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ME02627B - 6-alkinil piridini kao smac mimetici - Google Patents

6-alkinil piridini kao smac mimetici

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Publication number
ME02627B
ME02627B MEP-2017-53A MEP201753A ME02627B ME 02627 B ME02627 B ME 02627B ME P201753 A MEP201753 A ME P201753A ME 02627 B ME02627 B ME 02627B
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Montenegro
Prior art keywords
alkyl
optionally
compound according
phenyl
substituted
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Application number
MEP-2017-53A
Other languages
German (de)
English (en)
French (fr)
Inventor
Ulrich Reiser
Gerd Bader
Walter Spevak
Andreas Steffen
Alastair L Parkes
Original Assignee
Boehringer Ingelheim Int
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Filing date
Publication date
Application filed by Boehringer Ingelheim Int filed Critical Boehringer Ingelheim Int
Publication of ME02627B publication Critical patent/ME02627B/me

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Claims (32)

1. Jedinjenje prema Formuli (I) (I) gdje R1 je -H ili -C1-5 alkil; R2, R2a su nezavisno odabrani između -H ili -C1-5 alkila opciono supstituisani sa jednim ili više -F; R3 je odabran između -C6-10 arila, 5-14 članog heteroarila, od kojih svaka grupa može biti opciono i nezavisno supstituisana sa jednim ili više, nezavisno odabranih, R6; ili R3 je odabran između -C1-6 alkila, -C4-7 cikloalkila, -C4-7 cikloalkenila, ili 5-14 članog aromatičnog sistema prstena, od kojih svaka grupa može biti opciono i nezavisno supstituisana sa jednim ili više, nezavisno odabranih, R6a; R6 je odabran između -CN, halogena, -C1-3 alkila, -O-C1-3 alkila, -C(O)-R12, 5-6 članog heteroarila, gde 5-6 člana heteroaril grupa može opciono da bude supstitiusana sa -C1-3 alkilom; ili R6 je fenil, gdje fenil može da bude opciono supstituisan sa -O-C1-3 alkilom R6a je odabran između =O, -CN, halogena, -C1-3 alkila, -O-C1-3 alkila, -C(O)-R12, 5-6 članog heteroarila, gdje 5-6 člana heteroaril grupa može biti opciono supstituisana sa -C1-3 alkilom; ili R6a je fenil, gdje fenil može biti opciono supstituisan sa -O-C1-3 alkilom; R12 je odabran između -NH2, -NH-C1-3 alkila, 5-7 članog ne aromatičnog heterociklila, ili -O-C1-3 alkila, gdje -C1-3 alkil grupe mogu biti opciono supstituisane sa 5-7 članim ne aromatičnim heterociklilom; R4 je odabran između -H, -C6-10 arila, 5-14 članog heteroarila, od kojih svaka grupa je opciono i nezavisno supstituisana sa jednim ili više, nezavisno odabranih, R7, ili R4 je odabran između C1-6 alkila, 5-14 članog aromatičnog sistema prstena, -C5-7 cikloalkila, od kojih svaka grupa je opciono i nezavisno supstituisana sa jednim ili više, nezavisno odabranih, R7a, ili R4 je odabran između -N(R8,R9) gdje R8, R9 su nezavisno odabrani između H, -C1-3 alkila, -C(O)-R10 -S(O)2-R11 R10, R11 su nezavisno odabrani između 5-7 članog ne aromatičnog heterociklila, -C5-7 cikloalkila, -C6-10 arila, 5-10 članog heteroarila; R7 je odabran između -CN, halogena, -CF3, -NO2, -C1-3 alkila, -S-C1-3 alkila, -NH-C1-3 alkila, -N(C1-3 alkila)2, -NHC(O)-C1-3 alkila, -C(O)-R13, -O-C1-3 alkila, 5-14 članog heteroarila, -O-fenila, -CH2-fenila, fenila, od kojih svaka fenil grupa može biti opciono supstituisana sa halogenom, ili 5-6 članim ne aromatičnim heterociklilom, gdje 5-6 člani ne aromatični heterociklil može biti opciono supstituisan sa -C1-3 alkilom; R7a je odabran između =O, -CN, halogena, -CF3, -NO2, -C1-3 alkila, -S-C1-3 alkila, -NH-C1-3 alkila, -N(C1-3 alkila)2, -NHC(O)-C1-3 alkila, -C(O)-R13, -O-C1-3 alkila, 5-14 članog heteroarila, -O-fenila, -CH2-fenila, fenila, od kojih svaka fenil grupa može biti opciono supstituisana sa halogenom, ili 5-6 članim ne aromatičnim heterociklilom, gdje 5-6 člani ne aromatični heterociklil može biti opciono supstituisan sa -C1-3 alkilom; gdje R13 je odabran između -OH, -NH2, -NH-C1-3 alkila, -C1-3 alkila; R5 je odabran između -H, halogena, -C1-3 alkila, -O-C1-3 alkila, gdje -C1-3 alkil grupe mogu opciono biti supstituisane sa jednim ili više halogena; ili R4 i R5 uzete zajedno obrazuju -C6-10 aril ili 5-14 člani heteroaril, i pri čemu jedinjenja formule (I) mogu opciono biti prisutne u obliku soli.
