HRP20172002T1 - Makrociklički inhibitori faktora xia kondenzirani sa heterociklusima - Google Patents

Makrociklički inhibitori faktora xia kondenzirani sa heterociklusima Download PDF

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HRP20172002T1
HRP20172002T1 HRP20172002TT HRP20172002T HRP20172002T1 HR P20172002 T1 HRP20172002 T1 HR P20172002T1 HR P20172002T T HRP20172002T T HR P20172002TT HR P20172002 T HRP20172002 T HR P20172002T HR P20172002 T1 HRP20172002 T1 HR P20172002T1
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independently selected
image
chf
alkyl
pharmaceutically acceptable
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HRP20172002TT
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Andrew K. Dilger
James R. Corte
Indawati De Lucca
Tianan Fang
Wu Yang
Yufeng Wang
Kumar Balashanmuga PABBISETTY
William R. Ewing
Yeheng Zhu
Ruth R. Wexler
Donald J.P. Pinto
Michael J. Orwat
Leon M. Smith Ii
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Bristol-Myers Squibb Company
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Publication of HRP20172002T1 publication Critical patent/HRP20172002T1/hr

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    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/18—Bridged systems
    • 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
    • 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
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Claims (12)

1. Spoj sa Formulom (Ia): [image] ili stereoizomer, tautomer, njegova farmaceutski prihvatljiva sol, gdje: --- je opcionalna veza; prsten A je nezavisno odabran od [image] R1 je nezavisno odabrano od H, F, OH, i C1-4 alkil; R2 je nezavisno odabrano od H, F, i OH; R3 je nezavisno odabrano od H, C1-4 alkil, C1-4haloalkil, -(CH2)n-OR5, -(CH2)n-C(O)OR5, C3-6 cikloalkil po izboru supstituiran sa halogenom, i 5- do 6-očlani heteroaril koji sadrži ugljikove atome i 1-2 atoma dušika i po izboru supstituiran sa R1; pod uvjetom da je samo jedna R3 grupa prisutna na prstenu; R4 je nezavisno odabrano od H, OH, F, OC1-4 alkil, C1-4 alkil, i CN; R5 je nezavisno odabrano od H i C1-4 alkil; R6 je nezavisno odabrano od H, F, Cl, Br, CN, OCH3, CH3, C(O)CH3, CHF2, CCH3F2, CF3, OCHF2, NHC(O)C1-4 alkil, C3-6 cikloalkil, i 5-očlani heterociklus supstituiran sa R9; R7 je nezavisno odabrano od H i F; R8 je nezavisno odabrano od H, F, Cl, i OCH3; R9 je nezavisno odabrano od H, cijano, C1-4 alkil, haloalkil, i halogen; i n, u svakom slučaju, je cijeli broj izabran od 1 i 2.
2. Spoj iz patentnog zahtjeva 1 koji ima Formulu (IIa): [image] ili stereoizomer, tautomer, njegova farmaceutski prihvatljiva sol, gdje: prsten A je nezavisno odabran od [image] R1 je nezavisno odabrano od H i C1-3 alkil; R2 je nezavisno odabrano od H i F; R3 je nezavisno odabrano od H, C1-3 alkil, C1-3haloalkil, -(CH2)n-OR5, -(CH2)n-C(O)OR5, i C3-4 cikloalkil po izboru supstituiran sa halogenom; R4 je nezavisno odabrano od H i F; R5 je nezavisno odabrano od H i C1-4 alkil; R6 je nezavisno odabrano od H, F, Cl, Br, CN, CF3, C(O)CH3, CHF2, CCH3F2, CF3, OCHF2, [image] R7 je nezavisno odabrano od H i F; R8 je nezavisno odabrano od H, F, Cl, i OCH3; R9 je nezavisno odabrano od H, CHF2, i CF3; R9' je nezavisno odabrano od H, F, Cl, CN, CHF2, i CF3; i n, u svakom slučaju, je cijeli broj izabran od 1 i 2.
