DK2822953T3 - Makrocykliske derivater til behandling af proliferative sygdomme - Google Patents
Makrocykliske derivater til behandling af proliferative sygdomme Download PDFInfo
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- DK2822953T3 DK2822953T3 DK13717555.0T DK13717555T DK2822953T3 DK 2822953 T3 DK2822953 T3 DK 2822953T3 DK 13717555 T DK13717555 T DK 13717555T DK 2822953 T3 DK2822953 T3 DK 2822953T3
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Claims (17)
1. Forbindelse med formlen (I)
hvor: X er udvalgt fra gruppen bestående af -(CR5R6)qO(CR5R6)r-, -(CR5R6)qN(R1)(CR5R6)r-, -(CR5R6)qC(0)N(R1)(CR5R6)r- og -(CR5R6)qN(R1)C(0)(CR5R6)r-; Y og Z hver især uafhængigt er N eller CH, under den forudsætning, at når Y er N, er Z CH, og når Z er N, er Y CH; A er en ring udvalgt blandt C6-Ci2-aryl og 5-6-leddet heteroaryl; R1 er udvalgt fra gruppen bestående af hydrogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet heteroaryl, hvor hver hydrogen på nævnte Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2.aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet heteroaryl kan være uafhængigt eventuelt substitueret med halogen, -OH, -NH2, -S(0),R9, -S(0)2NR9R1°, -S(0)20R9, -N02, -CN, -OR9, -C(0)R9, -0C(0)R9, -NR9C(0)R10, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R10 eller -C(0)NR9R1°; hver R2 uafhængigt er udvalgt fra gruppen bestående af halogen, CrC6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk, 5-6-leddet heteroaryl, -S(0)tR7, -S(0)2NR7R8, -S(0)20R7, -N02, -(CR5R6)qNR7R8, - N(CR5R6)(CR5R6)qNR7R8, -OR7, -0(CR5R6)(CR5R6)q0R7, -0(CR5R6)(CR5R6)qR7, -CN, -C(0)R7, -0C(0)R7, -0(CR5R6)qR7, -NR7C(0)R8, -(CR5R6)qC(0)0R7, -(CR5R6)qNR7R8, -C(=NR7)NR7R8, -NR7C(0)NR7R8, -NR7S(0)2R8 og -(CR5R6)qC(0)NR7R8; hvor hver hydrogen på nævnte CrC6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet heteroaryl uafhængigt kan være eventuelt substitueret med halogen, -OH,-NH2, -S(0)tR9, -S(0)2NR9R1°, -S(0)20R9, -N02, -OR9, -CN, -C(0)R9, -0C(0)R9, -NR9C(0)R1°, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R1°, -NR9S(0)2R10 eller -C(0)NR9R1°; R3 og R4 hver især uafhængigt er udvalgt blandt hydrogen, CrC6-alkyl og C3-C6-cycloalkyl, hvor hver hydrogen på CrC6-alkyl og C3-C6-cycloalkyl uafhængigt kan være eventuelt substitueret med halogen, -OH, -NH2, -S(0),R9, -S(0)2NR9R1°, -S(0)20R9, -NO2, -CN, -OR9, -C(0)R9, -0C(0)R9, -NR9C(0)R1°, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R1° eller-C(0)NR9R1°; hver R5 og R6 hver især uafhængigt er udvalgt fra gruppen bestående af hydrogen, CrCe-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk, 5-6-leddet heteroaryl, -OH, -NH2, -S(0)tR9, -S(0)2NR9R1°, -S(0)20R9, -N02, -CN, -OR9, -C(0)R9, -0C(0)R9, -NR9C(0)R1°, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R10 og -C(0)NR9R1°; hvor hver hydrogen på nævnte CrC6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet heteroaryl uafhængigt kan være eventuelt substitueret med halogen, -OH, -NH2, -S(0),R9, -S(0)2NR9R1°, -S(0)20R9, -NO2, -CN, -OR9, -C(0)R9, -0C(0)R9, -NR9C(0)R1°, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R10 eller -C(0)NR9R1°; hver R7 og R8 hver især uafhængigt er udvalgt fra gruppen bestående af hydrogen, CrCe-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6 leddet heteroaryl, hvor hver hydrogen på nævnte Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6 leddet heteroaryl uafhængigt kan være eventuelt substitueret med halogen, -OH, -NH2, -S(0)tR9, -S(0)2NR9R1°, -S(0)20R9, -N02, -OR9, -CN, -C(0)R9, -0C(0)R9, -NR9C(0)R1°, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R10 eller-C(0)NR9R1°; hver R9 og R10 uafhængigt er udvalgt blandt hydrogen, CrC6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet heteroaryl; m er O, 1,2 eller 3; n er 0, 1,2 eller 3; p er 0,1,2, 3 eller 4; hver q uafhængigt er Q, 1,2 eller 3; hver r uafhængigt er 0,1,2 eller 3; og hver t uafhængigt er 0,1 eller 2; eller et farmaceutisk acceptabelt salt deraf.
