DK3063143T3 - Aminoheteroarylbenzamider som kinaseinhibitorer - Google Patents

Aminoheteroarylbenzamider som kinaseinhibitorer Download PDF

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DK3063143T3
DK3063143T3 DK14800191.0T DK14800191T DK3063143T3 DK 3063143 T3 DK3063143 T3 DK 3063143T3 DK 14800191 T DK14800191 T DK 14800191T DK 3063143 T3 DK3063143 T3 DK 3063143T3
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mmol
alkyl
amino
lcms
reaction mixture
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DK14800191.0T
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Jeffrey T Bagdanoff
Yu Ding
Wooseok Han
Zilin Huang
Qun Jiang
Jeff Xianming Jin
Xiang Kou
Patrick Lee
Mika Lindvall
Zhongcheng Min
Yue Pan
Sabina Pecchi
Keith Bruce Pfister
Daniel Poon
Vivek Rauniyar
Xiaojing Michael Wang
Qiong Zhang
Jianguang Zhou
Shejin Zhu
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Novartis Ag
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Claims (22)

  1. 1. Forbindelse med formlen (I):
    eller et farmaceutisk acceptabelt salt deraf, hvor: R1 er en eventuelt substitueret gruppe valgt blandt C3-8 cycloalkyl, 5-8 leddet heterocyclyl indeholdende 1-2 heteroatomer valgt blandt N, O og S som ringelementer, phenyl, - SC>2-phenyl, -C(O)-phenyl, -C(R8)2-phenyl og 5-6 leddet heteroarylring, hvor den nævnte heterocyclyl og heteroaryl indeholder 1-2 heteroatomer valgt blandt N, O og S som ringelementer, og hvor de eventuelle substituenter for R1 er 1-3 grupper uafhængigt valgt blandt D, halogen, hydroxy, amino, -N(R8)2, CN, C1-4 alkyl, C1-4 alkoxy, -S(Ci-4 alkyl), C1-4 halogenalkyl, C1-4 halogenalkoxy, C3-6 cycloalkyl, 3-6 leddet heterocyclyl indeholdende 1-2 heteroatomer valgt blandt N, O og S, oxo (med undtagelse af aromatiske ringe), COOR8, CON(R8)2, -NR8-C(O)R8, -NR8-C(O)OR8-SO2R8, -NR8SO2R8 og SO2N(R8)2, hvor hver R8 uafhængigt er H eller C1-4 alkyl; L er
    hvor R" er methyl eller ethyl, og eventuelt er substitueret med fluor, amino, hydroxy, methylamino, ethylamino, dimethylamino, -OP(O)(OH)2, methoxy eller ethoxy; X og Y er uafhængigt valgt blandt H, D, halogen, CN, amino, hydroxy, C1-4 alkyl, Cm halogenalkyl, C1-4 alkoxy og C1-4 halogenalkoxy; R2 er H, C1-4 alkyl eller aryl-C-i-2-alkyl-, hvor det nævnte aryl og C1-4 alkyl eventuelt er substitueret med halogen, CN, C1-4 alkyl, C1-4 halogenalkyl, C3-6 cycloalkyl, C1-4 alkoxy, C1-4 halogenalkoxy eller C1-4 alkylsulfonyl; eller R2 og L er forbundet indbyrdes for dannelse af en heterocyclisk gruppe valgt blandt morpholin, piperidin, thiomorpholin, piperazin og pyrrolidin, som er forbundet med R1 og også eventuelt er substitueret med én eller to grupper uafhængigt valgt blandt Cm alkyl, C1-4 alkoxy, oxo, CN, COOR7, CON(R7)2 og -SO2R7, hvor hvert R7 uafhængigt er H eller C1-4 alkyl; Z er N eller CR4; R4 er H, D, halogen, C1-4 alkyl, C1-4 halogenalkyl eller C1-4 alkoxy; R5 er valgt blandt -C(O)-R5a og R5a; hvor R5a er en eventuelt substitueret C3-8 cycloalkyl, C3-8 cycloalkenyl, mættet eller umættet 3-8 leddet heterocyclisk ring indeholdende 1-2 heteroatomer valgt blandt N, O og S, phenyl eller 5-6 leddet heteroaryl ring indeholdende 1-3 heteroatomer valgt blandt N, O og S, hvor de eventuelle substituenterfor R5 er 1-4 grupper uafhængigt valgt blandt D, halogen, hydroxy, amino, CN, C1-4 alkyl, C1-4 alkoxy, C1-4 halogenalkyl, C1-4 hydroxyalkyl, C1-4 halogenalkoxy, C3-6 cycloalkyl, 3-6 leddet heterocyclyl indeholdende 1-2 heteroatomer valgt blandt N, O og S, oxo (med undtagelse af aromatiske ringe), -COOR9, -C(O)R9, CON(R9)2, -NR9C(O)R9, -NR9CO2R9, -SO2R9, -NR9SO2R9 og -SO2N(R9)2, hvor hvert R9 uafhængigt er H eller C1-4 alkyl eventuelt substitueret med 1-3 grupper uafhængigt valgt blandt D, halogen, OH, NH2, NHMe og NMe2; og to substituenter på det samme eller tilstødende carbonatomer i R5 kan eventuelt tages sammen for dannelse af en 5-6 leddet ring, som kan være mættet eller aromatisk og indeholder 1-2 heteroatomer valgt blandt N, O og S og kan eventuelt være substitueret med 1-2 grupper uafhængigt valgt blandt D, Me, halogen, OH, oxo, O(Ci-4 alkyl), NH2, C1-4 alkylamino, di(Ci-4 alkyl)amino; og R6 er H, D, halogen, C1-4 alkyl eller C1-4 halogenalkyl.
  2. 2. Forbindelse ifølge krav 1 eller et farmaceutisk acceptabelt salt deraf, hvor Z er N.
  3. 3. Forbindelse ifølge krav 1 eller krav 2 eller et farmaceutisk acceptabelt salt deraf, hvor R2 er H eller Me.
  4. 4. Forbindelse ifølge ethvert af kravene 1 til 3 eller et farmaceutisk acceptabelt salt deraf, hvor R6 er H.
  5. 5. Forbindelse ifølge ethvert af kravene 1 til 4 eller et farmaceutisk acceptabelt salt deraf, hvor R5 er valgt blandt -C(O)-R5a og R5a; hvor R5a er valgt blandt C3-8 cycloalkyl, 5-8 leddet heterocyclyl indeholdende 1-2 heteroatomer valgt blandt N, O og S, phenyl,
    og 5-6 leddet heteroaryl, og eventuelt er substitueret med 1-3 grupper uafhængigt valgt blandt D, halogen, CN, hydroxy, C1-4 alkoxy, C1-4 alkyl, C1-4 halogenalkyl, Cm hydroxyalkyl, C1-4 halogenalkoxy, -SO2R', -NR'-C(O)-R' og -SO2NR2, hvor hvert R' uafhængigt er H eller C1-4 alkyl.
  6. 6. Forbindelse ifølge ethvert af kravene 1 til 4 eller et farmaceutisk acceptabelt salt deraf, hvor R5 er valgt blandt -C(O)-R5a og R5a; hvor R5a er valgt blandt cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, tetrahydropyran, dihydropyran, tetrahydrofuran, oxetan, azetidin, pyrrolidin, piperidin, piperazin, morpholin, tetrahydrothiopyran (thiacyclohexan) og tetrahydrothiofuran (thiacyclopentan), som hver især eventuelt er substitueret med 1-3 grupper uafhængigt valgt blandt halogen, D, CN, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 halogenalkyl, C1-4 hydroxyalkyl, C1-4 halogenalkoxy, oxo, COOR9, CON(R9)2, -NHC(O)R9, -NHCOOR9, -NHSO2R9 og -SO2R9, hvor hvert R9 uafhængigt er H eller C1-4 alkyl.
  7. 7. Forbindelse ifølge ethvert af kravene 1-6 eller et farmaceutisk acceptabelt salt deraf, hvor R1 er phenyl og eventuelt er substitueret med én eller tre grupper uafhængigt valgt blandt halogen, D, CN, Cm alkoxy, C1-4 alkyl, C1-4 halogenalkyl, C1-4 halogenalkoxy, -SO2R', -N(R')2, - NR'-C(O)-R' og -SO2NR2, hvor hvert R' uafhængigt er H eller C1-4 alkyl.
  8. 8. Forbindelse ifølge ethvert af kravene 1-7 eller et farmaceutisk acceptabelt salt deraf, hvor Y er H, methyl eller halogen.
  9. 9. Forbindelse ifølge krav 1, som er med formlen IB:
    hvor R5 er en 4-7 leddet cyclisk ether eller C5-6 cycloalkyl og R5 kan være substitueret med op til fire grupper uafhængigt valgt blandt D, F, Cl, CN, amino, -CH2OH, -NHC(O)Me, - NHCOOMe, -NHSO2Me, Me, OMe, OH, oxo, Et, iPr, OEt, og CF3; YerH, F, Cl eller Me; R10 er -CH2-R*, hvor R* er H, -OH, F, -NH2, -NHMe, -OP(O)(OH)2, -NMe2 eller -OMe; og R1 er phenyl, eventuelt substitueret med 1-2 grupper uafhængigt valgt blandt halogen, CN , Ci-4 alkyl, C1-4 alkoxy, C1-4 halogenalkyl, C1-4 halogenalkoxy, COOR8, CON(R8)2 og -SO2R8, hvor hvert R8 uafhængigt er H eller Cm alkyl; eller et farmaceutisk acceptabelt salt deraf.
  10. 10. Forbindelse ifølge ethvert af kravene 1-4 eller 9, hvor R5 er cyclohexyl substitueret med 1-3 grupper uafhængigt valgt blandt D, F, Cl, CN, amino, Me, NHSO2Me, NHCOMe, OMe, OH, Et, CN, -CH2OH og CF3.
  11. 11. Forbindelse ifølge krav 1, hvor R1 er phenyl substitueret med 0, 1 eller 2 grupper uafhængigt valgt blandt F, Cl, Br, I, SMe, SO2Me og CH3.
  12. 12. Forbindelse ifølge krav 1 eller et farmaceutisk acceptabelt salt deraf valgt blandt gruppen bestående af:
  13. 13. Forbindelse ifølge krav 1, som er:
    eller et farmaceutisk acceptabelt salt deraf.
  14. 14. Forbindelse ifølge krav 1, som er:
    eller et farmaceutisk acceptabelt salt deraf.
  15. 15. Forbindelse ifølge krav 1, som er:
    eller et farmaceutisk acceptabelt salt deraf.
  16. 16. Forbindelse ifølge krav 1, som er:
    eller et farmaceutisk acceptabelt salt deraf.
  17. 17. Forbindelse ifølge krav 1, som er4-(3-amino-6-((1S,3S,4S)-3-fluor-4-hydroxy-cyclohexyl)pyrazin-2-yl)-N-((S)-1-(3-brom-5-fluorphenyl)-2-(methylamino)ethyl)-2-fluorbenzamid i hydrochloridsaltform.
  18. 18. Farmaceutisk sammensætning omfattende en forbindelse ifølge ethvert af kravene 1-17 eller et farmaceutisk acceptabelt salt deraf, iblandet i det mindste ét farmaceutisk acceptabelt excipiens.
  19. 19. Farmaceutisk sammensætning ifølge krav 18, som yderligere omfatter et terapeutisk co-agens.
  20. 20. Forbindelse ifølge ethvert af kravene 1-17 eller et farmaceutisk acceptabelt salt deraf, eller en farmaceutisk sammensætning ifølge krav 18 eller krav 19, til anvendelse ved behandlingen af cancer.
  21. 21. Forbindelse eller sammensætning til anvendelse ifølge krav 20, hvor canceren er valgt blandt adenom, blærecancer, hjernecancer, brystcancer, cervicalcancer, colo-rektalcancer, coloncancer, epidermal carcinom, follikulær carcinom, genitourinære cancere, glioblastom, hoved- og halscancere, Hodgkin's sygdom, ikke-Hodgkin's lymfomer, hepatom, nyrecancer, lungecancere, såsom småcellet- eller ikke-småcellet lungecancer, leukæmi, såsom AML eller CML, multipel myelom, lymfoide lidelser, hudcancere inkl. melanom, neuroblastom, ovariecancer, pankreascancer, prostata-cancer, rektalcancer, sarcom, testikulær cancer og thyroid cancer.
  22. 22. Forbindelse ifølge ethvert af kravene 1-17 eller et farmaceutisk acceptabelt salt deraf i kombination med en forbindelse valgt blandt vemurafinib, debrafinib, LGX818, trametinib, MEK162, LEE011, PD-0332991, panobinostat, verinostat, romidepsin, cetuximab, gefitinib, erlotinib, lapatinib, panitumumab, vandetanib, INC280, everolimus, simolimus, BMK120, BYL719, og CLR457.
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