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HRP20170045T1 - Difluorlaktamski spojevi kao selektivni agonisti ep4 receptora za uporabu za liječenje bolesti i stanja posredovanih s ep4 receptorom - Google Patents

Difluorlaktamski spojevi kao selektivni agonisti ep4 receptora za uporabu za liječenje bolesti i stanja posredovanih s ep4 receptorom Download PDF

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Publication number
HRP20170045T1
HRP20170045T1 HRP20170045TT HRP20170045T HRP20170045T1 HR P20170045 T1 HRP20170045 T1 HR P20170045T1 HR P20170045T T HRP20170045T T HR P20170045TT HR P20170045 T HRP20170045 T HR P20170045T HR P20170045 T1 HRP20170045 T1 HR P20170045T1
Authority
HR
Croatia
Prior art keywords
difluoro
methyl
hydroxy
oxopyrrolidin
propyl
Prior art date
Application number
HRP20170045TT
Other languages
English (en)
Inventor
Stephen Douglas Barrett
Fred Lawrence Ciske
Joseph Michael Colombo
Gregory William Endres
Bradlee David Germain
Andriy Kornilov
James Bernard Kramer
Adam Uzieblo
Kirk M. Maxey
Original Assignee
Cayman Chemical Company, Incorporated
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 Cayman Chemical Company, Incorporated filed Critical Cayman Chemical Company, Incorporated
Publication of HRP20170045T1 publication Critical patent/HRP20170045T1/hr

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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 to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 to other ring carbon atoms
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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  • Cosmetics (AREA)

Claims (20)

1. Spoj s formulom (Ia) [image] ili njegova farmaceutski prihvatljiva sol, naznačen time da: L1 je a) C3-C7alkilen, C3-C7alkenilen, ili C3-C7alkinilen, pri čemu su C3-C7alkilen, C3-C7alkenilen, ili C3-C7alkinilen svaki proizvoljno supstituirani s 1, 2, 3, ili 4 fluorovih supstituenata; b) -(CH2)t-G-(CH2)p-; pri čemu t je 0, 1, ili 2, p je 0, 1, 2, ili 3, i t+p = 0, 1,2, 3, ili 4; ili c) -(CH2)n-G1-(CH2)p-, -(CH2)n-G2-(CH2)p-, -(CH2)n-C≡C-G2-, ili - (CH2)n-C(R13)=C(R13)-G2-, pri čemu n je 1, 2, 3, 4, ili 5, p je 0, 1, 2, ili 3, i n+p = 1, 2, 3, 4, 5, ili 6; G je [image] ili [image] G1 je O, C(O), S, S(O), S(O)2, ili NR8; pri čemu R8 je H, C1-C4 alkil, ili C1-C4alkilkarbonil; G2 je [image] [image] pri čemu G2 je proizvoljno supstituiran s 1, 2, ili 3 supstituenta koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, i C1-C3haloalkoksi; R1 je COOR10, CONR10R11, CH2OR10, SO3R10, SO2NR10R11, PO(OR10)2, ili tetrazol-5-il; R10 je H, C1-C4 alkil, ili aril; R11 je H, C1-C4 alkil, COR12, OR10, ili SO2R12; R12 je C1-C4 alkil; R13, kod svakog pojavljivanja, je neovisno H ili C1-C4alkil; L4 je -C(R2)2-C(R3)2-, -C(R2)=C(R3)-, -C≡C-, ili [image] pri čemu R2 i R3 su svaki H, CH3, fluor, ili klor; L2 je -CH2- ili veza; R4 i R5 su svaki neovisno H, F, CF3, ili C1-C4 alkil; ili R4 i R5 zajedno s ugljikom na koji su oni vezani tvore C3-C5 cikloalkil, [image] R6 je aril, heteroaril, C3-C10alkil, C3-C10alkenil, C3-C10alkinil, C3-C10haloalkil, C3-C10haloalkenil, C3-C10haloalkinil, ili L3-R7; pri čemu su aril i heteroaril proizvoljno supstituirani s 1, 2, 3, ili 4 supstituenata koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, C1-C3haloalkoksi; i -C1-C3alkilen-C1-C3alkoksi; i