2. Forbindelse ifølge krav 1 med formlen (V)
hvor: A er en ring udvalgt blandt C6-Ci2-aryl og 5-6-leddet heteroaryl; R1 er udvalgt fra gruppen bestående af hydrogen, CrC6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet heteroaryl, hvor hver hydrogen på nævnte CrC6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet heteroaryl uafhængigt kan være eventuelt substitueret med halogen, -OH, -NH2, -S(0),R9, -S(0)2NR9R1°, -S(0)2R9, -N02, -CN, -OR9, -C(0)R9, -0C(0)R9, -NR9C(0)R1°, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R10 eller -C(0)NR9R1°; hver R2 hver især uafhængigt er udvalgt fra gruppen bestående af halogen, CrCe-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk, 5-6-leddet heteroaryl, -S(0)tR7, -S(0)2NR7R8, -S(0)20R7, -N02, -(CR5R6)qNR7R8, - N(CR5R6)(CR5R6)qNR1R8, -OR7, -0(CR5R6)(CR5R6)q0R7, -0(CR5R6)(CR5R6)qR7, -CN, -C(0)R7, -0C(0)R7, -0(CR5R6)qR7, -NR7C(0)R8, -(CR5R6)qC(0)0R7, -(CR5R6)qNR7R8, -C(=NR7)NR7R8, -NR7C(0)NR7R8, -NR7S(0)2R8 og -(CR5R6)qC(0)NR7R8; hvor hver hydrogen på nævnte Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-Ce-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet hete-roaryl uafhængigt kan være eventuelt substitueret med halogen, -OH, -NH2, -S(0)tR9, -S(0)2NR9R1°, -S(0)20R9, -N02, -OR9, -CN, -C(0)R9, -0C(0)R9, -NR9C(0)R10, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R10 eller-C(0)NR9R1°; R3 og R4 hver især uafhængigt er udvalgt blandt hydrogen, CrC6-alkyl og C3-C6-cycloalkyl, hvor hver hydrogen på CrC6-alkyl og C3-C6-cycloalkyl uafhængigt kan være eventuelt substitueret med halogen, -OH, -NH2, -S(0),R9, -S(0)2NR9R1°, -S(0)20R9, -N02j -CN, -OR9, -C(0)R9, -0C(0)R9, -NR9C(0)R1°, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R10 eller-C(0)NR9R10; hver R5 og R6 uafhængigt er udvalgt fra gruppen bestående af hydrogen, Cr Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk, 5-6-leddet heteroaryl, -OH, -NH2, -S(0)tR9, -S(0)2NR9R1°, -S(0)20R9, -N02, -CN, -OR9, -C(0)R9, -0C(0)R9, -NR9C(0)R1°, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R10 og -C(0)NR9R1°; hvor hver hydrogen på nævnte CrC6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet heteroaryl uafhængigt kan være eventuelt substitueret med halogen, -OH, -NH2, -S(0),R9, -S(0)2NR9R10, -S(0)20R9, -N02i -CN, -OR9, -C(0)R9, -0C(0)R9, -NR9C(0)R1°, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R10 eller -C(0)NR9R1°; hver R7 og R8 uafhængigt er udvalgt fra gruppen bestående af hydrogen, Cr Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet heteroaryl, hvor hver hydrogen på nævnte CrC6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet heteroaryl uafhængigt kan være eventuelt substitueret med halogen, -OH, -NH2, -S(0)tR9, -S(0)2NR9R1°, -S(0)2oR9, -N02 -OR9, -CN, -C(0)R9, -0C(0)R9, -NR9C(0)R1°, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R10 eller -C(0)NR9R1°; hver R9 og R10 uafhængigt er udvalgt blandt hydrogen, CrC6-alkyl, C2-C6- alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyk- lisk og 5-6 leddet heteroaryl; p er 0,1,2, 3 eller 4; hver q uafhængigt er 0,1,2 eller 3; og hver t uafhængigt er 0,1 eller 2; eller et farmaceutisk acceptabelt salt deraf.