3. Spoj iz patentnog zahtjeva 2, ili stereoizomer, tautomer, njegova farmaceutski prihvatljiva sol, gdje: R1 je nezavisno odabrano od H, CH3, i CH(CH3)2; R2 je nezavisno odabrano od H i F; R3 je nezavisno odabrano od H, CH3, CD3, CH2CH3, -CHF2, -CH2CHF2, -CH2CF3, -CH2CH2OH, CH2CH2OC(CH3)3, -CH2C(O)OH, ciklopropil po izboru supstituiran sa F, i ciklobutil; R6 je nezavisno odabrano od H, F, Cl, Br, CN, CF3, C(O)CH3, CHF2, CCH3F2, CF3, OCHF2, [image] R7 je nezavisno odabrano od H i F; R8 je nezavisno odabrano od H, F, Cl, i OCH3; R9 je nezavisno odabrano od H, CHF2, i CF3; i R9' je nezavisno odabrano od H, F, Cl, CN, CHF2, i CF3.
4. Spoj iz patentnog zahtjeva 1 koji ima Formulu (IIIa): [image] ili stereoizomer, tautomer, njegova farmaceutski prihvatljiva sol, gdje: prsten A je nezavisno odabran od [image] R1 je nezavisno odabrano od H, CH3, i CH(CH3)2; R2 je nezavisno odabrano od H i F; R3 je nezavisno odabrano od H, CH2C(=O)OH, CH2C(=O)OCH2CH3, [image] R4 je nezavisno odabrano od H i F; R6 je nezavisno odabrano od H, F, Cl, Br, CN, CF3, C(O)CH3, CHF2, CCH3F2, CF3, OCHF2, [image] R7 je nezavisno odabrano od H i F; R8 je nezavisno odabrano od H, F, Cl, i OCH3; R9 je nezavisno odabrano od H, CHF2, i CF3; i R9' je nezavisno odabrano od H, F, Cl, CN, CHF2, i CF3.
5. Spoj iz patentnog zahtjeva 1, ili stereoizomer, tautomer, njegova farmaceutski prihvatljiva sol, gdje: R3 je nezavisno odabrano od H, CH3, CD3, CH2CH3, -CHF2, -CH2CHF2, -CH2CF3, -CH2CH2OH, CH2CH2OC(CH3)3, -CH2C(O)OH, CH2C(=O)OH, CH2C(=O)OCH2CH3, ciklopropil po izboru supstituiran sa F, i ciklobutil, [image] R6 je nezavisno odabrano od H, F, Cl, Br, CN, CF3, C(O)CH3, CHF2, CCH3F2, CF3, OCHF2, [image] R7 je nezavisno odabrano od H i F; R8 je Cl; R9 je nezavisno odabrano od H, CHF2, i CF3; i R9' je nezavisno odabrano od H, F, Cl, CN, CHF2, i CF3;
6. Spoj koji ima Formulu (IV): [image] ili stereoizomer, tautomer, njegova farmaceutski prihvatljiva sol, gdje: prsten A je nezavisno odabran od [image] R1 je nezavisno odabrano od H i C1-3alkil; R2 je nezavisno odabrano od H i F; R3 je nezavisno odabrano od H, CD3, CHF2, i CH3; R4 je nezavisno odabrano od H i halogen; R7 je nezavisno odabrano od H i F; R8 je nezavisno odabrano od H, F, Cl, i OCH3; i R9 je nezavisno odabrano od H, F, Cl, CN, i CF3.
7. Spoj koji ima Formulu (V): [image] ili stereoizomer, tautomer, njegova farmaceutski prihvatljiva sol, gdje: prsten A je nezavisno odabran od [image] R1 je nezavisno odabrano od H i C1-3alkil; R2 je nezavisno odabrano od H i F; R3 je nezavisno odabrano od H, CD3, CHF2, i CH3; R4 je nezavisno odabrano od H i halogen; R6 je nezavisno odabrano od H, F, Cl, Br, CN, CF3, C(O)CH3, CHF2, CCH3F2, CF3, OCHF2, [image] R7 je nezavisno odabrano od H i F; R8 je nezavisno odabrano od H, F, Cl, i OCH3; R9 je nezavisno odabrano od H, CHF2, i CF3; i R9' je nezavisno odabrano od H, F, Cl, CN, CHF2, i CF3.