pri čemu su C3-C10alkil, C3-C10alkenil, C3-C10alkinil, C3-C10haloalkil, C3-C10haloalkenil, i C3-C10haloalkinil proizvoljno supstituirani sa supstituentom odabranim iz skupine koju čine COOR10', CONR10'R11', CH2OR10', SO3R10', SO2NR10'R11', PO(OR10')2, i tetrazol-5-il; R10' je H, C1-C4 alkil, ili aril; R11' je H, C1-C4 alkil, COR12', OR10', ili SO2R12'; R12' je C1-C4 alkil; L3 je C1-C6alkilen, C2-C6alkenilen, C2-C6alkinilen, -(CH2)m-G3-(CH2)q-, -(CH2)m-G4-(CH2)q-, ili -G5-C≡C-; pri čemu su C1-C6alkilen, C2-C6alkenilen, i C2-C6alkinilen proizvoljno supstituirani s 1, 2, 3, ili 4 fluorovih supstituenata; i pri čemu m i q su svaki neovisno 0, 1, 2, ili 3 i m + q = 0, 1, 2, 3, ili 4; G3 je O, C(O), S, S(O), S(O)2, ili NR9; pri čemu R9 je H, C1-C4 alkil, ili C1-C4alkilkarbonil; G4 je [image] ili [image] pri čemu G4 je proizvoljno supstituiran s 1, 2, ili 3 supstituenta koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, i C1-C3haloalkoksi; G5 je [image] pri čemu Q5 je proizvoljno supstituiran s 1, 2, ili 3 supstituenta koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, i C1-C3haloalkoksi; R7 je C3-C8cikloalkil, aril, heteroaril, ili heterociklil; pri čemu je R7 proizvoljno supstituiran s 1, 2, 3, ili 4 supstituenata koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, C1-C3haloalkoksi, i -C1-C3alkilen-C1-C3alkoksi; r je 0 ili 1; i s je 0 ili 1.
2. Spoj prema zahtjevu 1, ili njegova farmaceutski prihvatljiva sol, naznačen time da: L1 je a) C3-C7alkilen, pri čemu je C3-C7alkilen proizvoljno supstituiran s 1, 2, 3, ili 4 fluorovih supstituenata; ili c) -(CH2)n-G2-(CH2)p-, -(CH2)n-C≡C-G2-, ili -(CH2)n-C(H)=C(H)-G2-, pri čemu n je 1, 2, 3, 4, ili 5, p je 0, 1, 2, ili 3, i n+p = 1, 2, 3, 4, 5, ili 6; G2 je [image] pri čemu G2 je proizvoljno supstituiran s 1, 2, ili 3 supstituenta koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, i C1-C3haloalkoksi; R1 je COOR10; i R10 je H ili C1-C4 alkil.
3. Spoj prema zahtjevu 1, ili njegova farmaceutski prihvatljiva sol, naznačen time da: [image] L4 je -C(R2)=C(R3)-; R2 i R3 su svaki vodik; i R5 su neovisno H ili C1-C4 alkil; R6 je C3-C10alkil, C3-C10alkinil, ili L3-R7; L3 je C1-C6alkilen ili C2-C6alkinilen; pri čemu su C1-C6alkilen i C2-C6alkinilen proizvoljno supstituirani s 1, 2, 3, ili 4 fluorovih supstituenata; i R7 je aril, pri čemu R7 je proizvoljno supstituiran s 1, 2, 3, ili 4 supstituenata koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, C1-C3haloalkoksi, i -C1-C3alkilen-C1-C3alkoksi.
4. Spoj prema zahtjevu 2, ili njegova farmaceutski prihvatljiva sol, naznačen time da: [image] L4 je -C(R2)2-C(R3)2-, -C(R2)=C(R3)-, -C≡C-, ili [image] pri čemu R2 i R3 su svaki H, CH3, fluor, ili klor; R4 i R5 su svaki neovisno H, F, CF3, ili C1-C4 alkil; ili R4 i R5 zajedno s ugljikom na koji su oni vezani tvore C3-C5 cikloalkil; R6 je aril, C3-C10alkil, C3-C10alkenil, C3-C10alkinil, C3-C10haloalkil, C3-C10haloalkenil, C3-C10haloalkinil, ili L3-R7; L3 je C1-C6alkilen, C2-C6alkenilen, ili C2-C6alkinilen pri čemu su C1-C6alkilen, C2-C6alkenilen, i C2-C6alkinilen proizvoljno supstituirani s 1, 2, 3, ili 4 fluorovih supstituenata; i R7 je aril, pri čemu R7 je proizvoljno supstituiran s 1, 2, 3, ili 4 supstituenata koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, C1-C3haloalkoksi, i -C1-C3alkilen-C1-C3alkoksi.
