DK2820008T3 - Amido-spirocycliske amid- og sulfonamidderivativer - Google Patents

Amido-spirocycliske amid- og sulfonamidderivativer Download PDF

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DK2820008T3
DK2820008T3 DK13755811.0T DK13755811T DK2820008T3 DK 2820008 T3 DK2820008 T3 DK 2820008T3 DK 13755811 T DK13755811 T DK 13755811T DK 2820008 T3 DK2820008 T3 DK 2820008T3
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alkyl
mmol
equiv
methyl
cancer
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DK13755811.0T
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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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Claims (15)

  1. AMIDO-SPIROCYCLISKE AMID- OG SULFONAMIDDERIVATIVER
    1. Forbindelse med formlen I: hvori:
    R er (a) en 8-, 9- eller 10-leddet bicyklisk heteroaryl omfattende ét heteroatom udvalgt fra N, S og O og et, to eller tre yderligere N-atomer, hvori den bicycliske heteroaryl er ikke-substitueret eller er substitueret med en eller flere substituenter udvalgt fra gruppen bestående af deuterium, amino, alkylamino, dialkylamino, alkyl, halo, cyano, haloalkyl, hydroxy, hydroxyalkyl og alkoxy, og hvori et eller flere af den bicycliske heteroaryls N-atomer eventuelt er N-oxid; eller (b) en fem- eller seksleddet nitrogen-koblet heterocycloalkyl-ring kondenseret til en phenyl- eller monocyklisk fem- eller seksleddet heteroaryl, hvori phenylen er ikke-substitueret eller er substitueret med en eller flere substituenter udvalgt fra gruppen bestående af deuterium, amino, alkylamino, dialkylamino, alkyl, halo, cyano, haloalkyl, hydroxy, hydroxyalkyl og alkoxy; og RI er H, -(Cl-4alkylen)0-1C(0)Ra, -(Cl-4alkylen)0-lCO2Ra, -(Cl-4alkylen)O-IS(0)Ra, -(Cl-4alkylen)0-lSO2Ra, -C(0)NH(Ra),-C(0)N(Ra)2 eller -C(0)C(0)NH(Ra) ; hvori hver Ra uafhængigt er (1) alkyl, ikke-substitueret eller substitueret med en eller flere Rm -substituenter, hvori hver Rm er uafhængigt udvalgt fra gruppen bestående af hydroxy, - NRbRc, alkoxy, cyano, halo, -C(O)alkyl, - C02alkyl, -CONRbRc, -S(O)alkyl, -S02alkyl, -S02NRbRc, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, phenoxy og -O-alkyl-OH; hvori Rb er H eller alkyl; Rc er H, alkyl, alkoxyalkyl, haloalkyl, -C(0)alkyl, -C02alkyl, -S02alkyl, -C(0)NH2 eller C(0)H; og hver aryl-, heteroaryl-, cycloalkyl- og heterocycloalkyl-gruppe inden for Rm er ikke-substitueret eller substitueret med en eller flere substituenter uafhængigt udvalgt fra gruppen bestående af alkyl, haloalkyl, hydroxy, -NRbRc, alkoxy, haloalkoxy, cyano, halo, oxo, -C(0)alkyl, -C02alkyl, -C(0)-heterocycloalkyl, -CONRbRc, -S(0)alkyl, -S02alkyl, -S02-haloalkyl, - S02NRbRc, aryl, heteroaryl, cycloalkyl og heterocycloalkyl; hvori hver alkyl eller alkoxy er ikke-substitueret eller substitueret med -NRbRc, heterocycloalkyl, heteroaryl eller -C(0)alkyl; og hver aryl, heteroaryl, cycloalkyl og heterocycloalkyl er ikke-substitueret eller er substitueret med alkyl, halo eller -C(O)alkyl; (2) phenyl, cycloalkyl, heteroaryl eller heterocycloalkyl, hver ikke-substitueret eller substitueret med en eller flere substituenter udvalgt fra gruppen bestående af alkyl, haloalkyl, hydroxy, -NRbRc, alkoxy, haloalkoxy, cyano, halo, oxo,-C(0)alkyl, -C02alkyl, -C(0)-heterocycloalkyl, -CONRbRc, -S(0)alkyl, -S02alkyl, -S02-haloalkyl, -S02NRbRc, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; hvori hver alkyl eller alkoxy er ikke-substitueret eller substitueret med -NRbRc, heterocycloalkyl, heteroaryl eller -C(O)alkyl; og hver aryl, heteroaryl, cycloalkyl og heterocycloalkyl er ikke-substitueret eller substitueret med alkyl, halo eller -C(0)alkyl; eller (3) -NkxRy, hvor Rx er H eller alkyl; og Ry er H, alkyl, alkoxyalkyl, haloalkyl, -C(0)alkyl, -C02alkyl eller -S02alkyl; R2 og R3 hver uafhængigt er H eller deuterium; og n er 1 eller 2; eller en stereoisomer deraf eller et farmaceutisk acceptabelt salt af en sådan forbindelse eller stereoisomer.
  2. 2. Forbindelse ifølge krav 1, hvori R er en 8- eller 9-leddet heteroaryl, ikke-substitueret eller substitueret som beskrevet i krav 1.
  3. 3. Forbindelse ifølge krav 1 eller 2, hvori R er:
    c hver ikke-substitueret eller substitueret som beskrevet for krav 1.
  4. 4. Forbindelse ifølge krav 1, hvori R er en fem- eller seksleddet nitrogen-koblet heterocycloalkyl-ring kondenseret til en ikke-substitueret eller substitueret phenyl- eller monocyklisk heteroaryl, som defineret i krav 1.
  5. 5. Forbindelse ifølge krav 1, hvori Ri er H, -C(0)Ra, -C02Ra, -S(0)Ra eller -S02Ra.
  6. 6. Forbindelse ifølge et hvilket som helst af kravene 1 til 5,hvori Ra er methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, isopentyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazoyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoindolinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl eller tetrahydrothiophenyl, hver ikke-substitueret eller substitueret.
  7. 7. Forbindelse ifølge et hvilket som helst af kravene 1 til 6, hvori Ra er phenyl, cycloalkyl, heteroaryl eller heterocycloalkyl, hver ikke-substitueret eller substitueret med en eller flere substituenter udvalgt fra gruppen bestående af fluor, oxo, methyl, -C0NH2, acetyl, -S02methyl, -C(0)-isopropyl, pyridazinyl, triazolyl, dimethylaminomethyl, cyano, methyl-triazolylmethoxy, trifluormethoxy, pyrrolidinylmethyl, acetylamino, tetrazolylmethyl, methyl-tetrazolylmethyl, methyl-imidazolyl-methyl, -NHS02methyl, 1,1-dioxothiomorpholinyl, 4-methyl-piperazinylmethyl, -NHC0NH2, -S02CF3, morpholinylmethyl, imidazolyl, -S02NH2, methylpiperidinyl, methyl-piperazinyl, -C(0)(4-methyl-piperazinyl), morpholinyl, trifluormethyl, cyclopropyl, ethyl, isoxazolyl, tetrazolyl, isopropyl, phenyl, fluor-phenyl, tert-butyl, benzyl, Nmethylpyrrolidinyl, N-acetyl-pyrrolidinyl, isobutyl, propyl, methylpyrazolyl, trifluorethyl, pyrimidinyl, oxo, acetyl, cyano, -C02-tert-butyl og amino.
  8. 8. Forbindelse ifølge et hvilket som helst af kravene 1 til 6, hvori Ra er alkyl, ikke-substitueret eller substitueret med en eller flere substituenter udvalgt fra gruppen bestående af fluor, tert-butoxy, -C(0)NMe2, -NHCHO, methoxy, phenoxy, cyano, acetyl, hydroxy, -0CH2C(CH3)=0H,-NH(acetyl) og -N(Me)(acetyl).
  9. 9. Forbindelse ifølge krav 1, hvori RI er -S02Ra, hvor Ra er methyl, ethyl, phenyl, benzyl eller 2,2-dimethylpropyl.
  10. 10. Forbindelse ifølge krav 1, hvori RI er -C(0)NHRa, hvori Ra er methyl, ethyl, propyl, isopropyl, tertobutyl, cyclohexyl, -CH2-cyclohexyl, oxetanyl eller methyloxetanyl, eller Ra er en phenyl- eller benzyl-gruppe, hver eventuelt substitueret med en eller flere substituenter udvalgt fra gruppen bestående af cyano, methyl, fluor, methoxy og chlor.
  11. 11. Forbindelse ifølge krav 1, der er udvalgt fra gruppen bestående af:
    og stereoisomerer deraf og farmaceutisk acceptable salte af sådanne forbindelser og stereoisomerer.
  12. 12. Farmaceutisk sammensætning omfattende: (a) en effektiv mængde af mindst én forbindelse ifølge krav 1; og (b) et farmaceutisk acceptabelt bærestof.
  13. 13. Farmaceutisk sammensætning ifølge krav 12 endvidere omfattende et nød-middel udvalgt fra gruppen bestående af nicotinamid, nicotinsyre og nicotinamidmononucleotid (NMN) eller terapeutisk effektive mængder af en eller flere yderligere supplerende aktive midler, hvori det ene eller de flere yderligere supplerende aktive midler er udvalgt fra gruppen bestående af cytotoksisk middel, cisplatin, doxorubicin, taxotere, taxol, etoposid, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilonerne, tamoxifen, 5-fluoruracil, methoxtrexat, temozolomid, cyclophosphamid, SCH 66336, tipifarnib (Zarnestra®), R115777, L778,123, BMS 214662, Iressa®, Tarceva®, C225, GLEEVEC®, intron®, Peg-Intron®, aromatasekombinationer, ara-C, adriamycin, cytoxan, gemcitabin, Uracilsennep, Chlormethin, Ifosfamid, Melphalan, Chlorambucil, Pipobroman, Triethylenmelamin, Triethylenthiophosphoramin, Busulfan, Carmustin, Lomustin, Streptozocin, Dacarbazin, Floxuridin, Cytarabin, 6-Mercaptopurin, 6-Thioguanin, Fludarabinphosphat, leucovirin, oxaliplatin (ELOXATIN®), Pentostatin, Vinblastin, Vineristin, Vindesin, Bleomycin, Dactinomycin, Daunorubicin, Epirubicin, Idarubicin, Mithramycin™, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposid 17a-Ethinylestradiol, Diethylstilbestrol, Testosteron, Prednison, Fluoxymesteron, Dromostanolonpropionat, Testolacton, Megestrolacetat, Methylprednisolon, Methyltestosteron, Prednisolon, Triamcinolon, Chlortrianisen, Hydroxyprogesteron, Aminoglutethimid, Estramustin, Medroxyprogesteronacetat, Leuprolid, Flutamid, Toremifen, goserelin, Carboplatin, Hydroxyurea, Amsacrin, Procarbazin, Mitotan, Mitoxantron, Levamisol, Navelbine, Anastrazol, Letrazol, Capecitabin, Reloxafin, Droloxafin, Hexamethylmelamin, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbin, Porflmer, Erbitux, Liposomal, Thiotepa, Altretamin, Melphalan, Trastuzumab, Lerozol, Fulvestrant, Exemestan, Ifosfomid, Rituximab, Campath, leueovorin og dexamethason, bicalutamid, carboplatin, chlorambucil, megestrol, valrubicin og NIASPAN®.
  14. 14. Forbindelse ifølge krav 1 eller et farmaceutisk acceptabelt salt deraf til anvendelse i behandlingen af en sygdom eller lidelse, som et subjekt lider af eller er diagnosticeret med, medieret af NAMPT-aktivitet, såsom en solid eller flydende tumor, ikke-småcellet lungecancer, leukæmi, lymfom, ovariecancer, gliom, brystcancer, uteruscancer, coloncancer, cervixcancer, lungecancer, prostatacancer, hudcancer, rhino-gastriske tumorer, colorectalcancer, CNS-cancer, blærecancer, pancreascancer, Hodgkins sygdom, rheumatoid arthritis, diabetes, aterosklerose, sepsis, aldring eller inflammation.
  15. 15. Forbindelse til anvendelse ifølge krav 14, hvori forbindelsen til anvendelse endvidere omfatter et nød-middel udvalgt fra gruppen bestående af nicotinamid, nicotinsyre og nicotinamidmononucleotid (NMN), eller mindst én forbindelse udvalgt fra gruppen bestående af: et cytotoksisk middel, cisplatin, doxorubicin, taxotere, taxol, etoposid, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilonerne, tamoxifen, 5-fluoruracil, methoxtrexat, temozolomid, cyclophosphamid, SCH 66336, tipifarnib (Zarnestra®), R115777, L778,123, BMS 214662, Iressa®, Tarceva®, C225, GLEEVEC®, intron®, Peg-Intron®, aromatasekombinationer, ara-C, adriamycin, cytoxan, gemcitabin, Uracilsennep, Chlormethin, Ifosfamid, Melphalan, Chlorambucil, Pipobroman, Triethylenmelamin, Triethylenthiophosphoramin, Busulfan, Carmustin, Lomustin, Streptozocin, Dacarbazin, Floxuridin, Cytarabin, 6-Mercaptopurin, 6-Thioguanin, Fludarabinphosphat, leucovirin, oxaliplatin (ELOXATIN®), Pentostatin, vineristin, Vindesin, Bleomycin, Dactinomycin, Daunorubicin, Epirubicin, Idarubicin, Mithramycin™, Deoxycoformycin, Mitomycin-C, L-Asparaginas, Teniposid 17a-Ethinylestradiol, Diethylstilbestrol, Testosteron, Prednison, Fluoxymesteron, Dromostanolonpropionat, Testolacton, Megestrolacetat, Methylprednisolon, Methyltestosteron, Prednisolon, Triamcinolon, Chlortrianisen, Hydroxyprogesteron, Aminoglutethimid, Estramustin, Medroxyprogesteronacetat, Leuprolid, Flutamid, Toremifen, goserelin, Carboplatin, Hydroxyurea, Amsacrin, Procarbazin, Mitotan, Mitoxantron, Levamisol, Navelbine, Anastrazol, Letrazol, Capecitabin, Reloxafin, Droloxafin, Hexamethylmelamin, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbin, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamin, Melphalan, Trastuzumab, Lerozol, Fulvestrant, Exemestan, Ifosfomid, Rituximab, Campath, leueovorin, dexamethason, bicalutamid, chlorambucil, megestrol, valrubicin, vinblastin og NIASPAN®.
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