US20140031547A1 - CASEIN KINASE 1delta (CK 1delta) INHIBITORS AND THEIR USE IN THE TREATMENT OF NEURODE-GENERATIVE DISEASES SUCH AS TAUOPATHIES - Google Patents

CASEIN KINASE 1delta (CK 1delta) INHIBITORS AND THEIR USE IN THE TREATMENT OF NEURODE-GENERATIVE DISEASES SUCH AS TAUOPATHIES Download PDF

Info

Publication number
US20140031547A1
US20140031547A1 US13/993,288 US201113993288A US2014031547A1 US 20140031547 A1 US20140031547 A1 US 20140031547A1 US 201113993288 A US201113993288 A US 201113993288A US 2014031547 A1 US2014031547 A1 US 2014031547A1
Authority
US
United States
Prior art keywords
alkyl
aryl
heteroaryl
conh
groups
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
US13/993,288
Other languages
English (en)
Inventor
Joseph M. Sheridan
Jonathan R. Heal
William D.O. Hamilton
Ian Pike
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.)
Proteome Sciences PLC
Original Assignee
Electrophoretics 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
Priority claimed from GBGB1021161.3A external-priority patent/GB201021161D0/en
Priority claimed from GBGB1109162.6A external-priority patent/GB201109162D0/en
Application filed by Electrophoretics Ltd filed Critical Electrophoretics Ltd
Assigned to ELECTROPHORETICS LIMITED reassignment ELECTROPHORETICS LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HAMILTON, WILLIAM D.O., HEAL, JONATHAN R, PIKE, IAN, SHERIDAN, JOSEPH M
Publication of US20140031547A1 publication Critical patent/US20140031547A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered 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
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/41—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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/42—Oxazoles
    • 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
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic 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
    • A61K31/41—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
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles 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
    • A61K31/41—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
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic 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
    • A61K31/41—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
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • the invention relates to pharmaceutical compositions comprising casein kinase 1 delta (CK1 ⁇ ) inhibitors and to the use of said inhibitors in the treatment of neurodegenerative disorders such as Alzheimer's disease.
  • CK1 ⁇ casein kinase 1 delta
  • Alzheimer's disease also known as senile dementia of the Alzheimer type (SDAT), primary degenerative dementia of the Alzheimer's type (PDDAT), or Alzheimer's
  • SDAT senile dementia of the Alzheimer type
  • PDAT primary degenerative dementia of the Alzheimer's type
  • Alzheimer's is the most common form of dementia. Most often, Alzheimer's disease is diagnosed in people over 65 years of age, although the less-prevalent early-onset Alzheimer's can occur much earlier. In 2006, there were 26.6 million sufferers worldwide. Alzheimer's is predicted to affect 1 in 85 people globally by 2050.
  • Alzheimer's disease is a neurodegenerative disease characterised by the presence of senile plaques and neurofibrillary tangles in the brain.
  • the degree of dementia at death correlates better with neurofibrillary tangle numbers than with senile plaques counts.
  • the presence of neurofibrillary tangles in neurons results in the death of those neurons, implying that prevention of tangle formation is an important therapeutic goal.
  • the principal protein that forms the neurofibrillary tangle is the microtubule-associated protein, tau, which assembles into filaments that have the appearance of twisting about each other in pairs and are referred to as paired helical filaments (PHF).
  • PHF paired helical filaments
  • Intraneuronal deposits of tau in the form of typical neurofibrillary tangles of AD or other morphologically distinct tau aggregates in a number of other neurodegenerative diseases is the basis for grouping these conditions as tauopathies.
  • the main examples of the tauopathies are frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), Pick's disease, corticobasal degeneration, and multisystem atrophy (MSA).
  • the intracellular tau deposits (usually neuronal but can also be glial) are all filamentous and mostly in a hyperphosphorylated state compared to the level of phosphorylation of tau from control human brain. In the case of AD, this hyperphosphorylated tau is often referred to as PHF-tau because it is derived from the PHF.
  • Tau is a phosphoprotein, the function of phosphorylation remaining to be unequivocally established.
  • increased phosphorylation of tau on multiple serine and threonine residues reduces the ability of tau to promote microtubule assembly and to stabilise assembled microtubules, effects that have been demonstrated both in vitro and in cells.
  • Many studies have shown that PHF-tau from AD brain is more heavily phosphorylated on serine and threonine than tau from control brain.
  • casein kinase 1 Mammalian casein kinase-1 exists as multiple isoforms CK1 ⁇ , CK1 ⁇ , CK1y1, CK1y2, CK1y3, CK1 ⁇ and CK1 ⁇ .
  • the role of CK1 ⁇ as a potential tau kinase is of particular interest since it has been reported that CK1 ⁇ protein is increased more than 30-fold in the hippocampus of Alzheimer brain compared to equivalent controls (Ghoshal, N. et al (1999) Am. J.
  • Pathol 155, 1163-1172 while its mRNA content is increased 24-fold (Yasojima, K. et al (2000) Brain Res 865, 116-120) and CK1 has also been shown to be tightly associated with PHF (Kuret, J. et al (1997) J. Neurochem 69, 2506-2515).
  • CK1 ⁇ has also been reported to phosphorylate tau at two epitopes detecting using phospho-specific monoclonal antibodies to tau, and exogenous expression of CK1 ⁇ in non-neuronal cells reduces binding of tau to microtubules (Li, G. et al (2004) J. Biol. Chem. 279, 15938-15945).
  • CK1 activity is stimulated by amyloid beta-peptide (A ⁇ ), a component of the senile neuritic plaques that, together with tangles, characterise Alzheimer brain (Chauhan, A. et al (1993) Brain Res. 629, 47-52). Additional evidence for possible involvement of CK1 in Alzheimer's disease comes from the reported influence of CK1 in the regulation of A ⁇ production in neurons (Flajolet, M. et al (2007) PNAS USA 104, 4159-4164). Further work has confirmed that at least 6 newly identified phosphorylation sites in PHF-tau (all on serine or threonine residues) can be generated by CK1 ⁇ .
  • a ⁇ amyloid beta-peptide
  • CK1 ⁇ inhibitors which may be of potential therapeutic benefit in the treatment of neurodegenerative diseases, such as tauopathies including Alzheimer's disease, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), Pick's disease, corticobasal degeneration, and multisystem atrophy (MSA).
  • tauopathies including Alzheimer's disease, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), Pick's disease, corticobasal degeneration, and multisystem atrophy (MSA).
  • a pharmaceutical composition comprising a compound of formula (IA) or a pharmaceutically acceptable salt or solvate thereof:
  • Het A represents a 4 or 5 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is optionally fused to one or more (e.g. 1-3) further rings to form a polycyclic ring system comprising up to 4 rings;
  • X and Y independently represent a bond, —C(R 7a )(R 8a )-, (CH 2 ) 2 , —O—, —S—, —CH 2 —O—, —(CH 2 ) 2 —O—, NR 6a , —N(R 6a )—C(R 7a )(R 8a )-, —N(R 6a )-(CH 2 ) 2 -, —N(R 6a )-(CH 2 ) 3 -, —CH 2 —N(R 6a )-(CH 2 ) 2 -, —N(R 6a )—CO—, —CH
  • R 5a represents hydrogen, C 1-6 alkyl or cyano
  • R 6a represents hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, —CH 2 —C 3-8 cycloalkyl, aryl, heteroaryl, —C 1-6 alkylene-aryl, —CO-aryl, —CO-heteroaryl or —C(R 7a )(R 8a )-heteroaryl, wherein said aryl groups of R 6a may be optionally substituted by one or more halogen or C 1-6 alkoxy groups;
  • R 7a and R 8a independently represent hydrogen or C 1-6 alkyl
  • R 1a and R 2a independently represent aryl, C 3-8 cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1a and R 2a may be substituted by one or more (e.g. 1, 2 or 3) R 4a groups;
  • R 4a represents halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-8 cycloalkyl, haloC 1-6 alkyl, hydroxyl, C 1-6 alkoxy, —O—C 1-6 alkenyl, haloC 1-6 alkoxy, —COOH, —CO—C 1-6 alkyl, —COO—C 1-6 alkyl, —CONH 2 , —CH 2 —CONH 2 , —NH—C 1-6 alkyl, —NH—C 2-6 alkenyl, —NH—CO—C 1-6 alkyl, —CO—NH—C 1-6 alkyl, —O—CH 2 —CO—NH—C 1-6 alkyl, —CH 2 —CH 2 —CO—NH—C 1-6 alkyl, —S—C 1-6 alkyl, —SO—C 1-6 alkyl, —SO 2 —C 1-6 alkyl
  • n an integer from 0 to 3;
  • the compound is other than compound number 38, 138, 212, 243, 378, 415, 441, 480, 577, 579, 580, 587-589, 593, 598, 600, 629, 636, 678, 684, 747, 760, 802, 861, 871, 873, 879, 883, 897-899, 904-905, 907, 909, 915, 917-919, 922-923, 925, 929-930, 938-939, 961.
  • the compound of formula (IA) is selected from any of compounds: 1, 4-17, 19-25, 36-37, 39-40, 42, 44-45, 52, 61, 71-76, 80-83, 86-91, 93-97, 102-107, 110-112, 114, 117-122, 139-143, 149-151, 153, 158-160, 163-170, 174-177, 185-197, 200, 202-203, 208-209, 211, 213-221, 223-224, 226, 228-229, 232, 234, 237-240, 256, 261-264, 267-268, 270, 272, 275-283, 296, 304, 313, 319, 321-323, 326-328, 332, 334-335, 342-345, 350, 356, 361-365, 367-369, 372, 377, 379, 383, 393, 398, 403, 406, 412-413, 416-423, 431-432, 434, 436, 438-
  • the compound of formula (IA) is selected from any of compounds:
  • the compound of formula (IA) is selected from any of compounds:
  • the compound of formula (IA) is selected from any of compounds:
  • the compound of formula (IA) is selected from any of compounds:
  • the compound of formula (IA) is selected from any of compounds:
  • the compound of formula (IA) is selected from any of compounds:
  • composition comprising a compound of formula (IB) or a pharmaceutically acceptable salt or solvate thereof:
  • Het B represents a 5 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is fused to one or more (e.g. 1-3) further rings to form a polycyclic ring system comprising up to 4 rings;
  • R 5b represents hydrogen, C 1-6 alkyl or cyano
  • R 6b represents hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, COOH, —COOC 1-6 alkyl, C 3-8 cycloalkyl, —CH 2 —C 3-8 cycloalkyl, aryl, heteroaryl, —C 1-6 alkylene-aryl, —CO-aryl, —O—CO—heteroaryl, —CO-heteroaryl or —C(R 7b )(R 8b )-heteroaryl, wherein said aryl groups of R 6b may be optionally substituted by one or more halogen or C 1-6 alkoxy groups;
  • R 7b and R 8b independently represent hydrogen or C 1-6 alkyl
  • R 1b represents aryl, C 3-8 cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1b may be substituted by one or more (e.g. 1, 2 or 3) R 4b groups;
  • R 4b represents halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-8 cycloalkyl, haloC 1-6 alkyl, hydroxyl, C 1-6 alkoxy, —O—C 1-6 alkenyl, haloC 1-6 alkoxy, -COOH, —CO—C 1-6 alkyl, —COO—C 1-6 alkyl, -CONH 2 , —CH 2 —CONH 2 , -NH—C 1-6 alkyl, -NH—C 2-6 alkenyl, —NH—CO—C 1-6 alkyl, —CO—NH—C 1-6 alkyl, —O—CH 2 —CO—NH—C 1-6 alkyl, —CH 2 —CH 2 —CO—NH—C 1-6 alkyl, —S—C 1-6 alkyl, —SO—C 1-6 alkyl, —SO 2 —C 1-6 alkyl
  • n an integer from 0 to 3;
  • the compound is other than compound number 54, 373, 458, 496, 585, 590, 594, 596-597, 601-602, 649, 703, 778, 877, 891, 910, 912, 926 and 962-963.
  • the compound of formula (IB) is selected from any of compounds 2-3, 26-28, 30-33, 35, 47-48, 51, 57-60, 63-64, 78, 84, 113, 123, 127-129, 145, 155-157, 171-173, 204, 206-207, 210, 225, 227, 233, 235-236, 241-242, 244, 249, 269, 285, 288, 303, 307-312, 314-316, 320, 324-325, 333, 336, 351, 357-360, 374-375, 384-391, 396, 399-402, 404-405, 407-411, 414, 424-425, 427-428, 437, 448, 456-457, 482, 484-485, 489-491, 495, 497-498, 505, 507, 516, 519, 524, 526, 553, 559-560, 568, 570, 575, 609, 615-616
  • the compound of formula (IB) is selected from any of compounds:
  • the compound of formula (IB) is selected from any of compounds:
  • the compound of formula (IB) is selected from any of compounds:
  • a pharmaceutical composition comprising a compound of formula (IC) or a pharmaceutically acceptable salt or solvate thereof:
  • Het C represents a 6 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is optionally fused to one or more (e.g. 1-3) further rings to form a polycyclic ring system comprising up to 4 rings;
  • X c and Y c independently represent a bond, —C(R 7c )(R 8c )-, (CH 2 ) 2 , —O—, —S—, -CH 2 -O-, (CH 2 ) 2 —O—, NR 6c , —N(R 6c )—C(R 7c )(R 8c )-, —N(R 6c )—(CH 2 ) 2 -, —N(R 6c )—(CH 2 ) 3 -, —CH 2 —N(R 6c —(CH 2 ) 2 - , —N(R 6c )—CO—, -CH
  • R 5c represents hydrogen, C 1-6 alkyl or cyano
  • R 6c represents hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, —CH 2 —C 3-8 cycloalkyl, aryl, heteroaryl, —C 1-6 alkylene-aryl, —CO-aryl, —CO-heteroaryl or —C(R 7c )(R 8c )-heteroaryl, wherein said aryl groups of R 6c may be optionally substituted by one or more halogen or C 1-6 alkoxy groups;
  • R 7c and R 8c independently represent hydrogen or C 1-6 alkyl
  • R 1c and R 2c independently represent aryl, C 3-8 cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1c and R 2c may be substituted by one or more (e.g.
  • R 4c groups R o o represents halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-8 cycloalkyl, haloC 1-6 alkyl, hydroxyl, C 1-6 alkoxy, —O—C 1-6 alkenyl, haloC 1-6 alkoxy, —COOH, —CO—C 1-6 alkyl, -COO—C 1 - 6 alkyl, -CONH 2 , -CH 2 —CONH 2 , -NH—C 1-6 alkyl, -NH—C 2-6 alkenyl, -NH—COO 1-6 alkyl, —CO—NH—C 1-6 alkyl, —O—CH 2 —CO—NH—C 1-6 alkyl, —O—CH 2 —CO—NH—C 1-6 alkyl, —O—CH 2 —CO—NH—C 1-6 alkyl, —O—CH 2 —CO—
  • p represents an integer from 0 to 3;
  • the compound is other than compound number 161, 648, 658, 680, 726, 824, 867, 880, 892, 896, 901, 903, 906, 928 and 944.
  • Het C represents a 6 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is optionally fused to one further ring to form a bicyclic ring system.
  • Het C represents a 6 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is optionally fused to a phenyl ring to form a bicyclic ring system.
  • Het C represents a 6 membered heterocyclic ring system containing 1 or 2 nitrogen atoms, wherein said ring system is optionally fused to a phenyl ring to form a bicyclic ring system.
  • Het C represents pyridinyl, pyrimidinyl or quinazolinyl.
  • Het C represents quinazolinyl.
  • X c and Y c independently represent a bond or NR 6c . In a further embodiment, X c and Y c independently represent a bond or NH. In a yet further embodiment, one of X c and Y c represents a bond and the other represents a bond or NH. In a yet further embodiment, one of X c and Y c represents a bond and the other represents NH.
  • R 1c and R 2c independently represent aryl, bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1c and R 2c may be substituted by one or more (e.g. 1, 2 or 3) R 4c groups.
  • R 1c and R 2c independently represent aryl (e.g. phenyl), bicyclic heterocyclyl (e.g. benzodioxinyl), monocyclic heteroaryl (e.g. pyridinyl, pyrazolyl or thiophenyl) or bicyclic heteroaryl ring system (e.g.
  • R 1c and R 2c may be substituted by one or more (e.g. 1, 2 or 3) R 4c groups.
  • R 1c and R 2c independently represent aryl (e.g. phenyl), bicyclic heterocyclyl (e.g. benzodioxinyl), monocyclic heteroaryl (e.g. pyridinyl, pyrazolyl or thiophenyl) or bicyclic heteroaryl ring system (e.g. benzoxazolyl), wherein R 1c and R 2c may be substituted by one or more (e.g. 1) R 4c groups selected from hydroxyl, C 1-6 alkoxy (e.g. methoxy) or CONH 2 .
  • R 1c and R 2c independently represent aryl (e.g. phenyl) or monocyclic heteroaryl (e.g. pyridinyl, pyrazolyl or thiophenyl) wherein R 1c and R 2c may be substituted by one or more (e.g. 1) R 4c groups selected from hydroxyl, C 1-6 alkoxy (e.g. methoxy) or CON H 2 .
  • R 1c and R 2c independently represent unsubstituted aryl (e.g. phenyl) or unsubstituted monocyclic heteroaryl (e.g. pyridinyl or pyrazolyl).
  • one of R 1c and R 2c represents unsubstituted aryl (e.g. phenyl) and the other represents unsubstituted monocyclic heteroaryl (e.g. pyridinyl or pyrazolyl).
  • aryl e.g. phenyl
  • monocyclic heteroaryl e.g. pyridinyl or pyrazolyl
  • p represents an integer from 0 to 2. In one embodiment, p represents 0. In an alternative embodiment, p represents 1. In an alternative embodiment, p represents 2.
  • R 3c represents a monocyclic heteroaryl ring system (e.g. pyridinyl).
  • R 3c O and cyano.
  • the compound of formula (IC) is selected from any of compounds:
  • the compound of formula (IC) is selected from any of compounds:
  • the compound of formula (IC) is selected from any of compounds:
  • the compound of formula (IC) is selected from any of compounds:
  • the compound of formula (IC) is selected from any of compounds:
  • the compound of formula (IC) is selected from any of compounds:
  • the compound of formula (IC) is selected from any of compounds:
  • a pharmaceutical composition comprising a compound of formula (ID) or a pharmaceutically acceptable salt or solvate thereof:
  • Het D represents a 6 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is fused to one or more (e.g. 1-3) further rings to form a polycyclic ring system comprising up to 4 rings;
  • R 5d represents hydrogen, C 1-6 alkyl or cyano
  • R 6d represents hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, -CH 2 —C 3-8 cycloalkyl, aryl, heteroaryl, —C 1-6 alkylene-aryl, —CO-aryl, —CO-heteroaryl or —C(R 7d )(R 8d )- heteroaryl, wherein said aryl groups of R 6d may be optionally substituted by one or more halogen or C 1-6 alkoxy groups;
  • R 7d and R 8d independently represent hydrogen or C 1-6 alkyl
  • R 1d represents aryl, C 3-8 cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1d may be substituted by one or more (e.g. 1, 2 or 3) R 4d groups;
  • R 4d represents halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-8 cycloalkyl, haloC 1-6 alkyl, hydroxyl, C 1-6 alkoxy, —O—C 1-6 alkenyl, haloC 1-6 alkoxy, -COOH, —CO—C 1-6 alkyl, -COO—C 1-6 alkyl, -CONH 2 , -CH 2 —CONH 2 , -NH—C 1-6 alkyl, -NH—C 2-6 alkenyl, -NH—CO—C 1-6 alkyl, —CO—NH—C 1-6 alkyl, —O—CH 2 —CO—NH—C 1-6 alkyl, -CH 2 —CH 2 —CO—NH—C 1-6 alkyl, —S—C 1-6 alkyl, —SO—C 1-6 alkyl, —SO 2 —C 1-6 alkyl
  • q represents an integer from 0 to 3;
  • the compound is other than compound number 273, 286, 467, 533, 544, 571, 591, 662, 783, 795, 806, 884, 887, 895, 902, 908, 921, 932, 934, 942, 959-960 and 1001.
  • the compound of formula (ID) is selected from any of compounds:
  • the compound of formula (ID) is selected from any of compounds:
  • the compound of formula (ID) is selected from any of compounds:
  • the compound of formula (ID) is selected from any of compounds:
  • the compound of formula (ID) is selected from any of compounds:
  • a pharmaceutical composition comprising a compound of formula (IE) or a pharmaceutically acceptable salt or solvate thereof:
  • Het E represents a 6 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S;
  • R 5e represents hydrogen, C 1-8 alkyl or cyano
  • R 6e represents hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, cyano, C 3 - 8 cycloalkyl, - CH 2 —C 3-8 cycloalkyl, aryl, heteroaryl, —C 1-8 alkylene-aryl, —C 1-8 alkylene-heteroaryl, -NH—CO- aryl, —CO-aryl, —CO-heteroaryl or —C(R 7e )(R 8e )-heteroaryl, wherein said aryl groups of Rhe may be optionally substituted by one or more halogen or C 1-8 alkoxy groups;
  • R 7e and R 8e independently represent hydrogen or C 1-8 alkyl
  • R 1e represents aryl, C 3-8 cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1d may be substituted by one or more (e.g. 1, 2 or 3) R 4e groups;
  • R 4e represents halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkynyl, C 3-8 cycloalkyl, haloC 1-8 alkyl, hydroxyl, C 1-8 alkoxy, —O—C 1-8 alkenyl, haloC 1-8 alkoxy, -COOH, —CO—C 1-8 alkyl, -COO—C 1-6 alkyl, -CONH 2 , —SO 2 NH 2 , -CH 2 —CONH 2 , -NH—C 1-8 alkyl, -NH—C 2-8 alkenyl, -NH—CO—C 1 - 6 alkyl, —CO—NH—C 1-8 alkyl, -NH-NH 2 , —O—CH 2 —CO—NH—C 1-6 alkyl, -CH 2 —CH 2 —CO—NH—C 1-8 alkyl, —S—C 1-6 alkyl, —SO—
  • r represents an integer from 0 to 3;
  • the compound of formula (IE) is selected from any of compounds:
  • the compound of formula (IE) is selected from any of compounds:
  • the compound of formula (IE) is selected from any of compounds:
  • the compound of formula (IE) is selected from any of compounds:
  • a pharmaceutical composition comprising a compound of formula (IF) or a pharmaceutically acceptable salt or solvate thereof:
  • Het F represents a heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S, wherein said ring system is fused to one or more (e.g. 1-3) further rings to form a polycyclic ring system comprising up to 4 rings;
  • R 1f represents halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-8 cycloalkyl, haloC 1-6 alkyl, hydroxyl, C 1-6 alkoxy, —O—C 1-6 alkenyl, haloC 1-6 alkoxy, -COOH, —CO—C 1-6 alkyl, -COO—C 1-6 alkyl, -CONH 2 , -CH 2 —CONH 2 , -NH—C 1-6 alkyl, -NH—C 2-6 alkenyl, -NH—CO—C 1-6 alkyl, —CO—NH—C 1-6 alkyl, —O—CH 2 —CO—NH—C 1-6 alkyl, -CH 2 —CH 2 —CO—NH—C 1-6 alkyl, —S—C 1-6 alkyl, —SO—C 1-6 alkyl, —SO 2 —C 1-6 alkyl
  • s represents an integer from 1 to 3;
  • the compound of formula (IF) is selected from any of compounds:
  • the compound of formula (IF) is selected from any of compounds:
  • the compound of formula (IF) is Compound 205 as described herein or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of this embodiment was tested in the CK1 ⁇ inhibition assay as described herein and exhibited inhibition of greater than 50%.
  • a pharmaceutical composition comprising a compound of formula (IG) or a pharmaceutically acceptable salt or solvate thereof:
  • R 5g represents hydrogen, C 1-6 alkyl or cyano
  • R 6g represents hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, -CH 2 —C 3-8 cycloalkyl, aryl, heteroaryl, —C 1-6 alkylene-aryl, —CO-aryl, —CO-heteroaryl or —C(R 7g )(R 8g )- heteroaryl, wherein said aryl groups of R 6g may be optionally substituted by one or more halogen or C 1-6 alkoxy groups;
  • R 7g and R 8g independently represent hydrogen or C 1-6 alkyl
  • R 1g represents aryl, C 3-8 cycloalkyl, monocyclic or bicyclic heterocyclyl or a monocyclic or bicyclic heteroaryl ring system, wherein R 1g may be substituted by one or more (e.g. 1, 2 or 3) R 4g groups;
  • R 4g represents halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-8 cycloalkyl, haloC 1-6 alkyl, hydroxyl, C 1-6 alkoxy, —O—C 1-6 alkenyl, haloC 1-6 alkoxy, -COOH, —CO—C 1-6 alkyl, -COO—C 1-6 alkyl, -CONH 2 , -CH 2 —CONH 2 , -NH—C 1-6 alkyl, -NH—C 2-6 alkenyl, -NH—CO—C 1-6 alkyl, —CO—NH—C 1-6 alkyl, —O—CH 2 —CO—NH—C 1-6 alkyl, -CH 2 —OH 2 —CO—NH—C 1-6 alkyl, —S—C 1-6 alkyl, —SO—C 1-6 alkyl, —SO 2 —C 1-6 alkyl
  • t represents an integer from 0 to 3;
  • the compound of formula (IG) is selected from any of compounds:
  • the compound of formula (IG) is selected from any of compounds:
  • the compound of formula (IG) is compound 825 as described herein or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of formula (IG) is selected from any of compounds: 825, 881-882, 935, 956, 968, 972 and 996 as described herein or a pharmaceutically acceptable salt or solvate thereof.
  • the compounds of this embodiment were tested in the CK1 ⁇ inhibition assay as described herein and exhibited inhibition of greater than 5%.
  • the compound of formula (IG) is Compound 972 as described herein or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of this embodiment was tested in the CK1 ⁇ inhibition assay as described herein and exhibited inhibition of greater than 50%.
  • a pharmaceutical composition comprising a compound of formula (IH) or a pharmaceutically acceptable salt or solvate thereof:
  • Het H1 and Het H2 independently represent a 5 membered heterocyclic ring system containing 1 to 3 heteroatoms selected from O, N or S;
  • R 5h represents hydrogen, C 1-6 alkyl or cyano
  • R 6h represents hydrogen, C 1-6 alkyl, C 1-6 alkoxy, cyano, C 3-8 cycloalkyl, -CH 2 —C 3-8 cycloalkyl, aryl, heteroaryl, —C 1-6 alkylene-aryl, —CO-aryl, —CO-heteroaryl or —C(R 7h )(R 8h )- heteroaryl, wherein said aryl groups of R 6h may be optionally substituted by one or more halogen or C 1-6 alkoxy groups;
  • R 7h and R 8h independently represent hydrogen or C 1-6 alkyl
  • R 1h and R 2h independently represent halogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-8 cycloalkyl, haloC 1-6 alkyl, hydroxyl, C 1-6 alkoxy, —O-C 1-6 alkenyl, haloC 1-6 alkoxy, -COOH, —CO—C 1-6 alkyl, -COO—C 1-6 alkyl, -CONH 2 , -CH 2 —CONH 2 , -NH—C 1-6 alkyl, -NH—C 2-6 alkenyl, —NH—CO—C 1-6 alkyl, —CO—NH—C 1-6 alkyl, —O—OH 2 —CO—NH—C 1-6 alkyl, -CH 2 —OH 2 —CO—NH—C 1-6 alkyl, —S—C 1-6 alkyl, —SO—C 1-6 alkyl, —SO 2 —C
  • u and v independently represent an integer from 0 to 3;
  • the compound of formula (IH) is selected from any of compounds: 395, 433, 689 and 786 as described herein or a pharmaceutically acceptable salt or solvate thereof.
  • salts are intended to indicate salts which are not harmful to the patient.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts and pharmaceutically acceptable akaline addition salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids.
  • suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like.
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
  • alkaline salts include, for example, sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, ethylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, pyridine, piperidine, piperazine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine.
  • bases such as, for example, methylamine, ethylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris(hydroxymethyl)aminomethane, ethanolamine, pyridine, piperidine, piperazine, picoline, dicyclohexylamine, morpholine, benzyl
  • the compounds of formulae (IA)-(IH) can be in racemic forms, as well as in the form of pure enantiomers or non racemic (scalemic) mixture of enantiomers, including when the compounds of formulae (IA)-(IH) have more than one stereogenic centre.
  • the compounds of formulae (IA)-(IH) have unsaturated carbon carbon double bonds, both the cis (Z) and trans (E) isomers and their mixtures belong to the invention.
  • halogen means a fluorine, chlorine, bromine or iodine atom.
  • C 1-6 alkyl means any linear, branched hydrocarbon groups having 1 to 6 carbon atoms, or cyclic hydrocarbon groups having 3 to 6 carbon atoms.
  • Representative examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, n-pentyl, isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • References to “haloC 1-6 alkyl” mean a C 1-6 alkyl group substituted by one or more halogen atoms as herein defined.
  • C 1-6 alkylene means a saturated divalent hydrocarbon chain having the specified number of member atoms.
  • C 1-6 alkylene refers to a bond or an alkylene group having from 1 to 6 member atoms.
  • Alkylene groups may be straight or branched. Representative branched alkylene groups have one or two branches.
  • Alkylene includes methylene, ethylene, propylene (n-propylene and isopropylene) and butylene (n-butylene, isobutylene, and t-butylene).
  • C 2-6 alkenyl means any linear, branched hydrocarbon groups of 2 to 6 carbon atoms, or cyclic hydrocarbon group having 3 to 6 carbon atoms having at least one double bond.
  • alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
  • C 2-6 alkynyl means any linear, or branched hydrocarbon groups of 2 to 6 carbon atoms, having at least one triple bond.
  • Representative examples of such alkynyl groups include ethynyl, propargyl and butynyl.
  • C 1-6 alkoxy means an —O—C 1-6 alkyl group wherein C 1-6 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like.
  • C 3-8 cycloalkyl means a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and the like.
  • aryl means a C 6-12 monocyclic or bicyclic hydrocarbon ring wherein at least one ring is aromatic. Examples of such groups include phenyl, indyl or naphthyl and the like.
  • heteroatom means a nitrogen, sulphur, or oxygen atom.
  • heterocyclyl means a saturated or unsaturated non-aromatic ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heterocyclyl groups containing more than one heteroatom may contain different heteroatoms. Heterocyclyl groups may be optionally substituted with one or more substituents as defined herein. Heterocyclyl groups are monocyclic ring systems or fused bicyclic or polycyclic ring systems or bicyclic structures known as heterocyclic “spiro” ring systems. In certain embodiments, heterocyclyl is saturated. In other embodiments, heterocyclyl is unsaturated and non-aromatic.
  • Non-limiting examples of monocyclic heterocyclyl ring systems include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 1 ,3-dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3- oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, and azetidinyl.
  • heteroaryl means an aromatic ring containing from 1 to 4 heteroatoms as member atoms in the ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl groups may be optionally substituted with one or more substituents as defined herein. Heteroaryl groups are monocyclic ring systems or are fused bicyclic or polycyclic ring systems. Monocyclic heteroaryl rings have 5 or 6 member atoms. Bicyclic heteroaryl rings have from 7 to 11 member atoms.
  • Bicyclic heteroaryl rings include those rings wherein phenyl and a monocyclic heterocyclyl ring are attached forming a fused bicyclic ring system, and those rings wherein a monocyclic heteroaryl ring and a monocyclic cycloalkyl, cycloalkenyl, heterocyclyl, or heteroaryl ring are attached forming a fused bicyclic ring system.
  • heteroaryl includes pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, furazanyl, thienyl, triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, benzimidazolyl, benopyranyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, furopyridinyl, and
  • heterocyclic ring system mean either a heterocyclyl ring system or a heteroaryl ring system as hereinbefore defined.
  • Representative compounds of the invention include compounds 1-1002 as set forth below:
  • composition comprising any one of the compounds of formulae (IA)-(IH) for use in the treatment of a neurodegenerative disorder, such as tauopathies.
  • compositions of the invention may comprise, in addition to one of the above substances, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • a pharmaceutically acceptable excipient e.g. oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal routes.
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may include a solid carrier such as gelatin or an adjuvant.
  • Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil.
  • Physiological saline solution dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection.
  • Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
  • the compounds of formulae (IA)-(IH) are believed to be casein kinase 1 delta (CK1 ⁇ ) inhibitors.
  • Certain compounds of formulae (IA)-(IH) have inhibitory activity of greater than 5%, in particular greater than 10%, more particularly greater than 25%, yet more particularly greater than 50%, especially greater than 75%, such as greater than 90%.
  • Such compounds may be useful in the treatment in neurodegenerative disorders such as tauopathies.
  • Tauopathies are conditions which are characterised by neurofibrillary tangles or aggregates of the tau protein.
  • Tauopathies are a recognised class of conditions known to those skilled in the art and include Alzheimer's disease, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy (PSP), Pick's disease, corticobasal degeneration, multisystem atrophy (MSA), neurobasal degeneration with iron accumulation, type 1 (Hallervorden-Spatz), argyrophilic grain dementia, Down's syndrome, diffuse neurofibrillary tangles with calcification, dementia pugilistica, Gerstmann-Straussler-Scheinker disease, myotonic dystrophy, Niemann-Pick disease type C, progressive subcortical gliosis, prion protein cerebral amyloid angiopathy, tangle only dementia, postencephalitic parkinsonism, subacute sclerosing panencephalitis, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis/parkinsonism-dementia complex
  • the intracellular tau deposits are usually neuronal or glial and are filamentous and generally in a hyperphosphorylated state as compared to the level of phosphorylation in tau from control human brain.
  • this hyperphosphorylated tau is often referred to a paired helical filament tau (PHF) tau because it is derived from the PHF.
  • the tauopathy comprises Alzheimer's disease.
  • a method of treating a neurodegenerative disorder such as tauopathies, which comprises administering a therapeutically effective amount of a compound of formulae (IA)-(IH).
  • the compounds of the invention may be tested for inhibition of casein kinase 1 delta (CK1 ⁇ ) in accordance with the assay protocols described in US 2010/0152157, EP 1,636,375 or Hanger et al (2007) J. Biol. Chem. 282, 23645-23654.
  • the assay was conducted in accordance with the following protocol :
  • Base Reaction buffer 20 mM Hepes (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO It should be noted that required cofactors are added individually to each kinase reaction.
  • Recombinant human full-length construct GST-tagged, expressed in insect cells.
  • compounds 10, 324, 654, 856, 859, 931, 947, 952, 987, 990 and 999 exhibited inhibition of greater than 90%.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Psychology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Toxicology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Quinoline Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pyrrole Compounds (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Furan Compounds (AREA)
US13/993,288 2010-12-14 2011-12-14 CASEIN KINASE 1delta (CK 1delta) INHIBITORS AND THEIR USE IN THE TREATMENT OF NEURODE-GENERATIVE DISEASES SUCH AS TAUOPATHIES Abandoned US20140031547A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GBGB1021161.3A GB201021161D0 (en) 2010-12-14 2010-12-14 Casein kinase 1delta (CK1Delta) inhibitors
GB1021161.3 2010-12-14
GB1109162.6 2011-06-01
GBGB1109162.6A GB201109162D0 (en) 2011-06-01 2011-06-01 Casein kinase 1Delta (CK1Delta) inhibitors
PCT/GB2011/052475 WO2012080729A2 (en) 2010-12-14 2011-12-14 CASEIN KINASE 1δ (CK1δ) INHIBITORS