5. Spoj prema zahtjevu 4, ili njegova farmaceutski prihvatljiva sol, naznačen time da: L4 je [image] R4 i R5 su neovisno H ili C1-C4 alkil; R6 je C3-C10alkil, C3-C10alkenil, C3-C10alkinil, C3-C10haloalkil, C3-C10haloalkenil, C3-C10haloalkinil, ili L3-R7; L3 je C1-C6alkilen, C2-C6alkenilen, ili C2-C6alkinilen; pri čemu su C1-C6alkilen, C2-C6alkenilen, i C2-C6alkinilen proizvoljno supstituirani s 1, 2, 3, ili 4 fluorovih supstituenata; i R7 je aril, pri čemu R7 je proizvoljno supstituiran s 1, 2, 3, ili 4 supstituenata koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, C1-C3haloalkoksi, i -C1-C3alkilen-C1-C3alkoksi.
6. Spoj prema zahtjevu 5, ili njegova farmaceutski prihvatljiva sol, naznačen time da: R4 i R5 su neovisno H ili CH3; R6 je C3-C10alkil, C3-C10alkinil, ili L3-R7; L3 je C1-C6alkilen ili C2-C6alkinilen; pri čemu su C1-C6alkilen i C2-C6alkinilen proizvoljno supstituirani s 1, 2, 3, ili 4 fluorovih supstituenata; i R7 je aril, pri čemu je R7 proizvoljno supstituiran s 1, 2, 3, ili 4 supstituenata koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, C1-C3haloalkoksi, i -C1-C3alkilen-C1-C3alkoksi.
7. Spoj prema zahtjevu 6, ili njegova farmaceutski prihvatljiva sol, naznačen time da: L1 je a) C3-C7alkilen; ili c) -(CH2)n-G2-, pri čemu n je 2 ili 3; G2 je [image] R6 je propil, butil, pentil, propinil, butinil, pentinil, heksinil, ili L3-R7; L3 je propilen, butilen, pentilen, propinilen, ili butinilen; i R7 je fenil.
8. Spoj prema zahtjevu 7, ili njegova farmaceutski prihvatljiva sol, naznačen time da: L1 je a) n-heksilen; ili c) -(CH2)n-G2-, pri čemu n je 2 ili 3; G2 je [image] R1 je COOR10; R10 je H ili CH3; R6 je n-butil, but-2-in-1-il, pent-2-in-1-il, heks-2-in-1-il, ili L3-R7; L3 je n-propilen, n-butilen, n-pentilen, ili -CH2-C=C-; i R7 je fenil.
9. Spoj prema zahtjevu 5, ili njegova farmaceutski prihvatljiva sol, naznačen time da: R6 je C3-C10alkil, C3-C10alkenil, C3-C20alkinil, C3-C10haloalkil, C3-C10haloalkenil, ili C3-C10haloalkinil.
10. Spoj prema zahtjevu 5, ili njegova farmaceutski prihvatljiva sol, naznačen time da: R6 je L3-R7; L3 je C1-C6alkilen, C2-C6alkenilen, ili C2-C6alkinilen; pri čemu su C1-C6alkilen, C2-C6alkenilen, i C2-C6alkinilen proizvoljno supstituirani s 1, 2, 3, ili 4 fluorovih supstituenata; i R7 je aril, pri čemu je R7 proizvoljno supstituiran s 1, 2, 3, ili 4 supstituenata koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, C1-C3haloalkoksi, i -C1-C3alkilen-C1-C3alkoksi.
11. Spoj prema zahtjevu 5, ili njegova farmaceutski prihvatljiva sol, naznačen time da: L1 je C3-C7alkilen, pri čemu je C3-C7alkilen proizvoljno supstituiran s 1, 2, 3, ili 4 fluorovih supstituenata.
12. Spoj prema zahtjevu 5, ili njegova farmaceutski prihvatljiva sol, naznačen time da: L1 je -(CH2)n-G2-(CH2)p-, -(CH2)n-C≡C-G2-, ili -(CH2)n-C(H)=C(H)-G2-, pri čemu n je 1, 2, 3, 4, ili 5, p je 0, 1, 2, ili 3, i n+p = 1, 2, 3, 4, 5, ili 6; i G2 je [image] pri čemu je G2 proizvoljno supstituiran s 1, 2, ili 3 supstituenta koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, i C1-C3haloalkoksi.
