US20180339993A1 - Azaspiro derivatives as trpm8 antagonists - Google Patents

Azaspiro derivatives as trpm8 antagonists Download PDF

Info

Publication number
US20180339993A1
US20180339993A1 US16/050,514 US201816050514A US2018339993A1 US 20180339993 A1 US20180339993 A1 US 20180339993A1 US 201816050514 A US201816050514 A US 201816050514A US 2018339993 A1 US2018339993 A1 US 2018339993A1
Authority
US
United States
Prior art keywords
diazaspiro
dione
phenyl
decane
oxoethyl
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
US16/050,514
Inventor
Yuji Shishido
Masashi Ohmi
Kazuo Ando
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.)
Raqualia Pharma Inc
Original Assignee
Raqualia Pharma Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Raqualia Pharma Inc filed Critical Raqualia Pharma Inc
Priority to US16/050,514 priority Critical patent/US20180339993A1/en
Publication of US20180339993A1 publication Critical patent/US20180339993A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • 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
    • 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
    • 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
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/422—Oxazoles 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
    • A61K31/42—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
    • A61K31/425—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
    • A61K31/435—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
    • 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
    • A61K31/4355—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 oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—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
    • A61K31/4353—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
    • A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/435—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
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine 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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—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
    • A61K31/535—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • 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
    • C07D401/10—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 carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D403/10—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 aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—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 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
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—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
    • C07D413/02—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
    • C07D413/10—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 aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C07D473/00—Heterocyclic compounds containing purine ring 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Abstract

The present invention relates to azaspiro derivatives of the formula (I) or a pharmaceutically acceptable salt thereof or a prodrug thereof, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders which are mediated via the TRPM8 receptor,
Figure US20180339993A1-20181129-C00001

