DK2776397T3 - Quinoliner som fgfr-kinasemodulatorer - Google Patents

Quinoliner som fgfr-kinasemodulatorer Download PDF

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DK2776397T3
DK2776397T3 DK12794744.8T DK12794744T DK2776397T3 DK 2776397 T3 DK2776397 T3 DK 2776397T3 DK 12794744 T DK12794744 T DK 12794744T DK 2776397 T3 DK2776397 T3 DK 2776397T3
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alkyl
substituted
cancer
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galkyl
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Valerio Berdini
Patrick Rene Angibaud
Steven John Woodhead
Gordon Saxty
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Astex Therapeutics Ltd
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Claims (15)

1. Forbindelse med formlen (I):
der indbefatter en hvilken som helst tautomer eller stereokemisk, isomer form deraf, hvor W er -N(R3)- eller -C(R3aR3b)-; hver R2 er uafhængigt udvalgt fra hydroxyl, halogen, cyano, Ci-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, Ci-4-alkoxy, hydroxyCi-4-alkyl, hydroxyCi-4-alkoxy, haloCi-4-alkyl, haloCi-4-alkoxy, hydro xyhaloCi-4-alkyl, hydroxyhaloCi-4-alkoxy, Ci-4-alkoxyCi_4-alkyl, haloCi-4-alkoxyCi-4-alkyl, Ci-4-alkoxyCi-4-alkyl, hvor hver Ci-4-alkyl eventuelt kan være substitueret med én eller to hydroxylgrupper, hydroxyhaloCi-4-alkoxyCi_4-alkyl, R13, Ci-4-alkyl substitueret med R13, Ci-4-alkyl substitueret med -C(=0)-R13, Ci-4-alkoxy substitueret med R13, Ci-4-alkoxy substitueret med -C(=0)-R13, -C(=0)-R13, Ci-4-alkyl substitueret med -NR7R8, Ci-4-alkyl substitueret med -C(=0)-NR7R8, Ci-4-alkoxy substitueret med -NR7R8, Ci-4-alkoxy substitueret med -C(=0)-NR7R8, -NR7R8 og -C(=0)-NR7R8; eller når to R2 grupper er bundet til tilstødende carbonatomer, kan de tages sammen for at danne et radikal med formlen: -0-(C(R17)2)p-0-; -X-CH=CH-; eller -X-CH=N-; hvor R17 repræsenterer hydrogen eller fluor, p repræsenterer 1 eller 2 og X repræsenterer O eller S; Y repræsenterer -E-D; D repræsenterer en 3 til 12-ringleddet monocyklisk eller bicyklisk carbocyclyl eller en 3 til 12 ring leddet monocyklisk eller bicyklisk heterocyclyl, der indeholder mindst ét heteroatom udvalgt fra N, O eller S, hvor carbocyclyl og heterocyclyl hver eventuelt kan være substitueret med én eller flere (f.eks. 1, 2 eller 3) R1 -grupper; E repræsenterer en binding; R1 repræsenterer hydrogen, halo, cyano, Ci-6-alkyl, Ci-6-alkoxy, -C(=0)-0-Ci-6-alkyl, C2-4-alkenyl, hydroxyCi-6-alkyl, haloCi-6-alkyl, hydroxyhaloCi-6-alkyl, cyanoCi-4-alkyl, Ci-6-alkoxyCi-6-alkyl, hvor hver Ci-6-alkyl eventuelt kan være substitueret med én eller to