2. Jedinjenje prema zahtjevu 1, gdje R1 je odabran između -CH3, -CH2-CH3.
3. Jedinjenje prema zahtjevu 1 ili 2, gdje R2 i R2a su nezavisno odabrani između ‑H, -CH3, -CH2-CH3, -CH-(CH3)2, -(CH2)2-CH3.
4. Jedinjenje prema bilo kom od zahtjeva 1 do 3, gdje R5 je odabran između -H, -Cl, -F, ‑CF3, -OCH3, -CH3.
5. Jedinjenje prema bilo kom od zahtjeva 1 do 4, gdje R3 je odabran između -C6-10 arila, 5-14 članog heteroarila, od kojih svaka grupa može biti opciono i nezavisno supstituisana sa jednim ili više, nezavisno odabranih, R6, ili R3 je odabran između -C5-7 cikloalkenila, 5-14 članog aromatičnog sistemskog prstena, od kojih svaka grupa može biti opciono i nezavisno supstituisana sa jednim ili više, nezavisno odabranih R6a, ili R3 je -CH2-fenil, gde fenil može biti opciono supstituisan sa -O-C1-3 alkilom, i gdje R6 i R6a su kao što su definisani u zahtjevu 1.
6. Jedinjenje prema bilo kom od zahtjeva 1 do 5, gdje R3 je odabran između -C6-10 arila, 5-14 članog heteroarila, od kojih svaka grupa može biti opciono i nezavisno supstituisana sa jednim ili više, nezavisno odabrani, R6, ili R3 je odabran između 5-14 članog aromatičnog sistemskog prstena, gdje grupe mogu biti opciono i nezavisno supstituisane sa jednim ili više, nezavisno odabrani, R6a, gdje R6 i R6a su kao što su definisani u zahtjevu 1.
7. Jedinjenje prema bilo kom od zahteva 1 do 5, gdje R3 je odabran između –CH2-fenila, ; ;; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;; ; ; ; ; ; od kojih je svaka grupa opciono supstituisana kao što je definisano u zahtjevu 1.
8. Jedinjenje prema bilo kom od zahtjeva 1 do 7, gdje R4 je odabran između -H, -C6-10 arila, 5-14 članog heteroarila, od kojih je svaka grupa opciono i nezavisno supstituisana sa jednim ili više, nezavisno odabrani, R7, ili R4 je odabran između -C1-6 alkila, 5-14 članog aromatičnog sistemskog prstena i -C5-7 cikloalkila, od kojih je svaka grupa opciono i nezavisno supstituisana sa jednim ili više, nezavisno odabrani, R7a, ili R4 je odabran između -N(R8,R9), gdje R7, R7a, R8 i R9 su kao što su definisani u zahtjevu 1.
9. Jedinjenje prema bilo kom od zahtjeva 1 do 8, gdje R4 je odabran između -C6-10 arila, 5-14 članog heteroarila, od kojih je svaka grupa opciono i nezavisno supstituisana sa jednim ili više, nezavisno odabrani, R7, ili R4 je odabran između 5-14 članog aromatičnog sistemskog prstena, -C5-7 cikloalkila, od kojih je svaka grupa opciono i nezavisno supstituisana sa jednim ili više, nezavisno odabrani, R7a, ili R4 je odabran između ‑N(R8,R9), gde R7, R7a, R8 i R9 su kao što su definisani u zahtjevu 1.
10. Jedinjenje prema bilo kom od zahtjeva 1 do 9, gdje R4 je odabran između -C6-10 arila, 5-14 članog heteroarila, od kojih je svaka grupa opciono i nezavisno supstituisana sa jednim ili više, nezavisno odabrani, R7, ili R4 je 5-14 člani aromatični sistemski prsten, od kojih je svaka grupa opciono i nezavisno supstituisana sa jednim ili više, nezavisno odabrani, R7a, gdje R7 i R7a su kao što su definisani u zahtjevu 1.
11. Jedinjenje prema bilo kom od zahtjeva 1 do 9, gdje R4 je odabran između –H, -C1-3 alkila, -CH2-fenila, -N(CH3)-SO2-fenila, -N(CH3)CO-R10; -NH-CO-R10, gdje R10 je nezavisno odabran između morfolina, ciklopentila, fenila, ili R4 je odabran između ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; od kojih je svaka grupa opciono supstituisana kao što je definisano u zahtjevu 1.
12. Jedinjenje prema bilo kom od zahtjeva 1 do 11, gdje R6 je odabran između -F, -Cl, -CN ‑CH3, -O-CH3, -C(O)NHCH3, -C(O)NH2, C(O)OCH3, -C(O)-morfolinil, -C(O)-O-CH2-tetrahidropiran, fenil, , , , , , , , ili R6a je odabran između =O, -F, -Cl, -CN -CH3, -O-CH3, -C(O)NHCH3, -C(O)NH2, C(O)OCH3, -C(O)-morfolinil, -C(O)-O-CH2-tetrahidropiran, fenil, , , , , , , , .
13. Jedinjenje prema bilo kom od zahtjeva 1 do 12, gdje R7 je odabran između -CN, -F, -Cl, ‑CF3, -NO2, -CH3, -CH2CH3, -CH2(CH3)2, -S-CH3, -NH-CH3, -N(CH3)2, -C(O)OH, -C(O)NH2, -C(O)NH-CH3, -NHC(O)CH3, -O-CH3, -O-CH2CH3, piridil, fenil, -O-Fenil, -CH2-fenil, , , , , ili R7a je odabran između =O, -CN, -F, -Cl, -CF3, -NO2, -CH3, ‑CH2CH3, -CH2(CH3)2, -S-CH3, -NH-CH3, -N(CH3)2, -C(O)OH, ‑C(O)NH2, -C(O)NH-CH3, -NHC(O)CH3, -O-CH3, -O-CH2CH3, piridil, fenil, -O-Fenil, -CH2-fenil, , , , , .
14. Jedinjenje prema bilo kom od zahtjeva 1 do 3 i 5 do 7, gdje R4 i R5 uzeti zajedno obrazuju fenil.
15. Jedinjenje prema bilo kom od zahtjeva 1 do 14, gdje R3 je odabran između , , , , i.
16. Jedinjenje prema bilo kom od zahtjeva 1 do 13 i 15, gdje R4 je odabran između ; ; ; ; .
17. Jedinjenje prema zahtjevu 1, odabrano između # Molekulska Struktura # Molekulska Struktura 26 27 28 29 30 31 33 34 35 36 37 39 41 42 44 45 46 47 48 49 50 52 53 54 58 60 61 63 64 66 69 70 71 72 74 75 77 78 79 80 81 82 87 88 89 90 92 93 94 95 96 100 108 113 118 121 122 123 125 126 127 129 130 132 138 145 147 149 161 165 168 174 175 176 177 182 184 185 186 187 189 191 192 194 195 198 203 204 206 208 213 215 217 223 226 228 229 232 234 240
18. Jedinjenje prema zahtjevu 1 (26), gdje jedinjenje može opciono da bude prisutno u obliku soli.
19. Jedinjenje prema zahtjevu 1 (35), , gdje jedinjenje može opciono da bude prisutno u obliku soli.
20. Jedinjenje prema zahtjevu1 (28), , gdje jedinjenje može opciono da bude prisutno u obliku soli.
21. Jedinjenje prema zahtjevu 1 (29), , gdje jedinjenje može opciono da bude prisutno u obliku soli.
22. Jedinjenje prema zahtjevu 1 (30), , gdje jedinjenje može opciono da bude prisutno u obliku soli.
23. Jedinjenje prema zahtjevu 1 (47), , gdje jedinjenje može opciono da bude prisutno u obliku soli.
24. Jedinjenje prema zahtjevu 1 (88), , gdje jedinjenje može opciono da bude prisutno u obliku soli.
25. Jedinjenje prema zahtjevu 1 (89), , gdje jedinjenje može opciono da bude prisutno u obliku soli.
26. Jedinjenje prema zahtjevu 1 (174), , gdje jedinjenje može opciono da bude prisutno u obliku soli.
27. Jedinjenje prema zahtjevu 1 (185), gdje jedinjenje može opciono da bude prisutno u obliku soli.
28. Jedinjenje prema bilo kom od zahtjeva 1 do 27, za korišćenje u liječenju kancera.
29. Jedinjenje prema bilo kom od zahtjeva 1 do 27 za korišćenje u liječenju i/ili prevenciji karcinoma grudi, prostate, mozga ili jajnika, ne malih ćelija bronhijalnih karcinoma (NSCLC), melanoma i hroničnih limfatičnih leukemija (CLL).
30. Farmaceutska kompozicija koja obuhvata jedinjenje prema bilo kom od zahtjeva 1 do 27.
31. Farmaceutska kompozicija koja obuhvata jedinjenje prema bilo kom od zahtjeva 1 do 27 za korišćenje u liječenju i/ili prevenciji kancera.
32. Farmaceutska kompozicija koja obuhvata jedinjenje prema bilo kom od zahtjeva 1 do 27 za korišćenje u liječenju i/ili prevenciji karcinoma grudi, prostate, mozga ili jajnika, ne malih ćelija bronhijalnih karcinoma (NSCLC), melanoma i hroničnih limfatičnih leukemija (CLL).
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