3. Forbindelse ifølge krav 1 med formlen (VI)
hvor: A er en ring udvalgt blandt C6-Ci2-aryl og 5-6-leddet heteroaryl; R1 er udvalgt fra gruppen bestående af hydrogen, CrCe-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet heteroaryl, hvor hver hydrogen på nævnte CrC6-alkyl, C2-C6-alke-nyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet heteroaryl uafhængigt kan være eventuelt substitueret med halogen, -OH, -NH2, -S(0),R9, -S(0)2NR9R10, -S(0)20R9, -N02, -CN, -OR9, -C(0)R9, -0C(0)R9, -NR9C(0)R1°, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R10 eller -C(0)NR9R1°; hver R2 uafhængigt er udvalgt fra gruppen bestående af halogen, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk, 5-6-leddet heteroaryl, -S(0)tR7, -S(0)2NR7R8, -S(0)30R7, -N02, -(CR5R6)qNR7R8, -N(CR5R6)(CR5R6)qNR7R8, -OR7, -0(CR5R6)(CR5R6)q0R7, -0(CR5R6)(CR5R6)qR7, -CN, -C(0)R7, -0C(0)R7, -0(CR5R6)qR7, -NR7C(0)R8, -(CR5R6)qC(0)0R7, -(CR5R6)qNR7R8, -C(=NR7)NR7R8, -NR7C(0)NR7R8, -NR7S(0)2R8 og -(CR5R6)qC(0)NR7R8; hvor hver hydrogen på nævnte Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet heteroaryl uafhængigt kan være eventuelt substitueret med halogen, -OH, -NH2, -S(0)tR9, -S(0)2NR9R1°, -S(0)20R9, -N02, -OR9, -CN, -C(0)R9, -0C(0)R9, -NR9C(0)R10, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R10 eller -C(0)NR9R1°; R3 og R4 hver især uafhængigt er udvalgt blandt hydrogen, CrC6-alkyl og C3-C6-cycloalkyl, hvor hver hydrogen på CrC6-alkyl og C3-C6-cycloalkyl uafhængigt kan være eventuelt substitueret med halogen, -OH, -NH2, -S(0)tR9, -S(0)2NR9R1°, -S(0)20R9, -N02, -CN, -OR9, -C(0)R9, -0C(0)R9, -NR9C(0)R1°, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R10 eller-C(0)NR9R1°; hver R5 og R6 uafhængigt er udvalgt fra gruppen bestående af hydrogen, Cr Ce-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk, 5-6-leddet heteroaryl, -OH, -NH2, -S(0)tR9, -S(0)2NR9R1°, -S(0)20R9, -N02j -CN, -OR9, -C(0)R9, -0C(0)R9, -NR9C(0)R1°, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R10 og -C(0)NR9R1°; hvor hver hydrogen på nævnte CrC6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet heteroaryl uafhængigt kan være eventuelt substitueret med halogen, -OH, -NH2, -S(0),R9, -S(0)2NR9R10, -S(0)20R9, -NO2, -CN, -OR9, -C(0)R9, -0C(0)R9, -NR9C(0)R1°, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R10 eller -C(0)NR9R1°; hver R7 og R8 uafhængigt er udvalgt fra gruppen bestående af hydrogen, Cr C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk, og 5-6-leddet heteroaryl, hvor hver hydrogen på nævnte CrC6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet heteroaryl uafhængigt kan være eventuelt substitueret med halogen, -OH, -NH2, -S(0)tR9, -S(0)2NR9R10, -S(0)20R9, -N02j -OR9, -CN, -C(0)R9, -0C(0)R9, -NR9C(0)R1°, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R10 eller -C(0)NR9R1°; hver R9 og R10 uafhængigt er udvalgt blandt hydrogen, CrC6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C6-Ci2-aryl, 3-12-leddet heteroalicyklisk og 5-6-leddet heteroaryl; p er 0,1,2, 3 eller 4; hver q uafhængigt er O, 1,2 eller 3; og hver t uafhængigt er O, 1 eller 2; eller et farmaceutisk acceptabelt salt deraf.