hydroxylgrupper, -NR4R5, Ci-6-alkyl substitueret med -0-C(=0)-Ci-6-alkyl, Ci-6-alkyl substitueret med -NR4R5, -C(=0)-NR4R5, -C(=0)-Ci-6-alkyl-NR4R5, Ci-6-alkyl substitueret med -C(=0)-NR4R5, -S(=0)2-C 1-6-alkyl, -S(=0)2-haloCi-6-alkyl, -S(=0)2-NR14R15, Ci-e-alkyl substitueret med -S(=0)2-Ci-6-alkyl, Ci-6-alkyl substitueret med -S(=0)2-haloCi-6-alkyl, Ci-6-alkyl substitueret med -S(=0)2-NR14R15, Ci-6-alkyl substitueret med -NH-S(=0)2-Ci-6-alkyl, Ci-6-alkyl substitueret med -NH-S(=0)2-haloCi-6-alkyl, Ci-6-alkyl substitueret med -NR12-S(=0)2-NR14R15, R6, Ci-6-alkyl substitueret med R6, -C(=0)-R6, Ci-6-alkyl substitueret med -C(=0)-R6, hydroxyCi-6-alkyl substitueret med R6, Ci-6-alkyl substitueret med -Si(CH3)3, Ci-6-alkyl substitueret med -P(=0)(0H)2 eller Ci-6-alkyl substitueret med -P(=0)(0Ci-6-alkyl)2; R3a repræsenterer -NR10Rn, hydroxyl, Ci-6-alkoxy, hydroxyCi-6-alkoxy, Ci-6-alkoxy substitueret med -NR10Rn, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, haloCi-6-alkyl eventuelt substitueret med -0-C(=0)-Ci-6-alkyl, hydroxyCi-6-alkyl eventuelt substitueret med -0-C(=0)-Ci-6-alkyl, hydroxyC2-6-alkenyl, hydroxyC2-6-alkynyl, hydroxyhaloCi-6-alkyl, cyanoCi-6-alkyl, Ci-6-alkyl substitueret med carboxyl, Ci-6-alkyl substitueret med -C(=0)-Ci-6-alkyl, Ci-6-alkyl substitueret med -C(=0)-0-Ci-6-alkyl, Ci-6-alkyl substitueret med Ci-6-alkoxyCi-6-alkyl-0-C(=0)-, Ci-6-alkyl substitueret med Ci-6-alkoxyCi-6-alkyl-C(=0)-, Ci-6-alkyl substitueret med -0-C(=0)-Ci-6-alkyl, Ci-6-alkoxyCi-6-alkyl, hvor hver Ci-6-alkyl eventuelt kan være substitueret med én eller to hydroxylgrupper eller med -0-C(=0)-Ci-6-alkyl, C2-6-alkenyl substitueret med Ci-6-alkoxy, C2-6-alkynyl substitueret med Ci-6-alkoxy, Ci-6-alkyl substitueret med R9 og eventuelt substitueret med -0-C(=0)-Ci-6-alkyl, Ci-6-alkyl substitueret med -C(=0)-R9, Ci-6-alkyl substitueret med hydroxyl og R9, C2-6-alkenyl substitueret med R9, C2-6-alkynyl substitueret med R9, Ci-6-alkyl substitueret med -NR10Rn, C2-6-alkenyl substitueret med -NR10RU, C2_6-alkynyl substitueret med -NR10Rn, Ci-6-alkyl substitueret med hydroxyl og -NR10Rn, Ci-6-alkyl substitueret med ét eller to halogener og -NR10Rn, -Ci-6-alkyl-C(R12)=N-0-R12, Ci-6-alkyl substitueret med -C(=O)-NR10Rn, Ci-6-alkyl substitueret med -O-C(=O)-NR10Rn, -S(=0)2-Ci-6-alkyl, -S(=0)2-haloCi-6-alkyl, -S(=0)2-NR14R15, Ci-6-alkyl substitueret med -S(=0)2-Ci-6-alkyl, Ci-6-alkyl substitueret med -S(=0)2-haloCi-6-alkyl, Ci-6-alkyl substitueret med -S(=0)2-NR14R15, Ci-6-alkyl substitueret med -NR12-S(=0)2-Ci-6-alkyl, Ci-6-alkyl substitueret med -NH-S(=0)2-haloCi-6-alkyl, Ci-6-alkyl substitueret med -NR12-S(=0)2-NR14R15, R13, Ci-6-alkyl substitueret med -P(=0)(0H)2 eller Ci-6-alkyl substitueret med -P(=0)(0Ci-6-alkyl)2; R3b repræsenterer hydrogen eller hydroxyl; forudsat, hvis R3a repræsenterer -NR10Rn, at R3b så repræsenterer hydrogen; eller R3a og R3b tages sammen for at danne =0, for at danne =NR10, for at danne cyclopropyl sammen med det carbonatom, hvortil de er bundet, for at danne =CH-Co-4-alkyl substitueret med R3c, eller for at danne
hvor ring A er en monocyklisk 5- til 7-leddet, mættet, heterocyklus, der indeholder ét heteroatom udvalgt ffa N, O eller S, hvilket heteroatom ikke er placeret i alfapositionen af dobbeltbindingen, hvor ring A eventuelt er substitueret med cyano, Ci-4-alkyl, hydroxyCi-4-alkyl, H2N-Ci-4-alkyl, (Ci-4-alkyl)NH-Ci-4-alkyl, (Ci-4-alkyl)2N-Ci-4-alkyl, (haloCi-4-alkyl)NH-Ci-4-alkyl, C i-4-alkoxyC i-4-alkyl, -C(=0)-NH2, -C(=0)-NH(Ci.4-alkyl), -C(=0)-N(Ci-4-alkyl)2; R3c repræsenterer hydrogen, hydroxyl, Ci-6-alkoxy, R9, -NR10RU, cyano, -C(=0)-Ci-6-alkyl eller -CH(OH)-Ci-6-alkyl; R3 repræsenterer hydroxyl, Ci-6-alkoxy, hydroxyCi-6-alkoxy, Ci-6-alkoxy substitueret med -NR10Rn, Ci-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, haloCi-6-alkyl eventuelt substitueret med -0-C(=0)-Ci-6-alkyl, hydroxyCi-6-alkyl eventuelt substitueret med -0-C(=0)-Ci-6-alkyl, hydroxyC2-6-alkenyl, hydroxyC2-6-alkynyl, hydroxyhaloCi-6-alkyl, cyanoCi-6-alkyl, Ci-6-alkyl substitueret med carboxyl, Ci-6-alkyl substitueret med -C(=0)-Ci-6-alkyl, Ci-6-alkyl substitueret med -C(=0)-0-Ci-6-alkyl, Ci-6-alkyl substitueret med Ci-6-alkoxyCi-6-alkyl-0-C(=0)-, Ci-6-alkyl substitueret med Ci-6-alkoxyCi-6-alkyl-C(=0)-, Ci-6-alkyl substitueret med -0-C(=0)-Ci-6-alkyl, Ci_6-alkoxyCi-6-alkyl, hvor hver Ci-6-alkyl eventuelt kan være substitueret med én eller to hydroxylgrupper eller med -0-C(=0)-Ci-6-alkyl, C2-6-alkenyl substitueret med Ci-6-alkoxy, C2-6-alkynyl substitueret med Ci-6-alkoxy, Ci-6-alkyl substitueret med R9 og eventuelt substitueret med -0-C(=0)-Ci-6-alkyl, Ci-6-alkyl substitueret med -C(=0)-R9, Ci-6-alkyl substitueret med hydroxyl og R9, C2_6-alkenyl substitueret med R9, C2-6-alkynyl substitueret med R9, Ci-6-alkyl substitueret med -NR10Rn, C2_6-alkenyl substitueret med -NR10Rn, C2-6-alkynyl substitueret med -NR10Rn, Ci-6-alkyl substitueret med hydroxyl og -NR10Rn, Ci-6-alkyl substitueret med ét eller to halogener og -NR10Rn, -Ci-6-alkyl-C(R12)=N-0-R12, Ci-6-alkyl substitueret med -C(=O)-NR10Rn, Ci-6-alkyl substitueret med -O-C(=O)-NR10Rn, -S(=0)2-Ci-6-alkyl, -S(=0)2-haloCi-6-alkyl, -S(=0)2-NR14R15, Ci-6-alkyl substitueret med -S(=0)2-Ci-6-alkyl, Ci-6-alkyl substitueret med -S(=0)2-haloCi-6-alkyl, Ci-6-alkyl substitueret med -S(=0)2-NR14R15, Ci-6-alkyl substitueret med -NR12-S(=0)2-Ci-6-alkyl, Ci-6-alkyl substitueret med -NH-S(=0)2-haloCi-6-alkyl, Ci-6-alkyl substitueret med -NR12-S(=0)2-NR14R15, R13, Ci-6-alkyl substitueret med -P(=0)(0H)2 eller Ci-6-alkyl substitueret med -P(=0)(0Ci-6-alkyl)2; R4 og R5 hver uafhængigt repræsenterer hydrogen, Ci-6-alkyl, Ci-6-alkyl substitueret med -NR14R15, hydroxyCi-6-alkyl, haloCi-6-alkyl, hydroxyhaloCi-6-alkyl, C i -6-alkoxyC i-6-alkyl, hvor hver Ci-6-alkyl eventuelt kan være substitueret med én eller to hydroxylgrupper, -S(=0)2-Ci-6-alkyl, -S(=0)2-haloCi-6-alkyl, -S(=0)2-NR14R15, -C(=0)-NR14R15, -C(=0)-0-Ci-6-alkyl, -C(=0)-R13, Ci-6-alkyl substitueret med -S(=0)2-Ci-6-alkyl, Ci-6-alkyl substitueret med -S(=0)2-haloCi-6-alkyl, Ci-6-alkyl substitueret med -S(=0)2-NR14R15, Ci-6-alkyl substitueret med -NH-S(=0)2-Ci-6-alkyl, Ci-6-alkyl substitueret med -NH-S(=0)2-haloCi-6-alkyl, Ci-6-alkyl substitueret med -NH-S(=0)2-NR14R15, R13 eller Ci-6-alkyl substitueret med R13; R6 repræsenterer C3-8-cycloalkyl, C3-8-cycloalkenyl, phenyl, 4- til 7-leddet monocyklisk heterocyclyl, der indeholder mindst ét heteroatom udvalgt fra N, O eller S; hvor C3-8-cycloalkyl, C3-8-cycloalkenyl, phenyl, 4- til 7-leddet monocyklisk heterocyclyl, eventuelt og hver uafhængigt er substitueret med 1,2,3,4 eller 5 substituenter, hvor hver substituent uafhængigt er udvalgt fra cyano, Ci-6-alkyl, cyanoCi-6-alkyl, hydroxyl, carboxyl, hydroxyC i-6-alkyl, halogen, haloCi-6-alkyl, hydroxyhaloCi-6-alkyl, Ci-6-alkoxy, Ci-6-alkoxyCi-6-alkyl, Ci-6-alkyl-0-C(=0)-, -NR14R15, -C(=0)-NR14R15, Ci-6-alkyl substitueret med -NR14R15, Ci-6-alkyl substitueret med -C(=0)-NR14R15, -S(=0)2-Ci-6-alkyl, -S(=0)2-haloCi-6-alkyl, -S(=0)2-NR14R15, Ci-e-alkyl substitueret med -S(=0)2-Ci-6-alkyl, Ci-6-alkyl substitueret med -S(=0)2-haloCi-6-alkyl, Ci-6-alkyl substitueret med -S(=0)2-NR14R15, Ci-6-alkyl substitueret med -NH-S(=0)2-Ci-6-alkyl, Ci-6-alkyl substitueret med -NH-S(=0)2-haloCi-6-alkyl eller Ci-6-alkyl substitueret med -NH-S(=0)2-NR14R15; R7 og R8 hver uafhængigt repræsenterer hydrogen, Ci-6-alkyl, hydroxyCi-6-alkyl, haloCi-6-alkyl, hydroxyhaloCi-6-alkyl eller Ci-6-alkoxyCi-6-alkyl; R9 repræsenterer C3-8-cycloalkyl, C3-8-cycloalkenyl, phenyl, naphthyl, eller 3 til 12-leddet monocyklisk eller bicyklisk heterocyclyl, der indeholder mindst ét heteroatom udvalgt fra N, O eller S, hvor C3-8-cycloalkyl, C3-8-cycloalkenyl, phenyl, naphthyl, eller 3 til 12-leddet monocyklisk eller bicyklisk heterocyclyl hver eventuelt og hver uafhængigt er substitueret med 1, 2, 3, 4 eller 5 