13. Spoj prema zahtjevu 9, ili njegova farmaceutski prihvatljiva sol, naznačen time da: L1 je C3-C7alkilen, pri čemu je C3-C7alkilen proizvoljno supstituiran s 1, 2, 3, ili 4 fluorovih supstituenata.
14. Spoj prema zahtjevu 9, ili njegova farmaceutski prihvatljiva sol, naznačen time da: L1 je -(CH2)n-G2-(CH2)p-, -(CH2)n-C≡C-G2-, ili -(CH2)n-C(H)=C(H)-G2-, pri čemu n je 1, 2, 3, 4, ili 5, p je 0, 1, 2, ili 3, i n+p = 1, 2, 3, 4, 5, ili 6; i G2 je [image] pri čemu G2 je proizvoljno supstituiran s 1, 2, ili 3 supstituenta koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, i C1-C3haloalkoksi.
15. Spoj prema zahtjevu 10, ili njegova farmaceutski prihvatljiva sol, naznačen time da: L1 je C3-C7alkilen, pri čemu je alkilen proizvoljno supstituiran s 1, 2, 3, ili 4 fluorovih supstituenata.
16. Spoj prema zahtjevu 10, ili njegova farmaceutski prihvatljiva sol, naznačen time da: L1 je -(CH2)n-G2-(CH2)p-, -(CH2)n-C≡C-G2-, ili -(CH2)n-C(H)=C(H)-G2-, pri čemu n je 1, 2, 3, 4, ili 5, p je 0, 1, 2, ili 3, i n+p = 1, 2, 3, 4, 5, ili 6; i G2 je [image] pri čemu G2 je proizvoljno supstituiran s 1, 2, ili 3 supstituenta koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, i C1-C3haloalkoksi.
17. Spoj s formulom (II) prema zahtjevu 1, ili njegova farmaceutski prihvatljiva sol, naznačen time da: [image] L1 je a) C3-C7alkilen, C3-C7alkenilen, ili C3-C7alkinilen, pri čemu su C3-C7alkilen, C3-C7alkenilen, ili C3-C7alkinilen svaki proizvoljno supstituirani s 1, 2, 3, ili 4 fluorovih supstituenata; b) -(CH2)t-G-(CH2)p-; pri čemu t je 0, 1, ili 2, p je 0, 1, 2, ili 3, i t+p = 0, 1, 2, 3, ili 4; ili c) -(CH2)n-G1-(CH2)p-, -(CH2)n-G2-(CH2)p-, -(CH2)n-C≡C-G2-, ili - (CH2)n-C(R13)=C(R13)-G2-, pri čemu n je 1, 2, 3, 4, ili 5, p je 0, 1, 2, ili 3, i n+p = 1, 2, 3, 4, 5, ili 6; G je [image] ili [image] G1 je O, C(O), S, S(O), S(O)2, ili NR8; pri čemu R8 je H, C1-C4 alkil, ili C1-C4alkilkarbonil; G2 je [image] [image] pri čemu G2 je proizvoljno supstituiran s 1, 2, ili 3 supstituenta koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, i C1-C3haloalkoksi; R1 je COOR10, CONR10R11, CH2OR10, SO3R10, SO2NR10R11, PO(OR10)2, ili tetrazol-5-il; R10 je H, C1-C4 alkil, ili aril; R11 je H, C1-C4 alkil, COR12, OR10, ili SO2R12; R12 je C1-C4 alkil; R13, kod svakog pojavljivanja, je neovisno H ili C1-C4alkil; R4 i R5 su svaki neovisno H, F, CF3, ili C1-C4 alkil; ili R4 i R5 zajedno s ugljikom na koji su oni vezani tvore C3-C5 cikloalkil, [image] R6 je aril, heteroaril, C3-C10alkil, C3-C10alkenil, C3-C10alkinil, C3-C10haloalkil, C3-C10haloalkenil, C3-C10haloalkinil, ili L3-R7; pri čemu su aril i heteroaril proizvoljno supstituirani s 1, 2, 3, ili 4 supstituenata koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, C1-C3haloalkoksi; i -C1-C3alkilen-C1-C3alkoksi; i pri čemu su C3-C10alkil, C3-C10alkenil, C3-C10alkinil, C3-C10haloalkil, C3-C10haloalkenil, i C3-C10haloalkinil proizvoljno supstituirani sa supstituentom koji je odabran iz skupine koju čine COOR10, CONR10R11, CH2OR10, SO3R10, SO2NR10R11, PO(OR10)2, i tetrazol-5-il; L3 je C1-C6alkilen, C2-C6alkenilen, C2-C6alkinilen, -(CH2)m-G3-(CH2)q-, -(CH2)m-G4-(CH2)q-, ili -G5-C≡C-; pri čemu su C1-C6alkilen, C2-C6alkenilen, i C2-C6alkinilen proizvoljno supstituirani s 1, 2, 3, ili 4 fluorovih supstituenata; i pri čemu m i q su svaki neovisno 0, 1, 2, ili 3 i m + q = 0, 1, 2, 3, ili 4; G3 je O, C(O), S, S(O), S(O)2, ili NR9; pri čemu R9 je H, C1-C4 alkil, ili C1-C4alkilkarbonil; G4 je [image] ili [image] pri čemu G4 je proizvoljno supstituiran s 1, 2, ili 3 supstituenta koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, i C1-C3haloalkoksi; G5 je [image] pri čemu je G5 proizvoljno supstituiran s 1, 2, ili 3 supstituenta koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, i C1-C3haloalkoksi; R7 je C3-C8cikloalkil, aril, heteroaril, ili heterociklil; pri čemu R7 je proizvoljno supstituiran s 1, 2, 3, ili 4 supstituenata koji su odabrani iz skupine koju čine C1-C4alkil, C1-C3haloalkil, cijano, halogen, C1-C3alkoksi, C1-C3haloalkoksi, i -C1-C3alkilen-C1-C3alkoksi; i r je 0 ili 1.
18. Spoj prema zahtjevu 1, ili njegova farmaceutski prihvatljiva sol, naznačen time da je odabran iz skupine koju čine: metil 7-((5R)-3,3-difluor-5-((E)-3-hidroksi-4-metilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((5R)-3,3-difluor-5-((3S,E)-3-hidroksi-4-metilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((5R)-3,3-difluor-5-((3R,E)-3-hidroksi-4-metilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((R)-3,3-difluor-5-((3R,4S,E)-3-hidroksi-4-metilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((R)-3,3-difluor-5-((3R,4R,E)-3-hidroksi-4-metilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3R,4S,E)-3-hidroksi-4-rnetilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3R,4R,E)-3-hidroksi-4-metilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanska kiselina; metil 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((R)-3,3-difluor-5-((3R,4S,E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3R,4S,E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanska kiselina; metil 7-((5R)-3,3-difluor-5-((E)-3-hidroksi-4-metildek-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metildek-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metildek-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanska kiselina; metil 7-((5R)-3,3-difluor-5-((E)-3-hidroksi-4-metil-7-fenilhept-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanska kiselina; metil 7-((5R)-3,3-difluor-5-((E)-3-hidroksi-4-metilokt-1-en-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metilokt-1-en-1-il)-2-oksopirolidin-1-il)heptanoat; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metilokt-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; metil 7-((5R)-3,3-difluor-5-((E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((5R)-3,3-difluor-5-((3S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((5R)-3,3-difluor-5-((3R,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanoat; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((5R)-3,3-difluor-5-((3R,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; metil 7-((5R)-3,3-difluor-5-((E)-3-hidroksinon-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((5R)-3,3-difluor-5-((3S,E)-3-hidroksinon-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; 7-((5R)-3,3-difluor-5-((3S,E)-3-hidroksinon-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanska kiselina; metil 7-((5R)-3,3-difluor-5-((E)-3-hidroksi-7-fenilhept-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((5R)-3,3-difluor-5-((3S,E)-3-hidroksi-7-fenilhept-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanoat; 7-((5R)-3,3-difluor-5-((3S,E)-3-hidroksi-7-fenilhept-1-en-6-in-1-il)-2-oksopirolidin-1-il)heptanska kiselina; metil 7-((5R)-3,3-difluor-5-((E)-3-hidroksiokt-1-en-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((R)-3,3-difluor-5-((S,E)-3-hidroksiokt-1-en-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((R)-3,3-difluor-5-((R,E)-3-hidroksiokt-1-en-1-il)-2-oksopirolidin-1-il)heptanoat; 7-((R)-3,3-difluor-5-((S,E)-3-hidroksiokt-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((R,E)-3-hidroksiokt-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; metil 7-((5R)-3,3-difluor-5-((E)-3-hidroksi-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((R)-3,3-difluor-5-((S,E)-3-hidroksi-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanoat; metil 7-((R)-3,3-difluor-5-((R,E)-3-hidroksi-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanoat; 7-((R)-3,3-difluor-5-((S,E)-3-hidroksi-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((R,E)-3-hidroksi-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 4-(2-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)etil)benzojeva kiselina; metil 4-(2-((5R)-3,3-difluor-5-((E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)etil)benzoat; metil 4-(2-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)etil)benzoat; metil 4-(2-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)etil)benzoat; metil 4-(2-((5R)-3,3-difluor-5-((3R,E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)etil)benzoat; 4-(2-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)etil)benzojeva kiselina; 4-(2-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)etil)benzojeva kiselina; 4-(2-((5R)-3,3-difluor-5-((3R,E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)etil)benzojeva kiselina; 4-(2-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metildek-1-en-6-in-1-il)-2-oksopirolidin-1-il)etil)benzojeva kiselina; 