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DK3013814T3 - Substituerede tetrahydrocarbazol- og carbazolcarboxamidforbindelser, der kan anvendes som kinasehæmmere - Google Patents

Substituerede tetrahydrocarbazol- og carbazolcarboxamidforbindelser, der kan anvendes som kinasehæmmere Download PDF

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DK3013814T3
DK3013814T3 DK14740094.9T DK14740094T DK3013814T3 DK 3013814 T3 DK3013814 T3 DK 3013814T3 DK 14740094 T DK14740094 T DK 14740094T DK 3013814 T3 DK3013814 T3 DK 3013814T3
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methyl
carbazole
fluoro
carboxamide
chloro
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Joseph A Tino
Anurag S Srivastava
Soo Sung Ko
Michael A Galella
George V Delucca
Qingjie Liu
Douglas G Batt
Qing Shi
Myra Beaudoin Bertrand
Charles M Langevine
Scott Hunter Watterson
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Bristol Myers Squibb Co
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Claims (14)

  1. SUBSTITUEREDE TETRAHYDROCARBAZOL- OG CARBAZOLCARBOXAMIDFORBENDELSER, DER KAN ANVENDES SOM KINASEHÆMMERE
    1. Forbindelse med formlen (I):
    hvor: de to punkterede linjer repræsenterer enten to enkelt- eller to dobbeltbindinger;
    Rt er F, Cl, -CN, eller-CH3; R2 er Cl eller -CH3; R3 er -C(CH3)2OH eller -CH2CH2OH; Ra er H eller -CH3; hver Rb uafhængigt er F, Cl, -CH3, og/eller -OCH3; og n er nul, 1 eller 2.
  2. 2. Forbindelse ifølge krav 1, der har formlen ifølge strukturen (IA):
  3. 3. Forbindelse ifølge et hvilket som helst af kravene 1-2, hvor:
  4. 4. Forbindelse ifølge et hvilket som helst af kravene 1-3, der har strukturen ifølge formlen (IIA-1):
    hvor R3 er -C(CH3)2OH.
  5. 5. Forbindelse ifølge krav 1, der har strukturen ifølge formlen (IB):
  6. 6. Forbindelse ifølge et hvilket som helst af kravene 1 og 5, hvor:
    Q er: _____
  7. 7. Forbindelse ifølge et hvilket som helst af kravene 1 og 5-6, der har strukturen ifølge formlen (IIB-1):
    hvor R3 er -C(CH3)2OH.
  8. 8. Forbindelse ifølge et hvilket som helst af kravene 1 og 5-6, der har strukturen ifølge formlen (IIIB-2):
    hvor R3 er -C(CH3)2OH.
  9. 9. Forbindelse ifølge krav 1, hvor forbindelsen er udvalgt fra: 3-chlor-4-(R)-(3-(R)-(8-fluor-l-methyl-2,4-dioxo-l,2-dihydroqumazolm-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-1 -carboxamid (1); 3-chlor-4-(R)-(3-(S)-(8-fluor-l-methyl-2,4-dioxo-l,2-dihydroquinazolm-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (2); 3-chlor-7-(2-hydroxypropan-2-yl)-4-(R)-(2-methyl-3-(l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)phenyl)-9H-carbazol-l-carboxamid (3); 3-chlor-4-(R)-(3-(l,8-dimethyl-2,4-dioxo-l,2-dihydroqumazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (4); 3-chlor-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(R)-(7-methoxy-l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazol-l-carboxaniid (5); 3-chlor-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(S)-(7-methoxy-l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazol-l-carboxainid (6); 3-chlor-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(8-mcthoxy-1-mcthyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-9H-carbazol-l-carboxamid (7); 3-chlor-4-(R)-(3-(6-fluor-l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (8); 3-chlor-4-(R)-(3-(7-fluor-l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (9); 3-chlor-4-(R)-(3-(6,8-difluor-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (10); 3-chlor-4-(R)-(3-(S)-(8-fluor-l-methyl(d3)-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (11); 3-chlor-4-(R)-(3-(R)-(8-fluor-l-methyl(d3)-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (12); 3-chlor-4-(R)-(3-(8-fluor-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (13); 3-chlor-4-(R)-(3-(R)-(8-fluor-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-1 -carboxamid (14); 3-cyan-4-(S)-(3-(8-fluor-l-mcthyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-mcthylphcnyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (15 og 16); 3-fluor-4-(R)-(3-(8-fluor-l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (17); 3-fluor-4-(R)-(3-(S)-(8-fluor-l-methyl-2,4-dioxo-l,2-dihydroqmnazolin-3(4H)-yl)-2-mcthylphcnyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (18); 3-fluor-4-(R)-(3-(S)-(8-fluor-l-methyl-2,4-dioxo-l,2-dihydroqmnazolm-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (19); 3-fluor-4-(R)-(3-(8-fluor-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (20); 3-fluor-4-(R)-(3-(R)-(8-fluor-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (21); 3-fluor-4-(R)-(3-(S)-(8-fluor-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (22); 3-chlor-4-(R)-(3-(3-(4-lluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-l(6II)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (23); 3- chlor-4-(R)-(3-(3-(4-fluorophenyl)-2,6-dioxo-2,3-dihydropyrimidin-l(6H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (24); 