HRP20180538T1 - Inhibitori za erk i postupci njihove uporabe - Google Patents

Inhibitori za erk i postupci njihove uporabe Download PDF

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HRP20180538T1
HRP20180538T1 HRP20180538TT HRP20180538T HRP20180538T1 HR P20180538 T1 HRP20180538 T1 HR P20180538T1 HR P20180538T T HRP20180538T T HR P20180538TT HR P20180538 T HRP20180538 T HR P20180538T HR P20180538 T1 HRP20180538 T1 HR P20180538T1
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10hetaryl
10aryl
nr31c
10alkynyl
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HRP20180538TT
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Liansheng Li
Tao Wu
Jun Feng
Pingda Ren
Yi Liu
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Kura Oncology, Inc.
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • 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
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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Claims (15)

1. Spoj, naznačen time, da ima formulu II-E: [image] ili njegova farmaceutski prihvatljiva sol; gdje: R1 je [image] od kojih je svaki nesupstituiran ili je supstituiran s jednim ili više neovisnih R10 ili R11 supstituenata; R21 je vodik, halogen, -OH, -CF3, -OCF3, -OR31, -NR31R32, -C(O)R31, -CO2R31, -C(=O)NR31, -NO2, -CN, -S(O)0-2R31, -SO2NR31R32, -NR31C(=O)R32, -NR31C(=O)OR32, -NR31C(=O)NR32R33, -NR31S(O)0-2R32, -C(=S)OR31, -C(=O)SR31, -NR31C(=NR32)NR32R33, -NR31C(=NR32)OR33, -NR31C(=NR32)SR33, -OC(=O)OR33, -OC(=O)NR31R32, -OC(=O)SR31, -SC(=O)SR31, -P(O)OR31OR32, -SC(=O)NR31R32, -L-C1-10alkil, -L-C2-10alkenil, -L-C2-10alkinil, -L-C1-10heteroalkil, -L-C3-10aril, -L-C1-10hetaril, -L-C3-10cikloalkil, -L-C1-10heterociklil, -L-C1-10alkil-C3-10aril, -L-C1-10alkil-C1-10hetaril, -L-C1-10alkil-C3-10cikloalkil,-L-C1-10alkil-C1-10heterociklil, -L-C2-10alkenil-C3-10aril, -L-C2-10alkenil-C1-10hetaril, -L-C2-10alkenil-C3-10cikloalkil, -L-C2-10alkenil-C1-10heterociklil, -L-C2-10alkinil-C3-10aril, -L-C2-10alkinil-C1-10hetaril, -L-C2-10alkinil-C3-10cikloalkil, -L-C2-10alkinil-C1-10heterociklil, -L-C1-10alkoksi-C3-10aril, -L-C1-10alkoksi-C1-10hetaril, -L-C1-10alkoksi-C3-10cikloalkil, -L-C1-10alkoksi-C1-10heterociklil, -L-C1-10heteroalkil-C3-10aril, -L-C1-10heteroalkil-C1-10hetaril, -L-C1-10heteroalkil-C3-10cikloalkil, -L-C1-10heteroalkil-C1-10heterociklil, -L-C3-10aril-C1-10alkil, -L-C3-10aril-C2-10alkenil, -L-C3-10aril-C2-10alkinil, -L-C3-10aril-C1-10hetaril, -L-C3-10aril-C3-10cikloalkil, -L-C3-10aril-C1-10heterociklil, -L-C1-10hetaril-C1-10alkil, -L-C1-10hetaril-C2-10alkenil, -L-C1-10hetaril-C2-10alkinil, -L-C1-10hetaril-C3-10aril, -L-C1-10hetaril-C3-10cikloalkil,-L-C1-10hetaril-C1-10heterociklil, -L-C3-10cikloalkil-C1-10alkil, -L-C3-10cikloalkil-C2-10alkenil, -L-C3-10cikloalkil-C2-10alkinil, -L-C3-10cikloalkil-C3-10aril, -L-C3-10cikloalkil-C1-10hetaril, -L-C3-10cikloalkil-C1-10heterociklil, -L-C1-10heterociklil-C1-10alkil, -L-C1-10heterociklil-C2-10alkenil, -L-C1-10heterociklil-C2-10alkinil, -L-C1-10heterociklil-C3-10aril, -L-C1-10heterociklil-C1-10hetaril, ili -L-C1-10heterociklil-C3-10cikloalkil, od kojih je svaki nesupstituiran ili je supstituiran s jednim ili više neovisnih R12 supstituenata; L je veza, -O-, -N(R31)-, -S(O)0-2-, -C(=O)-, -C(=O)O-, -OC(=O)-, -C(=O)N(R31)-, -N(R31)C(=O)-, -NR31C(=O)O-, -NR31C(=O)NR32-, -NR31S(O)0-2-, -S(O)0-2N(R31)-, -C(=S)O-, -C(=O)S-, -NR31C(=NR32)NR32-, -NR31C(=NR32)O-, -NR31C(=NR32)S-, -OC(=O)O-, -OC(=O)NR31-, -OC(=O)S-, -SC(=O)S-, -P(O)OR31O-, ili -SC(=O)NR31-; R72 je vodik, -C1-10alkil, -C2-10alkenil, -C2-10alkinil, -C1-10heteroalkil, -C3-10aril, -C1-10hetaril, -C3-10cikloalkil, -C1-10heterociklil, -OH, -CF3, -C(O)R31, -CO2R31, -C(=O)NR31, -S(O)0-2R31, -C(=S)OR31, ili -C(=O)SR31; R10 je -C1-10alkil, -C2-10alkenil, -C2-10alkinil, -C1-10heteroalkil, -C3-10aril, -C1-10hetaril, -C3-10cikloalkil, ili -C1-10heterociklil, od kojih je svaki nesupstituiran ili je supstituiran s jednim ili više neovisnih R11 supstituenata; R11 i R12 su neovisno vodik, halogen, -C1-10alkil, -C2-10alkenil, -C2-10alkinil, -C1-10heteroalkil, -C3-10aril, -C1-10hetaril, -C3-10cikloalkil, -C1-10heterociklil, -OH, -CF3, -OCF3, -OR31, -NR31R32, -C(O)R31, -CO2R31, -C(=O)NR31, -NO2, -CN, -S(O)0-2R31, -SO2NR31R32, -NR31C(=O)R32, -NR31C(=O)OR32, -NR31C(=O)NR32R33, -NR31S(O)0-2R32, -C(=S)OR31, -C(=O)SR31, -NR31C(=NR32)NR32R33, -NR31C(=NR32)OR33, -NR31C(=NR32)SR33, -OC(=O)OR33, -OC(=O)NR31R32, -OC(=O)SR31, -SC(=O)SR31, -P(O)OR31OR32, ili -SC(=O)NR31NR32; dok svaki od R31, R32 i R33 neovisno predstavlja vodik, halogen, -C1-10alkil, -C2-10alkenil, -C2-10alkinil, -C1-10heteroalkil, -C3-10aril, -C1-10hetaril, -C3-10cikloalkil, ili -C1-10heterociklil, ili R31 zajedno s R32 tvori heterociklički prsten.
2. Spoj prema patentnom zahtjevu 1, naznačen time, da je R21 odabran iz skupine koju čine -L-C1-10heteroalkil, -L-C3-10aril, -L-C1-10hetaril, -L-C3-10cikloalkil, i -L-C1-10heterociklil, od kojih je svaki nesupstituiran ili je supstituiran s jednim ili više neovisnih R12 supstituenata; te time, da L predstavlja vezu.
3. Spoj prema patentnom zahtjevu 2, naznačen time, da R21 predstavlja -L-C1-10hetaril koji je nesupstituiran ili je supstituiran s jednim ili više neovisnih R12 supstituenata; te time, da L predstavlja vezu.
4. Spoj prema patentnom zahtjevu 3, naznačen time, da C1-10hetaril iz R21 sadrži jednoga ili više dušikovih atoma.
5. Spoj prema patentnom zahtjevu 4, naznačen time, da je C1-10hetaril iz R21 odabran iz skupine koju čine pirazolil, piridinil, pirazinil, pirimidinil i piridazinil.
6. Spoj prema patentnom zahtjevu 5, naznačen time, da je C1-10hetaril iz R21 nesupstituiran.
7. Spoj prema patentnom zahtjevu 5, naznačen time, da je C1-10hetaril iz R21 supstituiran s jednim, dva ili tri neovisna R12 supstituenta.
8. Spoj prema bilo kojem od zahtjeva 2 do 5 ili 7, naznačen time, da je svaki R12 supstituent neovisno odabran iz skupine koju čine -C1-10alkil, -C2-10alkenil, -C2-10alkinil, -C1-10heteroalkil, -C3-10aril, -C1-10hetaril, -C3-10cikloalkil, -C1-10heterociklil, -OH, -CF3, -OCF3 i -OR31; pri čemu svaki R31 neovisno predstavlja vodik ili -C1-10alkil.
9. Spoj prema zahtjevu 8, naznačen time, da je svaki R12 supstituent neovisno odabran iz skupine koju čine -Me, -Et, -i-Pr, -n-Pr, -OH, -OMe, -OEt i -OPr.
10. Spoj prema bilo kojem od zahtjeva 1 do 9, naznačen time, da R72 predstavlja H.
11. Spoj prema bilo kojem od zahtjeva 1 do 10, naznačen time, da se upotrebljava u inhibiranju aktivnosti kinaze proteina.
12. Spoj za uporabu prema zahtjevu 11, naznačen time, da se kod kinaze proteina radi o ERK.
13. Spoj prema bilo kojem od zahtjeva 1 do 10, naznačen time, da se upotrebljava u liječenju raka, dok je prema potrebi rak odabran iz skupine koju čine rak dojke, rak gušterače, rak ne-malih stanica pluća (NSCLC), rak štitnjače, seminomi, melanom, rak mjehura, rak jetre, rak bubrega, mijelodisplastični sindrom (MDS), akutna mijelogena leukemija (AML) i kolorektalni rak.
14. Farmaceutski pripravak, naznačen time, da obuhvaća spoj prema bilo kojem od zahtjeva 1 do 10, te farmaceutski prihvatljivo pomoćno sredstvo, dok se prema potrebi pripravak formulira u oralnoj dozi.
15. Spoj prema zahtjevu 1, naznačen time, da je spoj odabran od sljedećih: [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] i [image]
HRP20180538TT 2013-10-03 2018-04-04 Inhibitori za erk i postupci njihove uporabe HRP20180538T1 (hr)

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Application Number Priority Date Filing Date Title
US201361886552P 2013-10-03 2013-10-03
US201462032446P 2014-08-01 2014-08-01
EP14850964.9A EP3052096B8 (en) 2013-10-03 2014-10-03 Inhibitors of erk and methods of use
PCT/US2014/059197 WO2015051341A1 (en) 2013-10-03 2014-10-03 Inhibitors of erk and methods of use

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