Description

    TECHNICAL FIELD
  • This invention relates to azaspiro derivatives that act as modulators of the TRPM8 receptor. The present invention also relates to processes for the preparation of novel azaspiro derivatives and to their use in the treatment of a wide range of diseases, syndromes, and disorders, in particular for the treatment of inflammatory, pain and urological diseases or disorders.
    • BACKGROUND ART
  • Transient receptor potential (TRP) channels are one of the largest groups of ion channels, and they are divided into 6 sub-families (TRPV, TRPM, TRPA, TRPC, TRPP and TRPML). TRP channels are cation-selective channels that are activated by a variety of physical (e.g., temperature, osmolarity, mechanical) and chemical stimuli. TRPM8 is a member of TRP channel family. The receptor was cloned in 2002 (NPL 1; NPL 2) and it was found to be sensitive to cold temperature and menthol, and therefore named as cold menthol receptor-1 (CMR-1). TRPM8 can sense temperature changes in the range of both innocuous cold (15-28° C.) and noxious cold (<15° C.) as well as by chemical agents such as menthol and icilin.
  • TRPM8 is located on primary nociceptive neurons including A-delta and C-fibers and is also modulated by inflammation-mediated second messenger signals (NPL 3; NPL 4). The localization of TRPM8 on both A-delta and C-fibers may provide a basis for abnormal cold sensitivity in pathologic conditions wherein these neurons are altered, resulting in pain, often of a burning nature (NPL 5; NPL 6; NPL 7, NPL 8, NPL 9). Gauchan et al. reported that the expression of TRPM8 in the primary afferents was increased in oxaliplatin-induced cold allodynia model in mice (NPL 10). Oxaliplatin, a third-generation platinum-based chemotherapy drug, induces serious sensory neurotoxicity in patients, which is aggravated by exposure to cold. Recently, Glenmark group reported that the small molecular TRPM8 antagonists produced a dose-dependent inhibition of nocifensive paw licking in oxaliplatin-induced cold allodynia in mice (NPL 11).
  • Cold intolerance and paradoxical burning sensations induced by chemical or thermal cooling closely parallel symptoms seen in a wide range of clinical disorders and thus provide a strong rationale for the development of TRPM8 modulators as novel antihyperalgesic or antiallodynic agents. TRPM8 is also known to be expressed in the brain, odontoblasts, lung, bladder, gastrointestinal tract, blood vessels, prostate and immune cells, thereby providing the possibility for therapeutic modulation in a wide range of maladies.
  • International patent application WO 2006/040136 (PTL 1) purportedly describes substituted 4-benzyloxy-phenylethylamide derivatives as cold menthol receptor-1 (CMR-1) antagonists for the treatment of urological disorders. International patent application WO 2006/040103 (PTL 2) purportedly describes methods and pharmaceutical compositions for treatment and/or prophylaxis of respiratory diseases or disorders. Recently, International patent application WO 2014/025651 (PTL 3) from Amgen Inc. purportedly describes chroman compounds and derivatives as TRPM8 inhibitors for the treatment of migraines and neuropathic pain.
  • The compounds of the present invention which have TRPM8 receptor antagonist activity are structurally quite different from prior arts.
  • WO 2010/037081(PTL 4) and U.S. Pat. No. 5,739,336A (PTL 5) disclose spiropiperidine derivatives. However, the chemical structures of the compounds disclosed in the both patents are quite different from the compounds of the present invention. In addition, the compounds disclosed in the both patents relate to melanocortin receptor inhibitors and selective 5HT2c receptor antagonists, respectively, which is quite different from TRPM8 receptor antagonist.
  • WO 2012/174342 (PTL 6) and WO 2011/148962 (PTL 7) disclose spiro[cyclohexane-oxazolidinone] derivatives. However, the chemical structures of the compounds disclosed in the both patents are quite different from the compounds of the present invention. In addition, the compounds disclosed in the both patents relate to TRPV4 antagonists and antibacterial agents, respectively, which is quite different from TRPM8 receptor antagonist. The invention in WO 2005/044978 (PTL 8) discloses spiro derivatives which relate an activated αIIbβ3 (alphaIIbbeta3) receptor antagonist, is different from the present invention in the both aspects of chemical structures and biological activities.
  • Therefore the azaspiro derivatives in the present invention which have TRPM8 receptor antagonist activity have never been disclosed in prior arts.
    • CITATION LIST Patent Literature
    • {PTL 1} WO 2006/040136
    • {PTL 2} WO 2006/040103
    • {PTL 3} WO 2014/025651
    • {PTL 4} WO 2010/037081
    • {PTL 5} U.S. Pat. No. 5,739,336A
    • {PTL 6} WO 2012/174342
    • {PTL 7} WO 2011/148962
    • {PTL 8} WO 2005/044978
    Non Patent Literature
    • {NPL 1} McKemy, D. D., et al., Nature 416, 52-58, 2002
    • {NPL 2} Peier, A. D., Cell 108, 705-715, 2002
    • {NPL 3} Abe, J., et al., Neurosci Lett, 397(1-2), 140-144, 2006
    • {NPL 4} Premkumar, L. S., et al., J. Neurosci, 25(49), 11322-11329, 2005
    • {NPL 5} Kobayashi, K., et al., J Comp Neurol, 493(4), 596-606, 2005
    • {NPL 6} Roza, C, et al., Pain, 120(1-2), 24-35, 2006
    • {NPL 7} Xing, H., et al., J Neurophysiol, 95(2), 1221-30, 2006
    • {NPL 8} European Journal of Pharmacology, Volume 716, Issues 1-3, 61-76, 2013
    • {NPL 9} PAIN, Volume 152, Issue 10, 2211-2223, 2011
    • {NPL 10} Gauchan, P., et al., Neurosci Lett, 458, 93-95, 2009
    • {NPL 11} Sachin, S. Chaudhari, et al., Bioorg. Med. Chem, 21, 6542-6553, 2013
    SUMMARY OF INVENTION Technical Problem
  • There is a need in the art for TRPM8 antagonists that can be used to treat a disease, syndrome, or condition in a mammal in which the disease, syndrome, or condition is affected by the modulation of TRPM8 receptors, such as wherein the condition or disorder is one or more of inflammatory, pain and urological diseases or disorders, including wherein the condition or disorder is one or more of inflammatory, pain and urological diseases or disorders, including chronic pain; neuropathic pain including cold allodynia and diabetic neuropathy; postoperative pain; osteoarthritis; rheumatoid arthritic pain; cancer pain; neuralgia; neuropathies; algesia; dentin hypersensitivity; nerve injury; migraine; cluster and tension headaches; ischaemia; irritable bowel syndrome; Raynaud's syndrome; neurodegeneration; fibromyalgia; stroke; itch; psychiatric disorders including anxiety and depression; inflammatory disorders including asthma, chronic obstructive pulmonary, airways disease including COPD, pulmonary hypertension; anxiety including other stress-related disorders; and urological diseases or disorders including detrusor overactivity or overactive bladder, urinary incontinence, neurogenic detrusor overactivity or detrusor hyperflexia, idiopathic detrusor overactivity or detrusor instability, benign prostatic hyperplasia, and lower urinary tract symptoms; and combinations thereof.
  • TRPM8 antagonists should be well absorbed from the GI tract, be metabolically stable and possess favorable pharmacokinetic properties. They should be non-toxic. Furthermore, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated. In particular, it has been desired that compounds would have to bind potently to the TRPM8 receptor and show functional activity as antagonists. The present invention provides novel compounds which have excellent TRPM8 antagonistic activities.
    • Solution to Problem
  • With respect to other compounds disclosed in the art, the compounds of the present invention may show less toxicity, good absorption and distribution, good solubility, less plasma protein binding, less drug-drug interaction, good metabolic stability, reduced inhibitory activity at HERG channel, and/or reduced QT prolongation.
  • The present invention provides:
  • [1] a compound of the following formula (I)
  • Figure US20180339993A1-20181129-C00002
  • wherein
  • A is aryl and heteroaryl;
  • B is aryl and heteroaryl;
  • L is independently selected from the group consisting of a chemical bond, oxygen, sulfur, —NR4—, —(CRCRD)t—, —O(CRCRD)t—, —(CRCRD)tO—, —N(R4)(CRCRD)t—, —(CRCRD)tN(R4)—, —N(R4)(CRCRD)tO—, and —O(CRCRD)t N(R4)—
  • X is independently selected from the group consisting of —CH2—, oxygen, sulfur and NH;
      • RA and RB are independently selected from the group consisting of;
      • (1) hydrogen, (2) halogen, (3) (C1-C10)alkyl, (4) (C3-C10)cycloalkyl and (5) (C1-C10)haloalkyl; or RA and RB may form oxo group (═O); or RA and RB may form a 3 to 8 membered ring which may contain one or more heteroatoms independently selected from oxygen, sulfur and nitrogen; and said ring is optionally substituted with 1 to 6 substituents independently selected from (1) hydrogen, (2) halogen, (3) hydroxy, (4) (C1-C10)alkyl, (5) (C3-C10)cycloalkyl, (6) (C1-C10)haloalkyl, (7) (C1-C10)alkoxy and (8) (C1-C10)haloalkoxy;
  • RC and RD are independently selected from the group consisting of (1) hydrogen, (2) halogen, (3) (C1-C10)alkyl, (4) (C3-C10)cycloalkyl and (5) (C1-C10)haloalkyl; or RC and RD may form a 3 to 8 membered ring which may contain one or more heteroatoms independently selected from oxygen, sulfur and nitrogen; and said ring is optionally substituted with 1 to 6 substituents independently selected from (1) hydrogen, (2) halogen, (3) hydroxy, (4) (C1-C10)alkyl, (5) (C3-C10)cycloalky, (6) (C1-C10)haloalkyl, (7) (C1-C10)alkoxy and (8) (C1-C10)haloalkoxy;
  • R1 is independently selected from the group consisting of (1) hydrogen, (2) halogen, (3) amino, (4) cyano, (5) hydroxyl, (6) (C1-C10)alkyl, (7) (C3-C10)cycloalkyl, (8) (C1-C10)haloalkyl, (9) (C1-C10)alkoxy and (10) (C1-C10)haloalkoxy; two R1 on the same carbon or the different carbons are possible to form a 3 to 8 membered ring which may contain an atom selected from oxygen, sulfur and nitrogen; and said ring is optionally substituted with 1 to 6 substituents independently selected from (1) hydrogen, (2) halogen, (3) hydroxy, (4) (C1-C10)alkyl, (5) (C3-C10)cycloalkyl, (6) (C1-C10)haloalkyl, (7) (C1-C10)alkoxy, and (8) (C1-C10)haloalkoxy;
  • R2 is independently selected from the group consisting of (1) hydrogen, (2) halogen, (3) amino, (4) —NH(C1-C10)alkyl, (5) —N[(C1-C6)alkyl]2 wherein the alkyl is same or different, (6) cyano, (7) hydroxyl, (8) nitro, (9) (C1-C6)alkylthio, (10) (C1-C10)alkyl, (11) (C3-C10)cycloalkyl, (12) (C1-C10)alkoxy, (13) (C1-C10)haloalkyl and (14) (C1-C10)haloalkoxy;
  • R3 is independently selected from the group consisting of (1) hydrogen, (2) halogen, (3) cyano, (4) nitro, (5) hydroxyl, (6) (C1-C6)alkylthio, (7) (C1-C6)alkylsulfinyl, (8) (C1-C6)alkylsulfonyl, (9) —NR5R6, (10) —C(═O)NR5R6, (11) tri(C1-C6)alkylsilyl, (12) (C1-C10)alkyl, (13) (C3-C10)cycloalkyl, (14) (C1-C6)alkoxy(C0-C5)alkyl, (15) (C3-C10)cycloalkoxy, (16) —C(═O)(C1-C6)alkyl, (17) —C(═O)O(C1-C6)alkyl and (18) —C(═O)OH; said (C1-C10)alkyl, (C3-C10)cycloalkyl, (C1-C6)alkoxy(C0-C6)alkyl and (C3-C10)cycloalkoxy are optionally substituted with 1 to 6 substituents independently selected from (1) hydrogen, (2) halogen, (3) hydroxyl, (4) cyano, (5) (C3-C10)cycloalkyl, (6) (C1-C10)haloalkyl, (7) (C1-C10)alkoxy, (8) (C1-C10)haloalkoxy and (9) —NR6R5;
    wherein R5 and R6, together with nitrogen atom to which they are attached, may form a 3 to 10 membered ring which may contain an atom selected from oxygen, sulfur and nitrogen; and said ring is optionally substituted with 1 to 6 substituents independently selected from (1) hydrogen, (2) halogen, (3) hydroxyl, (4) (C1-C10)alkyl, (5) (C3-C10)cycloalkyl, (6) (C1-C10)haloalkyl, (7) (C1-C10)alkoxy and (8) (C1-C10)haloalkoxy;
  • R4, R5 and R6 are independently selected from the group consisting of (1) hydrogen, (2) (C1-C10)alkyl, (3) (C3-C10)cycloalkyl, (4) (C1-C10)haloalkyl, (5) hydroxyl(C1-C10)alkyl, (6) (C1-C10)alkoxy(C1-C10)alkyl, (7) H2N—(C1-C10)alkyl, (8) [(C1-C10)alkyl]NH—(C1-C10)alkyl, (9) [(C1-C10)alkyl]2N—(C1-C10)alkyl, (10) (C1-C10)alkylcarbonyl and (11) (C1-C10)alkylsulfonyl;
      • p is 1, 2, 3 or 4;
      • q is 1, 2, 3 or 4; when q is two or more than two, R1 is same or different,
      • r is 1, 2, 3 or 4; when r is two or more than two, R2 is same or different,
      • s is 1, 2, 3, 4, 5, 6 or 7; when s is two or more than two, R3 is same or different,
      • t is 1, 2 or 3; when t is two or more than two, RC and RD are same or different,
        or a pharmaceutically acceptable salt thereof or a prodrug thereof;
        [2] the compound described in [1] wherein
  • A is 6 membered aryl or 5 to 6 membered heteroaryl or a pharmaceutically acceptable salt thereof or a prodrug thereof;
  • [3] the compound described in [1] or [2] wherein A is independently selected from the group consisting of benzene, pyridine, pyridazine, pyrazine, pyrimidine, triazine, thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, and triazole.
    or a pharmaceutically acceptable salt thereof or a prodrug thereof;
    [4] The compound as described in any one of [1] to [3] which is selected from:
    • 3-(2-(2,5-dimethyl-1-(5-methylisoxazol-3-yl)-1H-pyrrol-3-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(2,5-dimethyl-1-phenyl-1H-imidazol-4-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 6-(4-(2-(2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)picolinonitrile;
    • 3-(2-(1-(3-chlorophenyl)-2,5-dimethyl-1H-imidazol-4-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(1-(3-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(1,4-dimethyl-5-phenyl-1H-pyrazol-3-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(6-m ethylpyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 6-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)picolinonitrile;
    • 8,8-difluoro-3-(2-(2′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(3-methyl pyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(2,5-dimethyl-1-phenyl-1H-imidazol-4-yl)-2-oxoethyl)-8,8-difluoro-1-oxa-3-azaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(2-(hydroxymethyl)pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(4-(hydroxymethyl)pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(2,5-dimethyl-1-(5-methylisoxazol-3-yl)-1H-pyrrol-3-yl)-2-oxoethyl)-8,8-difluoro-1-oxa-3-azaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(5-(2-(hydroxymethyl)phenyl)-4-methylthiophen-2-oxoethyl)-1,3-diaza spiro[4.5]decane-2,4-dione;
    • 3-(2-(4-(3-(hydroxymethyl)pyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(1,4-dim ethyl-5-phenyl-1H-pyrazol-3-yl)-2-oxoethyl)-8,8-difluoro-1-oxa-3-azaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)pyrazine-2-carbonitrile;
    • 3-(2-(1,4-dimethyl-5-phenyl-1H-pyrrol-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(3-(hydroxymethyl)pyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(6-(methyl(pyridin-2-yl)amino)pyridin-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)picolinonitrile;
    • 8,8-difluoro-3-(2-oxo-2-(4-(quinolin-8-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(4-(1H-indol-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-oxo-2-(4-(quinolin-2-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(isoquinolin-8-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(isoquinolin-1-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(furo[3,2-c]pyridin-4-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(6-(methyl(pyridin-2-yl)amino)pyridin-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(6-(methyl(phenyl)amino)pyridin-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(3-fluoropyridin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)isonicotinonitrile,
    • 8,8-difluoro-3-(2-(4-(2-methoxypyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(4-methoxypyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-oxo-2-(4-(2-oxoindolin-4-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(4-(1H-pyrrolo[3,2-c]pyridin-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(4-(3-chloropyridin-2-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(2-methyl-1H-benzo[d]imidazol-1-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(4-(1H-indazol-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(6-(1H-indazol-4-yl)pyridin-3-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(4-(1H-benzo[d]imidazol-1-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(5-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)-1,3-dimethyl-1H-pyrrol-2-yl)benzonitrile;
    • 3-(2-(4-(1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(3-fluoro-4-(quinolin-8-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(5-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)-1-methyl-1H-pyrrol-2-yl)benzonitrile;
    • 3-(5-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)-3-methylthiophen-2-yl)benzonitrile;
    • 8,8-difluoro-3-(2-(4-(2-(2-hydroxyethoxy)pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(5-(3-fluorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(5-(3-chlorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(5-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)-1,3-dimethyl-1H-pyrrol-2-yl)benzamide;
    • 8,8-difluoro-3-(2-(5-(2-fluorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(4-(l H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(4-(l H-pyrazolo[4,3-c]pyridin-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(4-(I H-indazol-1-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(5-(3-fluorophenyl)-1-methyl-1H-imidazol-2-yl)-2-oxoethyl)-1,3-diazaspiro[4,4]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-oxo-2-(4-(pyridin-2-yloxy)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(5-(3,5-difluorophenyl)-1,4-dimethyl-1H-pyrrol-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(2′-methyl-[3,3′-bipyridin]-6-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(4-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(6-(1H-pyrrolo[2,3-c]pyridin-4-yl)pyridin-3-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(3-(2-hydroxyethoxy)pyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-oxo-2-(4-(phthalazin-1-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dion
    • 3-(2-(4-(3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)-4-methylthiazol-5-yl)benzonitrile;
    • 3-(2-(1,4-dimethyl-5-phenyl-1H-imidazol-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(5-(3-fluorophenyl)-1,4-dimethyl-1H-imidazol-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)-1,4-dimethyl-1H-imidazol-5-yl)benzonitrile;
    • 8,8-difluoro-3-(2-(5-(isoquinolin-8-yl)-1,4-dimethyl-1H-imidazol-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(5-(2-(hydroxymethyl)phenyl)-1,4-dimethyl-1H-imidazol-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(5-(3-fluorophenyl)-1,4-dimethyl H-pyrrol-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)-1,3-dimethyl-1H-pyrrol-2-yl)benzonitrile;
    • 3-(2-(5-(1H-benzo[d]imidazol-1-yl)pyrazin-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(4-(2,7-naphthyridin-1-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-oxo-2-(4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(5-(2-(hydroxymethyl)phenyl)pyrazin-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(5-(4-methoxypyridin-3-yl)pyrazin-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(5-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)-2,4-dimethylthiophen-3-yl)benzamide;
    • 3-(2-(5-(3,5-difluorophenyl)-1,4-dimethyl-1H-imidazol-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-oxo-2-(4-(pyridazin-3-yloxy)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-oxo-2-(4-(2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(5-(3,5-difluorophenyl)-4-methyl thiazol-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 4′-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)-2′-methoxy-[1,1′-biphenyl]-2-carbonitrile;
    • 2-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenoxy)nicotinonitrile;
    • 3-(2-(4-((3-chloropyridin-2-yl)oxy)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(3-(hydroxymethyl)pyridin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(2′-(aminomethyl)-[1,1′-biphenyl]-4-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-oxo-2-(6-(quinolin-8-yl)pyridin-3-yl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(5-(2-methyl pyridin-3-yl)pyrazin-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(4-(2,7-naphthyridin-1-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1-oxa-3-azaspiro[4.5]decane 2,4-dione;
    • 3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile;
    • 8,8-difluoro-3-(2-oxo-2-(4-(2-oxobenzo[d]oxazol-3(2H)-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(4-(2,5-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(5-(2-methyl-1H-benzo[d]imidazol-1-yl)pyrazin-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(2-methoxy-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(5-methyl-2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(2-(4-(2-(difluoromethyl)-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(5-methyl-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 6-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenoxy)picolinonitrile;
    • 8,8-difluoro-3-(2-(4-(5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(3-methoxypyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)-3-fluorophenyl)pyrazine-2-carbonitrile;
    • 8,8-difluoro-3-(2-(4-(imidazo[1,2-b]pyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(2′-(2-hydroxyethyl)-[1,1-biphenyl]-4-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 2-(4′-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)-[1,1′-biphenyl]-2-yl)acetonitrile;
    • 3-(2-(4-(1H-imidazo[4,5-b]pyrazin-1-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(4-(4-methyl pyridazin-3-yl)phenyl-2-oxoethyl)-1-oxa-3-azaspiro[4.5]decane-2,4-dione;
    • 3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenoxy)pyridazine-4-carbonitrile;
    • 8,8-difluoro-3-(2-(4-(2-(hydroxymethyl)-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-oxo-2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 4-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)nicotinonitrile;
    • 8,8-difluoro-3-(2-(2-fluoro-4-(4-methylpyridazin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
    • 8,8-difluoro-3-(2-(2-fluoro-4-(3-(hydroxymethyl)pyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; and
    • 2-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)nicotinonitrile
      or a pharmaceutically acceptable salt thereof or a prodrug thereof.
      [5] a use of a compound described in any one of [1] to [4] or a pharmaceutically acceptable salt thereof or a prodrug thereof for the manufacture of a medicament for the treatment of a condition or disorder mediated by TRPM8 receptor antagonistic activity;
      [6] a use as described in [5], wherein the condition or disorder is one or more of inflammatory, pain and urological diseases or disorders, including chronic pain; neuropathic pain including cold allodynia and diabetic neuropathy; postoperative pain; osteoarthritis; rheumatoid arthritic pain; cancer pain; neuralgia; neuropathies; algesia; dentin hypersensitivity; nerve injury; migraine; cluster and tension headaches; ischaemia; irritable bowel syndrome; Raynaud's syndrome; neurodegeneration; fibromyalgia; stroke; itch; psychiatric disorders including anxiety and depression; inflammatory disorders including asthma, chronic obstructive pulmonary, airways disease including COPD, pulmonary hypertension; anxiety including other stress-related disorders; and urological diseases or disorders including detrusor overactivity or overactive bladder, urinary incontinence, neurogenic detrusor overactivity or detrusor hyperflexia, idiopathic detrusor overactivity or detrusor instability, benign prostatic hyperplasia, and lower urinary tract symptoms; and combinations thereof.
      [7] a method for the treatment of a condition or disorder mediated by TRPM8 receptor antagonistic activity in a mammalian subject, including a human, which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound described in any one of [1] to [4] or a pharmaceutically acceptable salt thereof or a prodrug thereof or a prodrug thereof;
      [8] a method as described in [7], wherein the condition or disorder is one or more of inflammatory, pain and urological diseases or disorders, including chronic pain; neuropathic pain including cold allodynia and diabetic neuropathy; postoperative pain; osteoarthritis; rheumatoid arthritic pain; cancer pain; neuralgia; neuropathies; algesia; dentin hypersensitivity; nerve injury; migraine; cluster and tension headaches; ischaemia; irritable bowel syndrome; Raynaud's syndrome; neurodegeneration; fibromyalgia; stroke; itch; psychiatric disorders including anxiety and depression; inflammatory disorders including asthma, chronic obstructive pulmonary, airways disease including COPD, pulmonary hypertension; anxiety including other stress-related disorders; and urological diseases or disorders including detrusor overactivity or overactive bladder, urinary incontinence, neurogenic detrusor overactivity or detrusor hyperflexia, idiopathic detrusor overactivity or detrusor instability, benign prostatic hyperplasia, and lower urinary tract symptoms; and combinations thereof.
      [9] a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof or a prodrug thereof, as described in any one of [1] to [4], and a pharmaceutically acceptable carrier;
      [10] a pharmaceutical composition as described in [9], further comprising another pharmacologically active agent;
      [11] a compound described in any one of [1] to [4] or a pharmaceutically acceptable salt thereof or a prodrug thereof for use in the treatment of a condition or disorder mediated by TRPM8 receptor antagonistic activity; and
      [12] a process for preparing a pharmaceutical composition, wherein the process comprising mixing a compound described in any one of [1] to [4] or a pharmaceutically acceptable salt thereof or a prodrug thereof and a pharmaceutically acceptable carrier or excipient.
  • Examples of conditions or disorders mediated by TRPM8 receptor activity include, but are not limited to, TRPM8 related diseases.
    • Advantageous Effects of Invention
  • The compounds of the present invention show the TRPM8 receptor antagonistic activity. The compounds of the present invention may show less toxicity, good absorption, distribution, good solubility, less protein binding affinity other than TRPM8 receptor, less drug-drug interaction, and good metabolic stability.
    • DESCRIPTION OF EMBODIMENTS
  • As used herein, the term “alkyl” as a group or part of a group e.g. alkoxy or hydroxyalkyl refers to a straight or branched alkyl group in all isomeric forms. The term “C1-C4 alkyl” refers to an alkyl group, as defined above, containing at least 1, and at most 4 carbon atoms. Examples of such alkyl groups include methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or tert-butyl. Examples of such alkoxy groups include methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, sec-butoxy and tert-butoxy.
  • The term “cycloalkyl”, as used herein, means a mono- or bicyclic ring, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl groups and the like.
  • Then cyclopropylmethyl and cyclopentylmethyl are as follows:
  • Figure US20180339993A1-20181129-C00003
  • The term “halogen” refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) and the term “halo” refers to the halogen: fluoro (—F), chloro (—Cl), bromo (—Br) and iodo (—I).
  • The term “haloalkyl”, as used herein, means an alkyl radical which is substituted by halogen atom(s) as defined above including, but not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 3-fluoropropyl, 4-fluorobutyl, chloromethyl, trichloromethyl, iodomethyl and bromomethyl groups and the like.
  • The term “haloalkoxy”, as used herein, means haloalkyl-O—, including, but not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, chloromethoxy, trichloromethoxy, iodomethoxy and bromomethoxy groups and the like.
  • The term “alkoxy”, as used herein, means an O-alkyl group wherein “alkyl” is defined above.
  • The term “heterocyclyl”, as used herein, means a saturated 3- to 16-membered ring which comprises one or more heteroatoms selected from nitrogen, oxygen and sulfur. For purposes of this invention, the heterocyclyl may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems. Examples of such heterocyclyl groups include azetidinyl, 1,4-dioxanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, thiomorpholinyl, tetrahydrothienyl, 2-oxo-pyrrolidinyl, 2-oxo-piperidinyl, 2-oxo-imidazolidinyl, 2-oxo-oxazolidinyl, quinuclidinyl, azabicyclo[3.2.1]octyl, 2-oxa-6-azaspiro[3.4]octyl and N-oxides thereof and S-oxides thereof.
  • The term “aryl”, as used herein, means unsaturated and partially saturated 6- to 15-membered ring which consists of carbon atoms; Examples of such unsaturated aryl include, but are not limited to, phenyl, naphthyl, indanyl, indenyl, 1,2,3,4-tetrahydronaphthyl, and 1,2-dihydronaphthyl.
  • The term “heteroaryl” as used herein, means 5- to 15-membered ring, preferably 6- to 15-membered ring, in which an aromatic heteroatom containing ring is fused to a non-aromatic ring, such as heterocyclyl ring or cycloalkyl ring, and also means 5- to 15-membered ring, preferably 6- to 15-membered ring, in which an aryl ring is fused to a non-aromatic heteroatom containing ring, such as heterocyclyl ring.
  • Namely, the term “heteroaryl” as used herein, means the following;
  • 1) unsaturated and partially saturated 5- to 15-membered ring, preferably 6- to 15-membered ring, which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
    2) unsaturated and partially saturated 5- to 15-membered ring, preferably 6- to 15-membered ring, in which a non-aromatic ring, such as heterocyclyl ring or cycloalkyl ring, is fused to a heteroaryl defined above
    3) unsaturated and partially saturated 5- to 15-membered ring, preferably 6- to 15-membered ring, in which an aryl ring is fused to a heterocyclyl ring.
  • Examples of such heteroaryl include, but are not limited to, thiophenyl, thiazolyl, isoxazolyl, pyrazolyl, tetrazolyl, furanyl, pyrrolyl, imidazolyl, oxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzotriazolyl, indolyl, indazolyl, benzoimidazolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyridyl, pyrazolopyrimidinyl, imidazopyridinyl, furopyridyl, benzoisoxazolyl, imidazopyrazinyl, imidazopyridazinyl, imidazopyrimidinyl, quinolyl, isoquinolyl, quinazolinyl, phthalazinyl, quinoxalinyl, naphthyridinyl, pyridopyrimidinyl, and N-oxides thereof and S-oxides thereof.
  • Examples of such heteroaryl also include the heteroaryl ring radical consisting of the following rings.
  • Figure US20180339993A1-20181129-C00004
  • The term “C0”, as used herein, means direct bond.
  • The substituents on the ring of the compound of the present invention may exist on the any atoms if it is chemically allowed.
  • The term “protecting group”, as used herein, means a hydroxy or amino protecting group which is selected from typical hydroxy or amino protecting groups described in Protective Groups in Organic Synthesis Forth Edition edited by T. W. Greene et al. (John Wiley & Sons, 2006);
  • The term “treating” and “treatment”, as used herein, refers to curative, palliative and prophylactic treatment, including reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • As used herein, the article “a” or “an” refers to both the singular and plural form of the object to which it refers unless indicated otherwise.
  • The symbol letter is written the corresponding English word in the present specification.
  • For example, the symbols a, P, and 8 are written alpha, beta, and delta, respectively.
  • Included within the scope of the “compounds of the invention” are all salts, solvates, hydrates, complexes, polymorphs, prodrugs, radiolabeled derivatives, stereoisomers and optical isomers of the compounds of formula (I).
  • The compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci, 66, 1-19, 1977, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, formic, acetic, trifluoroacetic, propionic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms. In addition, certain compounds containing an acidic function such as a carboxy can be isolated in the form of their inorganic salt in which the counter ion can be selected from sodium, potassium, lithium, calcium, magnesium and the like, as well as from organic bases.
  • Also within the scope of the invention are so-called “prodrugs” of the compounds of formula (I). Thus certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves, when administered into or onto the body, can be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as “prodrugs”. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention, for example, can be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in Design of Prodrugs by H Bundgaard (Elsevier, 1985). Some examples of prodrugs in accordance with the invention include:
  • (i) where the compound of formula (I) contains an alcohol functionality (—OH), compounds wherein the hydroxy group is replaced with a moiety convertible in vivo into the hydroxy group. Said moiety convertible in vivo into the hydroxy group means a moiety transformable in vivo into a hydroxyl group by e.g. hydrolysis and/or by an enzyme, e.g. an esterase. Examples of said moiety include, but are not limited to, ester and ether groups which may be hydrolyzed easily in vivo. Preferred are the moieties replaced the hydrogen of hydroxy group with acyloxyalkyl, 1-(alkoxycarbonyloxy)alkyl, phthalidyl and acyloxyalkyloxycarbonyl such as pivaloyloxymethyloxycarbonyl.
  • (ii) where the compound of the formula (I) contains an amino group, an amide derivative prepared by reacting with a suitable acid halide or a suitable acid anhydride is exemplified as a prodrug. A particularly preferred amide derivative as a prodrug is —NHCO(CH2)2OCH3, —NHCOCH(NH2)CH3 or the like.
  • Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.
  • The compounds of formula (I), salts thereof and prodrugs thereof may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated.
  • This invention includes within its scope stoichiometric hydrates or solvates as well as compounds containing variable amounts of water and/or solvent.
  • Salts and solvates having non-pharmaceutically acceptable counter-ions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts.
  • Additionally, the compounds of formula (I) may be administered as prodrugs. As used herein, a “prodrug” of a compound of formula (I) is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of formula (I) in vivo. Administration of a compound of formula (I) as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of action of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, which include the preparation of phosphates, amides, esters, thioesters, carbonates, and carbamates, are well known to those skilled in the art.
  • In certain of the compounds of formula (I), there may be some chiral carbon atoms. In such cases, compounds of formula (I) exist as stereoisomers. The invention extends to all optical isomers such as stereoisomeric forms of the compounds of formula (I) including enantiomers, diastereoisomers and mixtures thereof, such as racemates. The different stereoisomeric forms may be separated or resolved one from the other by conventional methods or any given isomer may be obtained by conventional stereoselective or asymmetric syntheses.
  • Certain of the compounds herein can exist in various tautomeric forms and it is to be understood that the invention encompasses all such tautomeric forms.
  • The invention also includes isotopically-labeled compounds, which are identical to those described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 3H, 11C, 14C, 18F, 123I and 125I. Compounds of the invention that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H, 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. 11C and 18F isotopes are particularly useful in PET (positron emission tomography), and 125I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, then substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • The potencies and efficacies of the compounds of this invention for TRPM8 can be determined by reporter assay performed on the human cloned receptor as described herein. Compounds of formula (I) have demonstrated antagonistic activity at the TRPM8 receptor, using the functional assay described herein.
  • Compounds of formula (I) and pharmaceutically acceptable salts thereof are therefore of use in the treatment of conditions or disorders which are mediated via the TRPM8 receptor. In particular the compounds of formula (I) and pharmaceutically acceptable salts thereof are of use in the treatment of a wide range of diseases, syndromes, and disorders, in particular for the treatment of inflammatory, pain and urological diseases or disorders, such as wherein the condition or disorder is one or more of inflammatory, pain and urological diseases or disorders, including chronic pain; neuropathic pain including cold allodynia and diabetic neuropathy; postoperative pain; osteoarthritis; rheumatoid arthritic pain; cancer pain; neuralgia; neuropathies; algesia; dentin hypersensitivity; nerve injury; migraine; cluster and tension headaches; ischaemia; irritable bowel syndrome; Raynaud's syndrome; neurodegeneration; fibromyalgia; stroke; itch; psychiatric disorders including anxiety and depression; inflammatory disorders including asthma, chronic obstructive pulmonary, airways disease including COPD, pulmonary hypertension; anxiety including other stress-related disorders; and urological diseases or disorders including detrusor overactivity or overactive bladder, urinary incontinence, neurogenic detrusor overactivity or detrusor hyperflexia, idiopathic detrusor overactivity or detrusor instability, benign prostatic hyperplasia, and lower urinary tract symptoms; and combinations thereof.
  • Activities of the compound (I) for each diseases, syndromes, and disorders described above can be confirmed in the suitable model known to skilled in the arts. For example, activities of compounds of formula (I) for neuropathic pain have been confirmed in chronic constriction injury (CCI)-induced model, such as cold allodynia and static allodynia model.
  • It is to be understood that “treatment” as used herein includes prophylaxis as well as alleviation of established symptoms as described above.
  • A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administered compositions are generally preferred. Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); tabletting lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycolate); and acceptable wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g. lecithin or acacia), non-aqueous vehicles (which may include edible oils e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid), and, if desired, conventional flavourings or colorants, buffer salts and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound or pharmaceutically acceptable salt thereof.
  • For parenteral administration, fluid unit dosage forms are prepared utilising a compound of formula (I) or pharmaceutically acceptable salt thereof and a sterile vehicle. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose, utilising a compound of formula (I) or pharmaceutically acceptable salt thereof and a sterile vehicle, optionally with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative.
  • The compounds of formula (I) or pharmaceutically acceptable salts thereof may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • The compounds of formula (I) or pharmaceutically acceptable salts may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • Thus, for example, the compounds of formula (I) or pharmaceutically acceptable salts may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • For intranasal administration, the compounds formula (I) or pharmaceutically acceptable salts thereof may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device. Thus compounds of formula (I) or pharmaceutically acceptable salts thereof may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose). The compounds of formula (I) and pharmaceutically acceptable salts thereof may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye may be manufactured in a sterile manner using sterilized components.
  • A TRPM8 antagonist may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of inflammatory, pain and urological diseases or disorders. For example, a TRPM8 antagonist, particularly a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined above, may be administered simultaneously, sequentially or separately in combination with one or more agents selected from:
      • an opioid analgesic, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;
      • a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;
      • a barbiturate sedative, e.g. amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, thiamylal or thiopental;
      • a benzodiazepine having a sedative action, e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;
      • an H1 antagonist having a sedative action, e.g. diphenhydramine, pyrilamine, promethazine, chlorpheniramine or chlorcyclizine;
      • a sedative such as glutethimide, meprobamate, methaqualone or dichloralphenazone;
      • a skeletal muscle relaxant, e.g. baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;
      • an NMDA receptor antagonist, e.g., dextromethorphan ((+)-3-methoxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex(registered trademark), a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g. ifenprodil, traxoprodil or
  • (−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl}-3,4-dihydro-2(1H)-quinolinone;
      • an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;
      • a tricyclic antidepressant, e.g. desipramine, imipramine, amitriptyline or nortriptyline;
      • an anticonvulsant, e.g. carbamazepine, lamotrigine, topiramate or valproate;
      • a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6,13-dione (TAK-637), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869, aprepitant), lanepitant, dapitant or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]methylamino]-2-phenylpiperidine (2S,3S);
      • a muscarinic antagonist, e.g. oxybutynin, tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, temiverine and ipratropium;
      • a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib;
      • a coal-tar analgesic, in particular paracetamol;
      • a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin; iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion(registered trademark) or sarizotan;
      • a vanilloid receptor agonist (e.g. resiniferatoxin) or antagonist (e.g. capsazepine);
      • a transient receptor potential cation channel subtype (V1, V2, V3, V4, M8, M2, A1) agonist or antagonist;
      • a beta-adrenergic such as propranolol;
      • a local anaesthetic such as mexiletine;
      • a corticosteroid such as dexamethasone;
      • a 5-HT receptor agonist or antagonist, particularly a 5-HT1B/1D agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan;
      • a 5-HT2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);
      • a cholinergic (nicotinic) analgesic, such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;
      • Tramadol(registered trademark);
      • a PDEV inhibitor, such as
    • 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil),
    • (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-m ethylenedioxyphenyl)pyrazino[2′,1′: 6,1]pyrido[3,4-b]indole-1,4-dione (IC-351 or tadalafil),
    • 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil),
    • 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
    • 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
    • 5-[2-ethoxy-5-(4-ethyl piperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,
    • 4-[(3-chloro-4-m ethoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,
    • 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;
      • an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin, (3-(aminomethyl)-bicyclo[3.2.0]hept-3-yl)acetic acid, (3S,5R)-3-(aminomethyl)-5-methylheptanoic acid, (3S,5R)-3-amino-5-methylheptanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)proline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-((1-(aminomethyl)cyclohexyl)methyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-((1H-tetrazol-5-yl)methyl)cycloheptyl]methylamine, (3S,4S)-(1-(aminomethyl)-3,4-dimethylcyclopentyl)acetic acid, (3S,5R)-3-(aminomethyl)-5-methyloctanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid, (3S,5R)-3-amino-5-methyloctanoic acid, (3R,4R,5R)-3-amino-4,5-dimethylheptanoic acid, and (3R,4R,5R)-3-amino-4,5-dimethyloctanoic acid;
      • a cannabinoid;
      • a metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;
      • a serotonin reuptake inhibitor such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;
      • a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion, bupropron metabolite hydroxybupropion, nomifensine and viloxazine (Vivalan (registered trademark)), especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;
      • a dual serotonin-noradrenaline reuptake inhibitor, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;
      • an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarbonitrile; 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, or guanidinoethyldisulfide;
      • an acetylcholinesterase inhibitor such as donepezil;
      • a prostaglandin E2 subtype 4 (EP4) antagonist such as N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamide or 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;
      • a leukotriene B4 antagonist; such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-11870,
      • a 5-lipoxygenase inhibitor, such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504);
      • a sodium channel blocker, such as lidocaine;
      • a calcium channel blocker, such as ziconotide, zonisamide, mibefradil;
      • a 5-HT3 antagonist, such as ondansetron;
      • a chemotherapy drug such as oxaliplatin, 5-fluorouracil, leukovorin, paclitaxel;
      • a calcitonin gene related peptide (CGRP) antagonist;
      • a bradykinin (BK1 and BK2) antagonist;
      • a voltage gated sodium dependent channel blocker (Nav1.3, Nav.7, Nav1.8);
      • a voltage dependent calcium channel blocker (N-type, T-type);
      • a P2X (ion channel type ATP receptor) antagonist;
      • an acid-sensing ion channel (ASIC1a, ASIC3) antagonist;
      • an angiotensin AT2 antagonist;
      • a chemokine CCR2B receptor antagonist;
      • a cathepsin (B, S, K) inhibitor;
      • a sigma1 receptor agonist or antagonist;
      • a calcium/magnesium
      • a goshajinkigan
      • and the pharmaceutically acceptable salts and solvates thereof.
  • Such combinations offer significant advantages, including synergistic activity, in therapy.
  • The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • A therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof includes a dose range from about 0.05 mg to about 3000 mg, in particular from about 1 mg to about 1000 mg or, more particularly, from about 10 mg to about 500 mg of active ingredient in a regimen of about once a day or more than once a day, for example two, three or four times a day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for active compounds of the invention will vary as will the diseases, syndromes, conditions, and disorders being treated.
  • For oral administration, a pharmaceutical composition is preferably provided in the form of tablets containing about 0.01, about 10, about 50, about 100, about 150, about 200, about 250, and about 500 milligrams of the inventive compound as the active ingredient.
  • Advantageously, a compound of formula (I) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three and four times daily.
  • Optimal dosages of a compound of formula (I) to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation, and the advancement of the disease, syndrome, condition, or disorder. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust the dose to achieve an appropriate therapeutic level.
  • The above dosages are thus exemplary of the average case. There can be, of course, individual instances wherein higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Compounds of formula (I) may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of a compound of formula (I) is required for a subject in need thereof.
  • As antagonists of the TRPM8 ion channel, the compounds of formula (I) are useful in methods for treating and preventing a disease, a syndrome, a condition, or a disorder in a subject, including an animal, a mammal and a human in which the disease, the syndrome, the condition, or the disorder is affected by the modulation of TRPM8 receptors. Such methods comprise, consist of, and consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment or prevention a therapeutically effective amount of a compound, salt, or solvate of formula (I). In particular, the compounds of formula (I) are useful for preventing or treating pain, or diseases, syndromes, conditions, or disorders causing such pain, or pulmonary or vascular dysfunction. More particularly, the compounds of formula (I) are useful for preventing or treating inflammatory pain, inflammatory hypersensitivity conditions, neuropathic pain, anxiety, depression, and cardiovascular disease aggravated by cold, including peripheral vascular disease, vascular hypertension, pulmonary hypertension, Raynaud's disease, and coronary artery disease, by administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).
  • Examples of inflammatory pain include pain due to a disease, condition, syndrome, disorder, or a pain state including inflammatory bowel disease, visceral pain, migraine, post operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases, skin diseases, toothache, pyrosis, burn, sunburn, snake bite, venomous snake bite, spider bite, insect sting, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, Raynaud's syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis, sinus headache, tension headache, or arachnoiditis.
  • One type of inflammatory pain is inflammatory hyperalgesia, which can be further distinguished as inflammatory somatic hyperalgesia or inflammatory visceral hyperalgesia. Inflammatory somatic hyperalgesia can be characterized by the presence of an inflammatory hyperalgesic state in which a hypersensitivity to thermal, mechanical and/or chemical stimuli exists. Inflammatory visceral hyperalgesia can also be characterized by the presence of an inflammatory hyperalgesic state, in which an enhanced visceral irritability exists.
  • Examples of inflammatory hyperalgesia include a disease, syndrome, condition, disorder, or pain state including inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal diseases, skin diseases, post operative pain, headaches, toothache, burn, sunburn, insect sting, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, enteritis, irritable bowel syndrome, Raynaud's syndrome, inflammatory bowel diseases including Crohn's Disease or ulcerative colitis.
  • One embodiment of the present invention is directed to a method for treating inflammatory somatic hyperalgesia in which a hypersensitivity to thermal, mechanical and/or chemical stimuli exists, comprising the step of administering to a mammal in need of such treatment a therapeutically effective amount of a compound, salt or solvate of formula (I).
  • A further embodiment of the present invention is directed to a method for treating inflammatory visceral hyperalgesia in which a enhanced visceral irritability exists, comprising, consisting of, and/or consisting essentially of the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound, salt or solvate of formula (I).
  • A further embodiment of the present invention is directed to a method for treating neuropathic cold allodynia in which a hypersensitivity to a cooling stimuli exists, comprising, consisting of, and/or consisting essentially of the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound, salt or solvate of formula (I).
  • Examples of an inflammatory hypersensitivity condition include urinary incontinence, benign prostatic hypertrophy, cough, asthma, rhinitis and nasal hypersensitivity, itch, contact dermatitis and/or dermal allergy, and chronic obstructive pulmonary disease.
  • Examples of a neuropathic pain include pain due to a disease, syndrome, condition, disorder, or pain state including cancer, neurological disorders, spine and peripheral nerve surgery, brain tumor, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, neuralgias (trigeminal neuralgia, glossopharyngeal neuralgia, postherpetic neuralgia and causalgia), lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathies associated with spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, bony fractures, oral neuropathic pain, Charcot's pain, complex regional pain syndrome I and II (CRPS I/II), radiculopathy, Guillain-Barre syndrome, meralgia paraesthetica, burning-mouth syndrome, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis, Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital nouralgia, red neuralgia, Sluder's neuralgia, sphenopalatine neuralgia, supraorbital neuralgia, vulvodynia, or vidian neuralgia.
  • One type of neuropathic pain is neuropathic cold allodynia, which can be characterized by the presence of a neuropathy-associated allodynic state in which a hypersensitivity to cooling stimuli exists. Examples of neuropathic cold allodynia include allodynia due to a disease, condition, syndrome, disorder or pain state including neuropathic pain or neuralgia, pain arising from spine and peripheral nerve surgery or trauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex regional pain syndrome I and II (CRPS I/II) and radiculopathy.
  • Examples of anxiety include social anxiety, post traumatic stress disorder, phobias, social phobia, special phobias, panic disorder, obsessive compulsive disorder, acute stress disorder, separation anxiety disorder, and generalized anxiety disorder.
  • Examples of depression include major depression, bipolar disorder, seasonal affective disorder, post natal depression, manic depression, and bipolar depression.
    • General Synthesis
  • Throughout the instant application, the following abbreviations are used with the following meanings:
  • AcOH: Acetic acid
    aq.: aqueous
    BINAP: 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl
    tBuXPhos: 2-Di-tert-Butylphosphino-2′,4′,6′-triisopropylbiphenyl
    • CDI: Carbonyldiimidazole
  • Cs2CO3: Cesium carbonate
    DBN: 1,5-diazabicyclo[4.3.0]non-5-ene
    • DavePhos: 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl
  • DABCO: 1,4-diazabicyclo[2.2.2]octane
    DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene
    • DCM: Dichloromethane
  • DEAD: Diethyl azodicarboxylate
    • DIPEA: Diisopropylethylamine DMF: N,N-Dimethylformamide DMA: N,N-Dimethylacetamide DME: 1,2-Dimethoxyethane
  • DMSO: Dimethyl sulfoxide
    Dess-Martin Periodinane: 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one
    • ESI: Electrospray Ionization Et: Ethyl
  • EtOAc: Ethyl acetate
    • EtOH: Ethanol
  • eq.: equivalent
    • HPLC: High-Performance Liquid Chromatography INT: Intermediate
  • IPE: Isopropyl ether
    K2CO3: Potassium carbonate
    K3PO4: Potassium phosphate
    KO t-Bu: Potassium tert-butoxide
    • LC: Liquid Chromatography
  • LDA: Lithium diisopropylamide
    • LG: Leaving Group tR: Retention Time Me: Methyl MeCN: Acetonitrile MeOH: Methanol
  • min: minute
    • NaHCO3: Sodium Bicarbonate
  • Na2SO4: Sodium Sulfate
    Na2S2O3: Sodium thiosulfate
    NaO t-Bu: Sodium tert-butoxide
    • MHz: Megahertz
  • mp: melting point
    • MS: Mass Spectrometry
  • NMP: N-methyl-2-pyrrolidone
    • NMR: Nuclear Magnetic Resonance
  • Oxone (Registered Trademark): Potassium peroxymonosulfate
    • PG: Protecting Group
  • Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0)
    Pd(OAc)2: Palladium (II) acetate
    PdCl2(dppf) CH2Cl2: [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), Dichloromethane Adduct
    PdCl2(Amphos)2: Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) PEPPSI(Trademark)-IPr: [1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride
    Pd(PPh3)4: Tetrakis(triphenylphosphine)palladium (0)
    POCl3: Phosphorus(V) oxychloride
    quant.: quantitative
    rt: room temperature
    sat.: saturated
    • TEA: Triethylamine TFA: Trifluoroacetic Acid THF: Tetrahydrofuran THP: 2-Tetrahydropyranyl
  • p-TsOH: p-Toluenesulfonic acid
    XPhos: 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl
    Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
  • The term of “base” is likewise no particular restriction on the nature of the bases used, and any base commonly used in reactions of this type may equally be used here. Examples of such bases include: alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide; alkali metal hydrides, such as lithium hydride, sodium hydride, and potassium hydride; alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, and potassium t-butoxide; alkali metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate; alkali metal hydrogencarbonates, such as lithium hydrogencarbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 2,6-di(t-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), lutidine, and colidine; alkali metal amides, such as lithium amide, sodium amide, potassium amide, lithium diisopropyl amide, potassium diisopropyl amide, sodium diisopropyl amide, lithium bis(trimethylsilyl)amide and potassium bis(trimethylsilyl)amide. Of these, triethylamine, diisopropylethylamine, DBU, DBN, DABCO, pyridine, lutidine, colidine, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium carbonate, potassium hydrogencarbonate, potassium hydroxide, potassium phosphate, barium hydroxide, and cesium carbonate are preferred.
  • The reactions are normally and preferably effected in the presence of inert solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve reagents, at least to some extent. Examples of suitable solvents include, but not limited to: halogenated hydrocarbons, such as DCM, chloroform, carbon tetrachloride, and dichloroethane; ethers, such as diethyl ether, diisopropyl ether, THF, and dioxane; aromatic hydrocarbons, such as benzene, toluene and nitrobenzene; amides, such as, DMF, DMA, and hexamethylphosphoric triamide; amines, such as N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, N,N-dimethylaniline, and N,N-diethylaniline; alcohols, such as methanol, ethanol, propanol, isopropanol, and butanol; nitriles, such as acetonitrile and benzonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO) and sulfolane; ketones, such as acetone and diethylketone. Of these solvents, including but not limited to DMF, DMA, DMSO, THF, diethylether, diisopropylether, dimethoxyethane, acetonitrile, DCM, dichloroethane and chloroform are preferred.
    • EXAMPLES
  • The invention is illustrated in the following non-limiting examples in which, unless stated otherwise: all reagents are commercially available, all operations are carried out at room or ambient temperature, that is, in the range of about 18 to 25° C.; evaporation of solvent is carried out using a rotary evaporator under reduced pressure with a bath temperature of up to about 60° C.; reactions are monitored by thin layer chromatography (TLC) and reaction times are given for illustration only; the structure and purity of all isolated compounds are assured by at least one of the following techniques: TLC (Merck silica gel 60 F254 precoated TLC plates or Merck NH2 F254 precoated HPTLC plates), mass spectrometry or nuclear magnetic resonance (NMR). Microwave reaction is conducted by Intiator (registered trademark) Sixty (Biotage). Yields are given for illustrative purposes only. The column chromatography systems are conducted by Yamazen flash chromatography and Biotage (SP1, Isolera one). Flash column chromatography is carried out using Merck silica gel 60 (230-400 mesh ASTM), Fuji Silysia Chromatorex (registered trademark) DM2035 (Amino Type, 30-50 micrometer), Biotage silica (32-63 mm, KP-Sil), Biotage amino bounded silica (45-75 mm, KP-NH), Wakogel (registered trademark)C-300HGT, Hi-Flash (registered trademark) column (YAMAZEN, silica gel, 40 micro meters, 60 angstrom), Hi-Flash (registered trademark) column (YAMAZEN, amino, 40 micro meters, 60 angstrom). LC-MS analysis for intermediates and Examples are carried out by Waters 2695 Alliance HPLC with ZQ 2000 mass spectrometer and 2996 PDA detector. Analytical conditions (method-A, method-B, method-C, method-D, method-E and method-F) are as follows.
    • Conditions for Method-A, Method-B, and Method-C:
  • Column Waters XTerra C18 2.1 × 30 mm, 3.5 micrometer
    Column temperature 45° C.
    Flow rate 0.5 mL/min
    PDA detection 210-400 nm scan (Extracted wave length: 254 nm)
    MS detection ESI positive & negative mode
    Mobile phases A: MeCN (HPLC grade)
    B: 0.5% aqueous HCO2H
    C: 0.2% aqueous NH3
    D: H2O (Milli-Q water)
  • Method-A
    Time (min) A (%) B (%) C (%) D (%)
    0 4 4.8 4.8 86.4
    2 96 0.2 0.2 3.6
    run time: 4 min
  • Method-B
    Time (min) A (%) B (%) C (%) D (%)
    0 4 0 4.8 91.2
    2 96 0 0.2 3.8
    run time: 4 min
  • Method-C
    Time (min) A (%) B (%) C (%) D (%)
    0 32 3.4 3.4 61.2
    2 96 0.2 0.2 3.6
    run time: 4 min
  • Conditions for Method-D and Method-E:
  •
    Column Waters SunFire C18 4.6 × 50 mm, 5 micrometer
    Column temperature: 45° C.
    Flow rate: 0.8 mL/min
    PDA detection: 210-400 nm scan (Extracted wave length:
    215 nm)
    MS detection: ESI positive & negative mode
    Mobile phases A: MeCN (HPLC grade)
    B: 0.5% aqueous HCO2H
    C: 0.2% aqueous NH3
    D: H2O (Milli-Q water)
  • Method-D
    Time (min) A (%) B (%) C (%) D (%)
    0 5 2.5 2.5 90
    0.5 5 2.5 2.5 90
    3.5 95 2.5 2.5 0
    4 95 2.5 2.5 0
    run time: 4.5 min
  • Method-E
    Time (min) A (%) B (%) C (%) D (%)
    0 5 0 5 90
    0.5 5 0 5 90
    3.5 95 0 5 0
    4 95 0 5 0
    run time: 4.5 min
  • The purification of compounds using HPLC (preparative LC-MS) is-performed by the following apparatus and conditions.
  • Apparatus; Waters MS-trigger AutoPurification(trademark) system
  • Column; Waters XTerra C18, 19×50 mm, 5 micrometer particle
  • Condition A: Methanol or acetonitrile/0.01% (v/v) ammonia aqueous solution
  • Condition B: Methanol or acetonitrile/0.05% (v/v) formic acid aqueous solution Low-resolution mass spectral data (ESI) are obtained by the following apparatus and conditions: Apparatus; Waters Alliance HPLC system on ZQ or ZMD mass spectrometer and UV detector. LC/MS/MS data are determined at the triple quadrupole mass spectrometry (AB SCIEX AP14000) with HPLC (Agilent 1100 series) and autosampler (AMR CTC-PAL). NMR data are determined at 270 MHz (JEOL JNM-LA 270 spectrometer), 300 MHz (JEOL JNM-LA300) or 600 MHz (Bruker Avance 600) using deuterated chloroform (99.8% D) or dimethylsulfoxide (99.9% D) as solvent unless indicated otherwise, relative to tetramethylsilane (TMS) as internal standard in parts per million (ppm); conventional abbreviations used are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad, etc. Chemical symbols have their usual meanings; M (mol(s) per liter), L(liter(s)), mL (milliliter(s)), g (gram(s)), mg(milligram(s)), mol (moles), mmol (millimoles).
  • Each prepared compound is generally named by ChemBioDraw (Ultra, version 12.0, CambridgeSoft).
    • Conditions for Determining HPLC Retention Time:
  • Method: QC1
      • Apparatus: Waters ACQUITY Ultra Performance LC with TUV Detector and ZQ mass spectrometer
      • Column: Waters ACQUITY C18, 2.1×100 mm, 1.7 micrometer particle size
        • Column Temperature: 60° C.
        • Flow rate: 0.7 mL/min
        • Run time: 3 min
        • UV detection: 210 nm
        • MS detection: ESI positive/negative mode
        • Mobile phases:
          • A1: 10 mM Ammonium acetate
          • B1: acetonitrile
      • Gradient program: (QC_neutral_full_3 min)
  • Time (min) A1 (%) B1 (%)
    0 95 5
    0.1 95 5
    1.8 5 95
    2.3 95 5
  • Method: QC2
      • Apparatus: Waters 2795 Alliance HPLC with ZQ2000 mass spectrometer and 2996 PDA Detector
        • Column: XBridge C18, 2.1×50 mm, 3.5 micrometer particle size
        • Column Temperature: 45° C.
        • Flow rate: 1.2 mL/min
        • Run time: 4.5 min
        • UV detection: 210-400 nm scan
        • MS detection: ESI positive/negative mode
        • Mobile phases:
          • A: Water
          • B: MeCN
          • C: 1% aqueous HCO2H solution
          • D: 1% aqueous NH3 solution
  • Gradient program:
  • Time (min) A (%) B (%) C (%) D (%)
    0 85 10 2.5 2.5
    0.2 85 10 2.5 2.5
    3.2 0 95 2.5 2.5
    3.7 0 95 2.5 2.5
    3.71 85 10 2.5 2.5
    4.5 85 10 2.5 2.5
  • All of the azaspiro derivatives of the formula (I) can be prepared by the procedures described in the general methods presented below or by the specific methods described in the Example synthesis part and Intermediate synthesis part, or by routine modifications thereof. The present invention also encompasses any one or more of these processes for preparing the azaspiro derivatives of formula (I), in addition to any novel intermediates used therein.
  • In the following general methods, descriptors are as previously defined for the azaspiro derivatives of the formula (I) unless otherwise stated.
  • Figure US20180339993A1-20181129-C00005
  • In this scheme-1, an azaspiro compound of the general formula (I) can be prepared by the N-alkylation reaction of an azaspiro compound of formula (II) with the alpha-haloketone compound of formula (III) in the presence of a base in an inert solvent. A preferred base is selected from, for example, but not limited to: an alkali or alkaline earth metal hydroxide, alkoxide, carbonate, halide or hydride, such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, cesium carbonate, sodium carbonate, potassium carbonate, potassium phosphate, potassium fluoride, sodium hydride or potassium hydride; or an amine such as TEA, tributylamine, diisopropylethylamine, 2,6-lutidine, pyridine or 4-dimethylaminopyridine. Examples of suitable inert aqueous or non-aqueous organic solvents include: ethers, such as THF or 1,4-dioxane; acetone; N,N-Dimethylformamide; DMSO; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane or chloroform; and pyridine; or mixtures thereof. The reaction can be carried out at a temperature in the range of from −80° C. to 200° C., preferably in the range of from −10° C. to 150° C. Reaction times are, in general, from 10 minutes to 4 days, preferably from 10 minutes to 24 h. A microwave oven may optionally be used to increase reaction rates.
  • Figure US20180339993A1-20181129-C00006
  • In scheme-2, a compound of the general formula (IV) can be prepared from a compound (III) using a suitable reduction reagent (for example, sodium borohydride) in an inert solvent (for example, methanol). Then, a compound of the general formula (V) can be prepared from a compound (IV) according to the N-alkylation described in the generally synthetic method in scheme-1. Finally, a compound of the general formula (I) can be prepared from a compound (V) using a suitable oxidation reagent (for example, Dess-Martin reagent) in an inert solvent (for example, dichloromethane).
  • Figure US20180339993A1-20181129-C00007
  • In scheme-3, a compound of the general formula (I-a) can be prepared by the cross coupling reaction of a halide compound of formula (VI) with a boronic (or boronic ester) compound of formula (VII) in organic solvent or water-organic co-solvent mixture under coupling conditions in the presence of a suitable transition metal catalyst and in the presence or absence of a base. In a representation of BR′w, R′ means OH, O-low alkyl or fluorine, and w is 2 or 3, B is boron atom. As the concrete representation of substituent, B(OH)2, B(O-lower alkyl)2, B(lower alkyl)2, potassium trifluoroborate (BF3 −)(BF3K) are described, but when B(O-lower alkyl)2 may form the cyclic ring between the lower alkyl groups. Furthermore, a compound of the general formula (I-a) can also be prepared by the same cross coupling reaction from a halide compound of formula (IX) with a boronic (or boronic ester) compound of formula (VIII) converted from the halide compound of formula (VI). The boronic (or boronic ester) compounds of formula (VII) and (VIII) are utilized as the isolated reagents or the reagents generated in in situ for the cross coupling reaction.
  • Examples of suitable transition metal catalysts include: tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, copper(0), copper(I) acetate, copper(I) bromide, copper(I) chloride, copper(I) iodide, copper(I) oxide, copper(II) trifluoromethanesulfonate, copper (II) acetate, copper(II) bromide, copper(IIII) chloride, copper(IIII) iodide, copper(IIII) oxide, copper(IIII) trifluoromethanesulfonate, palladium(II) acetate, palladium(II) chloride, bis(acetonitrile)dichloropalladium(II), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0) and [1,1′-bis(diphenylphosphino)ferrocene] palladium(II) dichloride. Preferred catalysts are tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) chloride, palladium(II) acetate, palladium(II) chloride, bis(acetonitrile)dichloropalladium(0), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)dipalladium(0) and [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride.
  • Examples of suitable organic solvent for the anhydrous solvent and the water-organic co-solvent mixture include: THF; 1,4-dioxane; DME; DMF; acetonitrile; alcohols, such as methanol or ethanol; halogenated hydrocarbons, such as DCM, 1,2-dichloroethane, chloroform or carbon tetrachloride; and diethylether. This reaction can be carried out in the presence or absence of a base such as potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate and potassium phosphate. This reaction can be carried out in the presence of a suitable additive agent.
  • Examples of such additive agents include: triphenylphosphine, tri-tert-butylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, tri-2-furylphosphine, tri-o-tolylphosphine, 2-(dichlorohexylphosphino)biphenyl, triphenylarsine, tetrabutylammonium chloride, tetrabutylammonium fluoride, lithium acetate, lithium chloride, triethylamine, potassium or sodium methoxide, sodium hydroxide, cesium carbonate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, and/or sodium iodide. The reaction can be carried out at a temperature of from 0° C. to 200° C., more preferably from 20° C. to 150° C. Reaction times are, in general, from 5 minutes to 96 h, more preferably from 30 minutes to 24 h. In an alternative case, the reaction can be carried out in a microwave system in the presence of a base in an inert solvent. The reaction can be carried out at a temperature in the range of from 100° C. to 200° C., preferably in the range of from 120° C. to 150° C. Reaction times are, in general, from 10 minutes to 3 h, preferably from 15 minutes to 1 h. Other than a Suzuki-Miyaura cross coupling shown above, Stille cross coupling reaction using trialkyltin instead of BR′w substituent, and Negishi coupling reaction using zinc-halogen, wherein as a halogen, chlorine, bromine, iodide are cited, instead of BR′w substituent can be used.
  • Figure US20180339993A1-20181129-C00008
  • In the step-1 of scheme-4, a alpha-haloketone compound of the general formula (IIII) can be prepared by the alpha-halogenation reaction (Hal=Cl, Br, I) of compound (X) using an appropriate halogenation reagent. As an appropriate halogenation reagent, for example, bromine, chlorine, iodide, sulfuryl chloride, hydrogen bromine, N-bromosuccinimide (NBS), copper (II) bromide, 5,5-dibromo-2,2-dimethyl-4,6-dioxo-1,3-dioxane, trimethylphenylammonium tribromide, benzyltrimethylammonium tribromide, and benzyltrimethylammonium dichloroiodate are cited. As an appropriate organic solvent, for example, acetic acid, 25% hydrogen bromide-acetic acid solution, 48% hydrogen bromide solution, carbon disulfide, diethyl ether, tetrahydrofuran, N,N-dimethylformamide (DMF), halogenated hydrocarbon such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride can be used. The reaction period is about 5 minutes to 96 h, and is generally about 30 minutes to 24 h. The reaction temperature is about 0° C. to 250° C., and is generally about 30° C. to 150° C. Further, in the step-2 of scheme-4, alpha-haloketone compound of the general formula (III) can also be prepared from an ester compound (XI) according to the procedure described in Tetrahedron Letters, 38, 3175, 1997. Typically, compound of formula (III) is prepared by the reaction with an ester compound (XI) under the condition of iodochloromethane and lithium diisopropylamide (LDA) in tetrahydrofuran (THF) at −78° C.
  • Figure US20180339993A1-20181129-C00009
  • In scheme-5, an alpha-haloketone compound of the general formula (XIII) can be prepared by the Friedel-Crafts reaction of a pyrrole compound (XII) using chloroacetyl chloride and appropriate Lewis acid (for example, aluminum chloride) in an inert solvent (for example, dichloromethane).
  • Figure US20180339993A1-20181129-C00010
  • In scheme-6, a compound of the general formula (XV)(the general formula (II): RA and RB are oxo, X is NH) can be prepared from compounds of the general formula (XIV) by the methodology (Bucherer-Bergs reaction) described in the literature (for example, Chem. Rev., 46 (3), pp 403-470, 1950). Typically, compound of formula (XV) is prepared by the reaction of a ketone compound of formula (XIV) under the condition of potassium cyanide (or trimethylsilyl cyanide) and ammonium carbonate in ethanol/water (1:1 v/v) at 70° C. for 20 h.
  • Figure US20180339993A1-20181129-C00011
  • In Scheme-7, a compound of formula (XVII) (the general formula (II): RA and RB are oxo, and X is O) can be prepared from a cyanohydrin compound of the general formula (XVI).
  • The compound of formula (XVI) can be prepared from a ketone compound of the general formula (XIV) by the condition of trimethylsilyl cyanide and the catalytic zinc (II) iodide, followed by deprotection of O-trimethylsilyl moiety under the acidic condition in the step-1. Further, a compound of formula (XVI) can be converted to a 2,4-oxazolidinedione derivative of formula (XVII) according to the procedure described in Synthesis, p 697 (1991). Typically, a compound of formula (XVII) is prepared by the reaction of a compound of formula (XVI) with chlorosulfonyl isocyanate, followed by acid hydrolysis in the step-2.
  • Figure US20180339993A1-20181129-C00012
  • In Scheme-8, a compound of the general formula (XX) (the general formula (II): RA and RB are hydrogen, and X is O) can be prepared from a compound of the general formula (XVIII) (an intermediate compound of formula (XVI)). A compound of the general formula (XIX) can be prepared under the condition of reduction reaction by using the reduction reagent, such as borane-dimethylsulfide complex, in this step-1. Further, a compound of the general formula (XIX) can be converted to an oxazolidin-2-one derivative of formula (XX) by the reaction with the 1,1′-carbonyldiimidazole (CDI) in this step-2.
  • Figure US20180339993A1-20181129-C00013
  • In Scheme-9, a compound of the general formula (XXIV) (the general formula (II): RA is alkyl; RB is hydrogen or alkyl, and X is O) can be prepared from a compound of the general formula (XIV). A compound of the general formula (XXIII) can be prepared by the Reformatsky reaction of the activated reagent (XXI) prepared from zinc metal and alpha-bromoacetic acid ester derivatives with a compound of the general formula (XIV) in this step-1, followed by the alkali hydrolysis of a compound of the general formula (XXII). Further, a compound of the general formula (XXIII) can be converted to an oxazolidin-2-one derivative of formula (XXIV) by the reaction with the diphenylphosphoryl azide (DPPA) in this step-3.
  • Figure US20180339993A1-20181129-C00014
  • In scheme-10, a compound of the general formula (XXVIII) can be prepared by the reaction of a halide compound of formula (XXV) with compound of formula (XXVI)(step-1). Alternatively the compound of the general formula (XXVIII) can be also prepared by the reaction of a phenol compound of formula (XXVII) with compound of formula (IX)(step-2) by using the selected procedure from palladium coupling reaction, nucleophilic substitution reaction and ullmann reaction. The coupling reaction can be carried out by the combination a suitable palladium catalyst, ligand and base in organic solvent or water-organic co-solvent mixture. Examples of suitable transition metal catalysts include: palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0) and [1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene] (3-chloropyridyl)palladium(II) dichloride. Examples of suitable organic solvent for the anhydrous solvent and the water-organic co-solvent mixture include: THF; DME; 1,4-dioxane; DMF; acetonitrile and alcohols, such as methanol, ethanol and tert-butyl alcohol. Examples of suitable base include: sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium tert-butoxide and potassium tert-butoxide. This reaction can be carried out in the presence of a suitable ligand agent. Examples of such ligand agents include: 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl(BINAP), 2-Dicyclohexylphosphino-2′-(N, N-dimethylamino)biphenyl(DavePhos), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene(Xantphos) and 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl(XPhos). The nucleophilic substitution reaction can be carried out in organic solvent or water-organic co-solvent mixture under coupling conditions in the presence of a base. Examples of suitable organic solvent include N,N-dimethylformamide, dimethylsulfoxide and N-methyl-2-pyrrolidinone. Examples of suitable base include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, sodium hydride, sodium tert-butoxide and potassium tert-butoxide. Furthermore, the Ullmann reaction can be carried out under the coupling conditions by using a suitable copper reagent, ligand and base in organic solvent. As an appropriate copper reagent, for example, copper (I) iodide, copper (I) bromide, and copper (I) chloride can be used. As an appropriate ligand and base, for example, ligand such as N,N-dimethylglycine, L-proline, N,N′-dimethylethylenediamine and trans-N,N′-dimethylcyclohexane-1,2-diamine and base such as sodium carbonate, potassium carbonate and cesium carbonate. Examples of suitable organic solvent include THF, 1,4-dioxane, N,N-dimethylformamide, dimethylsulfoxide and N-methyl-2-pyrrolidinone. These reaction can be carried out at a temperature of from 20° C. to 200° C., more preferably from 100° C. to 160° C. Reaction times are, in general, from 5 minutes to 96 h, more preferably from 30 minutes to 24 h. In an alternative case, the reaction can be carried out in a microwave system in the presence of a base in an inert solvent. The reaction can be carried out at a temperature in the range of from 100° C. to 200° C., preferably in the range of from 120° C. to 150° C. Reaction times are, in general, from 10 minutes to 3 h, preferably from 15 minutes to 1 h.
  • Figure US20180339993A1-20181129-C00015
  • In scheme-11, a compound of the general formula (XXXII) can be prepared by the reaction of a halide compound of formula (XXV) with compound of formula (XXIX), (XXX) or (XXXI) by using the selected procedure from palladium coupling reaction, nucleophilic substitution reaction or the Ullmann reaction according to the general synthetic method in scheme-10.
    • Preparation of Intermediate Intermediate-1-1-A (INT-1-1-A): 8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00016
  • A mixture of 4,4-difluorocyclohexane (3.00 g, 22.37 mmol), potassium cyanide (2.91 g, 44.7 mmol) and ammonium carbonate (8.60 g, 89.0 mmol) in ethanol/water (1:1 v/v, 90 mL) is heated at 70° C. for 20 h. After cooling to rt, the organic solvent (ethanol) is evaporated in vacuo until half volume. The residue is diluted with cold water (250 mL) and stirred for 60 min. The precipitated solid is filtered and dried in vacuum pump at 40° C. (inner temp) using phosphorus pentoxide to give the titled compound (3.75 g, slightly gray solid).
  • 1H-NMR (270 MHz, DMSO-d): delta 10.77 (br.s, 1H), 8.53 (s, 1H), 2.20-1.65 (m, 8H).
  • The following hydantoin derivative (INT-1-2-A) is prepared according to the procedure (INT-1-1-A) from the known or synthesized ketone derivatives in Table 1.
  • TABLE 1
    Ketones Hydantoins Yield and Analytical data
    Figure US20180339993A1-20181129-C00017
    Figure US20180339993A1-20181129-C00018
         		4.7% yield (white solid) 1H-NMR (300 MHz, DMSO-d6): delta 10.50 (br.s, 1H), 8.37 (s, 1H), 2.50-2.30 (m, 2H), 2.05-1.35 (m, 12H).
    • Intermediate-1-3-A (INT-1-3-A): 8,8-difluoro-1-oxa-3-azaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00019
  • The titled compound is prepared according to the procedure described in Synthesis, p 697 (1991) from 4,4-difluoro-1-hydroxycyclohexanecarbonitrile (495 mg, 3.07 mmol) and chlorosulfonyl isocyanate (281 microL, 3.23 mmol) and triethylamine (450 microL, 3.23 mmol) in anhydrous benzene (10 mL) to give the product (600 mg, 95% yield) as a slightly yellow solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 12.01 (br.s, 1H), 2.25-1.85 (m, 8H).
    • Intermediate-1-4-A (INT-1-4-A): 8,8-difluoro-1-oxa-3-azaspiro[4.5]decan-2-one
  • Figure US20180339993A1-20181129-C00020
  • A mixture of 1-(aminomethyl)-4,4-difluorocyclohexanol hydrochloride (5.15 g, 25.5 mmol), CDI (12.42 g, 77 mmol) and triethylamine (7.68 mL, 51.1 mmol) in THF (100 mL) is heated at 75° C. for 20 h. To this is added 2 M NaOH aq. solution (6 eq.) and the mixture is stirred at rt for 5 h. The mixture is extracted with DCM (×3) and the combined organic extracts are evaporated in vacuo to give a yellow oil. The crude product is dissolved in DCM (300 mL) and washed with 2 M HCl aq. solution (×1) then saturated NaHCO3 solution, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product (a slightly yellow solid), which is purified by column chromatography (Biotage) on silica gel (100 g) eluting with 65-100% ethyl acetate in hexane to give the titled compound (3.34 g, 68% yield) as a white solid.
  • 1H-NMR (270 MHz, CDCl3): delta 5.79 (br.s, 1H), 3.38 (s, 2H), 2.35-1.75 (m, 8H).
    • Intermediate-1-5-A (INT-1-5-A): 8,8-difluoro-2-azaspiro[4.5]decane-1,3-dione
  • Figure US20180339993A1-20181129-C00021
    • <Step-1>: Intermediate-1-5-1 (INT-1-5-1): ethyl 2-cyano-2-(4,4-difluorocyclohexylidene)acetate
  • Figure US20180339993A1-20181129-C00022
  • A mixture of 4,4-difluorocyclohexanone (1.00 g, 7.46 mmol), ethyl 2-cyanoacetate (1.10 g, 9.69 mmol), molecular sieves 4 angstrom (1.00 g) and Et3N (2.08 mL, 14.91 mmol) in DCM (10 mL) is stirred at rt for 1 day. The mixture is filtered and concentrated. The residual oil is used for next step without further purification. MS (ESI) m/z: 228.3 (M−H)−.
    • <Step-2>: Intermediate-1-5-2 (INT-1-5-2): 1-(cyanomethyl)-4,4-difluorocyclohexanecarbonitrile
  • Figure US20180339993A1-20181129-C00023
  • A mixture of INT-1-5-1 (7.46 mmol, crude mixture from 4,4-difluorocyclohexanone) and potassium cyanide (1.46 g, 22.38 mmol) in EtOH (20 mL)-H2O (4 mL) is stirred at 75° C. for 1 day. After the removal of solvent, the residual oil is diluted with sat. NaHCO3 solution and extracted with EtOAc. The combined organic solution is dried over Na2SO4, filtered and concentrated. The residual oil is purified by column chromatography on silica gel eluting with 0-20% ethyl acetate in hexane to give the titled compound (1.01 g, 74% yield in 2 steps) as an off-white solid.
  • 1H-NMR (300 MHz, CDCl3): delta 2.75 (s, 2H), 2.32-2.05 (m, 6H), 2.92-2.77 (m, 2H).
    • <Step-3>: Intermediate-1-5-A (INT-1-5-A): 8,8-difluoro-2-azaspiro[4.5]decane-1,3-dione
  • Figure US20180339993A1-20181129-C00024
  • A mixture of INT-1-5-2 (200 mg, 1.09 mmol) in H2SO4 (0.3 mL) and AcOH (1.5 mL) is stirred at 125° C. for 1 h. The mixture is poured into ice water. Then, the mixture is neutralized with 2 M NaOH aq. solution and extracted with DCM. The combined organic solution is dried over Na2SO4, filtered and concentrated. The residual oil is purified by column chromatography on silica gel eluting with 0-50% ethyl acetate in hexane to give the the titled compound (80 mg, 36% yield) as an off-white solid.
  • 1H-NMR (300 MHz, CDCl3): delta 8.08 (br s, 1H), 2.63 (s, 2H), 2.41-2.06 (m, 4H), 1.96-1.69 (m, 4H).
  • MS (ESI) m/z: 202.2 (M−H)−.
    • Intermediate-1-6-A (INT-1-6-A): 8,8-difluoro-4-methyl-1-oxa-3-azaspiro[4.5]decan-2-one
  • Figure US20180339993A1-20181129-C00025
    • <Step-1>: Intermediate-1-6-1 (INT-1-6-1): ethyl 2-(4,4-difluoro-1-hydroxycyclohexyl)propanoate
  • Figure US20180339993A1-20181129-C00026
  • A mixture of 4,4-difluorocyclohexanone (1.00 g, 7.46 mmol), ethyl 2-bromopropanoate (1.35 g, 7.46 mmol), zinc powder (561 mg, 8.57 mmol) in dioxane (20 mL) is stirred at 100° C. for 1 day. The mixture is filtered by using Celite pad. After the removal of solvent, the residual oil is purified by column chromatography on silica gel eluting with 0-30% ethyl acetate in hexane to give the titled compound (1.50 g, 85% yield) as a pale yellow oil.
  • 1H-NMR (270 MHz, CDCl3): delta 4.19 (q, J=7.3 Hz, 2H,), 3.33 (d, J=2.0 Hz, 1H), 2.75-1.82 (m, 6H), 1.73-1.59 (m, 2H), 1.54-1.36 (m, 1H), 1.28 (t, J=7.3 Hz, 3H), 1.23 (d, J=7.3 Hz, 3H).
    • <Step-2>: Intermediate-1-6-2 (INT-1-6-2): 2-(4,4-difluoro-1-hydroxycyclohexyl)propanoic acid
  • Figure US20180339993A1-20181129-C00027
  • A mixture of INT-1-6-1 (1.50 g, 6.35 mmol), 2 M NaOH aq. solution (5 mL, 10 mmol) in THF (10 mL) is stirred at 60° C. for 5 h. The mixture is acidified with 2 M HCl aq. solution and extracted with DCM. The combined organic solution is dried over Na2SO4, filtered and concentrated to give the titled compound (1.43 g) as a crude oil.
  • MS (ESI) m/z; 207.1 (M−H)−.
    • <Step-3>: Intermediate-1-6-A (INT-1-6-A): 8,8-difluoro-4-methyl-1-oxa-3-azaspiro[4.5]decan-2-one
  • A mixture of INT-1-6-2 (1.43 g, crude mixture), diphenyl phosphorazidate (2.27 g, 8.24 mmol), TEA (1.44 mL, 10.3 mmol) in toluene (30 mL) is stirred at 100° C. for 2 h. The mixture is quenched with 2 M NaOH aq. solution and extracted with EtOAc. The organic layer is washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residual oil is purified by column chromatography on silica gel eluting with 0-70% ethyl acetate in hexane to give the titled compound (507 mg, 39% yield in 2 steps) as a pale yellow solid.
  • 1H-NMR (270 MHz, CDCl3): delta 5.61 (br s, 1H), 3.66 (q, J=6.6 Hz, 1H), 2.38-1.95 (m, 6H), 1.88-1.59 (m, 2H), 1.20 (d, J=6.6 Hz, 3H).
  • MS (ESI) m/z: 206.1 (M+H)+.
    • Intermediate-1-7-A (INT-1-7-A): 8,8-difluoro-4,4-dimethyl-1-oxa-3-azaspiro[4.5]decan-2-one
  • Figure US20180339993A1-20181129-C00028
    • <Step-1>: Intermediate-1-7-1 (INT-1-7-1): ethyl 2-(4,4-difluoro-1-hydroxycyclohexyl)-2-methylpropanoate
  • Figure US20180339993A1-20181129-C00029
  • A mixture of 4,4-difluorocyclohexanone (1.00 g, 7.46 mmol), ethyl 2-bromo-2-methylpropanoate (1.45 g, 7.46 mmol), zinc powder (561 mg, 8.57 mmol) in dioxane (20 mL) is stirred at 85° C. for 2 days. The mixture is filtered by using Celite pad. After the removal of solvent, the residual oil is purified by column chromatography on silica gel eluting with 0-30% ethyl acetate in hexane to give the titled compound (1.14 g, 61% yield) as a pale yellow oil.
  • MS (ESI) m/z: 249.1 (M−H)−.
    • <Step-2>: Intermediate-1-7-2 (INT-1-7-2): 2-(4,4-difluoro-1-hydroxycyclohexyl)-2-methyloropanoic acid
  • Figure US20180339993A1-20181129-C00030
  • A mixture of INT-1-7-1 (1.14 g, 4.55 mmol), 4 M NaOH aq. (5 mL, 20 mmol) in THF (5 mL) is stirred at 90° C. for 2 days. After the removal of undesired material by IPE, the aqueous layer is acidified with 2 M HCl aq. solution and extracted with DCM. The combined organic solution is dried over Na2SO4, filtered and concentrated in vacuo to give the titled compound (0.77 g, 76% yield) as a crude solid.
  • MS (ESI) m/z: 221.1 (M−H)−.
    • <Step-3>: Intermediate-1-7-A (INT-1-7-A): 8,8-difluoro-4,4-dimethyl-1-oxa-3-azaspiro[4.5]decan-2-one
  • A mixture of INT-1-7-2 (770 mg, 3.46 mmol), diphenyl phosphorazidate (1.14 g, 4.16 mmol), TEA (0.724 mL, 5.20 mmol) in toluene (15 mL) is stirred at 85° C. for 1 day. The mixture is quenched with 2 M NaOH aq. solution and extracted with EtOAc. The organic layer is washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo.
  • The residual oil is purified by column chromatography on silica gel eluting with 0-70% ethyl acetate in hexane to give the titled compound (567 mg, 75% yield) as a pale yellow solid.
  • 1H-NMR (270 MHz, CDCl3): delta 5.80 (br s, 1H), 2.33-2.02 (m, 6H), 1.80-1.60 (m, 2H), 1.27 (s, 3H), 1.27 (s, 3H).
  • MS (ESI) m/z: 220.2 (M+H)+.
    • Intermediate-1-8-A (INT-1-8-A): 8,8-difluoro-4-isopropyl-1-oxa-3-azaspiro[4.5]decan-2-one
  • Figure US20180339993A1-20181129-C00031
    • <Step-1>: Intermediate-1-8-1 (INT-1-8-1): ethyl 2-(4,4-difluoro-1-hydroxycyclohexyl)-3-methylbutanoate
  • Figure US20180339993A1-20181129-C00032
  • A mixture of 4,4-difluorocyclohexanone (1.00 g, 7.46 mmol), ethyl 2-bromo-3-methylbutanoate (1.56 g, 7.46 mmol), zinc powder (561 mg, 8.57 mmol) in dioxane (20 mL) is stirred at 85° C. for 2 days. After the removal of solvent, the filtrate is concentrated in vacuo. The residual oil is purified by column chromatography on silica gel eluting with 0-30% ethyl acetate in hexane to give the titled compound (1.46 g, 74% yield) as a pale yellow oil.
    • <Step-2>: Intermediate-1-8-2 (INT-1-8-2): 2-(4,4-difluoro-1-hydroxycyclohexyl)-3-methylbutanoic acid
  • Figure US20180339993A1-20181129-C00033
  • A mixture of INT-1-8-1 (1.25 g, 4.73 mmol), 6 M NaOH aq. solution (5 mL, 30 mmol) in EtOH (5 mL) is stirred at 80° C. for 1 day. After the removal of undesired material by IPE, the aqueous layer is acidified with 2 M HCl aq. solution and extracted with DCM. The combined organic solution is dried over Na2SO4, filtered and concentrated in vacuo to give the titled compound (0.88 g, 68% yield) as a crude solid.
  • MS (ESI) m/z: 235.1 (M−H)−.
    • <Step-3>: Intermediate-1-8-A (INT-1-8-A): 8,8-difluoro-4-isopropyl-1-oxa-3-azaspiro[4.5]decan-2-one
  • A mixture of INT-1-8-2 (880 mg, 3.72 mmol), diphenyl phosphorazidate (1.23 g, 4.47 mmol), TEA (0.779 mL, 5.59 mmol) in toluene (15 mL) is stirred at 85° C. for 1 day. The mixture is quenched with 2 M NaOH aq. solution and extracted with EtOAc. The organic layer is washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residual oil is purified by column chromatography on silica gel eluting with 0-70% ethyl acetate in hexane to give the titled compound (476 mg, 55% yield) as a pale yellow solid.
  • 1H-NMR (270 MHz, CDCl3): delta 6.37 (br s, 1H), 3.21 (d, J=7.9 Hz, 1H), 2.35-2.18 (m, 1H), 2.18-1.98 (m, 5H), 1.98-1.73 (m, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H).
  • MS (ESI) m/z: 234.2 (M+H)+.
    • Intermediate-2-1-A (INT-2-1-A): 5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-methylisoxazole
  • Figure US20180339993A1-20181129-C00034
  • The mixture of 3-methylisoxazol-5-amine (1.50 g, 15.29 mmol), hexane-2,5-dione (1.75 g, 15.29 mmol) and p-TsOH monohydrate (291 mg, 1.53 mmol) in ethanol (25 mL) is heated at 80° C. for 15 h. After the removal of solvent, the residue is quenched with sat. sodium bicarbonate solution. The aqueous layer is extracted with ethyl acetate (2 times) and the combined solution is washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product is purified by column chromatography (Biotage) on silica gel (100 g) eluting with 5-10% ethyl acetate in hexane to give the titled compound (2.13 g, 79% yield) as a dark red solid.
  • 1H-NMR (300 MHz, CDCl3): delta 5.92 (s, 1H), 5.90 (s, 2H), 2.37 (s, 3H), 2.19 (s, 6H).
  • The following pyrrole derivatives (INT-2-2-A and INT-2-6-A) are prepared according to the procedure of intermediate 2-1-A from the known or synthesized aniline derivatives in Table 2.
  • TABLE 2
    Anilines Products Yield and Analytical data
    Figure US20180339993A1-20181129-C00035
    Figure US20180339993A1-20181129-C00036
         		90% yield (a pale yellow solid) 1H-NMR (270 MHz, CDCl3): delta 7.69-7.63 (m, 2H), 7.54(d, J = 7.9 Hz, 1H), 7.40-7.34 (m, 1H), 6.00 (s, 2H), 2.15 (s, 6H). MS (ESI) m/z: 213.3 (M + H)+.
    Figure US20180339993A1-20181129-C00037
    Figure US20180339993A1-20181129-C00038
         		54% yield (slightly yellow solid) 1H-NMR (300 MHz, CDCl3): delta 8.49 (s, 1H), 8.34 (s, 1H), 7.38 (s, 1H), 5.93 (s, 2H), 2.42 (s, 3H), 2.04 (s, 6H) MS (ESI) m/z: 187.33 (M + H)+.
    Figure US20180339993A1-20181129-C00039
    Figure US20180339993A1-20181129-C00040
         		72% yield (yellow oil) 1H-NMR (300 MHz, CDCl3): delta 8.45 (s, 1H), 8.38 (s, 1H), 5.94 (s, 2H), 2.62 (s, 3H), 2.16 (s, 6H) MS (ESI) m/z: 188.24(M + H)+.
    Figure US20180339993A1-20181129-C00041
    Figure US20180339993A1-20181129-C00042
         		12% yield (yellow oil) 1H-NMR (270 MHz, CDCl3): delta 8.33-8.23 (m, 1H), 8.11 (d, J = 7.9 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.83-7.70 (m, 1H), 7.65-7.55 (m, 1H), 7.40-7.32 (m, 1H), 5.95 (s, 2H), 2.21 (s, 6H) MS (ESI) m/z: 223.3 (M + H)+.
    Figure US20180339993A1-20181129-C00043
    Figure US20180339993A1-20181129-C00044
         		95% yield (colorless amorphous solid) 1H-NMR (300 MHz, CDCl3): delta 5.92 (s, 2H), 4.39 (s, 3H), 2.26 (s, 6H). MS (ESI) m/z: 178.3 (M + H)+.
    • Intermediate-3-1-A (INT-3-1-A): Ethyl 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylate
  • Figure US20180339993A1-20181129-C00045
  • The titled compound is prepared according to the procedure described in WO 2011/005052 from aniline (3.73 g, 40.1 mmol) and ethyl 2-acetamido-3-oxobutanoate (2.50 g, 13.4 mmol). The purification is carried out by column chromatography on silica gel eluting with hexane-EtOAc (1:3 v/v) to give the product (4.06 g, 62% yield) as a slightly brown solid.
  • 1H-NMR (270 MHz, CDCl3): delta 7.60-7.50 (m, 3H), 7.24-7.15 (m, 2H), 4.41 (q, J=7.3 Hz, 2H), 2.32 (s, 3H), 2.23 (s, 3H), 1.42 (t, J=7.3 Hz, 3H).
  • MS (ESI) m/z: 245.2 (M+H)+.
  • The following imidazole derivatives (INT-3-2-A to INT-3-4-A) are prepared according to the procedure of intermediate 3-1-A from the known or synthesized aniline derivatives and ethyl 2-acetamido-3-oxobutanoate in Table 3.
  • TABLE 3
    Anilines Products Yield and Analytical data
    Figure US20180339993A1-20181129-C00046
    Figure US20180339993A1-20181129-C00047
         		51% yield (pale yellow solid) 1H-NMR (270 MHz, DMSO-d6): delta 7.52-7.49 (m, 2H), 7.22 (br, 1H), 7.12-7.08 (m, 1H), 4.40 (q, J = 7.2 Hz, 2H), 2.33 (s, 3H), 2.24 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H).
    Figure US20180339993A1-20181129-C00048
    Figure US20180339993A1-20181129-C00049
         		72% yield (a pale yellow solid) 1H-NMR (270 MHz, DMSO-d6): delta 7.48 (t, J = 6.6 Hz, 1H), 7.37(d, J = 6.6 Hz, 1H), 7.28-7.17(m, 2H), 4.22 (q, J = 6.6 Hz, 2H), 2.39 (s, 3H), 2.21 (s, 3H), 2.09 (S, 3H), 1.27 (t, J = 6.6 Hz, 3H). MS (ESI) m/z: 259.3 (M + H)+.
    Figure US20180339993A1-20181129-C00050
    Figure US20180339993A1-20181129-C00051
         		56% yield (colorless amorphous solid) 1H-NMR (270 MHz, CDCl3): delta 7.58-7.50 (m, 1H), 7.29 7.25 (m, 1H), 7.03-6.93 (m, 2H), 4.40 (q, J = 7.2 Hz, 2H), 2.33 (s, 3H), 2.24 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). MS (ESI) m/z: 263.3 (M + H)+.
    • Intermediate-3-5-A (INT-3-5-A): Ethyl 1,4-dimethyl-5-(pyridin-3-yl)-1H-pyrazole-3-carboxylate
  • Figure US20180339993A1-20181129-C00052
  • A mixture of ethyl 1,4-dimethyl-5-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-3-carboxylate (500 mg, 1.58 mmol), pyridin-3-yl boronic acid (214 mg, 1.74 mmol), Pd(PPh3)4 (183 mg, 0.158 mmol) and 2M Na2CO3 aq. solution (3.2 mL, 6.32 mmol) in DME (5 mL) is irradiated with microwave at 120° C. for 30 min. After cooling, the reaction mixture is filtered through Celite pad and the filter cake is washed with EtOAc. The filtrate and washings are washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography (Biotage) on silica gel (25 g) eluting with 10-100% ethyl acetate in hexane to give the titled compound (136 mg, 35% yield) as a brown amorphous solid.
  • 1H-NMR (270 MHz, CDCl3): delta 9.07 (dd, J=4.6, 1.3 Hz, 1H), 8.06 (d, J=8.5 Hz, 2H), 7.84 (dd, J=9.2, 4.6 Hz, 1H), 7.59-7.55 (m, 1H), 7.36 (d, J=8.5 Hz, 2H), 2.60 (s, 3H).
  • MS (ESI) m/z: 246.3 (M+H)+.
    • Intermediate-4-1-A (INT-4-1-A): 2-chloro-1-(2,5-dimethyl-1-(3-methylisoxazol-5-yl)-1H-pyrrol-3-yl)ethanone
  • Figure US20180339993A1-20181129-C00053
  • To a stirred solution of 5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-methylisoxazole (2120 mg, 12.03 mmol)(INT-2-1-A) in DCM (40 mL) is added 2-chloroacetyl chloride (1.15 mL, 14.44 mmol) via a syringe with ice-cooling. To this added the crushed aluminum chloride (3210 mg, 24.06 mmol) in one portion at the same temperature and the mixture is stirred at rt for 1.5 h. After quenching with ice water followed by the adjustment to pH>8 with sat. sodium bicarbonate solution, the mixture is filtered through a pad of celite and the filter cake is washed with DCM. The organic layer is separated and the aqueous layer is extracted with DCM (2 times). The combined organic solution is washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which is purified by column chromatography (Biotage) on silica gel (100 g) eluting with 10-40% ethyl acetate in hexane to give the desired product. Finally, the product is recrystallized from ethyl acetate-hexane to give the title compound (983 mg, 32% yield) as a pale tan solid.
  • 1H-NMR (270 MHz, CDCl3): delta 6.31 (s, 1H), 6.10 (s, 1H), 4.45 (s, 2H), 2.46 (s, 3H), 2.41 (s, 3H), 2.15 (s, 3H).
  • MS (ESI) m/z: 253.17 (M+H)+.
  • The following alpha-chloroacetyl derivatives (INT-4-2-A to INT-4-12-A) are prepared according to the procedure of intermediate 4-1-A from the known or synthesized pyrrole derivatives in Table 4.
  • TABLE 4
    Pyrroles Products Yield and Analytical data
    Figure US20180339993A1-20181129-C00054
    Figure US20180339993A1-20181129-C00055
         		47% yield (a pale yellow amorphous solid) 1H-NMR (270 MHz, CDCl3): delta 7.75-7.66 (m, 2H), 7.50-7.39 (m, 2H), 6.42 (s, 1H), 4.51 (s, 2H), 2.45 (s, 3H), 2.12 (s, 3H). MS (ESI) m/z: 289.2 (M + H)+.
    Figure US20180339993A1-20181129-C00056
    Figure US20180339993A1-20181129-C00057
         		56% yield (yellow amorphous solid) 1H-NMR (270 MHz, CDCl3): delta 9.40 (s, 1H), 8.47 (s, 1H), 8.20-8.10 (m, 1H), 7.80-6.98 (m, 2H), 7.24- 7.18 (m, 1H), 6.45 (s, 1H), 4.55 (s, 2H), 2.24 (s, 3H), 1.90 (s, 3H). MS (ESI) m/z: 299.3 (M + H)+.
    Figure US20180339993A1-20181129-C00058
    Figure US20180339993A1-20181129-C00059
         		78% yield (white solid) 1H-NMR (300 MHz, CDCl3): delta 8.58 (br.s, 1H), 8.31 (br.s, 1H), 7.37 (br.s, 1H), 6.34 (s, 1H), 4.49 (s, 2H), 2.46 (s, 3H), 2.34 (s, 3H), 2.00 (s, 3H). MS (ESI) m/z: 263.23 (M + H)+.
    Figure US20180339993A1-20181129-C00060
    Figure US20180339993A1-20181129-C00061
         		39% yield 1H-NMR (270 MHz, CDCl3): delta 7.47 (s, 1H), 4.49 (s, 2H), 2.24 (s, 3H).
    Figure US20180339993A1-20181129-C00062
    Figure US20180339993A1-20181129-C00063
         		42% yield 1H-NMR (270 MHz, CDCl3): delta 6.69 (s, 1H), 4.47 (s, 2H), 2.52 (s, 3H), 2.50 (s, 3H).
    Figure US20180339993A1-20181129-C00064
    Figure US20180339993A1-20181129-C00065
         		63% yield (a plae yellow amorphous solid) 1H-NMR (270 MHz, DMSO-d6): delta 8.15 (td, J = 8.1, 1.3 Hz, 1H), 7.73(d, J = 7.3 Hz, 1H), 7.62(d, J = 6.6 Hz, 1H), 6.49 (s, 1H), 4.79 (s, 2H), 2.32 (s, 3H), 2.04 (s, 3H). MS (ESI) m/z: 283.2 (M + H)+.
    Figure US20180339993A1-20181129-C00066
    Figure US20180339993A1-20181129-C00067
         		40% yield (pale yellow solid) 1H-NMR (300 MHz, CDCl3): delta 6.31 (s, 1H), 6.07 (s, 1H), 4.47 (s, 2H), 2.55 (s, 3H), 2.48 (s, 3H), 2.15 (s, 3H). MS (ESI) m/z: 253.1 (M + H)+.
    Figure US20180339993A1-20181129-C00068
    Figure US20180339993A1-20181129-C00069
         		72% yield (brown amorphous solid) 1H-NMR (270 MHz, CDCl3): delta 8.58 (s, 1H), 8.40 (s, 1H), 6.34 (s, 1H), 4.49 (s, 2H), 2.66 (s, 3H), 2.42 (s, 3H), 2.09 (s, 3H). MS (ESI) m/z: 264.3 (M + H)+.
    Figure US20180339993A1-20181129-C00070
    Figure US20180339993A1-20181129-C00071
         		70% yield (yellow oil) 1H-NMR (270 MHz, CDCl3): delta 8.38 (d, J = 8.6 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.88-7.79 (m, 1H), 7.73-7.63 (m, 1H), 7.34 (d, J = 7.9 Hz, 1H), 6.36 (s, 1H), 4.52 (s, 2H), 2.46 (s, 3H), 2.13 (s, 3H). MS (ESI) m/z: 299.3 (M + H)+.
    Figure US20180339993A1-20181129-C00072
    Figure US20180339993A1-20181129-C00073
         		53% yield (white solid) 1H-NMR (270 MHz, CDCl3): delta 6.33 (s, 1H), 4.48 (s, 2H), 4.46 (s, 3H), 2.51 (s, 3H), 2.18 (s, 3H). MS (ESI) m/z: 254.2 (M + H)+.
    Figure US20180339993A1-20181129-C00074
    Figure US20180339993A1-20181129-C00075
         		77% yield (pale purple solid) 1H-NMR (300 MHz, CDCl3): delta 7.10 (s, 1H), 6.85 (s, 1H), 6.27 (s, 1H), 4.49 (s, 2H), 2.56 (s, 3H), 2.42 (s, 3H), 2.38 (s, 3H), 2.05 (s, 3H). MS (ESI) m/z: 277.23 (M + H)+.
    • Intermediate-5-1-A (INT-5-1-A): 2-chloro-1-(2,5-dimethyl-1-phenyl-1H-imidazol-4-yl)ethanone
  • Figure US20180339993A1-20181129-C00076
  • To a solution of ethyl 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylate (INT-3-1-A)(600 mg, 2.46 mmol) and chloroiodomethane (1300 mg, 7.37 mmol) in anhydrous THF (20 mL) is added LDA (1.09 M in THF solution; 6.76 mL, 7.34 mmol) at −80° C. and the resulting mixture is stirred at same temperature for 1.5 h. The mixture is quenched with sat. NH4Cl solution (20 mL) and extracted with DCM (×3). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which is purified by column chromatography on silica gel (45 g) eluting with 30-40% EtOAc in hexane to give the titled compound (385 mg, 63% yield) as a slightly yellow solid.
  • 1H-NMR (270 MHz, CDCl3): delta 7.62-7.52 (m, 3H), 7.24-7.17 (m, 2H), 4.88 (s, 2H), 2.35 (s, 3H), 2.21 (s, 3H).
  • MS (ESI) m/z: 249.2 (M+H)+.
  • The following alpha-chloromethyl ketone derivatives (INT-5-2-A to INT-5-19-A) are prepared according to the procedure of intermediate 5-1-A from the known or synthesized ester derivatives in Table 5.
  • TABLE 5
    Esters Products Yield and Analytical data
    Figure US20180339993A1-20181129-C00077
    Figure US20180339993A1-20181129-C00078
         		56% yield 1H-NMR (270 MHz, CDCl3): delta 7.57-7.48 (m, 2H), 7.32-7.21 (m, 1H), 7.11(ddd, 1H, J = 6.6, 2.0, 2.0 Hz), 4.87 (s, 2H), 2.36 (s, 3H), 2.23 (s, 3H).
    Figure US20180339993A1-20181129-C00079
    Figure US20180339993A1-20181129-C00080
         		31% yield (a brown amorphous solid) 1H-NMR (270 MHz, CDCl3): delta 7.44 (t, J = 6.6 Hz, 1H), 7.34 (d, J = 6.6 Hz, 1H), 6.99 (s, 2H), 4.88 (s, 2H), 2.44 (s, 3H), 2.34 (s, 3H), 2.21 (s, 3H). MS (ESI) m/z: 263.2 (M + H)+.
    Figure US20180339993A1-20181129-C00081
    Figure US20180339993A1-20181129-C00082
         		45% yield (slightly yellow solid) 1H-NMR (270 MHz, CDCl3): delta 7.56-7.36 (m, 5H), 4.98 (s, 2H), 3.98 (s, 3H). MS (ESI) m/z: 235.26 (M + H)+.
    Figure US20180339993A1-20181129-C00083
    Figure US20180339993A1-20181129-C00084
         		48% yield (a brown amorphous solid) 1H-NMR (270 MHz, CDCl3): delta 7.52-7.44 (m, 4H), 7.29 (d, J = 1.3 Hz, 1H), 6.71 (d, J = 2.6 Hz, 1H), 6.61 (d, J = 3.3 Hz, 1H), 4.53 (s, 2H), 2.48 (s, 3H). MS (ESI) m/z: 234.2 (M + H)+.
    Figure US20180339993A1-20181129-C00085
    Figure US20180339993A1-20181129-C00086
         		32% yield (brown solid) 1H-NMR (300 MHz, CDCl3): delta 9.33-9.25 (m, 2H), 8.73 (dd, J = 5.1, 1.5 Hz, 1H), 8.48- 8.35 (m, 2H), 7.93 (d, J = 8.8 Hz, 1H), 7.47 (dd, J = 8.8, 5.1 Hz, 1H), 4.72 (s, 2H). MS (ESI) m/z: 233.1 (M + H)+.
    Figure US20180339993A1-20181129-C00087
    Figure US20180339993A1-20181129-C00088
         		41% yield (slightly dark yellow solid) 1H-NMR (270 MHz, CDCl3): delta 8.27 (s, 1H), 8.20-8.12 (m, 2H), 8.00-7.80 (m, 4H), 7.56- 7.47 (m, 1H), 7.35-7.25 (m, 1H), 4.75 (s, 2H). MS (ESI) m/z: 271.18 (M + H)+.
    Figure US20180339993A1-20181129-C00089
    Figure US20180339993A1-20181129-C00090
         		75% yield 1H-NMR (270 MHz, CDCl3): delta 6.78 (s, 1H), 6.69 (s, 1H), 4.45 (s, 2H), 3.89 (s, 3H), 2.08 (s, 3H).
    Figure US20180339993A1-20181129-C00091
    Figure US20180339993A1-20181129-C00092
         		39% yield 1H-NMR (270 MHz, CDCl3): delta 7.22 (d, J = 2.0 Hz, 1H), 6.40 (br.s, 1H), 4.39 (s, 2H), 3.64 (s, 3H), 2.29 (s, 3H).
    Figure US20180339993A1-20181129-C00093
    Figure US20180339993A1-20181129-C00094
         		45% yield MS (ESI) m/z: 262 (M + H)+.
    Figure US20180339993A1-20181129-C00095
    Figure US20180339993A1-20181129-C00096
         		80% yield 1H-NMR (270 MHz, CDCl3): delta 7.63-7.57 (m, 2H), 7.44-7.38 (m, 2H), 7.33-7.29 (m, 2H), 7.12-7.04 (m, 1H), 4.74 (s, 2H), 3.91 (s, 3H). MS (ESI) m/z: 277 (M − H)−.
    Figure US20180339993A1-20181129-C00097
    Figure US20180339993A1-20181129-C00098
         		47% yield 1H-NMR (270 MHz, CDCl3): delta 7.74 (d, J = 7.9 Hz, 1H), 7.68-7.75 (m, 3H), 7.49-7.42 (m, 2H), 7.37 (d, J = 7.3 Hz, 1H), 4.73 (s, 2H), 3.89 (s, 3H). MS (ESI) m/z: 286 (M + H)+, 284 (M − H)−
    Figure US20180339993A1-20181129-C00099
    Figure US20180339993A1-20181129-C00100
         		49% yield (pale brown oil) MS (ESI) m/z: 248.1 (M + H)+.
    Figure US20180339993A1-20181129-C00101
    Figure US20180339993A1-20181129-C00102
         		39% yield (slightly yellow solid) 1H-NMR (270 MHz, CDCl3): delta 7.56-7.42 (m, 3H), 7.34-7.25 (m, 2H), 4.87 (s, 2H), 3.80 (s, 3H), 2.23 (s, 3H). MS (ESI) m/z: 249.2 (M + H)+.
    Figure US20180339993A1-20181129-C00103
    Figure US20180339993A1-20181129-C00104
         		52% yield (brown solid) 1H-NMR (270 MHz, CDCl3): delta 7.60-7.52 (m, 1H), 7.31-7.26 (m, 1H), 7.04-6.94 (m, 2H), 4.87 (s, 2H), 2.36 (s, 3H), 2.23 (s, 3H). MS (ESI) m/z: 267.2 (M + H)+.
    Figure US20180339993A1-20181129-C00105
    Figure US20180339993A1-20181129-C00106
         		quant, (brown amorphous solid) 1H-NMR (270 MHz, CDCl3): delta 8.75-8.73 (m, 1H), 8.61-8.60 (m, 1H), 7.70-7.64 (m, 1H), 7.49-7.46 (m, 1H), 4.86 (s, 2H), 3.84 (s, 3H), 2.26 (s, 3H). MS (ESI) m/z: 250.2 (M + H)+.
    Figure US20180339993A1-20181129-C00107
    Figure US20180339993A1-20181129-C00108
         		53% yield (slightly yellow solid) 1H-NMR (270 MHz, CDCl3): delta 8.19-8.13 (m, 1H), 7.96 (d, J = 8.6 Hz, 2H), 7.66-7.54 (m, 3H), 6.95-6.81 (m, 2H), 5.46 (s, 2H), 4.71 (s, 2H). MS (ESI) m/z: 262.0 (M + H)+.
    Figure US20180339993A1-20181129-C00109
    Figure US20180339993A1-20181129-C00110
         		37% yield (brown oil) 1H-NMR (270 MHz, CDCl3): delta 8.53 (d, J = 4.6 Hz, 2H), 8.01 (d, J = 8.6 Hz, 2H), 7.78 (d, J = 8.6 Hz, 2H), 7.05 (t, J = 4.6 Hz, 1H), 4.73 (s, 2H). MS (ESI) m/z: 265.0 (M + H)+.
    Figure US20180339993A1-20181129-C00111
    Figure US20180339993A1-20181129-C00112
         		67% yield (pale yellow oil) 1H-NMR (270 MHz, CDCl3): delta 8.07 (s, 1H), 7.48-7.17 (m, 4H), 4.52 (s, 2H), 2.40 (s, 3H), 2.04 (s, 3H). MS (ESI) m/z: 249.2 (M + H)+.
    • Halogenation Via Ketone Derivatives (Method-A): Chlorination Using Benzyltrimethylammonium Dichloroiodate Intermediate-6-1-A (INT-6-1-A: 1-(5-bromo-1-methyl-1H-pyrrol-2-yl)-2-chloroethanone
  • Figure US20180339993A1-20181129-C00113
  • To a stirred solution of 1-(5-bromo-1-methyl-1H-pyrrol-2-yl)ethanone (480 mg, 2.38 mmol) in THF (8 mL) is added benzyltrimethylammonium dichloroiodate (1.24 g, 3.56 mmol) in one portion at rt. The mixture is heated at 70° C. for 2 h (yellow to dark brown suspension). After cooling, the mixture is diluted with ethyl acetate and washed with 2 M HCl aq. solution, sat. sodium thiosulfide solution and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product is purified by column chromatography on silica gel eluting with 10-50% EtOAc in hexane to give the titled compound (498 mg, 89% yield).
    • (Method-B) Bromination Using Copper (II) Bromide Intermediate-6-3-A (INT-6-3-A): 2-bromo-1-(1,4-dimethyl-5-phenyl-1H-pyrrol-2-yl)ethanone
  • Figure US20180339993A1-20181129-C00114
  • A mixture of copper (II) bromide (1.05 g, 4.69 mmol) and 1-(1,4-dimethyl-5-phenyl-1H-pyrrol-2-yl)ethanone (500 mg, 2.34 mmol) in ethyl acetate (10 mL) is heated under reflux for 4 h. After cooling to room temperature, the mixture is filtered through a pad of silica gel and the filter cake is washed with ethyl acetate. The combined organic fractions are evaporated to afford the titled compound (41 mg, 6% yield).
    • (Method-C) Bromination Using Bromine in 25% HBr-Acetic Acid Solution Intermediate-6-4-A (INT-6-4-A): 2-bromo-1-(5-bromo-1,4-dimethyl-1H-imidazol-2-yl)ethanone hydrobromide
  • Figure US20180339993A1-20181129-C00115
  • A mixture of 1-(5-bromo-1,4-dimethyl-1H-imidazol-2-yl)ethanone (260 mg, 1.20 mmol) and bromine (201 mg, 1.26 mmol) in 25% HBr in AcOH (5 mL) is stirred at 60° C. for 2 h. The mixture is concentrated. The residual solid is triturated with IPE to give the titled compound (451 mg, quantitive yield).
  • The following alpha-halomethyl ketone derivatives (INT-6-1-A to INT-6-15-A) are prepared according to the procedure of methods (A-C) from the known or synthesized methyl ketone derivatives in Table 6.
  • TABLE 6
    ketones alpha-haloketones Yield and Analytical data
    Figure US20180339993A1-20181129-C00116
    Figure US20180339993A1-20181129-C00117
         		89% yield (method A) 1H-NMR (270 MHz, CDCl3): delta 7.00 (d, J = 4.6 Hz, 1H), 6.29 (d, J = 4.6 Hz, 1H), 4.46 (s, 2H), 3.97 (s, 3H).
    Figure US20180339993A1-20181129-C00118
    Figure US20180339993A1-20181129-C00119
         		67% yield (method A) 1H-NMR (270 MHz, CDCl3): delta 7.50-7.42 (m, 5H), 4.97 (s, 2H), 2.57 (s, 3H).
    Figure US20180339993A1-20181129-C00120
    Figure US20180339993A1-20181129-C00121
         		6% yield (method B) 1H-NMR (270 MHz, CDCl3): delta 7.46-7.28 (m, 6H), 4.22 (s, 2H), 3.52 (s, 3H), 2.23 (s, 3H).
    Figure US20180339993A1-20181129-C00122
    Figure US20180339993A1-20181129-C00123
         		100% yield (pale yellow solid)(method C) 1H-NMR (270 MHz, DMSO-d6): delta 4.77 (s, 2H), 3.89 (s, 3H), 2.19 (s, 3H). MS (ESI) m/z: 296.9 (M + H)+.
    Figure US20180339993A1-20181129-C00124
    Figure US20180339993A1-20181129-C00125
         		100% yield (a pale yellow solid)(method C) MS (ESI) m/z: 322.9 (M + H)+.
    Figure US20180339993A1-20181129-C00126
    Figure US20180339993A1-20181129-C00127
         		87% yield (pale yellow solid)(method C) MS (ESI) m/z: 239.1 (M + H)+.
    Figure US20180339993A1-20181129-C00128
    Figure US20180339993A1-20181129-C00129
         		100% yield (off-white solid)(method A) 1H-NMR (270 MHz, CDCl3): delta 8.73 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.99 (s, 1H), 5.06 (s, 2H). MS (ESI) m/z: 234.1 (M + H)+.
    Figure US20180339993A1-20181129-C00130
    Figure US20180339993A1-20181129-C00131
         		100% yield (brown solid)(method C) MS (ESI) m/z: 280.9 (M + H)+.
    Figure US20180339993A1-20181129-C00132
    Figure US20180339993A1-20181129-C00133
         		88% yield (pale yellow solid)(method A) 1H-NMR (270 MHz, CDCl3): delta 8.78 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 4.64 (s, 2H), 2.47 (s, 3H). MS (ESI) m/z: 204.1 (M + H)+.
    Figure US20180339993A1-20181129-C00134
    Figure US20180339993A1-20181129-C00135
         		75% yield (method A) 1H-NMR (270 MHz, CDCl3): delta 4.89 (s, 2H), 2.48 (s, 3H).
    Figure US20180339993A1-20181129-C00136
    Figure US20180339993A1-20181129-C00137
         		89% yield (method A) 1H-NMR (270 MHz, CDCl3): delta 7.58-7.52 (m, 2H), 4.62 (s, 2H).
    Figure US20180339993A1-20181129-C00138
    Figure US20180339993A1-20181129-C00139
         		80% yield (off-white solid)(method C) 1H-NMR (270 MHz, CDCl3): delta 8.04 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 4.92 (s, 2H). MS (ESI) m/z: 281.0 (M + H)+.
    Figure US20180339993A1-20181129-C00140
    Figure US20180339993A1-20181129-C00141
         		60% yield (white solid) (method A) 1H-NMR (270 MHz, DMSO-d6): delta 8.69 (d, J = 4.6 Hz, 2H), 8.07 (d, J = 8.5 Hz, 2H), 7.41-7.32 (m, 3H), 5.24 (s, 2H). MS (ESI) m/z: 249.1 (M + H)+.
    Figure US20180339993A1-20181129-C00142
    Figure US20180339993A1-20181129-C00143
         		69% yield (white solid) (method A) 1H-NMR (270 MHz, DMSO-d6): delta 8.65 (d, J = 1.3 Hz, 1H), 8.46 (d, J = 2.6 Hz, 1H). 8.26 (dd, J = 2.6, 1.3 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 5.23 (s, 2H). MS (ESI) m/z: 249.1 (M + H)+.
    Figure US20180339993A1-20181129-C00144
    Figure US20180339993A1-20181129-C00145
         		47% yield (pale yellow solid) (method A) 1H-NMR (270 MHz, DMSO-d6): delta 9.08 (dd, J = 4.6, 1.3 Hz, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.84 (dd, J = 8.5, 4.6 Hz, 1H), 7.61-7.57 (m, 1H), 7.39 (d, J = 8.5 Hz, 2H), 5.24 (s, 2H). MS (ESI) m/z: 249.1 (M + H)+.
    • Intermediate-6-2 (INT-6-2): 1-(4-methyl-5-phenylthiazol-2-yl)ethanone
  • Figure US20180339993A1-20181129-C00146
  • Potassium carbonate (1.47 g, 10.62 mmol), palladium acetate (2 mmol %)(32 mg, 0.142 mmol), tricyclohexylphosphine tetrafluoroborate (4 mol %)(104 mg, 0.283 mmol), and pivalic acid (30 mol %)(217 mg, 2.13 mmol) are weighed to air and placed in a screw-cap vial equipped with a magnetic stir bar. The vial is purged with argon, and DMA (24 mL) is added. The 1-(4-methylthiazol-2-yl)ethanone (1.00 g, 7.08 mmol) and bromobenzene (1.11 g, 7.08 mmol) are added. The reaction mixture is then vigorously stirred at 100° C. for 16 h. The solution is then cooled to rt, diluted with EtOAc, washed with H2O, dried over MgSO4, filtered, and evaporated under reduced pressure. The crude product is purified by column chromatography on silica gel eluting with 10-50% ethyl acetate in hexane to afford the corresponding product. This product is washed with ethyl acetate-hexane mixture to give the titled compound (586 mg, 38% yield).
  • 1H-NMR (270 MHz, CDCl3): delta 7.48-7.40 (m, 5H), 2.71 (s, 3H), 2.57 (s, 3H).
    • Intermediate-6-3 (INT-6-3): 1-(1,4-dimethyl-5-phenyl-1H-pyrrol-2-yl)ethanone
  • Figure US20180339993A1-20181129-C00147
  • N,N-dimethyl acetoamide (0.714 mL, 7.71 mmol) is cooled at 0-5° C. and to this is added phosphoryl trichloride (0.699 mL, 7.71 mmol) slowly in a dropwise manner. The resulting mixture is then stirred at room temperature for 20 minutes. The reaction mixture is then diluted with 1, 2-dichloroethane (30 mL) and cooled to 0° C. To the cooled reaction mixture is then added a solution of 1, 3-dimethyl-1H-pyrrole (1.20 g, 7.01 mmol) in 1, 2-dichloroethane (30 mL) dropwise. The reaction mixture is then heated to reflux for 30 minutes. The mixture so obtained is allowed to cool to room temperature and is diluted with sodium acetate trihydrate aq. solution (10 g in 25 mL water). The mixture is further heated to reflux for 30 minutes and two layers are separated. The aqueous layer is extracted with dichloromethane (3×50 mL). The combined organic layer is washed with water (1×50 mL) and dried over anhydrous Na2SO4. The solvent from the reaction mixture is evaporated under reduced pressure to obtain a crude product. This crude product is purified by column chromatography on silica gel eluting with 0-30% ethyl acetate in hexane to obtain the titled compound (1.23 g, 83% yield).
  • 1H-NMR (270 MHz, CDCl3): delta 7.51-7.37 (m, 3H), 7.30-7.26 (m, 2H), 6.88 (s, 1H), 3.75 (s, 3H), 2.45 (s, 3H), 2.02 (s, 3H).
    • Intermediate-6-4 (INT-6-4): 1-(5-bromo-1,4-dimethyl-1H-imidazol-2-yl)ethanone
  • Figure US20180339993A1-20181129-C00148
    • <Step-1>: Intermediate-6-4-1 (INT-6-4-1): 1-(4-bromo-1-methyl-1H-imidazol-2-yl)ethanone
  • Figure US20180339993A1-20181129-C00149
  • To a solution of 1-(1-methyl-1H-imidazol-2-yl)ethanone (3.67 g, 29.6 mmol) in MeCN (50 mL) is added N-bromosuccinimide (5.52 g, 31.0 mmol). The mixture is stirred at 60° C. for 1 day. After the removal of solvent, the residual solid is purified by column chromatography on silica gel eluting with 0-50% ethyl acetate in hexane to give the titled compound (3.83 g, 64% yield) as a brown solid.
  • 1H-NMR (270 MHz, CDCl3): delta 7.00 (s, 1H), 3.98 (s, 3H), 2.63 (s, 3H).
  • MS (ESI) m/z: 205.1 (M+H)+.
    • <Step-2>: Intermediate-6-4-2 (INT-6-4-2): 1-(1,4-dimethyl-1H-imidazol-2-yl)ethanone
  • Figure US20180339993A1-20181129-C00150
  • A mixture of 1-(4-bromo-1-methyl-1H-imidazol-2-yl)ethanone (INT-6-4-1) (500 mg, 2.46 mmol), trimethylboroxine (1.55 g, 12.3 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (101 mg, 0.12 mmol) in 1,4-dioxane (10 mL)-sat. NaHCO3 solution (10 mL) is stirred at 80° C. for 1 day. The mixture is diluted with water and extracted with EtOAc. The combined organic solution is dried over Na2SO4, filtered and concentrated. The residual oil is purified by column chromatography on silica gel eluting with 0-30% ethyl acetate in hexane to give the titled compound (140 mg, 41% yield) as a yellow oil.
  • 1H-NMR (270 MHz, CDCl3): delta 6.77 (s, 1H), 3.93 (s, 3H), 2.63 (s, 3H), 2.26 (s, 3H).
  • MS (ESI) m/z: 139.2 (M+H)+.
    • <Step-3>: Intermediate-6-4 (INT-6-4): 1-(5-bromo-1,4-dimethyl-1H-imidazol-2-yl)ethanone
  • Figure US20180339993A1-20181129-C00151
  • To a solution of 1-(1,4-dimethyl-1H-imidazol-2-yl)ethanone (INT-6-4-2)(220 mg, 1.59 mmol) in MeCN (5 mL) is added N-bromosuccinimide (312 mg, 1.75 mmol). The mixture is stirred at 60° C. for 1 h. After the removal of solvent in vacuo, the residual solid is purified by column chromatography on silica gel eluting with 0-25% ethyl acetate in hexane to give the titled compound (270 mg, 78% yield) as a pale yellow oil.
  • 1H-NMR (270 MHz, CDCl3): delta 3.96 (s, 3H), 2.62 (s, 3H), 2.26 (s, 3H).
  • MS (ESI) m/z: 219.1 (M+H)+.
    • Intermediate-6-5 (INT-6-5): 1-(5-bromo-4-cyclopropyl-1-methyl-1H-imidazol-2-yl)ethanone
  • Figure US20180339993A1-20181129-C00152
    • <Step-1>: Intermediate-6-5-1 (INT-6-5-1): 1-(4-cyclopropyl-1-methyl-1H-imidazol-2-yl)ethanone
  • Figure US20180339993A1-20181129-C00153
  • A mixture of 1-(4-bromo-1-methyl-1H-imidazol-2-yl)ethanone (INT-6-4-1) (500 mg, 2.46 mmol), cyclopropylboronic acid (635 mg, 7.39 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (101 mg, 0.12 mmol) in dioxane (10 mL)-sat. NaHCO3 solution (10 mL) is refluxed for 2 days. The mixture is diluted with H2O and extracted with EtOAc (×2). The combined organic solution is dried over Na2SO4, filtered and concentrated. The residual oil is purified by column chromatography on silica gel eluting with 0-50% ethyl acetate in hexane to give the titled compound (103 mg, 26% yield) as a yellow oil.
  • 1H-NMR (600 MHz, CDCl3): delta 6.70 (s, 1H), 3.91 (s, 3H), 2.61 (s, 3H), 1.88-1.82 (m, 1H), 0.91-0.86 (m, 2H), 0.73-0.69 (m, 2H).
  • MS (ESI) m/z: 165.2 (M+H)+.
    • <Step-2>: Intermediate-6-5 (INT-6-5):1-(5-bromo-4-cyclopropyl-1-methyl-1H-imidazol-2-yl)ethanone
  • Figure US20180339993A1-20181129-C00154
  • To a solution of 1-(4-cyclopropyl-1-methyl-1H-imidazol-2-yl)ethanone (INT-6-5-1)(103 mg, 0.63 mmol) in MeCN (5 mL) is added N-bromosuccinimide (128 mg, 0.72 mmol). The mixture is stirred at 60° C. for 30 min. After the removal of solvent in vacuo, the residual solid is purified by column chromatography on silica gel eluting with 0-25% ethyl acetate in hexane to give the titled compound (96 mg, 63% yield) as a pale yellow oil.
  • 1H-NMR (270 MHz, CDCl3): delta 3.94 (s, 3H), 2.57 (s, 3H), 1.92-1.80 (m, 1H), 0.95-0.88 (m, 4H).
  • MS (ESI) m/z: 243.1 (M+H)+.
    • Intermediate-6-6 (INT-6-6): 1-(5-chloro-1-methyl-1H-imidazol-2-yl)ethanone
  • Figure US20180339993A1-20181129-C00155
  • To a solution of 5-chloro-1-methyl-1H-imidazole (500 mg, 4.29 mmol) and acetyl chloride (0.31 mL, 4.29 mmol) in DCM (30 mL) is added DIPEA (1.50 mL, 8.58 mmol) at 0° C. The mixture is stirred at rt for 1 day. The mixture is quenched with 2 M NaOH aq. solution and extracted with DCM. The combined organic solution is dried over Na2SO4, filtered and concentrated. The residual oil is purified by column chromatography on silica gel eluting with 0-30% ethyl acetate in hexane to give the titled compound (172 mg, 25% yield) as an off-white solid.
  • 1H-NMR (270 MHz, CDCl3): delta 7.11 (s, 1H), 3.95 (s, 3H), 2.63 (s, 3H).
  • MS (ESI) m/z: 159.2 (M+H)+.
    • Intermediate-6-15 (INT-6-15): 1-(4-(pyridazin-3-yloxy)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00156
  • A mixture of 1-(4-hydroxyphenyl)ethanone (283 mg, 2.08 mmol), 3-chloropyridazine (238 mg, 2.08 mmol) and potassium carbonate (574 mg, 4.16 mmol) in DMF (5 mL) is irradiated in a microwave reactor (Biotage Initiator) for 60 min. at 140° C. After cooling, the reaction mixture is filtered through Celite pad and the filter cake is washed with EtOAc. The filtrate and washings are washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography (Biotage) on silica gel (25 g) eluting with 10-80% ethyl acetate in DCM to give the titled compound (58 mg, 13% yield) as a white solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 9.07 (dd, J=4.6, 1.3 Hz, 1H), 8.06 (d, J=8.5 Hz, 2H), 7.84 (dd, J=9.2, 4.6 Hz, 1H), 7.59-7.55 (m, 1H), 7.36 (d, J=8.5 Hz, 2H), 2.60 (s, 3H).
  • MS (ESI) m/z: 215.1 (M+H)+.
  • The following alpha-bromomethyl ketone derivatives (INT-6-16-A to INT-6-31-A) are prepared according to the procedure of intermediate 6-4-A (Method C) or intermediate 6-1-A (Method A) from the known or synthesized methyl ketone derivatives in Table 7.
  • TABLE 7
    Ketones alpha-haloketones Yield and Analytical data
    Figure US20180339993A1-20181129-C00157
    Figure US20180339993A1-20181129-C00158
         		quant. (HBr salt) (orange solid)(method C) 1H-NMR (270 MHz, CD3OD): delta 9.85 (s, 1H), 8.38 (d, J = 9.2 Hz, 2H), 8.00- 7.96 (m, 3H), 7.76-7.73 (m, 3H), 4.76 (s, 2H). MS (ESI) m/z: 317.2 (M + H)+.
    Figure US20180339993A1-20181129-C00159
    Figure US20180339993A1-20181129-C00160
         		95% yield (HBr salt) (orange solid)(method C) 1H-NMR (270 MHz, CD3OD): delta 8.39 (d, J = 8.6 Hz, 2H), 7.86 (d, J = 8.6 Hz, 2H), 7.68-7.58 (m, 4H), 4.78 (s, 2H), 2.79 (s, 3H) MS (ESI) m/z: 331.1 (M + H)+.
    Figure US20180339993A1-20181129-C00161
    Figure US20180339993A1-20181129-C00162
         		96% yield (HBr salt) (pale yellow solid)(method C) 1H-NMR (270 MHz, DMSO-d6): delta 9.35 (s, 1H), 8.55 (dd, J = 4.6, 1.3 Hz, 1H), 8.30 (dd, J = 7.9, 1.3 Hz, 1H), 8.25 (s, 4H), 7.51 (dd, J = 8.5, 4.6 Hz, 1H), 5.01 (s, 2H) MS (ESI) m/z: 316.1 (M + H)+.
    Figure US20180339993A1-20181129-C00163
    Figure US20180339993A1-20181129-C00164
         		97% yield (HBr salt) (yellow solid)(method C) 1H-NMR (270 MHz, DMSO-d6): delta 8.51 (d, J = 3.3 Hz, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.30 (d, J = 8.5 Hz, 2H), 7.89 (d, J = 8.5 Hz, 2H), 7.65-7.59 (m, 1H), 5.07 (s, 2H), 2.72 (s, 3H). MS (ESI) m/z: 331.9 (M + H)+.
    Figure US20180339993A1-20181129-C00165
    Figure US20180339993A1-20181129-C00166
         		82% yield (HBr salt)(pale yellow solid)(method C) 1H-NMR (270 MHz, DMSO-d6): delta 9.17 (s, 1H), 8.63 (d, J = 5.3 Hz, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.27 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.5 Hz, 2H). 7.56-7.51 (m, 1H), 5.03 (s, 2H)
    Figure US20180339993A1-20181129-C00167
    Figure US20180339993A1-20181129-C00168
         		quant. (HBr salt)(pale pink solid)(method C) 1H-NMR (270 MHz, DMSO-d6): delta 9.57 (s, 1H), 9.25 (d, J = 2.0 Hz, 1H), 8.63 (dd, J = 8.5, 2.0 Hz, 1H), 8.49 (d, J = 7.2 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.57-7.46 (m, 2H), 5.07 (s, 2H). MS (ESI) m/z: 318.0 (M + H)+.
    Figure US20180339993A1-20181129-C00169
    Figure US20180339993A1-20181129-C00170
         		quant. (HBr salt)(yellow solid)(method C) 1H-NMR (270 MHz, DMSO-d6): delta 9.35 (d, J = 2.0 Hz, 1H), 8.75 (dd, J = 8.5, 2.0 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.91- 7.87 (m, 1H), 7.75-7.72 (m, 1H), 7.59-7.53 (m, 2H), 5.12 (s, 2H), 2.84 (S, 3H). MS (ESI) m/z: 331.9 (M + H)+.
    Figure US20180339993A1-20181129-C00171
    Figure US20180339993A1-20181129-C00172
         		quant. (HBr salt)(tan solid)(method C) 1H-NMR (270 MHz, DMSO-d6): delta 8.36-8.26 (m, 3H), 7.90 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.6 Hz, 1H), 5.08 (s, 2H), 2.72 (s, 3H), 2.57 (s, 3H). MS (ESI) m/z: 344.0 (M + H)+.
    Figure US20180339993A1-20181129-C00173
    Figure US20180339993A1-20181129-C00174
         		quant. (HBr salt)(slightly yellow solid)(method C) MS (ESI) m/z: 373.1 (M + H)+.
    Figure US20180339993A1-20181129-C00175
    Figure US20180339993A1-20181129-C00176
         		quant. (HBr salt) (brown amorphous solid)(method C) MS (ESI) m/z: 398.0 (M + H)+.
    Figure US20180339993A1-20181129-C00177
    Figure US20180339993A1-20181129-C00178
         		29% yield (white solid)(method A) 1H-NMR (270 MHz, DMSO-d6): delta 8.41 (s, 1H), 8.36 (s, 1H), 8.06 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H), 5.23 (s, 2H), 2.36 (s, 3H). MS (ESI) m/z: 263.0 (M + H)+.
    Figure US20180339993A1-20181129-C00179
    Figure US20180339993A1-20181129-C00180
         		35% yield (orange solid)(method A) 1H-NMR (270 MHz, DMSO-d6): delta 9.04 (d, J = 4.6 Hz, 1H), 7.90 (d, J = 7.3 Hz, 1H), 7.84-7.79 (m, 2H), 7.69-7.53 (m, 3H), 5.24 (s, 2H). MS (ESI) m/z: 215.1 (M + H)+.
    Figure US20180339993A1-20181129-C00181
    Figure US20180339993A1-20181129-C00182
         		85% yield (HBr salt)(pale yellow solid) (method C) MS (ESI) m/z: 329.0 (M + H)+.
    Figure US20180339993A1-20181129-C00183
    Figure US20180339993A1-20181129-C00184
         		87% yield (HBr salt)(pale yellow solid) (method C) MS (ESI) m/z: 327.0 (M + H)+.
    Figure US20180339993A1-20181129-C00185
    Figure US20180339993A1-20181129-C00186
         		8% yield (orange solid)(method A) 1H-NMR (270 MHz, DMSO-d6): delta 9.12 (d, J = 5.3 Hz, 1H), 8.13 (d, J = 8.3 Hz, 2H), 7.81(d, J = 8.3 Hz, 2H), 7.69 (d, J = 5.3 Hz, 1H), 5.30 (s, 2H), 2.34 (s, 3H). MS (ESI) m/z: 247.2 (M + H)+.
    Figure US20180339993A1-20181129-C00187
    Figure US20180339993A1-20181129-C00188
         		90% yield (white solid) (method C) 1H-NMR (270 MHz, DMSO-d6): delta 7.99 (s, 1H), 7.68-7.60 (m, 2H), 7.56-7.48 (m, 3H), 4.32 (s, 2H), 3.98 (s, 3H). MS (ESI) m/z: 279.2 (M + H)+.
    • Synthesis of Ketone Derivatives Intermediate-6-19 (INT-6-19): 1-(4-(2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00189
    • <Step-1>: Intermediate-6-19-1 (INT-6-19-1): 1-(4-((2-nitrophenyl)amino)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00190
  • A mixture of 2-chloro-3-nitropyridine (951 mg, 6.00 mmol), 1-(4-aminophenyl)ethanone (811 mg, 6.00 mmol), sodium iodide (90 mg, 0.60 mmol), racemic-BINAP (224 mg, 0.36 mmol), palladium acetate (81 mg, 0.36 mmol) and potassium carbonate (1659 mg, 12.0 mmol) in toluene (30 mL) is heated at 100° C. for 20 h. After cooling to rt, the mixture is diluted with EtOAc and water and filtered through a pad of celite. The filter cake is washed with EtOAc and the filtrate and washings are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which is purified by column chromatography (Biotage) on silica gel (100 g) eluting with 3-5% ethyl acetate in DCM to give the titled compound (1273 mg, 82% yield) as a reddish yellow solid.
  • 1H-NMR (270 MHz, CDCl3): delta 10.36 (br.s, 1H), 8.62-8.54 (m, 2H), 8.05-7.96 (m, 2H), 7.88-7.80 (m, 2H), 7.00-6.92 (m, 1H), 2.61 (s, 3H).
  • MS (ESI) m/z: 258.1 (M+H)+.
    • <Step-2>: Intermediate-6-19-2(INT-6-19-2): 1-(4-((2-aminophenyl)amino)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00191
  • A mixture of INT-6-19-1 (2.6 g, 10.11 mmol), Iron (3.39 g, 60.6 mmol) and solid ammonium chloride (1.62 g, 30.3 mmol) in EtOH/water (4/1 v/v)(50 mL) is heated at reflux for 2.5 h. After cooling to rt, the reaction mixture is filtered through a pad of Celite, and the filtrate is concentrated. The residue is partitioned between EtOAc and 2 M NaOH aq. solution. The organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the titled compound (2.22 g, 97% yield) as a brown solid.
  • 1H-NMR (270 MHz, DMSO-de): delta 8.28 (s, 1H), 7.85 (d, J=8.5 Hz, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.57 (dd, J=4.6, 1.3 Hz, 1H), 6.98 (dd, J=7.9, 1.3 Hz, 1H), 6.75 (dd, J=7.9, 4.6 Hz, 1H), 5.20 (s, 2H), 2.46 (s, 3H).
  • MS (ESI) m/z: 228.1 (M+H)+.
    • <Step-3>: Intermediate-6-19-3 (INT-6-19-3): N-(2-((4-acetylphenyl)amino)phenyl)acetamide
  • Figure US20180339993A1-20181129-C00192
  • A mixture of INT-6-19-2 (2.22 g, 9.77 mmol), acetic anhydride (1.05 g, 10.26 mmol) and triethylamine (2.97 g, 29.3 mmol) in DCM (40 mL) is stirred at rt for 4 h. The mixture is concentrated in vacuo to give the titled compound, which is used for the next step without the further purification.
  • 1H-NMR (270 MHz, DMSO-d6): delta 9.56 (s, 1H), 8.62 (s, 1H), 8.08 (d, J=3.3 Hz, 1H), 7.89 (d, J=9.2 Hz, 2H), 7.76-7.71 (m, 3H), 6.95 (dd, J=7.3, 4.6 Hz, 1H), 2.50 (s, 3H), 2.12 (s, 3H).
  • MS (ESI) m/z: 270.1 (M+H)+.
    • <Step-4>: Intermediate-6-19 (INT-6-19): 1-(4-(2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)ethanone
  • To a solution of INT-6-19-3 (2.63 g, 9.77 mmol) in acetic acid (40 mL) is stirred at 100° C. for 15 h. After cooling, the reaction mixture is concentrated in vacuo. The residual oil is diluted with EtOAc and the mixture is basified to pH>10 with sat. NaHCO3 solution. The extracted organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residual solid is purified by column chromatography (Biotage) on silica gel (100 g) eluting with 10-100% ethyl acetate in DCM to give the titled compound (2.32 g, 95% yield) as a light brown solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 8.25 (dd, J=5.3, 1.3 Hz, 1H), 8.18 (d, J=8.5 Hz, 2H), 8.06 (dd, J=7.9, 1.3 Hz, 1H), 7.77 (d, J=8.5 Hz, 2H), 7.32 (dd, J=7.9, 5.3 Hz, 1H), 2.68 (s, 3H), 2.53 (s, 3H).
  • MS (ESI) m/z: 252.1 (M+H)+.
    • Intermediate-6-18 (INT-6-18): 1-(4-(3H-imidazo[4,5-b]pyridin-3-yl)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00193
  • A mixture of INT-6-19-2 (1.49 g, 6.56 mmol) and triethoxymethane (30 mL, 180 mmol) is heated at reflux for 15 h. After cooling, the reaction mixture is diluted with EtOAc and water. The organic layer is separated and the aqueous layer is extracted with EtOAc. The combined organic solution is washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residual oil is purified by column chromatography (Biotage) on silica gel (50 g) eluting with 10-80% ethyl acetate in DCM to give the titled compound (1.32 g, 85% yield) as a pale brown solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 9.07 (s, 1H), 8.49 (dd, J=4.6, 1.3 Hz, 1H), 8.27-8.17 (m, 5H), 7.44 (dd, J=7.9, 4.6 Hz, 1H), 2.66 (s, 3H).
  • MS (ESI) m/z: 238.1 (M+H)+.
    • Intermediate-6-20 (INT-6-20): 1-(4-(1H-imidazo[4,5-b]pyridin-1-yl)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00194
  • To a mixture of 60% sodium hydride (170 mg, 4.34 mmol) in DMF (15 mL) is added 1H-imidazo[4,5-b]pyridine (310 mg, 2.61 mmol) at 0° C. After addition, to the mixture is added 1-(4-fluorophenyl)ethanone (300 mg, 2.17 mmol) at 0° C. and The mixture is stirred at 60° C. overnight. After cooling, the reaction mixture is quenched with water and extracted with EtOAc. The combined organic layers are washed with brine, dried over sodium sulfate filtered and concentrated in vacuo. The residue is purified by column chromatography (Biotage) on silica gel (25 g) eluting with 20% MeOH in DCM to give the titled compound (100 mg, 19% yield) as a yellow solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 8.99 (s, 1H), 8.55 (d, J=4.6 Hz, 1H), 8.22-8.19 (m, 3H), 7.92 (d, J=8.6 Hz, 2H), 7.41 (dd, J=7.9, 4.6 Hz), 2.67 (s, 3H).
  • MS (ESI) m/z: 238.3 (M+H)+.
    • Intermediate-6-21 (INT-6-21): 1-(6-(1H-benzo[d]imidazol-1-yl)pyridin-3-yl)ethanone
  • Figure US20180339993A1-20181129-C00195
  • A mixture of 1-(6-chloropyridin-3-yl)ethanone (593 mg, 3.81 mmol), 1H-benzo[d]imidazole (150 mg, 1.27 mmol) and K2CO3 (702 mg, 5.08 mmol) in DMSO (10 mL) is irradiated in a microwave reactor (Biotage Initiator) for 30 min. at 180° C. After cooling, the reaction mixture is quenched with water and extracted with EtOAc. The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography (Biotage) on silica gel (25 g) eluting with 10-100% ethyl acetate in DCM to give the titled compound (217 mg, 72% yield) as a yellow solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 9.19 (s, 1H), 9.12 (s, 1H), 8.51 (dd, J=8.5, 1.3 Hz, 1H), 8.45 (d, J=7.9 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.46-7.35 (m, 2H), 2.68 (s, 3H).
  • MS (ESI) m/z: 238.1 (M+H)+.
    • Intermediate-6-22 (INT-6-22): 1-(6-(2-methyl-1H-benzo[d]imidazol-1-yl)pyridin-3-yl)ethanone
  • Figure US20180339993A1-20181129-C00196
  • The titled compound is prepared according to the procedure of INT-6-21 from the 1-(6-chloropyridin-3-yl)ethanone (200 mg, 1.29 mmol) and 2-methyl-1H-benzo[d]imidazole (57 mg, 0.428 mmol) to give the product (43 mg, 40% yield) as a yellow solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 9.25 (d, J=2.0 Hz, 1H), 8.59-8.56 (m, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.68-7.65 (m, 1H), 7.55-7.52 (m, 1H), 7.29-7.25 (m, 2H), 2.72 (s, 3H), 2.65 (s, 3H).
  • MS (ESI) m/z: 252.0 (M+H)+.
    • Intermediate-6-23 (INT-6-23): 1-(4-(2,5-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00197
    • <Step-1>: Intermediate-6-23-1 (INT-6-23-1): 1-(4-((6-methyl-3-nitropyridin-2-yl)amino)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00198
  • The titled compound is prepared according to the procedure of INT-6-19-1 from 2-chloro-6-methyl-3-nitropyridine (951 mg, 5.51 mmol), 1-(4-aminophenyl)ethanone (745 mg, 5.51 mmol), sodium iodide (83 mg, 0.551 mmol), racemic-BINAP (206 mg, 0.331 mmol), palladium acetate (74 mg, 0.331 mmol) and potassium carbonate (1659 mg, 12.0 mmol) in toluene (30 mL) to give the product (1290 mg, 86% yield) as a reddish yellow solid.
  • 1H-NMR (270 MHz, CDCl3): delta 10.46 (br. s, 1H), 8.45 (d, J=7.9 Hz, 1H), 8.05-7.95 (m, 2H), 7.93-7.85 (m, 2H), 6.79 (d, J=7.9 Hz, 1H), 2.61 (s, 3H), 2.59 (s, 3H).
  • MS (ESI) m/z: 272.1 (M+H)+.
    • <Step-2>: Intermediate-6-23-2 (INT-6-23-2): 1-(4-((3-amino-6-methylpyridin-2-yl)amino)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00199
  • The titled compound is prepared according to the procedure of INT-6-19-2 from INT-6-23-1 (400 mg, 1.47 mmol), ammonium chloride (237 mg, 4.42 mmol) and iron powder (494 mg, 8.85 mmol) in EtOH (12 mL)-water (3 mL) to give the product (369 mg, quant.) as a dark yellow amorphous solid.
  • 1H-NMR (270 MHz, CDCl3): delta 7.90 (d, J=8.6 Hz, 2H), 7.32 (d, J=8.6 Hz, 2H), 7.01 (d, J=7.9 Hz, 1H), 6.73 (d, J=7.9 Hz, 1H), 6.65 (br.s, 1H), 3.33 (br.s, 2H), 2.55 (s, 3H), 2.43 (s, 3H).
  • MS (ESI) m/z: 242.2 (M+H)+.
    • <Step-3>: Intermediate-6-23 (INT-6-23): 1-(4-(2,5-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)ethanone
  • The titled compound is prepared according to the procedure of INT-6-19-3 and INT-6-19 from INT-6-23-2 (350 mg, 1.45 mmol) to give the product (179 mg, 47% yield in two steps) as a dark yellow solid.
  • 1H-NMR (270 MHz, CDCl3): delta 8.22-8.14 (m, 2H), 7.93 (d, J=7.9 Hz, 1H), 7.77-7.69 (m, 2H), 7.17 (d, J=7.9 Hz, 1H), 2.68 (s, 3H), 2.48 (s, 6H).
  • MS (ESI) m/z: 266.2 (M+H)+.
    • Intermediate-6-24 (INT-6-24): 3-(4-acetylphenyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile
  • Figure US20180339993A1-20181129-C00200
    • <Step-1>: Intermediate-6-24-1 (INT-6-24-1): 1-(4-((6-chloro-3-nitropyridin-2-yl)amino)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00201
  • A mixture of 2, 6-dichloro-3-nitropyridine (1500 mg, 7.77 mmol), 1-(4-aminophenyl)ethanone (525 mg, 3.89 mmol) and potassium carbonate (1343 mg, 9.72 mmol) in 1,4-dioxane (16 mL) is irradiated with microwave at 170° C. for 60 min. After the usual workup, the crude product is purified by column chromatography on silca gel (100 g) with DCM only to give the titled compound (817 mg, 72% yield) as a yellow solid.
  • 1H-NMR (270 MHz, CDCl3): delta 10.45 (br.s, 1H), 8.51 (d, J=8.6 Hz, 1H), 8.08-7.97 (m, 2H), 7.87-7.75 (m, 2H), 6.92 (d, J=8.6 Hz, 1H), 2.61 (s, 3H).
    • <Step-2>: Intermediate-6-24-2 (INT-6-24-2): 1-(4-((3-amino-6-chloropyridin-2-yl)amino)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00202
  • The titled compound is prepared according to the procedure of INT-6-19-2 from INT-6-24-1 (1640 mg, 5.62 mmol), ammonium chloride (902 mg, 16.87 mmol) and iron (1884 mg, 33.7 mmol) in ethanol (60 mL)-water (15 mL) to give the product (1100 mg, 72% yield) as a green solid.
  • 1H-NMR (270 MHz, DMSO-de): delta 8.45 (br.s, 1H), 7.90 (d, J=8.6 Hz, 2H), 7.69 (d, J=8.6 Hz, 2H), 7.01 (d, J=7.9 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 5.35 (s, 2H), 2.50 (s, 3H).
  • MS (ESI) m/z: 262.2 (M+H)+.
    • <Step-3>: Intermediate-6-24-3 (INT-6-24-3): 1-(4-(5-chloro-2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00203
  • The titled compound is prepared according to the procedure of INT-6-19-3 (use of acetyl chloride instead of acetic anhydride) and INT-6-19 (irradiation at 170° C. for 1 h in microwave system) from INT-6-24-2 (1100 mg, 4.20 mmol) to give the product (1111 mg, 93% yield in two steps) as a slightly tan solid.
  • 1H-NMR (270 MHz, CDCl3): delta 8.24-8.13 (m, 2H), 7.96 (d, J=7.9 Hz, 1H), 7.60-7.50 (m, 2H), 7.27 (d, J=7.9 Hz, 1H), 2.69 (s, 3H), 2.58 (s, 3H).
  • MS (ESI) m/z: 286.2 (M+H)+.
    • <Step-4>: Intermediate-6-24 (INT-6-24): 3-(4-acetyl phenyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile
  • A mixture of INT-6-24-3 (555 mg, 1.94 mmol), zinc cyanide (456 mg, 3.88 mmol) and Pd(PPh3)4 (449 mg, 0.388 mmol) in DMF (16 mL) is irradiated with microwave at 140° C. for 30 min. After the usual workup, the product is purified by column chromatography on silica gel (100 g) eluting with 45-50% ethyl acetate in DCM to give the titled compound (820 mg, 76% yield) as a slightly yellow solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 8.29 (d, J=7.9 Hz, 1H), 8.22 (d, J=8.6 Hz, 2H), 7.95 (d, J=7.9 Hz, 1H), 7.80 (d, J=8.6 Hz, 2H), 2.69 (s, 3H), 2.58 (s, 3H).
  • MS (ESI) m/z: 277.3 (M+H)+.
    • Intermediate-6-25 (INT-6-25): 1-(4-(2-methyl-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00204
    • <Step-1>: Intermediate-6-25-1 (INT-6-25-1): 1-(4-((3-nitro-6-(trifluoromethyl)pyridin-2-yl)amino)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00205
  • The titled compound is prepared according to the procedure of INT-6-19-1 from 2-chloro-3-nitro-6-(trifluoromethyl)pyridine (827 mg, 3.47 mmol), 1-(4-aminophenyl)ethanone (469 mg, 3.47 mmol), sodium iodide (52 mg, 0.347 mmol), racemic-BINAP (130 mg, 0.208 mmol), palladium acetate (46.7 mg, 0.208 mmol) and potassium carbonate (959 mg, 6.94 mmol) in toluene (30 mL) to give the product (1072 mg, 95% yield) as a ocher solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 10.37 (br.s, 1H), 8.74 (d, J=8.6 Hz, 1H), 8.08-7.98 (m, 2H), 7.90-7.82 (m, 2H), 7.28 (dd, J=8.6, 2.0 Hz, 1H), 2.62 (s, 3H).
    • <Step-2>: Intermediate-6-25-2 (INT-6-25-2): 1-(4-((3-amino-6-(trifluoromethyl)pyridin-2-yl)amino)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00206
  • The titled compound is prepared according to the procedure of INT-6-19-2 from INT-6-25-1 (1060 mg, 3.26 mmol), ammonium chloride (523 mg, 9.78 mmol) and iron (1092 mg, 19.55 mmol) in ethanol (40 mL)-water (10 mL) to give the product (962 mg, quant.) as a dark red solid.
  • MS (ESI) m/z: 296.2 (M+H)+.
    • <Step-3>: Intermediate-6-25-A (INT-6-25-A): 1-(4-(2-methyl-5-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)ethanone
  • The titled compound is prepared according to the procedure of INT-6-19-3 (use of acetyl chloride instead of acetic anhydride) and INT-6-19 (irradiation at 170° C. for 1 h in microwave system) from INT-6-25-2 (˜3.26 mmol) to give the product (699 mg, 67% yield in two steps) as a slightly brown solid.
  • 1H-NMR (270 MHz, CDCl3): delta 8.24-8.16 (m 2H), 8.13 (d, J=8.6 Hz, 1H), 7.70-7.64 (m, 1H), 7.62-7.55 (m, 2H), 2.70 (s, 3H), 2.65 (s, 3H).
  • MS (ESI) m/z: 320.1 (M+H)+.
    • Intermediate-6-26 (INT-6-26): 1-(4-((6-methylpyrazin-2-yl)oxy)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00207
  • The titled compound is prepared according to the procedure of INT-6-15 from 1-(4-hydroxyphenyl)ethanone (200 mg, 1.47 mmol), 2-chloro-6-methylpyrazine (264 mg, 2.06 mmol) and potassium carbonate (406 mg, 2.94 mmol) to give the product (190 mg, 57%, chemical purity of 40%) as a pale yellow solid.
  • 1H-NMR (270 MHz, CDCl3): delta 8.39 (s, 1H), 8.35 (s, 3H), 8.04 (d, J=8.6 Hz, 2H), 7.32 (d, J=8.6 Hz, 2H), 2.59 (s, 3H), 2.36 (s, 3H).
  • MS (ESI) m/z: 229.13 (M+H)+.
    • Intermediate-6-27 (INT-6-27): 1-(3-(pyridazin-3-yloxy)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00208
  • A mixture of 1-(3-hydroxyphenyl)ethanone (466 mg, 3.42 mmol), 3-chloropyridazine (784 mg, 6.85 mmol), tBuXPhos (495 mg, 1.17 mmol), Pd2(dba)3 (313 mg, 0.342 mmol) and K3PO4 (2180 mg, 10.27 mmol) in 1,4-dioxane (15 mL) is irradiated with microwave at 160° C. for 90 min. The mixture is filtered through a pad of celite, and the filter cake is washed with EtOAc (50 mL). The filtrate and washings are washed brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel (25 g) eluting with 5-60% ethyl acetate in DCM to give the titled compound (513 mg, 70% yield) as a pale brown solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 9.04 (d, J=4.6 Hz, 1H), 7.89 (d, J=6.6 Hz, 1H), 7.84-7.76 (m, 2H), 7.63 (t, J=7.9 Hz, 1H), 7.56-7.51 (m, 2H), 2.61 (s, 3H).
    • Intermediate-6-28 (INT-6-28): 1-(5-chloro-6-(pyridin-3-yloxy)pyridin-3-yl)ethanone
  • Figure US20180339993A1-20181129-C00209
  • A mixture of 1-(5,6-dichloropyridin-3-yl)ethanone (100 mg, 0.526 mmol), pyridin-3-ol (60 mg, 0.631 mmol), cesium carbonate (343 mg, 1.052 mmol) in DMSO (0.5 mL) is stirred at rt for 2 h. The mixture is diluted water and extracted with DCM. After the removal of solvent in vacuo, the residual oil is purified by column chromatography on silica gel eluting with 0-100% ethyl acetate in hexane to give the titled compound (120 mg, 92% yield) as a pale yellow solid.
  • 1H-NMR (270 MHz, CDCl3): delta 8.58-8.54 (m, 3H), 8.35 (d, J=2.0 Hz, 1H), 7.61-7.53 (m, 1H), 7.41 (dd, J=8.6, 4.6 Hz, 1H), 2.58 (s, 3H).
  • MS (ESI) m/z: 249.2 (M+H)+.
    • Intermediate-6-29 (INT-6-29): 1-(3-chloro-4′-methyl-[2,3′-bipyridin]-5-yl)ethanone
  • Figure US20180339993A1-20181129-C00210
  • A mixture of 1-(5,6-dichloropyridin-3-yl)ethanone (75 mg, 0.395 mmol), (4-methylpyridin-3-yl)boronic acid (81 mg, 0.592 mmol), saturated NaHCO3 solution (0.6 mL), and PdCl2(dppf) CH2Cl2 (32 mg, 0.039 mmol) in 1,4-dioxane (0.6 mL) is irradiated with microwave at 120° C. for 20 min. The mixture is diluted water and extracted with DCM-MeOH. The combined organic solution is dried over Na2SO4, filtered and concentrated in vacuo. The residual oil is purified by column chromatography on amino silica gel eluting with 0-100% ethyl acetate in hexane to give the titled compound (64 mg, 66% yield) as a pale yellow solid.
  • MS (ESI) m/z: 247.2 (M+H)+.
    • Intermediate-6-30 (INT-6-30): 1-(4-(4-methylpyridazin-3-yl)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00211
  • A mixture of (4-acetylphenyl)boronic acid (561 mg, 3.42 mmol), 3-chloro-4-methylpyridazine (440 mg, 3.42 mmol) and PdCl2(dppf) CH2Cl2 (279 mg, 0.342 mol) in 1,4-dioxane (5 mL) and sat. NaHCO3 solution (5 mL) is stirred at 80° C. for 3 h. The mixture is quenched with water and extracted with EtOAc. The organic phase is washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a black solid. The crude product is purified by column chromatography on silica gel (50 g) eluting with 0-80% EtOAc in DCM to give the titled compound (265 mg, 36% yield) as a pale brown solid.
  • 1H-NMR (270 MHz, DMSO-d): delta 9.12 (d, J=5.3 Hz, 1H), 8.11 (d, J=8.6 Hz, 2H), 7.78 (d, J=8.6 Hz, 2H), 7.69 (d, J=5.3 Hz, 1H), 2.66 (s, 3H), 2.34 (s, 3H).
  • MS (ESI) m/z: 213.3 (M+H)+.
    • Intermediate-7-1-A (INT-7-1-A): 3-(2-(4-bromophenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00212
  • To a stirred solution of 8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione (INT-1-1-A)(10.2 g, 49.9 mmol) and anhydrous potassium carbonate (20.59 g, 149.0 mmol) in anhydrous DMF (110 mL) under nitrogen atmosphere is added 2,4′-dibromoacetophenone (13.84 g, 49.9 mmol) in a drop wise manner over a period of 10 min. After 2 h at 80° C., the mixture is poured into crushed ice and extracted with DCM (2×100 mL). The combined organic layers are dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to afford the crude product, which is purified by column chromatography on silica gel eluting with 10-20% EtOAc in DCM to afford the product including a little bit of impure compound. Finally, this compound is triturated with tert-butyl methyl ether to afford the titled compound (17.0 g, 79% yield) as an off white solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 9.03 (s, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.81 (d, J=8.6 Hz, 2H), 4.97 (s, 2H), 2.25-1.75 (m, 8H).
  • MS (ESI) m/z: 399.0 (M−H)−.
  • The following hydantoin derivatives (INT-7-2-A to INT-7-20-A) are prepared according to the procedure of intermediate 7-1-A from the known or synthesized alpha-haloacetyl derivatives and azaspiro derivatives in Table 8.
  • TABLE 8
    Halides Products Yield and Analytical data
    Figure US20180339993A1-20181129-C00213
    Figure US20180339993A1-20181129-C00214
         		53% yield 1H-NMR (270 MHz, CDCl3): delta 7.81 (s, 1H), 7.69-7.58 (m, 2H), 5.98 (br.s, 1H), 4.86 (s, 2H), 2.46 (s, 3H), 2.00-1.60 (m, 8H), 1.50-1.30 (m, 2H).
    Figure US20180339993A1-20181129-C00215
    Figure US20180339993A1-20181129-C00216
         		79% yield 1H-NMR (270 MHz, CDCl3): delta 7.81 (s, 1H), 7.69-7.59 (m, 2H), 6.42 (br.s, 1H), 4.87 (s, 2H), 2.47 (s, 3H), 2.5-2.18 (m, 4H), 2.10-1.88 (m, 4H).
    Figure US20180339993A1-20181129-C00217
    Figure US20180339993A1-20181129-C00218
         		58% yield 1H-NMR (270 MHz, CDCl3): delta 8.03 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.68 (dd, J = 8.3, 2.0 Hz, 1H), 6.42 (br.s, 1H), 4.86 (s, 2H), 2.5-2.18 (m, 4H), 2.10-1.88 (m, 4H).
    Figure US20180339993A1-20181129-C00219
    Figure US20180339993A1-20181129-C00220
         		66% yield (brown solid) 1H-NMR (300 MHz, DMSO-d6): delta 8.87 (br s, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.1 Hz, 2H), 4.91 (s, 2H), 1.78-1.46 (m, 9H), 1.38-1.20 (m, 1H). MS (ESI) m/z: 367.0 (M + H)+.
    Figure US20180339993A1-20181129-C00221
    Figure US20180339993A1-20181129-C00222
         		22% yield (pale yellow oil) 1H-NMR (300 MHz, CDCl3): delta 7.85 (t, J = 8.1 Hz, 1H), 7.46-7.38 (m, 2H), 6.12 (br s, 1H), 4.82 (d, J = 3.7 Hz, 2H), 2.02-1.66 (m, 8H), 1.52-1.32 (m, 2H). MS (ESI) m/z: 384.9 (M + H)+.
    Figure US20180339993A1-20181129-C00223
    Figure US20180339993A1-20181129-C00224
         		57% yield (white solid) 1H-NMR (270 MHz, DMSO-d6): delta 9.04 (s, 1H), 8.05-7.95 (m, 2H), 7.83 (d, J = 7.3 Hz, 1H), 5.00 (s, 2H), 2.18-1.85 (m, 8H). MS (ESI) m/z: 417.1 (M − H)−.
    Figure US20180339993A1-20181129-C00225
    Figure US20180339993A1-20181129-C00226
         		29% yield 1H-NMR (270 MHz, CDCl3): delta 7.53 (d, J = 5.9 Hz, 2H), 4.85 (S, 2H), 2.55-1.82 (m, 8H).
    Figure US20180339993A1-20181129-C00227
    Figure US20180339993A1-20181129-C00228
         		27% yield 1H-NMR (270 MHz, CDCl3): delta 7.48 (s, 1H), 4.76 (s, 2H), 2.25 (s, 3H), 2.50-1.90 (m, 8H) a signal due to NH is not observed.
    Figure US20180339993A1-20181129-C00229
    Figure US20180339993A1-20181129-C00230
         		33% yield 1H -NMR (270 MHz, CDCl3): delta 7.46 (s, 1H), 5.80 (br.s, 1H), 4.75 (s, 2H), 2.24 (s, 3H), 2.00-1.70 (m, 8H), 1.40-1.20 (m, 2H).
    Figure US20180339993A1-20181129-C00231
    Figure US20180339993A1-20181129-C00232
         		82% yield 1H -NMR (270 MHz, CDCl3): delta 6.44 (br,s. 1H), 4.68 (s, 2H), 2.56 (s, 3H), 2.50 (s, 3H), 2.50-1.80 (m, 8H).
    Figure US20180339993A1-20181129-C00233
    Figure US20180339993A1-20181129-C00234
         		60% yield 1H -NMR (270 MHz, CDCl3): delta 7.05 (d, J = 4.3 Hz, 1 H), 6.81 (br.s, 1H), 6.30 (d, J = 4.3 Hz, 1H), 4.71 (s, 2H), 3.93 (s, 3H), 2.50-1.90 (m, 8H).
    Figure US20180339993A1-20181129-C00235
    Figure US20180339993A1-20181129-C00236
         		97% yield 1H -NMR (270 MHz, CDCl3): delta 6.92 (S,1H), 4.69 (s, 2H), 3.91 (s, 3H), 2.08 (s, 3H), 2.50-1.80 (m, 8H), a signal due to NH is not observed.
    Figure US20180339993A1-20181129-C00237
    Figure US20180339993A1-20181129-C00238
         		83% yield 1H -NMR (270 MHz, CDCl3): delta 7.42 (s, 1H), 4.62 (s, 2H), 3.65 (s, 3H), 2.45-2.3 (m, 4H), 2.23 (s, 3H), 2.18-1.85 (m, 4H).
    Figure US20180339993A1-20181129-C00239
    Figure US20180339993A1-20181129-C00240
         		72% yield (pale yellow solid) 1H-NMR (270 MHz, CDCl3): delta 7.13 (br s, 1H), 5.01 (s, 2H), 3.94 (s, 3H), 2.45-2.17 (m, 4H), 2.27 (s, 3H), 2.10-1.87 (m, 4H). MS (ESI) m/z: 420.9 (M + H)+.
    Figure US20180339993A1-20181129-C00241
    Figure US20180339993A1-20181129-C00242
         		35% yield (pale yellow solid) 1H-NMR (270 MHz, CDCl3): delta 6.43 (br s, 1H), 4.97 (s, 2H), 3.92 (s, 3H), 2.49-2.15 (m, 4H), 2.08-1.80 (m, 5H), 0.98-0.86 (m, 4H). MS (ESI) m/z: 446.9 (M + H)+.
    Figure US20180339993A1-20181129-C00243
    Figure US20180339993A1-20181129-C00244
         		100% yield (pale yellow solid) 1H-NMR (270 MHz, CDCl3): delta 8.59 (br s, 1H), 7.15 (s, 1H), 5.00 (s, 2H), 3.94 (s, 3H), 2.32-1.73 (m, 8H). MS (ESI) m/z: 361.1 (M + H)+.
    Figure US20180339993A1-20181129-C00245
    Figure US20180339993A1-20181129-C00246
         		71% yield (yellow solid) 1H-NMR (270 MHz, CDCl3): delta 7.82 (d, J = 8.6 Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 4.92 (s, 2H), 2.41-2.00 (m, 8H). MS (ESI) m/z: 401.8 (M − H)−.
    Figure US20180339993A1-20181129-C00247
    Figure US20180339993A1-20181129-C00248
         		72% yield (white solid) 1H-NMR (270MHz, DMSO-d6): delta 9.02 (br.s, 1H), 8.20-8.10 (m, 2H), 7.48-7.36 (m, 2H), 4.97 (s, 2H), 2.28-1.74 (m, 8H). MS (ESI) m/z: 341.1 (M + H)+.
    Figure US20180339993A1-20181129-C00249
    Figure US20180339993A1-20181129-C00250
         		92% yield (yellow solid) 1H-NMR (270 MHz, DMSO-d6): delta 9.01 (br.s, 1H), 7.89-7.80 (m, 2H), 7.63 (dd, J = 8.6, 2.0 Hz, 1H), 4.79 (d, J = 2.6 Hz, 2H), 2.27-1.72 (8H, m). MS (ESI) m/z: 421.0 (M + H)+.
    Figure US20180339993A1-20181129-C00251
    Figure US20180339993A1-20181129-C00252
         		49% yield (yellow solid) 1H-NMR (270 MHz, CDCl3): delta 7.89 (d, J = 2.0 Hz, 1H), 7.62 (dd, J = 8.6, 2.0 Hz, 1H), 7.55-7.45 (m, 2H), 6.43 (br.s, 1H), 4.93 (S, 2H), 2.50-2.15 (m, 4H), 2.08-1.80 (m, 4H). MS (ESI) m/z: 440.9 (M − H)−.
    Figure US20180339993A1-20181129-C00253
    Figure US20180339993A1-20181129-C00254
         		57% yield (off-white solid) 1H-NMR (270 MHz, DMSO-d6): delta 9.03 (br.s, 1H), 8.05-7.91 (m, 2H), 7.86-7.77 (m, 1H), 4.99 (s, 2H), 2.30-1.70 (m, 8H). MS (ESI) m/z: 417.2 (M − H)−.
    • Intermediate-7-9 (INT-7-9):1-(4-bromo-3,5-dimethylthiophen-2-yl)-2-chloroethanone
  • Figure US20180339993A1-20181129-C00255
  • A stirred suspension of aluminum trichloride (1.09 g, 8.16 mmol) in chloroform (10 mL) at room temperature is treated sequentially with 2-chloro-1-(3,5-dimethylthiophen-2-yl)ethanone (INT-4-6-A)(700 mg, 3.71 mmol) and bromine (623 mg, 3.90 mmol), stirred for 17 h, poured into iced water and diluted with DCM. The organic phase is separated and the aqueous phase is extracted with DCM. The combined organic layers are washed with water and brine, dried over sodium sulfate and concentrated. The crude product is purified by column chromatography on silica gel eluting with 0-30% EtOAc in hexane to give the titled compound (890 mg, 90% yield)
  • 1H-NMR (270 MHz, CDCl3): delta 4.48 (s, 2H), 2.58 (s, 3H), 2.48 (s, 3H).
    • Intermediate-7-11 (INT-7-11): 1-(5-bromo-1,4-dimethyl-1H-pyrrol-2-yl)-2-chloroethanone
  • Figure US20180339993A1-20181129-C00256
  • N-bromosuccinimide (674 mg, 3.79 mmol) is added portion wise to a solution of INT-5-8-A (500 mg, 2.91 mmol) in THF (50 mL) at −10° C. The mixture is stirred at the same temperature for 2 h. After the removal of solvent under reduced pressure, the residue is dissolved in DCM (100 mL) and the organic phase is washed with water (3×50 mL) and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with 10-50% EtOAc in hexane to give the titled compound (597 mg, 82% yield).
  • 1H-NMR (270 MHz, CDCl3): delta 6.88 (s, 1H), 4.42 (s, 2H), 3.95 (s, 3H), 2.07 (s, 3H).
    • Intermediate-7-12 (INT-7-12): 1-(5-bromo-1,4-dimethyl-1H-pyrrol-3-yl)-2-chloroethanone
  • Figure US20180339993A1-20181129-C00257
  • The titled compound is prepared according to the procedure of intermediate-7-11 (INT-7-11) from the INT-5-9-A (193 mg, 1.13 mmol) and N-bromosuccinimide (200 mg, 1.13 mmol) at −78° C. to the ambient temperature to give the product (229 mg, 81% yield).
  • 1H-NMR (270 MHz, CDCl3): delta 7.38 (s, 1H), 4.36 (s, 2H), 3.64 (s, 3H), 2.27 (s, 3H).
    • Intermediate-8-1-A (INT-8-1-A): 3-(2-(6-chloropyridin-3-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00258
  • The titled compound is prepared according to the procedure described in N-alkylation reaction of intermediate-7-1-A from 8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione (INT-1-1-A)(1.62 g, 5.22 mmol), 2-chloro-1-(6-chloropyridin-3-yl)ethanone (991 mg, 5.22 mmol) and K2CO3 (2.16 g, 15.6 mmol) in DMF (15 mL). The purification is carried out by column chromatography on silica gel eluting with 10-80% EtOAc in DCM to give the product (850 mg, 40% yield) as a pale yellow solid
  • 1H-NMR (270 MHz, DMSO-d6): delta 9.08 (d, J=2.6 Hz, 1H), 9.04 (s, 1H), 8.41 (dd, J=8.6, 2.6 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H), 5.05 (s, 2H), 2.25-1.65 (m, 8H).
  • MS (ESI) m/z: 358.2 (M+H)+.
  • The following hydantoin derivatives (INT-8-2-A to INT-8-5-A) are prepared according to the procedure of intermediate 8-1-A from the known or synthesized alpha-haloacetyl derivatives and hydantoin derivatives in Table 9.
  • TABLE 9
    Halides Products Yield and Analytical data
    Figure US20180339993A1-20181129-C00259
    Figure US20180339993A1-20181129-C00260
         		17% yield (a brown solid) 1H-NMR (270 MHz, CDCl3): delta 8.77 (d, J = 2.0 Hz, 1H), 8.01 (dd, J = 8.6, 2.0 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 5.15 (s, 2H), 2.50-2.16 (m, 4H), 2.10- 1.88 (m, 4H), a signal due to NH is not observed. MS (ESI) m/z: 404.0 (M + H)+.
    Figure US20180339993A1-20181129-C00261
    Figure US20180339993A1-20181129-C00262
         		64% yield (orange solid) 1H-NMR (270 MHz, CDCl3): delta 8.97 (d, J = 2.0 Hz, 1H), 8.20 (dd, J = 8.6, 2.0 Hz, 1H), 8.57 (d, J = 8.6 Hz, 1H), 6.55 (br.s, 1H), 4.89 (s, 2H), 2.00-1.60 (m, 8H), 1.53-1.33 (m, 2H). MS (ESI) m/z: 322.3 (M + H)+.
    Figure US20180339993A1-20181129-C00263
    Figure US20180339993A1-20181129-C00264
         		57% yield (a pale brown solid) 1H-NMR (270 MHz, DMSO-d6): delta 8.79 (d, J = 2.6 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 6.29 (s, 1H), 4.87 (s, 2H), 2.46 (s, 3H), 1.97-1.65 (m, 10H). MS (ESI) m/z: 336.1 (M + H)+.
    Figure US20180339993A1-20181129-C00265
    Figure US20180339993A1-20181129-C00266
         		15% yield (pale yellow solid) 1H-NMR (270 MHz, CDCl3): delta 7.97 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 5.29 (s, 2H), 2.50- 2.14 (m, 2H), 2.14-1.90 (m, 4H). MS (ESI) m/z: 405.1 (M + H)+.
    • Intermediate-9-1-A (INT-9-1-A): 3-(2-(5-bromopyrazin-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00267
    • <Step-1>: Intermediate-9-1-1 (INT-9-1-1): 2-bromo-1-(5-bromopyrazin-2-yl)ethanol
  • Figure US20180339993A1-20181129-C00268
  • To a solution of 2-bromo-1-(5-bromopyrazin-2-yl)ethanone hydrobromide (INT-6-8-A)(crude solid, 3.35 mmol) in MeOH (15 mL) is added sodium borohydride (317 mg, 8.38 mmol) at 0° C. The mixture is stirred at rt for 1 h. The mixture is quenched with water and extracted with DCM. The combined organic solution is dried over Na2SO4, filtered and concentrated to give the titled compound as a yellow crude oil (740 mg, 78% yield).
  • MS (ESI) m/z: 282.9 (M+H)+.
    • <Step-2>: Intermediate-9-1-2 (INT-9-1-2): 3-(2-(5-bromopyrazin-2-yl)-2-hydroxyethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00269
  • A mixture of 8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione (INT-1-1-A)(536 mg, 2.62 mmol), 2-bromo-1-(5-bromopyrazin-2-yl)ethanol (INT-9-1-1)(740 mg, 2.62 mmol) and Cs2CO3 (1.28 g, 3.94 mmol) in DMSO (5 mL) is stirred at 60° C. for 1 h. The mixture is diluted with H2O and extracted with DCM. The combined organic solution is dried over Na2SO4, filtered and concentrated in vacuo. The residual oil is purified by column chromatography (Biotage) on silica gel eluting with 0-70% ethyl acetate in hexane to give titled compound (490 mg, 46% yield) as a pale yellow solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 8.82 (s, 1H), 8.77 (s, 1H), 8.71 (s, 1H), 6.19 (d, J=5.3 Hz, 1H), 4.87 (td, J=6.6, 5.3 Hz, 1H), 3.64 (ABqd, J=13.8, 6.6 Hz, 2H), 2.20-1.65 (m, 8H).
  • MS (ESI) m/z: 406.8 (M+H)+.
    • <Step-3>: Intermediate-9-1-A (INT-9-1-A): 3-(2-(5-bromopyrazin-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00270
  • A mixture of INT-9-1-2 (560 mg, 1.38 mmol), potassium 2-iodo-5-methylbenzenesulfonate (23 mg, 0.069 mmol), OXONE (Registered Trademark), (552 mg, 0.898 mmol) in MeCN (10 mL) is stirred at 60° C. for 1 day. The mixture is quenched with 5% Na2S2O3 aq. solution-sat. NaHCO3 solution (1:1 v/v) and extracted with DCM. The combined organic solution is dried over Na2SO4, filtered and concentrated. The residual solid is purified by column chromatography (Biotage) on silica gel eluting with 0-50% ethyl acetate in hexane to give the titled compound (397 mg, 71% yield) as an off-white solid.
  • 1H-NMR (270 MHz, DMSO-d): delta 9.09 (d, J=1.3 Hz, 1H), 9.08 (s, 1H), 8.96 (s, 1H), 5.00 (s, 2H), 2.25-1.78 (m, 8H).
  • MS (ESI) m/z: 404.9 (M+H)+.
    • Intermediate-9-2-A (INT-9-2-A): 3-(2-(5-bromo-4-methylthiazol-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00271
    • <Step-1>: Intermediate-9-2-1 (INT-9-2-1): 1-(5-bromo-4-methylthiazol-2-yl)-2-chloroethanol
  • Figure US20180339993A1-20181129-C00272
  • The titled compound is prepared according to the procedure of INT-9-1-1 from the INT-6-10-A (1.0 g, 3.93 mmol) to give the product (796 mg, 79% yield).
  • MS (ESI) m/z: 258.0 (M+H)+.
    • <Step-2>: Intermediate-9-2-2 (INT-9-2-2): 3-(2-(5-bromo-4-methylthiazol-2-yl)-2-hydroxyethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00273
  • The titled compound is prepared according to the procedure of INT-9-1-2 from the INT-9-2-1 (796 mg, 3.90 mmol) to give the product (968 mg, 59% yield).
  • 1H-NMR (270 MHz, DMSO-d6): delta 8.84 (br.s, 1H), 6.75 (d, J=5.3 Hz, 1H), 4.95 (td, J=7.2, 5.3 Hz, 1H), 3.58 (dd, J=7.2, 1.3 Hz, 2H), 2.24 (s, 3H), 2.25-1.3 (m, 8H).
    • <Step-3> Intermediate-9-2-A (INT-9-2-A): 3-(2-(5-bromo-4-methylthiazol-2-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00274
  • To a suspension of INT-9-2-2 (600 mg, 1.41 mmol) in DCM (5 mL) is added 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin reagent)(1.02 g, 2.40 mmol) at rt. The mixture is stirred at rt for 1 h. The mixture is quenched with 5% Na2S2O3 aq. solution, then sat. NaHCO3 solution. The resulting mixture is extracted with DCM and the combined organic solution is dried over Na2SO4, filtered and concentrated. The residual solid is recrystallized with ethyl acetate (6 mL) to give the titled compound (230 mg, 38.5% yield) as a white solid. The mother liquid is concentrated and the resulting solid is purified by column chromatography on silica gel eluting with 20-80% EtOAC in hexane to give 2nd crop of the titled compound (279 mg, 46.7% yield) as a white solid.
  • 1H-NMR (270 MHz, CDCl3): delta 6.36 (br.s, 1H), 5.02 (s, 2H), 2.50 (s, 3H), 2.50-2.15 (m, 4H), 2.10-1.90 (m, 4H).
  • The following alcohol derivatives (INT-10-1-A to INT-10-6-A) are prepared according to the procedure of intermediate 9-1-1 from the synthesized alpha-haloacetyl derivatives in Table 10.
  • TABLE 10
    Halides Products Yield and Analytical data
    Figure US20180339993A1-20181129-C00275
    Figure US20180339993A1-20181129-C00276
         		(crude: yellow oil) MS (ESI) m/z: 318.2 (M + H)+.
    Figure US20180339993A1-20181129-C00277
    Figure US20180339993A1-20181129-C00278
         		(crude: yellow amorphous solid) MS (ESI) m/z: 252.2 (M + H)+. (identified as the epoxide derivative)
    Figure US20180339993A1-20181129-C00279
    Figure US20180339993A1-20181129-C00280
         		(crude: yellow amorphous solid) MS (ESI) m/z: 332.9 (M + H)+. A mixture of product and epoxide derivative (2:1)
    Figure US20180339993A1-20181129-C00281
    Figure US20180339993A1-20181129-C00282
         		95% yield (crude: yellow oil) MS (ESI) m/z: 319.0 (M + H)+. 1H-NMR (270 MHz, CDCl3): 8.11 (s, 1H), 7.93-7.84 (m, 1H), 7.63 (d, J = 8.6 Hz, 2H), 7.60-7.49 (m, 1H), 7.55 (d, J = 8.6 Hz, 2H), 7.38-7.32 (m, 2H), 5.10-5.03 (m, 1H), 3.73 (dd, J = 10.6, 3.3 Hz, 1H), 3.61 (dd, J = 10.6, 9.1 Hz, 1H), 2.90-2.82 (m, 1H). MS (ESI) m/z: 319.0 (M + H)+.
    Figure US20180339993A1-20181129-C00283
    Figure US20180339993A1-20181129-C00284
         		(crude: brown amorphous solid) MS (ESI) m/z: 251.1 (M + H)+.
    Figure US20180339993A1-20181129-C00285
    Figure US20180339993A1-20181129-C00286
         		(crude: colorless amorphous solid) MS (ESI) m/z: 346.0 (M + H)+.
  • The following alcohol derivatives (INT-11-1-A to INT-11-6-A) are prepared according to the procedure of intermediate 9-1-2 from the synthesized 2-haloethanol derivatives and INT-1-4-A in Table 11.
  • TABLE 11
    Halides Products Yield and Analytical data
    Figure US20180339993A1-20181129-C00287
    Figure US20180339993A1-20181129-C00288
         		37% yield (in 2 steps)(pale yellow amorphous solid) 1H-NMR (270 MHz, DMSO-d6): delta 8.92 (s, 1H), 8.44 (dd, J = 4.6, 1.3 Hz, 1H), 8.22 (dd, J = 7.9, 1.3 Hz, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.59 (d, J = 7.9 Hz, 2H), 7.40 (dd, J = 7.9, 4.6 Hz, 1H), 5.78 (d, J = 4.6 Hz, 1H), 4.91-4.83 (m, 1H), 3.51 (d, J = 9.2 Hz, 1H), 3.35 (s, 2H), 3.17 (d, J = 5.3 Hz, 1H), 2.00-1.80 (m, 8H). MS (ESI) m/z: 429.1 (M + H)+.
    Figure US20180339993A1-20181129-C00289
    Figure US20180339993A1-20181129-C00290
         		18% yield (in 2 steps) (pale yellow amorphous solid) MS (ESI) m/z: 443.1 (M + H)+.
    Figure US20180339993A1-20181129-C00291
    Figure US20180339993A1-20181129-C00292
         		40% yield (in 2 steps) (a colorless amorphous solid) 1H-NMR (270 MHz, DMSO-d6): delta 7.62 (d, J = 7.9 Hz, 3H), 7.53 (d, J = 7.9 Hz, 2H), 7.23-7.17 (m, 2H), 7.09-7.06 (m, 1H), 5.8 (d, J = 3.9 Hz, 1H), 4.95-4.89 (m, 1H), 3.17 (d, J = 5.3 Hz, 1H), 2.54 (s, 2H), 2.42 (s, 3H), 2.00-1.85 (m, 8H). MS (ESI) m/z: 442.1 (M + H)+.
    Figure US20180339993A1-20181129-C00293
    Figure US20180339993A1-20181129-C00294
         		74% yield (in 2 steps)(yellow gum) MS (ESI) m/z: 428.2 (M + H)+. 1H-NMR (270 MHz, CDCl3): delta 7.97 (s, 1H), 7.88-7.80 (m, 1H), 7.62 (d, J = 8.6 Hz, 2H), 7.60-7.45 (m, 1H), 7.50 (d, J = 8.6 Hz, 2H), 7.40-7.30 (m, 2H), 5.13 (dd, J = 8.6, 3.3 Hz, 1H), 3.63-3.37 (m. 2H), 3.49 (s, 2H), 2.32- 1.70 (m, 8H).
    Figure US20180339993A1-20181129-C00295
    Figure US20180339993A1-20181129-C00296
         		57% yield (in 2 steps) (pale yellow amorphous solid) MS (ESI) m/z: 406.0 (M + H)+.
    Figure US20180339993A1-20181129-C00297
    Figure US20180339993A1-20181129-C00298
         		Crude 51 mg (in 2 steps) MS (ESI) m/z: 457.0 (M + H)+.
    • Intermediate 12-1-A (INT-12-1-A): 8,8-difluoro-3-(2-oxo-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00299
  • A mixture of 3-(2-(4-bromophenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione (INT-7-1-A) (2.00 g, 4.99 mmol), bis(pinacolato)diboron (1.46 g, 5.73 mmol), potassium acetate (1.22 g, 12.5 mmol) and PdCl2(dppf) CH2Cl2 (204 mg, 0.249 mmol) in 1, 4-dioxane (20 mL) is stirred at 80° C. for 3 h. After cooling to rt, the reaction mixture is filtered through a pad of celite and the filter pad is washed with 1, 4-dioxane. The filtrate and washings are concentrated in vacuo to give the residual oil, which is triturated with DCM/hexane to give the titled compound (2.03 g, 91% yield) as a pale yellow solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 9.02 (s, 1H), 8.04 (d, J=7.9 Hz, 2H), 7.84 (d, J=7.9 Hz, 2H), 4.97 (s, 2H), 2.25-1.75 (m, 8H), 1.32 (s, 12H).
  • MS (ESI) m/z: 449.2 (M+H)+.
    • Intermediate-12-2-A (INT-12-2-A): 8,8-difluoro-3-(2-oxo-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1-oxa-3-azaspiro[4.5]decan-2-one
  • Figure US20180339993A1-20181129-C00300
    • <Step-1>: Intermediate-12-2-1 (INT-12-2-1): 3-(2-(4-bromophenyl)-2-hydroxyethyl)-8,8-difluoro-1-oxa-3-azaspiro[4.5]decan-2-one
  • Figure US20180339993A1-20181129-C00301
  • A mixture of INT-1-4-A (500 mg, 2.62 mmol), cesium carbonate (1.70 g, 5.23 mmol) and 2-(4-bromophenyl)oxirane (599 mg, 3.01 mmol) in DMSO (5 mL) is stirred at 75° C. for 5 h. The mixture is diluted with water and extracted with EtOAc-hexane (2:1). The combined organic solution is washed with brine, dried over Na2SO4, filtered and concentrated. The purification is carried out by column chromatography on silica gel eluting with a gradient of 0-70% EtOAc in hexane to give the titled compound (972 mg, 95% yield) as an off-white solid.
  • 1H-NMR (270 MHz, CDCl3): delta 7.51 (d, J=7.9 Hz, 2H), 7.27 (d, J=7.9 Hz, 2H), 5.03-4.92 (m, 1H), 3.59-3.23 (m, 4H), 2.90 (br.s, 1H), 2.31-1.95 (m, 6H), 1.83-1.68 (m, 2H).
  • MS (ESI) m/z: 390.1 (M+H)+.
    • <Step-2>: Intermediate-12-2-2 (INT-12-2-2): 3-(2-(4-bromophenyl)-2-oxoethyl)-8,8-difluoro-1-oxa-3-azaspiro[4.5]decan-2-one
  • Figure US20180339993A1-20181129-C00302
  • To a solution of INT-12-2-1 (390 mg, 0.999 mmol) in DCM (20 mL) is added Dess-Martin periodinane (721 mg, 1.699 mmol) at rt. The mixture is stirred at rt for 1 h. The mixture is quenched with 5% Na2S2O3 aq. solution, followed by sat. NaHCO3 solution and extracted with EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated. The purification is carried out by column chromatography on silica gel eluting with a gradient of 0-50% EtOAc in hexane to give the titled compound (315 mg, 81% yield) as an off-white solid.
  • 1H-NMR (270 MHz, CDCl3): delta 7.80 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.6 Hz, 2H), 4.67 (s, 2H), 3.47 (s, 2H), 2.38-2.00 (m, 6H), 2.00-1.80 (m, 2H).
  • MS (ESI) m/z: 390.1 (M+H)+.
    • <Step-3>: Intermediate-12-2-A (INT-12-2-A): 8,8-difluoro-3-(2-oxo-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1-oxa-3-azaspiro[4.5]decan-2-one
  • A mixture of INT-12-2-2 (200 mg, 0.515 mmol), bis(pinacolato)diboron (150 mg, 0.592 mmol), PdCl2(dppf) CH2Cl2 (21 mg, 0.026 mmol) and potassium acetate (126 mg, 1.288 mmol) in 1,4-dioxane (3 mL) is stirred at 80° C. for 3 h. The reaction mixture (3 mL in dioxane) is used for the next Suzuki-Miyaura cross coupling reaction.
    • Intermediate 12-3-A (INT-12-3-A): 3-(2-(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00303
  • A mixture of INT-7-4-A (1.15 g, 3.15 mmol), PdCl2(dppf) CH2Cl2 (203 mg, 0.252 mmol), potassium acetate (1.24 g, 12.6 mmol), and 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (854 mg, 3.78 mmol) in DMSO (10 mL) is stirred at 80° C. for 1.5 h. The mixture is diluted with water and extracted with EtOAc-hexane (2:1). The combined organic solution is dried over Na2SO4, filtered and concentrated. The purification is carried out by column chromatography on silica gel eluting with a gradient of 0-70% EtOAc in hexane to give the titled compound (475 mg, 38% yield) as a pale yellow solid.
    • Intermediate-12-4-A (INT-12-4-A): 3-(2-oxo-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00304
  • A mixture of INT-7-4-A (120 mg, 0.329 mmol), PdCl2(dppf) CH2Cl2 (21 mg, 0.026 mmol), potassium acetate (97 mg, 0.986 mmol) and bis(pinacolato)diboron (100 mg, 0.394 mmol) in DMSO (1 mL) is stirred at 80° C. for 4 h. After completion of the reaction, the reaction mixture is used for the next Suzuki-Miyaura cross coupling reaction without the further purification.
    • Intermediate-12-5-A (INT-12-5-A): 8,8-difluoro-3-(2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00305
  • A mixture of INT-7-6-A (50 mg, 0.119 mmol), bis(pinacolato)diboron (36 mg, 0.143 mmol), PdCl2(dppf) CH2Cl2 (8 mg, 0.0095 mmol) and potassium acetate (35 mg, 0.358 mmol) in 1, 4-dioxane (2 mL) is stirred at 80° C. for 3 h. After cooling, the reaction mixture is used for the next step without the further purification.
  • MS (ESI) m/z: 383.2 (M−H)− (as the boronic acid derivatives).
    • Intermediate-12-6-A (INT-12-6-A): 8,8-difluoro-3-(2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00306
  • A mixture of INT-7-18-A (120 mg, 0.286 mmol), bis(pinacolato)diboron (84 mg, 0.329 mmol), PdCl2(dppf) CH2Cl2 (19 mg, 0.023 mmol) and potassium acetate (84 mg, 0.859 mmol) in DMF (0.9 mL) is stirred at 80° C. for 1.5 h. After cooling, the reaction mixture is used for the next step without the further purification.
    • Intermediate-12-7-A (INT-12-7-A): 8,8-difluoro-3-(2-oxo-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1-oxa-3-azaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00307
  • A mixture of INT-7-16-A (303 mg, 0.753 mmol), bis(pinacolato)diboron (230 mg, 0.904 mmol), PdCl2(dppf) CH2Cl2 (49 mg, 0.060 mmol) and potassium acetate (222 mg, 2.26 mmol) in 1,4-dioxane (3 mL) is stirred at 80° C. for 1.5 h. After cooling, the reaction mixture is concentrated in vacuo. The residual oil is purified by column chromatography on silica gel eluting with 0-30% ethyl acetate in hexane to give the titled compound (332 mg, 98%) as a yellow solid.
  • MS (ESI) m/z: 448.1 (M−H)−.
    • Intermediate-13-1-A (INT-13-1-A): 3-(2-(4-bromophenyl)-2-oxoethyl)-1-oxa-3-azaspiro[4.5]decan-2-one
  • Figure US20180339993A1-20181129-C00308
    • <Step-1>: Intermediate-13-1-1 (INT-13-1-1): 3-(2-(4-bromophenyl)-2-hydroxyethyl)-1-oxa-3-azaspiro[4.5]decan-2-one
  • Figure US20180339993A1-20181129-C00309
  • A mixture of 1-oxa-3-azaspiro[4.5]decan-2-one (200 mg, 1.29 mmol), cesium carbonate (840 mg, 2.58 mmol) and 2-(4-bromophenyl)oxirane (385 mg, 1.93 mmol) in DMSO (2 mL) is stirred at 75° C. for 3 h. The mixture is diluted with water and extracted with EtOAc-hexane (2:1). The combined organic solution is washed with brine, dried over Na2SO4, filtered and concentrated. The purification is carried out by column chromatography on silica gel eluting with a gradient of 0-80% EtOAc in hexane to give the titled compound (441 mg, 97% yield) as an off-white solid.
  • 1H-NMR (270 MHz, CDCl3): delta 7.50 (d, J=7.9 Hz, 2H), 7.28 (d, J=7.9 Hz, 2H), 4.97 (dt, J=7.9, 3.3 Hz, 1H), 3.52 (dd, J=15.2, 3.3 Hz, 1H), 3.39 (dd, J=15.2, 7.9 Hz, 1H), 3.19 (s, 2H), 3.20-3.14 (m, 1H), 1.85-1.63 (m, 4H), 1.60-1.32 (m, 6H).
  • MS (ESI) m/z: 356.0 (M+H)+.
    • <Step-2>: Intermediate-13-1-A (INT-13-1-A): 3-(2-(4-bromophenyl)-2-oxoethyl)-1-oxa-3-azaspiro[4.5]decan-2-one
  • To a solution of INT-13-1-1 (116 mg, 0.327 mmol) in DCM (5 mL) is added Dess-Martin periodinane (278 mg, 0.655 mmol) at rt. The mixture is stirred at rt for 3 h. The mixture is quenched with 5% Na2S2O3 aq. solution, followed by saturated NaHCO3 solution and extracted with EtOAc. The combined organic layer is dried over Na2SO4, filtered and concentrated. The purification is carried out by column chromatography on silica gel eluting with a gradient of 0-50% EtOAc in hexane to give the titled compound (106 mg, 92% yield) as an off-white solid.
  • 1H-NMR (270 MHz, CDCl3): delta 7.81 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5 Hz, 2H), 4.65 (s, 2H), 3.39 (s, 2H), 2.00-1.32 (m, 10H).
  • MS (ESI) m/z: 354.0 (M+H)+.
    • Intermediate-13-2-A (INT-13-2-A): 3-(2-(4-bromophenyl)-2-oxoethyl)-8,8-difluoro-4-methyl-1-oxa-3-azaspiro[4.5]decan-2-one
  • Figure US20180339993A1-20181129-C00310
    • <Step-1>: Intermediate-13-2-1 (INT-13-2-1): 3-(2-(4-bromophenyl)-2-hydroxyethyl)-8,8-difluoro-4-methyl-1-oxa-3-azaspiro[4.5]decan-2-one
  • Figure US20180339993A1-20181129-C00311
  • A mixture of INT-1-6-A (150 mg, 0.731 mmol), 2-(4-bromophenyl)oxirane (145 mg, 0.731 mmol) and cesium carbonate (476 mg, 1.462 mmol) in DMSO (5 mL) is stirred at 75° C. for 5 h. The mixture is diluted with water and extracted with EtOAc-hexane (2:1). The organic layer is washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The purification is carried out by column chromatography on silica gel eluting with a gradient of 0-70% EtOAc in hexane to give the titled compound (245 mg, 83% yield, mixture of diastereomers) as an off-white solid.
  • MS (ESI) m/z: 387.9 (M+H—OH)+.
    • <Step-2>: Intermediate-13-2-A (INT-13-2-A): 3-(2-(4-bromophenyl)-2-oxoethyl)-8,8-difluoro-4-methyl-1-oxa-3-azaspiro[4.5]decan-2-one
  • To a solution of INT-13-2-1 (245 mg, 0.606 mmol) in DCM (10 mL) is added Dess-Martin periodinane (450 mg, 1.061 mmol) at rt. The mixture is stirred at rt for 1 h. The mixture is quenched with 5% Na2S2O3 aq. solution, followed by sat. NaHCO3 solution and extracted with DCM. The combined organic layer is dried over Na2SO4, filtered and concentrated in vacuo. The purification is carried out by column chromatography on silica gel eluting with a gradient of 0-50% EtOAc in hexane to give the titled compound (217 mg, 89% yield) as an off-white solid.
  • 1H-NMR (270 MHz, CDCl3): delta 7.82 (d, J=8.6 Hz, 2H), 7.65 (d, J=8.6 Hz, 2H), 4.92 (d, J=18.5 Hz, 1H), 4.33 (d, J=18.5 Hz, 1H), 3.82 (q, J=6.6 Hz, 1H), 2.40-1.98 (m, 6H), 1.93-1.66 (m, 2H), 1.15 (d, J=6.6 Hz, 3H).
  • MS (ESI) m/z: 403.8 (M+H)+.
    • Intermediate-13-3-A (INT-13-3-A): 3-(2-(4-bromophenyl)-2-oxoethyl)-8,8-difluoro-4,4-dimethyl-1-oxa-3-azaspiro[4.5]decan-2-one
  • Figure US20180339993A1-20181129-C00312
    • <Step-1>: Intermediate-13-3-1 (INT-13-3-1): 3-(2-(4-bromophenyl)-2-hydroxyethyl)-8,8-difluoro-4,4-dimethyl-1-oxa-3-azaspiro[4.5]decan-2-one
  • Figure US20180339993A1-20181129-C00313
  • A mixture of INT-1-7-A (175 mg, 0.798 mmol), 2-(4-bromophenyl)oxirane (159 mg, 0.798 mmol) and cesium carbonate (520 mg, 1.597 mmol) in DMSO (2 mL) is stirred at 85° C. for 1 day. The mixture is diluted with water and extracted with EtOAc-hexane (2:1). The combined organic solution is washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the titled compound as a crude oil.
  • MS (ESI) m/z: 419.8 (M+H)+.
    • <Step-2>: Intermediate-13-3-A (INT-13-3-A): 3-(2-(4-bromophenyl)-2-oxoethyl)-8,8-difluoro-4,4-dimethyl-1-oxa-3-azaspiro[4.5]decan-2-one
  • To a solution of INT-13-3-1 (crude) in DCM (10 mL) is added Dess-Martin periodinane (592 mg, 1.397 mmol) at rt. The mixture is stirred at rt for 1 h. The mixture is quenched with 5% Na2S2O3 aq. solution, followed by saturated NaHCO3 solution and extracted with DCM. The combined organic solution is dried over Na2SO4, filtered and concentrated in vacuo. The purification is carried out by column chromatography on silica gel eluting with a gradient of 0-40% EtOAc in hexane to give the titled compound (265 mg, 80% yield in 2 steps) as a pale yellow solid.
  • 1H-NMR (270 MHz, CDCl3): delta 7.83 (d, J=8.6 Hz, 2H), 7.65 (d, J=8.6 Hz, 2H), 4.52 (s, 2H), 2.39-2.02 (m, 6H), 1.85-1.64 (m, 2H), 1.17 (s, 6H).
  • MS (ESI) m/z: 417.8 (M+H)+.
    • Intermediate-13-4-A (INT-13-4-A): 3-(2-(4-bromophenyl)-2-oxoethyl)-8,8-difluoro-4-isopropyl-1-oxa-3-azaspiro[4.5]decan-2-one
  • Figure US20180339993A1-20181129-C00314
    • <Step-1>: Intermediate-13-4-1 (INT-13-4-1): 3-(2-(4-bromophenyl)-2-hydroxyethyl)-8,8-difluoro-4-isopropyl-1-oxa-3-azaspiro[4.5]decan-2-one
  • Figure US20180339993A1-20181129-C00315
  • A mixture of INT-1-8-A (186 mg, 0.798 mmol), 2-(4-bromophenyl)oxirane (159 mg, 0.798 mmol) and cesium carbonate (520 mg, 1.597 mmol) in DMSO (2 mL) is stirred at 85° C. for 1 day. The mixture is diluted with water and extracted with EtOAc-hexane (2:1). The combined organic solution is washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the titled compound as a crude oil.
  • MS (ESI) m/z: 433.8 (M+H)+.
    • <Step-2>: Intermediate-13-4-A (INT-13-4-A): 3-(2-(4-bromophenyl)-2-oxoethyl)-8,8-difluoro-4-isopropyl-1,3-diazaspiro[4.5]decan-2-one
  • To a solution of INT-13-4-1 (crude) in DCM (10 mL) is added Dess-Martin periodinane (592 mg, 1.397 mmol) at rt. The mixture is stirred at rt for 1 h. The mixture is quenched with 5% Na2S2O3aq. solution, followed by sat. NaHCO3 solution and extracted with DCM. The combined organic solution is dried over Na2SO4, filtered and concentrated in vacuo. The purification is carried out by column chromatography on silica gel eluting with a gradient of 0-40% EtOAc in hexane to give the titled compound (268 mg, 78% yield in 2 steps) as a pale yellow solid.
  • 1H-NMR (270 MHz, CDCl3): delta 7.81 (d, J=8.6 Hz, 2H), 7.65 (d, J=8.6 Hz, 2H), 5.22 (d, J=18.5 Hz, 1H), 4.40 (d, J=18.5 Hz, 1H), 3.60 (d, J=2.0 Hz, 1H), 2.62-2.49 (m, 1H), 2.41-1.72 (m, 8H), 1.04 (d, J=6.6 Hz, 6H).
  • MS (ESI) m/z: 431.8 (M+H)+.
    • Intermediate-14-1-A (INT-14-1-A): 8,8-difluoro-3-(2-(4-hydroxyphenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00316
  • To a stirred solution of 2-bromo-1-(4-((tert-butyldiphenylsilyl)oxy)phenyl)ethanone (1295 mg, 2.86 mmol) in DMF (30 mL) is added INT-1-1-A (612 mg, 3.00 mmol) and potassium carbonate (987 mg, 7.14 mmol). The mixture is heated at 85° C. for 3.5 h. After cooling to rt., the mixture is quenched with 1 M HCl aq. solution and extracted with ethyl acetate-toluene (8:1). The combined organic solution is washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product (pale yellow oil). The crude product is purified by column chromatography on silica gel (100 g) with 30-70% ethyl acetate in hexane to give the titled compound (789 mg, 82% yield) as a white solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 10.58 (br.s, 1H), 8.98 (s, 1H), 7.92 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 4.84 (s, 2H), 2.25-1.70 (m, 8H).
  • MS (ESI) m/z: 339.06 (M+H)+.
    • Intermediate-15-1-A (INT-15-1-A): 3-(2-(4-((3-aminopyridin-2-yl)amino)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00317
    • <Step-1>: Intermediate-15-1-1 (INT-15-1-1): 2-bromo-1-(4-((3-nitropyridin-2-yl)amino)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00318
  • A mixture of 1-(4-((3-nitropyridin-2-yl)amino)phenyl)ethanone (INT-6-19-1)(1.0 g, 3.89 mmol) and bromine (0.621 g, 3.89 mmol) in 25% HBr-AcOH (20 mL) is stirred at rt for 1.5 h. The reaction mixture is concentrated by nitrogen flow. The residue is triturated with a mixture of IPE and MeOH (2/1 v/v) to give the titled compound mono-hydrobromide (1.56 g, quant.) as a yellow solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 10.1 (s, 1H), 8.63-8.59 (m, 2H), 8.01 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.5 Hz, 2H), 7.14 (dd, J=7.9, 4.6 Hz, 1H), 4.89 (s, 2H).
  • MS (ESI) m/z: 337.9 (M+H)+.
    • <Step-2>: Intermediate-15-1-2 (INT-15-1-2): 8,8-difluoro-3-(2-(4-((3-nitropyridin-2-yl)amino)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00319
  • A mixture of INT-1-1-A (104 mg, 0.507 mmol), INT-15-1-1 (235 mg, 0.563 mmol) and potassium carbonate (234 mg, 1.69 mmol) in DMF (5 mL) is stirred under microwave irradiation at 120° C. for 20 min. After cooling, the reaction mixture is quenched with water and extracted with EtOAc. The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography (Biotage) on silica gel (10 g) eluting with 10-80% ethyl acetate in DCM to give the titled compound (0.138 g, 53% yield) as a pale yellow solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 10.2 (s, 1H), 9.02 (s, 1H), 8.62-8.57 (m, 2H), 8.05 (d, J=8.5 Hz, 2H), 7.94 (d, J=8.5 Hz, 2H), 7.15 (dd, J=7.9, 4.6 Hz, 1H), 4.94 (s, 2H), 2.18-1.81 (m, 8H).
  • MS (ESI) m/z: 460.0 (M+H)+.
    • <Step-3>: Intermediate-15-1-A (INT-15-1-A): 3-(2-(4-((3-aminopyridin-2-yl)amino)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • A mixture of INT-15-1-2 (138 mg, 0.300 mmol), Iron (101 mg, 1.80 mmol) and solid ammonium chloride (48 mg, 0.901 mmol) in EtOH/water (4/1 v/v)(10 mL) is heated at reflux for 2.5 h. After coiling to rt, the reaction mixture is filtered through a pad of celite and the filtrate and washings are concentrated in vacuo. The residue is partitioned between EtOAc and 2 M NaOH aq. solution. The separated organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the titled compound (75 mg, 58% yield) as a brown solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 8.98 (s, 1H), 8.41 (s, 1H), 7.92 (d, J=9.2 Hz, 2H), 7.72 (d, J=9.2 Hz, 2H), 7.59 (dd, J=4.6, 1.3 Hz, 1H), 7.02-6.98 (m, 1H), 6.78 (dd, J=7.9, 4.6 Hz, 1H), 5.22 (s, 2H), 4.84 (s, 2H), 2.17-1.85 (m, 8H).
  • MS (ESI) m/z: 430.1 (M+H)+.
    • Intermediate-15-2-A (INT-15-2-A): 3-(2-(4-((3-amino-6-methylpyridin-2-yl)amino)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4,5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00320
    • <Step-1>: Intermediate-15-2-1 (INT-15-2-1): 2-bromo-1-(4-((6-methyl-3-nitropyridin-2-yl)amino)phenyl)ethanone hydrobromide
  • Figure US20180339993A1-20181129-C00321
  • The titled compound is prepared according to the procedure of INT-15-1-1 from INT-6-23-1 (740 mg, 2.73 mmol), bromine (126 microL, 2.46 mmol) in 25% HBr-AcOH (20 mL) to give the product (1232 mg, quant., chemical purity of mono-bromo product: 90%) as a yellow solid. This is used for the next step without the further purification.
  • 1H-NMR (270 MHz, DMSO-d6): delta 10.23 (br.s, 1H), 8.53-8.45 (m, 1H), 8.06-7.92 (m, 4H), 7.04-6.96 (m, 1H), 4.90 (s, 2H), 2.52 (s, 3H).
  • MS (ESI) m/z: 350.1 (M+H)+.
    • <Step-2>: Intermediate-15-2-2 (INT-15-2-2): 8,8-difluoro-3-(2-(4-((6-methyl-3-nitropyridin-2-yl)amino)phenyl)-2-oxoethyl)-1,3-diazaspiro[4,5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00322
  • The titled compound is prepared according to the procedure of INT-15-1-2 from INT-15-2-1 (700 mg, 1.62 mmol), INT-1-1-A (298 mg, 1.46 mmol) and potassium carbonate (786 mg, 5.68 mmol) in DMF (15 mL) to give the product (314 mg, 41% yield) as a yellow solid.
  • 1H-NMR (270 MHz, DMSO-d): delta 10.25 (br.s, 1H), 9.02 (br.s, 1H), 8.53-8.46 (m, 1H), 8.10-7.95 (m, 4H), 7.05-6.97 (m, 1H), 4.94 (s, 2H), 2.53 (s, 3H), 2.27-1.75 (m, 8H).
  • MS (ESI) m/z: 474.0 (M+H)+.
    • <Step-3>: Intermediate-15-2-A (INT-15-2-A): 3-(2-(4-((3-amino-6-methylpyridin-2-yl)amino)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • The titled compound is prepared according to the procedure of INT-15-1-A (step-3) from INT-15-2-2 (310 mg, 0.655 mmol), ammonium chloride (105 mg, 1.96 mmol) and iron (219 mg, 3.93 mmol) in ethanol-water (4:1)(20 mL) to give the product (281 mg, 97% yield) as a dark yellow solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 8.98 (br.s, 1H), 8.37 (br.s, 1H), 7.92 (d, J=8.6 Hz, 2H), 7.74 (d, J=8.6 Hz, 2H), 6.93 (d, J=7.9 Hz, 1H), 6.63 (d, J=7.9 Hz, 1H), 4.98 (br.s, 2H), 4.84 (br.s, 2H), 2.29 (s, 3H), 2.26-1.75 (m, 8H).
  • MS (ESI) m/z: 444.0 (M+H)+.
    • Intermediate-16-1-A (INT-16-1-A): 4′-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4,5]decan-3-yl)acetyl)-[1,1′-biphenyl]-2-carboxylic acid
  • Figure US20180339993A1-20181129-C00323
    • <Step-1>: Intermediate-16-1-1 (INT-16-1-1): tert-butyl 4′-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)-1,1′-biphenyl-2-carboxylate
  • Figure US20180339993A1-20181129-C00324
  • A mixture of 8,8-difluoro-3-(2-oxo-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione (INT-12-1-A) (300 mg, 0.67 mmol), tert-butyl 2-iodobenzoate (244 mg, 0.80 mmol), potassium phosphate (284 mg, 1.34 mmol) and PdCl2(dppf) CH2Cl2 (109 mg, 0.134 mmol) in DMF (8 mL) is stirred at 100° C. for 2 h. After cooling to rt, the reaction mixture is diluted with EtOAc, and washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography (Biotage) on silica gel (25 g) eluting with 50% ethyl acetate in hexane to give the titled compound (245 mg, 73% yield) as a white solid.
  • 1H-NMR (270 MHz, CDCl3): delta 8.00 (d, J=7.9 Hz, 2H), 7.86 (d, J=7.9 Hz, 1H), 7.53-7.46 (m, 4H), 7.30 (d, J=7.3 Hz, 1H), 6.56 (s, 1H), 4.97 (s, 2H), 2.48-2.21 (m, 4H), 2.12-1.90 (m, 4H), 1.29 (s, 9H).
  • MS (ESI) m/z: 497.2 (M−H)−.
    • <Step-2>: Intermediate-16-1-A (INT-16-1-A): 4′-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)-[1,1′-biphenyl]-2-carboxylic acid
  • Figure US20180339993A1-20181129-C00325
  • A mixture of INT-16-1-1 (245 mg, 0.491 mmol), TFA (2 mL) and DCM (4 mL) is stirred at rt for 1 h. The solvent is concentrated in vacuo to give the titled compound (217 mg, >99% yield) as a white solid.
  • MS (ESI) m/z: 441.2 (M−H)−.
    • Intermediate-16-2-A (INT-16-2-A): 4-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)-1H-indole-2-carboxylic acid
  • Figure US20180339993A1-20181129-C00326
  • A mixture of INT-12-1-A (150 mg, 0.335 mmol), 4-bromo-1H-indole-2-carboxylic acid (80 mg, 0.335 mmol), saturated NaHCO3 solution (0.6 mL) and PdCl2(dppf) CH2Cl2 (27 mg, 0.033 mmol) in 1,4-dioxane (0.6 mL) is irradiated in a microwave system at 120° C. for 20 min. The mixture is acidified with 2 M HCl aq. solution and extracted with DCM. The organic layer is dried over Na2SO4, filtered and concentrated in vacuo. The residual oil is purified by PE-AX to give the titled compound (100 mg, 62%) as a brown solid.
  • MS (ESI) m/z: 480.3 (M−H)−.
    • Intermediate-17-1-A (INT-17-1-A): 3-(2-(4-(2-(chloromethyl)-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00327
  • To a stirred solution of INT-15-2-A (70 mg, 0.158 mmol) and triethylamine (88 microL, 0.631 mmol) in THF (2.5 mL) is added a solution of chloroacetyl chloride (23 mg, 0.205 mmol) in THF (0.5 mL) via a syringe at rt. After stirring at rt for 2 h, the starting material is disappeared on TLC. After the removal of solvent, the crude product is dissolved in AcOH (3 mL) and heated at 100° C. for 2 h. After the removal of solvent, the residue is dissolved in DCM and washed with sat. NaHCO3 solution (pH>10) and brine. The organic solution is dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which is purified by column chromatography on silica gel (12 g) eluting with 40-100% ethyl acetate in DCM to give the titled compound (53.1 mg, 67% yield) as a slightly orange amorphous solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 9.05 (br.s, 1H), 8.30 (d, J=8.6 Hz, 2H), 8.09 (d, J=7.9 Hz, 1H), 7.85 (d, J=8.6 Hz, 2H), 7.29 (d, J=7.9 Hz, 1H), 5.09 (br.s, 2H), 4.96 (br.s, 2H), 2.52 (s, 3H), 2.28-1.78 (m, 8H).
  • MS (ESI) m/z: 502.2 (M+H)+.
    • Intermediate-17-2-A (INT-17-2-A): (3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)-3H-imidazo[4,5-b]pyridin-2-yl)methyl acetate
  • Figure US20180339993A1-20181129-C00328
  • The titled compound is prepared according to the procedure of INT-17-1 from the INT-15-1-A (50 mg, 0.116 mmol) and acetoxyacetyl chloride (25.4 mg, 0.186 mmol) to give the product (55 mg, 92% yield) as a yellow amorphous solid.
  • MS (ESI) m/z: 512.0 (M+H)+.
    • Intermediate-17-3-A (INT-17-3-A): (3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)-5-methyl-3H-imidazo[4,5-b]pyridin-2-yl)methyl acetate
  • Figure US20180339993A1-20181129-C00329
  • The titled compound is prepared according to the procedure of INT-17-1 from the INT-15-2-A (70 mg, 0.158 mmol) and acetoxyacetyl chloride (43.1 mg, 0.316 mmol) to give the product (75.9 mg, 91% yield) as a slightly orange amorphous solid.
  • MS (ESI) m/z: 526.3 (M+H)+.
    • EXAMPLES Example-1-1: 3-(2-(2,5-dimethyl-1-(5-methylisoxazol-3-yl)-1H-pyrrol-3-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00330
  • A mixture of 2-chloro-1-(2,5-dimethyl-1-(5-methylisoxazol-3-yl)-1H-pyrrol-3-yl)ethanone (INT-4-8-A)(200 mg, 0.791 mmol), 8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione (INT-1-1-A)(170 mg, 0.831 mmol) and anhydrous K2CO3 (273 mg, 1.98 mmol) in DMF (8 mL) is irradiated in a microwave reactor (Biotage Initiator, Trademark) for 15 minutes at 160° C. The mixture is diluted with 10% toluene in EtOAc and water. The organic layer is separated and the aqueous layer is extracted with 10% toluene in EtOAc (2 times). The combined organic extracts are washed with water (2 times), then brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which is purified by column chromatography on silica gel eluting with 50-65% EtOAc in hexane to give the titled compound (257 mg, 77% yield) as a yellow amorphous solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 8.95 (s, 1H), 6.70 (s, 1H), 6.65 (s, 1H), 4.59 (s, 2H), 2.52 (s, 3H), 2.36 (s, 3H), 2.12 (s, 3H), 2.25-1.70 (m, 8H).
  • MS (ESI) m/z: 421.3 (M+H)+.
  • The following Examples (1-2 to 1-15) are prepared according to the procedure of Example-1 from the intermediate-4-8-A (INT-4-8-A) or known alpha-haloketone derivatives and the known or synthesized azaspiro derivatives in Table 12. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 12.
  • TABLE 12
    alpha- azaspiro observed tR/
    Examples haloketones derivatives MS method
    Figure US20180339993A1-20181129-C00331
    Figure US20180339993A1-20181129-C00332
    Figure US20180339993A1-20181129-C00333
         		420.2 1.76 min. (QC1)
    Example-1-2 INT-4-8-A INT-1-3-A
    Figure US20180339993A1-20181129-C00334
    Figure US20180339993A1-20181129-C00335
    Figure US20180339993A1-20181129-C00336
         		386.1 1.82 min. (QC1)
    Example-1-3 INT-4-8-A
    Figure US20180339993A1-20181129-C00337
    Figure US20180339993A1-20181129-C00338
    Figure US20180339993A1-20181129-C00339
         		397.3 1.64 min. (QC1)
    Example 1-4 INT-4-8-A
    Figure US20180339993A1-20181129-C00340
    Figure US20180339993A1-20181129-C00341
    Figure US20180339993A1-20181129-C00342
         		453.2 1.68 min. (QC1)
    Example 1-5 INT-4-8-A
    Figure US20180339993A1-20181129-C00343
    Figure US20180339993A1-20181129-C00344
    Figure US20180339993A1-20181129-C00345
         		406.3 2.27 min (QC2)
    Example 1-6 INT-4-8-A INT-1-4-A
    Figure US20180339993A1-20181129-C00346
    Figure US20180339993A1-20181129-C00347
    Figure US20180339993A1-20181129-C00348
         		372.2 1.73 min. (QC1)
    Example 1-7 INT-4-8-A
    Figure US20180339993A1-20181129-C00349
    Figure US20180339993A1-20181129-C00350
    Figure US20180339993A1-20181129-C00351
         		413.3 1.75 min. (QC1)
    Example 1-8 INT-4-8-A
    Figure US20180339993A1-20181129-C00352
    Figure US20180339993A1-20181129-C00353
    Figure US20180339993A1-20181129-C00354
         		418.5 1.70 min. (QC1)
    Example 1-9 INT-4-8-A INT-1-5-A
    Figure US20180339993A1-20181129-C00355
    Figure US20180339993A1-20181129-C00356
    Figure US20180339993A1-20181129-C00357
         		437.2 1.84 min. (QC1)
    Example 1-10 INT-4-8-A
    Figure US20180339993A1-20181129-C00358
    Figure US20180339993A1-20181129-C00359
    Figure US20180339993A1-20181129-C00360
         		441.3 1.91 min. (QC1)
    Example 1-11 INT-4-8-A
    Figure US20180339993A1-20181129-C00361
    Figure US20180339993A1-20181129-C00362
    Figure US20180339993A1-20181129-C00363
         		425.2 1.81 min. (QC1)
    Example 1-12 INT-4-8-A INT-1-2-A
    Figure US20180339993A1-20181129-C00364
    Figure US20180339993A1-20181129-C00365
    Figure US20180339993A1-20181129-C00366
         		435.2 1.67 min. (QC1)
    Example 1-13 INT-1-1-A
    Figure US20180339993A1-20181129-C00367
    Figure US20180339993A1-20181129-C00368
    Figure US20180339993A1-20181129-C00369
         		399.3 1.67 min. (QC1)
    Example 1-14
    Figure US20180339993A1-20181129-C00370
    Figure US20180339993A1-20181129-C00371
    Figure US20180339993A1-20181129-C00372
         		413.4 1.73 min. (QC1)
    Example 1-15 INT-4-8-A
  • The following examples (2-1 to 2-18) are prepared according to the procedure of Example-1 from the known or synthesized alpha-haloketone derivatives and azaspiro derivatives in Table 13. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 13.
  • TABLE 13
    alpha- azaspiro observed tR/
    Examples haloketones derivatives MS method
    Figure US20180339993A1-20181129-C00373
    Figure US20180339993A1-20181129-C00374
    Figure US20180339993A1-20181129-C00375
         		382.1 1.78 min. (QC1)
    Example-2-1 INT-5-1-A
    Figure US20180339993A1-20181129-C00376
    Figure US20180339993A1-20181129-C00377
    Figure US20180339993A1-20181129-C00378
         		417.2 1.55 min. (QC1)
    Example-2-2 INT-5-1-A INT-1-1-A
    Figure US20180339993A1-20181129-C00379
    Figure US20180339993A1-20181129-C00380
    Figure US20180339993A1-20181129-C00381
         		418.1 1.72 min. (QC1)
    Example-2-3 INT-5-1-A INT-1-3-A
    Figure US20180339993A1-20181129-C00382
    Figure US20180339993A1-20181129-C00383
    Figure US20180339993A1-20181129-C00384
         		381.2 1.53 min. (QC1)
    Example-2-4 INT-5-1-A
    Figure US20180339993A1-20181129-C00385
    Figure US20180339993A1-20181129-C00386
    Figure US20180339993A1-20181129-C00387
         		393.5 1.60 min. (QC1)
    Example-2-5 INT-5-1-A
    Figure US20180339993A1-20181129-C00388
    Figure US20180339993A1-20181129-C00389
    Figure US20180339993A1-20181129-C00390
         		368.3 1.67 min. (QC1)
    Example-2-6 INT-5-1-A
    Figure US20180339993A1-20181129-C00391
    Figure US20180339993A1-20181129-C00392
    Figure US20180339993A1-20181129-C00393
         		404.1 2.19 min. (QC2)
    Example-2-7 INT-5-1-A INT-1-4-A
    Figure US20180339993A1-20181129-C00394
    Figure US20180339993A1-20181129-C00395
    Figure US20180339993A1-20181129-C00396
         		430.2 1.74 min. (QC1)
    Example-2-8 INT-5-3-A INT-1-5-A
    Figure US20180339993A1-20181129-C00397
    Figure US20180339993A1-20181129-C00398
    Figure US20180339993A1-20181129-C00399
         		407.3 1.69 min. (QC1)
    Example 2-9 INT-5-1-A
    Figure US20180339993A1-20181129-C00400
    Figure US20180339993A1-20181129-C00401
    Figure US20180339993A1-20181129-C00402
         		365.5 1.45 min. (QC1)
    Example-2-10 INT-5-1-A
    Figure US20180339993A1-20181129-C00403
    Figure US20180339993A1-20181129-C00404
    Figure US20180339993A1-20181129-C00405
         		433.3 1.56 min. (QC1)
    Example-2-11 INT-5-15-A INT-1-1-A
    Figure US20180339993A1-20181129-C00406
    Figure US20180339993A1-20181129-C00407
    Figure US20180339993A1-20181129-C00408
         		429.2 2.19 min. (QC2)
    Example-2-12 INT-5-3-A INT-1-1-A
    Figure US20180339993A1-20181129-C00409
    Figure US20180339993A1-20181129-C00410
    Figure US20180339993A1-20181129-C00411
         		393.2 2.14 min. (QC2)
    Example-2-13 INT-5-3-A
    Figure US20180339993A1-20181129-C00412
    Figure US20180339993A1-20181129-C00413
    Figure US20180339993A1-20181129-C00414
         		449.3 1.64 min. (QC1)
    Example-2-14 INT-5-2-A INT-1-1-A
    Figure US20180339993A1-20181129-C00415
    Figure US20180339993A1-20181129-C00416
    Figure US20180339993A1-20181129-C00417
         		413.3 1.63 min. (QC1)
    Example-2-15 INT-5-2-A
    Figure US20180339993A1-20181129-C00418
    Figure US20180339993A1-20181129-C00419
    Figure US20180339993A1-20181129-C00420
         		436.3 1.69 min. (QC1)
    Example-2-16 INT-5-2-A INT-1-4-A
    Figure US20180339993A1-20181129-C00421
    Figure US20180339993A1-20181129-C00422
    Figure US20180339993A1-20181129-C00423
         		418.1 2.34 min. (QC2)
    Example-2-17 INT-5-3-A INT-1-4-A
    Figure US20180339993A1-20181129-C00424
    Figure US20180339993A1-20181129-C00425
    Figure US20180339993A1-20181129-C00426
         		420.3 1.61 min. (QC1)
    Example-2-18 INT-5-15-A INT-1-4-A
  • The following examples (3-1 to 3-27) are prepared according to the procedure of Example-1 from the known or synthesized alpha-haloketone derivatives and azaspiro derivatives in Table 14. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 14.
  • TABLE 14
    azaspiro observed tR/
    Examples alpha-haloketones derivatives MS method
    Figure US20180339993A1-20181129-C00427
    Figure US20180339993A1-20181129-C00428
    Figure US20180339993A1-20181129-C00429
         		419.2 1.57 min. (QC1)
    Example-3-1 INT-4-1-A INT-1-1-A
    Figure US20180339993A1-20181129-C00430
    Figure US20180339993A1-20181129-C00431
    Figure US20180339993A1-20181129-C00432
         		430.2 1.96 min. (QC2)
    Example-3-2 INT-4-9-A INT-1-1-A
    Figure US20180339993A1-20181129-C00433
    Figure US20180339993A1-20181129-C00434
    Figure US20180339993A1-20181129-C00435
         		396.2 1.50 min. (QC1)
    Example-3-3 INT-4-9-A
    Figure US20180339993A1-20181129-C00436
    Figure US20180339993A1-20181129-C00437
    Figure US20180339993A1-20181129-C00438
         		414.2 2.34 min. (QC2)
    Example-3-4 INT-1-1-A
    Figure US20180339993A1-20181129-C00439
    Figure US20180339993A1-20181129-C00440
    Figure US20180339993A1-20181129-C00441
         		430.2 1.83 min. (QC1)
    Example-3-5 INT-1-1-A
    Figure US20180339993A1-20181129-C00442
    Figure US20180339993A1-20181129-C00443
    Figure US20180339993A1-20181129-C00444
         		394.3 1.83 min. (QC1)
    Example-3-6
    Figure US20180339993A1-20181129-C00445
    Figure US20180339993A1-20181129-C00446
    Figure US20180339993A1-20181129-C00447
         		448.5 1.82 min. (QC1)
    Example-3-7 INT-1-1-A
    Figure US20180339993A1-20181129-C00448
    Figure US20180339993A1-20181129-C00449
    Figure US20180339993A1-20181129-C00450
         		438.2 1.71 min. (QC1)
    Example-3-8
    Figure US20180339993A1-20181129-C00451
    Figure US20180339993A1-20181129-C00452
    Figure US20180339993A1-20181129-C00453
         		415.2 1.88 min (QC2)
    Example-3-9 INT-1-1-A
    Figure US20180339993A1-20181129-C00454
    Figure US20180339993A1-20181129-C00455
    Figure US20180339993A1-20181129-C00456
         		407.3 1.57 min. (QC1)
    Example-3-10 INT-4-4-A
    Figure US20180339993A1-20181129-C00457
    Figure US20180339993A1-20181129-C00458
    Figure US20180339993A1-20181129-C00459
         		395.3 1.51 min. (QC1)
    Example-3-11 INT-4-4-A
    Figure US20180339993A1-20181129-C00460
    Figure US20180339993A1-20181129-C00461
    Figure US20180339993A1-20181129-C00462
         		415.2 1.96 min (QC2)
    Example-3-12 INT-1-1-A
    Figure US20180339993A1-20181129-C00463
    Figure US20180339993A1-20181129-C00464
    Figure US20180339993A1-20181129-C00465
         		431.2 1.59 min. (QC1)
    Example-3-13 INT-1-1-A
    Figure US20180339993A1-20181129-C00466
    Figure US20180339993A1-20181129-C00467
    Figure US20180339993A1-20181129-C00468
         		409.3 1.66 min. (QC1)
    Example-3-14
    Figure US20180339993A1-20181129-C00469
    Figure US20180339993A1-20181129-C00470
    Figure US20180339993A1-20181129-C00471
         		463.2 1.67 min. (QC1)
    Example-3-15
    Figure US20180339993A1-20181129-C00472
    Figure US20180339993A1-20181129-C00473
    Figure US20180339993A1-20181129-C00474
         		445.3 1.67 min. (QC1)
    Example-3-16 INT-4-12-A INT-1-1-A
    Figure US20180339993A1-20181129-C00475
    Figure US20180339993A1-20181129-C00476
    Figure US20180339993A1-20181129-C00477
         		435.5 1.64 min. (QC1)
    Example-3-17 INT-1-1-A
    Figure US20180339993A1-20181129-C00478
    Figure US20180339993A1-20181129-C00479
    Figure US20180339993A1-20181129-C00480
         		455.3 1.74 min. (QC1)
    Example-3-18 INT-4-2-A INT-1-1-A
    Figure US20180339993A1-20181129-C00481
    Figure US20180339993A1-20181129-C00482
    Figure US20180339993A1-20181129-C00483
         		465.3 1.62 min. (QC1)
    Example-3-19 INT-4-3-A INT-1-1-A
    Figure US20180339993A1-20181129-C00484
    Figure US20180339993A1-20181129-C00485
    Figure US20180339993A1-20181129-C00486
         		465.3 1.73 min. (QC1)
    Example-3-20 INT-4-10-A INT-1-1-A
    Figure US20180339993A1-20181129-C00487
    Figure US20180339993A1-20181129-C00488
    Figure US20180339993A1-20181129-C00489
         		420.3 1.49 min. (QC1)
    Example-3-21 INT-4-11-A INT-1-1-A
    Figure US20180339993A1-20181129-C00490
    Figure US20180339993A1-20181129-C00491
    Figure US20180339993A1-20181129-C00492
         		418.1 2.24 min. (QC2)
    Example-3-22 INT-1-4-A
    Figure US20180339993A1-20181129-C00493
    Figure US20180339993A1-20181129-C00494
    Figure US20180339993A1-20181129-C00495
         		381.3 1.97 min. (QC1)
    Example-3-23
    Figure US20180339993A1-20181129-C00496
    Figure US20180339993A1-20181129-C00497
    Figure US20180339993A1-20181129-C00498
         		382.3 1.66 min. (QC1)
    Example-3-24 INT-4-4-A
    Figure US20180339993A1-20181129-C00499
    Figure US20180339993A1-20181129-C00500
    Figure US20180339993A1-20181129-C00501
         		424.3 1.70 min. (QC1)
    Example-3-25 INT-1-4-A
    Figure US20180339993A1-20181129-C00502
    Figure US20180339993A1-20181129-C00503
    Figure US20180339993A1-20181129-C00504
         		381.2 2.13 min (QC2)
    Example-3-26 INT-4-9-A
    Figure US20180339993A1-20181129-C00505
    Figure US20180339993A1-20181129-C00506
    Figure US20180339993A1-20181129-C00507
         		368.3 1.58 min. (QC1)
    Example-3-27
    • Example 3-28 3-(2-(1-(6-(cyclopropylmethoxy)pyridin-2-)-2-yl)-2,5-dimethyl-1H-pyrrol-3-yl)-2-oxoethyl)-1,3-diazaspiro[4,5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00508
    • <Step-1>: Intermediate-3-28-1 (INT-3-28-1): 3-(2-(1-(6-chloropyridin-2-yl)-2,5-dimethyl-1H-pyrrol-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00509
  • The titled compound is prepared according to the procedure of example-1 from INT-4-7-A (1.00 g, 3.53 mmol), 1,3-diazaspiro[4.5]decane-2,4-dione (624 mg, 3.71 mmol) and potassium carbonate (1.22 g, 8.83 mmol) in DMF (20 mL) in a microwave irradiation system at 160° C. for 10 min. The residue is purified by column chromatography (Biotage) on silica gel (100 g) eluting with 10-80% ethyl acetate in DCM to give the compound (1.33 g, 91% yield) as a pale yellow amorphous solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 8.79 (s, 1H), 8.15 (t, J=7.2 Hz, 1H), 7.73 (d, J=6.6 Hz 1H), 7.62 (d, J=7.2 Hz, 1H), 6.61 (s, 1H), 4.56 (s, 2H), 2.29 (s, 3H), 2.06 (s, 3H), 1.72-1.57 (m, 8H).
  • MS (ESI) m/z: 415.2 (M+H)+.
    • <Step-2>: Example 3-28: 3-(2-(1-(6-(cyclopropylmethoxy)pyridin-2-yl)-2,5-dimethyl-1H-pyrrol-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • To a solution of 60% sodium hydride (14 mg, 0.362 mmol) in DMA (2 mL) is added cyclopropylmethanol (10 mg, 0.133 mmol) at 0° C. After the completion of addition, to this mixture is added INT-3-28-1 (50 mg, 0.121 mmol) at 0° C. and stirred at rt for 5 h. The reaction mixture is quenched sat. NH4Cl solution (pH=5-6) and extracted with EtOAc. The combined organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography (Biotage) on silica gel (10 g) eluting with 10-80% ethyl acetate in Hexane to give the titled compound (9 mg, 16% yield) as a pale brown amorphous. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 451.2
  • tR/method: 1.86 min./(QC1)
    • Example 3-29 3-(2-(1-(6-(3-hydroxypiperidin-1-yl)pyridin-2-yl)-2,5-dimethyl-1H-pyrrol-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00510
  • To a solution of INT-3-28-1 (20 mg, 0.048 mmol) in DMSO (1 mL) is added piperidin-3-ol (8 mg, 0.096 mmol) and cesium carbonate (79 mg, 0.241 mmol). The mixture is stirred at 80° C. for 15 h. The reaction mixture is filtered through a pad of celite and washed with EtOAc. The filtrate and washings are washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography (Biotage) on silica gel (10 g) eluting with 10-100% ethyl acetate in hexane to give the titled compound (8 mg, 35% yield) as a pale yellow amorphous solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 480.2
  • tR/method: 1.58 min./(QC1)
  • The following examples (4-1 to 4-12) are prepared according to the procedure of Example-1 from the known or synthesized alpha-haloketone derivatives and azaspiro derivatives in Table 15. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 15.
  • TABLE 15
    azaspiro observed tR/
    Examples alpha-haloketones derivetives MS method
    Figure US20180339993A1-20181129-C00511
    Figure US20180339993A1-20181129-C00512
    Figure US20180339993A1-20181129-C00513
         		415.2 1.73 min. (QC1)
    Example-4-1 INT-5-14-A INT-1-1-A
    Figure US20180339993A1-20181129-C00514
    Figure US20180339993A1-20181129-C00515
    Figure US20180339993A1-20181129-C00516
         		379.3 1.72 min. (QC1)
    Example-4-2 INT-5-14-A
    Figure US20180339993A1-20181129-C00517
    Figure US20180339993A1-20181129-C00518
    Figure US20180339993A1-20181129-C00519
         		414.3 2.28 min. (QC2)
    Example-4-3 INT-6-3-A INT-1-1-A
    Figure US20180339993A1-20181129-C00520
    Figure US20180339993A1-20181129-C00521
    Figure US20180339993A1-20181129-C00522
         		401.4 1.61 min. (QC1)
    Example-4-4 INT-5-4-A INT-1-1-A
    Figure US20180339993A1-20181129-C00523
    Figure US20180339993A1-20181129-C00524
    Figure US20180339993A1-20181129-C00525
         		418.3 1.81 min. (QC1)
    Example-4-5 INT-6-2-A INT-1-1-A
    Figure US20180339993A1-20181129-C00526
    Figure US20180339993A1-20181129-C00527
    Figure US20180339993A1-20181129-C00528
         		400.5 1.67 min. (QC1)
    Example-4-6 INT-5-5-A INT-1-1-A
    Figure US20180339993A1-20181129-C00529
    Figure US20180339993A1-20181129-C00530
    Figure US20180339993A1-20181129-C00531
         		416.3 1.42 min. (QC1)
    Example-4-7 INT-5-16-A INT-1-1-A
    Figure US20180339993A1-20181129-C00532
    Figure US20180339993A1-20181129-C00533
    Figure US20180339993A1-20181129-C00534
         		380.4 1.40 min. (QC1)
    Example-4-8 INT-5-16-A
    Figure US20180339993A1-20181129-C00535
    Figure US20180339993A1-20181129-C00536
    Figure US20180339993A1-20181129-C00537
         		389.3 1.73 min. (QC1)
    Example-4-9 INT-5-5-A INT-1-4-A
    Figure US20180339993A1-20181129-C00538
    Figure US20180339993A1-20181129-C00539
    Figure US20180339993A1-20181129-C00540
         		416.3 1.90 min. (QC1)
    Example-4-10 INT-5-14-A INT-1-3-A
    Figure US20180339993A1-20181129-C00541
    Figure US20180339993A1-20181129-C00542
    Figure US20180339993A1-20181129-C00543
         		403.1 1.46 min. (QC1)
    Example-4-11 INT-6-31-A INT-1-1-A
    Figure US20180339993A1-20181129-C00544
    Figure US20180339993A1-20181129-C00545
    Figure US20180339993A1-20181129-C00546
         		417.1 1.59 min. (QC1)
    Example-4-12 INT-5-19-A INT-1-1-A
  • The following examples (5-1 to 5-5) are prepared according to the procedure of Example-1 from the known or synthesized alpha-haloketone derivatives and hydantoin derivatives in Table 16. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 16.
  • TABLE 16
    azaspiro observed tR/
    Examples alpha-haloketones derivetives MS method
    Figure US20180339993A1-20181129-C00547
    Figure US20180339993A1-20181129-C00548
    Figure US20180339993A1-20181129-C00549
         		399.4 1.34 min. (QC1)
    Example-5-1 INT-5-6-A INT-1-1-A
    Figure US20180339993A1-20181129-C00550
    Figure US20180339993A1-20181129-C00551
    Figure US20180339993A1-20181129-C00552
         		365.3 1.34 min. (QC1)
    Example-5-2 INT-5-6-A
    Figure US20180339993A1-20181129-C00553
    Figure US20180339993A1-20181129-C00554
    Figure US20180339993A1-20181129-C00555
         		428.4 1.48 min. (QC1)
    Example-5-3 INT-5-10-A INT-1-1-A
    Figure US20180339993A1-20181129-C00556
    Figure US20180339993A1-20181129-C00557
    Figure US20180339993A1-20181129-C00558
         		445.5 1.80 min. (QC1)
    Example-5-4 INT-5-11-A INT-1-1-A
    Figure US20180339993A1-20181129-C00559
    Figure US20180339993A1-20181129-C00560
    Figure US20180339993A1-20181129-C00561
         		452.2 1.66 min. (QC1)
    Example-5-5 INT-5-12-A INT-1-1-A
  • The following examples (5-6 to 5-14) are prepared according to the procedure of Example-1 from the known or synthesized alpha-haloketone derivatives and hydantoin derivatives in Table 17. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 17.
  • TABLE 17
    azaspiro observed tR/
    Examples alpha-haloketones derivetives MS method
    Figure US20180339993A1-20181129-C00562
    Figure US20180339993A1-20181129-C00563
    Figure US20180339993A1-20181129-C00564
         		437.3 1.73 min. (QC1)
    Example-5-6 INT-5-7-A INT-1-1-A
    Figure US20180339993A1-20181129-C00565
    Figure US20180339993A1-20181129-C00566
    Figure US20180339993A1-20181129-C00567
         		437.3 1.51 min. (QC1)
    Example-5-7 INT-6-16-A INT-1-1-A
    Figure US20180339993A1-20181129-C00568
    Figure US20180339993A1-20181129-C00569
    Figure US20180339993A1-20181129-C00570
         		451.3 1.51 min. (QC1)
    Example-5-8 INT-6-17-A INT-1-1-A
    Figure US20180339993A1-20181129-C00571
    Figure US20180339993A1-20181129-C00572
    Figure US20180339993A1-20181129-C00573
         		438.3 1.42 min. (QC1)
    Example-5-9 INT-6-18-A INT-1-1-A
    Figure US20180339993A1-20181129-C00574
    Figure US20180339993A1-20181129-C00575
    Figure US20180339993A1-20181129-C00576
         		452.3 1.38 min. (QC1)
    Example-5-10 INT-6-19-A INT-1-1-A
    Figure US20180339993A1-20181129-C00577
    Figure US20180339993A1-20181129-C00578
    Figure US20180339993A1-20181129-C00579
         		438.3 1.32 min. (QC1)
    Example-5-11 INT-6-20-A INT-1-1-A
    Figure US20180339993A1-20181129-C00580
    Figure US20180339993A1-20181129-C00581
    Figure US20180339993A1-20181129-C00582
         		438.4 1.49 min. (QC1)
    Example-5-12 INT-6-21-A INT-1-1-A
    Figure US20180339993A1-20181129-C00583
    Figure US20180339993A1-20181129-C00584
    Figure US20180339993A1-20181129-C00585
         		429.5 1.59 min. (QC1)
    Example-5-13 INT-6-17-A
    Figure US20180339993A1-20181129-C00586
    Figure US20180339993A1-20181129-C00587
    Figure US20180339993A1-20181129-C00588
         		452.3 1.45 min. (QC1)
    Example-5-14 INT-6-22-A INT-1-1-A
    • Example-5-15: 8,8-difluoro-3-(2-(4-(2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00589
    • <Step-1>: Intermediate-5-15-1 (INT-5-15-1): N-(2-((4-acetylphenyl)amino)phenyl)-2-(benzyloxy)acetamide
  • Figure US20180339993A1-20181129-C00590
  • A mixture of 1-(4-((2-aminophenyl)amino)phenyl)ethanone (170 mg, 0.751 mmol), 2-(benzyloxy)acetyl chloride (170 mg, 0.902 mmol) and triethylamine (228 mg, 2.25 mmol) in DCM (5 mL) is stirred at rt for 1 h. After the removal of solvent, the residue is purified by column chromatography (Biotage) on silica gel (25 g) eluting with 5-80% ethyl acetate in DCM to give the titled compound (0.289 g, quant.) as a yellow amorphous solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 8.71 (s, 1H), 7.89-7.74 (m, 3H), 7.36-7.17 (m, 8H), 6.74-6.70 (m, 2H), 6.27 (s, 1H), 4.50 (s, 2H), 4.09 (s, 2H), 2.51 (s, 3H).
  • MS (ESI) m/z: 375.1 (M+H)+.
    • <Step-2>: Intermediate-5-15-2 (INT-5-15-2): 1-(4-(2-((benzyloxy)methyl)-1H-benzo[d]imidazol-1-yl)phenyl)ethanone
  • Figure US20180339993A1-20181129-C00591
  • To a solution of INT-5-15-1 (289 mg, 0.772 mmol) in acetic acid (5 mL) is heated at 60° C. for 15 h. The reaction mixture is concentrated in vacuo to the crude product, which is purified by column chromatography (Biotage) on silica gel (25 g) eluting with 10-100% ethyl acetate in DCM to give the titled compound (246 mg, 92% yield) as a yellow amorphous solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 8.18 (d, J=8.5 Hz, 2H), 7.80-7.75 (m, 3H), 7.34-7.25 (m, 6H), 7.14-7.11 (m, 2H), 4.72 (s, 2H), 4.45 (s, 2H), 2.68 (s, 3H), 2.46 (s, 3H).
  • MS (ESI) m/z: 0.357.1 (M+H)+.
    • <Step-3>: Intermediate-5-15-3 (INT-5-15-3): (1-(4-(2-bromoacetyl)phenyl)-1H-benzo[d]imidazol-2-yl)methyl acetate hydrobromide
  • Figure US20180339993A1-20181129-C00592
  • A mixture of INT-5-15-2 (246 mg, 0.690 mmol) and bromine (110 mg, 0.690 mmol) in 25% HBr-AcOH (5 mL) is stirred at rt for 1.5 h. The reaction mixture is concentrated by nitrogen flow. The residue is triturated with a mixture of IPE and MeOH (2/1 v/v) to give a mixture of the titled compound (352 mg, chemical purity of 80%) as a dark yellow amorphous solid.
  • MS (ESI) m/z: 270.1 (M+H)+.
    • <Step-4>: Example-5-15: 8,8-difluoro-3-(2-(4-(2-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • A mixture of INT-1-1-A (154 mg, 0.752 mmol), INT-5-15-3 (352 mg, 2.26 mmol) and potassium carbonate (312 mg, 2.26 mmol) in DMF (5 mL) is heated at 80° C. for 3 h. After cooling, to the reaction mixture is added water and the mixture is stirred for 10 min. After the extraction with EtOAc, the combined organic layer is washed brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography (Biotage) on silica gel (25 g) eluting with 10-80% ethyl acetate in DCM to give the titled compound (209 mg, 59% yield) as a pale yellow solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 9.06 (s, 1H), 8.30 (d, J=8.5 Hz, 2H), 7.84 (d, J=8.5 Hz, 2H), 7.32-7.28 (m, 4H), 5.61 (t, J=5.9 Hz, 1H), 5.07 (s, 2H), 4.65 (d, J=5.9 Hz, 2H), 2.19-1.76 (m, 8H).
  • MS (ESI) m/z: 469.1 (M+H)+.
    • Example-5-16: 3-(2-(4-(2-(aminomethyl)-1H-benzo[d]imidazol-1-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00593
    • <Step-1>: Intermediate-5-16-1 (INT-5-16-1): 3-(2-(4-(2-(azidomethyl)-1H-benzo[d]imidazol-1-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00594
  • To a solution of example-5-15 (50 mg, 0.107 mmol) in THF (2 mL) is added diphenyl phosphorazidate (DPPA)(41 mg, 0.149 mmol) at 0° C. After 5 min, DBU (19 mg, 0.128 mmol) is added to this and the reaction mixture is stirred for 2 h at 0° C. After 5 h at rt, the reaction mixture is quenched with water and extracted with EtOAc. The combined organic layers are dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography (Biotage) on silica gel (10 g) eluting with 10-80% ethyl acetate in DCM to give the titled compound (32 mg, 61% yield) as a colorless amorphous solid.
  • MS (ESI) m/z: 493.9 (M+H)+.
    • <Step-2>: Example-5-16: 3-(2-(4-(2-(aminomethyl)-1H-benzo[d]imidazol-1-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • To a solution of INT-5-16-1 (32 mg, 0.065 mmol) in THF (1 mL) is added triphenylphosphine (24 mg, 0.091 mmol) and water (0.17 mL). The mixture is stirred at rt for 3 h. Then, it is treated with 25% ammonium hydroxide aq. solution (0.17 mL) and stirred at rt for an additional 1 h. The reaction mixture is quenched with water and extracted with EtOAc.
  • The combined layers are dried over sodium sulfate, filtered and concentrated in vacuo. The residue is loaded onto an SCX cartridge (Biotage, ISOLUTE SCX-2; 1 g/6 mL×2) conditioned with 1 mL of MeOH, rinsed with 5 mL of MeOH and eluted with 5 mL of 1M NH3/MeOH. Volatiles are removed by nitrogen flow to give the titled compound (23 mg, 76% yield) as a colorless amorphous. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 466.5
  • tR/method: 1.37 min./(QC1)
  • The following examples (5-17 to 5-42) are prepared according to the procedure of Example-1 from the known or synthesized alpha-haloketone derivatives and azaspiro derivatives in Table 18. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 18.
  • TABLE 18
    azaspiro observed tR/
    Examples alpha-haloketones derivetives MS method
    Figure US20180339993A1-20181129-C00595
    Figure US20180339993A1-20181129-C00596
    Figure US20180339993A1-20181129-C00597
         		414.2 1.57 min. (QC1)
    Example-5-17 INT-1-1-A
    Figure US20180339993A1-20181129-C00598
    Figure US20180339993A1-20181129-C00599
    Figure US20180339993A1-20181129-C00600
         		378.3 1.56 min. (QC1)
    Example-5-18
    Figure US20180339993A1-20181129-C00601
    Figure US20180339993A1-20181129-C00602
    Figure US20180339993A1-20181129-C00603
         		379.2 1.78 min. (QC1)
    Example-5-19
    Figure US20180339993A1-20181129-C00604
    Figure US20180339993A1-20181129-C00605
    Figure US20180339993A1-20181129-C00606
         		415.5 1.39 min. (QC1)
    Example-5-20 INT-6-13-A INT-1-1-A
    Figure US20180339993A1-20181129-C00607
    Figure US20180339993A1-20181129-C00608
    Figure US20180339993A1-20181129-C00609
         		415.5 1.46 min. (QC1)
    Example-5-21 INT-6-14-A INT-1-1-A
    Figure US20180339993A1-20181129-C00610
    Figure US20180339993A1-20181129-C00611
    Figure US20180339993A1-20181129-C00612
         		415.2 1.35 min. (QC1)
    Example-5-22 INT-6-15-A INT-1-1-A
    Figure US20180339993A1-20181129-C00613
    Figure US20180339993A1-20181129-C00614
    Figure US20180339993A1-20181129-C00615
         		416.2 1.64 min. (QC1)
    Example-5-23 INT-5-13-A INT-1-1-A
    Figure US20180339993A1-20181129-C00616
    Figure US20180339993A1-20181129-C00617
    Figure US20180339993A1-20181129-C00618
         		380.2 1.64 min. (QC1)
    Example-5-24 INT-5-13-A
    Figure US20180339993A1-20181129-C00619
    Figure US20180339993A1-20181129-C00620
    Figure US20180339993A1-20181129-C00621
         		449.6 1.44 min. (QC1)
    Example-5-25 INT-6-29-A INT-1-1-A
    Figure US20180339993A1-20181129-C00622
    Figure US20180339993A1-20181129-C00623
    Figure US20180339993A1-20181129-C00624
         		393.7 1.40 min. (QC1)
    Example-5-26 INT-6-30-A
    Figure US20180339993A1-20181129-C00625
    Figure US20180339993A1-20181129-C00626
    Figure US20180339993A1-20181129-C00627
         		468.2 1.44 min. (QC1)
    Example-5-27 INT-6-23-A INT-1-1-A
    Figure US20180339993A1-20181129-C00628
    Figure US20180339993A1-20181129-C00629
    Figure US20180339993A1-20181129-C00630
         		455.4 1.54 min. (QC1)
    Example-5-28 INT-6-19-A INT-1-3-A
    Figure US20180339993A1-20181129-C00631
    Figure US20180339993A1-20181129-C00632
    Figure US20180339993A1-20181129-C00633
         		497.2 1.69 min. (QC2)
    Example-5-29 INT-6-24-A INT-1-1-A
    Figure US20180339993A1-20181129-C00634
    Figure US20180339993A1-20181129-C00635
    Figure US20180339993A1-20181129-C00636
         		460.4 1.60 min. (QC1)
    Example-5-30 INT-6-23-A
    Figure US20180339993A1-20181129-C00637
    Figure US20180339993A1-20181129-C00638
    Figure US20180339993A1-20181129-C00639
         		522.5 1.58 min. (QC1)
    Example-5-31 INT-6-25-A INT-1-1-A
    Figure US20180339993A1-20181129-C00640
    Figure US20180339993A1-20181129-C00641
    Figure US20180339993A1-20181129-C00642
         		432.6 1.43 min. (QC1)
    Example-5-32 INT-6-19-A
    Figure US20180339993A1-20181129-C00643
    Figure US20180339993A1-20181129-C00644
    Figure US20180339993A1-20181129-C00645
         		418.7 1.34 min. (QC1)
    Example-5-33 INT-6-19-A
    Figure US20180339993A1-20181129-C00646
    Figure US20180339993A1-20181129-C00647
    Figure US20180339993A1-20181129-C00648
         		404.6 1.26 min. (QC1)
    Example-5-34 INT-6-19-A
    Figure US20180339993A1-20181129-C00649
    Figure US20180339993A1-20181129-C00650
    Figure US20180339993A1-20181129-C00651
         		431.3 1.52 min. (QC1)
    Example-5-35 INT-6-26-A INT-1-1-A
    Figure US20180339993A1-20181129-C00652
    Figure US20180339993A1-20181129-C00653
    Figure US20180339993A1-20181129-C00654
         		417.3 1.36 min. (QC1)
    Example-5-36 INT-6-27-A INT-1-1-A
    Figure US20180339993A1-20181129-C00655
    Figure US20180339993A1-20181129-C00656
    Figure US20180339993A1-20181129-C00657
         		451.5 1.51 min. (QC1)
    Example-5-37 INT-6-28-A INT-1-1-A
    Figure US20180339993A1-20181129-C00658
    Figure US20180339993A1-20181129-C00659
    Figure US20180339993A1-20181129-C00660
         		430.3 1.65 min. (QC1)
    Example-5-38 INT-5-17-A INT-1-1-A
    Figure US20180339993A1-20181129-C00661
    Figure US20180339993A1-20181129-C00662
    Figure US20180339993A1-20181129-C00663
         		433.1 2.03 min. (QC2)
    Example-5-39 INT-5-18-A INT-1-1-A
    Figure US20180339993A1-20181129-C00664
    Figure US20180339993A1-20181129-C00665
    Figure US20180339993A1-20181129-C00666
         		381.6 1.33 min. (QC1)
    Example-5-40 INT-6-15-A
    Figure US20180339993A1-20181129-C00667
    Figure US20180339993A1-20181129-C00668
    Figure US20180339993A1-20181129-C00669
         		395.6 1.41 min. (QC1)
    Example-5-41 INT-6-15-A
    Figure US20180339993A1-20181129-C00670
    Figure US20180339993A1-20181129-C00671
    Figure US20180339993A1-20181129-C00672
         		367.6 1.24 min. (QC1)
    Example-5-42 INT-6-15-A
    • General Procedure (Condition-A)
  • Figure US20180339993A1-20181129-C00673
  • To a solution of INT-12-1-A (0.067 mmol) in 1,4-dioxane (1 mL) is added halide derivative (0.067 mmol), saturated NaHCO3 solution (0.5 mL) and PdCl2(dppf) CH2Cl2 (10% mol). The mixture is stirred at 100° C. for 3-15 h in oil bath or irradiated in a microwave system (MW)(Biotage, initiator) under the conditions of Table 19. To the reaction mixture is added water and ethyl acetate and the mixture is filtered through a pad of celite. The separated organic solution is washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification of neutral compound: short filtration using amine silica gel or the purification by column chromatography.
  • Purification of basic compound: The residue is loaded onto an SCX cartridge (Varian Bond Elute, 1 g/6 mL) conditioned with 1 mL of MeOH, rinsed with 5 mL of MeOH and eluted with 5 mL of 1M NH3/MeOH. Volatiles are removed by nitrogen flow to give the crude title compound. If necessary, the purification by column chromatography is carried out before the purification using SCX.
  • The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are noted in Table 20.
  • Other than the above condition A, the following conditions (B-F) are also summarized in Table 19.
  • TABLE 19
    Condition Pd catalyst Base Solvent Temperature/Times
    A PdCl2(dppf)•CH2Cl2 NaHCO3 1,4-dioxane- 80-150° C./3-15 h (oil bath)
    water 100-150° C./20-60 min (MW)
    B PdCl2(dppf)•CH2Cl2 K3PO4 DMF 80-150° C./3-15 h (oil bath)
    100-150° C./20-60 min (MW)
    C Pd(Amphos)2Cl2 NaHCO3 1,4-dioxane- 80-150° C./3-15 h (oil bath)
    water 100-150° C./20-60 min (MW)
    D Pd(PPh3)4 NaHCO3 1,4-dioxane- 100-120° C./20-60 min (MW)
    water
    E PdCl2(dppf)•CH2Cl2 CsOAc 1,4-dioxane 170° C./20 min (MW)
    F PdCl2(dppf)•CH2Cl2 CuI DMF 120° C./20 min (MW)
  • The following examples (6-1 to 6-53) are prepared according to the condition A to F in Table 19 from the synthesized aryl boronic acid derivative (INT-12-1-A) and the known or synthesized halide derivatives in Table 20. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 20.
  • TABLE 20
    Boronic acid
    Examples derivative halides conditions observed MS tR/method
    Figure US20180339993A1-20181129-C00674
    Figure US20180339993A1-20181129-C00675
    Figure US20180339993A1-20181129-C00676
         		A 438.3 1.39 min. (QC1)
    Example-6-1 INT-12-1-A
    Figure US20180339993A1-20181129-C00677
    Figure US20180339993A1-20181129-C00678
    Figure US20180339993A1-20181129-C00679
         		A 449.3 1.53 min. (QC1)
    Example-6-2 INT-12-1-A
    Figure US20180339993A1-20181129-C00680
    Figure US20180339993A1-20181129-C00681
    Figure US20180339993A1-20181129-C00682
         		A 424.2 1.93 min. (QC2)
    Example-6-3 INT-12-1-A
    Figure US20180339993A1-20181129-C00683
    Figure US20180339993A1-20181129-C00684
    Figure US20180339993A1-20181129-C00685
         		A 438.3 1.33 min. (QC1)
    Example-6-4 INT-12-1-A
    Figure US20180339993A1-20181129-C00686
    Figure US20180339993A1-20181129-C00687
    Figure US20180339993A1-20181129-C00688
         		A 437.3 1.38 min. (QC1)
    Example-6-5 INT-12-1-A
    Figure US20180339993A1-20181129-C00689
    Figure US20180339993A1-20181129-C00690
    Figure US20180339993A1-20181129-C00691
         		A 429.3 1.59 min. (QC2)
    Example-6-6 INT-12-1-A
    Figure US20180339993A1-20181129-C00692
    Figure US20180339993A1-20181129-C00693
    Figure US20180339993A1-20181129-C00694
         		A 427.2 1.50 min. (QC1)
    Example-6-7 INT-12-1-A
    Figure US20180339993A1-20181129-C00695
    Figure US20180339993A1-20181129-C00696
    Figure US20180339993A1-20181129-C00697
         		A 438.3 1.36 min. (QC1)
    Example-6-8 INT-12-1-A
    Figure US20180339993A1-20181129-C00698
    Figure US20180339993A1-20181129-C00699
    Figure US20180339993A1-20181129-C00700
         		A 428.3 1.36 min. (QC1)
    Example-6-9 INT-12-1-A
    Figure US20180339993A1-20181129-C00701
    Figure US20180339993A1-20181129-C00702
    Figure US20180339993A1-20181129-C00703
         		A 428.3 1.28 min. (QC1)
    Example-6-10 INT-12-1-A
    Figure US20180339993A1-20181129-C00704
    Figure US20180339993A1-20181129-C00705
    Figure US20180339993A1-20181129-C00706
         		A 413.2 1.43 min. (QC1)
    Example-6-11 INT-12-1-A
    Figure US20180339993A1-20181129-C00707
    Figure US20180339993A1-20181129-C00708
    Figure US20180339993A1-20181129-C00709
         		A 418.3 1.51 min. (QC1)
    Example-6-12 INT-12-1-A
    Figure US20180339993A1-20181129-C00710
    Figure US20180339993A1-20181129-C00711
    Figure US20180339993A1-20181129-C00712
         		A 437.3 1.47 min. (QC1)
    Example-6-13 INT-12-1-A
    Figure US20180339993A1-20181129-C00713
    Figure US20180339993A1-20181129-C00714
    Figure US20180339993A1-20181129-C00715
         		A 413.2 1.71 min. (QC2)
    Example-6-14 INT-12-1-A
    Figure US20180339993A1-20181129-C00716
    Figure US20180339993A1-20181129-C00717
    Figure US20180339993A1-20181129-C00718
         		A 423.3 1.50 min. (QC1)
    Example-6-15 INT-12-1-A
    Figure US20180339993A1-20181129-C00719
    Figure US20180339993A1-20181129-C00720
    Figure US20180339993A1-20181129-C00721
         		A 423.3 1.47 min. (QC1)
    Example-6-16 INT-12-1-A
    Figure US20180339993A1-20181129-C00722
    Figure US20180339993A1-20181129-C00723
    Figure US20180339993A1-20181129-C00724
         		A 458.3 1.47 min. (QC1)
    Example-6-17 INT-12-1-A
    Figure US20180339993A1-20181129-C00725
    Figure US20180339993A1-20181129-C00726
    Figure US20180339993A1-20181129-C00727
         		C 449.3 1.43 min. (QC1)
    Example-6-18 INT-12-1-A
    Figure US20180339993A1-20181129-C00728
    Figure US20180339993A1-20181129-C00729
    Figure US20180339993A1-20181129-C00730
         		A 413.4 1.59 min. (QC1)
    Example-6-19 INT-12-1-A
    Figure US20180339993A1-20181129-C00731
    Figure US20180339993A1-20181129-C00732
    Figure US20180339993A1-20181129-C00733
         		A 438.3 1.35 min. (QC1)
    Example-6-20 INT-12-1-A
    Figure US20180339993A1-20181129-C00734
    Figure US20180339993A1-20181129-C00735
    Figure US20180339993A1-20181129-C00736
         		A 437.3 1.43 min. (QC1)
    Example-6-21 INT-12-1-A
    Figure US20180339993A1-20181129-C00737
    Figure US20180339993A1-20181129-C00738
    Figure US20180339993A1-20181129-C00739
         		A 432.3 1.61 min. (QC1)
    Example-6-22 INT-12-1-A
    Figure US20180339993A1-20181129-C00740
    Figure US20180339993A1-20181129-C00741
    Figure US20180339993A1-20181129-C00742
         		A 439.4 1.33 min. (QC1)
    Example-6-23 INT-12-1-A
    Figure US20180339993A1-20181129-C00743
    Figure US20180339993A1-20181129-C00744
    Figure US20180339993A1-20181129-C00745
         		A 437.3 1.40 min. (QC1)
    Example-6-24 INT-12-1-A
    Figure US20180339993A1-20181129-C00746
    Figure US20180339993A1-20181129-C00747
    Figure US20180339993A1-20181129-C00748
         		A 448.4 1.67 min. (QC1)
    Example-6-25 INT-12-1-A
    Figure US20180339993A1-20181129-C00749
    Figure US20180339993A1-20181129-C00750
    Figure US20180339993A1-20181129-C00751
         		A 423.2 1.59 min. (QC1)
    Example-6-26 INT-12-1-A
    Figure US20180339993A1-20181129-C00752
    Figure US20180339993A1-20181129-C00753
    Figure US20180339993A1-20181129-C00754
         		A 416.3 1.58 min. (QC1)
    Example-6-27 INT-12-1-A
    Figure US20180339993A1-20181129-C00755
    Figure US20180339993A1-20181129-C00756
    Figure US20180339993A1-20181129-C00757
         		A 413.2 1.52 min. (QC1)
    Example-6-28 INT-12-1-A
    Figure US20180339993A1-20181129-C00758
    Figure US20180339993A1-20181129-C00759
    Figure US20180339993A1-20181129-C00760
         		A 417.3 1.81 min. (QC1)
    Example-6-29 INT-12-1-A
    Figure US20180339993A1-20181129-C00761
    Figure US20180339993A1-20181129-C00762
    Figure US20180339993A1-20181129-C00763
         		A 449.3 1.58 min. (QC1)
    Example-6-30 INT-12-1-A
    Figure US20180339993A1-20181129-C00764
    Figure US20180339993A1-20181129-C00765
    Figure US20180339993A1-20181129-C00766
         		A 438.4 1.58 min. (QC1)
    Example-6-31 INT-12-1-A
    Figure US20180339993A1-20181129-C00767
    Figure US20180339993A1-20181129-C00768
    Figure US20180339993A1-20181129-C00769
         		A 437.3 1.58 min. (QC1)
    Example-6-32 INT-12-1-A
    Figure US20180339993A1-20181129-C00770
    Figure US20180339993A1-20181129-C00771
    Figure US20180339993A1-20181129-C00772
         		A 463.3 1.57 min. (QC1)
    Example-6-33 INT-12-1-A
    Figure US20180339993A1-20181129-C00773
    Figure US20180339993A1-20181129-C00774
    Figure US20180339993A1-20181129-C00775
         		A 413.4 1.37 min. (QC1)
    Example-6-34 INT-12-1-A
    Figure US20180339993A1-20181129-C00776
    Figure US20180339993A1-20181129-C00777
    Figure US20180339993A1-20181129-C00778
         		A 413.3 1.54 min. (QC1)
    Example-6-35 INT-12-1-A
    Figure US20180339993A1-20181129-C00779
    Figure US20180339993A1-20181129-C00780
    Figure US20180339993A1-20181129-C00781
         		A 428.3 1.29 min. (QC1)
    Example-6-36 INT-12-1-A
    Figure US20180339993A1-20181129-C00782
    Figure US20180339993A1-20181129-C00783
    Figure US20180339993A1-20181129-C00784
         		A 449.3 1.43 min. (QC1)
    Example-6-37 INT-12-1-A
    Figure US20180339993A1-20181129-C00785
    Figure US20180339993A1-20181129-C00786
    Figure US20180339993A1-20181129-C00787
         		A 437.3 1.47 min. (QC1)
    Example-6-38 INT-12-1-A
    Figure US20180339993A1-20181129-C00788
    Figure US20180339993A1-20181129-C00789
    Figure US20180339993A1-20181129-C00790
         		A 442.3 1.75 min. (QC1)
    Example-6-39 INT-12-1-A
    Figure US20180339993A1-20181129-C00791
    Figure US20180339993A1-20181129-C00792
    Figure US20180339993A1-20181129-C00793
         		A 441.4 1.58 min. (QC1)
    Example-6-40 INT-12-1-A
    Figure US20180339993A1-20181129-C00794
    Figure US20180339993A1-20181129-C00795
    Figure US20180339993A1-20181129-C00796
         		A 466.3 1.62 min. (QC1)
    Example-6-41 INT-12-1-A
    Figure US20180339993A1-20181129-C00797
    Figure US20180339993A1-20181129-C00798
    Figure US20180339993A1-20181129-C00799
         		A 453.4 1.32 min. (QC1)
    Example-6-42 INT-12-1-A
    Figure US20180339993A1-20181129-C00800
    Figure US20180339993A1-20181129-C00801
    Figure US20180339993A1-20181129-C00802
         		C 424.5 1.38 min. (QC1)
    Example-6-43 INT-12-1-A
    Figure US20180339993A1-20181129-C00803
    Figure US20180339993A1-20181129-C00804
    Figure US20180339993A1-20181129-C00805
         		A 449.5 1.42 min. (QC1)
    Example-6-44 INT-12-1-A
    Figure US20180339993A1-20181129-C00806
    Figure US20180339993A1-20181129-C00807
    Figure US20180339993A1-20181129-C00808
         		A 449.5 1.49 min. (QC1)
    Example-6-45 INT-12-1-A
    Figure US20180339993A1-20181129-C00809
    Figure US20180339993A1-20181129-C00810
    Figure US20180339993A1-20181129-C00811
         		A 457.3 1.43 min. (QC1)
    Example-6-46 INT-12-1-A
    Figure US20180339993A1-20181129-C00812
    Figure US20180339993A1-20181129-C00813
    Figure US20180339993A1-20181129-C00814
         		A 457.4 1.32 min. (QC1)
    Example-6-47 INT-12-1-A
    Figure US20180339993A1-20181129-C00815
    Figure US20180339993A1-20181129-C00816
    Figure US20180339993A1-20181129-C00817
         		A 469.3 1.41 min. (QC1)
    Example-6-48 INT-12-1-A
    Figure US20180339993A1-20181129-C00818
    Figure US20180339993A1-20181129-C00819
    Figure US20180339993A1-20181129-C00820
         		A 453.3 1.58 min. (QC1)
    Example-6-49 INT-12-1-A
    Figure US20180339993A1-20181129-C00821
    Figure US20180339993A1-20181129-C00822
    Figure US20180339993A1-20181129-C00823
         		A 453.4 1.65 min. (QC1)
    Example-6-50 INT-12-1-A
    Figure US20180339993A1-20181129-C00824
    Figure US20180339993A1-20181129-C00825
    Figure US20180339993A1-20181129-C00826
         		A 450.3 1.40 min. (QC1)
    Example-6-51 INT-12-1-A
    Figure US20180339993A1-20181129-C00827
    Figure US20180339993A1-20181129-C00828
    Figure US20180339993A1-20181129-C00829
         		A 466.3 1.46 min. (QC1)
    Example-6-52 INT-12-1-A
    Figure US20180339993A1-20181129-C00830
    Figure US20180339993A1-20181129-C00831
    Figure US20180339993A1-20181129-C00832
         		A 475.3 1.54 min. (QC1)
    Example-6-53 INT-12-1-A
    • Example-6-54: 8,8-difluoro-3-(2-(4-(3-(2-hydroxyethoxy)pyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00833
    • <Step-1>: Intermediate-6-54-1 (INT 6-54-1): 2-chloro-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyrazine
  • Figure US20180339993A1-20181129-C00834
  • To a solution of 2,3-dichloropyrazine (397 mg, 2.67 mmol) and 2-((tetrahydro-2H-pyran-2-yl)oxy)ethanol (300 mg, 2.05 mmol) in DMSO (2 mL) is added t-BuOK (299 mg, 2.67 mmol) at 0° C. The mixture is stirred at rt for 1 h. The mixture is diluted with water and extracted with EtOAc-hexane (2:1, ×2). The combined organic layers are dried over Na2SO4, filtered and concentrated. The purification is carried out by column chromatography on silica gel eluting with a gradient of 0-30% EtOAc in hexane to give the titled compound (350 mg, 66% yield) as a pale yellow oil.
  • 1H-NMR (270 MHz, CDCl3): delta 8.01 (d, J=2.7 Hz, 1H), 7.93 (d, J=2.7 Hz, 1H), 4.75 (t, J=3.0 Hz, 1H), 4.65-4.55 (m, 2H), 4.19-4.05 (m, 1H), 4.00-3.80 (m, 2H), 3.60-3.50 (m, 1H), 1.89-1.48 (m, 6H).
    • <Step-2>: Intermediate-6-54-2 (INT 6-54-2): 8,8-difluoro-3-(2-oxo-2-(4-(3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyrazin-2-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00835
  • The titled compound is prepared according to the procedure described in Suzuki-Miyaura cross coupling reaction of condition-C from INT 12-1-A (30 mg, 0.067 mmol), INT 6-54-1 (17 mg, 0.067 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5.5 mg, 0.0067 mmol) instead of PdCl2(dppf) in a microwave irradiation system at 120° C. for 20 min. The crude brown oil (36 mg) is obtained and this compound is used for next step without purification.
  • MS (ESI) m/z: 545.2 (M+H)+.
    • <Step-3>: Example-6-54: 8,8-difluoro-3-(2-(4-(3-(2-hydroxyethoxy)pyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • To a solution of INT 6-54-2 (crude oil prepared in step-2 of example 6-54) in THF (1 mL) is added 2 M HCl aq. solution (1 mL) and the mixture is stirred at rt for 3 h. The mixture is quenched with saturated sodium carbonate solution and extracted with DCM. The combined organic layers are dried over Na2SO4, filtered and concentrated. The purification is carried out by column chromatography on silica gel eluting with a gradient of 30-100% EtOAc in hexane to give the titled compound (20 mg, 66% yield in 2 steps) as a pale yellow solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • 1H-NMR (270 MHz, CDCl3): delta 8.33 (d, J=2.6 Hz, 1H), 8.24 (d, J=8.6 Hz, 2H), 8.11 (d, J=2.6 Hz, 1H), 8.05 (d, J=8.6 Hz, 2H), 6.05 (br.s, 1H), 4.97 (s, 2H), 4.65-4.57 (m, 2H), 4.08-4.00 (m, 2H), 2.58-2.19 (m, 5H), 2.12-1.90 (m, 4H).
  • Observed MS: 459.3
  • tR/method: 1.41 min./(QC1)
    • Example-6-55: 3-(2-(2′-(aminomethyl)-[1,1′-biphenyl]-4-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione hydrochloride
  • Figure US20180339993A1-20181129-C00836
    • <Step-1>: Intermediate-6-55-1 (INT-6-55-1): tert-butyl((4′-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl-[1,1′-biphenyl]-2-yl)methyl) carbamate
  • Figure US20180339993A1-20181129-C00837
  • The titled compound is prepared according to the procedure described in Suzuki-Miyaura cross coupling reaction of condition-A from INT-12-1-A (838 mg, 1.87 mmol), tert-butyl 2-bromobenzylcarbamate (642 mg, 2.24 mmol) under microwave irradiation at 120° C. for 20 min. The reaction mixture is filtered through Celite pad and the Celite pad is washed with EtOAc. The filtrate and washings are extracted with EtOAc and the combined organic solution is washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography (Biotage) on silica gel (50 g) eluting with 10-80% ethyl acetate in DCM to give the titled compound (756 mg, 77% yield) as a white solid.
  • 1H-NMR (270 MHz, CDCl3): delta 8.04 (d, J=8.5 Hz, 2H), 7.50-7.35 (m, 4H), 7.28-7.24 (m, 2H), 6.94 (br.s, 1H), 4.98 (s, 2H), 4.68 (br.s, 1H), 4.29 (d, J=5.3 Hz, 2H), 2.38-2.24 (m, 4H), 2.04-1.98 (m, 4H), 1.63 (s, 3H), 1.43 (s, 9H).
  • MS (ESI) m/z: 526.4 (M−H)−.
    • <Step-2>: Example-6-55: 3-(2-(2′-(aminomethyl)-[1,1′-biphenyl]-4-yl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione hydrochloride
  • To a solution of INT-6-55-1 (756 mg, 1.43 mmol) in 1,4-dioxane (3 mL) is added 4 M HCl-dioxane (10 mL). The mixture is stirred at rt for 3 h. The precipitated solid is collected by filtration to give the titled compound (600 mg, 90% yield) as a white solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 9.05 (s, 1H), 8.33 (s, 2H), 8.16 (d, J=8.5 Hz, 2H), 7.71 (d, J=7.2 Hz, 1H), 7.62-7.48 (m, 4H), 7.37 (d, J=7.2 Hz, 1H), 5.03 (s, 2H), 3.97 (s, 2H), 2.19-1.81 (m, 8H).
  • MS (ESI) m/z: 428.3 (M−H)−.
    • Example-6-56: 3-(2-(4-(2-(aminomethyl)pyridine-3-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00838
    • <Step-1>: Intermediate-6-56-1 (INT-6-56-1): 3-(2-(4-(2-(aminomethyl)pyridin-3-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • The titled compound is prepared according to the procedure described in Suzuki-Miyaura cross coupling reaction of condition-A from INT-12-1-A and (3-bromopyridin-2-yl)methanamine to give the product (173 mg, 21% yield; chemical purity of 73%) as a dark red solid.
  • MS (ESI) m/z: 429.29 (M+H)+.
    • <Step-2>: Intermediate-6-56-2 (INT-6-56-2): tert-butyl((3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)pyridin-2-yl)methyl) carbamate
  • Figure US20180339993A1-20181129-C00839
  • To a stirred solution of the crude INT-6-56-1 (178 mg, 0.415 mmol) and triethylamine (116 microL, 0.831 mmol) in THF (5 mL) is added di-tert-butyl dicarbonate (90 microL, 0.416 mmol) at rt. The mixture is stirred at rt for 3 days. After the removal of solvent, the crude product is purified by column chromatography on silica gel (45 g) eluting with 3-20% methanol in DCM followed by preparative TLC (1 mm×4) with MeOH-DCM (1:20)(eluting with 10% MeOH in DCM) to give the titled compound (103.6 mg, yellow amorphous solid)
  • 1H-NMR (270 MHz, CDCl3): delta 8.64-8.58 (m, 1H), 8.10-8.00 (m, 2H), 7.62-7.55 (m, 1H), 7.53-7.45 (m, 2H), 7.36-7.28 (m, 1H), 7.00 (br.s, 1H), 6.00 (br.s, 1H), 4.96 (s, 2H), 4.38 (d, J=3.9 Hz, 2H), 2.50-1.90 (m, 8H), 1.65 (s, 3H), 1.43 (s, 9H).
  • MS (ESI) m/z: 529.41 (M+H)+.
    • <Step-3>: Example-6-56: 3-(2-(4-(2-(aminomethyl)pyridin-3-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • A mixture of INT-6-56-2 (98 mg, 0.185 mmol) in MeOH (3 mL) is treated with 10% HCl-methanol (8 mL). After 2.5 h at 50° C., the solvent is evaporated in vacuo. The residue is basified to pH>8 with saturated sodium bicarbonate solution and extracted with DCM (×3).
  • The combined solution is washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the titled compound (74.3 mg, 94% yield) as a pale brown˜yellow solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • 1H-NMR (270 MHz, DMSO-d6): delta 9.03 (br.s, 1H), 8.65-8.60 (m, 1H), 8.18-8.10 (m, 2H), 7.75-7.40 (m, 3H), 7.44-7.35 (m, 1H), 5.02 (s, 2H), 3.73 (s, 2H), 2.30-1.75 (m, 8H). (A signal due to NH is not observed.)
  • Observed MS: 427.3
  • tR/method: 1.23 min./(QC1)
    • Synthesis of Example-6-57: N-((3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)pyridin-2-yl)methyl)acetamide
  • Figure US20180339993A1-20181129-C00840
  • To a stirred suspension of Example-6-56 (38.1 mg, 0.089 mmol) in DCM (3 mL)-THF (1 mL) is added triethylamine (25 microL, 0.179 mmol) followed by acetic anhydride (10 microL, 0.107 mmol) at rt. The mixture is stirred at rt for 5 h. After the removal of solvent, the residue is purified by column chromatography (Biotage) on amine silica gel (10 g) with 50-100% EtOAc in hexane to give the titled compound (38.6 mg, 92% yield) as a colorless amorphous solid.
  • The further purification is carried out by preparative LC-MS system in the usual manner.
  • 1H-NMR (270 MHz, DMSO-d6): delta 9.03 (s, 1H), 8.65-8.60 (m, 1H), 8.24-8.20 (m, 1H), 8.18-8.10 (m, 2H), 7.75-7.60 (m, 3H), 7.48-7.40 (m, 1H), 5.03 (s, 2H), 4.32 (d, J=4.3 Hz, 2H), 2.30-1.75 (m, 8H), 1.80 (s, 3H).
  • Observed MS: 469.4
  • tR/method: 1.33 min./(QC1)
    • Example-6-58: 3-(2-(4-(4-(aminomethyl)pyridin-3-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C00841
    • <Step-1>: Intermediate-6-58-1 (INT-6-58-1): tert-butyl((3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)pyridin-4-yl)methyl) carbamate
  • Figure US20180339993A1-20181129-C00842
  • The titled compound is prepared according to the procedure described in Suzuki-Miyaura cross coupling reaction of condition-A from INT-12-1-A (60 mg, 0.134 mmol), tert-butyl((3-bromopyridin-4-yl)methyl)carbamate (46 mg, 0.161 mmol) in a microwave irradiation system at 120° C. for 20 min. The residue is purified by column chromatography (Biotage) on silica gel (10 g) eluting with 10-80% ethyl acetate in DCM to give the product (63 mg, 89% yield) as a pale yellow solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 9.02 (s, 1H), 8.59 (d, J=5.3 Hz, 1H), 8.43 (s, 1H), 8.14 (d, J=7.9 Hz, 2H), 7.64 (d, J=7.9 Hz, 2H), 7.51 (t, J=5.3 Hz, 1H), 7.39 (d, J=4.6 Hz, 1H), 5.02 (s, 2H), 4.11 (d, J=5.3 Hz, 2H), 2.17-1.86 (m, 8H), 1.36 (s, 9H).
  • MS (ESI) m/z: 529.3 (M−H)−.
    • <Step-2>: Example-6-58: 3-(2-(4-(4-(aminomethyl)pyridin-3-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • To a solution of INT-6-58-1 (63 mg, 0.119 mmol) in DCM (1 mL) is added trifluoroacetic acid (0.5 mL). The mixture is stirred at rt for 2 h. The reaction mixture is concentrated by nitrogen flow. The residue is loaded onto an SCX cartridge (Biotage, ISOLUTE-SCX-2, 1 g/6 mL) conditioned with 1 mL of MeOH, rinsed with 5 mL of MeOH and eluted with 5 mL of 1M NH3/MeOH. Volatiles are removed by nitrogen flow to give the titled compound (41 mg, 76% yield) as a pale yellow amorphous solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 427.4
  • tR/method: 1.19 min./(QC1)
  • The following examples (6-59 to 6-123) are prepared according to the condition A to F in Table 19 from the synthesized aryl boronic acid derivative (INT-12-1-A) and the known or synthesized halide derivatives in Table 21. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 21.
  • TABLE 21
    Examples Boronic acid derivative halides conditions observed MS tR/method
    Figure US20180339993A1-20181129-C00843
    Figure US20180339993A1-20181129-C00844
    Figure US20180339993A1-20181129-C00845
         		C 452.2 1.30 min. (QC1)
    Figure US20180339993A1-20181129-C00846
    Figure US20180339993A1-20181129-C00847
    Figure US20180339993A1-20181129-C00848
         		A 454.1 1.51 min. (QC1)
    Figure US20180339993A1-20181129-C00849
    Figure US20180339993A1-20181129-C00850
    Figure US20180339993A1-20181129-C00851
         		A 403.3 1.32 min. (QC1)
    Figure US20180339993A1-20181129-C00852
    Figure US20180339993A1-20181129-C00853
    Figure US20180339993A1-20181129-C00854
         		A 440.1 1.41 min. (QC1)
    Figure US20180339993A1-20181129-C00855
    Figure US20180339993A1-20181129-C00856
    Figure US20180339993A1-20181129-C00857
         		A 439.2 2.09 min. (QC2)
    Figure US20180339993A1-20181129-C00858
    Figure US20180339993A1-20181129-C00859
    Figure US20180339993A1-20181129-C00860
         		A 439.1 2.05 min. (QC2)
    Figure US20180339993A1-20181129-C00861
    Figure US20180339993A1-20181129-C00862
    Figure US20180339993A1-20181129-C00863
         		A 453.6 1.45 min. (QC1)
    Figure US20180339993A1-20181129-C00864
    Figure US20180339993A1-20181129-C00865
    Figure US20180339993A1-20181129-C00866
         		A 440.6 1.30 min. (QC1)
    Figure US20180339993A1-20181129-C00867
    Figure US20180339993A1-20181129-C00868
    Figure US20180339993A1-20181129-C00869
         		A 439.6 1.55 min. (QC1)
    Figure US20180339993A1-20181129-C00870
    Figure US20180339993A1-20181129-C00871
    Figure US20180339993A1-20181129-C00872
         		A 440.6 1.47 min. (QC1)
    Figure US20180339993A1-20181129-C00873
    Figure US20180339993A1-20181129-C00874
    Figure US20180339993A1-20181129-C00875
         		A 453.5 1.47 min. (QC1)
    Figure US20180339993A1-20181129-C00876
    Figure US20180339993A1-20181129-C00877
    Figure US20180339993A1-20181129-C00878
         		A 414.8 1.48 min. (QC1)
    Figure US20180339993A1-20181129-C00879
    Figure US20180339993A1-20181129-C00880
    Figure US20180339993A1-20181129-C00881
         		A 415.1 1.47 min. (QC1)
    Figure US20180339993A1-20181129-C00882
    Figure US20180339993A1-20181129-C00883
    Figure US20180339993A1-20181129-C00884
         		C 440.8 1.60 min. (QC1)
    Figure US20180339993A1-20181129-C00885
    Figure US20180339993A1-20181129-C00886
    Figure US20180339993A1-20181129-C00887
         		A 415.3 2.82 min. (Method -E)
    Figure US20180339993A1-20181129-C00888
    Figure US20180339993A1-20181129-C00889
    Figure US20180339993A1-20181129-C00890
         		B 431.6 1.36 min. (QC1)
    Figure US20180339993A1-20181129-C00891
    Figure US20180339993A1-20181129-C00892
    Figure US20180339993A1-20181129-C00893
         		B 415.6 1.38 min. (QC1)
    Figure US20180339993A1-20181129-C00894
    Figure US20180339993A1-20181129-C00895
    Figure US20180339993A1-20181129-C00896
         		C 429.6 1.33 min. (QC1)
    Figure US20180339993A1-20181129-C00897
    Figure US20180339993A1-20181129-C00898
    Figure US20180339993A1-20181129-C00899
         		A 427.6 1.89 min. (QC1)
    Figure US20180339993A1-20181129-C00900
    Figure US20180339993A1-20181129-C00901
    Figure US20180339993A1-20181129-C00902
         		A 427.6 1.90 min. (QC1)
    Figure US20180339993A1-20181129-C00903
    Figure US20180339993A1-20181129-C00904
    Figure US20180339993A1-20181129-C00905
         		C 431.7 1.41 min. (QC1)
    Figure US20180339993A1-20181129-C00906
    Figure US20180339993A1-20181129-C00907
    Figure US20180339993A1-20181129-C00908
         		C 415.7 1.33 min. (QC1)
    Figure US20180339993A1-20181129-C00909
    Figure US20180339993A1-20181129-C00910
    Figure US20180339993A1-20181129-C00911
         		C 439.7 1.41 min. (QC1)
    Figure US20180339993A1-20181129-C00912
    Figure US20180339993A1-20181129-C00913
    Figure US20180339993A1-20181129-C00914
         		A 414.8 1.53 min. (QC1)
    Figure US20180339993A1-20181129-C00915
    Figure US20180339993A1-20181129-C00916
    Figure US20180339993A1-20181129-C00917
         		A 414.8 1.59 min. (QC1)
    Figure US20180339993A1-20181129-C00918
    Figure US20180339993A1-20181129-C00919
    Figure US20180339993A1-20181129-C00920
         		A 430.6 1.51 min. (QC1)
    Figure US20180339993A1-20181129-C00921
    Figure US20180339993A1-20181129-C00922
    Figure US20180339993A1-20181129-C00923
         		A 440.7 1.39 min. (QC1)
    Figure US20180339993A1-20181129-C00924
    Figure US20180339993A1-20181129-C00925
    Figure US20180339993A1-20181129-C00926
         		A 425.7 1.51 min. (QC1)
    Figure US20180339993A1-20181129-C00927
    Figure US20180339993A1-20181129-C00928
    Figure US20180339993A1-20181129-C00929
         		A 425.7 1.46 min. (QC1)
    Figure US20180339993A1-20181129-C00930
    Figure US20180339993A1-20181129-C00931
    Figure US20180339993A1-20181129-C00932
         		A 439.7 1.38 min. (QC1)
    Figure US20180339993A1-20181129-C00933
    Figure US20180339993A1-20181129-C00934
    Figure US20180339993A1-20181129-C00935
         		A 430.8 1.45 min. (QC1)
    Figure US20180339993A1-20181129-C00936
    Figure US20180339993A1-20181129-C00937
    Figure US20180339993A1-20181129-C00938
         		A 430.8 1.49 min. (QC1)
    Figure US20180339993A1-20181129-C00939
    Figure US20180339993A1-20181129-C00940
    Figure US20180339993A1-20181129-C00941
         		A 430.7 1.53 min. (QC1)
    Figure US20180339993A1-20181129-C00942
    Figure US20180339993A1-20181129-C00943
    Figure US20180339993A1-20181129-C00944
         		A 439.8 1.56 min. (QC1)
    Figure US20180339993A1-20181129-C00945
    Figure US20180339993A1-20181129-C00946
    Figure US20180339993A1-20181129-C00947
         		C 426.8 1.43 min. (QC1)
    Figure US20180339993A1-20181129-C00948
    Figure US20180339993A1-20181129-C00949
    Figure US20180339993A1-20181129-C00950
         		C 417.8 1.48 min. (QC1)
    Figure US20180339993A1-20181129-C00951
    Figure US20180339993A1-20181129-C00952
    Figure US20180339993A1-20181129-C00953
         		C 406.7 1.53 min. (QC1)
    Figure US20180339993A1-20181129-C00954
    Figure US20180339993A1-20181129-C00955
    Figure US20180339993A1-20181129-C00956
         		A 450.7 1.57 min. (QC1)
    Figure US20180339993A1-20181129-C00957
    Figure US20180339993A1-20181129-C00958
    Figure US20180339993A1-20181129-C00959
         		A 431.6 1.59 min. (QC1)
    Figure US20180339993A1-20181129-C00960
    Figure US20180339993A1-20181129-C00961
    Figure US20180339993A1-20181129-C00962
         		B 425.6 1.44 min. (QC1)
    Figure US20180339993A1-20181129-C00963
    Figure US20180339993A1-20181129-C00964
    Figure US20180339993A1-20181129-C00965
         		A 442.6 1.36 min. (QC1)
    Figure US20180339993A1-20181129-C00966
    Figure US20180339993A1-20181129-C00967
    Figure US20180339993A1-20181129-C00968
         		C 401.7 1.42 min. (QC1)
    Figure US20180339993A1-20181129-C00969
    Figure US20180339993A1-20181129-C00970
    Figure US20180339993A1-20181129-C00971
         		A 443.7 1.52 min. (QC1)
    Figure US20180339993A1-20181129-C00972
    Figure US20180339993A1-20181129-C00973
    Figure US20180339993A1-20181129-C00974
         		A 441.8 1.63 min. (QC1)
    Figure US20180339993A1-20181129-C00975
    Figure US20180339993A1-20181129-C00976
    Figure US20180339993A1-20181129-C00977
         		A 456.7 1.57 min. (QC1)
    Figure US20180339993A1-20181129-C00978
    Figure US20180339993A1-20181129-C00979
    Figure US20180339993A1-20181129-C00980
         		A 482.7 1.56 min. (QC1)
    Figure US20180339993A1-20181129-C00981
    Figure US20180339993A1-20181129-C00982
    Figure US20180339993A1-20181129-C00983
         		A 496.7 1.83 min. (QC1)
    Figure US20180339993A1-20181129-C00984
    Figure US20180339993A1-20181129-C00985
    Figure US20180339993A1-20181129-C00986
         		A 443.7 1.56 min. (QC1)
    Figure US20180339993A1-20181129-C00987
    Figure US20180339993A1-20181129-C00988
    Figure US20180339993A1-20181129-C00989
         		C 454.8 1.31 min. (QC1)
    Figure US20180339993A1-20181129-C00990
    Figure US20180339993A1-20181129-C00991
    Figure US20180339993A1-20181129-C00992
         		C 438.7 1.64 min. (QC1)
    Figure US20180339993A1-20181129-C00993
    Figure US20180339993A1-20181129-C00994
    Figure US20180339993A1-20181129-C00995
         		C 415.8 1.20 min. (QC1)
    Figure US20180339993A1-20181129-C00996
    Figure US20180339993A1-20181129-C00997
    Figure US20180339993A1-20181129-C00998
         		C 442.7 1.37 min. (QC1)
    Figure US20180339993A1-20181129-C00999
    Figure US20180339993A1-20181129-C01000
    Figure US20180339993A1-20181129-C01001
         		C 441.8 1.63 min. (QC1)
    Figure US20180339993A1-20181129-C01002
    Figure US20180339993A1-20181129-C01003
    Figure US20180339993A1-20181129-C01004
         		C 428.8 1.52 min. (QC1)
    Figure US20180339993A1-20181129-C01005
    Figure US20180339993A1-20181129-C01006
    Figure US20180339993A1-20181129-C01007
         		A 415.7 1.40 min. (QC1)
    Figure US20180339993A1-20181129-C01008
    Figure US20180339993A1-20181129-C01009
    Figure US20180339993A1-20181129-C01010
         		C 443.7 1.74 min. (QC1)
    Figure US20180339993A1-20181129-C01011
    Figure US20180339993A1-20181129-C01012
    Figure US20180339993A1-20181129-C01013
         		A 440.3 1.33 min. (QC1)
    Figure US20180339993A1-20181129-C01014
    Figure US20180339993A1-20181129-C01015
    Figure US20180339993A1-20181129-C01016
         		A 440.2 1.91 min. (QC2)
    Figure US20180339993A1-20181129-C01017
    Figure US20180339993A1-20181129-C01018
    Figure US20180339993A1-20181129-C01019
         		A 416.6 1.30 min. (QC1)
    Figure US20180339993A1-20181129-C01020
    Figure US20180339993A1-20181129-C01021
    Figure US20180339993A1-20181129-C01022
         		A 427.7 1.84 min. (QC1)
    Figure US20180339993A1-20181129-C01023
    Figure US20180339993A1-20181129-C01024
    Figure US20180339993A1-20181129-C01025
         		A 414.7 1.47 min. (QC1)
    Figure US20180339993A1-20181129-C01026
    Figure US20180339993A1-20181129-C01027
    Figure US20180339993A1-20181129-C01028
         		A 438.7 1.66 min. (QC1)
    Figure US20180339993A1-20181129-C01029
    Figure US20180339993A1-20181129-C01030
    Figure US20180339993A1-20181129-C01031
         		A 468.6 1.59 min. (QC1)
    Figure US20180339993A1-20181129-C01032
    Figure US20180339993A1-20181129-C01033
    Figure US20180339993A1-20181129-C01034
         		A 438.8 1.55 min. (QC1)
    Figure US20180339993A1-20181129-C01035
    Figure US20180339993A1-20181129-C01036
    Figure US20180339993A1-20181129-C01037
         		A 418.7 1.48 min. (QC1)
  • The following examples (7-1 to 7-28) are prepared according to the condition A to F in Table 19 from the synthesized aryl boronic acid derivatives and the known or synthesized halide derivatives in Table 22. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 22.
  • TABLE 22
    Examples Boronic acid derivatives halides conditions observed MS tR/method
    Figure US20180339993A1-20181129-C01038
    Figure US20180339993A1-20181129-C01039
    Figure US20180339993A1-20181129-C01040
         		A 376.4 1.48 min. (QC1)
    Figure US20180339993A1-20181129-C01041
    Figure US20180339993A1-20181129-C01042
    Figure US20180339993A1-20181129-C01043
         		A 376.4 1.49 min. (QC1)
    Figure US20180339993A1-20181129-C01044
    Figure US20180339993A1-20181129-C01045
    Figure US20180339993A1-20181129-C01046
         		A 381.3 1.81 min. (QC1)
    Figure US20180339993A1-20181129-C01047
    Figure US20180339993A1-20181129-C01048
    Figure US20180339993A1-20181129-C01049
         		A 391.4 1.49 min. (QC1)
    Figure US20180339993A1-20181129-C01050
    Figure US20180339993A1-20181129-C01051
    Figure US20180339993A1-20181129-C01052
         		A 387.4 1.59 min. (QC1)
    Figure US20180339993A1-20181129-C01053
    Figure US20180339993A1-20181129-C01054
    Figure US20180339993A1-20181129-C01055
         		A 365.5 1.43 min. (QC1)
    Figure US20180339993A1-20181129-C01056
    Figure US20180339993A1-20181129-C01057
    Figure US20180339993A1-20181129-C01058
         		A 392.1 1.28 min. (QC1)
    Figure US20180339993A1-20181129-C01059
    Figure US20180339993A1-20181129-C01060
    Figure US20180339993A1-20181129-C01061
         		A 387.3 1.49 min. (QC1)
    Figure US20180339993A1-20181129-C01062
    Figure US20180339993A1-20181129-C01063
    Figure US20180339993A1-20181129-C01064
         		A 392.2 1.27 min. (QC1)
    Figure US20180339993A1-20181129-C01065
    Figure US20180339993A1-20181129-C01066
    Figure US20180339993A1-20181129-C01067
         		A 393.3 1.25 min. (QC1)
    Figure US20180339993A1-20181129-C01068
    Figure US20180339993A1-20181129-C01069
    Figure US20180339993A1-20181129-C01070
         		A 392.3 1.35 min. (QC1)
    Figure US20180339993A1-20181129-C01071
    Figure US20180339993A1-20181129-C01072
    Figure US20180339993A1-20181129-C01073
         		A 387.2 1.48 min. (QC1)
    Figure US20180339993A1-20181129-C01074
    Figure US20180339993A1-20181129-C01075
    Figure US20180339993A1-20181129-C01076
         		A 377.2 1.41 min. (QC1)
    Figure US20180339993A1-20181129-C01077
    Figure US20180339993A1-20181129-C01078
    Figure US20180339993A1-20181129-C01079
         		A 377.5 1.41 min. (QC1)
    Figure US20180339993A1-20181129-C01080
    Figure US20180339993A1-20181129-C01081
    Figure US20180339993A1-20181129-C01082
         		A 411.3 1.56 min. (QC1)
    Figure US20180339993A1-20181129-C01083
    Figure US20180339993A1-20181129-C01084
    Figure US20180339993A1-20181129-C01085
         		A 415.3 1.35 min. (QC1)
    Figure US20180339993A1-20181129-C01086
    Figure US20180339993A1-20181129-C01087
    Figure US20180339993A1-20181129-C01088
         		A 414.3 1.55 min. (QC1)
    Figure US20180339993A1-20181129-C01089
    Figure US20180339993A1-20181129-C01090
    Figure US20180339993A1-20181129-C01091
         		A 415.3 1.43 min. (QC1)
    Figure US20180339993A1-20181129-C01092
    Figure US20180339993A1-20181129-C01093
    Figure US20180339993A1-20181129-C01094
         		A 400.3 1.49 min. (QC1)
    Figure US20180339993A1-20181129-C01095
    Figure US20180339993A1-20181129-C01096
    Figure US20180339993A1-20181129-C01097
         		A 410.4 1.56 min. (QC1)
    Figure US20180339993A1-20181129-C01098
    Figure US20180339993A1-20181129-C01099
    Figure US20180339993A1-20181129-C01100
         		C 416.1 1.51 min. (QC1)
    Figure US20180339993A1-20181129-C01101
    Figure US20180339993A1-20181129-C01102
    Figure US20180339993A1-20181129-C01103
         		C 452.4 1.59 min. (QC1)
    Figure US20180339993A1-20181129-C01104
    Figure US20180339993A1-20181129-C01105
    Figure US20180339993A1-20181129-C01106
         		A 379.7 1.31 min. (QC1)
    Figure US20180339993A1-20181129-C01107
    Figure US20180339993A1-20181129-C01108
    Figure US20180339993A1-20181129-C01109
         		A 401.1 1.72 min. (QC1)
    Figure US20180339993A1-20181129-C01110
    Figure US20180339993A1-20181129-C01111
    Figure US20180339993A1-20181129-C01112
         		A 426.0 1.75 min. (QC1)
    Figure US20180339993A1-20181129-C01113
    Figure US20180339993A1-20181129-C01114
    Figure US20180339993A1-20181129-C01115
         		A 402.1 1.67 min. (QC1)
    Figure US20180339993A1-20181129-C01116
    Figure US20180339993A1-20181129-C01117
    Figure US20180339993A1-20181129-C01118
         		A 402.2 1.40 min. (QC1)
    Figure US20180339993A1-20181129-C01119
    Figure US20180339993A1-20181129-C01120
    Figure US20180339993A1-20181129-C01121
         		A 418.2 1.33 min. (QC1)
  • The following examples (8-1 to 8-9) are prepared according to the condition A to F in Table 19 from the aryl boronic acid derivative prepared in situ and the known or synthesized halide derivatives in Table 23. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 23.
  • TABLE 23
    observed
    Examples Boronic acid derivatives halides conditions MS tR/method
    Figure US20180339993A1-20181129-C01122
    Figure US20180339993A1-20181129-C01123
    Figure US20180339993A1-20181129-C01124
         		A 442.3 1.52 min. (QC1)
    Figure US20180339993A1-20181129-C01125
    Figure US20180339993A1-20181129-C01126
    Figure US20180339993A1-20181129-C01127
         		A 446.3 1.32 min. (QC1)
    Figure US20180339993A1-20181129-C01128
    Figure US20180339993A1-20181129-C01129
    Figure US20180339993A1-20181129-C01130
         		A 431.3 1.47 min. (QC1)
    Figure US20180339993A1-20181129-C01131
    Figure US20180339993A1-20181129-C01132
    Figure US20180339993A1-20181129-C01133
         		A 441.3 1.54 min. (QC1)
    Figure US20180339993A1-20181129-C01134
    Figure US20180339993A1-20181129-C01135
    Figure US20180339993A1-20181129-C01136
         		A 446.3 1.39 min. (QC1)
    Figure US20180339993A1-20181129-C01137
    Figure US20180339993A1-20181129-C01138
    Figure US20180339993A1-20181129-C01139
         		C 433.8 1.37 min. (QC1)
    Figure US20180339993A1-20181129-C01140
    Figure US20180339993A1-20181129-C01141
    Figure US20180339993A1-20181129-C01142
         		C 433.8 1.37 min. (QC1)
    Figure US20180339993A1-20181129-C01143
    Figure US20180339993A1-20181129-C01144
    Figure US20180339993A1-20181129-C01145
         		C 444.5 1.52 min. (QC1)
    Figure US20180339993A1-20181129-C01146
    Figure US20180339993A1-20181129-C01147
    Figure US20180339993A1-20181129-C01148
         		C 449.5 1.31 min. (QC1)
  • The following examples (9-1 to 13-72) are prepared according to the condition A to F in Table 19 from the synthesized halide derivatives and the known or synthesized boronic acid derivatives in Table 24-28. (The boronic acid derivatives of example 9-22 to 9-27 are prepared in situ from the corresponding bromo derivatives.) The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 24-28.
  • TABLE 24
    observed tR/
    Examples halides Boronic acid derivatives conditions MS method
    Figure US20180339993A1-20181129-C01149
    Figure US20180339993A1-20181129-C01150
    Figure US20180339993A1-20181129-C01151
         		A 377.1 1.35 min. (QC1)
    Figure US20180339993A1-20181129-C01152
    Figure US20180339993A1-20181129-C01153
    Figure US20180339993A1-20181129-C01154
         		A 376.2 1.65 min. (QC1)
    Figure US20180339993A1-20181129-C01155
    Figure US20180339993A1-20181129-C01156
    Figure US20180339993A1-20181129-C01157
         		A 392.1 1.61 min. (QC1)
    Figure US20180339993A1-20181129-C01158
    Figure US20180339993A1-20181129-C01159
    Figure US20180339993A1-20181129-C01160
         		A 380.3 1.63 min. (QC1)
    Figure US20180339993A1-20181129-C01161
    Figure US20180339993A1-20181129-C01162
    Figure US20180339993A1-20181129-C01163
         		A 392.1 1.43 min. (QC1)
    Figure US20180339993A1-20181129-C01164
    Figure US20180339993A1-20181129-C01165
    Figure US20180339993A1-20181129-C01166
         		A 430.2 1.68 min. (QC1)
    Figure US20180339993A1-20181129-C01167
    Figure US20180339993A1-20181129-C01168
    Figure US20180339993A1-20181129-C01169
         		A 377.1 1.32 min. (QC1)
    Figure US20180339993A1-20181129-C01170
    Figure US20180339993A1-20181129-C01171
    Figure US20180339993A1-20181129-C01172
         		A 387.3 1.51 min. (QC1)
    Figure US20180339993A1-20181129-C01173
    Figure US20180339993A1-20181129-C01174
    Figure US20180339993A1-20181129-C01175
         		A 387.1 1.57 min. (QC1)
    Figure US20180339993A1-20181129-C01176
    Figure US20180339993A1-20181129-C01177
    Figure US20180339993A1-20181129-C01178
         		A 437.3 1.51 min. (QC1)
    Figure US20180339993A1-20181129-C01179
    Figure US20180339993A1-20181129-C01180
    Figure US20180339993A1-20181129-C01181
         		A 412.3 2.16 min. (QC2)
    Figure US20180339993A1-20181129-C01182
    Figure US20180339993A1-20181129-C01183
    Figure US20180339993A1-20181129-C01184
         		A 449.3 1.48 min. (QC1)
    Figure US20180339993A1-20181129-C01185
    Figure US20180339993A1-20181129-C01186
    Figure US20180339993A1-20181129-C01187
         		A 449.3 1.55 min. (QC1)
    Figure US20180339993A1-20181129-C01188
    Figure US20180339993A1-20181129-C01189
    Figure US20180339993A1-20181129-C01190
         		A 438.3 1.40 min. (QC1)
    Figure US20180339993A1-20181129-C01191
    Figure US20180339993A1-20181129-C01192
    Figure US20180339993A1-20181129-C01193
         		A 413.3 1.34 min. (QC1)
    Figure US20180339993A1-20181129-C01194
    Figure US20180339993A1-20181129-C01195
    Figure US20180339993A1-20181129-C01196
         		A 449.3 1.48 min. (QC1)
    Figure US20180339993A1-20181129-C01197
    Figure US20180339993A1-20181129-C01198
    Figure US20180339993A1-20181129-C01199
         		A 428.3 1.44 min. (QC1)
    Figure US20180339993A1-20181129-C01200
    Figure US20180339993A1-20181129-C01201
    Figure US20180339993A1-20181129-C01202
         		A 449.3 1.47 min. (QC1)
    Figure US20180339993A1-20181129-C01203
    Figure US20180339993A1-20181129-C01204
    Figure US20180339993A1-20181129-C01205
         		A 453.3 1.37 min. (QC1)
    Figure US20180339993A1-20181129-C01206
    Figure US20180339993A1-20181129-C01207
    Figure US20180339993A1-20181129-C01208
         		A 426.3 2.33 min. (QC2)
    Figure US20180339993A1-20181129-C01209
    Figure US20180339993A1-20181129-C01210
    Figure US20180339993A1-20181129-C01211
         		A 449.3 1.44 min. (QC1)
    Figure US20180339993A1-20181129-C01212
    Figure US20180339993A1-20181129-C01213
    Figure US20180339993A1-20181129-C01214
         		A 438.4 1.37 min. (QC1)
    Figure US20180339993A1-20181129-C01215
    Figure US20180339993A1-20181129-C01216
    Figure US20180339993A1-20181129-C01217
         		A 438.4 1.30 min. (QC1)
    Figure US20180339993A1-20181129-C01218
    Figure US20180339993A1-20181129-C01219
    Figure US20180339993A1-20181129-C01220
         		A 429.2 1.21 min. (QC1)
    Figure US20180339993A1-20181129-C01221
    Figure US20180339993A1-20181129-C01222
    Figure US20180339993A1-20181129-C01223
         		A 429.3 1.26 min. (QC1)
    Figure US20180339993A1-20181129-C01224
    Figure US20180339993A1-20181129-C01225
    Figure US20180339993A1-20181129-C01226
         		A 439.4 1.41 min. (QC1)
    Figure US20180339993A1-20181129-C01227
    Figure US20180339993A1-20181129-C01228
    Figure US20180339993A1-20181129-C01229
         		A 439.3 1.27 min. (QC1)
  • TABLE 25
    observed
    Examples halides Boronic acid derivatives conditions MS tR/method
    Figure US20180339993A1-20181129-C01230
    Figure US20180339993A1-20181129-C01231
    Figure US20180339993A1-20181129-C01232
         		A 413.4 1.44 min. (QC1)
    Figure US20180339993A1-20181129-C01233
    Figure US20180339993A1-20181129-C01234
    Figure US20180339993A1-20181129-C01235
         		A 412.3 1.80 min. (QC1)
  • TABLE 26
    Observed
    Examples halides Boronic acid derivatives Condition MS tR/method
    Figure US20180339993A1-20181129-C01236
    Figure US20180339993A1-20181129-C01237
    Figure US20180339993A1-20181129-C01238
         		B 401.3 1.53 min. (QC1)
    Figure US20180339993A1-20181129-C01239
    Figure US20180339993A1-20181129-C01240
    Figure US20180339993A1-20181129-C01241
         		A 376.3 1.63 min. (QC1)
  • TABLE 27
    observed
    Examples halides Boronic acid derivatives condition MS tR/method
    Figure US20180339993A1-20181129-C01242
    Figure US20180339993A1-20181129-C01243
    Figure US20180339993A1-20181129-C01244
         		C 414.2 1.39 min. (QC1)
    Figure US20180339993A1-20181129-C01245
    Figure US20180339993A1-20181129-C01246
    Figure US20180339993A1-20181129-C01247
         		C 413.2 1.73 min. (QC1)
    Figure US20180339993A1-20181129-C01248
    Figure US20180339993A1-20181129-C01249
    Figure US20180339993A1-20181129-C01250
         		A 429.5 1.45 min. (QC1)
    Figure US20180339993A1-20181129-C01251
    Figure US20180339993A1-20181129-C01252
    Figure US20180339993A1-20181129-C01253
         		A 430.5 1.62 min. (QC1)
    Figure US20180339993A1-20181129-C01254
    Figure US20180339993A1-20181129-C01255
    Figure US20180339993A1-20181129-C01256
         		A 430.5 1.37 min. (QC1)
    Figure US20180339993A1-20181129-C01257
    Figure US20180339993A1-20181129-C01258
    Figure US20180339993A1-20181129-C01259
         		A 450.5 1.65 min. (QC1)
    Figure US20180339993A1-20181129-C01260
    Figure US20180339993A1-20181129-C01261
    Figure US20180339993A1-20181129-C01262
         		C 413.3 1.64 min. (QC1)
  • TABLE 28
    Con- Ob- tR/
    Boronic acid di- served meth-
    Examples halides derivatives tion MS od
    Figure US20180339993A1-20181129-C01263
    Figure US20180339993A1-20181129-C01264
    Figure US20180339993A1-20181129-C01265
         		A 391.5 1.53 min. (QC1)
    Figure US20180339993A1-20181129-C01266
    Figure US20180339993A1-20181129-C01267
    Figure US20180339993A1-20181129-C01268
         		D 364.3 1.44 min. (QC1)
    Figure US20180339993A1-20181129-C01269
    Figure US20180339993A1-20181129-C01270
    Figure US20180339993A1-20181129-C01271
         		A 391.5 1.77 min. (QC1)
    Figure US20180339993A1-20181129-C01272
    Figure US20180339993A1-20181129-C01273
    Figure US20180339993A1-20181129-C01274
         		A 375.5 1.85 min. (QC1)
    Figure US20180339993A1-20181129-C01275
    Figure US20180339993A1-20181129-C01276
    Figure US20180339993A1-20181129-C01277
         		D 375.3 1.85 min. (QC1)
    Figure US20180339993A1-20181129-C01278
    Figure US20180339993A1-20181129-C01279
    Figure US20180339993A1-20181129-C01280
         		A 389.3 1.92 min. (QC1)
    Figure US20180339993A1-20181129-C01281
    Figure US20180339993A1-20181129-C01282
    Figure US20180339993A1-20181129-C01283
         		B 412.4 1.50 min. (QC1)
    Figure US20180339993A1-20181129-C01284
    Figure US20180339993A1-20181129-C01285
    Figure US20180339993A1-20181129-C01286
         		B 430.4 1.59 min. (QC1)
    Figure US20180339993A1-20181129-C01287
    Figure US20180339993A1-20181129-C01288
    Figure US20180339993A1-20181129-C01289
         		B 436.4 1.69 min. (QC1)
    Figure US20180339993A1-20181129-C01290
    Figure US20180339993A1-20181129-C01291
    Figure US20180339993A1-20181129-C01292
         		B 466.4 1.44 min. (QC1)
    Figure US20180339993A1-20181129-C01293
    Figure US20180339993A1-20181129-C01294
    Figure US20180339993A1-20181129-C01295
         		B 436.4 1.71 min. (QC1)
    Figure US20180339993A1-20181129-C01296
    Figure US20180339993A1-20181129-C01297
    Figure US20180339993A1-20181129-C01298
         		B 441.4 1.59 min. (QC1)
    Figure US20180339993A1-20181129-C01299
    Figure US20180339993A1-20181129-C01300
    Figure US20180339993A1-20181129-C01301
         		B 454.4 1.44 min. (QC1)
    Figure US20180339993A1-20181129-C01302
    Figure US20180339993A1-20181129-C01303
    Figure US20180339993A1-20181129-C01304
         		B 411.4 1.83 min. (QC1)
    Figure US20180339993A1-20181129-C01305
    Figure US20180339993A1-20181129-C01306
    Figure US20180339993A1-20181129-C01307
         		B 462.4 1.68 min. (QC1)
    Figure US20180339993A1-20181129-C01308
    Figure US20180339993A1-20181129-C01309
    Figure US20180339993A1-20181129-C01310
         		B 447.4 1.86 min. (QC1)
    Figure US20180339993A1-20181129-C01311
    Figure US20180339993A1-20181129-C01312
    Figure US20180339993A1-20181129-C01313
         		B 429.4 1.83 min. (QC1)
    Figure US20180339993A1-20181129-C01314
    Figure US20180339993A1-20181129-C01315
    Figure US20180339993A1-20181129-C01316
         		D 382.2 1.48 min. (QC1)
    Figure US20180339993A1-20181129-C01317
    Figure US20180339993A1-20181129-C01318
    Figure US20180339993A1-20181129-C01319
         		D 406.2 1.70 min. (QC1)
    Figure US20180339993A1-20181129-C01320
    Figure US20180339993A1-20181129-C01321
    Figure US20180339993A1-20181129-C01322
         		D 381.3 1.82 min. (QC1)
    Figure US20180339993A1-20181129-C01323
    Figure US20180339993A1-20181129-C01324
    Figure US20180339993A1-20181129-C01325
         		A 466.3 1.70 min. (QC1)
    Figure US20180339993A1-20181129-C01326
    Figure US20180339993A1-20181129-C01327
    Figure US20180339993A1-20181129-C01328
         		A 466.3 1.61 min. (QC1)
    Figure US20180339993A1-20181129-C01329
    Figure US20180339993A1-20181129-C01330
    Figure US20180339993A1-20181129-C01331
         		B 446.2 1.58 min. (QC1)
    Figure US20180339993A1-20181129-C01332
    Figure US20180339993A1-20181129-C01333
    Figure US20180339993A1-20181129-C01334
         		B 432.2 1.53 min. (QC1)
    Figure US20180339993A1-20181129-C01335
    Figure US20180339993A1-20181129-C01336
    Figure US20180339993A1-20181129-C01337
         		B 456.2 1.70 min. (QC1)
    Figure US20180339993A1-20181129-C01338
    Figure US20180339993A1-20181129-C01339
    Figure US20180339993A1-20181129-C01340
         		B 450.1 1.63 min. (QC1)
    Figure US20180339993A1-20181129-C01341
    Figure US20180339993A1-20181129-C01342
    Figure US20180339993A1-20181129-C01343
         		B 461.2 1.60 min. (QC1)
    Figure US20180339993A1-20181129-C01344
    Figure US20180339993A1-20181129-C01345
    Figure US20180339993A1-20181129-C01346
         		B 474.2 1.46 min. (QC1)
    Figure US20180339993A1-20181129-C01347
    Figure US20180339993A1-20181129-C01348
    Figure US20180339993A1-20181129-C01349
         		B 482.2 1.68 min. (QC1)
    Figure US20180339993A1-20181129-C01350
    Figure US20180339993A1-20181129-C01351
    Figure US20180339993A1-20181129-C01352
         		B 448.4 1.56 min. (QC1)
    Figure US20180339993A1-20181129-C01353
    Figure US20180339993A1-20181129-C01354
    Figure US20180339993A1-20181129-C01355
         		B 458.5 1.68 min. (QC1)
    Figure US20180339993A1-20181129-C01356
    Figure US20180339993A1-20181129-C01357
    Figure US20180339993A1-20181129-C01358
         		B 463.1 1.58 min. (QC1)
    Figure US20180339993A1-20181129-C01359
    Figure US20180339993A1-20181129-C01360
    Figure US20180339993A1-20181129-C01361
         		B 458   1.69 min. (QC1)
    Figure US20180339993A1-20181129-C01362
    Figure US20180339993A1-20181129-C01363
    Figure US20180339993A1-20181129-C01364
         		A 427.2 1.54 min. (QC1)
    Figure US20180339993A1-20181129-C01365
    Figure US20180339993A1-20181129-C01366
    Figure US20180339993A1-20181129-C01367
         		A 412.3 1.50 min. (QC1)
    Figure US20180339993A1-20181129-C01368
    Figure US20180339993A1-20181129-C01369
    Figure US20180339993A1-20181129-C01370
         		A 448.4 1.62 min. (QC1)
    Figure US20180339993A1-20181129-C01371
    Figure US20180339993A1-20181129-C01372
    Figure US20180339993A1-20181129-C01373
         		A 448.3 1.62 min. (QC1)
    Figure US20180339993A1-20181129-C01374
    Figure US20180339993A1-20181129-C01375
    Figure US20180339993A1-20181129-C01376
         		A 412.3 1.48 min. (QC1)
    Figure US20180339993A1-20181129-C01377
    Figure US20180339993A1-20181129-C01378
    Figure US20180339993A1-20181129-C01379
         		A 428.3 1.44 min. (QC1)
    Figure US20180339993A1-20181129-C01380
    Figure US20180339993A1-20181129-C01381
    Figure US20180339993A1-20181129-C01382
         		A 437.3 1.51 min. (QC1)
    Figure US20180339993A1-20181129-C01383
    Figure US20180339993A1-20181129-C01384
    Figure US20180339993A1-20181129-C01385
         		A 448.3 1.60 min. (QC1)
    Figure US20180339993A1-20181129-C01386
    Figure US20180339993A1-20181129-C01387
    Figure US20180339993A1-20181129-C01388
         		A 436.3 1.63 min. (QC1)
    Figure US20180339993A1-20181129-C01389
    Figure US20180339993A1-20181129-C01390
    Figure US20180339993A1-20181129-C01391
         		A 448.3 1.61 min. (QC1)
    Figure US20180339993A1-20181129-C01392
    Figure US20180339993A1-20181129-C01393
    Figure US20180339993A1-20181129-C01394
         		A 452.3 1.45 min. (QC1)
    Figure US20180339993A1-20181129-C01395
    Figure US20180339993A1-20181129-C01396
    Figure US20180339993A1-20181129-C01397
         		A 428.3 1.66 min. (QC1)
    Figure US20180339993A1-20181129-C01398
    Figure US20180339993A1-20181129-C01399
    Figure US20180339993A1-20181129-C01400
         		A 448.3 1.71 min. (QC1)
    Figure US20180339993A1-20181129-C01401
    Figure US20180339993A1-20181129-C01402
    Figure US20180339993A1-20181129-C01403
         		A 448.3 1.71 min. (QC1)
    Figure US20180339993A1-20181129-C01404
    Figure US20180339993A1-20181129-C01405
    Figure US20180339993A1-20181129-C01406
         		A 398.4 1.44 min. (QC1)
    Figure US20180339993A1-20181129-C01407
    Figure US20180339993A1-20181129-C01408
    Figure US20180339993A1-20181129-C01409
         		F 398.4 1.54 min. (QC1)
    Figure US20180339993A1-20181129-C01410
    Figure US20180339993A1-20181129-C01411
    Figure US20180339993A1-20181129-C01412
         		A 456.3 1.46 min. (QC1)
    Figure US20180339993A1-20181129-C01413
    Figure US20180339993A1-20181129-C01414
    Figure US20180339993A1-20181129-C01415
         		A 363.2 1.62 min. (QC1)
    Figure US20180339993A1-20181129-C01416
    Figure US20180339993A1-20181129-C01417
    Figure US20180339993A1-20181129-C01418
         		A 378.3 1.66 min. (QC1)
    Figure US20180339993A1-20181129-C01419
    Figure US20180339993A1-20181129-C01420
    Figure US20180339993A1-20181129-C01421
         		A 399.3 1.55 min. (QC1)
    Figure US20180339993A1-20181129-C01422
    Figure US20180339993A1-20181129-C01423
    Figure US20180339993A1-20181129-C01424
         		A 423.4 1.70 min. (QC1)
    Figure US20180339993A1-20181129-C01425
    Figure US20180339993A1-20181129-C01426
    Figure US20180339993A1-20181129-C01427
         		A 414.2 1.59 min. (QC1)
    Figure US20180339993A1-20181129-C01428
    Figure US20180339993A1-20181129-C01429
    Figure US20180339993A1-20181129-C01430
         		A 399.3 1.54 min. (QC1)
    Figure US20180339993A1-20181129-C01431
    Figure US20180339993A1-20181129-C01432
    Figure US20180339993A1-20181129-C01433
         		A 435.4 1.76 min. (QC1)
    Figure US20180339993A1-20181129-C01434
    Figure US20180339993A1-20181129-C01435
    Figure US20180339993A1-20181129-C01436
         		A 430.4 1.64 min. (QC1)
    Figure US20180339993A1-20181129-C01437
    Figure US20180339993A1-20181129-C01438
    Figure US20180339993A1-20181129-C01439
         		A 415.4 1.60 min. (QC1)
    Figure US20180339993A1-20181129-C01440
    Figure US20180339993A1-20181129-C01441
    Figure US20180339993A1-20181129-C01442
         		A 415.3 1.61 min. (QC1)
    Figure US20180339993A1-20181129-C01443
    Figure US20180339993A1-20181129-C01444
    Figure US20180339993A1-20181129-C01445
         		A 444.2 1.67 min. (QC1)
    Figure US20180339993A1-20181129-C01446
    Figure US20180339993A1-20181129-C01447
    Figure US20180339993A1-20181129-C01448
         		A 429.1 1.63 min. (QC1)
    Figure US20180339993A1-20181129-C01449
    Figure US20180339993A1-20181129-C01450
    Figure US20180339993A1-20181129-C01451
         		A 429.1 1.63 min. (QC1)
    Figure US20180339993A1-20181129-C01452
    Figure US20180339993A1-20181129-C01453
    Figure US20180339993A1-20181129-C01454
         		A 458.1 1.77 min. (QC1)
    Figure US20180339993A1-20181129-C01455
    Figure US20180339993A1-20181129-C01456
    Figure US20180339993A1-20181129-C01457
         		A 443.2 1.74 min. (QC1)
    Figure US20180339993A1-20181129-C01458
    Figure US20180339993A1-20181129-C01459
    Figure US20180339993A1-20181129-C01460
         		E 459.3 1.63 min. (QC1)
    Figure US20180339993A1-20181129-C01461
    Figure US20180339993A1-20181129-C01462
    Figure US20180339993A1-20181129-C01463
         		C 456.7 1.43 min. (QC1)
    Figure US20180339993A1-20181129-C01464
    Figure US20180339993A1-20181129-C01465
    Figure US20180339993A1-20181129-C01466
         		B 458.1 1.73 min. (QC1)
    Figure US20180339993A1-20181129-C01467
    Figure US20180339993A1-20181129-C01468
    Figure US20180339993A1-20181129-C01469
         		A 440.2 1.50 min. (QC1)
    Figure US20180339993A1-20181129-C01470
    Figure US20180339993A1-20181129-C01471
    Figure US20180339993A1-20181129-C01472
         		B 430.7 1.74 min. (QC1)
    Figure US20180339993A1-20181129-C01473
    Figure US20180339993A1-20181129-C01474
    Figure US20180339993A1-20181129-C01475
         		A 430.2 1.70 min. (QC1)
    Figure US20180339993A1-20181129-C01476
    Figure US20180339993A1-20181129-C01477
    Figure US20180339993A1-20181129-C01478
         		A 415.1 1.66 min. (QC1)
  • The following examples (14-1 to 18-13) are prepared according to the condition A to F in Table 19 from the synthesized halide derivatives and the known or synthesized boronic acid derivatives in Table 29-33 (The boronic acid derivative of example-14-6 is prepared in situ from the corresponding bromo derivatives). The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 29-33.
  • TABLE 29
    con- ob-
    Boronic acid di- served tR/
    Examples halides derivatives tions MS method
    Figure US20180339993A1-20181129-C01479
    Figure US20180339993A1-20181129-C01480
    Figure US20180339993A1-20181129-C01481
         		D 382.3 1.50 min. (QC1)
    Figure US20180339993A1-20181129-C01482
    Figure US20180339993A1-20181129-C01483
    Figure US20180339993A1-20181129-C01484
         		B 411.3 1.58 min. (QC1)
    Figure US20180339993A1-20181129-C01485
    Figure US20180339993A1-20181129-C01486
    Figure US20180339993A1-20181129-C01487
         		B 396.2 1.54 min. (QC1)
    Figure US20180339993A1-20181129-C01488
    Figure US20180339993A1-20181129-C01489
    Figure US20180339993A1-20181129-C01490
         		B 447.2 1.58 min. (QC1)
    Figure US20180339993A1-20181129-C01491
    Figure US20180339993A1-20181129-C01492
    Figure US20180339993A1-20181129-C01493
         		A 432.3 1.55 min. (QC1)
    Figure US20180339993A1-20181129-C01494
    Figure US20180339993A1-20181129-C01495
    Figure US20180339993A1-20181129-C01496
         		A 448.3 1.33 min. (QC1)
    Figure US20180339993A1-20181129-C01497
    Figure US20180339993A1-20181129-C01498
    Figure US20180339993A1-20181129-C01499
         		A 418.2 1.50 min. (QC1)
    Figure US20180339993A1-20181129-C01500
    Figure US20180339993A1-20181129-C01501
    Figure US20180339993A1-20181129-C01502
         		A 442.3 1.70 min. (QC1)
    Figure US20180339993A1-20181129-C01503
    Figure US20180339993A1-20181129-C01504
    Figure US20180339993A1-20181129-C01505
         		A 432.3 1.54 min. (QC1)
    Figure US20180339993A1-20181129-C01506
    Figure US20180339993A1-20181129-C01507
    Figure US20180339993A1-20181129-C01508
         		B 442.3 1.70 min. (QC1)
    Figure US20180339993A1-20181129-C01509
    Figure US20180339993A1-20181129-C01510
    Figure US20180339993A1-20181129-C01511
         		B 431.2 1.89 min. (QC1)
    Figure US20180339993A1-20181129-C01512
    Figure US20180339993A1-20181129-C01513
    Figure US20180339993A1-20181129-C01514
         		A 447.2 1.79 min. (QC1)
    Figure US20180339993A1-20181129-C01515
    Figure US20180339993A1-20181129-C01516
    Figure US20180339993A1-20181129-C01517
         		B 443.3 1.55 min. (QC1)
    Figure US20180339993A1-20181129-C01518
    Figure US20180339993A1-20181129-C01519
    Figure US20180339993A1-20181129-C01520
         		A 451.3 1.87 min. (QC1)
    Figure US20180339993A1-20181129-C01521
    Figure US20180339993A1-20181129-C01522
    Figure US20180339993A1-20181129-C01523
         		A 486.3 1.66 min. (QC1)
    Figure US20180339993A1-20181129-C01524
    Figure US20180339993A1-20181129-C01525
    Figure US20180339993A1-20181129-C01526
         		A 448.3 1.47 min. (QC1)
    Figure US20180339993A1-20181129-C01527
    Figure US20180339993A1-20181129-C01528
    Figure US20180339993A1-20181129-C01529
         		B 436.4 1.59 min. (QC1)
    Figure US20180339993A1-20181129-C01530
    Figure US20180339993A1-20181129-C01531
    Figure US20180339993A1-20181129-C01532
         		B 460.4 1.42 min. (QC1)
    Figure US20180339993A1-20181129-C01533
    Figure US20180339993A1-20181129-C01534
    Figure US20180339993A1-20181129-C01535
         		A 450.1 1.41 min. (QC1)
    Figure US20180339993A1-20181129-C01536
    Figure US20180339993A1-20181129-C01537
    Figure US20180339993A1-20181129-C01538
         		A 470.1 1.73 min. (QC1)
    Figure US20180339993A1-20181129-C01539
    Figure US20180339993A1-20181129-C01540
    Figure US20180339993A1-20181129-C01541
         		B 449.0 1.55 min. (QC1)
  • TABLE 30
    con- ob- tR/
    Boronic acid di- served meth-
    Examples halides derivatives tions MS od
    Figure US20180339993A1-20181129-C01542
    Figure US20180339993A1-20181129-C01543
    Figure US20180339993A1-20181129-C01544
         		B 456.2 1.74 min. (QC1)
    Figure US20180339993A1-20181129-C01545
    Figure US20180339993A1-20181129-C01546
    Figure US20180339993A1-20181129-C01547
         		A 432.3 1.54 min. (QC1)
    Figure US20180339993A1-20181129-C01548
    Figure US20180339993A1-20181129-C01549
    Figure US20180339993A1-20181129-C01550
         		B 456.3 1.75 min. (QC1)
    Figure US20180339993A1-20181129-C01551
    Figure US20180339993A1-20181129-C01552
    Figure US20180339993A1-20181129-C01553
         		B 446.3 1.58 min. (QC1)
    Figure US20180339993A1-20181129-C01554
    Figure US20180339993A1-20181129-C01555
    Figure US20180339993A1-20181129-C01556
         		B 433.3 1.44 min. (QC1)
    Figure US20180339993A1-20181129-C01557
    Figure US20180339993A1-20181129-C01558
    Figure US20180339993A1-20181129-C01559
         		B 450.4 1.62 min. (QC1)
    Figure US20180339993A1-20181129-C01560
    Figure US20180339993A1-20181129-C01561
    Figure US20180339993A1-20181129-C01562
         		B 474.5 1.48 min. (QC1)
    Figure US20180339993A1-20181129-C01563
    Figure US20180339993A1-20181129-C01564
    Figure US20180339993A1-20181129-C01565
         		A 433.1 1.88 min. (QC1)
    Figure US20180339993A1-20181129-C01566
    Figure US20180339993A1-20181129-C01567
    Figure US20180339993A1-20181129-C01568
         		B 447.2 1.94 min. (QC1)
    Figure US20180339993A1-20181129-C01569
    Figure US20180339993A1-20181129-C01570
    Figure US20180339993A1-20181129-C01571
         		B 477.2 1.32 min. (QC1)
    Figure US20180339993A1-20181129-C01572
    Figure US20180339993A1-20181129-C01573
    Figure US20180339993A1-20181129-C01574
         		A 447.1 1.96 min. (QC1)
    Figure US20180339993A1-20181129-C01575
    Figure US20180339993A1-20181129-C01576
    Figure US20180339993A1-20181129-C01577
         		B 463.1 1.60 min. (QC1)
  • TABLE 31
    con- ob- tR/
    Boronic acid di- served meth-
    Examples halides derivatives tions MS od
    Figure US20180339993A1-20181129-C01578
    Figure US20180339993A1-20181129-C01579
    Figure US20180339993A1-20181129-C01580
         		A 425.3 1.63 min. (QC1)
    Figure US20180339993A1-20181129-C01581
    Figure US20180339993A1-20181129-C01582
    Figure US20180339993A1-20181129-C01583
         		A 415.4 1.47 min. (QC1)
    Figure US20180339993A1-20181129-C01584
    Figure US20180339993A1-20181129-C01585
    Figure US20180339993A1-20181129-C01586
         		A 401.4 1.41 min. (QC1)
    Figure US20180339993A1-20181129-C01587
    Figure US20180339993A1-20181129-C01588
    Figure US20180339993A1-20181129-C01589
         		B 439.4 1.69 min. (QC1)
    Figure US20180339993A1-20181129-C01590
    Figure US20180339993A1-20181129-C01591
    Figure US20180339993A1-20181129-C01592
         		B 432.3 1.81 min. (QC1)
    Figure US20180339993A1-20181129-C01593
    Figure US20180339993A1-20181129-C01594
    Figure US20180339993A1-20181129-C01595
         		B 457.3 1.42 min. (QC1)
    Figure US20180339993A1-20181129-C01596
    Figure US20180339993A1-20181129-C01597
    Figure US20180339993A1-20181129-C01598
         		B 439.3 1.69 min. (QC1)
    Figure US20180339993A1-20181129-C01599
    Figure US20180339993A1-20181129-C01600
    Figure US20180339993A1-20181129-C01601
         		B 444.3 1.60 min. (QC1)
    Figure US20180339993A1-20181129-C01602
    Figure US20180339993A1-20181129-C01603
    Figure US20180339993A1-20181129-C01604
         		B 450.3 1.84 min. (QC1)
    Figure US20180339993A1-20181129-C01605
    Figure US20180339993A1-20181129-C01606
    Figure US20180339993A1-20181129-C01607
         		B 429.4 1.53 min. (QC1)
    Figure US20180339993A1-20181129-C01608
    Figure US20180339993A1-20181129-C01609
    Figure US20180339993A1-20181129-C01610
         		B 415.4 1.48 min. (QC1)
    Figure US20180339993A1-20181129-C01611
    Figure US20180339993A1-20181129-C01612
    Figure US20180339993A1-20181129-C01613
         		B 448.3 1.90 min. (QC1)
    Figure US20180339993A1-20181129-C01614
    Figure US20180339993A1-20181129-C01615
    Figure US20180339993A1-20181129-C01616
         		B 432.3 1.80 min. (QC1)
    Figure US20180339993A1-20181129-C01617
    Figure US20180339993A1-20181129-C01618
    Figure US20180339993A1-20181129-C01619
         		B 444.4 1.80 min. (QC1)
    Figure US20180339993A1-20181129-C01620
    Figure US20180339993A1-20181129-C01621
    Figure US20180339993A1-20181129-C01622
         		B 465.3 1.64 min. (QC1)
    Figure US20180339993A1-20181129-C01623
    Figure US20180339993A1-20181129-C01624
    Figure US20180339993A1-20181129-C01625
         		B 416.3 1.40 min. (QC1)
    Figure US20180339993A1-20181129-C01626
    Figure US20180339993A1-20181129-C01627
    Figure US20180339993A1-20181129-C01628
         		B 469.4 1.43 min. (QC1)
    Figure US20180339993A1-20181129-C01629
    Figure US20180339993A1-20181129-C01630
    Figure US20180339993A1-20181129-C01631
         		B 428.4 1.89 min. (QC1)
    Figure US20180339993A1-20181129-C01632
    Figure US20180339993A1-20181129-C01633
    Figure US20180339993A1-20181129-C01634
         		B 428.3 1.89 min. (QC1)
    Figure US20180339993A1-20181129-C01635
    Figure US20180339993A1-20181129-C01636
    Figure US20180339993A1-20181129-C01637
         		B 456.4 1.69 min. (QC1)
    Figure US20180339993A1-20181129-C01638
    Figure US20180339993A1-20181129-C01639
    Figure US20180339993A1-20181129-C01640
         		B 433.4 1.57 min. (QC1)
    Figure US20180339993A1-20181129-C01641
    Figure US20180339993A1-20181129-C01642
    Figure US20180339993A1-20181129-C01643
         		B 439.5 1.60 min. (QC1)
    Figure US20180339993A1-20181129-C01644
    Figure US20180339993A1-20181129-C01645
    Figure US20180339993A1-20181129-C01646
         		B 433.6 1.48 min. (QC1)
    Figure US20180339993A1-20181129-C01647
    Figure US20180339993A1-20181129-C01648
    Figure US20180339993A1-20181129-C01649
         		B 432.7 1.70 min. (QC1)
    Figure US20180339993A1-20181129-C01650
    Figure US20180339993A1-20181129-C01651
    Figure US20180339993A1-20181129-C01652
         		B 439.6 1.58 min. (QC1)
    Figure US20180339993A1-20181129-C01653
    Figure US20180339993A1-20181129-C01654
    Figure US20180339993A1-20181129-C01655
         		B 415.6 1.39 min. (QC1)
    Figure US20180339993A1-20181129-C01656
    Figure US20180339993A1-20181129-C01657
    Figure US20180339993A1-20181129-C01658
         		B 465.3 1.55 min. (QC1)
    Figure US20180339993A1-20181129-C01659
    Figure US20180339993A1-20181129-C01660
    Figure US20180339993A1-20181129-C01661
         		B 429.3 1.41 min. (QC1)
    Figure US20180339993A1-20181129-C01662
    Figure US20180339993A1-20181129-C01663
    Figure US20180339993A1-20181129-C01664
         		B 427.1 1.63 min. (QC1)
    Figure US20180339993A1-20181129-C01665
    Figure US20180339993A1-20181129-C01666
    Figure US20180339993A1-20181129-C01667
         		A 432.2 1.50 min. (QC1)
    Figure US20180339993A1-20181129-C01668
    Figure US20180339993A1-20181129-C01669
    Figure US20180339993A1-20181129-C01670
         		B 421.1 1.50 min. (QC1)
    Figure US20180339993A1-20181129-C01671
    Figure US20180339993A1-20181129-C01672
    Figure US20180339993A1-20181129-C01673
         		A 416.2 1.80 min. (QC1)
    Figure US20180339993A1-20181129-C01674
    Figure US20180339993A1-20181129-C01675
    Figure US20180339993A1-20181129-C01676
         		B 460.3 1.28 min. (QC1)
    Figure US20180339993A1-20181129-C01677
    Figure US20180339993A1-20181129-C01678
    Figure US20180339993A1-20181129-C01679
         		B 446.4 1.48 min. (QC1)
    Figure US20180339993A1-20181129-C01680
    Figure US20180339993A1-20181129-C01681
    Figure US20180339993A1-20181129-C01682
         		B 456.0 1.54 min. (QC1)
    Figure US20180339993A1-20181129-C01683
    Figure US20180339993A1-20181129-C01684
    Figure US20180339993A1-20181129-C01685
         		B 446.1 1.53 min. (QC1)
  • TABLE 32
    con- ob-
    Boronic acid di- served tR/
    Examples halides derivatives tions MS method
    Figure US20180339993A1-20181129-C01686
    Figure US20180339993A1-20181129-C01687
    Figure US20180339993A1-20181129-C01688
         		C 419.3 1.64 min. (QC1)
    Figure US20180339993A1-20181129-C01689
    Figure US20180339993A1-20181129-C01690
    Figure US20180339993A1-20181129-C01691
         		A 452.4 1.48 min. (QC1)
    Figure US20180339993A1-20181129-C01692
    Figure US20180339993A1-20181129-C01693
    Figure US20180339993A1-20181129-C01694
         		C 426.4 1.53 min. (QC1)
    Figure US20180339993A1-20181129-C01695
    Figure US20180339993A1-20181129-C01696
    Figure US20180339993A1-20181129-C01697
         		C 441.4 1.84 min. (QC1)
    Figure US20180339993A1-20181129-C01698
    Figure US20180339993A1-20181129-C01699
    Figure US20180339993A1-20181129-C01700
         		C 442.4 1.53 min. (QC1)
    Figure US20180339993A1-20181129-C01701
    Figure US20180339993A1-20181129-C01702
    Figure US20180339993A1-20181129-C01703
         		C 433.4 1.67 min. (QC1)
    Figure US20180339993A1-20181129-C01704
    Figure US20180339993A1-20181129-C01705
    Figure US20180339993A1-20181129-C01706
         		C 415.4 1.65 min. (QC1)
    Figure US20180339993A1-20181129-C01707
    Figure US20180339993A1-20181129-C01708
    Figure US20180339993A1-20181129-C01709
         		C 440.4 1.56 min. (QC1)
    Figure US20180339993A1-20181129-C01710
    Figure US20180339993A1-20181129-C01711
    Figure US20180339993A1-20181129-C01712
         		C 466.4 1.50 min. (QC1)
    Figure US20180339993A1-20181129-C01713
    Figure US20180339993A1-20181129-C01714
    Figure US20180339993A1-20181129-C01715
         		C 445.4 1.44 min. (QC1)
    Figure US20180339993A1-20181129-C01716
    Figure US20180339993A1-20181129-C01717
    Figure US20180339993A1-20181129-C01718
         		C 451.4 1.70 min. (QC1)
    Figure US20180339993A1-20181129-C01719
    Figure US20180339993A1-20181129-C01720
    Figure US20180339993A1-20181129-C01721
         		C 418.1 1.35 min. (QC1)
    Figure US20180339993A1-20181129-C01722
    Figure US20180339993A1-20181129-C01723
    Figure US20180339993A1-20181129-C01724
         		C 432.2 1.38 min. (QC1)
    Figure US20180339993A1-20181129-C01725
    Figure US20180339993A1-20181129-C01726
    Figure US20180339993A1-20181129-C01727
         		C 417.1 1.71 min. (QC1)
    Figure US20180339993A1-20181129-C01728
    Figure US20180339993A1-20181129-C01729
    Figure US20180339993A1-20181129-C01730
         		C 404.1 1.32 min. (QC1)
  • TABLE 33
    con- ob- tR/
    Boronic acid di- served meth-
    Examples halides derivatives tions MS od
    Figure US20180339993A1-20181129-C01731
    Figure US20180339993A1-20181129-C01732
    Figure US20180339993A1-20181129-C01733
         		B 419.3 1.49 min. (QC1)
    Figure US20180339993A1-20181129-C01734
    Figure US20180339993A1-20181129-C01735
    Figure US20180339993A1-20181129-C01736
         		B 433.3 1.52 min. (QC1)
    Figure US20180339993A1-20181129-C01737
    Figure US20180339993A1-20181129-C01738
    Figure US20180339993A1-20181129-C01739
         		B 443.2 1.68 min. (QC1)
    Figure US20180339993A1-20181129-C01740
    Figure US20180339993A1-20181129-C01741
    Figure US20180339993A1-20181129-C01742
         		B 448.3 1.56 min. (QC1)
    Figure US20180339993A1-20181129-C01743
    Figure US20180339993A1-20181129-C01744
    Figure US20180339993A1-20181129-C01745
         		B 436.3 1.81 min. (QC1)
    Figure US20180339993A1-20181129-C01746
    Figure US20180339993A1-20181129-C01747
    Figure US20180339993A1-20181129-C01748
         		B 443.2 1.66 min. (QC1)
    Figure US20180339993A1-20181129-C01749
    Figure US20180339993A1-20181129-C01750
    Figure US20180339993A1-20181129-C01751
         		B 461.3 1.41 min. (QC1)
    Figure US20180339993A1-20181129-C01752
    Figure US20180339993A1-20181129-C01753
    Figure US20180339993A1-20181129-C01754
         		B 433.3 1.51 min. (QC1)
    Figure US20180339993A1-20181129-C01755
    Figure US20180339993A1-20181129-C01756
    Figure US20180339993A1-20181129-C01757
         		B 437.3 1.57 min. (QC1)
    Figure US20180339993A1-20181129-C01758
    Figure US20180339993A1-20181129-C01759
    Figure US20180339993A1-20181129-C01760
         		B 469.2 1.64 min. (QC1)
    Figure US20180339993A1-20181129-C01761
    Figure US20180339993A1-20181129-C01762
    Figure US20180339993A1-20181129-C01763
         		B 454.2 1.84 min. (QC1)
    Figure US20180339993A1-20181129-C01764
    Figure US20180339993A1-20181129-C01765
    Figure US20180339993A1-20181129-C01766
         		B 473.2 1.41 min. (QC1)
    Figure US20180339993A1-20181129-C01767
    Figure US20180339993A1-20181129-C01768
    Figure US20180339993A1-20181129-C01769
         		B 446.1 1.52 min. (QC1)
    • Example 19-1 3-(2-(6-(methyl(m-toyl)amino)pyridin-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C01770
    • Condition-A
  • To a solution of INT-8-3-A (30 mg, 0.093 mmol) in DME (1 mL) is added N-Methyl-m-toluidine (12 mg, 0.103 mmol), potassium tert-butoxide (16 mg, 0.140 mmol) and Pd-PEPPSI(trademark)-IPr (1.3 mg, 1.86 mmol). The mixture is irradiated in a microwave reactor (Biotage Initiator) for 30 min. at 140° C. (or heated at 100-150° C. for 3-15 h in oil bath). The mixture is quenched with water and filtered through a pad of celite. The filter cake is washed with EtOAc and the filtrate and washings are washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue is purified by column chromatography on silica gel with 10-100% EtOAc in hexane to give the titled compound (13 mg, 34% yield). The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 405.4
  • tR/method: 1.76 min./(QC1)
  • Other than the above condition A, the following conditions (B-I) are also summarized in Table 34.
  • TABLE 34
    Times/
    Conditions Catalyst Ligand Base Solvent Temperature
    A Pd-PEPPSI KO t-Bu DME 30 min/140° C.
    (trademark)-
    IPr
    B Pd(OAc)2 racemic-BINAP Cs2CO3 1,4-dioxane 20 min/120° C.
    C Pd2(dba)3 DavePhos K3PO4 1,4-dioxane 30 min/140° C.
    D Pd2(dba)3 Xantphos K3PO4 1,4-dioxane 20 min/140° C.
    E Pd2(dba)3 DavePhos NaO t-Bu 1,4-dioxane 30 min/140° C.
    F Pd(OAC)2 XPhos NaO t-Bu 1,4- 30 min/120° C.
    dioxane-
    tert-BuOH
    G Cs2CO3 DMSO 60 min/rt
    H K2CO3 DMF 24 h/100-120° C.
    I Cs2CO3 NMP 50 min/160° C.
  • The following examples (19-2 to 19-40) are prepared according to the condition A to I in Table 34 from the synthesized halide derivatives and the known or synthesized amine derivatives in Table 35. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 35.
  • TABLE 35
    con- ob- tR/
    di- served meth-
    Examples halides Amines tions MS od
    Figure US20180339993A1-20181129-C01771
    Figure US20180339993A1-20181129-C01772
    Figure US20180339993A1-20181129-C01773
         		A 392.3 1.79 min. (QC2)
    Figure US20180339993A1-20181129-C01774
    Figure US20180339993A1-20181129-C01775
    Figure US20180339993A1-20181129-C01776
         		A 405.4 1.76 min. (QC1)
    Figure US20180339993A1-20181129-C01777
    Figure US20180339993A1-20181129-C01778
    Figure US20180339993A1-20181129-C01779
         		A 392.3 1.71 min. (QC2)
    Figure US20180339993A1-20181129-C01780
    Figure US20180339993A1-20181129-C01781
    Figure US20180339993A1-20181129-C01782
         		B 391.3 1.66 min. (QC1)
    Figure US20180339993A1-20181129-C01783
    Figure US20180339993A1-20181129-C01784
    Figure US20180339993A1-20181129-C01785
         		A 428.3 1.45 min. (QC1)
    Figure US20180339993A1-20181129-C01786
    Figure US20180339993A1-20181129-C01787
    Figure US20180339993A1-20181129-C01788
         		A 455.3 1.68 min. (QC1)
    Figure US20180339993A1-20181129-C01789
    Figure US20180339993A1-20181129-C01790
    Figure US20180339993A1-20181129-C01791
         		C 438.4 1.44 min. (QC1)
    Figure US20180339993A1-20181129-C01792
    Figure US20180339993A1-20181129-C01793
    Figure US20180339993A1-20181129-C01794
         		A 427.3 1.67 min. (QC1)
    Figure US20180339993A1-20181129-C01795
    Figure US20180339993A1-20181129-C01796
    Figure US20180339993A1-20181129-C01797
         		C 438.4 1.75 min. (QC1)
    Figure US20180339993A1-20181129-C01798
    Figure US20180339993A1-20181129-C01799
    Figure US20180339993A1-20181129-C01800
         		A 453/3 2.38 min. (QC2)
    Figure US20180339993A1-20181129-C01801
    Figure US20180339993A1-20181129-C01802
    Figure US20180339993A1-20181129-C01803
         		C 451.4 1.79 min. (QC1)
    Figure US20180339993A1-20181129-C01804
    Figure US20180339993A1-20181129-C01805
    Figure US20180339993A1-20181129-C01806
         		D 469.4 1.51 min. (QC1)
    Figure US20180339993A1-20181129-C01807
    Figure US20180339993A1-20181129-C01808
    Figure US20180339993A1-20181129-C01809
         		A 455.2 1.67 min. (QC1)
    Figure US20180339993A1-20181129-C01810
    Figure US20180339993A1-20181129-C01811
    Figure US20180339993A1-20181129-C01812
         		A 495.2 2.43 min. (QC2)
    Figure US20180339993A1-20181129-C01813
    Figure US20180339993A1-20181129-C01814
    Figure US20180339993A1-20181129-C01815
         		F 427.3 1.59 min. (QC1)
    Figure US20180339993A1-20181129-C01816
    Figure US20180339993A1-20181129-C01817
    Figure US20180339993A1-20181129-C01818
         		E 437.3 1.71 min. (QC1)
    Figure US20180339993A1-20181129-C01819
    Figure US20180339993A1-20181129-C01820
    Figure US20180339993A1-20181129-C01821
         		E 436.3 1.84 min. (QC1)
    Figure US20180339993A1-20181129-C01822
    Figure US20180339993A1-20181129-C01823
    Figure US20180339993A1-20181129-C01824
         		E 450.4 1.88 min. (QC1)
    Figure US20180339993A1-20181129-C01825
    Figure US20180339993A1-20181129-C01826
    Figure US20180339993A1-20181129-C01827
         		A 454.4 1.75 min. (QC1)
    Figure US20180339993A1-20181129-C01828
    Figure US20180339993A1-20181129-C01829
    Figure US20180339993A1-20181129-C01830
         		D 468.4 1.60 min. (QC1)
    Figure US20180339993A1-20181129-C01831
    Figure US20180339993A1-20181129-C01832
    Figure US20180339993A1-20181129-C01833
         		D 453.5 1.47 min. (QC1)
    Figure US20180339993A1-20181129-C01834
    Figure US20180339993A1-20181129-C01835
    Figure US20180339993A1-20181129-C01836
         		D 467.5 1.58 min. (QC1)
    Figure US20180339993A1-20181129-C01837
    Figure US20180339993A1-20181129-C01838
    Figure US20180339993A1-20181129-C01839
         		G 439.4 1.52 min. (QC1)
    Figure US20180339993A1-20181129-C01840
    Figure US20180339993A1-20181129-C01841
    Figure US20180339993A1-20181129-C01842
         		D 470.4 1.58 min. (QC1)
    Figure US20180339993A1-20181129-C01843
    Figure US20180339993A1-20181129-C01844
    Figure US20180339993A1-20181129-C01845
         		D 454.4 1.58 min. (QC1)
    Figure US20180339993A1-20181129-C01846
    Figure US20180339993A1-20181129-C01847
    Figure US20180339993A1-20181129-C01848
         		D 468.4 1.60 min. (QC1)
    Figure US20180339993A1-20181129-C01849
    Figure US20180339993A1-20181129-C01850
    Figure US20180339993A1-20181129-C01851
         		D 497.4 1.73 min. (QC1)
    Figure US20180339993A1-20181129-C01852
    Figure US20180339993A1-20181129-C01853
    Figure US20180339993A1-20181129-C01854
         		D 482.1 1.65 min. (QC1)
    Figure US20180339993A1-20181129-C01855
    Figure US20180339993A1-20181129-C01856
    Figure US20180339993A1-20181129-C01857
         		D 456.4 1.62 min. (QC1)
    Figure US20180339993A1-20181129-C01858
    Figure US20180339993A1-20181129-C01859
    Figure US20180339993A1-20181129-C01860
         		D 456.2 2.09 min. (QC2)
    Figure US20180339993A1-20181129-C01861
    Figure US20180339993A1-20181129-C01862
    Figure US20180339993A1-20181129-C01863
         		D 457.2 1.79 min. (QC2)
    Figure US20180339993A1-20181129-C01864
    Figure US20180339993A1-20181129-C01865
    Figure US20180339993A1-20181129-C01866
         		D 455.4 1.49 min. (QC1)
    Figure US20180339993A1-20181129-C01867
    Figure US20180339993A1-20181129-C01868
    Figure US20180339993A1-20181129-C01869
         		H 441.0 1.29 min. (QC1)
    Figure US20180339993A1-20181129-C01870
    Figure US20180339993A1-20181129-C01871
    Figure US20180339993A1-20181129-C01872
         		H 441.0 1.21 min. (QC1)
    Figure US20180339993A1-20181129-C01873
    Figure US20180339993A1-20181129-C01874
    Figure US20180339993A1-20181129-C01875
         		H 441.2 1.53 min. (QC2)
    Figure US20180339993A1-20181129-C01876
    Figure US20180339993A1-20181129-C01877
    Figure US20180339993A1-20181129-C01878
         		H 441.2 1.74 min. (QC2)
    Figure US20180339993A1-20181129-C01879
    Figure US20180339993A1-20181129-C01880
    Figure US20180339993A1-20181129-C01881
         		I 454.6 1.33 min. (QC1)
    Figure US20180339993A1-20181129-C01882
    Figure US20180339993A1-20181129-C01883
    Figure US20180339993A1-20181129-C01884
         		H 455.7 1.29 min. (QC1)
    Figure US20180339993A1-20181129-C01885
    Figure US20180339993A1-20181129-C01886
    Figure US20180339993A1-20181129-C01887
         		D 466.2 2.50 min. (QC2)
    • Example-19-41: 3-(2-(4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C01888
  • A mixture of INT-12-1-A (30 mg, 0.067 mmol), 3,5-dimethyl-1H-pyrazole (12.9 mg, 0.134 mmol) and copper (II) acetate (12.2 mg, 0.067 mmol) in pyridine (1 mL) is stirred at 60° C. for 20 h. The mixture is diluted with EtOAc and washed with 2 M HCl aq. solution, water, and brine. The organic layer is dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by column chromatography on amino bounded silica-gel eluting with EtOAc to give the crude titled compound. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 417.7
  • tR/method: 1.56 min./(QC1)
    • Example-20-1: 3-(2-(6-(3-chlorophenoxy)pyridin-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C01889
  • To a solution of INT-8-3-A (20 mg, 0.062 mmol) in DMSO (1 mL) is added 3-chlorophenol (9.6 mg, 0.075 mmol) and Cs2CO3 (61 mg, 0.186 mmol). The mixture is stirred at rt for 15 h. The mixture is filtered through a pad of celite and the filter cake is washed with EtOAc. The filtrate and washings are washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 10-100% EtOAc in hexane to give the titled compound (18 mg, 70% yield) as a white solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • The following examples (20-1 to 20-9) are prepared according to the procedure of example-20-1 from the synthesized halide derivatives and the known or synthesized phenol, thiol or alcohol derivatives in Table 36. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 36.
  • TABLE 36
    phenols ob- tR/
    alcohol served meth-
    Examples halides thiol MS od
    Figure US20180339993A1-20181129-C01890
    Figure US20180339993A1-20181129-C01891
    Figure US20180339993A1-20181129-C01892
         		412.1 1.77 min. (QC1)
    Figure US20180339993A1-20181129-C01893
    Figure US20180339993A1-20181129-C01894
    Figure US20180339993A1-20181129-C01895
         		379.2 1.37 min. (QC1)
    Figure US20180339993A1-20181129-C01896
    Figure US20180339993A1-20181129-C01897
    Figure US20180339993A1-20181129-C01898
         		392.2 1.73 min. (QC1)
    Figure US20180339993A1-20181129-C01899
    Figure US20180339993A1-20181129-C01900
    Figure US20180339993A1-20181129-C01901
         		421.3 2.23 min (QC2)
    Figure US20180339993A1-20181129-C01902
    Figure US20180339993A1-20181129-C01903
    Figure US20180339993A1-20181129-C01904
         		412.1 1.72 min. (QC1)
    Figure US20180339993A1-20181129-C01905
    Figure US20180339993A1-20181129-C01906
    Figure US20180339993A1-20181129-C01907
         		415.2 1.28 min. (QC1)
    Figure US20180339993A1-20181129-C01908
    Figure US20180339993A1-20181129-C01909
    Figure US20180339993A1-20181129-C01910
         		439.2 1.59 min. (QC1)
    Figure US20180339993A1-20181129-C01911
    Figure US20180339993A1-20181129-C01912
    Figure US20180339993A1-20181129-C01913
         		448.2 1.77 min. (QC1)
    Figure US20180339993A1-20181129-C01914
    Figure US20180339993A1-20181129-C01915
    Figure US20180339993A1-20181129-C01916
         		430.2 1.71 min. (QC1)
    • 2-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenoxy)nicotinonitrile
  • Figure US20180339993A1-20181129-C01917
  • A mixture of INT-14-1-A (35 mg, 0.10 mmol), 2-chloronicotinonitrile (20 mg, 0.145 mmol) and K2CO3 (29 mg, 0.207 mmol) in DMF (1.5 mL) is irradiated in a microwave reactor (Biotage Initiator) for 30 min at 140° C. The reaction mixture is filtered through a pad of celite and the filter cake is washed with EtOAc. The filtrate and washings are washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with 5-50% EtOAc in DCM to give the titled compound (43 mg, 94% yield) as a pale yellow amorphous solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 439.3
  • tR/method: 1.53 min./(QC1)
    • Example-21-2: 3-(2-(4-((3-chloropyridin-2-yl)oxy)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C01918
  • A mixture of INT-14-1-A (34 mg, 0.101 mmol), 2-bromo-3-chloropyridine (15 mg, 0.078 mmol), 2-(dimethylamino)acetic acid (2.4 mg, 0.023 mmol), copper(I) iodide (4.45 mg, 0.023 mmol) and Cs2CO3 (76 mg, 0.234 mmol) in 1,4-dioxane (1.5 mL) is irradiated with microwave at 170° C. for 1 h. After the usual workup (quenching with water, dilution with EtOAc, filtration through celite, and washing with EtOAc), the residue is purified by column chromatography on silica gel eluting with 5-50% EtOAc in DCM to give the titled compound (10 mg, 29% yield). The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 448.2
  • tR/method: 1.68 min./(QC1)
  • The following examples (21-3 to 21-10) are prepared according to the procedure of example-21-2 from the synthesized phenol derivative (INT-14-1-A) and the known or synthesized halide derivatives in Table 37. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 37.
  • TABLE 37
    Ob- tR/
    served meth-
    Examples phenols halides MS od
    Figure US20180339993A1-20181129-C01919
    Figure US20180339993A1-20181129-C01920
    Figure US20180339993A1-20181129-C01921
         		428.3 1.66 min. (QC1)
    Figure US20180339993A1-20181129-C01922
    Figure US20180339993A1-20181129-C01923
    Figure US20180339993A1-20181129-C01924
         		428.3 1.64 min (QC1)
    Figure US20180339993A1-20181129-C01925
    Figure US20180339993A1-20181129-C01926
    Figure US20180339993A1-20181129-C01927
         		441.3 1.58 min. (QC1)
    Figure US20180339993A1-20181129-C01928
    Figure US20180339993A1-20181129-C01929
    Figure US20180339993A1-20181129-C01930
         		430.3 1.64 min. (QC1)
    Figure US20180339993A1-20181129-C01931
    Figure US20180339993A1-20181129-C01932
    Figure US20180339993A1-20181129-C01933
         		431.2 1.45 min. (QC1)
    Figure US20180339993A1-20181129-C01934
    Figure US20180339993A1-20181129-C01935
    Figure US20180339993A1-20181129-C01936
         		442.1 1.54 min. (QC1)
    Figure US20180339993A1-20181129-C01937
    Figure US20180339993A1-20181129-C01938
    Figure US20180339993A1-20181129-C01939
         		467.1 1.53 min. (QC1)
    Figure US20180339993A1-20181129-C01940
    Figure US20180339993A1-20181129-C01941
    Figure US20180339993A1-20181129-C01942
         		431.6 1.41 min. (QC1)
    • Example-21-11: 8,8-difluoro-3-(2-(4-((4-methylpyridazin-3-yl)oxy)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C01943
  • A mixture of INT-14-1-A (30 mg, 0.089 mmol), 3-chloro-4-methylpyridazine (13.7 mg, 0.106 mmol), Pd2(dba)3 (8.1 mg, 0.0089 mmol), tBuXPhos (18.8 mg, 0.044 mmol) and K3PO4 (56.5 mg, 0.266 mmol) in 1,4-dioxane (1.5 mL) is irradiated with microwave at 160° C. for 45 min. After the usual workup (quenching with water, dilution with EtOAc, filtration through celite, and washing with EtOAc), the residue is purified by column chromatography on silica gel eluting with 5-80% EtOAc in DCM to give the titled compound (10 mg, 26% yield). The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 431.2
  • tR/method: 1.43 min./(QC1)
    • Example-21-12: 3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenoxy)pyridazine-4-carbonitrile
  • Figure US20180339993A1-20181129-C01944
  • The titled compound is prepared according to the procedure of example-21-11 from the INT-14-1-A (30 mg, 0.089 mmol) and 3-chloropyridazine-4-carbonitrile (30.9 mg, 0.222 mmol) to give the product (31 mg, 79% yield) as a brown amorphous solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 442.2
  • tR/method: 1.43 min./(QC1)
    • Example-21-13: 8,8-difluoro-3-(2-oxo-2-(4-(thiazol-2-yloxy)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C01945
  • A mixture of INT-14-1-A (30 mg, 0.089 mmol), 2-chlorothiazole (26.5 mg, 0.222 mmol), and Cs2CO3 (87 mg, 0.266 mmol) in DMF (1.5 mL) is irradiated with microwave at 140° C. for 0.5 h. After the usual workup (quenching with water, dilution with EtOAc, filtration through celite, and washing with EtOAc), the residue is purified by column chromatography on silica gel eluting with 10-100% EtOAc in DCM to give the titled compound (18 mg, 48% yield) as a yellow amorphous solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 422.1
  • tR/method: 1.56 min./(QC1)
    • Example-21-14: 8,8-difluoro-3-(2-oxo-2-(4-(pyridin-3-yloxy)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C01946
  • The titled compound is prepared according to the procedure of example-21-11 from the INT-7-1-A (60 mg, 0.15 mmol), pyridin-3-ol (17.1 mg, 0.179 mmol), t-BuXPhos (31.8 mg, 0.075 mmol), Pd2(dba)3 (13.7 mg, 0.015 mmol) and potassium phosphate (95 mg, 0.45 mmol) in 1,4-dioxane (3 mL) to give the product (19 mg, 30% yield) as a slightly yellow solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 416.4
  • tR/method: 1.47 min./(QC1)
  • The following examples (21-15 to 21-17) are prepared according to the procedure of example-21-11 from the halide derivatives (INT-7-1-A, INT-7-18-A and INT-7-20-A) and the known phenol derivatives in Table 38. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 38.
  • TABLE 38
    Ob- tR/
    served meth-
    Examples Halides Phenols MS od
    Figure US20180339993A1-20181129-C01947
    Figure US20180339993A1-20181129-C01948
    Figure US20180339993A1-20181129-C01949
         		417.4 1.40 min. (QC1)
    Figure US20180339993A1-20181129-C01950
    Figure US20180339993A1-20181129-C01951
    Figure US20180339993A1-20181129-C01952
         		434.5 1.50 min. (QC1)
    Figure US20180339993A1-20181129-C01953
    Figure US20180339993A1-20181129-C01954
    Figure US20180339993A1-20181129-C01955
         		434.5 1.49 min. (QC1)
    • Example-21-18: 8,8-difluoro-3-(2-oxo-2-(4-(pyridin-3-ylmethoxy)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C01956
  • To a solution of INT-14-1-A (30 mg, 0.089 mmol) and potassium carbonate (37 mg, 0.266 mmol) in DMF (2 mL) is added 3-(chloromethyl)pyridine (14 mg, 0.089 mmol) at rt. The mixture is stirred at 80° C. for 15 h. To this is added water and the mixture is extracted with EtOAc. The organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with 10-80% ethyl acetate in DCM to give the titled compound (33 mg, 87% yield) as a white solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 430.1
  • tR/method: 1.45 min./(QC1)
    • Example-21-19: 8,8-difluoro-3-(2-oxo-2-(4-(pyridin-4-ylmethoxy)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C01957
  • To a solution of INT-14-1-A (30 mg, 0.089 mmol) in THF (2 mL) is added pyridin-4-ylmethanol (10 mg, 0.089 mmol), DEAD (2.2 M in toluene solution, 0.060 mL, 0.133 mmol) and triphenylphosphine (35 mg, 0.133 mmol) at 0° C. After stirring at rt for 1 h, the reaction mixture is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with 10-100% ethyl acetate in DCM to give the titled compound (44 mg, quant.) as a colorless amorphous solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 430.2
  • tR/method: 1.44 min./(QC1)
    • Example-21-20: 8,8-difluoro-3-(2-oxo-2-(4-(pyrimidin-2-ylmethoxy)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C01958
  • The titled compound is prepared according to the procedure of example-21-17 from the INT-14-1-A (50 mg, 0.148 mmol), 2-(chloromethyl)pyrimidine (24 mg, 0.148 mmol) and cesium carbonate (144 mg, 0.443 mmol) in DMF (2 mL) to give the product (28 mg, 44% yield) as a colorless amorphous solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 431.2
  • tR/method: 1.34 min./(QC1)
  • The following examples (22-1 to 22-6) are prepared according to the procedure of step-3 in intermediate-9-2-A from the synthesized alcohol derivatives (INT-11-1-A to INT-11-6-A) in Table 39. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 39.
  • TABLE 39
    Ob-
    served tR/
    Examples Alcohols MS method
    Figure US20180339993A1-20181129-C01959
    Figure US20180339993A1-20181129-C01960
         		425.2 1.47 min. (QC1)
    Figure US20180339993A1-20181129-C01961
    Figure US20180339993A1-20181129-C01962
         		439.2 1.42 min. (QC1)
    Figure US20180339993A1-20181129-C01963
    Figure US20180339993A1-20181129-C01964
         		438.4 1.56 min. (QC1)
    Figure US20180339993A1-20181129-C01965
    Figure US20180339993A1-20181129-C01966
         		424.4 1.56 min. (QC1)
    Figure US20180339993A1-20181129-C01967
    Figure US20180339993A1-20181129-C01968
         		404.1 1.41 min. (QC1)
    Figure US20180339993A1-20181129-C01969
    Figure US20180339993A1-20181129-C01970
         		455.2 1.50 min. (QC1)
    • Example-23-1: 8,8-difluoro-3-(2-oxo-2-(4-(2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)phenyl)ethyl)-1,3-diazaspiro[4,5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C01971
  • To a stirred solution of INT-15-1-A (40 mg, 0.093 mmol) in THF (1.5 mL) is added CDI (38 mg, 0.233 mmol) and pyridine (18 mg, 0.233 mmol). The mixture is stirred at 65° C. for 4 h. After cooling, the reaction mixture is quenched with water and extracted with EtOAc. The combined organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography (Biotage) on silica gel (10 g) eluting with 10-100% ethyl acetate in DCM to give the titled compound (27 mg, 64% yield) as a white amorphous solid. The further purification is carried out by preparative LC-MS system in the usual manner to give the title compound (6.1 mg).
  • Observed MS: 454.4
  • tR/method: 1.34 min./(QC1)
    • Example-23-2: 8,8-difluoro-3-(2-(4-(5-methyl-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C01972
  • The titled compound is prepared according to the procedure of example-23-1 from the INT-15-2-A (80 mg, 0.18 mmol), CDI (73.1 mg, 0.451 mmol) and pyridine (36 microL, 0.451 mmol) in THF (3 mL) to give the product (75 mg, 89% yield) as a dark yellow solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 470.4
  • tR/method: 1.42 min./(QC1)
    • Example-24-1: 3-(2-(4-(2-(difluoromethyl)-1H-benzo[d]imidazol-1-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C01973
  • To a stirred solution of INT-15-1-A (50.0 mg, 0.116 mmol) and triethylamine (40 microL, 0.282 mmol) in THF (3 mL) is added 2,2-difluoroacetic anhydride (24, 5 mg, 0.141 mmol) at the ambient temperature. After 5 h at rt, the solvent is evaporated in vacuo to give the crude product (˜0.116 mmol) as an orange oil, which is dissolved in acetic acid (3 mL). The mixture is heated at 100° C. for 16 h. After the removal of solvent, the residue is basified to pH>10 with sat. sodium bicarbonate solution and extracted with ethyl acetate (×2). The combined solution is washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product (orange oil, 146.4 mg), which is purified by column chromatography on silica gel (10 g) eluting with 5-60% ethyl acetate in DCM to give the titled compound (36.8 mg, 65% yield) as an orange solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 490.1
  • tR/method: 2.05 min./(QC2)
  • The following examples (24-2 to 24-5) are prepared according to the procedure of Example-24-1 from INT-15-1-A and INT-15-2-A in Table 40. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 40.
  • TABLE 40
    Ob- tR/
    Acetylated served meth-
    Examples Starting Material reagents MS od
    Figure US20180339993A1-20181129-C01974
    Figure US20180339993A1-20181129-C01975
    Figure US20180339993A1-20181129-C01976
         		468.2 1.44 min. (QC1)
    Figure US20180339993A1-20181129-C01977
    Figure US20180339993A1-20181129-C01978
    Figure US20180339993A1-20181129-C01979
         		480.2 1.49 min. (QC1)
    Figure US20180339993A1-20181129-C01980
    Figure US20180339993A1-20181129-C01981
    Figure US20180339993A1-20181129-C01982
         		484.5 1.40 min. (QC1)
    Figure US20180339993A1-20181129-C01983
    Figure US20180339993A1-20181129-C01984
    Figure US20180339993A1-20181129-C01985
         		504.4 1.57 min. (QC1)
    • Example-24-6: 8,8-difluoro-3-(2-oxo-2-(4-(2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C01986
  • A mixture of INT-15-1-A (50 mg, 0.116 mmol) is dissolved in trifluoroacetic acid (1 mL) and the reaction is stirred at 70° C. for 18 h. After the removal of solvent, to this is added triethylamine and the mixture is stirred at 70° C. for 2 h. After the removal of solvent, the residual product is purified by column chromatography on silica gel (10 g) eluting with 10-90% ethyl acetate in DCM to give the titled compound (53 mg, 90% yield; chemical purity of 40%) as an orange solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 508.6
  • tR/method: 1.58 min./(QC1)
    • Example-24-7: 8,8-difluoro-3-(2-(4-(5-m ethyl-2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C01987
  • A mixture (suspension) of INT-15-2-A (50 mg, 0.113 mmol) in trifluoroacetic acid (1 mL) is irradiated with microwave at 100° C. for 30 min. The treatment of reaction is carried out according to the procedure of example-24-6 to give the titled compound (58 mg, 99% yield) as an orange solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 522.7
  • tR/method: 1.67 min./(QC1)
    • Example-25-1: 3-(2-(4-(2-((dimethylamino)methyl)-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C01988
  • A mixture of INT-17-1-A (30 mg, 0.06 mmol), 2 M dimethylamine in THF solution (90 microL, 0.18 mmol) and potassium carbonate (41.3 mg, 0.299 mmol) in THF (1.5 mL) is heated at 45° C. for 10 h. After the filtration through Celite pad, the filter cake is washed with THF. The filtrate and washings are concentrated in nitrogen flow to give the titled compound (35.1 mg) as an orange oil. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 511.7
  • tR/method: 1.48 min./(QC1)
  • The following examples (25-2 to 25-6) are prepared according to the procedure of Example-25-1 from INT-17-1-A and the corresponding amines in Table 41. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 41.
  • TABLE 41
    Ob-
    served tR/
    Examples Starting Material Amines MS method
    Figure US20180339993A1-20181129-C01989
    Figure US20180339993A1-20181129-C01990
    Figure US20180339993A1-20181129-C01991
         		537.8 1.56 min. (QC1)
    Figure US20180339993A1-20181129-C01992
    Figure US20180339993A1-20181129-C01993
    Figure US20180339993A1-20181129-C01994
         		551.8 1.69 min. (QC1)
    Figure US20180339993A1-20181129-C01995
    Figure US20180339993A1-20181129-C01996
    Figure US20180339993A1-20181129-C01997
         		523.8 1.43 min. (QC1)
    Figure US20180339993A1-20181129-C01998
    Figure US20180339993A1-20181129-C01999
    Figure US20180339993A1-20181129-C02000
         		553.8 1.46 min. (QC1)
    Figure US20180339993A1-20181129-C02001
    Figure US20180339993A1-20181129-C02002
    Figure US20180339993A1-20181129-C02003
         		567.8 1.51 min. (QC1)
    • Example-26-1: 8,8-difluoro-3-(2-(4-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4,5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C02004
  • A mixture of INT-15-1-A (50 mg, 0.116 mmol), tetramethoxymethane (0.16 mL, 1.199 mmol) and acetic acid (15 microL) in THF (1.5 mL) is heated at 85° C. for 18 h. After the removal of solvent, the residue (brown oil) is purified by column chromatography on silica gel (10 g) eluting with 5-70% ethyl acetate in DCM to give the titled compound (43 mg, 78% yield) as a slightly purple solid.
  • The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 470.2
  • tR/method: 2.02 min./(QC2)
  • The following examples (26-2 to 26-4) are prepared according to the procedure of Example-26-1 from INT-15-2-A in Table 42. Example-26-2 is carried out in the condition of p-TsOH (0.3 eq.) instead of AcOH. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 42.
  • TABLE 42
    Ob-
    served tR/
    Examples Starting Material Reagents MS method
    Figure US20180339993A1-20181129-C02005
    Figure US20180339993A1-20181129-C02006
    Figure US20180339993A1-20181129-C02007
         		454.3 1.51 min. (QC1)
    Figure US20180339993A1-20181129-C02008
    Figure US20180339993A1-20181129-C02009
    Figure US20180339993A1-20181129-C02010
         		484.4 1.57 min. (QC1)
    Figure US20180339993A1-20181129-C02011
    Figure US20180339993A1-20181129-C02012
    Figure US20180339993A1-20181129-C02013
         		498.6 1.63 min. (QC1)
    • Example-27-1: 3-(4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile
  • Figure US20180339993A1-20181129-C02014
  • A mixture (suspension) of example-5-29 (660 mg, 1.33 mmol) in phosphorus (V) oxychloride (32 mL) is irradiated with microwave at 120° C. for 30 min. The solvent is evaporated in vacuo to give the residual product, which is basified to pH>10 with sat. sodium bicarbonate solution and extracted with ethyl acetate (×2). The combined solution is washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which is purified by column chromatography on silica gel (100 g) eluting with EtOAc only to give the crude product (solid). The product is triturated with minimum AcOEt and excess hexane to give the titled product (324 mg, 51% yield) as a white solid.
  • MS (ESI) m/z: 479.3 (M+H)+.
  • The further purification for the assay sample is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 479.2
  • tR/method: 1.96 min./(QC2)
    • Example-28-1: 3-(2-(4-(2-(dimethylamino)-5-methyl-3H-imidazo[4.5-b]pyridin-3-yl)phenyl)-2-oxoethyl-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C02015
  • A mixture of INT-15-2-A (50 mg, 0.113 mmol), (dichloromethane)dimethyliminium chloride (43 mg, 0.338 mmol) and triethylamine (22 microL, 0.451 mmol) in 1,2-dichloroethane (3 mL) is heated at 80° C. for 2 h. The mixture is quenched with methanol and the solvent is evaporated in vacuo. The residue is dissolved in DCM (50 mL) and the organic solution is washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product (dark brown oil), which is purified by column chromatography on silica gel (10 g) eluting with 20-100% ethyl acetate in DCM to give the titled compound (14.2 mg, 20% yield, chemical purity of 80%) as a pale yellow film. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 497.8
  • tR/method: 1.51 min./(QC1)
    • Example-28-2: N-(2-((4-(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)amino)pyridin-3-yl)acetamide
  • Figure US20180339993A1-20181129-C02016
  • To a stirred mixture of INT-15-1-A (50 mg, 0.116 mmol) and triethylamine (40.6 microL, 0,291 mmol) in THF (3 mL) is added acetyl chloride (13.2 mg, 0.169 mmol) via a syringe at rt. After 45 min at rt, the mixture is quenched with water and extracted with ethyl acetate. The combined organic solution is washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product, which is purified by column chromatography on silica gel (10 g) eluting with ethyl acetate only to give the titled compound (34.4 mg, 62% yield) as a slightly tan solid.
  • 1H-NMR (270 MHz, DMSO-d6): delta 9.56 (s, 1H), 8.98 (s, 1H), 8.71 (s, 1H), 8.14-8.08 (m, 1H), 7.97 (d, J=8.6 Hz, 2H), 7.82-7.72 (m, 3H), 7.02-6.95 (m, 1H), 4.87 (s, 2H), 2.25-1.75 (m, 11H, including delta 2.12 (s, 3H)).
  • MS (ESI) m/z: 472.2 (M+H)+.
  • The further purification for the assay sample is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 472.7
  • tR/method: 1.35 min./(QC1)
    • Example-28-3: 3-(2-(4-(2-acetylisoindolin-4-yl)phenyl)-2-oxoethyl)-8,8-difluoro-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C02017
  • To a solution of example-6-115 (32 mg, 0.073 mmol) in DCM (2 mL) are added acetic anhydride (0.021 mL, 0.218 mmol) and TEA (0.030 mL, 0.218 mmol) at rt. The mixture is stirred at rt for 5 h. The mixture is quenched with sat. NaHCO3 solution and extracted with DCM. The organic solution is dried over Na2SO4, filtered and concentrated in vacuo. The purification is carried out by column chromatography on silica gel eluting with a gradient of 50-100% EtOAc then 0-5% MeOH in EtOAc to give the titled compound (27 mg, 77% yield) as a pale purple solid.
  • 1H-NMR (270 MHz, CDCl3): delta 8.10-8.06 (m, 2H), 7.61-7.53 (m, 2H), 7.49-7.27 (m, 3H), 6.67 (br s, 1H), 5.00-4.93 (m, 2H), 4.93-4.80 (m, 4H), 2.50-1.90 (m, 11H).
  • MS (ESI) m/z: 482.0 (M+H)+.
  • The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 482.3
  • tR/method: 1.51 min./(QC1)
    • Example-28-4: 8,8-difluoro-3-(2-(4-(2-(hydroxymethyl)-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C02018
  • A mixture of INT-17-2-A (52 mg, 0.102 mmol) and potassium carbonate (42 mg, 0.305 mmol) in methanol (3 mL) is stirred at rt for 16 h. After the filtration through Celite pad, the filtrate and washings are concentrated in vacuo. The residue is loaded onto an SCX cartridge (Varian Bond Elute, 1 g/6 mL) conditioned with 1 mL of MeOH, rinsed with 5 mL of MeOH and eluted with 5 mL of 1M NH3/MeOH. Volatiles are removed by nitrogen flow to give the titled compound (21 mg, 44% yield). The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 470.3
  • tR/method: 1.27 min./(QC1)
    • Example-28-5: 8,8-difluoro-3-(2-(4-(2-(hydroxymethyl)-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione
  • Figure US20180339993A1-20181129-C02019
  • The titled compound is prepared according to the procedure of example-28-4 from the INT-17-3-A (75.9 mg, 0.144 mmol) and potassium carbonate (60 mg, 0.433 mmol) in methanol (4 mM) to give the product (29 mg, 41% yield) as a white solid. The further purification is carried out by preparative LC-MS system in the usual manner.
  • Observed MS: 484.6
  • tR/method: 1.33 min./(QC1)
    • Example-29-1: 4′(2-(8,8-difluoro-2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)N,N-dimethyl-[1,1′-biphenyl]-2-carboxamide
  • Figure US20180339993A1-20181129-C02020
  • To a stirred solution of INT-16-1-A (20 mg, 0.045 mmol), N,N,N′N′-tetramethyl-O-(benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) (34 mg, 0.090 mmol) and TEA (0.025 mL, 0.181 mmol) in DMF (1 mL) is added 10% dimethylamine in THF (0.2 mL) at rt. After stirring at 50° C. for 1 h, the mixture is diluted with EtOAc (4 mL) and washed with water (4 mL×2). The organic fraction is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by column chromatography on amino bounded silica-gel (1 g) eluting with ethyl acetate to give the titled compound (20 mg, 94% yield) as a pale yellow gum. The further purification is carried out by preparative LC-MS system in the usual manner to give the title compound (12.7 mg).
  • Observed MS: 470.7
  • tR/method: 1.49 min./(QC1)
  • The following examples (29-2 to 29-7) are prepared according to the procedure of Example-29-1 from INT-16-1-A/INT-16-2-A and the corresponding amines in Table 43. The further purification is carried out by preparative LC-MS system in the usual manner. The retention time and observed MS by HPLC-QC method are summarized in Table 43.
  • TABLE 43
    Ob-
    served tR/
    Examples Starting Material Amines MS method
    Figure US20180339993A1-20181129-C02021
    Figure US20180339993A1-20181129-C02022
    Figure US20180339993A1-20181129-C02023
         		486.8 1.32 min. (QC1)
    Figure US20180339993A1-20181129-C02024
    Figure US20180339993A1-20181129-C02025
    Figure US20180339993A1-20181129-C02026
         		509.8 1.55 min. (QC1)
    Figure US20180339993A1-20181129-C02027
    Figure US20180339993A1-20181129-C02028
    Figure US20180339993A1-20181129-C02029
         		456.7 1.40 min. (QC1)
    Figure US20180339993A1-20181129-C02030
    Figure US20180339993A1-20181129-C02031
    Figure US20180339993A1-20181129-C02032
         		500.8 1.44 min. (QC1)
    Figure US20180339993A1-20181129-C02033
    Figure US20180339993A1-20181129-C02034
    Figure US20180339993A1-20181129-C02035
         		481.8 1.47 min. (QC1)
    Figure US20180339993A1-20181129-C02036
    Figure US20180339993A1-20181129-C02037
    Figure US20180339993A1-20181129-C02038
         		495.8 1.52 min. (QC1)
  • TABLE 44
    Examples Structure 1H-NMR Data
    Ex. 1-2
    Figure US20180339993A1-20181129-C02039
         		1H-NMR (270 MHz, DMSO-d6): delta 6.70 (s, 1H), 6.68 (s, 1H), 4.74 (s, 2H), 2.52 (s, 3H), 2.37 (s, 3H), 2.12 (s, 3H), 2.30-1.95 (m, 8H).
    Ex. 2-2
    Figure US20180339993A1-20181129-C02040
         		1H-NMR (270 MHz, DMSO-d6): delta 8.94 (s, 1H), 7.62-7.58 (m, 3H), 7.47-7.44 (m, 2H), 4.74 (s, 2H), 2.22 (s, 3H), 2.16 (s, 3H), 2.11-1.80 (m, 8H).
    Ex. 2-3
    Figure US20180339993A1-20181129-C02041
         		1H-NMR (270 MHz, DMSO-d6): delta 7.68-7.57 (m, 3H), 7.50-7.42 (m, 2H), 4.84 (s, 2H), 2.30-2.00 (m, 8H), 2.23 (s, 3H), 2.16 (m, 3H).
    Ex. 4-10
    Figure US20180339993A1-20181129-C02042
         		1H-NMR (270 MHz, DMSO-d6): delta 7.62-7.42 (m, 5H), 4.91 (s, 2H), 3.84 (s, 3H), 2.30-2.00 (m, 11H).
    Ex. 5-6
    Figure US20180339993A1-20181129-C02043
         		1H-NMR (270 MHz, DMSO-d6): delta 9.03 (s, 1H), 8.51 (s, 1H), 8.26 (d, J = 8.6 Hz, 2H), 8.05 (d, J = 7.9 Hz, 3H), 7.95 (d, J = 7.9 Hz, 1H), 7.63-7.53 (m, 1H), 7.40-7.30 (m, 1H), 5.03 (s, 2H), 2.27-1.75 (m, 8H).
    Ex. 5-8
    Figure US20180339993A1-20181129-C02044
         		1H-NMR (270 MHz, DMSO-d6): delta 9.06 (s, 1H), 8.30 (d, J = 7.9 Hz, 2H), 7.80 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 5.9 Hz, 1H), 7.23 (s, 3H), 5.08 (s, 2H), 2.50 (s, 3H), 2.18-1.87 (m, 8H).
    Ex. 5-9
    Figure US20180339993A1-20181129-C02045
         		1H-NMR (270 MHz, DMSO-d6): delta 9.12 (s, 1H), 9.06 (s, 1H), 8.50 (d, J = 4.0 Hz, 1H), 8.35-8.25 (m, 5H), 7.46 (dd, J = 7.9, 4.6 Hz, 1H), 5.06 (s, 2H), 2.19-1.83 (m, 8H).
    Ex. 5-10
    Figure US20180339993A1-20181129-C02046
         		1H-NMR (270 MHz, DMSO-d6): delta 9.06 (s, 1H), 8.30-8.25 (m, 3H), 8.07 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.33 (dd, J = 7.9, 5.3 Hz, 1H), 5.08 (s, 2H), 2.55 (s, 3H), 2.19-1.83 (m, 8H).
    Ex. 5-15
    Figure US20180339993A1-20181129-C02047
         		1H-NMR (270 MHz, DMSO-d6): delta 9.06 (s, 1H), 8.30 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 8.5 Hz, 2H), 7.34-7.28 (m, 4H), 5.61 (t, J = 5.9 Hz, 1H), 5.07 (s, 2H), 4.65 (d, J = 5.9 Hz, 2H), 2.19-1.76 (m, 8H).
    Ex. 5-17
    Figure US20180339993A1-20181129-C02048
         		1H-NMR (270 MHz, DMSO-d6): delta 9.01 (s, 1H), 8.26-8.19 (m, 1H), 8.15-8.06 (m, 2H), 7.98-7.87 (m, 1H), 7.35-7.12 (m, 4H), 4.96 (s, 2H), 2.26-1.75 (m, 8H).
    Ex. 5-20
    Figure US20180339993A1-20181129-C02049
         		1H-NMR (270 MHz, DMSO-d6): delta 9.03 (s, 1H), 8.70 (dd, J = 4.6, 1.3 Hz, 2H), 8.15-8.12 (m, 2H), 7.44-7.41 (m, 2H), 7.37-7.33 (m, 1H), 4.99 (s, 2H), 2.18-1.82 (m, 8H).
    Ex. 5-22
    Figure US20180339993A1-20181129-C02050
         		1H-NMR (270 MHz, DMSO-d6): delta 9.08 (d, J = 4.6 Hz, 1H), 9.03 (s, 1H), 8.15 (d, J = 8.5 Hz, 2H), 7.85 (dd, J = 8.5, 4.6 Hz, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.42 (d, J = 8.5 Hz, 2H), 4.99 (s, 2H), 2.17-1.86 (m, 8H).
    Ex. 5-27
    Figure US20180339993A1-20181129-C02051
         		1H-NMR (270 MHz, DMSO-d6): delta 9.05 (br.s, 1H), 8.33- 8.24 (m, 2H), 7.98-7.90 (m, 1H), 7.85-7.75 (m, 2H), 7.22- 7.14 (m, 1H), 5.08 (s, 2H), 2.54-2.46 (m, 6H, overlapped with DMSO peak), 2.30-1.75 (m, 8H).
    Ex. 6-3
    Figure US20180339993A1-20181129-C02052
         		1H-NMR (270 MHz, CDCl3): delta 8.90 (d, J = 2.6 Hz, 1H), 8.74 (d, J = 2.6 Hz, 1H), 8.17 (s, 4H), 7.00 (br s, 1H), 4.99 (s, 2H), 2.48-2.18 (m, 4H), 2.11-1.88 (m, 4H).
    Ex. 6-6
    Figure US20180339993A1-20181129-C02053
         		1H-NMR (270 MHz, DMSO-d6): delta 9.03 (s, 1H), 8.73 (d, J = 2.6 Hz, 1H), 8.71 (d, J = 2.6 Hz, 1H), 8.19 (d, J = 8.6 Hz, 2H), 7.96 (d, J = 8.6 Hz, 2H), 5.58 (t, J = 5.9 Hz, 1H), 5.04 (s, 2H), 4.59 (d, J = 5.9 Hz, 2H), 2.26-1.79 (m, 8H).
    Ex. 6-9
    Figure US20180339993A1-20181129-C02054
         		1H-NMR (270 MHz, DMSO-d6): delta 9.03 (s, 1H), 8.64 (d, J = 4.6 Hz, 1H), 8.14 (d, J = 7.9 Hz, 2H), 7.79 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 7.9 Hz, 2H), 7.47 (dd, J = 7.9, 4.6 Hz, 1H), 5.25 (t, J = 5.9 Hz, 1H), 5.03 (s, 2H), 4.48 (d, J = 5.9 Hz, 2H), 2.29-1.78 (m, 8H).
    Ex. 6-10
    Figure US20180339993A1-20181129-C02055
         		1H-NMR (270 MHz, DMSO-d6): delta 9.03 (s, 1H), 8.62 (d, J = 4.0 Hz, 1H), 8.45 (s, 1H), 8.14 (d, J = 7.9 Hz, 2H), 7.69- 7.60 (m, 3H), 5.84 (t, J = 5.3 Hz, 1H), 5.03 (s, 2H), 4.48 (d, J = 5.3 Hz, 2H), 2.26-1.78 (m, 8H).
    Ex. 6-11
    Figure US20180339993A1-20181129-C02056
         		1H-NMR (270 MHz, CDCl3): delta 8.55-8.51 (m, 2H), 8.09 (d, J = 7.9 Hz, 2H), 7.76 (d, J = 7.9 Hz, 2H), 6.99 (br s, 1H), 4.98 (s, 2H), 2.65 (s, 3H), 2.48-2.19 (m, 4H), 2.12-1.89 (m, 4H).
    Ex. 6-14
    Figure US20180339993A1-20181129-C02057
         		1H-NMR (270 MHz, DMSO-d6): delta 9.14 (d, J = 5.3 Hz, 1H), 9.05 (s, 1H), 8.20 (d, J = 8.6 Hz, 2H), 7.84 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 5.3 Hz, 1H), 5.06 (s, 2H), 2.35 (s, 3H), 2.26-1.78 (m, 8H).
    Ex. 6-15
    Figure US20180339993A1-20181129-C02058
         		1H-NMR (270 MHz, CDCl3): delta 8.78 (dd, J = 4.6, 1.3 Hz, 1H), 8.13 (d, J = 8.6 Hz, 2H), 6.90 (dd, J = 7.9, 1.3 Hz, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.65 (dd, J = 7.9, 1.3 Hz, 1H), 6.68 (s, 1H), 4.97 (s 2H), 2.5-2.2 (m, 4H), 2.1-1.9 (m, 4H).
    Ex. 6-16
    Figure US20180339993A1-20181129-C02059
         		1H-NMR (270 MHz, DMSO-d6): delta 9.03 (s, 1H), 8.99 (s, 1H), 8.90 (d, J = 5.3 Hz, 1H), 8.23 (d, J = 7.9 Hz, 2H), 8.05 (d, J = 5.3 Hz, 1H), 7.90 (d, J = 7.9 Hz, 2H), 5.05 (s, 2H), 2.29-1.78 (m, 8H).
    Ex. 6-17
    Figure US20180339993A1-20181129-C02060
         		1H-NMR (270 MHz, CDCl3): delta 8.17 (dd, J = 5.3, 2.0 Hz, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.73-7.66 (m, 3H), 7.06 (dd, J = 7.3, 5.3 Hz, 1H), 6.55 (br s, 1H), 4.96 (s, 2H), 4.57-4.52 (m, 2H), 3.99-3.92 (m, 2H), 3.75-3.65 (m, 1H), 2.51-2.18 (m, 4H), 2.10-1.90 (m, 4H).
    Ex. 6-22
    Figure US20180339993A1-20181129-C02061
         		1H-NMR (270 MHz, CDCl3): delta 8.64 (d, J = 4.6 Hz, 1H), 8.07 (d, J = 7.9 Hz, 2H), 7.90 (d, J = 7.9 Hz, 2H), 7.84 (d, J = 8.6 Hz, 1H), 7.30 (dd, J = 8.8, 4.6 Hz, 1H), 6.23 (br s, 1H), 4.97 (s, 2H), 2.52-2.19 (m, 4H), 2.11-1.90 (m, 4H).
    Ex. 6-26
    Figure US20180339993A1-20181129-C02062
         		1H-NMR (270 MHz, CDCl3): delta 8.20 (d, J = 8.6 Hz, 2H), 8.09 (d, J = 8.6 Hz, 2H), 8.06-7.92 (m, 2H), 7.71 (d, J = 7.3 Hz, 1H), 6.32 (br s, 1H), 4.97 (s, 2H), 2.51-2.19 (m, 4H), 2.10-1.90 (m, 4H).
    Ex. 6-27
    Figure US20180339993A1-20181129-C02063
         		1H-NMR (270 MHz, CDCl3): delta 8.58 (dd, J = 4.6, 1.3 Hz, 1H), 8.16 (d, J = 8.6 Hz, 2H), 8.07 (d, J = 8.6 Hz, 2H), 7.55 (dd, J = 11.2, 7.9 Hz, 1H), 7.40-7.31 (m, 1H), 4.98 (s, 2H), 2.51-2.19 (m, 4H), 2.12-1.89 (m, 4H). —NH is not observed.
    Ex. 6-28
    Figure US20180339993A1-20181129-C02064
         		1H-NMR (270 MHz, CDCl3): delta 8.90 (s, 1H), 8.47 (s, 1H), 8.19 (d, J = 8.6 Hz, 2H), 8.09 (d, J = 8.6 Hz, 2H), 6.52 (br s, 1H), 4.97 (s, 2H), 2.67 (s, 3H), 2.52-2.19 (m, 4H), 2.11-1.90 (m, 4H).
    Ex. 6-43
    Figure US20180339993A1-20181129-C02065
         		1H-NMR (270 MHz, DMSO-d6): delta 9.62 (d, J = 5.3 Hz, 1H), 9.03 (br.s, 1H), 8.45 (d, J = 5.3 Hz, 1H), 8.29 (d, J = 8.6 Hz, 2H), 8.13 (d, J = 8.6 Hz, 2H), 5.08 (s, 2H), 2.30-1.75 (m, 8H).
    Ex. 6-44
    Figure US20180339993A1-20181129-C02066
         		1H-NMR (270 MHz, DMSO-d6): delta 9.38 (s, 1H), 9.07 (s, 1H), 8.87 (d, J = 5.3 Hz, 1H), 8.80 (d, J = 5.3 Hz, 1H), 8.28 (d, J = 8.6 Hz, 2H), 8.05-7.95 (m, 4H), 5.09 (s 2H), 2.28-1.80 (m, 8H).
    EX. 6-87
    Figure US20180339993A1-20181129-C02067
         		1H-NMR (270 MHz, DMSO-d6): delta 9.03 (br.s, 1H), 9.01- 8.96 (m, 1H), 8.53-8.47 (m, 1H), 8.23 (d, J = 8.6 Hz, 2H), 8.05 (d, J = 8.6 Hz, 2H), 7.74-7.65 (m, 1H), 5.06 (s, 2H), 2.25-1.75 (m, 8H).
    EX. 6-97
    Figure US20180339993A1-20181129-C02068
         		1H-NMR (270 MHz, DMSO-d6): delta 9.03 (br.s, 1H), 8.40 (d, J = 2.6 Hz, 1H), 8.31 (d, J = 2.6 Hz, 1H), 8.24-8.12 (m, 4H), 5.02 (s, 2H), 4.02 (s, 3H), 2.25-1.75 (m, 8H).
    Ex. 6-98
    Figure US20180339993A1-20181129-C02069
         		1H-NMR (270 MHz, DMSO-d6): delta 9.18 (br.s, 1H), 9.06 (s, 1H), 9.00-8.90 (m, 1H), 8.24 (d, J = 8.6 Hz, 2H), 7.90 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 5.3 Hz, 1H), 5.06 (s, 2H), 2.30-1.75 (m, 8H)
    Ex. 7-10
    Figure US20180339993A1-20181129-C02070
         		1H-NMR (270 MHz, CDCl3): delta 8.67 (d, J = 2.6 Hz, 1H), 8.61 (d, J = 2.6 Hz, 1H), 8.10 (d, J = 7.9 Hz, 2H), 7.74 (d, J = 7.9 Hz, 2H), 5.96 (br s, 1H), 4.96 (s, 2H), 4.83 (d, J = 5.3 Hz, 2H), 3.93 (t, J = 5.3 Hz, 1H), 2.04-1.37 (m, 10 H).
    Ex. 8-7
    Figure US20180339993A1-20181129-C02071
         		1H-NMR (270 MHz, DMSO-d6): delta 9.15 (d, J = 5.3 Hz, 1H), 9.04 (br.s, 1H), 8.10-8.00 (m, 1H), 7.80-7.60 (m, 3H), 4.89 (s, 2H), 2.37 (s, 3H), 2.25-1.70 (m, 8H).
    Ex. 9-13
    Figure US20180339993A1-20181129-C02072
         		1H-NMR (270 MHz, DMSO-d6): delta 9.36 (s, 1H), 9.05 (s, 1H), 8.98 (dd, J = 4.0, 1.9 Hz, 1H), 8.53-8.46 (m, 2H), 8.40 (d, J = 8.5 Hz, 1H), 8.25 (d, J = 7.2 Hz, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.82-7.76 (m, 1H), 7.67-7.62 (m, 1H), 5.11 (s, 2H), 2.19-1.88 (m, 8H).
    Ex. 10-1
    Figure US20180339993A1-20181129-C02073
         		1H-NMR (270 MHz, DMSO-d6): delta 9.04 (s, 1H), 8.86 (d, J = 2.6 Hz, 1H), 8.57 (d, J = 4.6 Hz, 1H), 8.17 (dd, J = 7.9, 2.6 Hz, 1H), 8.08 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 7.3 Hz, 1H), 7.40 (dd, J = 7.3, 4.6 Hz, 1H), 5.08 (s, 2H), 2.48 (s, 3H), 2.29-1.79 (m, 8H).
    Ex. 12-1
    Figure US20180339993A1-20181129-C02074
         		1H-NMR (270 MHz, CDCl3): delta 9.32 (s, 1H), 8.85 (s, 1H), 8.67 (d, J = 4.6 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.40-7.20 (m, 1H), 6.47 (br.s, 1H). 5.20 (s, 2H), 2.55-1.90 (m, 8H), 1.59 (s, 3H).
    Ex. 12-3
    Figure US20180339993A1-20181129-C02075
         		1H-NMR (270 MHz, CDCl3): delta 9.24 (s, 1H), 9.03 (s, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.63-7.50 (m, 3H), 7.08 (br s, 1H), 5.21 (s, 2H), 4.74 (t, J = 7.3 Hz, 1H), 4.53 (d, J = 7.3 Hz, 2H), 2.50-2.18 (m, 4H), 2.13-1.91 (m, 4H).
    Ex. 12-5
    Figure US20180339993A1-20181129-C02076
         		1H-NMR (270 MHz, CDCl3): delta 9.30 (s, 1H), 9.25 (s, 1H), 9.07 (s, 1H), 8.63 (d, J = 5.9 Hz, 1H), 7.00 (d, J = 5.9 Hz, 1H), 6.27 (br s, 1H), 5.19 (s, 2H), 4.03 (s, 3H), 2.55-2.19 (m, 4H), 2.12-1.89 (m, 4H).
    Ex. 13-34
    Figure US20180339993A1-20181129-C02077
         		1H-NMR (270 MHz, DMSO-d6): delta 9.02 (s, 1H), 8.11 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 7.9 Hz, 3H), 7.47-7.35 (m, 2H), 7.28 (d, J = 7.2 Hz, 1H), 5.22 (t, J = 5.3 Hz, 1H), 5.01 (s, 2H), 4.41 (d, J = 5.3 Hz, 2H), 2.18-1.82 (m, 8H).
    Ex. 13-39
    Figure US20180339993A1-20181129-C02078
         		1H-NMR (270 MHz, CDCl3): delta 8.53 (d, J = 5.9 Hz, 1H), 8.47 (s, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.73 (br s, 1H), 7.67 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 5.9 Hz, 1H), 4.95 (s, 2H), 3.91 (s, 3H), 2.42-1.86 (m, 8H).
    Ex. 13-45
    Figure US20180339993A1-20181129-C02079
         		1H-NMR (270 MHz, CDCl3): delta 8.22 (d, J = 4.6 Hz, 1H), 8.02 (d, J = 7.9 Hz, 2H), 7.71 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 7.3 Hz, 1H), 7.02 (dd, J = 7.3, 4.6 Hz, 1H), 4.96 (s, 2H), 3.99 (s, 3H), 2.50-2.18 (m, 4H), 2.11-1.88 (m, 4H). —NH is not observed.
    Ex. 14-4
    Figure US20180339993A1-20181129-C02080
         		1H-NMR (270 MHz, CDCl3): delta 7.65 (s, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.48 (dd, J = 7.3, 7.3 Hz, 1H), 7.37 (dd, J = 7.3, 7.3 Hz, 1H), 7.26-7.23 (m, 1H), 6.22 (br. s, 1H), 4.85 (s, 2H), 4.57 (d, J = 5.9 Hz, 2H), 2.09 (s, 3H), 2.51-1.88 (m, 8H), 1.67 (t, J = 5.9 Hz, 1H).
    Ex. 17-6
    Figure US20180339993A1-20181129-C02081
         		1H-NMR (270 MHz, CDCl3): delta 7.53-7.43 (m, 1H), 7.23- 7.14 (m, 1H), 7.08 (d, J = 7.3 Hz, 1H), 7.06-6.98 (m, 1H), 6.35 (br s, 1H), 5.11 (s,2H), 3.81 (s, 3H), 2.51-2.18 (m, 4H), 2.25 (s, 3H), 2.10-1.88 (m, 4H).
    Ex. 17-7
    Figure US20180339993A1-20181129-C02082
         		1H-NMR (270 MHz, CDCl3): delta 7.55-7.45 (m, 3H), 7.32- 7.27 (m, 2H), 5.11 (s, 2H), 3.80 (s, 3H), 2.53-2.18 (m, 4H), 2.25 (s, 3H), 2.10-1.88 (m, 4H). —NH is not observed.
    Ex. 17-8
    Figure US20180339993A1-20181129-C02083
         		1H-NMR (270 MHz, CDCl3): delta 7.76 (dt, J = 7.9, 1.3 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.61 (br s, 1H), 7.55 (dt, J = 7.9, 1.3 Hz, 1H), 6.62 (br s, 1H), 5.10 (s, 2H), 3.81 (s, 3H), 2.50-2.16 (m, 4H), 2.24 (s, 3H), 2.11-1.88 (m, 4H).
    Ex. 17-9
    Figure US20180339993A1-20181129-C02084
         		1H-NMR (270 MHz, CDCl3): delta 8.89 (s, 1H), 8.65 (d, J = 5.9 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 5.9 Hz, 1H), 5.18 (s, 2H), 3.68 (s, 3H), 2.52-2.20 (m, 4H), 2.15 (s, 3H), 2.10- 1.92 (m, 4H). —NH is not observed.
    Ex. 17-10
    Figure US20180339993A1-20181129-C02085
         		1H-NMR (270 MHz, CDCl3): delta 7.65 (d, J = 7.3 Hz, 1H), 7.55 (dd, J = 7.9, 7.3 Hz, 1H), 7.43 (dd, J = 7.9, 7.3 Hz, 1H), 7.17 (d, J = 7.3 Hz, 1H), 6.85 (br s, 1H), 5.11 (s, 2H), 4.44 (d, J = 3.3 Hz, 2H), 3.63 (s, 3H), 2.50-2.15 (m, 4H), 2.10 (s, 3H), 2.08-1.80 (m, 4H). —OH is not observed.
    Ex. 17-11
    Figure US20180339993A1-20181129-C02086
         		1H-NMR (270 MHz, CDCl3): delta 6.99-6.89 (m, 1H), 6.89- 6.79 (m, 2H), 6.40 (br s, 1H), 5.10 (s, 2H), 3.82 (s, 3H), 2.50- 2.17 (m, 4H), 2.25 (s, 3H), 2.11-1.88 (m, 4H).
    Ex. 19-21
    Figure US20180339993A1-20181129-C02087
         		1H-NMR (270 MHz, DMSO-d6): delta 9.04 (s, 1H), 8.24 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.13-7.00 (m, 2H), 6.90 (td, J = 7.9, 1.3 Hz, 1H), 6.36 (dd, J = 7.9, 1.3 Hz, 1H), 5.04 (s, 2H), 4.84 (s, 2H), 2.18-1.87 (m, 8H).
    Ex. 19-24
    Figure US20180339993A1-20181129-C02088
         		1H-NMR (270 MHz, CDCl3): delta 9.21 (d, J = 1.3 Hz, 1H), 9.08 (d, J = 1.3 Hz, 1H), 8.74 (s, 1H), 8.24 (dd, J = 7.3, 2.0 Hz, 1H), 7.93 (dd, J = 9.2, 2.0 Hz, 1H), 7.54-7.41 (m, 2H), 5.18 (s, 2H), 2.55-2.21 (m, 4H), 2.09-1.91 (m, 4H). —NH is not observed.
    Ex. 19-30
    Figure US20180339993A1-20181129-C02089
         		1H-NMR (270 MHz, DMSO-d6): delta 9.05 (br. s, 1H), 8.27 (d, J = 7.9 Hz, 2H), 7.87 (d, J = 7.9 Hz, 2H), 7.53-7.44 (m, 1H), 7.30-7.22 (m. 3H), 5.04 (s, 2H), 2.25-1.80 (m, 8H).
    Ex. 21-1
    Figure US20180339993A1-20181129-C02090
         		1H-NMR (270 MHz, DMSO-d6): delta 9.03 (s, 1H), 8.48 (dd, J = 7.9, 2.0 Hz, 1H), 8.42-8.41 (m, 1H), 8.15 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.41-7.36 (m, 1H), 4.99 (s, 2H), 2.18-1.86 (m, 8H).
    Ex. 21-12
    Figure US20180339993A1-20181129-C02091
         		1H-NMR (270 MHz, DMSO-d6): delta 9.31 (d, J = 4.6 Hz, 1H), 9.01 (br.s, 1H), 8.41 (d, J = 4.6 Hz, 1H), 8.18 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.6 Hz, 2H), 5.00 (s, 2H), 2.25-1.75 (m, 8H).
    Ex. 22-1
    Figure US20180339993A1-20181129-C02092
         		1H-NMR (270 MHz, DMSO-d6): delta 9.11 (s, 1H), 8.51-8.49 (m, 1H), 8.33-8.21 (m, 5H), 7.48-7.43 (m, 1H), 4.87 (s, 2H), 3.47 (s, 2H), 2.10-1.91 (m, 8H).
    Ex. 23-1
    Figure US20180339993A1-20181129-C02093
         		1H-NMR (270 MHz, DMSO-d6): delta 11.6 (br. s, 1H), 9.05 (s, 1H), 8.22 (d, J = 8.6 Hz, 2H), 8.10-7.96 (m, 3H), 7.45 (d, J = 7.9 Hz, 1H), 7.16 (dd, J = 7.9, 5.3 Hz, 1H), 5.03 (s, 2H), 2.30-1.78 (m, 8H).
    EX 24-5
    Figure US20180339993A1-20181129-C02094
         		1H-NMR (270 MHz, DMSO-d6): delta 9.06 (br.s, 1H), 8.29 (d, J = 8.6 Hz, 2H), 8.23 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 7.9 Hz, 1H), 7.32 (t, J = 52.1 Hz, 1H), 5.09 (s, 2H), 2.54 (s, 3H), 2.30-1.75 (m, 8H).
    EX 24-7
    Figure US20180339993A1-20181129-C02095
         		1H-NMR (270 MHz, DMSO-d6): delta 9.05 (br.s, 1H), 8.35- 8.25 (m, 3H), 7.85 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 7.9 Hz, 1H), 5.10 (s, 2H), 2.55 (s, 3H), 2.30-1.75 (m, 8H).
    EX 26-3
    Figure US20180339993A1-20181129-C02096
         		1H-NMR (270 MHz, DMSO-d6): delta 9.03 (br.s, 1H), 8.24 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 8.6 Hz, 2H), 7.79 (d, J = 7.9 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H), 5.04 (s, 2H), 4.16 (s, 3H), 2.48 (S, 3H), 2.30-1.75 (m, 8H).
    EX 27-1
    Figure US20180339993A1-20181129-C02097
         		1H-NMR (270 MHz, DMSO-d6): delta 9.04 (br.s, 1H), 8.35- 8.26 (m, 3H), 7.96 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 8.6 Hz, 2H), 5.09 (s, 2H), 2.59 (s, 3H), 2.30-1.75 (m, 8H).
    • Measurement of the Menthol-Induced Ca2+ Influx in HEK293 Cells Stably Expressing Human TRPM8
  • A cell-based Ca2+ influx assay using HEK293 cells stably expressing human TRPM8 is used to identify the activity of compounds.
  • HEK293 cells stably expressing human TRPM8 are grown in T175 flasks at 37° C. in a 5% CO2 humidified incubator to about 80% confluence. Media composition consists of Dulbecco's Modified Eagle Medium (high glucose), 10% fetal calf serum (FCS), 100 units/mLPenicillin, 100 microg/mL Streptomycin and 600 microg/mL Geneticine. At 24 hours prior to assay, cells are seeded in poly-D-lysine coated 384-well plates (BD FALCON) at a density of 30,000 cells per well in culture medium and grown overnight in 5% CO2 at 37° C. On the assay day, growth media is removed and cells are loaded with 0.5 microM Fluo4-AM (Molecular Probes) and 0.005% Pluronic F-127 dissolved in assay buffer (Hank's balanced salt solution (HBSS), 19.4 mM HEPES pH7.4, 2.5 mM Probenecid) for 1 hour at room temperature. After washing with assay buffer, the cells are preincubated with various concentrations of the compounds for 5 min. The changes in intracellular calcium concentration by addition of 30 microM menthol are monitored by the cell imaging technology by Hamamatsu Photonics Functional Drug Screening System (FDSS). The IC50 values for compounds of the present invention are determined from 11-point dose-response studies. Curves are generated using the average of duplicate wells for each data point. Finally, the IC50 values are calculated with the best-fit dose curve determined by XLfit (ID Business Solutions Ltd.).
  • All tested compounds show less than about 3 microM of IC50 against TRPM8 in the above assays. Preferable compounds show less than about 500 nM of IC50 against TRPM8 in the above assays. More preferable compounds show less than about 100 nM of IC50 against TRPM8 in the above assays. Most preferable compounds show less than about 10 nM of IC50 against TRPM8 in the above assays.
  • Compounds with IC50 against TRPM8<500 nM are: 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-13, 1-14, 2-1, 2-2, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-11, 2-12, 2-13, 2-14, 2-15, 2-16, 2-17, 2-18, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12, 3-13, 3-14, 3-15, 3-16, 3-17, 3-18, 3-19, 3-20, 3-21, 3-22, 3-23, 3-24, 3-25, 3-26, 3-27, 3-28, 3-29, 4-1, 4-2, 4-3, 4-4, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 4-12, 5-1, 5-2, 5-3, 5-4, 5-5, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 5-12, 5-13, 5-14, 5-15, 5-16, 5-17, 5-18, 5-19, 5-20, 5-21, 5-22, 5-23, 5-24, 5-25, 5-26, 5-27, 5-28, 5-30, 5-31, 5-32, 5-33, 5-39, 5-40, 5-41, 6-1, 6-2, 6-3, 6-4, 6-5, 6-6, 6-7, 6-8, 6-9, 6-10, 6-11, 6-12, 6-13, 6-14, 6-15, 6-16, 6-17, 6-18, 6-19, 6-20, 6-21, 6-22, 6-23, 6-24, 6-25, 6-26, 6-27, 6-28, 6-29, 6-30, 6-31, 6-32, 6-33, 6-34, 6-35, 6-36, 6-37, 6-38, 6-39, 6-40, 6-41, 6-42, 6-43, 6-44, 6-45, 6-46, 6-47, 6-48, 6-49, 6-50, 6-51, 6-52, 6-53, 6-54, 6-55, 6-56, 6-57, 6-58, 6-59, 6-62, 6-63, 6-64, 6-65, 6-67, 6-68, 6-69, 6-71, 6-72, 6-76, 6-78, 6-80, 6-81, 6-82, 6-84, 6-85, 6-87, 6-90, 6-92, 6-93, 6-95, 6-96, 6-97, 6-98, 6-99, 6-100, 6-102, 6-104, 6-106, 6-108, 6-110, 6-113, 6-114, 6-116, 6-117, 6-119, 6-120, 6-122, 7-1, 7-2, 7-3, 7-4, 7-5, 7-6, 7-7, 7-8, 7-9, 7-10, 7-11, 7-12, 7-13, 7-14, 7-15, 7-16, 7-17, 7-18, 7-19, 7-20, 7-21, 7-22, 7-23, 7-24, 7-25, 7-26, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 8-7, 8-8, 8-9, 9-1, 9-2, 9-3, 9-4, 9-5, 9-6, 9-7, 9-8, 9-9, 9-10, 9-11, 9-12, 9-13, 9-14, 9-15, 9-16, 9-17, 9-18, 9-19, 9-20, 9-21, 9-22, 9-23, 9-24, 9-25, 9-26, 9-27, 10-1, 10-2, 11-1, 11-2, 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, 13-1, 13-2, 13-3, 13-4, 13-5, 13-6, 13-7, 13-8, 13-9, 13-10, 13-11, 13-12, 13-13, 13-14, 13-15, 13-16, 13-17, 13-18, 13-19, 13-20, 13-21, 13-22, 13-23, 13-24, 13-25, 13-26, 13-27, 13-28, 13-29, 13-30, 13-31, 13-32, 13-33, 13-34, 13-35, 13-36, 13-37, 13-38, 13-39, 13-40, 13-41, 13-42, 13-43, 13-44, 13-45, 13-46, 13-47, 13-48, 13-49, 13-50, 13-51, 13-52, 13-53, 13-54, 13-55, 13-56, 13-57, 13-68, 13-69, 13-71, 13-72, 14-1, 14-2, 14-3, 14-4, 14-5, 14-6, 14-7, 14-8, 14-9, 14-10, 14-11, 14-12, 14-13, 14-14, 14-15, 14-16, 14-17, 14-18, 14-19, 14-20, 14-21, 15-1, 15-2, 15-3, 15-4, 15-5, 15-6, 15-7, 15-8, 15-9, 15-10, 15-11, 15-12, 16-1, 16-2, 16-3, 16-4, 16-5, 16-6, 16-7, 16-8, 16-9, 16-10, 16-11, 16-12, 16-13, 16-14, 16-15, 16-16, 16-17, 16-18, 16-19, 16-20, 16-21, 16-22, 16-23, 16-24, 16-25, 16-26, 16-27, 16-28, 16-29, 16-30, 16-31, 16-32, 16-33, 16-34, 16-35, 16-36, 17-1, 17-2, 17-3, 17-4, 17-5, 17-6, 17-7, 17-8, 17-9, 17-10, 17-11, 17-12, 17-13, 17-14, 17-15, 18-1, 18-2, 18-3, 18-4, 18-5, 18-6, 18-7, 18-8, 18-9, 18-10, 18-11, 18-12, 18-13, 19-1, 19-2, 19-3, 19-4, 19-5, 19-6, 19-7, 19-8, 19-9, 19-10, 19-11, 19-12, 19-13, 19-14, 19-15, 19-16, 19-17, 19-18, 19-19, 19-20, 19-21, 19-22, 19-23, 19-24, 19-25, 19-26, 19-27, 19-30, 19-33, 19-34, 19-35, 19-37, 19-39, 20-1, 20-2, 20-3, 20-4, 20-5, 20-6, 20-7, 20-8, 20-9, 21-1, 21-2, 21-3, 21-4, 21-5, 21-6, 21-7, 21-8, 21-11, 21-12, 21-13, 21-14, 21-15, 21-16, 21-17, 22-1, 22-2, 22-3, 22-4, 22-6, 23-1, 23-2, 24-1, 24-2, 24-3, 24-4, 24-5, 24-6, 24-7, 25-3, 25-4, 26-1, 26-2, 26-3, 26-4, 27-1, 28-4, 28-5.
  • Compounds with IC50 against TRPM8<100 nM are: 1-1, 1-2, 1-3, 2-1, 2-2, 2-3, 2-4, 2-5, 2-11, 2-12, 2-13, 2-14, 2-15, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12, 3-13, 3-14, 3-15, 3-16, 3-17, 3-18, 3-19, 4-1, 4-2, 4-3, 4-4, 4-5, 4-6, 4-10, 5-1, 5-2, 5-3, 5-5, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 5-12, 5-13, 5-14, 5-15, 5-17, 5-18, 5-19, 5-20, 5-22, 5-25, 5-26, 5-27, 5-28, 5-30, 5-31, 5-32, 5-33, 5-39, 5-41, 6-1, 6-2, 6-3, 6-4, 6-5, 6-6, 6-7, 6-8, 6-9, 6-10, 6-11, 6-12, 6-13, 6-14, 6-15, 6-16, 6-17, 6-18, 6-19, 6-20, 6-21, 6-22, 6-23, 6-24, 6-25, 6-26, 6-27, 6-28, 6-29, 6-30, 6-31, 6-32, 6-33, 6-34, 6-35, 6-36, 6-37, 6-38, 6-39, 6-40, 6-41, 6-43, 6-44, 6-45, 6-54, 6-55, 6-57, 6-58, 6-63, 6-67, 6-68, 6-76, 6-81, 6-84, 6-87, 6-92, 6-97, 6-98, 6-106, 6-108, 6-114, 6-116, 6-122, 7-1, 7-2, 7-3, 7-4, 7-5, 7-6, 7-7, 7-8, 7-9, 7-10, 7-11, 7-12, 7-13, 7-14, 7-21, 7-22, 7-24, 7-25, 7-26, 8-1, 8-2, 8-3, 8-4, 8-5, 8-7, 8-8, 8-9, 9-1, 9-2, 9-3, 9-4, 9-5, 9-6, 9-7, 9-8, 9-9, 9-10, 9-11, 9-12, 9-13, 9-14, 9-15, 9-16, 9-17, 9-18, 9-19, 9-20, 9-21, 9-22, 9-23, 9-24, 9-25, 10-1, 10-2, 11-1, 11-2, 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 13-1, 13-2, 13-3, 13-4, 13-5, 13-6, 13-7, 13-8, 13-9, 13-10, 13-11, 13-12, 13-13, 13-14, 13-15, 13-16, 13-17, 13-18, 13-19, 13-20, 13-21, 13-22, 13-23, 13-24, 13-25, 13-26, 13-27, 13-28, 13-29, 13-30, 13-31, 13-32, 13-34, 13-35, 13-36, 13-37, 13-38, 13-39, 13-40, 13-41, 13-42, 13-43, 13-44, 13-45, 13-46, 13-47, 13-48, 13-49, 13-51, 13-53, 13-54, 13-55, 13-71, 13-72, 14-1, 14-2, 14-3, 14-4, 14-5, 14-6, 14-7, 14-8, 14-9, 14-10, 14-11, 14-12, 14-13, 14-14, 14-15, 14-16, 14-17, 15-1, 15-2, 15-3, 15-4, 15-5, 15-6, 15-7, 16-1, 16-2, 16-3, 16-4, 16-5, 16-6, 16-7, 16-8, 16-9, 16-10, 16-11, 16-12, 16-13, 16-14, 16-15, 16-16, 16-17, 16-18, 16-19, 16-20, 16-21, 16-22, 16-23, 16-24, 16-25, 16-27, 17-1, 17-2, 17-3, 17-4, 17-5, 17-6, 17-7, 17-8, 17-9, 17-10, 17-11, 18-1, 18-2, 18-3, 18-4, 18-5, 18-6, 18-9, 18-10, 18-11, 19-1, 19-2, 19-3, 19-4, 19-5, 19-6, 19-7, 19-8, 19-9, 19-10, 19-11, 19-12, 19-13, 19-14, 19-16, 19-17, 19-18, 19-20, 19-21, 19-22, 19-23, 19-24, 19-25, 19-26, 19-30, 19-33, 19-37, 20-1, 20-6, 20-7, 20-8, 21-1, 21-2, 21-5, 21-8, 21-12, 21-13, 21-14, 21-17, 22-1, 22-3, 22-4, 23-1, 23-2, 24-1, 24-5, 24-6, 24-7, 26-1, 26-2, 26-3, 26-4, 27-1, 28-5.
  • Compounds with IC50 against TRPM8<10 nM are: 5-7, 5-9, 5-10, 5-14, 5-27, 5-28, 6-1, 6-2, 6-3, 6-4, 6-5, 6-6, 6-7, 6-8, 7-1, 7-22, 9-1, 9-2, 9-3, 9-10, 9-11, 9-12, 12-1, 13-34, 13-35, 13-36, 13-37, 13-38, 13-71, 14-5, 15-6, 16-4, 17-6, 18-2, 19-14, 19-30, 19-33, 24-5, 24-7, 26-1, 26-3, 27-1.
    • Measurement of the Menthol-Induced Ca2+ Influx in a Human Malignant Melanoma Cell Lines
  • Since TRPM8 is expressed in a human malignant melanoma cell lines, G-361 (Health Science Research Resources Bank, Osaka, Japan), the G-361 cells are used for in vitro functional assay.
  • G-361 cells are grown in T175 flasks at 37° C. in a 5% CO2 humidified incubator to about 80% confluence. Media composition consists of McCoy's 5A medium and 10% FCS. At 48 hours prior to assay, cells are seeded in poly-D-lysine coated 96-well plates (Corning) at a density of 12,000 cells per well in culture medium and grown in 5% CO2 at 37° C. On the assay day, growth media is removed and cells are loaded with 5 microM Fluo-4 AM (Molecular Probes) and 0.005% Pluronic F-127 dissolved in assay buffer (HBSS, 19.4 mM HEPES pH7.4, 2.5 mM Probenecid) for 1 hour at room temperature. After washing with assay buffer, the cells are preincubated with various concentrations of the compounds for 5 min. The changes in intracellular calcium concentration by addition of 300 microM menthol are monitored by FDSS.
  • The IC50 values for compounds of the present invention are determined from dose-response studies. Curves are generated using the average of duplicate wells for each data point. Finally, the IC50 values are calculated with the best-fit dose curve determined by XLfit (ID Business Solutions Ltd.).
  • Compounds of this invention show good IC50 values, which show the above-mentioned practical use.
    • Chronic Constriction Injury (CCI)-Induced Model of Neuropathic Pain; Cold Allodynia
  • Male Sprague Dawley rats (7 weeks old at the start of experiment, n=7-10/treatment) purchased from Charles River Japan, Inc. are used. The CCI is made according to the method of Bennett G J and Xie Y K (Pain 1988, 33: 87-107). Rats are anesthetized with intraperitoneal injection of sodium pentobarbital. The left common sciatic nerve is exposed at the level of the middle of the thigh and four ligatures are loosely tided around it by using 4-0 silk thread (Ethicon Inc.) with about 1 mm space. Sham operation is performed in the same manner except of sciatic nerve ligation. One to two weeks following CCI surgery, cold allodynia is assessed using a cold plate (LHP-1700CP, TECA) with a temperature controller (Model3300-0, CAL Controls Inc.) as described by Tanimoto-Mori S et al. (Behav Pharmacol., 19: 85-90, 2008). The animals are habituated to the apparatus which consists of a transparent acrylic box (10×12×12 cm) on a stainless-steel plate (15×33 cm). The surface of the cold plate held on 10° C. and the temperature of the plate is monitored continuously with a precision of 10° C. For testing, the rat is placed on the cold plate and the paw withdrawal latency (PWL) is measured before and after the compound administration, with a cut-off value of 120 seconds. The compounds of the invention or their vehicles are administered perorally, subcutaneously or intraperitoneally. The percentages of inhibition are calculated as follows;
  • Inhibition ( % ) = PWL drug - PWL vehicle PWL sham - PWL vehicle × 100. { Math . 1 }
  • Compounds of this invention show potent activities in this model, which show the above-mentioned practical use.
    • Chronic Constriction Injury (CCI)-Induced Model of Neuropathic Pain; Static Allodynia
  • Male Sprague Dawley rats (7 weeks old at the start of experiment, n=7-10/treatment) purchased from Charles River Japan, Inc. are used. The CCI is made according to the method of Bennett G J and Xie Y K (Pain 1988, 33: 87-107). Rats are anesthetized with intraperitoneal injection of sodium pentobarbital. The left common sciatic nerve is exposed at the level of the middle of the thigh and four ligatures are loosely tided around it by using 4-0 silk thread (Ethicon Inc.) with about 1 mm space. Sham operation is performed in the same manner except of sciatic nerve ligation. Static allodynia is assessed using von Frey hairs (VFHs) at two to three weeks following CCI surgery as described by Field M J et al. (Pain 1999, 83: 303-311). The animals are habituated to grid bottom cages prior to the start of experiment. VFHs in ascending order of force (0.16, 0.4, 0.6, 1, 1.4, 2, 4, 6, 8, 10, 15 and 26 gram) are applied to the plantar surface of the hind paw. Each VFH is applied to the ipsilateral paw for 6 seconds or until a withdrawal response is occurred. Once a withdrawal response is happened, the paw is re-tested, starting with the next descending VFH until no response is occurred. The lowest amount of force required to elicit a response is recorded as paw withdrawal threshold (PWT). Static allodynia is defined as present if animals responded to or below the innocuous 1.4 gram VFH. The compounds of the invention or their vehicles are administered perorally, subcutaneously or intraperitoneally. The percentages of inhibition are calculated as follows;
  • Inhibition ( % ) = log 10 ( PWT drug ) - log 10 ( PWT vehicle ) log 10 ( PWT sham ) - log 10 ( PWT vehicle ) × 100. { Math . 2 }
  • Compounds of this invention show potent activities in this model, which show the above-mentioned practical use.
    • Oxaliplatin-Induced Model of Neuropathic Pain; Cold and Static Allodynia
  • Male Sprague Dawley rats (7 weeks old at the start of experiment, n=7-10/treatment) purchased from Charles River Japan, Inc. are used. The study is conducted according to the method of Gauchan P et al. (NeuroSci Lett, 2009, 458, 93-95). Oxaliplatin (Yakult Co., Ltd.) is dissolved in 5% glucose. Oxaliplatin (4 mg/kg) is injected intraperitoneally twice a week for two-week. Cold allodynia is assessed using a cold plate (LHP-1700CP, TECA) with a temperature controller (Model3300-0, CAL Controls Inc.) as described by Tanimoto-Mori S et al. (Behav Pharmacol., 19: 85-90, 2008). The animals are habituated to the apparatus which consists of a transparent acrylic box (10×12×12 cm) on a stainless-steel plate (15×33 cm). The surface of the cold plate held on 10° C. and the temperature of the plate is monitored continuously with a precision of 0.1° C. For testing, the animal is placed on the cold plate and PWL is measured before and after the compound administration, with a cut-off value of 120 seconds. Static allodynia is assessed using VFHs. The animals are habituated to grid or mesh bottom cages prior to the start of experiment. VFHs in ascending order of force (0.16, 0.4, 0.6, 1, 1.4, 2, 4, 6, 8, 10, 15 and 26 gram) are applied to the plantar surface of the hind paw. Once a withdrawal response is happened, the paw is re-tested, starting with the next descending VFH until no response is occurred. The lowest amount of force required to elicit a response is recorded as paw withdrawal threshold (PWT). For testing, PWT is measured before and after the compound administration. The compounds of the invention or their vehicles are administered perorally, subcutaneously or intraperitoneally.
  • Compounds of this invention show potent activities in this model, which show the above-mentioned practical use.
  • Oxaliplatin-induced model of neuropathic pain; cold hyperalgesia/allodynia
  • Male Sprague Dawley rats (7 weeks old, n=8-10/treatment) purchased from Charles River Japan, Inc. were used. Oxaliplatin (Wako Pure Chemical Industries, Ltd.) was dissolved in 5% glucose for injection to make 4 mg/mL solution. Oxaliplatin (4 mg/kg) was injected intraperitoneally twice a week for two-week (on Days 1, 2, 8, 9) in a volume of 1 mL/kg. First day of treatment was defined as Day 1. Cold hyperalgesia/allodynia was assessed by acetone test. The animals were habituated to grid or mesh bottom cages prior to the start of experiment. Acetone (50 mL) was applied to the plantar surface of the hind paw. After the application, nociceptive responses were scored as follows: 0; no response, 1; stamping and/or lifting of the paw, 2; licking/biting or flinching of the paw once, 3; repeated licking/biting and/or flinching of the paw. Acetone was repeatedly applied to the left and right hind paws (twice for each, total 4 applications), thus total score were maximum 12 and minimum 0. For testing, total score was measured before and after the compound administration. The compounds of the invention or their vehicles were administered perorally, subcutaneously or intraperitoneally.
  • Compounds of this invention showed potent activities in this model, which show the above-mentioned practical use
    • Icilin-Induced Wet-Dog Shakes in Rats
  • Male Sprague Dawley rats (6-7 weeks old, Charles River Japan, Inc., n=5-8/treatment) are used to evaluate the ability of the compounds of the invention to block the spontaneous wet-dog shakes (WDS) behavior induced by icilin. Rats are acclimated in observation boxes (21.5×26.5×25.0 cm) for at least 20 minutes before icilin injection. Icilin (Sigma) dissolved in PEG400 is administered intraperitoneally at 0.5, 1.0 or 2.5 mg/kg and spontaneous WDS are counted over 30 min post-icilin. The compounds of the invention or their vehicles are administered perorally, subcutaneously or intraperitoneally before icilin injection. The percentages of inhibition are calculated as follows;

  • % inhibition=[1−(compound WDS count/vehicle WDS count)]×100.  {Math. 3}
  • Compounds of this invention show potent activities in this model, which show the above-mentioned practical use.
    • Measurement of the Micturition Frequency in Guinea Pigs In Vivo
  • Female Guinea Pigs (300-450 g) are anaesthetized with urethane. A midline abdominal incision is performed, both ureters are exposed and ligated, a catheter is implanted in the bladder pole and the abdomen is closed. For administration of the compounds the vena jugularis is exposed and cannulated with a catheter. After this surgery the bladder catheter is connected via a t-shaped tube to an infusion pump and to a pressure transducer. Saline is infused and intrabladder pressure is registered. After 1 h of equilibration period and the establishment of constant voiding cycles, menthol (0.2-0.6 mM) is added to the infused saline. At this point also vehicle (control group) or TRPM8 antagonists are administered i.v. as bolus injection. The effect of treatment on the micturition interval (corresponding to bladder capacity) and micturition pressure is calculated and compared between vehicle-treated and compound-treated groups.
  • Compounds of this invention show potent activities in this model, which show the above-mentioned practical use.
    • Measurement of Over Active Bladder in Anesthetized Cystitis Rats
  • Female Sprague-Dawley rats (7-8 weeks/Japan SLC) are used. Cyclophosphamide (Wako) dissolved in saline (Otsuka) is administered intraperitoneally at 200 mg/kg. On the next day, rats are anesthetized by administration of urethane at 0.9 mg/kg, s.c. The abdomen is opened through a midline incision, and a polyethylene catheter is implanted into the bladder through the dome. The bladder catheter is connected via T-tube to a pressure transducer and a microinjection pump. Saline is infused at room temperature into the bladder at a rate of 3 mL/hour. Intravesical pressure is recorded continuously on a chart pen recorder for about 1 hour before a test compound administration.
  • A testing compound dissolved in PBS containing WellSolve (Celeste) is administered intravenously at 1 mg/kg, 3 mg/kg, 5 mg/kg or 10 mg/kg.
  • The micturition frequency calculated from micturition interval during 60 min after administration of testing compound was analyzed from the cystometry data. The testing compounds mediated inhibition of the frequency was evaluated using Dunnett’ method vs vehicle. A probability levels less than 5% is accepted as significant difference. Data are analyzed as this mean+/−SEM from 8-12 rats.
  • All tested compounds show significant effect on over active bladder in anesthetized cystitis rats.
    • Human Dofetilide Binding Assay
  • Human HERG transfected HEK293S cells are prepared and grown in-house. The collected cells are suspended in 50 mM Tris-HCl (pH 7.4 at 4° C.) and homogenized using a hand held Polytron PT 1200 disruptor set at full power for 20 sec on ice. The homogenates are centrifuged at 48,000×g at 4° C. for 20 min. The pellets are then resuspended, homogenized, and centrifuged once more in the same manner. The final pellets are resuspended in an appropriate volume of 50 mM Tris-HCl, 10 mM KCl, 1 mM MgCl2 (pH 7.4 at 4° C.), homogenized, aliquoted and stored at −80° C. until use. An aliquot of membrane fractions is used for protein concentration determination using BCA protein assay kit (PIERCE) and ARVOsx plate reader (Wallac). Binding assays are conducted in a total volume of 30 microL in 384-well plates. The activity is measured by PHERAstar (BMG LABTECH) using fluorescence polarization technology. Ten microL of test compounds are incubated with 10 microL of fluorescence ligand (6 nM Cy3B tagged dofetilide derivative) and 10 microL of membrane homogenate (6 microgram protein) for 120 minutes at room temperature. Nonspecific binding is determined by 10 microM E4031 at the final concentration.
  • All tested compounds of the invention show higher IC50 values in human dofetilide binding than IC50 values in TRPM8 functional assay described above.
  • The closest compound described as an example 2-121 in WO2014/130582 to the present invention is the following compound.
  • Figure US20180339993A1-20181129-C02098
  • The closest compound has 19 microM of IC50 and 6.5 microM of Ki values in human dofetilide binding assay, whereas the compounds of the present invention have the higher IC50 values in human dofetilide binding assay, which leads to reducing the risk of cardiovascular adverse events.
    • Metabolic Stability Assay:
  • Half-Life in Human Liver Microsomes (HLM)
  • Test compounds (1 microM) are incubated with 1 mM MgCl2 and 0.78 mg/mL HLM (HL101) or 0.74 mg/mL HLM (Gentest UltraPool 150) or 0.61 mg/mL HLM (XenoTech XTreme 200) in 100 mM potassium phosphate buffer (pH 7.4) at 37° C. on the 96-deep well plate. The reaction mixture is split into two groups, a non-P450 and a P450 group on necessary. NADPH is only added to the reaction mixture of the P450 group. (NADPH generation system is also used instead of NADPH.) An aliquot of samples of P450 group is collected at 0, 10, 30, and 60 min time point, where 0 min time point indicated the time when NADPH is added into the reaction mixture of P450 group. An aliquot of samples of non-P450 group is collected at −10 and 65 min time point. Collected aliquots are extracted with acetonitrile solution containing an internal standard. The precipitated protein is spun down in centrifuge (2000 rpm, 15 min). The compound concentration in supernatant is measured by LC/MS/MS system.
  • The half-life value is obtained by plotting the natural logarithm of the peak area ratio of compounds/internal standard versus time. The slope of the line of best fit through the points yield the rate of metabolism (k). This is converted to a half-life value using following equations:

  • Half-life=ln 2/k  {Math. 4}
  • The compounds of this invention show preferable stability, which show the above-mentioned practical use.
  • The closest compound described as an example 2-121 in WO2014/130582 has less than 5 minutes of the half-live in HLM and has the large intrinsic clearance (CLint) of more than 215 mL/min/kg, whereas the present invention has more than 5 minutes in the half-live in HLM and CLint of <100 mL/min/kg in metabolism stability assay, which leads to good pharmacokinetic properties.
    • Drug-Drug Interaction Assay
  • This method essentially involves determining the percent inhibition of metabolites formation from probes (Tacrine 2 microM or phenacetin 50 microM for CYP1A2, bupropion 3 microM for CYP2B6, amodiaquine 2 microM for CYP2C8, diclofenac 5 or 10 microM for CYP2C9, S-mephenytoin 40 microM for CYP2C19, dextromethorphan 5 microM or bufuralol 5 microM for CYP2D6, and midazolam 2 microM or 2.5 microM for CYP3A4) at 3 microM or 0.4-50 microM of the each compound.
  • More specifically, the assay is carried out as follows. The compounds (60 microM, 10 microL) are pre-incubated in 170 microL of mixture including 0.1 mg protein/mL or 0.05 mg protein/mL human liver microsomes, 100 mM potassium phosphate buffer (pH 7.4), 1 mM MgCl2 or 3.3 mM MgCl2 and probes as substrate for appropriate time (5 min or 30 min). Reaction is started by adding a 20 microL of 10 mM NADPH or 10 microL of 13 microM NADPH. The assay plate is incubated at 37° C. Acetonitrile or methanol is added to the incubate solution at appropriate time (8 min or 10 min).
  • The metabolites' concentration in the supernatant is measured by LC/MS/MS system. The degree of drug-drug interaction is interpreted based on generation % of metabolites in the presence or absence of test compound or IC50 values calculated from generation % of metabolites vs. compound concentration.
  • The compounds of this invention show preferable results, which show the above-mentioned practical use.
    • Plasma Protein Binding Assay
  • Plasma protein binding of the test compound (1 microM) is measured by the method of equilibrium dialysis using 96-well plate type equipment. HTD96a(registeredtrademark), regenerated cellulose membranes (molecular weight cut-off 12,000-14,000, 22 mm×120 mm) are soaked for over night in distilled water, then for 15 minutes in 30% ethanol, and finally for 20 minutes in dialysis buffer (Dulbecco's phosphate buffered saline, minus CaCl2 and MgCl2). Frozen plasma of human, Sprague-Dawley rats, and Beagle dogs are used. The dialysis equipment is assembled and added 150 microL of compound-fortified plasma to one side of each well and 150 microL of dialysis buffer to the other side of each well. After 4 hours incubation at 37° C. for 150 r.p.m, aliquots of plasma and buffer are sampled. The compound in plasma and buffer are extracted with 300 microL of acetonitrile or acetonitrile/methanol (1/1) containing internal standard compounds for analysis. The concentration of the compound is determined with LC/MS/MS analysis.
  • The fraction of the compound unbound is calculated by the following equation (A) or (B):