6-chlor-5-(R)-(3-(8-fluor-l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-111-carbazol-8-carboxamid (25); 6-chlor-5-(R)-(3-(S)-(8-fluor-l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-lH-carbazol-8-carboxamid (26); 6-lluor-5-(R)-(3-(S)-(8-fluor-l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(R)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-lH-carbazol-8-carboxamid (27); 6-fluor-5-(R)-(3-(S)-(8-fluor-l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-lH-carbazol-8-carboxamid (28); 4- (R)-(3-(S)-(8-fluor-l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-3-methyl-9H-carbazol- 1-carboxainid (29); 4-(R)-(3-(5-chlor-l,3-dioxo-lH-pyrido[l,2-c]pyrimidin-2(3H)-yl)-2-mcthylphcnyl)-3-fluor-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (30 og 31); 3-chlor-4-(R)-(3-(R)-(5-chlor-l,3-dioxo-lH-pyrido[l,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (32); 3-chlor-4-(R)-(3-(S)-(5-chlor-l,3-dioxo-lH-pyrido[l,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9II-carbazol-1 -carboxamid (33); 3-chlor-4-(R)-(3-(5-fluor-l,3-dioxo-lH-pyrido[l,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-1 -carboxamid (34); 3-chlor-4-(R)-(3-(5-fluor-l,3-dioxo-lH-pyrido[l,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (35 og 36); 3-chlor-7-(2-hydroxypropan-2-yl)-4-(R)-(3-(5-mcthoxy-l,3-dioxo-lH-pyrido[l,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-9H-carbazol-l-carboxamid (37); 3-chlor-4-(R)-(3-(5,7-dioxo-5H-thiazolo[3,2-c]pyrimidin-6(7H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (38 og 39); 3-fluor-4-(R)-(3-(5-fluor-l,3-dioxo-lH-pyrido[l,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (40 og 41); 3-chlor-4-(R)-(2-chlor-3-(l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (42); 3-chlor-4-(R)-(2-chlor-3-(R)-(l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (43); 3-chlor-4-(R)-(2-chlor-3-(8-fluor-l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (44); 3- chlor-4-(R)-(2-chlor-3-(R)-(8-fluor-l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (45); 4- (R)-(2-chlor-3-(8-fluor-l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4II)-yl)phenyl)-3-fluor-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (46); 3-chlor-4-(R)-(2-chlor-3-(8-fluor-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid (47);
    DK./cr 3U13814 -9-
  10. 11. Forbindelse ifølge krav 1, der har strukturen:
  11. 12. Forbindelse ifølge krav 1, hvor forbindelsen er: 3-chlor-4-(R)-(3-(S)-(8-fluor-l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)- 7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid i krystalform M-l som kendetegnet ved de fraktionskoordinater, der er opført nedenfor, beregnet ved en temperatur på ca. 203 K; atomkoordinater (xlO4)
    DK./cr 3U13814 -10-
    3-chlor-4-(R)-(3-(S)-(8-fluor-l-methyl(d3)-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid i krystalform H-l som kendetegnet ved de fraktionskoordinater, der er opført nedenfor, beregnet ved stuetemperatur; atomkoordinater (x 104)
    DK./cr 3U13814 _
    1 1 _ 3-chlor-4-(R)-(3-(S)-(8-fluor-l-methyl(d3)-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid i krystalform M-l som kendetegnet ved de fraktionskoordinater, der er opført nedenfor, beregnet ved stuetemperatur; atomkoordinater (x 104)
    DK./cr 3U13814 - 12-
    6-fluor-5-(R)-(3-(S)-(8-fluor-l-methyl-2,4-dioxo-l,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-lH-carbazol-8-carboxamid i krystalform M2-1 som kendetegnet ved de fraktionskoordinater, der er opført nedenfor, beregnet ved en temperatur på ca. 173 K; atomkoordinater (x 104)
    DK./cr 3U13814 - 13-
    eller 3-chlor-4-(R)-(3-(S)-(5-chlor-1,3-diox o-lH-pyrido[l,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazol-l-carboxamid i krystalform M2-1 som kendetegnet ved de fraktionskoordinater, der er opført nedenfor, 5 beregnet ved en temperatur på ca. 173 K; atomkoordinater (x 104)
    DK/EP 31Π38Ί4 - 14-
  12. 13. Farmaceutisk sammensætning omfallende en forbindelse ifølge et hvilket som helst af kravene 1-12 og en farmaceutisk acceptabel bærer.
  13. 14. Forbindelse ifølge et hvilket som helst af kravene 1-12 til anvendelse i terapi.
  14. 15. Forbindelse ifølge et hvilket som helst af kravene 1-12 til anvendelse i terapi i behandling af 5 autoimmun sygdom eller kronisk inflammatorisk sygdom.
DK14740094.9T 2013-06-25 2014-06-25 Substituerede tetrahydrocarbazol- og carbazolcarboxamidforbindelser, der kan anvendes som kinasehæmmere DK3013814T3 (da)

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US201361839141P 2013-06-25 2013-06-25
PCT/US2014/043978 WO2014210085A1 (en) 2013-06-25 2014-06-25 Substituted tetrahydrocarbazole and carbazole carboxamide compounds useful as kinase inhibitors

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PT3013814T (pt) 2017-08-10
US20140378475A1 (en) 2014-12-25
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