SI2997033T1 - Fuzionirane triciklične heterociklične spojine kot hiv integrazni inhibitorji - Google Patents

Fuzionirane triciklične heterociklične spojine kot hiv integrazni inhibitorji Download PDF

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SI2997033T1
SI2997033T1 SI201430563T SI201430563T SI2997033T1 SI 2997033 T1 SI2997033 T1 SI 2997033T1 SI 201430563 T SI201430563 T SI 201430563T SI 201430563 T SI201430563 T SI 201430563T SI 2997033 T1 SI2997033 T1 SI 2997033T1
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alkyl
membered monocyclic
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cycloalkyl
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Paul J. Coleman
Timothy J. Hartingh
Izzat T. Raheem
John Schreier
John T. Sisko
John Wai
Thomas Graham
Lihong Hu
Xuanjia Peng
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Merck Sharp & Dohme Corp.
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/535—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
    • A61K31/5383—1,4-Oxazines, e.g. morpholine 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
    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
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    • 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
    • C07D471/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/16—Peri-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
    • C07D491/12—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 three hetero rings
    • C07D491/16—Peri-condensed systems

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Claims (13)

  1. FUZIONIRANE TRICIKLIČNE HETEROCIKLIČNE SPOJINE KOT HIV INTEGRAZNI INHIBITORJI PATENTNI ZAHTEVKI
    1. Spojina s formulo:
    in njene farmacevtsko sprejemljive soli, pri čemer: A je C1-C4 alkilen, C2-C4 alkenilen, arilen, C3-C7 cikloalkil, 5 ali 6-členski monociklični heteroaril, 4 do 7-členski heterocikloalkil, -O-, -NH-C(O)-, -C(0)NH- ali -C(0)-; X je O, -N(Ci-C6 alkil)- ali -C(R10)(R11), tako da kadar je X = O ali -N(CrC6 alkil)-, potem R4, R5, R6 in R7 pomenita drugače kot -OR9, -N(R9)2 ali halo; vsak pojav m je neodvisno O ali 1; n je Ο ali 1, tako da kadar je n 0, potem R4 in R5 nista prisotna; R1 je CrC6 alkil, ki je po izbiri substituiran z do 3 skupinami, od katerih je vsaka neodvisno izbrana izmed C3-C7 cikloalkila, 5 ali 6-členskega monocikličnega heteroarila, 4-6-členskega monocikličnega heterocikloalkila, C6-Ci0 arila, halo, CrC6 haloalkil, -OR9, -N(R9)2, -C (O)R9, -C(0)N(R9)2, -NHC(0)R9 in -SR9, kjer je omenjena C3-C7 cikloalkil skupina, omenjena 5 ali 6-členska monociklična heteroarilna skupina, omenjena 4 do 6-členska monociklična heterocikloalkil skupina in omenjena C6-C10 arilna skupina lahko po izbiri in neodvisno substituirana z eno ali več skupinami, vsaka neodvisno izbrana izmed C1-C6 alkil, C3-C7 cikloalkil, 5 ali 6-členskega monocikličnega heteroaril, od 4 do 6-členskega monocikličnega heterocikloalkil, C6-Ci0 aril, halo, C1-C6 haloalkil, -OR9, -N(R9)2, -C(0)R9, -C(0)N(R9)2, -NHC(0)R9 in -SR9; R2, R5, R6, R7, R10 in R11 so vsakokrat neodvisno izbrani izmed H, Ci-C6 alkila, C3-C7 cikloalkila, halo, Ci-C6 haloalkil, -OR9, -N(R9)2, -C(0)R9, -C(0)N(R9)2 in -NHC(0)R9, kjer je omenjena C1-C6 alkilna skupina lahko po izbiri substituirana z eno ali več skupinami, od katerih je vsaka neodvisno izbrana izmed halo, -OH, -0(Ci-C6 alkil), -NH2, -NH(CrC6 alkil), -N(CrC6 alkil)2, -SH ali -S(CrC6 alkil); R3 je H, C^Ce alkil, C3-C7 cikloalkil, CrC6 haloalkil, -C(0)R9, -C(0)N(R9)2 in -NHC(0)R9, kjer je omenjena CrC6 alkilna skupina lahko po izbiri substituirana z eno ali več skupinami, od katerih je vsaka neodvisno izbrana izmed halo, -OH, -0(Ci-C6 alkil), -NH2, -NH(Ci-C6 alkil),-N(CrC6 alkil)2, -SH or -S(Ci-C6 alkil); R4 je H, ali R4 in R5 in skupni atom ogljika, na katerega sta vezana, se spojita, da tvorita endociklično -C(0)- skupino; R8 je izbran izmed C1-C6 alkil, -(C1-C3 alkilen)m-(C3-C7 cikloalkil), -(C1-C3 alkilen)m-(5 ali 6-členskega monocikličnega heteroarila), -(C1-C3 alkilen)m-(4 do 6-členskega monocikličnega heterocikloalkila) in -(C1-C3 alkilen)m-(Ce-Cio aril), kjer je omenjena C3-C7 cikloalkilna skupina, omenjena 5 ali 6-členska monociklična heteroarilna skupina, omenjena 4 do 6-členska monociklična heterocikloalkilna skupina in omenjena Ce-C-io arilna skupina lahko vsaka po izbiri in neodvisno substituirana z do 5 skupinami, od katerih je vsaka neodvisno izbrana izmed C1-C6 alkil, C3-C7 cikloalkil, 5 ali 6-členske monociklične heteroaril, 4-6-členske monociklične heterocikloalkil, C6-C10 aril, halo, CrC6 haloalkil, -OR9, -N(R9)2, -C(0)R9, -C(0)N(R9)2,-NHC(0)R9 in -SR9; in vsak pojav R9 je neodvisno izbran izmed H, C1-C6 alkil, C3-C7 cikloalkil, Οβ-C-ιο aril in benzil.
  2. 2. Spojina po zahtevku 1 s formulo:
    in njene farmacevtsko sprejemljive soli, pri čemer: A je 5 ali 6-členski monociklični heteroaril ali NH-C(O)-; X je O, -N(CrC6 alkil)- ali -C (R10)(R11), tako da kadar X = O ali -N(CrC6 alkil) -, potem R4, R5, R6 in R7 pomenita drugače kot -OR9, -N (R9)2 ali halo; n je 0 ali 1, tako da kadar je n 0, potem R4 in R5 nista prisotna; R1 je CrC6 alkil, ki je po izbiri substituiran s skupino, izbrano izmed fenil, C3-C7 cikloalkil, 5- ali 6- členski monociklični heteroaril in -OR9, kjer je omenjena fenilna skupina in omenjena 5 ali 6-členska monociklična heteroarilna skupina lahko vsaka po izbiri in neodvisno substituirana z do dvema skupinama, vsaka neodvisno izbrana izmed CrCe alkil, C3-C7 cikloalkil, 5 ali 6-členskega monociklični heteroaril, 4 do 6-členski monociklični heterocikloalkil, C6-Ci0 aril, halo, CrCe haloalkil, -OR9, -N (R9)2, -C(0)R9, -C (0)N(R9)2, -NHC(O) in -SR9; R4 je H, ali R4 in R5 in skupni atom ogljika, na katerega sta vezana, se spojita, da tvorita endociklično -C(O)- skupino; R5, R10 in R11 so vsak neodvisno izbrani izmed H, CrC6 alkil in -OR9; R7 je izbran izmed H, CrCe alkil, -OR9 in -OH; R8 je izbran izmed C1-C6 alkil ali benzil, pri čemer je lahko fenilni del omenjene benzilne skupine po izbiri in neodvisno substituiran z do 3 skupinami, vsaka neodvisno izbrana izmed C1-C6 alkil, C3-C7 cikloalkil, 5 ali 6-členski monociklični heteroaril, 4-6-členski monociklični heterocikloalkil, C6-Ci0 aril, halo, CrCe haloalkil, -OR9, -N(R9)2, -C(0)R9, -C(0)N(R9)2, -NHC(0)R9 in -SR9; in vsak pojav R9 je neodvisno izbran izmed H, C1-C6 alkil, C3-C7 cikloalkil, C6-C10 aril in benzil.
  3. 3. Spojina po zahtevku 1 s formulo (Ib):
    in njene farmacevtsko sprejemljive soli, pri čemer: A je pirazolil, tiadiazolil, triazolil, tiazolil, oksazolil, oksadiazolil ali -NHC(O)- j X je O, -N(CrC6 alkil)- ali -C(R10)(R11), tako da kadar X = O ali - N(CrC6 alkil)-, potem so R4, R5, R6 in R7 vsak drugačni kot -OR9, -N (R9)2 ali halo; n je 0 ali 1, tako da kadar je n 0, potem R4 in R5 nista prisotna; R1 je CrCe alkil, ki je po izbiri substituiran s skupino, izbrano izmed fenil, C3-C7 cikloalkil, 5- ali 6-členski monociklični heteroaril in -0-( C1-C6 alkil), kjer je omenjena fenilna skupina in omenjena 5 ali 6-členska monociklična heteroarilna skupina lahko vsaka po izbiri in neodvisno substituirana z do dvema skupinama, vsaka neodvisno izbrana izmed Cr C6 alkil, halo in -0-( Ci-C6 alkil); R4 je H, ali R4 in R5 in skupni atom ogljika, na katerega sta vezana, se spojita, da tvorita endociklično -C(O)- skupino; R5, R10 in R11 vsak neodvisno izbran izmed H, C1-C6 alki) in -0-(CrC6 alkil); R7 je izbran izmed H, C1-C6 alkil, -0-(CrC6 alkil) in -OH; R8 je izbran izmed Ci-C6 alkil ali benzil, pri čemer je lahko fenilni del omenjene benzilne skupine po izbiri in neodvisno substituiran z do 3 skupinami, vsaka neodvisno izbrana izmed CrC6 alkil, -0-(0ι-0β alkil) in halo; in vsak pojav R9 je neodvisno izbran izmed H, C1-C6 alkil, C3-C7 cikloalkil, C6-C10 aril in benzil.
  4. 4. Spojina po katerem koli od zahtevkov 1-3, kjer je A -NHC(O)-.
  5. 5. Spojina po katerem koli od zahtevkov 1-4, kjer je X -O-; n je 1; in R4, R5 in R7 so vsak H.
  6. 6. Spojina po katerem koli od zahtevkov 1-4, kjer je X -CH2-; n je 0; in R7 je H ali -OH.
  7. 7. Spojina po katerem koli od zahtevkov 1-6, kjer je R8 benzil, pri čemer je lahko fenilni del omenjene benzilne skupine po izbiri in neodvisno substituiran z do 3 skupinami, vsaka neodvisno izbrana izmed F, Cl in metil.
  8. 8. Spojina po katerem koli od zahtevkov 1-7, kjer je R1 Ci-C6 alkil, ki je po izbiri substituiran s skupino izbrano izmed fenil, 5 ali 6-členskega monocikličnega heteroaril, C3-C7 cikloalkil in metoksi, pri čemer je navedena fenilna skupina in omenjena 5 ali 6-členska monociklična heteroarilna skupina lahko vsaka po izbiri in neodvisno substituirana z do dvema skupinama, vsaka neodvisno izbrana izmed metoksi, C1-C6 alkil in fluora.
  9. 9. Spojina po zahtevku 1, ki ima strukturo:
    ali njena farmacevtsko sprejemljiva sol.
  10. 10. Farmacevtski sestavek, ki obsega učinkovito količino spojine po katerem koli od zahtevkov 1 do 9 ali njeno farmacevtsko sprejemljivo sol in farmacevtsko sprejemljiv nosilec.
  11. 11. Spojina po katerem koli od zahtevkov 1 do 9 ali njena farmacevtsko sprejemljiva sol za uporabo pri terapiji.
  12. 12. Spojina po katerem koli od zahtevkov 1 do 9 ali njena farmacevtsko sprejemljiva sol za uporabo pri inhibiciji HIV integraze, za zdravljenje ali profilakso okužbe s HIV, ali za zdravljenje, profilakso ali zamude pri pojavu ali napredovanju AIDS-a pri subjektu, ki to potrebuje.
  13. 13. Farmacevtski sestavek po zahtevku 10, ki nadalje obsega eno ali več dodatnih terapevtskih sredstev, izbranih izmed raltegravirja, lamivudina, abakavirja, ritonavirja, dolutegravirja, arunavirja, atazanavirja, emtricitabina, tenofovirja, elvitegravirja, rilpivirina in lopinavira.
SI201430563T 2013-05-17 2014-04-18 Fuzionirane triciklične heterociklične spojine kot hiv integrazni inhibitorji SI2997033T1 (sl)