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2011/052475 A-371-Of-International WO2012080729A2 (en) 2010-12-14 2011-12-14 CASEIN KINASE 1δ (CK1δ) INHIBITORS

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/171,582 Division US20160354375A1 (en) 2010-12-14 2016-06-02 CASEIN KINASE 1delta (CK 1delta) INHIBITORS AND THEIR USE IN THE TREATMENT OF NEURODEGENERATIVE DISEASES SUCH AS TAUOPATHIES

Publications (1)

Publication Number Publication Date
US20140031547A1 true US20140031547A1 (en) 2014-01-30

Family

ID=45444638

Family Applications (5)

Application Number Title Priority Date Filing Date
US13/993,288 Abandoned US20140031547A1 (en) 2010-12-14 2011-12-14 CASEIN KINASE 1delta (CK 1delta) INHIBITORS AND THEIR USE IN THE TREATMENT OF NEURODE-GENERATIVE DISEASES SUCH AS TAUOPATHIES
US13/993,303 Abandoned US20140018540A1 (en) 2010-12-14 2011-12-14 Casein kinase 1delta (ck 1delta) inhibitors
US14/677,273 Active US9789111B2 (en) 2010-12-14 2015-04-02 Casein kinase 1δ (CK 1δ) inhibitors
US14/842,155 Active US9763947B2 (en) 2010-12-14 2015-09-01 Casein kinase 1delta (CK1delta) inhibitors
US15/171,582 Abandoned US20160354375A1 (en) 2010-12-14 2016-06-02 CASEIN KINASE 1delta (CK 1delta) INHIBITORS AND THEIR USE IN THE TREATMENT OF NEURODEGENERATIVE DISEASES SUCH AS TAUOPATHIES

Family Applications After (4)

Application Number Title Priority Date Filing Date
US13/993,303 Abandoned US20140018540A1 (en) 2010-12-14 2011-12-14 Casein kinase 1delta (ck 1delta) inhibitors
US14/677,273 Active US9789111B2 (en) 2010-12-14 2015-04-02 Casein kinase 1δ (CK 1δ) inhibitors
US14/842,155 Active US9763947B2 (en) 2010-12-14 2015-09-01 Casein kinase 1delta (CK1delta) inhibitors
US15/171,582 Abandoned US20160354375A1 (en) 2010-12-14 2016-06-02 CASEIN KINASE 1delta (CK 1delta) INHIBITORS AND THEIR USE IN THE TREATMENT OF NEURODEGENERATIVE DISEASES SUCH AS TAUOPATHIES

Country Status (10)

Country Link
US (5) US20140031547A1 (cg-RX-API-DMAC7.html)
EP (3) EP2651404B1 (cg-RX-API-DMAC7.html)
JP (4) JP2014503528A (cg-RX-API-DMAC7.html)
CN (3) CN105920010A (cg-RX-API-DMAC7.html)
AU (2) AU2011343039B2 (cg-RX-API-DMAC7.html)
CA (1) CA2818903C (cg-RX-API-DMAC7.html)
DK (1) DK2835131T3 (cg-RX-API-DMAC7.html)
ES (2) ES2650744T3 (cg-RX-API-DMAC7.html)
HK (1) HK1214527A1 (cg-RX-API-DMAC7.html)
WO (2) WO2012080729A2 (cg-RX-API-DMAC7.html)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8809349B2 (en) 2011-01-10 2014-08-19 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
US8828998B2 (en) 2012-06-25 2014-09-09 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
US9206182B2 (en) 2009-07-15 2015-12-08 Intellikine Llc Substituted isoquinolin-1(2H)-one compounds, compositions, and methods thereof
US9328096B2 (en) 2014-05-07 2016-05-03 Pfizer Inc. Tropomyosin-related kinase inhibitors
US9815841B2 (en) 2014-01-29 2017-11-14 Glaxosmithkline Intellectual Property Development Limited Compounds
US9822131B2 (en) 2008-01-04 2017-11-21 Intellikine Llc Certain chemical entities, compositions and methods
US9868749B2 (en) * 2013-12-09 2018-01-16 Ucb Biopharma Sprl Fused imidazole and pyrazole derivatives as modulators of TNF activity
WO2018030762A1 (ko) * 2016-08-09 2018-02-15 세종대학교산학협력단 Ampk 억제기능에 기반한 뇌졸중 치료용 약학적 조성물
US10087186B2 (en) 2014-01-29 2018-10-02 Glaxosmithkline Intellectual Property Development Limited Compounds as LRRK2 kinase inhibitors
US10357489B2 (en) 2017-07-10 2019-07-23 Celgene Corporation Antiproliferative compounds and methods of use thereof
US10709714B2 (en) 2013-11-22 2020-07-14 Clifton Life Sciences LLC Gastrin antagonists for treatment and prevention of osteoporosis
US10894797B2 (en) 2018-09-18 2021-01-19 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as SRC homology-2 phosphatase inhibitors
US10947242B2 (en) 2016-11-02 2021-03-16 Janssen Pharmaceutica, Nv [1,2,4]triazolo[1,5and#8208;A]pyrimidine compounds as PDE2 inhibitors
US10947239B2 (en) 2015-11-02 2021-03-16 Janssen Pharmaceutica Nv [1,2,4]triazolo[1,5-a]pyrimidin-7-yl compound
US11053248B2 (en) 2016-11-02 2021-07-06 Janssen Pharmaceutica Nv [1,2,4]triazolo[1,5-a]pyrimidine compounds as PDE2 inhibitors
US11110096B2 (en) 2014-04-16 2021-09-07 Infinity Pharmaceuticals, Inc. Combination therapies
US11147818B2 (en) 2016-06-24 2021-10-19 Infinity Pharmaceuticals, Inc. Combination therapies
US11319321B2 (en) 2016-11-02 2022-05-03 Janssen Pharmaceutica Nv [1,2,4]triazolo[1,5-a]pyrimidine compounds as PDE2 inhibitors
US11613548B2 (en) 2021-02-19 2023-03-28 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors
US12084458B2 (en) 2021-02-19 2024-09-10 Sudo Biosciences Limited Substituted pyridines, pyridazines, and pyrimidines as TYK2 inhibitors
US12213983B2 (en) 2012-11-01 2025-02-04 Infinity Pharmaceuticals, Inc. Treatment of cancers using PI3 kinase isoform modulators
US12221430B2 (en) 2017-09-11 2025-02-11 Hodogaya Chemical Co., Ltd. Compound having pyrimidine ring structure and organic electroluminescence device