4. Forbindelse ifølge krav 1, 2 eller 3, hvor R1 er udvalgt fra gruppen bestående af hydrogen, CrC6-alkyl og C3-C6-cycloalkyl, eller et farmaceutisk acceptabelt salt deraf.
5. Forbindelse ifølge et af kravene 1 til 4, hvor hver R2 hver især uafhængigt er udvalgt fra gruppen bestående af CrC6-alkyl, C3-C6-cycloalkyl, -S(0)tR7, -S(0)2NR7R8, -OR7, -0(CR5R6)(CR5R6)q0R7, -0(CR5R6)(CR5R6)qR7 og -CN; hvor hver hydrogen på nævnte Ci-C6-alkyl og C3-C6-cycloalkyl uafhængigt kan være eventuelt substitueret med halogen, -OH, -NH2, -S(0)tR9, -S(0)2NR9R1°, -S(0)20R9, -N02, -OR9, -CN, -C(0)R9, -0C(0)R9, -NR9C(0)R1°, -C(0)0R9, -C(=NR9)NR9R10, -NR9C(0)NR9R10, -NR9S(0)2R1° eller -C(0)NR9R1°, eller et farmaceutisk acceptabelt salt deraf.
6. Forbindelse ifølge et af kravene 1 til 5, hvor A er en ring udvalgt fra gruppen bestående af phenyl, pyridin, pyrimidin, pyridazin, pyrazin, triazin, pyra-zol, imidazol, triazol, tetrazol, thiazol, isothiazol, oxazol og isoxazol, eller et farmaceutisk acceptabelt salt deraf.
7. Forbindelse ifølge et af kravene 1 til 6, hvor R3 og R4 hver især uafhængigt er udvalgt fra gruppen bestående af hydrogen og CrC6-alkyl, eller et farmaceutisk acceptabelt salt deraf.
8. Forbindelse ifølge krav 1, hvilken er (10/=?)-7-amino-12-fluor-2,10,16-tri-methyl-15-oxo-l 0,15,16,17-tetrahydro-2/-/-8,4-(metheno)pyrazolo[4,3-/?][2,5,11]benzoxadiazacyclotetradecin-3-carbonitril, eller et farmaceutisk acceptabelt salt deraf.
9. Forbindelse ifølge krav 1, hvilken er (10F?)-7-amino-12-fluor-2,10,16-tri-methyl-15-oxo-l 0,15,16,17-tetrahydro-2/-/-8,4-(metheno)pyrazolo[4,3- /?][2,5,11]benzoxadiazacyclotetradecin-3-carbonitril.
10. Farmaceutisk sammensætning omfattende en forbindelse ifølge et af kravene 1 til 9, eller et farmaceutisk acceptabelt salt deraf, og en farmaceutisk acceptabel bærer eller et hjælpestof.
11. Forbindelse ifølge et af kravene 1 til 9, eller et farmaceutisk acceptabelt salt deraf, til anvendelse som et medikament, fortrinsvis ved behandling af cancer hos et pattedyr.
12. Forbindelse ifølge krav 11, hvor canceren er medieret af anaplastisk lym-fomkinase (ALK).
13. Forbindelse ifølge krav 11, hvor canceren er medieret af et EML4-ALK-fusionsprotein.
14. Forbindelse ifølge krav 11, hvor canceren er medieret af et EML4-ALK-fusionsprotein med mindst en mutation.
15. Forbindelse ifølge krav 14, hvor mutationen er L1196M eller C1156Y.
16. Forbindelse ifølge et af kravene 11 til 15, hvor canceren er udvalgt fra gruppen bestående af småcellet lungecancer (NSCLC), pladecellekarcinom, hormonrefraktær prostatacancer, papillær renalcellekarcinom, kolorektal ade-nokarcinom, neuroblastom, anaplastisk storcellet lymfom (ALCL) og mave-cancer.
17. Kombination af en forbindelse ifølge et af kravene 1 til 9, eller et farmaceutisk acceptabelt salt deraf, og et yderligere anticancermiddel.
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