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US201361824739P 2013-05-17 2013-05-17
PCT/CN2014/075685 WO2014183532A1 (en) 2013-05-17 2014-04-18 Fused tricyclic heterocyclic compounds as hiv integrase inhibitors
EP14798188.0A EP2997033B1 (en) 2013-05-17 2014-04-18 Fused tricyclic heterocyclic compounds as hiv integrase inhibitors

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AR (1) AR096332A1 (sl)
AU (1) AU2014267951A1 (sl)
CY (1) CY1119842T1 (sl)
DK (1) DK2997033T3 (sl)
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HR (1) HRP20180081T1 (sl)
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NO (1) NO3058793T3 (sl)
PL (1) PL2997033T3 (sl)
PT (1) PT2997033T (sl)
RS (1) RS56701B1 (sl)
SI (1) SI2997033T1 (sl)
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US9643982B2 (en) 2017-05-09
US20160108059A1 (en) 2016-04-21
AR096332A1 (es) 2015-12-23
DK2997033T3 (da) 2018-01-29
AU2014267951A1 (en) 2015-11-19
EP2997033A1 (en) 2016-03-23
ES2656696T3 (es) 2018-02-28
EP2997033A4 (en) 2016-10-26
TW201524978A (zh) 2015-07-01
RS56701B1 (sr) 2018-03-30
EP3330272B1 (en) 2021-02-17
EP3330272A1 (en) 2018-06-06
TWI656122B (zh) 2019-04-11
PL2997033T3 (pl) 2018-04-30
LT2997033T (lt) 2018-02-12
ME02977B (me) 2018-10-20
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CY1119842T1 (el) 2018-06-27
EP2997033B1 (en) 2017-11-15
HRP20180081T1 (hr) 2018-02-23
HUE036384T2 (hu) 2018-07-30
WO2014183532A1 (en) 2014-11-20
HK1248685A1 (zh) 2018-10-19

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