Families Citing this family (215)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2635581C (en) 2005-12-28 2017-02-28 Vertex Pharmaceuticals Incorporated Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide
PL2448938T3 (pl) 2009-06-29 2014-11-28 Incyte Holdings Corp Pirymidynony jako inhibitory PI3K
WO2011075643A1 (en) 2009-12-18 2011-06-23 Incyte Corporation Substituted heteroaryl fused derivatives as pi3k inhibitors
WO2011123609A1 (en) * 2010-03-31 2011-10-06 Glaxo Group Limited Imidazolyl-imidazoles as kinase inhibitors
CA2796311A1 (en) 2010-04-14 2011-10-20 Incyte Corporation Fused derivatives as pi3k.delta. inhibitors
US9062055B2 (en) 2010-06-21 2015-06-23 Incyte Corporation Fused pyrrole derivatives as PI3K inhibitors
JP2014503528A (ja) * 2010-12-14 2014-02-13 エレクトロプホレトイクス リミテッド カゼインキナーゼ１δ（ＣＫ１δ）阻害剤及びタウオパチーなどの神経変性疾患の治療におけるその使用
CA2822070C (en) 2010-12-20 2019-09-17 Incyte Corporation N-(1-(substituted-phenyl)ethyl)-9h-purin-6-amines as pi3k inhibitors
US8754114B2 (en) 2010-12-22 2014-06-17 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
WO2012125629A1 (en) 2011-03-14 2012-09-20 Incyte Corporation Substituted diamino-pyrimidine and diamino-pyridine derivatives as pi3k inhibitors
GB201104267D0 (en) 2011-03-14 2011-04-27 Cancer Rec Tech Ltd Pyrrolopyridineamino derivatives
WO2012135009A1 (en) 2011-03-25 2012-10-04 Incyte Corporation Pyrimidine-4,6-diamine derivatives as pi3k inhibitors
AR087701A1 (es) 2011-08-31 2014-04-09 Japan Tobacco Inc Derivados de pirazol con actividad inhibidora de sglt1
PH12021552978A1 (en) 2011-09-02 2022-08-22 Incyte Holdings Corp Heterocyclylamines as pi3k inhibitors
UA115133C2 (uk) 2011-10-07 2017-09-25 Такеда Фармасьютікал Компані Лімітед Сполуки 1-арилкарбоніл-4-оксипіперидину, придатні для лікування нейродегенеративних захворювань
PH12014500820A1 (en) 2011-10-18 2014-05-19 Astellas Pharma Inc Bicyclic heterocyclic compound
AR090037A1 (es) 2011-11-15 2014-10-15 Xention Ltd Derivados de tieno y/o furo-pirimidinas y piridinas inhibidores de los canales de potasio
KR102000770B1 (ko) 2011-12-01 2019-07-16 케모센트릭스, 인크. Ｃｃｒ(4) 길항제로서의 치환된 아닐린
AR090548A1 (es) 2012-04-02 2014-11-19 Incyte Corp Azaheterociclobencilaminas biciclicas como inhibidores de pi3k
EP3495367B1 (en) 2012-06-13 2020-09-30 Incyte Holdings Corporation Substituted tricyclic compounds as fgfr inhibitors
CN104364239B (zh) 2012-06-13 2017-08-25 霍夫曼-拉罗奇有限公司 二氮杂螺环烷烃和氮杂螺环烷烃
JP6299591B2 (ja) * 2012-07-03 2018-03-28 小野薬品工業株式会社 ソマトスタチン受容体作動活性を有する化合物およびその医薬用途
WO2014009891A1 (en) * 2012-07-11 2014-01-16 Piramal Enterprises Limited Heterocyclic compounds for use in the treatment of cancers
WO2014026125A1 (en) 2012-08-10 2014-02-13 Incyte Corporation Pyrazine derivatives as fgfr inhibitors
CN113679717A (zh) * 2012-08-22 2021-11-23 康奈尔大学 用于抑制肌成束蛋白的方法
RU2641293C2 (ru) * 2012-08-24 2018-01-17 Тревентис Корпорейшн Бензофуразановые антимилоидные соединения и способы
CN102850341B (zh) * 2012-09-05 2015-02-18 浙江工业大学 一种噻二唑类化合物及其制备与应用
GB201216018D0 (en) 2012-09-07 2012-10-24 Cancer Rec Tech Ltd Pharmacologically active compounds
ES2753163T3 (es) 2012-09-25 2020-04-07 Hoffmann La Roche Derivados de hexahidropirrolo[3,4-c]pirrol y compuestos relacionados como inhibidores de la autotaxina (ATX) y como inhibidores de la producción de ácido lisofosfatídico (LPA) para tratar, por ejemplo, enfermedades renales
CN103739594A (zh) * 2012-10-17 2014-04-23 南京大学 一类含吡嗪环和三氮唑结构的席夫碱类衍生物及其制法
WO2014084778A1 (en) 2012-11-27 2014-06-05 Thomas Helledays Stiftelse För Medicinsk Forskning Pyrimidine-2,4-diamine derivatives for treatment of cancer
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
JP6284490B2 (ja) * 2012-12-28 2018-02-28 株式会社新日本科学 イミダゾピリジン誘導体を有効成分として含むｏｃｔ３活性阻害剤又はｏｃｔ３検出剤
NZ710444A (en) * 2013-02-11 2020-08-28 Univ California Compositions and methods for treating neurodegenerative diseases and cardiomyopathy
AR095079A1 (es) 2013-03-12 2015-09-16 Hoffmann La Roche Derivados de octahidro-pirrolo[3,4-c]-pirrol y piridina-fenilo
EP2970306A4 (en) 2013-03-15 2016-08-03 Epizyme Inc SUBSTITUTED 6.5-CONDENSED BICYCLIC HETEROARYL COMPOUNDS
US9045477B2 (en) 2013-03-15 2015-06-02 Epizyme, Inc. Substituted 6,5-fused bicyclic heteroaryl compounds
EP2967046A4 (en) 2013-03-15 2016-12-21 Whitehead Inst Biomedical Res BENZIMIDAZOLE DERIVATIVES AND USES THEREOF
DK2986610T5 (en) 2013-04-19 2018-12-10 Incyte Holdings Corp BICYCLIC HETEROCYCLES AS FGFR INHIBITORS
US9797882B2 (en) 2013-07-09 2017-10-24 The Translational Genomics Research Institute Method of screening for a compound for inhibitory activity of FN14-tweak interaction
US9238034B2 (en) * 2013-07-09 2016-01-19 The Translational Genomics Research Institute FN14 antagonists and therapeutic uses thereof
TWI649308B (zh) 2013-07-24 2019-02-01 小野藥品工業股份有限公司 喹啉衍生物
GB201314452D0 (en) 2013-08-13 2013-09-25 Ostara Biomedical Ltd Embryo implantation
RU2570907C2 (ru) * 2013-10-21 2015-12-20 Автономная Некоммерческая Организация "Научно-Исследовательский Центр Биотехнологии Антибиотиков И Других Биологически Активных Веществ "Биоан" Производные 3-ациламинопиридин-2(1h)-она, применимые как ингибиторы серин-треониновой протеинкиназы gsk3b в качестве лекарственных препаратов для лечения диабета ii типа.
CA2923523A1 (en) 2013-11-26 2015-06-04 F. Hoffmann-La Roche Ag New octahydro-cyclobuta [1,2-c;3,4-c']dipyrrol-2-yl
EP3091984B1 (en) * 2014-01-09 2020-04-22 The J. David Gladstone Institutes, A Testamentary Trust Established under The Will of J. David Gladstone Substituted benzoxazine and related compounds
AU2015217152A1 (en) 2014-02-11 2016-08-11 Mitokinin, Inc. Compositions and methods using the same for treatment of neurodegenerative and mitochondrial disease
US9527835B2 (en) 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
CN106164066B (zh) 2014-02-13 2020-01-17 因赛特公司 作为lsd1抑制剂的环丙胺
US9493442B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
JP6602779B2 (ja) 2014-02-13 2019-11-06 インサイト・コーポレイション Ｌｓｄ１阻害剤としてのシクロプロピルアミン類
US9573946B2 (en) 2014-02-20 2017-02-21 Novita Pharmaceuticals, Inc. Compounds and methods for inhibiting fascin
DK3110812T3 (da) * 2014-02-27 2019-07-08 Treventis Corp Anti-amyloidforbindelser indeholdende benzofurazan
JP6554481B2 (ja) 2014-03-26 2019-07-31 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ オートタキシン（ａｔｘ）及びリゾホスファチジン酸（ｌｐａ）産生の阻害剤としての縮合［１，４］ジアゼピン化合物
SG11201607839UA (en) 2014-03-26 2016-10-28 Hoffmann La Roche Bicyclic compounds as autotaxin (atx) and lysophosphatidic acid (lpa) production inhibitors
CN106164059A (zh) * 2014-04-11 2016-11-23 爱默蕾大学 用天冬酰胺内肽酶（aep）抑制剂以及相关组合物对神经退行性疾病的治疗
CN105085436B (zh) * 2014-04-19 2019-08-16 广东东阳光药业有限公司 磺酰胺类衍生物及其在药物上的应用
HUE057317T2 (hu) 2014-04-23 2022-04-28 Dart Neuroscience Llc Helyettesített [1,2,4]triazolo[1,5-A]pirimidin-7-IL vegyületeket tartalmazó készítmények mint PDE2 inhibítorok
CN104059060B (zh) * 2014-05-30 2017-08-01 西安交通大学 一种5‑(1h‑吲哚‑3‑亚甲基)‑1,3‑噻唑烷‑4‑酮类衍生物及其合成方法和应用
US10064869B2 (en) 2014-06-04 2018-09-04 Thomas Helledays Stiftelse For Medicinsk Forskning MTH1 inhibitors for treatment of inflammatory and autoimmune conditions
CA2949785A1 (en) 2014-06-04 2015-12-10 Thomas Helledays Stiftelse For Medicinsk Forskning Mth1 inhibitors for treatment of cancer
US10077277B2 (en) 2014-06-11 2018-09-18 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
US9695168B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors
WO2016007722A1 (en) 2014-07-10 2016-01-14 Incyte Corporation Triazolopyridines and triazolopyrazines as lsd1 inhibitors
TW201613925A (en) 2014-07-10 2016-04-16 Incyte Corp Imidazopyrazines as LSD1 inhibitors
WO2016007727A1 (en) 2014-07-10 2016-01-14 Incyte Corporation Triazolopyridines and triazolopyrazines as lsd1 inhibitors
EP3174877B1 (en) * 2014-07-31 2022-06-29 Merck Patent GmbH Indolizine derivatives which are applicable to neurodegenerative diseases
EP3189070A4 (en) 2014-08-04 2018-06-27 Drexel University Novel compounds and methods of treating or ameliorating an il-1r-mediated disease or disorder using same
JO3589B1 (ar) 2014-08-06 2020-07-05 Novartis Ag مثبطات كيناز البروتين c وطرق استخداماتها
JP6746569B2 (ja) 2014-10-07 2020-08-26 バーテックス ファーマシューティカルズ インコーポレイテッドＶｅｒｔｅｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃｏｒｐｏｒａｔｅｄ 嚢胞性線維症膜貫通コンダクタンス制御因子のモジュレーターの共結晶
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
GB201419579D0 (en) * 2014-11-03 2014-12-17 Iomet Pharma Ltd Pharmaceutical compound
US10239882B2 (en) 2014-11-05 2019-03-26 Dart Neuroscience (Cayman) Ltd. Substituted 5-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-amine compounds as PDE2 inhibitors
US10208034B2 (en) 2014-12-25 2019-02-19 Ono Pharmaceutical Co., Ltd. Quinoline derivative
GB201501302D0 (en) 2015-01-27 2015-03-11 Ostara Biomedical Ltd Embryo implantation
CR20170390A (es) 2015-02-20 2017-10-23 Incyte Holdings Corp Heterociclos biciclicos como inhibidores de fgfr
WO2016134294A1 (en) 2015-02-20 2016-08-25 Incyte Corporation Bicyclic heterocycles as fgfr4 inhibitors
MA41551A (fr) 2015-02-20 2017-12-26 Incyte Corp Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4
LT3262046T (lt) 2015-02-27 2021-01-11 Incyte Corporation Pi3k inhibitoriaus druskos ir jų gamybos būdai
CN113350353A (zh) * 2015-03-23 2021-09-07 墨尔本大学 呼吸性疾病的治疗
CN107660205B (zh) 2015-04-03 2021-08-27 因赛特公司 作为lsd1抑制剂的杂环化合物
MA41898A (fr) 2015-04-10 2018-02-13 Hoffmann La Roche Dérivés de quinazolinone bicyclique
US10370328B2 (en) * 2015-04-30 2019-08-06 Musc Foundation For Research Development Oxindole compounds and pharmaceutical compositions thereof
US9988401B2 (en) 2015-05-11 2018-06-05 Incyte Corporation Crystalline forms of a PI3K inhibitor
WO2016183060A1 (en) 2015-05-11 2016-11-17 Incyte Corporation Process for the synthesis of a phosphoinositide 3-kinase inhibitor
GB201508276D0 (en) 2015-05-14 2015-06-24 Electrophoretics Ltd A casein kinase 1 delta inhibitor
GB201509134D0 (en) 2015-05-28 2015-07-15 Electrophoretics Ltd Biomolecules involved in Alzheimer's disease
BR112017025851A2 (pt) * 2015-06-01 2018-10-16 Bantam Pharmaceutical, Llc compostos de pirazol e pirrol substituídos e métodos para usar os mesmos para inibição de iniciação de tradução e tratamento de doenças e distúrbios relacionados aos mesmo
WO2016202756A1 (en) 2015-06-18 2016-12-22 Bayer Pharma Aktiengesellschaft Substituted 2-(1h-pyrazol-1-yl)-1h-benzimidazole compounds
WO2016202758A1 (en) 2015-06-18 2016-12-22 Bayer Pharma Aktiengesellschaft Substituted 2-(1h-pyrazol-1-yl)-1h-benzimidazole compounds
WO2017000277A1 (en) 2015-07-01 2017-01-05 Merck Sharp & Dohme Corp. Substituted triazolo bicycliccompounds as pde2 inhibitors
CN108290855A (zh) * 2015-07-01 2018-07-17 西北大学 被取代的喹唑啉化合物及其调节葡糖脑苷脂酶活性的用途
EA035534B1 (ru) 2015-08-12 2020-06-30 Инсайт Корпорейшн Соли ингибитора lsd1
CN105061462B (zh) * 2015-08-18 2017-05-24 沈阳药科大学 含有酰胺的四氢苯并[4,5]噻吩并[2,3‑d]嘧啶类化合物及其应用
CA2992889A1 (en) 2015-09-04 2017-03-09 F. Hoffmann-La Roche Ag Phenoxymethyl derivatives
CA2997537C (en) 2015-09-18 2024-02-13 Kaken Pharmaceutical Co., Ltd. Biaryl derivative and medicine containing same
CA2983782A1 (en) 2015-09-24 2017-03-30 F. Hoffmann-La Roche Ag Bicyclic compounds as atx inhibitors
JP6877413B2 (ja) 2015-09-24 2021-05-26 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ 二重ａｔｘ／ｃａ阻害剤としての新規な二環式化合物
EP3353181B1 (en) 2015-09-24 2021-08-11 F. Hoffmann-La Roche AG Bicyclic compounds as dual atx/ca inhibitors
WO2017050792A1 (en) 2015-09-24 2017-03-30 F. Hoffmann-La Roche Ag Bicyclic compounds as atx inhibitors
GB201517523D0 (en) 2015-10-05 2015-11-18 Ostara Biomedical Ltd Methods and compositions for managing reproduction
WO2017062500A2 (en) 2015-10-05 2017-04-13 The Trustees Of Columbia University In The City Of New York Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies
WO2017063966A1 (en) 2015-10-13 2017-04-20 Bayer Pharma Aktiengesellschaft Substituted 2-(1h-pyrazol-1-yl)-benzothiazole compounds
ES2926781T3 (es) * 2015-12-07 2022-10-28 Hinova Pharmaceuticals Inc Compuestos de quinoleína, método de preparación de los mismos, y uso de los mismos como fármaco inhibidor del transportador de urato
WO2017106367A1 (en) * 2015-12-15 2017-06-22 D.E. Shaw Research, Llc Method of treating neurodegenerative disorders by rescuing alpha-synuclein toxicity
CN107840826B (zh) * 2016-09-19 2021-07-09 西华大学 1h-吲唑类衍生物及其作为ido抑制剂的用途
CN107033087B (zh) * 2016-02-04 2020-09-04 西华大学 1h-吲唑-4-胺类化合物及其作为ido抑制剂的用途