8. Spoj u skladu sa patentnim zahtjevom 1, 6 ili 7 odabran sa liste koja se sastoji od [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] ili stereoizomer, tautomer, njegova farmaceutski prihvatljiva sol.
9. Farmaceutska kompozicija koja sadrži jedan ili više spojeva u skladu sa bilo kojim od patentnih zahtjeva 1-8 i farmaceutski prihvatljiv nosač ili razblaživač.
10. Spoj u skladu sa bilo kojim od patentnih zahtjeva 1-8, ili stereoizomer, tautomer, ili njegova farmaceutski prihvatljiva sol ili kompozicija u skladu sa patentnim zahtjevom 9 za primjenu kao medikament.
11. Spoj u skladu sa bilo kojim od patentnih zahtjeva 1-8, ili stereoizomer, tautomer, ili njegova farmaceutski prihvatljiva sol za primjenu u liječenju i/ili profilaksi tromboembolijskog poremećaja, gdje tromboembolijski poremećaj je odabran od arterijskih kardiovaskularnih tromboembolijskih poremećaja, venskih tromboembolijskih poremećaja, i tromboembolijskih poremećaja u komorama srca ili u perifernoj cirkulaciji.
12. Spoj ili stereoizomer, tautomer, ili njegova farmaceutski prihvatljiva sol za primjenu u skladu sa patentnim zahtjevom 11, gdje tromboembolijski poremećaj je odabran od nestabilne angine, akutnog koronarnog sindroma, atrijalne fibrilacije, infarkta miokarda, prolaznog ishemijskog napada, moždanog udara, ateroskleroze, periferne okluzivne arterijske bolesti, venske tromboze, duboke venske tromboze, tromboflebitisa, arterijske embolije, koronarne arterijske tromboze, cerebralne arterijske tromboze, cerebralne embolije, bubrežne embolije, plućne embolije, i tromboze koja nastaje od medicinskih implantata, uređaja, ili procedura u kojima je krv izložena umjetnoj površini koja izaziva trombozu.
HRP20172002TT 2014-01-31 2015-01-30 Makrociklički inhibitori faktora xia kondenzirani sa heterociklusima HRP20172002T1 (hr)

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US201461933948P 2014-01-31 2014-01-31
EP15705427.1A EP3099688B1 (en) 2014-01-31 2015-01-30 Macrocyclic factor xia inhibitors condensed with heterocycles
PCT/US2015/013647 WO2015116882A1 (en) 2014-01-31 2015-01-30 Macrocyclic factor xia inhibitors condensed with heterocycles

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EP (1) EP3099688B1 (hr)
JP (1) JP6419836B2 (hr)
CN (1) CN106459051B (hr)
AR (1) AR099228A1 (hr)
BR (1) BR112016016741B1 (hr)
CA (1) CA2937738C (hr)
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DK (1) DK3099688T3 (hr)
EA (1) EA032650B1 (hr)
ES (1) ES2655540T3 (hr)
HR (1) HRP20172002T1 (hr)
HU (1) HUE038060T2 (hr)
LT (1) LT3099688T (hr)
MX (1) MX2016009385A (hr)
NO (1) NO2760821T3 (hr)
PL (1) PL3099688T3 (hr)
PT (1) PT3099688T (hr)
RS (1) RS56785B1 (hr)
SI (1) SI3099688T1 (hr)
SM (1) SMT201800024T1 (hr)
TW (1) TWI703144B (hr)
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