HRP20170411T1 - Amido spirocilični amidni i sulfonamidni derivati - Google Patents

Amido spirocilični amidni i sulfonamidni derivati Download PDF

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HRP20170411T1
HRP20170411T1 HRP20170411TT HRP20170411T HRP20170411T1 HR P20170411 T1 HRP20170411 T1 HR P20170411T1 HR P20170411T T HRP20170411T T HR P20170411TT HR P20170411 T HRP20170411 T HR P20170411T HR P20170411 T1 HRP20170411 T1 HR P20170411T1
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Croatia
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alkyl
heteroaryl
substituted
unsubstituted
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HRP20170411TT
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Kenneth W. Bair
Timm R. Baumeister
Peter Dragovich
Xiongcai LIU
Snahel PATEL
Mark Zak
Guiling Zhao
Yamin ZHANG
Xiaozhang Zheng
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Genentech, Inc.
Forma Tm, Llc.
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Publication of HRP20170411T1 publication Critical patent/HRP20170411T1/hr

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Claims (15)

1. Spoj Formule I: [image] pri čemu: R je (a) 8-, 9-, ili 10-člani biciklični heteroaril koji sadrži jedan heteroatom odabran između N, S, i O, i jedan, dva, ili tri dodatna N atoma, pri čemu je spomenuti biciklični heteroaril nesupstituiran ili je supstituiran s jednim ili više supstituenata odabranih iz skupine koju čine deuterij, amino, alkilamino, dialkilamino, alkil, halo, cijano, haloalkil, hidroksi, hidroksialkil, i alkoksi, i pri čemu je jedan ili više N atoma spomenutog bicikličnog heteroarila opcijski N-oksid; ili (b) peto ili šesto-člani dušikom-vezani heterocikloalkil prsten kondenziran s fenilom ili monocikličnim peto ili šesto-članim heteroarilom, pri čemu je spomenuti fenil ili heteroaril nesupstituiran ili je supstituiran s jednim ili više supstituenata odabranih iz skupine koju čine deuterij, amino, alkilamino, dialkilamino, alkil, halo, cijano, haloalkil, hidroksi, hidroksialkil, i alkoksi; i R1 je H, -(C1-4alkilen)0-1C(O)Ra, -(C1-4alkilen)0-1CO2Ra, -(C1-4alkilen)0-1S(O)Ra, -(C1-4alkilen)0-1SO2Ra, -C(O)NH(Ra),-C(O)N(Ra)2, ili -C(O)C(O)NH(Ra); pri čemu je svaki Ra neovisno (1) alkil, nesupstituiran ili supstituiran s jednim ili više Rm supstituenata, pri čemu je svaki Rm neovisno odabran iz skupine koju čine hidroksi, - NRbRc, alkoksi, cijano, halo, -C(O)alkil, -CO2alkil, -CONRbRc, -S(O)alkil, -SO2alkil, -SO2NRbRc, aril, heteroaril, cikloalkil, heterocikloalkil, fenoksi, i -O-alkil-OH; pri čemu Rb je H ili alkil; Rc je H, alkil, alkoksialkil, haloalkil, -C(O)alkil, -CO2alkil, -SO2alkil, -C(O)NH2, ili C(O)H; i svaka aril, heteroaril, cikloalkil, i heterocikloalkil grupa unutar Rm je nesupstituirana ili je supstituirana s jednim ili više supstituenata neovisno odabranih iz skupine koju čine od alkila, haloalkila, hidroksi, -NRbRc, alkoksi, haloalkoksi, cijano, halo, okso, -C(O)alkila, -CO2alkila, -C(O)-heterocikloalkila, -CONRbRc, -S(O)alkila, -SO2alkila, -SO2-haloalkila, - SO2NRbRc, arila, heteroarila, cikloalkila, i heterocikloalkila; pri čemu je svaki alkil ili alkoksi nesupstituiran ili je supstituiran sa -NRbRc, heterocikloalkilom, heteroarilom, ili -C(O)alkilom; i svaki aril, heteroaril, cikloalkil, i heterocikloalkil je nesupstituiran ili je supstituiran s alkilom, halo, ili -C(O)alkilom; (2) fenil, cikloalkil, heteroaril, ili heterocikloalkil, svaki nesupstituiran ili supstituiran s jednim ili više supstituenata odabranim iz grupe koju čine alkil, haloalkil, hidroksi, -NRbRc, alkoksi, haloalkoksi, cijano, halo, okso,-C(O)alkil, -CO2alkil, -C(O)-heterocikloalkil, -CONRbRc, -S(O)alkil, -SO2alkil, -SO2-haloalkil, -SO2NRbRc, aril, heteroaril, cikloalkil, i heterocikloalkil; pri čemu je svaki alkil ili alkoksi nesupstituiran ili je supstituiran s -NRbRc, heterocikloalkilom, heteroarilom, ili -C(O)alkilom; i svaki aril, heteroaril, cikloalkil, i heterocikloalkil je nesupstituiran ili je supstituiran s alkilom, halo, ili -C(O)alkilom; ili (3) -NkxRy, gdje Rx je H ili alkil; i Ry je H, alkil, alkoksialkil, haloalkil, -C(O)alkil, -CO2alkil, ili -SO2alkil; R2 i R3 su svaki neovisno H ili deuterij; i n je 1 ili 2; ili njegov stereoizomer, ili farmaceutski prihvatljiva sol takvog spoja ili stereoizomera.
2. Spoj prema zahtjevu 1, pri čemu R je 8- ili 9- člani heteroaril, nesupstituiran ili supstituiran kao što je opisano u zahtjevu 1,
3. Spoj prema zahtjevu 1 ili 2, pri čemu je R: [image] [image] a svaki je nesupstituiran ili je supstituiran kao što je navedeno u zahtjevu 1.
4. Spoj prema zahtjevu 1, pri čemu je R peto ili šesto-člani dušikom-vezani heterocikloalkil prsten kondenziran s nesupstituiranim ili supstituiranim fenilom ili monocikličnim heteroarilom, prema zahtjevu 1.
5. Spoj prema zahtjevu 1, pri čemu R1 je H, -C(O)Ra, -CO2Ra, -S(O)Ra, ili -SO2Ra.
6. Spoj prema bilo kojem od zahtjeva 1 do 5, pri čemu je Ra metil, etil, propil, izopropil, terc. butil, izobutil, izopentil, fenil, ciklopropil, ciklobutil, ciklopentil, cikloheksil, pirolil, furanil, tiofenil, imidazolil, pirazolil, oksazolil, izoksazolil, tiazolil, triazoil, piridil, pirimidinil, pirazinil, piridazinil, izoindolinil, azetidinil, oksetanil, pirolidinil, piperidinil, morfolinil, piperazinil, tetrahidrofuranil, tetrahidropiranil, ili tetrahidrotiofenil, svaki nesupstituiran ili supstituiran.
7. Spoj prema bilo kojem od zahtjeva 1 do 6, pri čemu je Ra fenil, cikloalkil, heteroaril, ili heterocikloalkil, svaki nesupstituiran ili supstituiran s jednim ili više supstituenata odabranih iz skupine koju čine fluoro, okso, metil, -CONH2, acetil, -SO2metil, -C(O)-izopropil, piridazinil, triazolil, dimetilaminometil, cijano, metil-triazolil-metoksi, trifluorometoksi, pirolidinilmetil, acetilamino, tetrazolilmetil, metil-tetrazolilmetil, metil-imidazolil-metil, -NHSO2metil, 1,1-dioksotiomorfolinil, 4-metil-piperazinilmetil, -NHCONH2, -SO2CF3, morfolinilmetil, imidazolil, -SO2NH2, metilpiperidinil, metilpiperazinil, -C(O)(4-metil-piperazinil), morfolinil, trifluorometil, ciklopropil, etil, izoksazolil, tetrazolil, izopropil, fenil, fluorofenil, terc. butil, benzil, N-metilpirolidinil, N-acetil-pirolidinil, izobutil, propil, metilpirazolil, trifluoroetil, pirimidinil, okso, acetil, cijano, -CO2-terc. butil, i amino.
8. Spoj prema bilo kojem od zahtjeva 1 do 6, pri čemu je Ra alkil, nesupstituiran ili supstituiran s jednim ili više supstituenata odabranih iz skupine koju čine fluoro, terc. butoksi, - C(O)NMe2, -NHCHO, metoksi, fenoksi, cijano, acetil, hidroksi, -OCH2C(CH3)=OH,-NH(acetil), i -N(Me)(acetil).
9. Spoj prema zahtjevu 1, pri čemu R1 je -SO2Ra, gdje je Ra metil, etil, fenil, benzil, ili 2,2-dimetilpropil.
10. Spoj prema zahtjevu 1, pri čemu R1 je -C(O)NHRa, pri čemu je Ra metil, etil, propil, izopropil, tertobutil, cikloheksil, -CH2-cikloheksil, oksetanil, ili metiloksetanil, ili je Ra fenil ili benzil skupina, svaka opcijski supstituirana s jednim ili više supstituenata odabranih iz skupine koju čine cijano, metil, fluoro, metoksi, i kloro.
11. Spoj prema zahtjevu 1 odabrano iz skupine koju čine slijedeći: [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] [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] [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] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] [image] i njihovih stereoizomera, i farmaceutski prihvatljivih soli takvih spojeva i stereoizomera.
12. Farmaceutski pripravak koja sadrži: (a) učinkovitu količinu najmanje jednog spoja prema zahtjevu 1; i (b) farmaceutski prihvatljivi nositelj.
13. Farmaceutski pripravak prema zahtjevu 12, naznačen time što sadrži sredstvo za rasterećenje biran iz skupine koju čine nikotinamid, nikotinska kiselina, i nikotinamid mononukleotid (NMN), ili terapijski učinkovite količinu jednog ili više dodatnih veznih aktivnih tvari, pri čemu su spomenuti jedan ili više dodatnih aktivnih sastojaka izabrani iz grupe koju čine slijedeći: citotoksično sredstvo, cisplatin, doksorubicin, taksoter, taksol, etopozid, irinotekan, kamptostar, topotekan, paklitaksel, docetaksel, epotiloni, tamoksifen, 5-fluorouracil, metokstreksat, temozolomid, ciklofosfamid, SCH 66336, tipifarnib (Zarnestra®), R115777, L778,123, BMS 214662, Iressa®, Tarceva®, C225, GLEEVEC®, intron®, Peg-Intron®, kombinacije aromataza, ara-C, adriamicin, citoksan, gemcitabin, uracil mustard, klormetin, ifosfamid, melfalan, klorambucil, pipobroman, trietilenmelamin, trietilentiofosforamin, busulfan, karmustin, lomustin, streptozocin, dakarbazin, floksuridin, citarabin, 6-merkaptopurin, 6-tiogvanin, fludarabin fosfat, leukovirin, oksaliplatin (ELOXATIN®), pentostatin, vinblastin, vinkristin, vindesin, bleomicin, daktinomicin, daunorubicin, epirubicin, idarubicin, mitramicin™, deoksicoformicin, mitomicin-C, L-asparaginaza, tenipozid 17α-etinilestradiol, dietilstilbestrol, testosteron, prednizon, fluoksimesteron, dromostanolon propionat, testolakton, megestrol acetat, metilprednizolon, metiltestosteron, prednizolon, triamcinolon, klorotrianizen, hidroksiprogesteron, aminoglutetimid, estramustin, medroksiprogesteron acetat, leuprolid, flutamid, toremifen, goserelin, karboplatin, hidroksiurea, amsakrin, prokarbazin, mitotan, mitoksantron, levamizol, navelben, anastrazol, letrazol, kapecitabin, reloksafin, droloksafin, heksametilmelamin, avastin, herceptin, beksar, velkad, zevalin, trisenoks, kseloda, vinorelbin, porfimer, erbituks, lipozomal, tiotep, altretamin, melfalan, trastuzumab, lerozol, fulvestrant, eksemestan, ifosfomid, rituksimab, kampat, leukovorin, i deksametazon, bikalutamid, klorambucil, megestrol, valrubicin, i NIASPAN®.
14. Spoj prema zahtjevu 1, ili njegove farmaceutski prihvatljive soli, za uporabu u liječenju subjekta koji pati ili mu je postavljena dijagnoza bolesti ili ovog medicinskog stanja posredovanog aktivnošću NAMPT, kao što su kruti i tekući tumori, karcinom ne-malih stanica pluća, leukemija, limfom, karcinom jajnika, glioma, karcinom dojke, karcinom materice, karcinom debelog crijeva, karcinom cerviksa, karcinom pluća, karcinom prostate, karcinom kože, nos-želučani karcinomi, karcinom debelog crijeva, karcinom CNS, karcinom mokraćnog mjehura, karcinom pankreasa i Hodgkinovu bolest, reumatoidni artritis, dijabetes, ateroskleroza, sepse, starenje ili upala.
15. Spoj za uporabu prema zahtjevu 14, naznačen time da spoj za uporabu dalje sadrži sredstvo za olakšanje biran iz skupine koju čine nikotinamid, nikotinska kiselina, i nikotinamid mononukleotid (NMN), ili najmanje jedan spoj biran iz skupine koja se sastoji od: citotoksično sredstvo, cisplatin, doksorubicin, taksoter, taksol, etopozid, irinotekan, kamptostar, topotekan, paklitaksel, docetaksel, epotiloni, tamoksifen, 5-fluorouracil, metokstreksat, temozolomid, ciklofosfamid, SCH 66336, tipifarnib (Zarnestra®), R115777, L778,123, BMS 214662, Iressa®, Tarceva®, C225, GLEEVEC®, intron®, Peg-Intron®, kombinacije aromataza, ara-C, adriamicin, citoksan, gemcitabin, uracil mustard, klormetin, ifosfamid, melfalan, klorambucil, pipobroman, trietilenmelamin, trietilentiofosforamin, busulfan, karmustin, lomustin, streptozocin, dakarbazin, floksuridin, citarabin, 6-merkaptopurin, 6-tiogvanin, fludarabin fosfat, leukovirin, oksaliplatin (ELOXATIN®), pentostatin, vinkristin, vindesin, bleomicin, daktinomicin, daunorubicin, epirubicin, idarubicin, mitramicin™, deoksicoformicin, mitomicin-C, L-asparaginaza, tenipozid 17α-etinilestradiol, dietilstilbestrol, testosteron, prednizon, fluoksimesteron, dromostanolon propionat, testolakton, megestrol acetat, metilprednizolon, metiltestosteron, prednizolon, triamcinolon, klorotrianizen, hidroksiprogesteron, aminoglutetimid, estramustin, medroksiprogesteron acetat, leuprolid, flutamid, toremifen, goserelin, karboplatin, hidroksiurea, amsakrin, prokarbazin, mitotan, mitoksantron, levamizol, navelben, anastrazol, letrazol, kapecitabin, reloksafin, droloksafin, heksametilmelamin, avastin, herceptin, beksar, velkad, zevalin, trisenoks, kseloda, vinorelbin, porfimer, erbituks, lipozomal, tiotep, altretamin, melfalan, trastuzumab, lerozol, fulvestrant, eksemestan, ifosfomid, rituksimab, kampat, leukovorin, deksametazon, bikalutamid, klorambucil, megestrol, valrubicin, vinblastin, i NIASPAN®.
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