DK2918588T3 - Makrocykliske forbindelser som TRK-kinasehæmmere - Google Patents

Makrocykliske forbindelser som TRK-kinasehæmmere Download PDF

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DK2918588T3
DK2918588T3 DK15150036.0T DK15150036T DK2918588T3 DK 2918588 T3 DK2918588 T3 DK 2918588T3 DK 15150036 T DK15150036 T DK 15150036T DK 2918588 T3 DK2918588 T3 DK 2918588T3
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fluoro
hexaazapentacyclo
heptaen
mmol
oxa
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Steven Wade Andrews
Kevin Ronald Condroski
Julia Haas
Yutong Jiang
Gabrielle R Kolakowski
Jeongbeob Seo
Hong-Woon Yang
Qian Zhao
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Array Biopharma Inc
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Claims (17)

1. Forbindelse med formlen I
eller et farmaceutisk acceptabelt salt deraf, hvor: ringen A er valgt blandt ringene A-l og A-2, som har strukturerne:
hvor bølgelinjen mærket 1 angiver stedet for binding af ringen A til ringen B, og bølgelinjen mærket 2 angiver stedet for binding af ringen A til W; X er N eller CH; Y er H eller F; R1 er H, (1-3 C)alkoxy eller halogen; hvor, når ringen B er B-l,
hvor bølgelinjen mærket 3 angiver stedet for binding til ringen A, og bølgelinjen mærket 4 angiver stedet for binding til pyrazolo[1,5-a]pyrimidinringen med formlen I; så er W 0, NH eller Cfb, hvor, når ringen A er A-2, så er W CH2; m er 0, 1 eller 2; D er carbon, R2 og R2a er uafhængigt H, F, (1-3 C) alkyl eller OH (forudsat at R2 og R2a ikke begge er OH) , og R3 og R3a er uafhængigt H, (1-3 C)alkyl eller hydroxy(1-3 C)alkyl, Z er *-NR4aC (=0)-, hvor stjernen angiver stedet for binding af Z til det carbonatom, der bærer R3; R4a er H, (1-6 C)alkyl, fluor(l-6 C)alkyl, difluor(1-6 C)alkyl, trifluor(l-6 C)alkyl, hydroxy((1-6 C)alkyl) eller dihydroxy((2-6 C)alkyl); og R5 og R6 er uafhængigt H, halogen, OH, (1-6 C) alkyl eller hydroxy (1-6 C)alkyl.
2. Forbindelse ifølge krav 1, hvor ringen A er ringen A-l, som har strukturen
3. Forbindelse ifølge krav 1, hvor ringen A er ringen A-2, som har strukturen
4. Forbindelse ifølge et hvilket som helst af kravene 1-3, hvor Y er F.
5. Forbindelse ifølge et hvilket som helst af kravene 1-4, hvor R1 er H.
6. Forbindelse ifølge et hvilket som helst af kravene 1-5, hvor R4a er hydrogen.
7. Forbindelse ifølge et hvilket som helst af kravene 1-6, hvor R2 og R2a hver er hydrogen.
8. Forbindelse ifølge et hvilket som helst af kravene 1-7, hvor W er CH2.
9. Forbindelse ifølge et hvilket som helst af kravene 1-8, hvor m er 0.
10. Forbindelse ifølge et hvilket som helst af kravene 1-8, hvor m er 1.
11. Forbindelse ifølge krav 1, som er valgt blandt: (6R)-9-fluor-2,11,15,19,20,23- hexaazapentacyclo [15.5.2.17'n0.2'6.020'24] pentacosa-1(23),7,9,17(24), 18,21-hexaen-16,2 5-dion; (6R)-9-fluor-13-oxa-2,11,17,21,22,25-hexaazapentacyclo [17.5.2.O2'6.O7'12.O22'26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-on; (6R)-9-fluor-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo [17.5.2.02'6.07'120.22'26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-on; (6R,13S)-9-fluor-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo- [15.5.2.1^^.0^6. O20'24] pen tacos a-1(23),7,9,17(24),18,21-hexaen-16,25-dion; (6R,15R)-9-fluor-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo- [17.5.2.02'6.O7'12.022'26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-on; (6R,13R)-9-fluor-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo-[15.5.2. ^7,ii.o2'6.020'24]pentacosa-1(23),7,9,17(24),18,21-hexaen-16,25-dion; (6R)-9-fluor-13-oxa-2,11,16,20,21,24-hexaazapentacyclo [16.5.2.O2,6.O7,12.021'25] pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-on; (6R)-9-fluor-13-oxa-2,11,18,22,23,26-hexaazapentacyclo [ 18.5.2 . O2' 6. O7'12. O23'27 ]heptacosa-1(26),7,9,11,20(27),21,24-heptaen-19-on; (6R)-9-fluor-2,11,16,20,21,24- hexaazapentacyclo [16.5.2.17'11.O2'6.021f25] hexacosa-1(24),7,9,18(25),19,22-hexaen-17,26-dion; (6R)-9-fluor-2,11,13,16,20,21,24- heptaazapentacyclo [16.5.2.02'6.O7'12.O21'25] pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-on; (6R)-9-fluor-2,11,13,17,21,22,25- heptaazapentacyclo [ 17.5.2 . O2'6. O7'12.o22'26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-on; (6R)-9-fluor-14-oxa-2,11,18,19,22- pentaazapentacyclo [14.5.2.17'11. O2'6. O19'23] tetracosa-1(22),7,9,16(23),17,20-hexaen-15,24-dion; (6R,13R)-9,13-difluor-2,11,15,19,20,23-hexaazapentacyclo [15.5.2.17'n.02'6.020'24] pentacosa-1(23),7,9,17(24),18,21 -hexaen-16,2 5-di on; (6R)-9-fluor-17-methyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo [17.5.2.O2'6.O7'12, o22'26] -hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-on; (6R)-9,15,15-trifluor-13-oxa-2,11,17,21,22,25-hexaazapentacyclo- [17.5.2.O2'6.O7'12.O22'26] hexacosa-1(25),7, 9, 11, 19 (26),20,23-heptaen-18-on; (6R)-9-fluor-2,11,16,20,21,24- hexaazapentacyclo [16.5.2.O2'6.O7'12.021'25] pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-on; (6R)-9-fluor-15-methyl-2,11,16,20,21,24-hexaazapentacyclo-[16.5.2.O2'5.O7'12. O21'25] pen tacos a-1 (24) , 7,9, 11,18 (25) , 19, 22-heptaen-17-on; (6R,13R)-9-fluor-13-methyl-2,11,15,19,20,23-hexaazapentacyclo-[15.5.2.17'n.02'6. O23'24] pen tacos a-1 (23) , 7,9, 17 (24) , 18,21-hexaen- 16.25- dion; (6R,13S)-9-fluor-13-methyl-2,11,15,19,20,23-hexaazapentacyclo-[15.5.2 .l7'11. 02'6.023'24]pentacosa-l (23), 7,9, 17 (24), 18,21-hexaen- 16.25- dion; (6R)-9-fluor-15,15-dimethyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo- [17.5.2.02,6.O7'12.022'26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-on; (6R)-9-fluor-15,15-dimethyl-2,11,16,20,21,24-hexaazapentacyclo- [16.5.2.O2,6.O7'12.021'25] pen tacos a-1(24) , 7, 9, 11, 18(25), 19,22-heptaen-17-on og (6R)-9-fluor-13,13-dimethyl-2,11,15,19,20,23-hexaazapentacyclo [15.5.2.17'n.02'6.020'24] -pentacosa-1(23),7,9,17(24),18,21-hexaen-16,25-dion; eller et farmaceutisk acceptabelt salt deraf.
12. Forbindelse ifølge krav 1, som er valgt blandt: (6R)-9-fluor-13-oxa-2,11,17,21,22,25-hexaazapentacyclo [17.5.2.02'6.07'12.022'26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-on; (6R)-9-fluor-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo [17.5.2.02-6.07'12.022'26] -hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-on; (6R,15R)-9-fluor-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo- [17.5.2.02'6.07'12.022'26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-on; (6R)-9-fluor-13-oxa-2,11,16,20,21,24-hexaazapentacyclo [16.5.2.02'6·07'12.021'25] pen tacos a-1(24),7,9,11,18(25),19,22-heptaen-17-on; (6R)-9-fluor-13-oxa-2,11,18,22,23,26-hexaazapentacyclo [18.5.2.02'6.07'12.023'27] hep tacos a-1(26),7,9,11,20 (27),21,24-heptaen-l9-on; (6R)-9-fluor-2,11,13,16,20,21,24- heptaazapentacyclo [16.5.2.02'6.07'12.021'25] pen tacos a-1(24),7,9,11,18(25),19,22-heptaen-17-on; (6R)-9-fluor-2,11,13,17,21,22,25- heptaazapentacyclo [17.5.2.02'6.07'12.022'26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-on; (6R)-9-fluor-17-methyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo [17.5.2.02'6.07'12.022'26] -hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-on; (6R)-9,15,15-trifluor-13-oxa-2,11,17,21,22,25-hexaazapentacyclo- [17.5.2.02'6.07'12.022'26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-on; (6R)-9-fluor-2,11,16,20,21,24- hexaazapentacyclo [16.5.2.02'6.07'12.021'25] pen tacos a-1(24),7,9,11,18(25),19,22-heptaen-17-on; (6R)-9-fluor-15-methyl-2,11,16,20,21,24-hexaazapentacyclo-[16.5.2.02'5.07'12.021'25]pentacosa-l (24) , 7, 9, 11,18 (25) , 19,22-heptaen-17-on; (6R)-9-fluor-15,15-dimethyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo- [17.5.2.02'6.07'12.022'26] hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-on og (6R)-9-fluor-15,15-dimethyl-2,11,16,20,21,24-hexaazapentacyclo- [16.5.2.02'6.07'12. o21'25] pen tacos a- 1(24),7,9,11,18(25),19,22-heptaen-17-on; eller et farmaceutisk acceptabelt salt deraf.
13. Forbindelse ifølge krav 1, som er valgt blandt: (6R)-9-fluor-2,11,15,19,20,23- hexaazapentacyclo [15.5.2.17'n.o2'6. o20'24] pentacosa-1(23),7,9,17(24),18,21-hexaen-16,25-dion; (6R,13S)-9-fluor-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo- [15.5.2.17'1:L.02'6.020'24] -pentacosa-1(23),7,9,17(24),18,21-hexaen-16,25-dion; (6R,13R)-9-fluor-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo- [15.5.2.17'1:L.02'6.020'24] -pentacosa-1(23),7,9,17(24),18,21-hexaen-16,25-dion; (6R)-9-fluor-2,11,16,20,21,24- hexaazapentacyclo [16.5.2.1^^.0^6. O21'25] hexacosa-1(24),7,9,18(25),19,22-hexaen-17,26-dion; (6R)-9-fluor-14-oxa-2,11,18,19,22- pentaazapentacyclo [14.5.2 . l7^11. O2'6, o19'23] tetracosa-1(22),7,9,16(23),17,20-hexaen-15,24-dion; (6R,13R)-9,13-difluor-2,11,15,19,20,23-hexaazapentacyclo [15.5.2.17'11.02'6.020'24] pen tacos a-1(23),7,9,17(24),18,21-hexaen-l6,25-dion; (6R, 13R)-9-fluor-13-methyl-2, 11,15,19,20,23-hexaazapentacyclo-[15.5.2. inn. o2'6. O23'24]pentacosa-1 (23) , 7,9, 17 (24) , 18,21-hexaen- 16.25- dion; (6R,13S)-9-fluor-13-methyl-2, 11,15,19,20,23-hexaazapentacyclo-[15.5.2.17-11. O2-6. O23- 24]pentacosa-1 (23) , 7,9, 17 (24) , 18,21-hexaen- 16.25- dion og (6R)-9-fluor-13,13-dimethyl-2,11,15,19,20,23-hexaazapentacyclo [15.5.2.17'11.02'6.O20'24] pen tacos a-1(23),7,9,17(24),18,21-hexaen-l6,25-dion; eller et farmaceutisk acceptabelt salt deraf.
14. Farmaceutisk sammensætning, som omfatter en forbindelse med formlen I ifølge et hvilket som helst af kravene 1-13, eller et farmaceutisk acceptabelt salt deraf, og et farmaceutisk acceptabelt fortyndingsmiddel eller en farmaceutisk acceptabel bærer.
15. Forbindelse med formlen I ifølge et hvilket som helst af kravene 1-12 eller et farmaceutisk acceptabelt salt deraf til anvendelse ved behandling af smerter, cancer, inflammation, neurodegenerativ sygdom eller infektion med Trypanosoma cruzi.
16. Forbindelse til anvendelse ifølge krav 15 til anvendelse ved behandling af cancer.
17. Forbindelse til anvendelse ifølge krav 16, hvor canceren er valgt fra gruppen bestående af: neuroblastom, ovariecancer, colorektal cancer, melanom, hoved- og halscancer, mavekarcinom, lungekarcinom, brystcancer, glioblastom, medulloblastom, sekretorisk brystcancer, spytkirtelcancer, papillært thyreoideakarcinom, myeloid leukæmi hos voksne, pancreascancer og prostatacancer.
DK15150036.0T 2010-05-20 2011-05-13 Makrocykliske forbindelser som TRK-kinasehæmmere DK2918588T3 (da)

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US34676710P 2010-05-20 2010-05-20
US201061426716P 2010-12-23 2010-12-23
EP11728970.2A EP2571883B1 (en) 2010-05-20 2011-05-13 Macrocyclic compounds as trk kinase inhibitors

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