WO2017133258A1 (zh) * 2016-02-04 2017-08-10 西华大学 1h-吲唑类衍生物及其作为ido抑制剂的用途
BR112018071585B1 (pt) 2016-04-22 2024-01-02 Incyte Corporation Formulações de um inibidor de lsd1, seus usos e método de preparação das mesmas
WO2017210545A1 (en) 2016-06-02 2017-12-07 Cadent Therapeutics, Inc. Potassium channel modulators
KR20230109185A (ko) 2016-06-07 2023-07-19 자코바이오 파마슈티칼스 컴퍼니 리미티드 Shp2 억제제로서 유용한 신규한 헤테로환형 유도체
US10906888B2 (en) 2016-07-14 2021-02-02 Pfizer Inc. Pyrimidine carboxamides as inhibitors of Vanin-1 enzyme
WO2018033918A1 (en) 2016-08-18 2018-02-22 Vidac Pharma Ltd. Piperazine derivatives, pharmaceutical compositions and methods of use thereof
TWI750218B (zh) 2016-09-02 2021-12-21 美商賽克瑞恩醫療公司 sGC 刺激劑
CN106432235B (zh) * 2016-10-19 2018-02-02 南通大学 靶向CDK和DNA的β‑咔啉衍生物及其制备方法和医药用途
US11970486B2 (en) 2016-10-24 2024-04-30 Janssen Pharmaceutica Nv Compounds and uses thereof
EP3538101B1 (en) 2016-11-14 2024-06-19 Virginia Commonwealth University Inhibitors of cancer and/or metastasis
EP3541378A4 (en) * 2016-11-16 2020-10-07 University of South Florida ALLOSTERIC ANTAGONISTS OF GPRC6A AND THEIR USE IN THE MITIGATION OF PROTEINOPATHIES
CN110392833A (zh) 2017-01-06 2019-10-29 优曼尼蒂治疗公司 治疗神经病症的方法
CN110494136A (zh) * 2017-01-10 2019-11-22 瑞士苏黎世联邦理工学院 细胞保护性化合物及其用途
CN106831573B (zh) * 2017-01-23 2019-05-24 南阳师范学院 (n-1,2,3,4-四氢异喹啉基)-阿魏酰胺化合物、制备方法及其应用
CN106748969B (zh) * 2017-01-23 2019-06-18 南阳师范学院 一种n-(4-苄基哌啶基)-阿魏酰胺化合物、制备方法及其用途
PL3571193T3 (pl) 2017-01-23 2022-04-25 Cadent Therapeutics, Inc. Modulatory kanału potasowego
JP6605763B2 (ja) 2017-01-26 2019-11-13 小野薬品工業株式会社 キノリン誘導体のエタンスルホン酸塩
ES2902885T3 (es) * 2017-02-01 2022-03-30 Yissum Res Dev Co Of Hebrew Univ Jerusalem Ltd Derivados de N1-(4-(5-(ciclopropilmetil)-1-metil-1H-pirazol-4-il)piridin-2-il)ciclohexano-1,4-diamina y compuestos relacionados como inhibidores de CK1 y/o IRAK1 para el tratamiento del cáncer
CN109700798A (zh) * 2017-03-01 2019-05-03 浙江大学 苯并吡喃黄酮结构类型雄激素受体拮抗剂及其应用
KR20190129924A (ko) 2017-03-16 2019-11-20 에프. 호프만-라 로슈 아게 이중 오토탁신(atx)/탄산 무수화효소(ca) 억제제로서 유용한 헤테로환형 화합물
WO2018167113A1 (en) 2017-03-16 2018-09-20 F. Hoffmann-La Roche Ag New bicyclic compounds as atx inhibitors
ES2788856T3 (es) 2017-03-20 2020-10-23 Forma Therapeutics Inc Composiciones de pirrolopirrol como activadores de quinasa de piruvato (PKR)
PT3601239T (pt) 2017-03-23 2024-10-24 Jacobio Pharmaceuticals Co Ltd Novos derivados heterocíclicos úteis como inibidores de shp2
JP7191298B2 (ja) 2017-04-26 2022-12-19 バジリア・ファルマスーチカ・インターナショナル・アーゲー，アルシュヴィル フラザノベンズイミダゾール類及びその結晶形の調製方法
US11136312B2 (en) * 2017-05-12 2021-10-05 Board of Trustees of the Southern Illinois University 3,4,5-trisubstituted-1,2,4-triazoles and 3,4,5-trisubstituted-3-thio-1,2,4-triazoles and uses thereof
AR111960A1 (es) 2017-05-26 2019-09-04 Incyte Corp Formas cristalinas de un inhibidor de fgfr y procesos para su preparación
JOP20190282A1 (ar) 2017-06-09 2019-12-05 Novartis Ag مركبات وتركيبات لحث تكوّن الغضاريف
JP2020523379A (ja) * 2017-06-14 2020-08-06 ヨーロピアン モレキュラー バイオロジー ラボラトリーＥｕｒｏｐｅａｎ Ｍｏｌｅｃｕｌａｒ Ｂｉｏｌｏｇｙ Ｌａｂｏｒａｔｏｒｙ 治療への使用のためのベンゾフランアミドおよびそれらの複素芳香族アナログ
AU2018290225A1 (en) 2017-06-21 2020-01-23 Mitokinin, Inc. Compositions and methods using the same for treatment of neurodegenerative and mitochondrial disease
GB201710851D0 (en) * 2017-07-06 2017-08-23 Galápagos Nv Novel compounds and pharmaceutical compositions thereof for the treatment of fibrosis
ES3008911T3 (en) 2017-07-11 2025-03-25 Vertex Pharma Carboxamides as modulators of sodium channels
CA3075880A1 (en) 2017-09-15 2019-03-21 Forma Therapeutics, Inc. Tetrahydro-imidazo quinoline compositions as cbp/p300 inhibitors
US11826363B2 (en) 2017-10-13 2023-11-28 Ono Pharmaceutical Co., Ltd. Therapeutic agent for solid cancers, which comprises Axl inhibitor as active ingredient
WO2019079578A1 (en) 2017-10-19 2019-04-25 Amgen Inc. BENZIMIDAZOLE DERIVATIVES AND USES THEREOF
WO2019084157A1 (en) 2017-10-24 2019-05-02 Yumanity Therapeutics, Inc. COMPOUNDS AND USES THEREOF
US20200325148A1 (en) * 2017-12-21 2020-10-15 Gliapharm Sa Compositions and methods of treatment for neurological disorders comprising motor neuron diseases
CA3083368A1 (en) * 2017-12-21 2019-06-27 Gliapharm Sa Compositions and methods of treatment for neurological disorders comprising a dementia
CA3092470A1 (en) 2018-02-27 2019-09-06 Incyte Corporation Imidazopyrimidines and triazolopyrimidines as a2a / a2b inhibitors
US20210040074A1 (en) * 2018-03-06 2021-02-11 The United States Of America,As Represented By The Secretary,Department Of Health And Human Services Positive allosteric modulators of dopamine 1 receptor and method of use thereof
EP3543231A1 (en) * 2018-03-19 2019-09-25 ETH Zurich Compounds for treating cns- and neurodegenerative diseases
AU2019238326B2 (en) 2018-03-23 2025-03-06 Janssen Pharmaceutica Nv Compounds and uses thereof
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
CN112566912A (zh) 2018-05-04 2021-03-26 因赛特公司 Fgfr抑制剂的盐
TWI815887B (zh) * 2018-05-15 2023-09-21 美商愛彼特生物製藥股份有限公司 經取代的2,2'-雙嘧啶基化合物、其類似物及其使用方法
WO2019222677A1 (en) 2018-05-18 2019-11-21 Incyte Corporation Fused pyrimidine derivatives as a2a / a2b inhibitors
CA3101323A1 (en) 2018-06-01 2019-12-05 Incyte Corporation Dosing regimen for the treatment of pi3k related disorders
GB201810092D0 (en) 2018-06-20 2018-08-08 Ctxt Pty Ltd Compounds
GB201810581D0 (en) 2018-06-28 2018-08-15 Ctxt Pty Ltd Compounds
MX2023013508A (es) 2018-06-29 2023-12-13 Forma Therapeutics Inc Inhibicion de la proteina de union a creb (cbp).
AU2019297361B2 (en) 2018-07-05 2024-06-27 Incyte Corporation Fused pyrazine derivatives as A2A / A2B inhibitors
US12195432B2 (en) * 2018-08-06 2025-01-14 The Board Of Trustees Of The Leland Stanford Junior University 2-arylbenzimidazoles as Ppargc1a activators for treating neurodegenerative diseases
WO2020047030A1 (en) 2018-08-29 2020-03-05 Chemocentryx, Inc. Combination therapy using c-c chemokine receptor 4 (ccr4) antagonists and one or more immune checkpoint inhibitors
US10968200B2 (en) 2018-08-31 2021-04-06 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
WO2020051206A1 (en) * 2018-09-04 2020-03-12 Brown University Compositions and methods for the modulation of crfbp and the treatment of alcoholism
WO2020061378A1 (en) 2018-09-19 2020-03-26 Forma Therapeutics, Inc. Treating sickle cell disease with a pyruvate kinase r activating compound
ES2989438T3 (es) 2018-09-19 2024-11-26 Novo Nordisk Healthcare Ag Activación de la piruvato cinasa R
CN112839935A (zh) 2018-09-26 2021-05-25 北京加科思新药研发有限公司 可用作shp2抑制剂的新型杂环衍生物
BR112021007552A2 (pt) 2018-10-22 2021-07-27 Cadent Therapeutics, Inc. formas cristalinas de moduladores de canal de potássio
WO2020086504A1 (en) * 2018-10-23 2020-04-30 Daiichi Sankyo Company, Limited Biaryl derivative
EP3877383A4 (en) 2018-11-07 2022-09-21 The University of Melbourne COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF RESPIRATORY DISEASES
CN109503563B (zh) * 2018-12-10 2020-05-12 济南大学 多功能乙酰胆碱酯酶抑制剂及其应用
KR102128509B1 (ko) * 2018-12-19 2020-07-01 한국과학기술연구원 말단 아민기에 아릴 또는 헤테로아릴기가 치환된 신규한 히드라존 유도체 및 이의 용도
JP7507162B2 (ja) * 2019-01-04 2024-06-27 ベルブルック ラボズ，エルエルシー 治療薬としてのｃＧＡＳ活性の阻害剤
WO2020146612A1 (en) 2019-01-10 2020-07-16 Vertex Pharmaceuticals Incorporated Esters and carbamates as modulators of sodium channels
US12441703B2 (en) 2019-01-10 2025-10-14 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
MA54829A (fr) 2019-01-24 2021-12-01 Yumanity Therapeutics Inc Composés et leurs utilisations
TWI829857B (zh) 2019-01-29 2024-01-21 美商英塞特公司 作為a2a / a2b抑制劑之吡唑并吡啶及三唑并吡啶
WO2020185532A1 (en) 2019-03-08 2020-09-17 Incyte Corporation Methods of treating cancer with an fgfr inhibitor
EP3937940A4 (en) 2019-03-15 2022-12-21 Forma Therapeutics, Inc. Inhibiting cyclic amp-responsive element-binding protein (creb)
JP7546596B2 (ja) * 2019-04-26 2024-09-06 セルジーン コーポレーション ヘテロ環式化合物ならびに蠕虫感染および疾患におけるその使用
UY38687A (es) 2019-05-17 2023-05-15 Novartis Ag Inhibidores del inflamasoma nlrp3, composiciones, combinaciones de los mismos y métodos para su uso
RS64931B9 (sr) 2019-06-18 2025-06-30 Pfizer Derivati benzizoxazol sulfonamida
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
JP7721501B2 (ja) 2019-07-31 2025-08-12 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｃｄ３８の阻害剤としてのヘテロ二環式アミド
RU2746423C2 (ru) * 2019-09-02 2021-04-13 Общество с ограниченной ответственностью "Научно-исследовательский институт ХимРар" (ООО "НИИ ХимРар") Ингибитор вируса гепатита В (ВГВ)
MA57202B1 (fr) 2019-09-19 2025-09-30 Novo Nordisk Health Care Ag Compositions d'activation de la pyruvate kinase r (pkr)
US12122767B2 (en) 2019-10-01 2024-10-22 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
GEAP202415945A (en) 2019-10-14 2024-04-25 Incyte Corp Bicyclic heterocycles as fgfr inhibitors
WO2021076728A1 (en) 2019-10-16 2021-04-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
EA202192047A1 (ru) 2019-11-13 2021-12-08 Юманити Терапьютикс, Инк. Соединения и их применение
CN114929217A (zh) 2019-11-14 2022-08-19 锌医疗公司 基于ampk抑制功能和锌稳态控制功能用于治疗多发性硬化的药物组合物
BR112022010664A2 (pt) 2019-12-04 2022-08-16 Incyte Corp Derivados de um inibidor de fgfr
EP4069696A1 (en) 2019-12-04 2022-10-12 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors
PT4069691T (pt) 2019-12-06 2024-12-18 Vertex Pharma Tetrahidrofuranos substituídos como moduladores dos canais de sódio
US12012409B2 (en) 2020-01-15 2024-06-18 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
AR122711A1 (es) * 2020-06-25 2022-09-28 Alchemedicine Inc COMPUESTO HETEROCÍCLICO COMO INHIBIDOR DE CASEÍNA QUINASA 1d Y/O QUINASA 5 TIPO RECEPTOR DE ACTIVINA
US20230265082A1 (en) * 2020-08-10 2023-08-24 Dana-Farber Cancer Institute, Inc. Substituted 1,2,4-oxadiazoles as small molecule inhibitors of ubiquitin-specific protease 28
KR20230069169A (ko) * 2020-09-17 2023-05-18 얀센 파마슈티카 엔.브이. 카제인 키나제 1 델타 조절제
US11801243B2 (en) 2020-09-23 2023-10-31 Forma Therapeutics, Inc. Bromodomain inhibitors for androgen receptor-driven cancers
US11795168B2 (en) 2020-09-23 2023-10-24 Forma Therapeutics, Inc. Inhibiting cyclic amp-responsive element-binding protein (CREB) binding protein (CBP)
GB202101734D0 (en) * 2021-02-08 2021-03-24 Cerevance Inc Novel Compounds
US12128035B2 (en) 2021-03-19 2024-10-29 Novo Nordisk Health Care Ag Activating pyruvate kinase R
TW202304459A (zh) 2021-04-12 2023-02-01 美商英塞特公司 包含ｆｇｆｒ抑制劑及ｎｅｃｔｉｎ－４靶向劑之組合療法
KR20230146639A (ko) * 2021-04-21 2023-10-19 장춘 진사이언스 파마슈티컬 씨오., 엘티디. 이미다졸 함유 축합고리계 유도체, 이의 제조방법 및 이의 의약적 용도
GEAP202416430A (en) 2021-06-04 2024-03-25 Vertex Pharma N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
WO2022261159A1 (en) 2021-06-09 2022-12-15 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors
JP2024522189A (ja) 2021-06-09 2024-06-11 インサイト・コーポレイション Ｆｇｆｒ阻害剤としての三環式ヘテロ環
CA3233233A1 (en) * 2021-10-15 2023-04-20 Ruben Abagyan Substituted 1h-pyrazolo [4,3-c] quinolines, methods of preparation, and use thereof
CN119677737A (zh) 2022-04-22 2025-03-21 沃泰克斯药物股份有限公司 用于治疗疼痛的杂芳基化合物
CN115466211B (zh) * 2022-06-09 2024-02-23 中国人民解放军空军军医大学 一种n-苯基喹啉-4-胺类化合物及其应用
CN119497615A (zh) * 2022-07-14 2025-02-21 上海日馨医药科技股份有限公司 Tpk激动剂及使用其治疗神经退行性疾病的方法
UY40374A (es) 2022-08-03 2024-02-15 Novartis Ag Inhibidores de inflamasoma nlrp3
TW202428579A (zh) * 2022-10-19 2024-07-16 大陸商長春金賽藥業有限責任公司 Ｎｋ３ｒ拮抗劑的晶型及其製備方法和用途
EP4646263A1 (en) * 2023-01-20 2025-11-12 Allianthera (Suzhou) Biopharmaceutical Co., Ltd. Sprk1 inhibitors and methods of use
AR131690A1 (es) * 2023-01-30 2025-04-23 Eurofarma Laboratorios S A COMPUESTOS FENÓLICOS BLOQUEADORES DE Nav 1.7 Y/O Nav 1.8, SUS PROCESOS DE OBTENCIÓN, SUS COMPOSICIONES, SUS USOS, LOS MÉTODOS DE TRATAMIENTO DE LOS MISMOS Y LOS KITS
EP4660182A1 (en) * 2023-01-30 2025-12-10 Eurofarma Laboratórios S.A. Nav1.7- and/or nav1.8-inhibiting aryl pyridine compounds, processes for the preparation thereof, compositions, uses, methods for treatment using same, and kits
CN118666857B (zh) * 2024-06-26 2025-02-25 江西农业大学 一种喹啉类化合物及其在农用杀菌剂中的应用
CN119060061B (zh) * 2024-08-26 2025-09-16 浙江师范大学 一类苯并嘧啶硫醚类化合物作为sting蛋白小分子抑制剂的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000012497A2 (en) * 1998-08-28 2000-03-09 Scios Inc. Quinazoline derivatives as medicaments
WO2004078733A1 (en) * 2003-03-03 2004-09-16 Vertex Pharmaceuticals Incorporated Quinazolines useful as modulators of ion channels
WO2005099711A1 (en) * 2004-04-13 2005-10-27 Icagen, Inc. Polycyclic pyrimidines as potassium ion channel modulators

