole derivative
US20150259344A1 (en) Imidazole derivative
US20220257774A1 (en) Aromatic amine ar ahd bet targeting protein degradation chimera compound and use
WO2012133509A1 (en) Novel benzimidazole derivative
JP6874014B2 (en) CGRP receptor antagonist
US10301286B2 (en) Piperazine derivative
CN102741239B (en) Bicyclic compounds as ligands for the α4β2 nicotinic acetylcholine receptor
WO2014054634A1 (en) Pyrimidine derivative
JP2014073982A (en) Pharmaceutical containing novel benzimidazole derivative
JP6088476B2 (en) A pharmaceutical comprising a novel 1-substituted indazole derivative
JP2015199722A (en) Medicine comprising imidazole derivative
JP2017100948A (en) 4-Arylimidazole derivative
WO2014038623A1 (en) 3-(4-piperidyl)-indazole derivative
JP2010533685A (en) Pyrazole 3,5 carboxylate derivatives, their preparation and therapeutic application
HK1223921B (en) New octahydro-cyclobuta [1,2-c;3,4-c']dipyrrol-2-yl
HK1195298A1 (en) Ethynyl derivatives as mglur5 allosteric modulators

Legal Events

Date Code Title Description
AS Assignment

Owner name: DAINIPPON SUMITOMO PHARMA CO., LTD., JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:USUI, SHINYA;YAMAGUCHI, HIROKI;NAKAI, YOKO;SIGNING DATES FROM 20140131 TO 20140203;REEL/FRAME:039943/0755

Owner name: SUMITOMO DAINIPPON PHARMA CO., LTD., JAPAN

Free format text: CHANGE OF NAME;ASSIGNOR:DAINIPPON SUMITOMO PHARMA CO., LTD.;REEL/FRAME:040231/0424

Effective date: 20140619

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION