HRP20220351T1 - 3,5-disupstituirani pirazoli korisni kao inhibitori kinaze 1 kontrolne točke (chk1), i njihove pripreme i primjene - Google Patents

3,5-disupstituirani pirazoli korisni kao inhibitori kinaze 1 kontrolne točke (chk1), i njihove pripreme i primjene Download PDF

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HRP20220351T1
HRP20220351T1 HRP20220351TT HRP20220351T HRP20220351T1 HR P20220351 T1 HRP20220351 T1 HR P20220351T1 HR P20220351T T HRP20220351T T HR P20220351TT HR P20220351 T HRP20220351 T HR P20220351T HR P20220351 T1 HRP20220351 T1 HR P20220351T1
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carbonitrile
pyrazol
pyrazine
ylamino
compound
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HRP20220351TT
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Xiong Cai
Changgeng Qian
Yanong Daniel Wang
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Pharmaengine, Inc.
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    • 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
    • A61K31/4965—Non-condensed pyrazines
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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
    • A61K31/4196—1,2,4-Triazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • A—HUMAN NECESSITIES
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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
    • A61K31/47—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
    • A61K31/535—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
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    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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    • A—HUMAN NECESSITIES
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • 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

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Claims (10)

1. Spoj formule (II): [image] pri čemu: R1 je -F, -Cl, ili -Br; R2 i R3 su svaki nezavisno -H, ili R2 i R3 zajedno sa atomom ugljika za koji su vezani formiraju ciklopropil; R4 je -H ili metil; i R5 je -CN, ili farmaceutski prihvatljiva sol, geometrijski izomer, enantiomer, dijastereomer, racemat, solvat, ili hidrat istog.
2. Spoj prema patentnom zahtjevu 1, koji je odabran od: 5-(5-(2-(3-aminopropoksi)-4-fluoro-6-metoksifenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; 5-(5-(2-(3-aminopropoksi)-4-kloro-6-metoksifenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; 5-(5-(2-(3-aminopropoksi)-4-bromo-6-metoksifenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; 5-(5-(2-(3-metilaminopropoksi)-4-fluoro-6-metoksifenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; 5-(5-(2-(3-metilaminopropoksi)-4-kloro-6-metoksifenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; 5-(5-(2-(3-metilaminopropoksi)-4-bromo-6-metoksifenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; 5-(5-(2-((1-(aminometil)ciklopropil)metoksi)-4-fluoro-6-metoksifenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; 5-(5-(2-((1-(aminometil)ciklopropil)metoksi)-4-kloro-6-metoksifenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; 5-(5-(2-((1-(aminometil)ciklopropil)metoksi)-4-bromo-6-metoksifenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; 5-(5-(4-fluoro-2-metoksi-6-((1-((metilamino)metil)ciklopropil)metoksi)fenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; 5-((5-(4-kloro-2-metoksi-6-((1-((metilamino)metil)ciklopropil)metoksi)fenil)-1H-pirazol-3-il)amino)pirazin-2-karbonitrila; ili 5-((5-(4-bromo-2-metoksi-6-((1-((metilamino)metil)ciklopropil)metoksi)fenil)-1H-pirazol-3-il)amino)pirazin-2-karbonitrila; ili farmaceutski prihvatljiva sol, geometrijski izomer, enantiomer, dijastereomer, racemat, solvat, ili hidrat istog.
3. Spoj prema patentnom zahtjevu 2, koji je odabran od: 5-(5-(2-(3-aminopropoksi)-4-fluoro-6-metoksifenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; 5-(5-(2-(3-aminopropoksi)-4-kloro-6-metoksifenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; 5-(5-(2-(3-aminopropoksi)-4-bromo-6-metoksifenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; 5-(5-(2-((1-(aminometil)ciklopropil)metoksi)-4-fluoro-6-metoksifenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; 5-(5-(2-((1-(aminometil)ciklopropil)metoksi)-4-kloro-6-metoksifenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; 5-(5-(2-((1-(aminometil)ciklopropil)metoksi)-4-bromo-6-metoksifenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; 5-(5-(4-fluoro-2-metoksi-6-((1-((metilamino)metil)ciklopropil)metoksi)fenil)-1H-pirazol-3-ilamino)pirazin-2-karbonitrila; ili farmaceutski prihvatljiva sol, geometrijski izomer, enantiomer, dijastereomer, racemat, solvat, ili hidrat istog.
4. Farmaceutska kompozicija koja sadrži terapijski efikasnu količinu spoja prema bilo kojem od patentnih zahtjeva 1 do 3 ili farmaceutski prihvatljivu sol, geometrijski izomer, enantiomer, dijastereomer, racemat, solvat, ili hidrat istog, i farmaceutski prihvatljiv nosač ili ekscipijens.
5. Spoj prema bilo kojem od patentnih zahtjeva 1 do 3 ili farmaceutski prihvatljiva sol, geometrijski izomer, enantiomer, dijastereomer, racemat, solvat, ili hidrat istog ili farmaceutska kompozicija prema patentnom zahtjevu 4 za primjenu u liječenju ili prevenciji raka kod subjekta kojem je to potrebno.
6. Spoj ili farmaceutski prihvatljiva sol, geometrijski izomer, enantiomer, dijastereomer, racemat, solvat, ili hidrat istog ili farmaceutska kompozicija za primjenu prema patentnom zahtjevu 5, pri čemu spoj ili farmaceutski prihvatljiva sol, geometrijski izomer, enantiomer, dijastereomer, racemat, prolijek, solvat, ili hidrat istog ili farmaceutska kompozicija se administrira subjektu u kombinaciji sa drugim sredstvom protiv raka, kirurškom terapijom, ionizirajućim zračenjem, ili njihovom kombinacijom.
7. Spoj ili farmaceutski prihvatljiva sol, geometrijski izomer, enantiomer, dijastereomer, racemat, solvat, ili hidrat istog ili farmaceutska kompozicija za primjenu prema patentnom zahtjevu 6, pri čemu drugo sredstvo protiv raka je odabrano od: ciljanih lijekova protiv raka, kao što su trastuzumab, ramucirumab, vismodegib, sonidegib, bevacizumab, everolimus, tamoksifen, toremifen, fulvestrant, anastrozol, eksemestan, lapatinib, letrozol, pertuzumab, ado-trastuzumab emtansin, palbociklib, cetuksimab, panitumumab, ziv-aflibercept, regorafenib, imatinib mezilat, lanreotid acetat, sunitinib, regorafenib, denosumab, alitretinoin, sorafenib, pazopanib, temsirolimus, everolimus, tretinoin, dasatinib, nilotinib, bosutinib, rituksimab, alemtuzumab, ofatumumab, obinutuksumab, ibrutinib, idelalisib, blinatumomab, soragenib, crizotinib, erlotinib, gefitinib, afatinib dimaleat, ceritnib, ramucirumab, nivolumab, pembrolizumab, osimertinib, i necitumumab; alkilirajućeg sredstva, kao što je busulfan, klorambucil, ciklofosfamid, ifosfamid, melfalan, dušik iperit, streptozocin, tiotepa, uracil dušik iperit, trietilenmelamin, temozolomid, i 2-kloroetil-3-sarkozinamid-1-nitrozourea (SarCNU); antibiotika ili biljnog alkaloida, kao što je aktinomicin-D, bleomicin, kriptoficini, daunorubicin, doksorubicin, idarubicin, irinotekan, L-asparaginaza, mitomicin-C, mitramicin, navelbin, paklitaksel, docetaksel, topotekan, vinblastin, vinkristin, tenipozid (VM-26), i etopozid (VP-16); hormona ili steroida, kao što je inhibitor 5α-reduktaze, aminoglutetimid, anastrozol, bikalutamid, klorotrianizen, dietilstilbestrol (DES), dromostanolon, estramustin, etinil estradiol, flutamid, fluoksimesteron, goserelin, hidroksiprogesteron, letrozol, leuprolid, medroksiprogesteron acetat, megestrol acetat, metil prednizolon, metiltestosteron, mitotan, nilutamid, prednizolon, arzoksifen (SERM-3), tamoksifen, testolakton, testosteron, triamcinolon, i zoladeks; sintetičkih, kao što je sve-trans retinoinska kiselina, karmustin (BCNU), karboplatin (CBDCA), lomustin (CCNU), cis-diamindikloroplatina (cisplatin), dakarbazin, gliadel, heksametilmelamin, hidroksiurea, levamizol, mitoksantron, o,p'-diklorodifenildikloroetan (o,p'-DDD) (također poznat kao lizodren ili mitotan), oksaliplatin, porfimer natrij, prokarbazin, i imatinib mezilat (Gleevec®); antimetabolita, kao što je klorodeoksiadenozin, citozin arabinozid, 2'-deoksikoformicin, fludarabin fosfat, 5-fluorouracil (5-FU), 5-fluoro-2'-deoksiuridin (5-FUdR), gemcitabin, kamptotecin, 6-merkaptopurin, metotreksat, 4-metiltioamfetamin (4-MTA), i tioguanin; i bioloških, kao što je alfa interferon, BCG (Bacillus Calmette-Guerin), faktor stimulacije kolonije granulocita (G-CSF), faktor stimulacije kolonije granulocita-makrofaga (GM-CSF), interleukin-2, i herceptin.
8. Spoj ili farmaceutski prihvatljiva sol, geometrijski izomer, enantiomer, dijastereomer, racemat, solvat, ili hidrat istog ili farmaceutska kompozicija za primjenu prema patentnom zahtjevu 6 ili 7, pri čemu drugo sredstvo protiv raka je irinotekan.
9. Spoj ili farmaceutski prihvatljiva sol, geometrijski izomer, enantiomer, dijastereomer, racemat, solvat, ili hidrat istog ili farmaceutska kompozicija za primjenu prema bilo kojem od patentnih zahtjeva 5 do 8, pri čemu rak je rak dojke, karcinom skvamoznih stanica, rak pluća, rak jednjaka, rak jetre, rak želuca, kolorektalni rak, rak mokraćnog mjehura, karcinom jajnika, rak prostate, giloblastom, rak gušterače, ili leukemija.
10. Postupak za pripremanje spoja prema bilo kojem od patentnih zahtjeva 1 do 3, koji obuhvaća: a. reagiranje spoja formule (1') [image] sa hidrazinom formule H2N-NH2, pri čemu R1 i R5 su kao što je definirano u patentnom zahtjevu 1; R6 je hidroksi zaštitna grupa; R7 je alkil; u prisustvu otapala da se dobije spoj formule (2'); [image] b. uklanjanje zaštite spoja formule (2), nakon čega slijedi reagiranje spoja bez zaštite sa spojem formule (3) [image] pri čemu R2, R3, i R4 su kao što je definirano u patentnom zahtjevu 1; i R9 je amino zaštitna grupa, u prisustvu sredstva za spajanje i otapala da se dobije spoj formule (4') [image] pri čemu R1, R2, R3, R4, R5 i R9 su kao što je gore definirano; i c. uklanjanje zaštite spoja formule (4') da se dobije spoj formule (II).
HRP20220351TT 2016-02-04 2016-02-04 3,5-disupstituirani pirazoli korisni kao inhibitori kinaze 1 kontrolne točke (chk1), i njihove pripreme i primjene HRP20220351T1 (hr)

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PCT/CN2016/073454 WO2017132928A1 (en) 2016-02-04 2016-02-04 3,5-disubstituted pyrazoles useful as checkpoint kinase 1 (chk1) inhibitors, and their preparations and applications
EP16888753.7A EP3411036B1 (en) 2016-02-04 2016-02-04 3,5-disubstituted pyrazoles useful as checkpoint kinase 1 (chk1) inhibitors, and their preparations and applications

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