Family Cites Families (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9506197D0 (en) 1995-03-27 1995-05-17 Hoffmann La Roche Inhibition of tau-tau association.
US5545656A (en) * 1995-04-05 1996-08-13 Pfizer Inc. 2-Oxidole-1-carboxamide pharmaceutical agents for the treatment of alzheimer's disease
US20030219427A1 (en) * 1998-08-18 2003-11-27 Allen Hamish J. TPL-2/COT kinase and methods of use
US6087363A (en) * 1999-07-16 2000-07-11 Harbor Branch Oceanographic Institution, Inc. Use of imidazole and indole compounds as inhibitors of nitric oxide synthase
TR200402342T4 (tr) * 2000-09-01 2004-11-22 Mitsubishi Pharma Corporation 2-Pirindinil-6,7,8,9- Tetrahidropyrimido[1,2-A] Pirimidin-4-On ve 7-Pirindinil-1,3-Dihydoimidazo[1,2-A]Pirimidin-5(1H) on Türevleri
JP2004509115A (ja) * 2000-09-15 2004-03-25 バーテックス　ファーマシューティカルズ　インコーポレイテッド プロテインキナーゼインヒビターとして有用なピラゾール化合物
US7045539B2 (en) * 2000-12-22 2006-05-16 Astrazeneca Ab Therapeutic benzoxazole compounds
WO2003051833A2 (en) * 2001-12-18 2003-06-26 Merck & Co., Inc. Heteroaryl substituted pyrazole modulators of metabotropic glutamate receptor-5
JP2003212859A (ja) * 2002-01-24 2003-07-30 Nippon Nohyaku Co Ltd 置換フェニルヘテロ環類及びこれを有効成分とする除草剤
US7405305B2 (en) * 2002-03-08 2008-07-29 Eli Lilly And Company Pyrrole-2, 5dione derivatives and their used as GSK-3 inhibitors
FR2836915B1 (fr) * 2002-03-11 2008-01-11 Aventis Pharma Sa Derives d'aminoindazoles, procede de preparation et intermediaires de ce procede a titre de medicaments et compositions pharmaceutiques les renfermant
WO2003097615A1 (en) * 2002-05-17 2003-11-27 Scios, Inc. TREATMENT OF FIBROPROLIFERATIVE DISORDERS USING TGF-β INHIBITORS
WO2003106439A1 (ja) * 2002-06-12 2003-12-24 株式会社ビーエフ研究所 アミロイド蓄積性疾患の画像診断プローブ化合物、老人斑／びまん性老人斑染色用化合物、ならびにアミロイド蓄積性疾患の治療薬
US7060698B2 (en) * 2003-05-19 2006-06-13 Hoffmann-La Roche Inc. Benzoxazepinone derivatives
US20060241150A1 (en) * 2003-06-06 2006-10-26 Weiner David B P38 kinase inhibitor compositions and methods of using the same
GB0314943D0 (en) 2003-06-25 2003-07-30 Proteome Sciences Plc Screening methods
JP4931814B2 (ja) * 2004-08-19 2012-05-16 アベンティス・ファーマスーティカルズ・インコーポレイテツド カゼインキナーゼＩεの阻害剤としての３−アリールチオインドール−２−カルボキサミド誘導体及びその類似体
WO2007015866A2 (en) * 2005-07-20 2007-02-08 Kalypsys, Inc. Inhibitors of p38 kinase and methods of treating inflammatory disorders
EP1842541A1 (en) * 2006-03-29 2007-10-10 G.I.M.-Gesellschaft Für Innovative Medizin Gmbh Nfg Ohg Plant components and extracts and uses thereof
TW200813035A (en) * 2006-06-19 2008-03-16 Astrazeneca Ab Novel heteroaryl substituted benzoxazoles
BRPI0711674A2 (pt) * 2006-06-21 2011-11-16 Du Pont Método de inibição da proliferação indesejada, composto, composição e método de inibição
US7622495B2 (en) * 2006-10-03 2009-11-24 Neurim Pharmaceuticals (1991) Ltd. Substituted aryl-indole compounds and their kynurenine/kynuramine-like metabolites as therapeutic agents
KR101176700B1 (ko) * 2006-11-02 2012-08-23 에프. 호프만-라 로슈 아게 미량 아민 결합된 수용체의 조절자로서 치환된 2-이미다졸
EP2081892A4 (en) * 2006-11-17 2014-03-05 Donald F Weaver COMPOUNDS AND METHOD FOR THE TREATMENT OF PROTEIN DISAPPEARANCE
ES2446269T3 (es) * 2006-12-19 2014-03-06 The Board Of Trustees Of The University Of Illinois 3-Benzofuranil-4-indolil-maleimidas como potentes inhibidores de GSK-3 para trastornos neurodegenerativos
US8445480B2 (en) * 2007-06-20 2013-05-21 Merck Sharp & Dohme Corp. CETP inhibitors derived from benzoxazole arylamides
FR2918061B1 (fr) * 2007-06-28 2010-10-22 Sanofi Aventis Derives de 6-cycloamino-3-(pyridin-4-yl)imidazo°1,2-b!- pyridazine,leur preparation et leur application en therapeutique.
FR2918986B1 (fr) * 2007-07-19 2009-09-04 Sanofi Aventis Sa Derives de 6-cycloamino-3-(pyridazin-4-yl)imidazo[1,2-b]- pyridazine, leur preparation et leur application en therapeutique
GB0715939D0 (en) * 2007-08-15 2007-09-26 Vastox Plc Method of treatment of duchenne muscular dystrophy
CA2707076A1 (en) * 2007-11-28 2009-06-11 Yale University Nogo receptor binding small molecules to promote axonal growth
CA2709784A1 (en) * 2007-12-21 2009-07-09 University Of Rochester Method for altering the lifespan of eukaryotic organisms
EP2149551A1 (de) 2008-07-30 2010-02-03 Bayer Schering Pharma AG N-(Indol-3-ylalkyl)-(hetero)arylamidderivate als Modulatoren des EP2-Rezeptors
FR2934994B1 (fr) * 2008-08-12 2010-09-17 Sanofi Aventis Derives de 2-alkyl-6cycloamino-3-(pyridin-4-yl)imidaz°1,2-b! pyridazine, leur preparation et leur application en therapeutique
KR101257695B1 (ko) * 2008-12-24 2013-04-24 제일모직주식회사 신규한 유기광전소자용 화합물 및 이를 포함하는 유기광전소자
FR2945289A1 (fr) * 2009-05-11 2010-11-12 Sanofi Aventis Derives de 2-cycloamino-5-(pyridin-4-yl)imidazo°2,1-b! °1,3,4!thiadiazole, leur preparation et leur application en therapeutique
JP2013518046A (ja) * 2010-01-25 2013-05-20 シーエイチディーアイ ファウンデーション，インコーポレーテッド 特定のキヌレニン−３−モノオキシゲナーゼインヒビターおよびその医薬組成物ならびにこれらの使用方法
JP2014503528A (ja) * 2010-12-14 2014-02-13 エレクトロプホレトイクス リミテッド カゼインキナーゼ１δ（ＣＫ１δ）阻害剤及びタウオパチーなどの神経変性疾患の治療におけるその使用
ES2773480T3 (es) 2011-05-09 2020-07-13 Eip Pharma Llc Composiciones y métodos para tratar la enfermedad de Alzheimer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000012497A2 (en) * 1998-08-28 2000-03-09 Scios Inc. Quinazoline derivatives as medicaments
WO2004078733A1 (en) * 2003-03-03 2004-09-16 Vertex Pharmaceuticals Incorporated Quinazolines useful as modulators of ion channels
WO2005099711A1 (en) * 2004-04-13 2005-10-27 Icagen, Inc. Polycyclic pyrimidines as potassium ion channel modulators

Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11433065B2 (en) 2008-01-04 2022-09-06 Intellikine Llc Certain chemical entities, compositions and methods
US9822131B2 (en) 2008-01-04 2017-11-21 Intellikine Llc Certain chemical entities, compositions and methods
US9216982B2 (en) 2008-01-04 2015-12-22 Intellikine Llc Certain chemical entities, compositions and methods
US9655892B2 (en) 2008-01-04 2017-05-23 Intellikine Llc Certain chemical entities, compositions and methods
US9206182B2 (en) 2009-07-15 2015-12-08 Intellikine Llc Substituted isoquinolin-1(2H)-one compounds, compositions, and methods thereof
US9522146B2 (en) 2009-07-15 2016-12-20 Intellikine Llc Substituted Isoquinolin-1(2H)-one compounds, compositions, and methods thereof
US9290497B2 (en) 2011-01-10 2016-03-22 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
US10550122B2 (en) 2011-01-10 2020-02-04 Infinity Pharmaceuticals, Inc. Solid forms of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one and methods of use thereof
USRE46621E1 (en) 2011-01-10 2017-12-05 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
US9840505B2 (en) 2011-01-10 2017-12-12 Infinity Pharmaceuticals, Inc. Solid forms of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1 (2H)-one and methods of use thereof
US11312718B2 (en) 2011-01-10 2022-04-26 Infinity Pharmaceuticals, Inc. Formulations of (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one
US8809349B2 (en) 2011-01-10 2014-08-19 Infinity Pharmaceuticals, Inc. Processes for preparing isoquinolinones and solid forms of isoquinolinones
US8828998B2 (en) 2012-06-25 2014-09-09 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
US9527847B2 (en) 2012-06-25 2016-12-27 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
US12213983B2 (en) 2012-11-01 2025-02-04 Infinity Pharmaceuticals, Inc. Treatment of cancers using PI3 kinase isoform modulators
US10709714B2 (en) 2013-11-22 2020-07-14 Clifton Life Sciences LLC Gastrin antagonists for treatment and prevention of osteoporosis
US9868749B2 (en) * 2013-12-09 2018-01-16 Ucb Biopharma Sprl Fused imidazole and pyrazole derivatives as modulators of TNF activity
US10087186B2 (en) 2014-01-29 2018-10-02 Glaxosmithkline Intellectual Property Development Limited Compounds as LRRK2 kinase inhibitors
US10618901B2 (en) 2014-01-29 2020-04-14 Glaxosmithkline Intellectual Property Development Limited LRRK2 inhibitors for the treatment of Parkinson's disease
US9815841B2 (en) 2014-01-29 2017-11-14 Glaxosmithkline Intellectual Property Development Limited Compounds
US11110096B2 (en) 2014-04-16 2021-09-07 Infinity Pharmaceuticals, Inc. Combination therapies
US11944631B2 (en) 2014-04-16 2024-04-02 Infinity Pharmaceuticals, Inc. Combination therapies
US9328096B2 (en) 2014-05-07 2016-05-03 Pfizer Inc. Tropomyosin-related kinase inhibitors
US10947239B2 (en) 2015-11-02 2021-03-16 Janssen Pharmaceutica Nv [1,2,4]triazolo[1,5-a]pyrimidin-7-yl compound
US11147818B2 (en) 2016-06-24 2021-10-19 Infinity Pharmaceuticals, Inc. Combination therapies
WO2018030762A1 (ko) * 2016-08-09 2018-02-15 세종대학교산학협력단 Ampk 억제기능에 기반한 뇌졸중 치료용 약학적 조성물
US10947242B2 (en) 2016-11-02 2021-03-16 Janssen Pharmaceutica, Nv [1,2,4]triazolo[1,5and#8208;A]pyrimidine compounds as PDE2 inhibitors
US11053248B2 (en) 2016-11-02 2021-07-06 Janssen Pharmaceutica Nv [1,2,4]triazolo[1,5-a]pyrimidine compounds as PDE2 inhibitors
US11319321B2 (en) 2016-11-02 2022-05-03 Janssen Pharmaceutica Nv [1,2,4]triazolo[1,5-a]pyrimidine compounds as PDE2 inhibitors
US11185543B2 (en) 2017-07-10 2021-11-30 Celgene Corporation Antiproliferative compounds and methods of use thereof
US12029738B2 (en) 2017-07-10 2024-07-09 Celgene Corporation Antiproliferative compounds and methods of use thereof
US10675281B2 (en) 2017-07-10 2020-06-09 Celgene Corporation Antiproliferative compounds and methods of use thereof
US10357489B2 (en) 2017-07-10 2019-07-23 Celgene Corporation Antiproliferative compounds and methods of use thereof
US12221430B2 (en) 2017-09-11 2025-02-11 Hodogaya Chemical Co., Ltd. Compound having pyrimidine ring structure and organic electroluminescence device
US11518772B2 (en) 2018-09-18 2022-12-06 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as Src homology-2 phosphate inhibitors
US10894797B2 (en) 2018-09-18 2021-01-19 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as SRC homology-2 phosphatase inhibitors
US11459340B2 (en) 2018-09-18 2022-10-04 Nikang Therapeutics, Inc. Tri-substituted heteroaryl derivatives as Src homology-2 phosphatase inhibitors
US11034705B2 (en) 2018-09-18 2021-06-15 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as Src homology-2 phosphate inhibitors
US12264167B2 (en) 2018-09-18 2025-04-01 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as SRC homology-2 phosphate inhibitors
US11613548B2 (en) 2021-02-19 2023-03-28 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors
US12084458B2 (en) 2021-02-19 2024-09-10 Sudo Biosciences Limited Substituted pyridines, pyridazines, and pyrimidines as TYK2 inhibitors
US12103937B2 (en) 2021-02-19 2024-10-01 Sudo Biosciences Limited Substituted pyridines and pyridazines as TYK2 inhibitors
US12122785B2 (en) 2021-02-19 2024-10-22 Sudo Biosciences Limited Substituted pyridines, pyridazines, pyrimidines, and 1,2,4-triazines as TYK2 inhibitors

