DK2785693T3 - Aryldihydropyridoner og piperidoner som mga2-inhibitorer - Google Patents

Aryldihydropyridoner og piperidoner som mga2-inhibitorer Download PDF

Info

Publication number
DK2785693T3
DK2785693T3 DK12821212.3T DK12821212T DK2785693T3 DK 2785693 T3 DK2785693 T3 DK 2785693T3 DK 12821212 T DK12821212 T DK 12821212T DK 2785693 T3 DK2785693 T3 DK 2785693T3
Authority
DK
Denmark
Prior art keywords
alkyl
independently selected
group
conh
compound
Prior art date
Application number
DK12821212.3T
Other languages
English (en)
Inventor
Huji Turdi
Jon J Hangeland
R Michael Lawrence
Dong Cheng
Saleem Ahmad
Wei Meng
Robert Paul Brigance
Pratik Devasthale
Guohua Zhao
Original Assignee
Bristol Myers Squibb Co
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 Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Application granted granted Critical
Publication of DK2785693T3 publication Critical patent/DK2785693T3/da

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic 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
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • 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
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed 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
    • 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
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/535—Organo-phosphoranes
    • C07F9/5352—Phosphoranes containing the structure P=C-
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/59—Hydrogenated pyridine rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Neurology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Urology & Nephrology (AREA)
  • Endocrinology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Child & Adolescent Psychology (AREA)
  • Dermatology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Claims (35)

  1. ARYLDIHYDROPYRIDONER OG PIPERIDONER SOM MGA2-INHIBITORER PATENTKRAV
    1. Forbindelse med formlen (I):
    (I) eller en stereoisomer, en tautomer, et farmaceutisk acceptabelt salt eller et solvat deraf, hvor: — betegner en enkelt eller dobbelt binding; x og y begge både kan være en enkelt binding; når x er en dobbelt binding, så er y en enkelt binding, og R4 og R16 er fraværende; når y er en dobbelt binding, så er x en enkelt binding, og R5 og R*6 er fraværende; R1 uafhængigt er udvalgt fra gruppen bestående af: -CONH(C418-alkyl), -CONHC2 8-haloalkyl, -CONH(CH2)18-Ph, -CONHCH2COC2 8-alkyl, -(CH2)m-(C31Q-carbocyklus substitueret med 0-2 Rb og 0-2 R8), -(CH2)m-(5- til 6-leddet heteroaryl der omfatter: carbonatomer og 1-4 heteroatomer, der er udvalgt fra N, NRe, O og S; hvor heteroarylen er substitueret med 0-1 Rb og 0-2 Rs), og en Ct 12-hydrocarbonkæde, der er substitueret med 0-3 Ra; hvor hydrocarbonkæden kan være lige eller forgrenet, mættet eller umættet; 2 R uafhængigt er udvalgt fra gruppen bestående af: 4-alkyl, C3 4-cycloalkyl og C^-haloalkyl; 3 R uafhængigt er udvalgt fra gruppen bestående af: H, F, Cl, C: 4-alkyl og CN; 45 R og R uafhængigt er udvalgt fra gruppen bestående af: H, F, Cl, og Cx 4-alkyl; o 3 4 nar x er en enkelt binding, kan R og R være kombineret med det carbonatom, hvortil de er bundet, for at danne en 3- til 6-leddet carbocyklus; 6 C R uafhængigt er udvalgt fra gruppen bestående af: H, halo, Ct 4-alkyl, N02, R, -(CH2)n-(X)t-(CH2)mRc, NH2, -CONH(C16-alkyl), -NHCOX^RJ, -NHCOCH2PO(OEt)2, -NHCOCORJ, -NHCOCH(OH)RJ, -NIICOCII/OR', -NHCONHRJ og -OCONR'R1; X uafhængigt er udvalgt fra gruppen bestående af: O, S, NH, CONH og NHCO; XI uafhængigt er C 4-hydrocarbonkæde eventuelt substitueret med C: 4-alkyl eller C3 4-cycloalkyl; når y er en enkelt binding, kan R5 og R6 kombineres med det carbonatom, hvortil de er bundet, for at danne en 3- til 6-leddet carbocyklus; 11 12 13 14 15 R , R , R , R og R uafhængigt er udvalgt fra gruppen bestående af: H, halo, Cl 4-alkyl substitueret med 0-2 R1, C14-alkoxy, C 4-haloalkyl, C 4-haloalkoxy, -(CH2)m-C3 6-cycloalkyl, CN, NRfRj, OR1, SR1, NHC02(C14-alkyl), NTIS()2(C| 4-alkyl), og en 4- til 6-leddet heterocyklus, der omfatter: e carbonatomer og 1-4 heteroatomer, der er udvalgt fra N, NR , O og S; 11 12 alternativt kombineres R og R , sammen med de carbonatomer, hvortil de er bundet, for at danne en 5- til 6-leddet carbocyklisk ring eller en 5- til 6-leddet heterocyklisk ring, der omfatter: carbonatomer og e 1-3 heteroatomer, der er udvalgt fra N, NR , O og S; 12 13 alternativt kombineres R og R , sammen med de carbonatomer, hvortil de er bundet, for at danne en 5- til 6-leddet carbocyklisk ring eller en 5- til 6-leddet heterocyklisk ring, der omfatter: carbonatomer og e 1-3 heteroatomer, der er udvalgt fra N, NR , O og S; R16 uafhængigt er udvalgt fra gruppen bestående af: H og C 4-alkyl; a R er, ved hver forekomst, uafhængigt udvalgt fra gruppen bestående af: halo, OH, C 6-alkoxy, Ci-6'haloalkyl, C^-haloalkoxy, N(CM-alkyl)2, -(CH2)n-(X)r(CH2)mRc og -(CH2)n-(CH20)m-(CH2)nRf; Rb er, ved hver forekomst, uafhængigt udvalgt fra gruppen bestående af: halo, OH, C -alkyl, Ci.iQ-alkoxy, C ^.-haloalkyl, (^ |(-haloalkoxy, Cllf.-alkylthio, C 10-haloalkylthio, N(C14-alkyl)2, -CONH(CH2)4 20H, -0(CH2) 0(C16-alkyl), Rc, -(CH2)n-(X)r(CH2)mRc og -(CH2)n-(CH20)m-(CH2)/; Rc er, ved hver forekomst, uafhængigt udvalgt fra gruppen bestående af: C3 6-cycloalkyl substitueret med 0-2 Rd, C3 6-cycloalkenyl substitueret med 0-2 Rd, -(CH2)m-(phenyl substitueret med 0-3 Rd), og en 5- til 6-leddet heterocyklus, der omfatter: carbonatomer og 1 -4 heteroatomer, der er udvalgt fra e d N, NR , O, og S; hvor heterocyklussen er substitueret med 0-2 R ; Rd er, ved hver forekomst, uafhængigt udvalgt fra gruppen bestående af: halo, OH, CN, N02, C -alkyl, C^-alkoxy, C14-haloalkyl, C14-haloalkoxy, tetrazolyl, OBn og phenyl substitueret med 0-2 Rh; Re er, ved hver forekomst, uafhængigt udvalgt fra gruppen bestående af: H, Ct 8-alkyl, Ct -haloalkyl, benzyl eventuelt substitueret med C14-alkoxy, CO(C|4-alkyl) og COBn; Rf er, ved hver forekomst, uafhængigt udvalgt fra gruppen bestående af: H og C -alkyl; Rs, Rh og R1 er, ved hver forekomst, uafhængigt udvalgt fra gruppen bestående af: halo, C -alkyl, C'| 4-alkoxy, C14-haloalkyl, og C|4-haloalkoxy; RJ er, ved hver forekomst, uafhængigt udvalgt fra gruppen bestående af: C'14-alkyl, C, 4-cycloalkyl og phenyl; n, ved hver forekomst, uafhængigt er 0 eller 1; m, ved hver forekomst, uafhængigt er 0, 1, 2, 3 eller 4; s, ved hver forekomst, uafhængigt er 1, 2 eller 3; og t, ved hver forekomst, uafhængigt er 0 eller 1; under forudsætning af at den følgende forbindelse er udelukket:
  2. 2. Forbindelse ifølge krav 1, hvor: R1 uafhængigt er udvalgt fra gruppen bestående af: -CONHC4 lg-alkyl, -CON 11(01^ g Ph, Ct n-alkyl substitueret med 0-2 Ra, C 12-alkenyl substitueret med 0-2 Ra, C3 12-alkynyl substitueret med 0-2 Ra, -(CH2)m-(phenyl substitueret med 0-1 Rb og 0-2 R8), -(('I I2)m-(C_, 6-cycloalkyl substitueret med 0-1 Rb), og -(CH ) -(5- til 6-leddet heteroaryl substitueret med 0-1 Rb og 0-2 R8), hvor heteroarylen er udvalgt fra: pyridyl, oxazolyl, thiazolyl og
  3. 3. Forbindelse ifølge krav 1 eller krav 2, hvor: RU og R15 uafhængigt er udvalgt fra gruppen bestående af: H, C | 4-alkyl og halo; 12 14 R og R uafhængigt er udvalgt fra gruppen bestående af: H, halo, C | 4-alkyl og C^-alkoxy; og R13 uafhængigt er udvalgt fra gruppen bestående af: H, halo, C | 4-alkyl substitueret med 0-1 R1, C'| 4-alkoxy, C|4-haloalkyl, C|4-haloalkoxy, -(CH,)m-C3 4 cycloalkyl, CN, NRfRj, SRj, NHCO,(C14-alkyl), NnS()2(C'| 4-alkyl), og en 4- til 6-leddet heterocyklus, der omfatter: carbonatomer og 1 -4 heteroatomer, der er udvalgt fra N, NRe, O og S.
  4. 4. Forbindelse ifølge et hvilket som helst af kravene 1 til 3, hvor forbindelsen er med formlen (II):
    (Π) eller en stereoisomer, en tautomer, et farmaceutisk acceptabelt salt eller et solvat deraf.
  5. 5. Forbindelse ifølge et hvilket som helst af kravene 1 til 4, hvor: R1 uafhængigt er udvalgt fra gruppen bestående af: C16-alkyl, C3 6-cycloalkyl, -CONHC4 lg-alkyl, -CONHC2 8-haloalkyl, -CONH(CH2)1 g Ph, -(CH2)m-(phenyl substitueret med 1 Rb og 0-2 RS), og en 5- til b g 6-leddet heteroaryl substitueret med 0-1 R og 0-2 R , hvor heteroarylen er udvalgt fra: pyridyl, oxazolyl, thiazolyl og
    2 R uafhængigt er udvalgt fra gruppen bestående af: C14-alkyl og C| 4-haloalkyl; R3 uafhængigt er udvalgt fra gruppen bestående af: H og F; 4 R uafhængigt er udvalgt fra gruppen bestående af: H og F; 6 c R uafhængigt er udvalgt fra gruppen bestående af: NH2, -CONH(C16-alkyl), R, -(CH2)n-(X)t-(CH2)mRc, -NI ICOiCI I;)SO;(C|4-alkyl), -NHCOCH2PO(OEt)2, -NHCOCO(C^-alkyl), -NHCOCH(OH)(C1 4-alkyl), -NHCOCH2CO(CM-alkyl), -NHCONH(Cw-alkyl) og -OCONH(CM-alkyl); R og R uafhængigt er udvalgt fra gruppen bestående af: H, C w-alkyl og halo; 12 14 R og R uafhængigt er udvalgt fra gruppen bestående af: H, halo, C | 4-alkyl og C| 4-alkoxy; 13 o R uafhængigt er udvalgt fra gruppen bestående af: H, halo, C^-alkyl substitueret med 0-1 C -alkoxy, ('|4-alkoxy, C': -haloalkyl, ( | 4-haloalkoxy, -(CH,)m-C3 4-cycloaJkyl, CN, N(C| 4-alkyl)2, NIK'O/C 4-alkyl), NHS02(C1 4-alkyl), pyrazolyl og morpholinyl; 12 13 alternativt kombineres R og R , sammen med de carbonatomer, hvortil de er bundet, for at danne en 5- til 6-leddet carbocyklisk ring eller en 5- til 6-leddet heterocyklisk ring, der omfatter: carbonatomer og e 1-3 heteroatomer, der er udvalgt fra N, NR , O og S; Rb er, ved hver forekomst, uafhængigt udvalgt fra gruppen bestående af: halo, OH, C2 8-alkyl, Ct -alkoxy, C2 g-haloalkyl, C 1Q-haloalkoxy, -0(0^)()((^ 6-alkyl), N(C14-alkyl)2, -CONH(CH2)6 2QH, -(( '112 )ni(('26-cΥc 10aIk VI), -(CH2)m(C4 6-cycloalkenyl), -0(CH2)m(C3 6-cycloalkyl), 4-C^-alkoxy-Ph, -()(('! I2) Ph, morpholinyl, pyridyl, 2-C 4-alkoxy-pyridin-5-yl, pyrimidinyl, pyrazinyl og -O-pyrimidinyl; Rs er, ved hver forekomst, uafhængigt udvalgt fra gruppen bestående af: halo, C14-alkyl, C -alkoxy, C 4-haloalkyl og C 4-haloalkoxy; m, ved hver forekomst, uafhængigt er 0, 1,2 eller 3; og s, ved hver forekomst, uafhængigt er 1, 2 eller 3.
  6. 6. Forbindelse ifølge et hvilket som helst af kravene 1 til 5, hvor: R1 uafhængigt er udvalgt fra gruppen bestående af: C16-alkyl, -CONHC^18 alkyl, -CONH(CH2)18Ph, og R9 ; R6 uafhængigt er udvalgt fra gruppen bestående af: NH2, -CONHiCj 6-alkyl), -NHCOCH2PO(OEt)2, -NHC0(CH2)S02(CM-alkyl), Rc, ORc, -CONHRc, og -NHCORc; 12 R uafhængigt er udvalgt fra gruppen bestående af: H, halo, C 4-alkyl og C 4-alkoxy; 13 R uafhængigt er udvalgt fra gruppen bestående af: H, halo, C2 4-alkyl substitueret med 0-1 C -alkoxy, C14-alkoxy, C2 4-haloalkyl, C2 4-haloalkoxy, -(CH2)m-C3 4-cycloalkyl, CN, N(C2 4-alkyl)2, NHC02(C14-alkyl), NHS02(C14-alkyl), pyrazolyl og morpholinyl; 12 13 alternativt kombineres R og R , sammen med de carbonatomer, hvortil de er bundet, for at danne en 5- til 6-leddet carbocyklisk ring eller en 5- til 6-leddet mættet heterocyklisk ring, der omfatter: carbonatomer og 1 -2 oxygenatomer; 14 R uafhængigt er udvalgt fra gruppen bestående af: H og C2 4-alkoxy; b R er, ved hver forekomst, uafhængigt udvalgt fra gruppen bestående af: halo, C 6-alkyl, C -alkoxy, C|fi-haloalkyl, C||(|-haloalkoxy, -0(CH2)0(C1fi-alkyl), -CONH(CH2)6 2QH, -(CH2)m(C3_6-cycloalkyl), -(CH2)m(C^6-cycloalkenyl), -0(CH2)m(C3 6-cycloalkyl), phenoxy, benzoxy, morpholinyl, 2-^ 4-alkoxy-pyridin-5-yl, pyrimidin-5-yl, pyrazin-2-yl og -O-pyrimidinyl; og Rc er, ved hver forekomst, uafhængigt udvalgt fra gruppen bestående af: C3 6-cycloalkyl substitueret med 0-2 Rd, -(CH2)m-(phenyl substitueret med 0-3 Rd), og en heteroaryl udvalgt fra: oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, og pyrazinyl; hvor heteroarylen er substitueret med 0-2 Rd.
  7. 7. Forbindelse ifølge et hvilket som helst af kravene 1 -6, hvor: 2 R uafhængigt er udvalgt fra gruppen bestående af: CF3 og Me; 3 R uafhængigt er udvalgt fra gruppen bestående af: F1 og F; 4 R uafhængigt er udvalgt fra gruppen bestående af: F1 og F; R6 uafhængigt er udvalgt fra gruppen bestående af: NF12, -CONHMe, OPh, -CONH(cyclopropyl), -CONH(cyclobutyl), -CONH(cyclopentyl), -CONH(cyclohexyl), -CONHPh, -CONH(4-F-Ph), -CONH(2-Cl-Ph), -CONH(4-Cl-Ph), -CONH(4-Me-Ph), -CONH(4-OH-Ph), -CONH(3-OMe-Ph), -CONH(4-OMe-Ph), -CONH(4-CF3-Ph), -CONH(4-OCF3-Ph), -CONH(l-Me-pyrazol-3-yl), -CONH(4-(lff-tetrazol-2-yl)-Ph), -CONII(4-(2W-tetrazol-3-yl)-Ph), -CONH(3-F^l-Me-Ph), -CONH(3-F-4-OMe-Ph), -CONH(CH2)2Ph, -CONH(5-OMe-pyrid-2-yl), -CONH(6-OMe-pyrid-3-yl), -CONH(5 -OMe-pyrazin-2-yl), -CONH(6-OMe-pyridazin-3-yl), -NHC0(CH2)S02Me, -NHCOPh, -NHCO(2-Me-Ph), -NHCO(3-Me-Ph), -NHCO(4-Me-Ph), -NHCO(2-Cl-Ph), -NHCO(3-Cl-Ph), -NHCO(2-Cl-4-F-Ph), -NHCO(2-Cl-5-F-Ph), -NHCO(isoxazol-5-yl), -NHCO(3-Me-isoxazol-5-yl), -NHCO(4-Me-isoxazol-5-yl), -NHCO(3-OMe-isoxazol-5-yl), -NHCO(3-Br-isoxazol-5-yl), -NHCO(3-(2-Cl-Ph)-isoxazol-5-yl), -NHCO(3-(3-F-Ph)-isoxazol-5-yl), -NHCO(3-OBn-isoxazol-5-yl), lif-imidazol-l -yl, -NHCO(5-Me-1,3,4-oxadiazol-2-yl), -NHCO( 1 -Me-1,2,3-triazol-4-yl), -NHCO(6-OMe-pyrid-3-yl), -NHCO(6-Cl-pyridazin-3-yl), 5-CF3-1,3,4-oxadiazol-2-yl, 1H-tetrazol-1 -yl, 1 W-tctrazol-3-yl og 2W-tctrazol-5-yl; RU og R15 uafhængigt er udvalgt fra gruppen bestående af: H, Me, F og Cl; 12 R uafhængigt er udvalgt fra gruppen bestående af: H, F, Cl, Me og OMe; 13 R uafhængigt er udvalgt fra gruppen bestående af: H, F, Cl, Br, Me, OMe, OEt, CH2OMe, CF3, CF12CF3, OCHF2, OCF3, CN, N(Me)2, cyclopropyl og cyclopropylmethyl; 12 13 alternativt kombineres R og R , sammen med de carbonatomer, hvortil de er bundet, for at danne en 5- til 6-leddet carbocyklisk ring eller en 5- til 6-leddet mættet heterocyklisk ring, der omfatter: carbonatomer og 1 -2 oxygenatomer; 14 R erH; Rb er, ved hver forekomst, uafhængigt udvalgt fra gruppen bestående af: n-pentyl, methoxy, n-butoxy, i-butoxy, i-pentoxy, -0(CH2)1_6CF3, -0(CH2)wCF2CF3, -CONH(CH2)6 2QH, cyclopropyl, cyclopent-l-en-l-yl, cyclohex-1 -en- 1-yl, -0(CH2)2(cyclopentyl), phenoxy, benzoxy, pyrimidin-5-yl, pyrazin-2-yl og -O-pyrimidin-2-yl; og R8 er F.
  8. 8. Forbindelse ifølge krav 4 eller krav 5, hvor: R1 er
    2 R uafhængigt er udvalgt fra CF3 og CH3; R6 uafhængigt er udvalgt fra: Rc, -CONHRc, -NHCORc, og -NI ICXX'I I2S()2(C| 4-alkyl); Rb uafhængigt er udvalgt fra: -0(CH2)16CF3, -0(CH2)MCF2CF3, -CONH(CH2)6 2QH, cyclopent-l-en-l-yl, cyclohex-l-en-l-yl, -0(CH2)2(cyclopentyl), phenoxy, benzoxy, pyrimidin-5-yl, pyrazin-2-yl og -O-pyrimidin-2-yl; R er, ved hver forekomst, uafhængigt udvalgt fra gruppen bestående af: -(CH2)m-(phenyl substitueret med 0-3 Rd), og en heteroaryl udvalgt fra: oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, og pyrazinyl; hvor heteroarylen er substitueret med 0-2 Rd; og Rd er, ved hver forekomst, uafhængigt udvalgt fra gruppen bestående af: halo, OH, CN, C| 4-alkyl, C 4-alkoxy, C 4-haloalkyl, C14-haloalkoxy, tetrazolyl og OBn.
  9. 9. Forbindelse ifølge et hvilket som helst af kravene 1 -6 eller 8, hvor: 13 0 R uafhængigt er udvalgt fra gruppen bestående af: H, halo, C14-alkyl substitueret med 0-1 C -alkoxy, C 4-alkoxy, C 4-haloalkyl, C 4-haloalkoxy, CN eller C'3 4-cycloalkyl.
  10. 10. Forbindelse ifølge et hvilket som helst af kravene 1-5, 8 eller 9, hvor: R1 uafhængigt er
  11. 11. Forbindelse ifølge et hvilket som helst af kravene 1-10, hvor: Rb uafhængigt er udvalgt fra: -0(CH2)1_6CF3, og -0(CH2)1_4CF2CF3.
  12. 12. Forbindelse ifølge et hvilket som helst af kravene 1 -5, hvor: R6 uafhængigt er 5-leddet nitrogenheteroaryl.
  13. 13. Forbindelse ifølge et hvilket som helst af kravene 1-12, hvor: R6 uafhængigt er: l//-imidazol-l-yl, l//-tetrazol-l-yl, 1 W-tetrazol-3-yl eller 2//-tetrazol-5-yl.
  14. 14. Forbindelse ifølge krav 1, hvor forbindelsen er udvalgt fra: 3-( I W-tctrazol-5-yl)-4-p-tolyl-6-(4-(4,4,4-trifluorbutoxy)phenyl)-6-(trifluormcthy 1)-5,6- dihydropyridin-2(l//)-on, (>S)-(3-(lZ/-tetrazol-5-yl)-)-4-p-tolyl-6-(4-(4,4,4-trifluorbutoxy)phenyl)-6-(trifluormethyl)-5,6- dihydropyridin-2(lZ/)-on, (R )-3-( I W-tetrazol-5-yl)-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(tnfhioromethyl )-5,6-dihydropyridin-2(lZ/)-on, yV-(4-methoxyphenyl)-2-oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)- 1.2.5.6- tetrahydropyridin-3-carboxamid, (R) -iV-(4-methoxyphenyl)-2-oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)- 1.2.5.6- tetrahydropyridin-3-carboxamid, (5)-iV-(4-methoxyphenyl)-2-oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)- 1.2.5.6- tetrahydropyridin-3-carboxamid, (S) -3-(2if-tetrazol-5-yl)-4-p-tolyl-6-(4-(6,6,6-trifluorohexyloxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(li/)-on, 3- (2-ethyl-2i/-tetrazol-5-yl)-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(lZ/)-on; 4- p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-3-(5-(trifluoromethyl)-l,3,4-oxadiazol-2-yl )-5,6-dihydropyridin-2(l W)-on; 6-methyl-2-oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-Af-(4-(trifluoromethoxy)-phenyl)- 1.2.5.6- tetrahydropyridin-3-carboxamid; 3-(2i/-tetrazol-5-yl)-4-p-tolyl-6-(trifluoromethyl)-6-(l-(5,5,5-trifluoropentyl)-l//-pyrazoM-yl)- 5.6- dihydropyridin-2(li/)-on, 3-nitro-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridm- 2(li/)-on; lV-(4-methoxyphenyl)-2-oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6- (trifluoromethyl)piperidin-3-carboxamid; forbindelser af formlen (Ila)
    (Ila) hvor R1, R2 og R6 er substituenteme, vist i nedestående tabel, og hvor R11 til R15 er hydrogen, medmindre andetsteds nævnt i nedestående tabel:
    A^-(4-methoxyphenyl)-2-methyl-6-oxo-4-/>tolyl-iV2-(4,4,4-trifluorc>butyl)-l,2,3,6- tetrahydropyridm-2,5-dicarboxamid; Af-(4-cyanophenyl)-5,5-difluoro-2-oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-1,2,5,6-tetrahydropyridin-3-carboxamid; (>S)-3-ammo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridm- 2(li/)-on; (5)-2-methyl-yV-(2-oxo-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-l,2,5,6- tetrahydropyridin-3-yl)benzamid; (>S)-3-phenoxy-4-p-tolyl-6-(4-(4,4,4-trifluorobutoxy)phenyl)-6-(trifluoromethyl)-5,6-dihydropyridin-2(lZ/)-on; og forbindelser af formel (II)
    (II) hvor R1, R2, R3, R4 og R6 er substi tuen terne vist i nedestående tabel, og hvor R1 til R15 er hydrogen, medmindre andetsteds nævnt i nedestående tabel:
    eller en stereoisomer, en tautomer, et farmaceutisk acceptabelt salt eller et solvat deraf.
  15. 15. Forbindelse ifølge krav 1, hvor forbindelsen har følgende formel:
    eller en stereoisomer, en tautomer eller et farmaceutisk acceptabelt salt deraf.
  16. 16. Forbindelse ifølge krav 15, hvor forbindelsen har følgende formel:
    eller en tautomer, eller et farmaceutisk acceptabelt salt deraf.
  17. 17. Forbindelse ifølge krav 15, hvor forbindelsen er:
  18. 18. Farmaceutisk acceptabelt salt med forbindelsen ifølge krav 15 eller krav 16.
  19. 19. Forbindelse ifølge krav 1, hvor forbindelsen har følgende formel:
    eller en stereoisomer, en tautomer, eller et farmaceutisk acceptabelt salt deraf.
  20. 20. Forbindelse ifølge krav 19, hvor forbindelsen har følgende formel:
    eller en tautomer eller et farmaceutisk acceptabelt salt deraf.
  21. 21. Forbindelse ifølge krav 19. hvor forbindelsen er:
  22. 22. Forbindelse ifølge krav 1, hvor forbindelsen har følgende formel:
    eller en stereoisomer, en tautomer eller et farmaceutisk acceptabelt salt deraf.
  23. 23. Forbindelse ifølge krav 22, hvor forbindelsen har følgende formel:
    eller en tautomer eller et farmaceutisk acceptabelt salt deraf.
  24. 24. Forbindelse ifølge krav 22, hvor forbindelsen er:
  25. 25. Forbindelse ifølge krav 1, hvor forbindelsen har følgende formel:
    eller en stereoisomer, en tautomer eller et farmaceutisk acceptabelt salt deraf.
  26. 26. Forbindelse ifølge krav 25, hvor forbindelsen har følgende formel:
    eller en tautomer eller et farmaceutisk acceptabelt salt deraf.
  27. 27. Forbindelse ifølge krav 25, hvor forbindelsen er:
  28. 28. Forbindelse ifølge krav 1, hvor forbindelsen har følgende formel:
    eller en stereoisomer, en tautomer eller et farmaceutisk acceptabelt salt deraf.
  29. 29. Forbindelse ifølge krav 28, hvor forbindelsen har følgende formel:
    eller en tautomer eller et farmaceutisk acceptabelt salt deraf.
  30. 30. Forbindelse ifølge krav 28, hvor forbindelsen er:
  31. 31. Farmaceutisk sammensætning, der omfatter en farmaceutisk acceptabel bærer og en forbindelse ifølge et hvilket som helst af kravene 1 til 30, eller en stereoisomer, en tautomer, eller et farmaceutisk acceptabelt salt deraf, og eventuelt en eller flere yderligere terapeutiske midler.
  32. 32. Farmaceutisk sammensætning ifølge krav 31, der endvidere omfatter ét eller flere andre egnede terapeutiske midler, der er udvalgt fra: antidiabetiske midler, antihyperglykæmiske midler, antihyperinsulinæmiske midler, antiretinopatiske midler, anti-neuropatiske midler, antinefropatiske midler, antiatherosklerotiske midler, antiiskæmiske midler, antihypertensive midler, antiobesitetsmidler, antidyslipidæmiske midler, antihyperlipidæmiske midler, antihypertriglyceridæmiske midler, antihyperkolesterolemiske midler, antirestenotiske midler, lipidsænkende midler, anorektiske midler og appetitsænkende midler.
  33. 33. Farmaceutisk sammensætning ifølge krav 31, der endvidere omfatter ét eller flere andre egnede terapeutiske midler, der er udvalgt fra: en dipeptidyl peptidase-IV-inhibitor, en natrium-glukose transporter-2-inhibitor og en 1 lb-FISD-l-inhibitor.
  34. 34. Forbindelse ifølge et hvilket som helst af kravene 1-30, eller en stereoisomer, en tautomer, et farmaceutisk acceptabelt salt eller et solvat deraf, eller en sammensætning ifølge et hvilket som helst af kravene 18-20, til anvendelse i terapi, eventuelt simultant, separat eller sekventielt med ét eller flere yderligere terapeutiske midler.
  35. 35. Forbindelse ifølge et hvilket som helst af kravene 1 til 30, eller en stereoisomer, en tautomer, et farmaceutisk acceptabelt salt eller et solvat deraf, eller en sammensætning ifølge et hvilket som helst af kravene 18-20, til anvendelse i forebyggelse, modulering eller behandling af diabetes, hyperglycæmi, nedsat glucosetolerance, graviditetsdiabetes, insulinresistance, hyperinsulinæmi, nonalkoholisk fedtleversygdom (NAFLD) herunder nonalkoholisk steatohepatitis (NASF1), retinopati, neuropati, nefropati, forsinket sårheling, atherosklerose og følgesygdomme, anormal hjertefunktion, myokardieiskæmi, apopleksi, metabolisk syndrom, hypertension, obesitet, dyslipidæmi, dyslipidæmi, hyperlipidæmi, hypertriglyceridæmi, hypercholesterolæmi, lavt højdensitetslipoprotein (HDL), høj lavdensitetslipoprotein (LDL), ikke-iskæmisk hjertesygdom, lipidsygdomme og glaukom, eventuelt til anvendelse simultant, separat eller sekventielt med et eller flere yderligere terapeutiske midler.
DK12821212.3T 2011-12-02 2012-11-30 Aryldihydropyridoner og piperidoner som mga2-inhibitorer DK2785693T3 (da)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201161566039P 2011-12-02 2011-12-02
US13/688,584 US8791091B2 (en) 2011-12-02 2012-11-29 Aryl dihydropyridinone and piperidinone MGAT2 inhibitors
PCT/US2012/067173 WO2013082345A1 (en) 2011-12-02 2012-11-30 Aryl dihydropyridinone and piperidinone as mgat2 inhibitors

Publications (1)

Publication Number Publication Date
DK2785693T3 true DK2785693T3 (da) 2016-09-05

Family

ID=48524439

Family Applications (1)

Application Number Title Priority Date Filing Date
DK12821212.3T DK2785693T3 (da) 2011-12-02 2012-11-30 Aryldihydropyridoner og piperidoner som mga2-inhibitorer

Country Status (35)

Country Link
US (8) US8791091B2 (da)
EP (2) EP3053912B1 (da)
JP (2) JP5806417B2 (da)
KR (2) KR101666729B1 (da)
CN (2) CN107266416B (da)
AR (1) AR090041A1 (da)
AU (1) AU2012345863B2 (da)
BR (1) BR112014013228B1 (da)
CA (1) CA2857689C (da)
CL (1) CL2014001437A1 (da)
CO (1) CO6990718A2 (da)
CY (1) CY1118128T1 (da)
DK (1) DK2785693T3 (da)
EA (1) EA026367B1 (da)
ES (2) ES2699905T3 (da)
HK (1) HK1197231A1 (da)
HR (1) HRP20161011T1 (da)
HU (1) HUE030547T2 (da)
IL (1) IL232727A (da)
IN (1) IN2014CN03803A (da)
MA (1) MA35753B1 (da)
MX (1) MX355988B (da)
MY (1) MY173478A (da)
PE (1) PE20141307A1 (da)
PH (1) PH12014501162B1 (da)
PL (1) PL2785693T3 (da)
PT (1) PT2785693T (da)
RS (1) RS54985B1 (da)
SG (2) SG10201607722TA (da)
SI (1) SI2785693T1 (da)
SM (1) SMT201600272B (da)
TN (1) TN2014000238A1 (da)
TW (1) TWI636044B (da)
WO (1) WO2013082345A1 (da)
ZA (1) ZA201404867B (da)

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8791091B2 (en) 2011-12-02 2014-07-29 Bristol-Myers Squibb Company Aryl dihydropyridinone and piperidinone MGAT2 inhibitors
BR112015010779A2 (pt) 2012-11-16 2017-07-11 Bristol Myers Squibb Co moduladores de di-hidropirazol gpr40
WO2014078611A1 (en) 2012-11-16 2014-05-22 Bristol-Myers Squibb Company Dihydropyrazole gpr40 modulators
CN105121426B (zh) 2012-11-16 2017-03-29 百时美施贵宝公司 吡咯烷gpr40调节剂
KR20150082617A (ko) 2012-11-16 2015-07-15 브리스톨-마이어스 스큅 컴퍼니 디히드로피라졸 gpr40 조절제
CA2887539C (en) 2012-11-29 2021-10-26 Merck Patent Gmbh Azaquinazoline carboxamide derivatives
WO2014193884A1 (en) 2013-05-29 2014-12-04 Bristol-Myers Squibb Company Dihydropyridinone mgat2 inhibitors
SG11201607392SA (en) * 2014-03-07 2016-10-28 Bristol Myers Squibb Co Dihydropyridinone mgat2 inhibitors for use in the treatment of metabolic disorders
TR201906325T4 (tr) * 2014-03-07 2019-05-21 Squibb Bristol Myers Co Tetrazolon sübstitüeli dihidropiridinon MGAT2 inhibitörleri.
US9974778B2 (en) 2014-06-11 2018-05-22 Bristol-Myers Squibb Company Substituted pyridinones as MGAT2 inhibitors
KR101750392B1 (ko) * 2014-12-03 2017-06-26 한국도로공사 교량 점검용 거더의 유도 레일장치 및 그 교량 점검장치
WO2017069224A1 (ja) * 2015-10-22 2017-04-27 塩野義製薬株式会社 Ｍｇａｔ２阻害活性を有するスピロ環誘導体
EP3395798A4 (en) * 2015-12-21 2019-07-17 Shionogi & Co., Ltd NON-AROMATIC HETEROCYCLIC DERIVATIVE HAVING MGAT2 INHIBITORY ACTIVITY
EP3301094A1 (en) * 2016-09-30 2018-04-04 Mutabilis Heterocyclic compounds and their use in preventing or treating bacterial infections
JP2020158390A (ja) * 2017-06-20 2020-10-01 塩野義製薬株式会社 Ｍｇａｔ２阻害活性を有する非芳香族複素環誘導体およびそれらを含有する医薬組成物
TWI782056B (zh) 2017-07-14 2022-11-01 日商鹽野義製藥股份有限公司 具有ｍｇａｔ２抑制活性的縮合環衍生物
CN107759498A (zh) * 2017-11-08 2018-03-06 南京大学 抗肿瘤化合物、制备方法及其用途
KR20210114001A (ko) 2019-01-11 2021-09-17 시오노기 앤드 컴파니, 리미티드 Mgat2 저해 활성을 갖는 다이하이드로피라졸로피라지논 유도체
US20220185815A1 (en) 2019-03-06 2022-06-16 Daiichi Sankyo Company, Limited Pyrrolopyrazole derivative

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3073838A (en) * 1963-01-15 Derivatives of hydkogenateb pyridones
US5614492A (en) 1986-05-05 1997-03-25 The General Hospital Corporation Insulinotropic hormone GLP-1 (7-36) and uses thereof
AU2005286648A1 (en) 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
WO2007002191A2 (en) * 2005-06-22 2007-01-04 Biocryst Pharmaceuticals, Inc. Methods for the preparation of 9-deazapurine derivatives
EP2078719A4 (en) * 2006-09-28 2009-11-11 Dainippon Sumitomo Pharma Co COMPOUND WITH BICYCLIC PYRIMIDINE STRUCTURE AND THE COMPOUND CONTAINING PHARMACEUTICAL COMPOSITION
US8232447B2 (en) 2007-01-31 2012-07-31 Msd K.K. Animal having modification in MGAT2 gene
CA2751244A1 (en) 2009-02-23 2010-08-26 Msd K.K. Pyrimidin-4(3h)-one derivatives
EP2687507B1 (en) 2011-03-14 2016-03-09 Taisho Pharmaceutical Co., Ltd. Nitrogen-containing condensed heterocyclic compound
US8791091B2 (en) 2011-12-02 2014-07-29 Bristol-Myers Squibb Company Aryl dihydropyridinone and piperidinone MGAT2 inhibitors
TR201906325T4 (tr) 2014-03-07 2019-05-21 Squibb Bristol Myers Co Tetrazolon sübstitüeli dihidropiridinon MGAT2 inhibitörleri.
SG11201607392SA (en) 2014-03-07 2016-10-28 Bristol Myers Squibb Co Dihydropyridinone mgat2 inhibitors for use in the treatment of metabolic disorders

Also Published As

Publication number Publication date
JP5806417B2 (ja) 2015-11-10
HK1197231A1 (zh) 2015-01-09
US20180133198A1 (en) 2018-05-17
BR112014013228A2 (pt) 2017-06-13
US10695328B2 (en) 2020-06-30
JP2015500237A (ja) 2015-01-05
CN107266416A (zh) 2017-10-20
CN104080768B (zh) 2017-05-24
CY1118128T1 (el) 2017-06-28
PH12014501162A1 (en) 2014-08-11
US9901572B2 (en) 2018-02-27
US20160031816A1 (en) 2016-02-04
IN2014CN03803A (da) 2015-10-16
US8791091B2 (en) 2014-07-29
CN107266416B (zh) 2020-07-10
PL2785693T3 (pl) 2016-11-30
AR090041A1 (es) 2014-10-15
MX355988B (es) 2018-05-08
US20210161869A1 (en) 2021-06-03
ES2584070T3 (es) 2016-09-23
EP3053912B1 (en) 2018-09-12
JP6078601B2 (ja) 2017-02-08
NZ626751A (en) 2016-07-29
JP2016028059A (ja) 2016-02-25
MY173478A (en) 2020-01-28
EA026367B1 (ru) 2017-03-31
SG11201402389PA (en) 2014-09-26
TN2014000238A1 (en) 2015-09-30
ZA201404867B (en) 2017-04-26
MX2014006318A (es) 2014-06-23
US20200281905A1 (en) 2020-09-10
US20130143843A1 (en) 2013-06-06
US20170216263A1 (en) 2017-08-03
KR101666729B1 (ko) 2016-10-17
SMT201600272B (it) 2016-08-31
CA2857689A1 (en) 2013-06-06
US20150315144A1 (en) 2015-11-05
AU2012345863B2 (en) 2017-07-27
AU2012345863A1 (en) 2014-07-24
US20190314346A1 (en) 2019-10-17
WO2013082345A8 (en) 2014-01-23
SG10201607722TA (en) 2016-11-29
RS54985B1 (sr) 2016-11-30
KR20160120797A (ko) 2016-10-18
HUE030547T2 (en) 2017-05-29
BR112014013228B1 (pt) 2021-02-17
KR20140099519A (ko) 2014-08-12
HRP20161011T1 (hr) 2016-10-07
IL232727A (en) 2017-09-28
WO2013082345A1 (en) 2013-06-06
PT2785693T (pt) 2016-07-29
US9187424B1 (en) 2015-11-17
EA201491079A1 (ru) 2014-09-30
PE20141307A1 (es) 2014-10-01
SI2785693T1 (sl) 2016-09-30
IL232727A0 (en) 2014-08-03
CN104080768A (zh) 2014-10-01
WO2013082345A9 (en) 2014-09-25
ES2699905T3 (es) 2019-02-13
CA2857689C (en) 2016-06-21
PH12014501162B1 (en) 2014-08-11
US9663466B2 (en) 2017-05-30
US10966967B2 (en) 2021-04-06
TWI636044B (zh) 2018-09-21
EP2785693B1 (en) 2016-05-18
EP2785693A1 (en) 2014-10-08
US10369140B2 (en) 2019-08-06
MA35753B1 (fr) 2014-12-01
EP3053912A1 (en) 2016-08-10
TW201329048A (zh) 2013-07-16
CO6990718A2 (es) 2014-07-10
CL2014001437A1 (es) 2014-10-03

Similar Documents

Publication Publication Date Title
DK2785693T3 (da) Aryldihydropyridoner og piperidoner som mga2-inhibitorer
EP3114121B1 (en) Dihydropyridinone mgat2 inhibitors for use in the treatment of metabolic disorders
CA2941951C (en) Tetrazolone-substituted dihydropyridinone mgat2 inhibitors
EP3004059B1 (en) Dihydropyridinone mgat2 inhibitors
WO2015191681A2 (en) Substituted pyridinones as mgat2 inhibitors
NZ626751B2 (en) Aryl dihydropyridinones and piperidinones as mgat2 inhibitors