  • {Math. 5}

  • fu=1−{([plasma]eq−[buffer]eq)/([plasma]eq)}  (A)
  • wherein [plasma]eq and [buffer]eq are the concentrations of the compound in plasma and buffer, respectively.
  • ( B ) fu ( % ) = Cb / Cis , b × 4 Cp / Cis , p × 4 3 × 100. { Math . 6 }
  • wherein Cp is the peak area of the compound in plasma sample;
    Cis,p is the peak area of the internal standard in plasma sample;
    Cb is the peak area of the compound in buffer sample;
    Cls,b is the peak area of the internal standard in buffer sample;
    4 and 4/3 is the reciprocal of the dilution rate in plasma and buffer, respectively.
  • The compounds of this invention show preferable plasma protein binding, which show the above-mentioned practical use.
    • Equilibrium Aqueous Solubility Study
  • The DMSO solution (2 microL, 30 mM) of each compound is dispensed into each well of a 96-well glass bottom plate. Potassium phosphate buffer solution (50 mM, 198 microL, pH 6.5) is added to each well, and the mixture is incubated at 37° C. with rotate shaking for 24 hours. After centrifugation at 2000 g for 5 minutes, the supernatant is filtered through the polycarbonate Isopore membrane. The concentration of samples is determined by a general gradient HPLC method (J. Pharm. Sci., 95, 2115-2122, 2006).
  • All publications, including but not limited to, issued patents, patent applications, and journal articles, cited in this application are each herein incorporated by reference in their entirety. Although the invention has been described above with reference to the disclosed embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.

Claims (13)

1. A compound of the following formula (I):
Figure US20180339993A1-20181129-C02099
wherein
A is selected from the group consisting of: phenyl, pyridine, pyridazine, pyrazine, pyrimidine, triazine, thiophene, furan, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, and triazole;
B is phenyl, 5 to 6 membered heteroaryl, or 9 to 10 membered bicyclic heteroaryl
wherein, when A is phenyl, B is not phenyl;
L is independently selected from the group consisting of: a chemical bond, oxygen, and —NR4—;
X is independently selected from the group consisting of: —CH2—, oxygen, and NH;
RA and RB are independently selected from the group consisting of: (1) hydrogen and (3) (C1-C6)alkyl; or RA and RB form an oxo group (═O);
R1 is independently selected from the group consisting of: (1) hydrogen and (6) (C1-C6) alkyl; or
alternatively, two R1 on the same carbon or different carbons form a 3 to 8 membered cycloalkyl ring;
R2 is independently selected from the group consisting of: (1) hydrogen, (2) fluorine, (3) chlorine, (4) iodine, (7) hydroxyl, (10) (C1-C6)alkyl, (12) (C1-C6)alkoxy, (13) (C1-C6)haloalkyl, and (14) (C1-C6)haloalkoxy;
R3 is independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) cyano, (5) hydroxyl, (8) (C1-C6)alkylsulfonyl, (9) —NR5R6, (10) —C(═O)NR5R6, (12) (C1-C6)alkyl, (14) (C1-C6)alkoxy(C0-C6)alkyl, and (16) —C(═O)(C1-C6)alkyl; wherein the (C1-C6)alkyl, and (C1-C6)alkoxy(C0-C6)alkyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4) cyano, and (9) —NR6R5;
wherein R5 and R6 together with nitrogen atom to which they are attached, may form a 3 to 7 membered ring which may contain an atom selected from oxygen and nitrogen; and the 3 to 7 membered ring is optionally substituted with a substituent independently selected from the group consisting of: (1) hydrogen, (3) hydroxyl, and (7) (C1-C6)alkoxy;
R4 is independently selected from the group consisting of: (1) hydrogen and (2) (C1-C6)alkyl;
R5 and R6 are independently selected from the group consisting of: (1) hydrogen, (2) (C1-C6)alkyl, (5) hydroxyl(C1-C6)alkyl, (6) (C1-C6)alkoxy(C1-C6)alkyl, and (7) H2N—(C1-C6)alkyl;
p is 1, 2, 3 or 4;
q is 1, 2, 3, or 4, and when q is 2 or more than 2, R1 is the same or different;
r is 1 or 2, and when r is 2, R2 is the same or different;
s is 1 or 2, when s is 2, R3 is the same or different;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, which is selected from the group consisting of:
3-(2-(2,5-dimethyl-1-phenyl-1H-imidazol-4-yl)-2-oxoethyl)-1-oxa-3-azaspiro[4.5]decane-2,4-dione;
3-(2-(2,5-dimethyl-1-(m-tolyl)-1H-imidazol-4-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
3-(2-(1,4-dimethyl-5-phenyl-1H-pyrazol-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
3-(2-([2,3′-bipyridin]-5-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
3-(2-(4-(2-methyl-1H-benzo[d]imidazol-1-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.6]undecane-2,4-dione;
3-(2-oxo-2-(4-(pyridin-2-yloxy)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
3-(2-(4-(2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.6]undecane-2,4-dione;
3-(2-(4-(2-methyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
3-(2-oxo-2-(4-(pyridazin-3-yl oxy)phenyl)ethyl)-1,3-diazaspiro[4.6]undecane-2,4-dione;
3-(2-(4-(2-methylpyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
3-(2-(4-(4-methylpyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
3-(2-(4-(3-methylthiophen-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
3-(2-(4-(3,6-dimethylpyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
6-(4-(2-(2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)picolinonitrile;
3-(4-(2-(2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)acetyl)phenyl)picolinonitrile;
3-(2-(4-(4-(hydroxymethyl)pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
3-(2-(4-(3-(hydroxymethyl)pyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
3-(2-(4-(3-methylpyrazin-2-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
3-(2-(4′-methyl-[2,3′-bipyridin]-5-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
3-(2-(2′-methyl-[2,3′-bipyridin]-5-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
3-(2-oxo-2-(4-(pyridin-3-yl)phenyl)ethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
3-(2-(2-fluoro-4-(pyridin-3-yl)phenyl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
3-(2-(4-methyl-5-(pyridin-3-yl)thiophen-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
3-(2-(4-methyl-5-(4-methylpyridin-3-yl)thiophen-2-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione; and
3-(2-(6-(methyl(pyridin-2-yl)amino)pyridin-3-yl)-2-oxoethyl)-1,3-diazaspiro[4.5]decane-2,4-dione;
or a pharmaceutically acceptable salt thereof.
3. A method of antagonizing a TRPM8 receptor in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
4. A method for treating a condition or disorder, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the condition or disorder is at least one selected from the group consisting of a pain disease or disorder, ischemia, irritable bowel syndrome, Raynaud's syndrome, neurodegeneration, fibromyalgia, stroke, itch, a psychiatric disorder, an inflammatory disorder, anxiety, and a urological disease or disorder.
5. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable carrier or excipient.
6. The pharmaceutical composition according to claim 5, which further comprises another pharmacologically active agent.
7. A process for preparing a pharmaceutical composition comprising mixing a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
8. The method according to claim 3, wherein the mammal is a human.
9. The method according to claim 4, wherein the pain disease or disorder is at least one selected from the group consisting of chronic pain, neuropathic pain, postoperative pain, osteoarthritis, rheumatoid arthritic pain, cancer pain, neuralgia, neuropathies, algesia, dentin hypersensitivity, nerve injury, migraine, cluster, and a tension headache.
10. The method according to claim 9, wherein the neuropathic pain is at least one selected from the group consisting of cold allodynia and diabetic neuropathy.
11. The method according to claim 4, wherein the psychiatric disorder is at least one selected from the group consisting of anxiety and depression.
12. The method according to claim 4, wherein the inflammatory disorder is at least one selected from the group consisting of asthma, chronic obstructive pulmonary, airways disease, COPD, and pulmonary hypertension.
13. The method according to claim 4, wherein the urological disease or disorder is at least one selected from the group consisting of detrusor overactivity, overactive bladder, urinary incontinence, neurogenic detrusor overactivity, detrusor hyperflexia, idiopathic detrusor overactivity, detrusor instability, benign prostatic hyperplasia, and a lower urinary tract symptom.
US16/050,514 2014-03-14 2018-07-31 Azaspiro derivatives as trpm8 antagonists Abandoned US20180339993A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US16/050,514 US20180339993A1 (en) 2014-03-14 2018-07-31 Azaspiro derivatives as trpm8 antagonists

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201461953521P 2014-03-14 2014-03-14
PCT/JP2015/001454 WO2015136947A1 (en) 2014-03-14 2015-03-16 Azaspiro derivatives as trpm8 antagonists
US201615125615A 2016-09-13 2016-09-13
US16/050,514 US20180339993A1 (en) 2014-03-14 2018-07-31 Azaspiro derivatives as trpm8 antagonists

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US15/125,615 Continuation US10093678B2 (en) 2014-03-14 2015-03-16 Azaspiro derivatives as TRPM8 antagonists
PCT/JP2015/001454 Continuation WO2015136947A1 (en) 2014-03-14 2015-03-16 Azaspiro derivatives as trpm8 antagonists

Publications (1)

Publication Number Publication Date
US20180339993A1 true US20180339993A1 (en) 2018-11-29

Family

ID=54071402

Family Applications (2)

Application Number Title Priority Date Filing Date
US15/125,615 Active US10093678B2 (en) 2014-03-14 2015-03-16 Azaspiro derivatives as TRPM8 antagonists
US16/050,514 Abandoned US20180339993A1 (en) 2014-03-14 2018-07-31 Azaspiro derivatives as trpm8 antagonists

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US15/125,615 Active US10093678B2 (en) 2014-03-14 2015-03-16 Azaspiro derivatives as TRPM8 antagonists

Country Status (12)

Country Link
US (2) US10093678B2 (en)
EP (1) EP3116858B1 (en)
JP (1) JP6643545B2 (en)
KR (1) KR102425400B1 (en)
CN (1) CN106103416B (en)
CA (1) CA2940621C (en)
ES (1) ES2850999T3 (en)
HK (1) HK1226064A1 (en)
MX (1) MX2016011632A (en)
RU (1) RU2683309C2 (en)
TW (1) TWI674257B (en)
WO (1) WO2015136947A1 (en)

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2011323245B2 (en) 2010-11-05 2016-01-21 Senomyx, Inc. Compounds useful as modulators of TRPM8
MX2016009809A (en) 2014-01-27 2016-12-02 Molecular Templates Inc De-immunized shiga toxin a subunit effector polypeptides for applications in mammals.
US20180258143A1 (en) 2015-05-30 2018-09-13 Molecular Templates, Inc. De-Immunized, Shiga Toxin A Subunit Scaffolds and Cell-Targeting Molecules Comprising the Same
MX2018001885A (en) 2015-08-14 2018-08-16 Bayer Cropscience Ag Triazole derivatives, intermediates thereof and their use as fungicides.
WO2017043092A1 (en) * 2015-09-11 2017-03-16 Raqualia Pharma Inc. Imidazolinone derivatives as trpm8 antagonists
CN108473484B (en) 2015-10-01 2021-06-29 弗门尼舍公司 Compounds useful as TRPM8 modulators
KR20220100719A (en) 2015-12-10 2022-07-15 피티씨 테라퓨틱스, 인크. Composition for treating huntington's disease
EA034898B1 (en) * 2016-01-13 2020-04-03 Грюненталь Гмбх 8-amino-2-oxo-1,3-diaza-spiro[4.5]decane derivatives
BR112018073700A2 (en) * 2016-05-19 2019-02-26 Glaxosmithkline Intellectual Property (No. trpv4 antagonist
MX2019006656A (en) 2016-12-07 2019-09-09 Molecular Templates Inc Shiga toxin a subunit effector polypeptides, shiga toxin effector scaffolds, and cell-targeting molecules for site-specific conjugation.
JP7082424B2 (en) 2017-01-25 2022-06-08 モレキュラー テンプレーツ，インク． Cell-targeted molecule containing deimmunized Shiga toxin A subunit effector and CD8 + T cell epitope
EP3580218A1 (en) * 2017-02-08 2019-12-18 Bayer CropScience Aktiengesellschaft Novel triazole derivatives
WO2018226622A1 (en) 2017-06-05 2018-12-13 Ptc Therapeutics, Inc. Compounds for treating huntington's disease
CA3067592A1 (en) 2017-06-28 2019-01-03 Ptc Therapeutics, Inc. Methods for treating huntington's disease
CN111182898B (en) 2017-06-28 2024-04-16 Ptc医疗公司 Methods for treating huntington's disease
KR102636384B1 (en) 2017-08-04 2024-02-14 스카이호크 테라퓨틱스, 인코포레이티드 Methods and compositions for modulating splicing
EA202092001A1 (en) * 2018-03-27 2021-01-29 ПиТиСи ТЕРАПЬЮТИКС, ИНК. COMPOUNDS FOR TREATMENT OF GENTINGTON'S DISEASE
MX2019009726A (en) 2018-04-17 2020-02-05 Molecular Templates Inc Her2-targeting molecules comprising de-immunized, shiga toxin a subunit scaffolds.
SG11202012674PA (en) 2018-06-27 2021-01-28 Ptc Therapeutics Inc Heterocyclic and heteroaryl compounds for treating huntington's disease
WO2020005882A1 (en) 2018-06-27 2020-01-02 Ptc Therapeutics, Inc. Heteroaryl compounds for treating huntington's disease
WO2020160464A1 (en) * 2019-02-01 2020-08-06 Marshall University Research Corporation Transient receptor potential melastatin 8 (trpm8) antagonists and related methods
KR20210135241A (en) 2019-02-05 2021-11-12 스카이호크 테라퓨틱스, 인코포레이티드 Methods and compositions for controlling splicing
KR20210135507A (en) 2019-02-06 2021-11-15 스카이호크 테라퓨틱스, 인코포레이티드 Methods and compositions for controlling splicing
WO2021055816A1 (en) 2019-09-18 2021-03-25 Molecular Templates, Inc. Pd-l1 binding molecules comprising shiga toxin a subunit scaffolds
CA3152752A1 (en) 2019-10-01 2021-04-08 Thomas Henley Genetic engineering of fungi to modulate tryptamine expression
CN111423353B (en) * 2020-04-29 2022-03-22 湖北省生物农药工程研究中心 Polysubstituted N-arylpyrrole compound and preparation method thereof
CN111518015A (en) * 2020-05-20 2020-08-11 上海合全药物研发有限公司 Preparation method of tert-butyl-8-oxylidene-2-azaspiro [4.5] decane-2-formic acid ester

Family Cites Families (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5739336A (en) 1995-06-23 1998-04-14 Syntex (U.S.A.) Inc. 1,3,8-triaza- and 3,8-diaza-1-oxaspiro 4,5! decane derivatives
WO2005044978A2 (en) 2003-07-15 2005-05-19 Washington University Methods of treating, preventing and inhibiting cancer metastasis and tumor formation
WO2006040103A1 (en) 2004-10-13 2006-04-20 Bayer Healthcare Ag Use of cold menthol receptor modulators for the treatment of respiratory disorders
US20080214654A1 (en) 2004-10-13 2008-09-04 Bayer Healthcare Ag Substituted Benzyloxy-Phenylmethylamide Derivatives
AR057579A1 (en) * 2005-11-23 2007-12-05 Merck & Co Inc SPIROCICLICAL COMPOUNDS AS INHIBITORS OF ACETYLASE HISTONE (HDAC)
EP2061775A2 (en) * 2006-09-13 2009-05-27 Astra Zeneca AB Spiro-oxazolidinone compounds and their use as metabotropic glutamate receptor potentiators
CA2709784A1 (en) * 2007-12-21 2009-07-09 University Of Rochester Method for altering the lifespan of eukaryotic organisms
WO2010037081A1 (en) 2008-09-29 2010-04-01 Palatin Technologies, Inc. Melanocortin receptor-specific spiro-piperidine compounds
US8232409B2 (en) * 2008-10-15 2012-07-31 Janssen Pharmaceutica N.V. Heterocyclic benzimidazoles as TRPM8 modulators
WO2010103381A1 (en) * 2009-03-13 2010-09-16 Glenmark Pharmaceuticals S.A. Spirocyclic piperidine derivatives as trpm 8 modulators
WO2011005052A2 (en) 2009-07-10 2011-01-13 Green Gross Corporation Novel arylpiperazine-containing imidazole 4-carboxamide derivatives and pharmaceutical composition comprising same
WO2011148962A1 (en) 2010-05-25 2011-12-01 大正製薬株式会社 Novel heterocyclic compound or salt thereof
EP2720546B1 (en) 2011-06-17 2016-04-06 Glaxosmithkline Intellectual Property (No. 2) Limited Spiro-cyclic trpv4 antagonists
WO2014025651A1 (en) 2012-08-06 2014-02-13 Amgen Inc. Chroman derivatives as trpm8 inhibitors
EP3461816B1 (en) 2013-02-19 2021-03-24 Firmenich Incorporated Five-membered heterocylic compounds useful as modulators of trpm8
US9446033B2 (en) 2013-03-01 2016-09-20 Clio, Inc. Pharmaceutical composition including migratory factor for guiding pluripotent stem cells to injury

Also Published As

Publication number Publication date
CA2940621A1 (en) 2015-09-17
HK1226064A1 (en) 2017-09-22
EP3116858B1 (en) 2020-11-11
KR20160132041A (en) 2016-11-16
JP2017507981A (en) 2017-03-23
RU2683309C2 (en) 2019-03-28
US10093678B2 (en) 2018-10-09
MX2016011632A (en) 2016-12-12
CN106103416B (en) 2021-03-02
CA2940621C (en) 2022-03-15
EP3116858A4 (en) 2017-11-22
WO2015136947A1 (en) 2015-09-17
KR102425400B1 (en) 2022-07-26
JP6643545B2 (en) 2020-02-12
EP3116858A1 (en) 2017-01-18
TWI674257B (en) 2019-10-11
RU2016140338A3 (en) 2018-10-24
CN106103416A (en) 2016-11-09
ES2850999T3 (en) 2021-09-02
US20170002016A1 (en) 2017-01-05
TW201623250A (en) 2016-07-01
RU2016140338A (en) 2018-04-19

Similar Documents

Publication Publication Date Title
US10093678B2 (en) Azaspiro derivatives as TRPM8 antagonists
US9051296B2 (en) Aryl carboxamide derivatives as TTX-S blockers
JP6605462B2 (en) Condensed piperidine amides as modulators of ion channels
EP2424517A1 (en) Sulfamoyl benzoic acid derivatives as trpm8 antagonists
US8999974B2 (en) Acyl piperazine derivatives as TTX-S blockers
JP7055528B1 (en) Ketoamide derivative as a protease inhibitor
US11802120B2 (en) Fused cyclic urea derivatives as CRHR2 antagonist
US8829026B2 (en) Sulfamoyl benzoic acid heterobicyclic derivatives as TRPM8 antagonists
US20240018103A1 (en) 3-hydroxyoxindole derivatives as crhr2 antagonist
WO2021145401A1 (en) Spiroheterocyclic derivatives as crhr2 antagonist
BR112016020223B1 (en) COMPOUND, USE OF THE SAME, PHARMACEUTICAL COMPOSITION, AND PROCESS FOR THE PREPARATION OF THE SAME
US20180305341A1 (en) Imidazolinone derivatives as trpm8 antagonists
RU2778641C2 (en) Derivatives of condensed cyclic urea in crhr2 antagonist
US20230373925A1 (en) Heteroaryl compounds for the treatment of pain

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

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