4-(2-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-6-in-1-il)-2-oksopirolidin-1-il)etil)benzojeva kiselina; 4-(2-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metilokt-1-en-1-il)-2-oksopirolidin-1-il)etil)benzojeva kiselina; 4-(2-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)etil)benzojeva kiselina; 4-(2-((R)-3,3-difluor-5-((S,E)-3-hidroksiokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)etil)benzojeva kiselina; 4-(2-((R)-3,3-difluor-5-((S,E)-3-hidroksinon-1-en-6-in-1-il)-2-oksopirolidin-1-il)etil)benzojeva kiselina; 4-(2-((R)-3,3-difluor-5-((S,E)-3-hidroksidek-1-en-6-in-1-il)-2-oksopirolidin-1-il)etil)benzojeva kiselina; 4-(2-((R)-3,3-difluor-5-((S,E)-3-hidroksi-7-fenilhept-1-en-6-in-1-il)-2-oksopirolidin-1-il)etil)benzojeva kiselina; metil 4-(2-((5R)-3,3-difluor-5-((E)-3-hidroksiokt-1-en-1-il)-2-oksopirolidin-1-il)etil)benzoat; metil 4-(2-((R)-3,3-difluor-5-((S,E)-3-hidroksiokt-1-en-1-il)-2-oksopirolidin-1-il)etil)benzoat; metil 4-(2-((R)-3,3-difluor-5-((R,E)-3-hidroksiokt-1-en-1-il)-2-oksopirolidin-1-il)etil)benzoat; 4-(2-((R)-3,3-difluor-5-((S,E)-3-hidroksiokt-1-en-1-il)-2-oksopirolidin-1-il)etil)benzojeva kiselina; 4-(2-((R)-3,3-difluor-5-((R,E)-3-hidroksiokt-1-en-1-il)-2-oksopirolidin-1-il)etil)benzojeva kiselina; 4-(2-((R)-3,3-difluor-5-((S,E)-3-hidroksi-7-fenilhept-l-en-1-il)-2-oksopirolidin-1-il)etil)benzojeva kiselina; 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; metil 5-(3-((5R)-3,3-ditluoro-5-((E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; metil 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; metil 5-(3-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; metil 5-(3-((5R)-3,3-difluor-5-((3R,E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((5R)-3,3-difluor-5-((3R,E)-3-hidroksi-4-metilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metildek-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metilokt-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((R)-3,3-difluor-5-((S,E)-3-hidroksiokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((R)-3,3-difluor-5-((S,E)-3-hidroksinon-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((R)-3,3-difluor-5-((S,E)-3-hidroksidek-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((R)-3,3-difluor-5-((S,E)-3-hidroksi-7-fenilhept-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; metil 5-(3-((5R)-3,3-difluor-5-((E)-3-hidroksiokt-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; metil 5-(3-((R)-3,3-difluor-5-((S,E)-3-hidroksiokt-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; metil 5-(3-((R)-3,3-difluor-5-((R,E)-3-hidroksiokt-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; 5-(3-((R)-3,3-difluor-5-((S,E)-3 -hidroksiokt-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((R)-3,3-difluor-5-((R,E)-3-hidroksiokt-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((R)-3,3-difluor-5-((S,E)-3-hidroksi-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; metil 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; metil 5-(3-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; 5-(3-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; metil 5-(3-((S)-3,3-difluor-5-((3R,4S)-3-hidroksi-4-metil-7-fenilheptil)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; metil 5-(3-((S)-3,3-difluor-5-((3R,4R)-3-hidroksi-4-metil-7-fenilheptil)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; 5-(3-((S)-3,3-difluor-5-((3R,4R)-3-hidroksi-4-metil-7-fenilheptil)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; metil 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-6-fenilheks-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; metil 5-(3-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metil-6-fenilheks-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; 5-(3-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metil-6-fenilheks-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; metil 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-8-fenilokt-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-8-fenilokt-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metil-8-fenilokt-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; metil 5-(3-((S)-3,3-difluor-5-((3R,4S)-3-hidroksi-4-metil-8-feniloktil)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; metil 