Also Published As

Publication number Publication date
AU2017200812B2 (en) 2019-01-03
WO2012080729A2 (en) 2012-06-21
US9763947B2 (en) 2017-09-19
US9789111B2 (en) 2017-10-17
CA2818903C (en) 2021-03-23
JP2016172757A (ja) 2016-09-29
ES2553610T3 (es) 2015-12-10
CN105920010A (zh) 2016-09-07
US20160058745A1 (en) 2016-03-03
JP2017025080A (ja) 2017-02-02
AU2011343039A1 (en) 2013-06-27
AU2011343039B2 (en) 2017-03-02
EP2835131A1 (en) 2015-02-11
US20140018540A1 (en) 2014-01-16
US20150209368A1 (en) 2015-07-30
WO2012080729A4 (en) 2012-11-08
JP5937102B2 (ja) 2016-06-22
DK2835131T3 (en) 2017-12-04
EP2651404B1 (en) 2015-10-14
JP2014503528A (ja) 2014-02-13
EP2835131B1 (en) 2017-09-06
WO2012080727A4 (en) 2012-10-26
ES2650744T3 (es) 2018-01-22
AU2017200812A1 (en) 2017-03-02
JP2014503527A (ja) 2014-02-13
CA2818903A1 (en) 2012-06-21
US20160354375A1 (en) 2016-12-08
HK1214527A1 (zh) 2016-07-29
HK1190622A1 (zh) 2014-07-11
EP2651404A2 (en) 2013-10-23
CN103298460A (zh) 2013-09-11
CN103298460B (zh) 2016-06-01
EP2651405A2 (en) 2013-10-23
CN104906103A (zh) 2015-09-16
JP6243472B2 (ja) 2017-12-06
WO2012080727A2 (en) 2012-06-21
WO2012080729A3 (en) 2012-08-02
WO2012080727A3 (en) 2012-08-23
CN104906103B (zh) 2018-05-18

Similar Documents

Publication Publication Date Title
US20140031547A1 (en) CASEIN KINASE 1delta (CK 1delta) INHIBITORS AND THEIR USE IN THE TREATMENT OF NEURODE-GENERATIVE DISEASES SUCH AS TAUOPATHIES
US8013153B2 (en) Substituted pyrimidine kinase inhibitors
US11155561B2 (en) Substituted glutarimides as Btk inhibitors
KR100823382B1 (ko) Ｆａｂ ｉ 억제제
US8883819B2 (en) Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension
US7338966B2 (en) Substituted oxindole derivatives as tyrosine kinase inhibitors
JP2002501532A (ja) 新規血管形成阻害薬
US20220402875A1 (en) S1P3 Antagonists
TW201536772A (zh) 磷脂酸肌醇３－激酶抑制劑
US20150119387A1 (en) Compound as WNT Signaling Inhibitor, Composition, and Use Thereof
US6730684B1 (en) Fab I inhibitors
TW201427944A (zh) 作爲ｐ２ｘ７受體拮抗劑之吲哚羧醯胺衍生物
CN112189012B (zh) 作为pi3激酶和自噬途径的调节剂的三取代芳基和杂芳基衍生物
US20060293343A1 (en) Pyrimidine derivatives
US9527850B2 (en) Benzyl piperidine compounds as lysophosphatidic acid (LPA) receptor antagonist
CN114341145B (zh) 化学化合物
US20150336991A1 (en) Novel glucokinase activator compounds, compositions containing such compounds, and methods of treatment
WO2024075815A1 (ja) ８－ヒドロキシキノリン化合物及びその用途
CN114075140A (zh) 作为ep4受体拮抗剂的吡唑酰胺衍生物及其在癌症和炎症中的用途
HK1190622B (en) Casein kinase 1delta (ck1delta) inhibitors
HK1196126B (en) Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension

Legal Events

Date Code Title Description
AS Assignment

Owner name: ELECTROPHORETICS LIMITED, UNITED KINGDOM

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SHERIDAN, JOSEPH M;HEAL, JONATHAN R;HAMILTON, WILLIAM D.O.;AND OTHERS;REEL/FRAME:031244/0570

Effective date: 20130902

STCB Information on status: application discontinuation

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