HRP20180331T1 - Spojevi n-pirolidinil, n'pirazolil- urea, tiourea, gvanidin i cijanogvanidin kao inhibitori trka kinaze - Google Patents

Spojevi n-pirolidinil, n'pirazolil- urea, tiourea, gvanidin i cijanogvanidin kao inhibitori trka kinaze Download PDF

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HRP20180331T1
HRP20180331T1 HRP20180331TT HRP20180331T HRP20180331T1 HR P20180331 T1 HRP20180331 T1 HR P20180331T1 HR P20180331T T HRP20180331T T HR P20180331TT HR P20180331 T HRP20180331 T HR P20180331T HR P20180331 T1 HRP20180331 T1 HR P20180331T1
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compound
formula
cancer
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Shelley Allen
Barbara J. Brandhuber
Timothy Kercher
Gabrielle R. KOLAKOWSKI
Shannon L. Winski
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Array Biopharma, Inc.
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    • 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
    • A61K31/41—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
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/14—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by doubly-bound oxygen atoms
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

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Claims (24)

1. Spoj koji je odabran - od spojeva s Formulom I: [image] ili stereoizomeri, tautomeri, ili njihove farmaceutski prihvatljive soli ili solvati, naznačen time da: Prsten B i skupina NH-C(=X)-NH su u trans konfiguraciji; Ra, Rb, Rc i Rd su neovisno odabrani od H i (1-3C)alkil, ili Rc i Rd su neovisno odabrani od H i (1-3C)alkil, i Ra i Rb zajedno s atomom na koji su oni vezani tvore ciklopropilni prsten; X je O, S, NH, ili N-CN; R1 je (1-3C alkoksi)(1-6C)alkil, (trifluorometoksi)(1-6C)alkil, (1-3C alkilsulfanil)(1-6C)alkil, monofluoro(1-6C)alkil, difluoro(1-6C)alkil, trifluoro(1-6C)alkil, tetrafluoro(2-6C)alkil, pentafluro(2-6C)alkil, cijano(1-6C)alkil, aminokarbonil(1-6C)alkil, hidroksi(1-6C)alkil, dihidroksi(2-6C)alkil, (1-6C)alkil, (1-3C alkilamino)(1-3C)alkil, (1-4C alkoksikarbonil)(1-6C)alkil, amino(1-6C)alkil, hidroksi(1-3C alkoksi)(1-6C)alkil, di(1-3C alkoksi)(1-6C)alkil, (1-3C alkoksi)trifluoro(1-6C)alkil, hidroksitrifluoro(1-6C)alkil, (1-4C alkoksikarbonil)(1-3C alkoksi)(1-6C)alkil ili hidroksikarbonil(1-3C alkoksi)(1-6C)alkil; R2 je H, F, ili OH; Prsten B je Ar1 ili hetAr1; Ar1 je fenil proizvoljno supstituiran s jednim ili više supstituenata koji su neovisno odabrani od halogena, CF3, CF3O-, (1-4C)alkoksi, hidroksi(1-4C)alkil, (1-6C)alkil i CN; hetAr1 je 5-6 člani heteroaril koji ima 1-3 prstenska heteroatoma koji su neovisno odabrani od N, S i O, i proizvoljno supstituiran s jednim ili više supstituenata koji su neovisno odabrani od (1-6C)alkil, halogen, OH, CF3, NH2 i hidroksi(1-2C)alkil; Prsten C je [image] R3 je H, (1-6C)alkil, hidroksi(1-6C)alkil, Ar2, hetCyc1, (3-7C)cikloalkil, hetAr2, ili C5-C8 premošteni karbociklički prsten; Ar2 je fenil proizvoljno supstituiran s jednim ili više supstituenata koji su neovisno odabrani od halogen i (1-6C)alkil; hetCyc1 je 5-6-člani zasićeni ili djelomično nezasićeni heterociklički prsten koji ima 1-2 prstenska heteroatoma koji su neovisno odabrani od N i O; hetAr2 je 5-6 člani heteroarilni prsten koji ima 1-3 prstenska heteroatoma koji su neovisno odabrani od N, O i S i proizvoljno supstituiran s jednim ili više supstituenata koji su neovisno odabrani od (1-6C)alkil i halogen; R4 je odabran od (1-6C alkil)SO2-, (1-6C alkil)C(=O)- i od struktura: [image] [image] [image] [image] Rm je (1-3C)alkil supstituiran s 1-3 fluora, ili (3-4C)cikloalkil; Rq je (1-3C)alkil proizvoljno supstituiran s 1-3 fluora; Ry je F ili (1-3C)alkil proizvoljno supstituiran s 1-3 fluora; p je 0, 1 ili 2; Rz je (3-4C)cikloalkil, ili (1-3C)alkil proizvoljno supstituiran s 1-3 fluora; i R5 je H, (1-6C)alkil, monofluoro(1-6C)alkil, difluoro(1-6C)alkil, trifluoro(1-6C)alkil, tetrafluoro(2-6C)alkil, pentafluoro(2-6C)alkil, halogen, CN, (1-4C)alkoksi, hidroksi(1-4C)alkil, (1-3C alkoksi)(1-4C)alkil, (1-4C alkil)OC(=O)-, (1-6C)alkilsulfanil, fenil [proizvoljno supstituiran s jednim ili više supstituenata koji su neovisno odabrani od halogen, (1-6C)alkil i (1-6C)alkoksi], (3-4C)cikloalkil, amino, aminokarbonil, ili trifluoro(1-3C alkil)amido; ili - od spojeva sa slijedećim formulama: [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] ili njihove farmaceutski prihvatljive soli ili solvati.
2. Spoj prema zahtjevu 1, naznačen time da je R4 odabran od struktura: [image] [image] [image] [image]
3. Spoj prema zahtjevu 1 ili 2, naznačen time da X je O.
4. Spoj prema bilo kojem od zahtjeva 1-3, naznačen time da R1 je (1-3C alkoksi)(1-6C)alkil.
5. Spoj prema bilo kojem od zahtjeva 1-4, naznačen time da Prsten B je Ar1, pri čemu Ar1 je fenil proizvoljno supstituiran s jednim ili više halogena.
6. Spoj prema bilo kojem od zahtjeva 1-4, naznačen time da je R4 odabran od struktura: [image]
7. Spoj prema bilo kojem od zahtjeva 1-6, naznačen time da R5 je (1-6C)alkil.
8. Spoj prema bilo kojem od zahtjeva 1-7, naznačen time da R3 je Ar2.
9. Spoj prema bilo kojem od zahtjeva 1-8, naznačen time da R2 je H.
10. Spoj prema bilo kojem od zahtjeva 1-9, naznačen time da Ra, Rb, Rc i Rd su H.
11. Spoj prema bilo kojem od zahtjeva 1-10, naznačen time da Prsten B i -NH-C(=X)-NH- skupina s Formulom I su trans u apsolutnoj konfiguraciji prikazanoj u strukturi C: [image]
12. Spoj prema zahtjevu 1, naznačen time da je odabran od [image] [image] [image] [image] i [image] ili njegova farmaceutski prihvatljiva sol.
13. Farmaceutski pripravak, naznačen time da sadrži spoj s formulom I kako je definirano u bilo kojem od zahtjeva 1 do 12 ili njegova farmaceutski prihvatljiva sol, te farmaceutski prihvatljivo sredstvo za otapanje ili nosač.
14. Spoj s formulom I kako je definirano u bilo kojem od zahtjeva 1 do 12, ili njegova farmaceutski prihvatljiva sol, naznačen time da je za uporabu za terapiju.
15. Spoj s formulom I kako je definirano u bilo kojem od zahtjeva 1 do 12, ili njegova farmaceutski prihvatljiva sol, naznačen time da je za uporabu za liječenje boli, raka, upale/upalnih bolesti, neurodegenerativnih bolesti, određenih zaraznih bolesti, Sjögrenovog sindroma, endometrioze, dijabetičke periferne neuropatije, prostatitisa ili sindroma boli u zdjelici.
16. Uporaba spoja s formulom I kako je definirano u bilo kojem od zahtjeva 1 do 12, ili njegova farmaceutski prihvatljiva sol, naznačena time da je za pripremanje lijeka za liječenje boli, raka, upale/upalnih bolesti, neurodegenerativnih bolesti, određenih zaraznih bolesti, Sjögrenovog sindroma, endometrioze, dijabetičke periferne neuropatije, prostatitisa ili sindroma boli u zdjelici.
17. Postupak za dobivanje spoja prema zahtjevu 1, koji sadrži: (a) za spoj s formulom I gdje X je O, sparivanje odgovarajućeg spoja koji ima formulu II [image] s odgovarajućim spojem koji ima formulu III [image] u prisutnosti karbonildiimidazola i baze; ili (b) za spoj s formulom I gdje X je S, sparivanje odgovarajućeg spoja koji ima formulu II [image] s odgovarajućim spojem koji ima formulu III [image] u prisutnosti di(1H-imidazol-2-il)metanetiona i baze; ili (c) za spoj s formulom I gdje X je O, sparivanje odgovarajućeg spoja koji ima formulu II [image] s odgovarajućim spojem koji ima formulu IV [image] gdje L1 je izlazna skupina, u prisutnosti baze; ili (d) za spoj s formulom I gdje X je O, sparivanje odgovarajućeg spoja koji ima formulu V [image] gdje L2 je izlazna skupina, s odgovarajućim spojem koji ima formulu III [image] u prisutnosti baze; ili (e) za spoj s formulom I gdje X je O, aktiviranje odgovarajućeg spoja koji ima formulu VI [image] s difenilfosforil azidom nakon čega slijedi sparivanje aktiviranog među produkta s odgovarajućim spojem koji ima formulu III [image] u prisutnosti baze; ili (f) za spoj s formulom I gdje X je O, sparivanje odgovarajućeg spoja koji ima formulu II [image] s odgovarajućim spojem koji ima formulu VII [image] u prisutnosti baze; ili (g) za spoj s formulom I gdje X je O, sparivanje odgovarajućeg spoja koji ima formulu VIII [image] s odgovarajućim spojem koji ima formulu III [image] u prisutnosti baze; ili (h) za spoj s formulom I gdje R1 je (trifluorometoksi)(1-6C)alkil, (1-3C alkilsulfanil)(1-6C)alkil, monofluoro(1-6C)alkil, difluoro(1-6C)alkil, trifluoro(1-6C)alkil, tetrafluoro(2-6C)alkil, ili pentafluoro(2-6C)alkil, reagiranje odgovarajućeg spoja koji ima formulu IX [image] s odgovarajućim spojem koji ima formulu (trifluorometoksi)(1-6C)alkil-L3, (1-3C alkilsulfanil)(1-6C)alkil-L3, monofluoro(1-6C)alkil-L3, difluoro(1-6C)alkil-L3, trifluoro(1-6C)alkil-L3, tetrafluoro(2-6C)alkil-L3, ili pentafluoro(2-6C)alkil-L3, gdje L3 je izlazni atom ili izlazna skupina, u prisutnosti baze; ili (i) reagiranje spoja koji ima formulu X: [image] gdje L4 je Br ili OTf, i R1, Ra, Rb, Cc, Rd, R2, R3 i R5 su kako je definirano za formulu I, pod uvjetom da R5 nije halogen, s odgovarajućim boroničnim esterom ili boroničnom kiselinom koja ima formulu: [image] odnosno, u prisutnosti paladijevog katalizatora i baze; i proizvoljno uklanjanje zaštitnih skupina i proizvoljno pripravljanje njegove farmaceutski prihvatljive soli.
18. Spoj za uporabu kako je definiran u zahtjevu 15, ili njegova farmaceutski prihvatljiva sol, naznačen time da je namijenjen upotrebi za liječenje boli.
19. Spoj za uporabu kako je definiran u zahtjevu 18, naznačen time da bol je kronična bol.
20. Spoj za uporabu kako je definiran u zahtjevu 18, naznačen time da bol je akutna bol.
21. Spoj za uporabu kako je definiran u zahtjevu 18, naznačen time da bol je upalna bol, neuropatska bol, bol povezana s rakom, bol povezana s operacijom, ili bol povezana s lomom kosti.
22. Spoj za uporabu kako je definiran u zahtjevu 15, ili njegova farmaceutski prihvatljiva sol, naznačen time da je za uporabu za liječenje raka.
23. Spoj za uporabu kako je definiran u zahtjevu 22, naznačen time da navedeni rak je rak koji ima poremećaj regulacije TrkA.
24. Spoj za uporabu kako je definiran u zahtjevu 22, naznačen time da je navedeni rak odabran od karcinoma pluća ne-malih stanica, papilarnog karcinoma štitnjače, glioblastoma multiforme, akutne mijeloidne leukemije, akutne mijeloidne leukemije, karcinoma debelog crijeva, neuroendokrinog karcinoma velikih stanica, raka prostate, neuroblastoma, karcinoma gušterače, melanoma, karcinoma skvamoznih stanica glave i vrata i karcinoma želuca.
HRP20180331TT 2012-11-13 2018-02-23 Spojevi n-pirolidinil, n'pirazolil- urea, tiourea, gvanidin i cijanogvanidin kao inhibitori trka kinaze HRP20180331T1 (hr)

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US201261725913P 2012-11-13 2012-11-13
EP13795946.6A EP2922844B1 (en) 2012-11-13 2013-11-12 N-pyrrolidinyl, n'-pyrazolyl- urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors
PCT/US2013/069729 WO2014078323A1 (en) 2012-11-13 2013-11-12 N-pyrrolidinyl, n'-pyrazolyl- urea, thiourea, guanidine and cyanoguanidine compounds as trka kinase inhibitors

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AU (2) AU2013344943B2 (hr)
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