5-(3-((S)-3,3-difluor-5-((3R,4R)-3-hidroksi-4-metil-8-feniloktil)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; 5-(3-((S)-3,3-difluor-5-((3R,4S)-3-hidroksi-4-metil-8-feniloktil)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((S)-3,3-difluor-5-((3R,4R)-3-hidroksi-4-metil-8-feniloktil)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; metil 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-9-fenilnon-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; metil 5-(3-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metil-9-fenilnon-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-9-fenilnon-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metil-9-fenilnon-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; metil 5-(3-((S)-3,3-difluor-5-((3R,4S)-3-hidroksi-4-metil-9-fenilnonil)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; metil 5-(3-((S)-3,3-difluor-5-((3R,4R)-3-hidroksi-4-metil-9-fenilnonil)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; 5-(3-((S)-3,3-difluor-5-((3R,4S)-3-hidroksi-4-metil-9-fenilnonil)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((S)-3,3-difluor-5-((3R,4R)-3-hidroksi-4-metil-9-fenilnonil)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; metil 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-5-fenilpent-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; metil 5-(3-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metil-5-fenilpent-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-5-fenilpent-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metil-5-fenilpent-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; metil 5-(3-((R)-3,3-difluor-5-((S,E)-3-hidroksi-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; metil 5-(3-((R)-3,3-difluor-5-((S,E)-3-hidroksi-7-fenilhept-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; metil 5-(3-((S)-3,3-difluor-5-((S)-3-hidroksi-7-fenilheptil)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; 5-(3-((S)-3,3-difluor-5-((S)-3-hidroksi-7-fenilheptil)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; metil 7-((S)-3,3-difluor-5-((3R,4S)-3-hidroksi-4-metil-7-fenilheptil)-2-oksopirolidin-1-il)heptanoat; metil 7-((S)-3,3-difluor-5-((3R,4R)-3-hidroksi-4-metil-7-fenilheptil)-2-oksopirolidin-1-il)heptanoat; 7-((S)-3,3-difluor-5-((3R,4S)-3-hidroksi-4-metil-7-fenilheptil)-2-oksopirolidin-1-il)heptanska kiselina; 7-((S)-3,3-difluor-5-((3R,4R)-3-hidroksi-4-metil-7-fenilheptil)-2-oksopirolidin-1-il)heptanska kiselina; metil 7-((S)-3,3-difluor-5-((3R,4S)-3-hidroksi-4-metil-8-feniloktil)-2-oksopirolidin-1-il)heptanoat; metil 7-((S)-3,3-difluor-5-((3R,4R)-3-hidroksi-4-metil-8-feniloktil)-2-oksopirolidin-1-il)heptanoat; 7-((S)-3,3-difluor-5-((3R,4S)-3-hidroksi-4-metil-8-feniloktil)-2-oksopirolidin-1-il)heptanska kiselina; 7-((S)-3,3-difluor-5-((3R,4R)-3-hidroksi-4-metil-8-feniloktil)-2-oksopirolidin-1-il)heptanska kiselina; metil 7-((S)-3,3-difluor-5-((3R,4S)-3-hidroksi-4-metil-9-fenilnonil)-2-oksopirolidin-1-il)heptanoat; metil 7-((S)-3,3-difluor-5-((3R,4R)-3-hidroksi-4-metil-9-fenilnonil)-2-oksopirolidin-1-il)heptanoat; 7-((S)-3,3-difluor-5-((3R,4S)-3-hidroksi-4-metil-9-fenilnonil)-2-oksopirolidin-1-il)heptanska kiselina; 7-((S)-3,3-difluor-5-((3R,4R)-3-hidroksi-4-metil-9-fenilnonil)-2-oksopirolidin-1-il)heptanska kiselina; metil 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-8-fenilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; metil 5-(3-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metil-8-fenilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-8-fenilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((R)-3,3-ditluoro-5-((3S,4R,E)-3-hidroksi-4-metil-8-fenilokt-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; metil 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-9-fenilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; metil 5-(3-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metil-9-fenilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilat; 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-9-fenilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 5-(3-((R)-3,3-difluor-5-((3S,4R,E)-3-hidroksi-4-metil-9-fenilnon-1-en-6-in-1-il)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; (R)-1-(6-(1H tetrazol-5-il)heksil)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)pirolidin-2-one; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)-N-etilheptanamid; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)-N-(metilsulfonil)heptanamid; 7-((R)-3,3-difluor-5-((3S,4S,Z)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 3-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)propil)benzojeva kiselina; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)hept-5-inska kiselina; (Z)-7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)hept-5-enska kiselina; 5-(3-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)prop-1-in-1-il)tiofen-2-karboksilna kiselina; 4-((2-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)etil)tio)butanska kiselina; 7-((S)-3,3-difluor-5-((3R,4S)-3-hidroksi-4-metil-7-fenilheptil)-2-oksopirolidin-1-il)heptanska kiselina; 5-(3-((S)-3,3-difluor-5-((3R,4S)-3-hidroksi-4-metil-7-fenilheptil)-2-oksopirolidin-1-il)propil)tiofen-2-karboksilna kiselina; 4-(2-((S)-3,3-difluor-5-((3R,4S)-3-hidroksi-4-metil-7-fenilheptil)-2-oksopirolidin-1-il)etil)benzojeva kiselina; 3-(3-((S)-3,3-difluor-5-((3R,4S)-3-hidroksi-4-metil-7-fenilheptil)-2-oksopirolidin-1-il)propil)benzojeva kiselina; 4-((2-((S)-3,3-difluor-5-((3R,4S)-3-hidroksi-4-metil-7-fenilheptil)-2-oksopirolidin-1-il)etil)tio)butanska kiselina; 7-((R)-3,3-difluor-5-((3S,4S)-3-hidroksi-4-metil-7-fenilhept-1-in-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3R,4S,E)-3-hidroksi-4-fenilpent-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-5-fenilpent-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-6-fenilheks-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-8-fenilokt-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-9-fenilnon-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-5-((3S,4S,E)-7-cikloheksil-3-hidroksi-4-metilhept-1-en-1-il)-3,3-difluor-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-ditluoro-5-((3S,4S,E)-3-hidroksi-4-metil-7-(naftalen-2-il)hept-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-(naftalen-1-il)hept-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3S,4S,E)-7-(3-fluorfenil)-3-hidroksi-4-metilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-7-(m-tolil)hept-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-5-((3S,4S,E)-7-(3-klorfenil)-3-hidroksi-4-metilhept-1-en-1-il)-3,3-difluor-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-7-(3-metoksifenil)-4-metilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-7-(3-(metoksimetil)fenil)-4-metilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-6-(feniltio)heks-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3S,4S,E)-3-hidroksi-4-metil-6-fenoksiheks-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-5-((3S,4S,E)-4-etil-3-hidroksi-7-fenilhept-1-en-1-il)-3,3-difluor-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3R,4R,E)-3-hidroksi-4-isopropil-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((3R,4S,E)-3-hidroksi-7-fenil-4-(trifluormetil)hept-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-5-((R,E)-4,4-difluor-3-hidroksi-7-fenilhept-1-en-1-il)-3,3-difluor-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-3,3-difluor-5-((R,E)-3-hidroksi-4-metilen-7-fenilhept-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina; 7-((R)-5-((R,E)-4-(difluormetilen)-3-hidroksi-7-fenilhept-1-en-1-il)-3,3-difluor-2-oksopirolidin-1-il)heptanska kiselina; i 7-((R)-3,3-difluor-5-((R,E)-3-hidroksi-3-(1-(3-fenilpropil)ciklobutil)prop-1-en-1-il)-2-oksopirolidin-1-il)heptanska kiselina.
19. Spoj prema bilo kojem od zahtjeva 1 do 18, ili njegova farmaceutski prihvatljiva sol, naznačen time da je za uporabu u liječenju povišenog intraokularnog tlaka, glaukoma, očne hipertenzije, suhog oka, makularnog edema, makularne degeneracije, alopecije, ductus arteriosis, ili neuropatske boli.
20. Spoj prema bilo kojem od zahtjeva 1 do 18, ili njegova farmaceutski prihvatljiva sol, naznačen time da je za uporabu u liječenju povišenog intraokularnog tlaka, glaukoma, ili očne hipertenzije.
HRP20170045TT 2012-07-19 2017-01-11 Difluorlaktamski spojevi kao selektivni agonisti ep4 receptora za uporabu za liječenje bolesti i stanja posredovanih s ep4 receptorom HRP20170045T1 (hr)

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