substituenter, hvor hver substituent uafhængigt er udvalgt fra =0, Ci-4-alkyl, hydroxyl, carboxyl, hydroxyCι-4-alkyl, cyano, cyanoCi-4-alkyl, Ci-4-alkyl-0-C(=0)-, Ci-4-alkyl substitueret med Ci-4-alkyl-0-C(=0)-, Ci-4-alkyl-C(=0)-, C i -4-alkoxyCi-4-alkyl, hvor hver Ci-4-alkyl eventuelt kan være substitueret med én eller to hydroxylgrupper, halogen, haloCi-4-alkyl, hydroxyhaloCi-4-alkyl, -NR14R15, -C(=0)-NR14R15, Ci-4-alkyl substitueret med -NR14R15, Ci-4-alkyl substitueret med -C(=0)-NR14R15, Ci-4-alkoxy, -S(=0)2-Ci-4-alkyl, -S(=0)2-haloCi-4-alkyl, -S(=0)2-NR14R15, Ci-4-alkyl substitueret med -S(=0)2-NR14R15, Ci-4-alkyl substitueret med -NH-S(=0)2-Ci-4-alkyl, Ci-4-alkyl substitueret med -NH-S(=0)2-haloCi-4-alkyl, Ci-4-alkyl substitueret med -NH-S(=0)2-NR14R15, R13, -C(=0)-R13, Ci-4-alkyl substitueret med R13, phenyl eventuelt substitueret med R16, phenylCi-6-alkyl, hvor phenyl eventuelt substitueret med R16, en 5- eller 6-leddet aromatisk monocyklisk heterocyclyl, der indeholder mindst ét heteroatom udvalgt fra N, O eller S, hvor heterocyclyl eventuelt er substitueret med R16; eller når to af substituenteme af R9 er bundet til det samme atom, kan de tages sammen for at danne en 4- til 7-leddet, mættet monocyklisk heterocyclyl, der indeholder mindst ét heteroatom udvalgt fra N, O eller S; R10 og R11 hver uafhængigt repræsenterer hydrogen, carboxyl, Ci-6-alkyl, cyanoCi-6-alkyl, Ci-6-alkyl substitueret med -NR14R15, Ci-6-alkyl substitueret med -C(=0)-NR14R15, haloCi-6-alkyl, hydroxyCi-6-alkyl, hydroxyhaloCi-6-alkyl, Ci-6-alkoxy, Ci-6-alkoxyCi-6-alkyl, hvor hver Ci-6-alkyl eventuelt kan være substitueret med én eller to hydroxylgrupper, R6, Ci-6-alkyl substitueret med R6, -C(=0)-R6, -C(=0)-Ci-6-alkyl, -C(=0)-hydroxyCi-6-alkyl, -C(=0)-haloCi-6-alkyl,-C(=0)-hydroxyhaloCi-6-alkyl, Ci-6-alkyl substitueret med -Si(CH3)3, -S(=0)2-Ci-6-alkyl, -S(=0)2-haloCi-6-alkyl, -S(=0)2-NR14R15, Ci-6-alkyl substitueret med -S(=0)2-Ci-6-alkyl, Ci-6-alkyl substitueret med -S(=0)2-haloCi-6-alkyl, Ci-6-alkyl substitueret med -S(=0)2-NR14R15, Ci-6-alkyl substitueret med -NH-S(=0)2-Ci-6-alkyl, Ci-6-alkyl substitueret med -NH-S(=0)2-haloCi-6-alkyl, Ci-6-alkyl substitueret med carboxyl, eller Ci-6-alkyl substitueret med -NH-S(=0)2-NR14R15; R12 repræsenterer hydrogen eller Ci-4-alkyl eventuelt substitueret med Ci-4-alkoxy; R13 repræsenterer C3-8-cycloalkyl eller en mættet 4- til 6-leddet, monocyklisk heterocyclyl, der indeholder mindst ét heteroatom udvalgt fra N, O eller S, hvor C3-8-cycloalkyl eller monocyklisk heterocyclyl eventuelt er substitueret med 1, 2 eller 3 substituenter hver uafhængigt udvalgt fra halogen, hydroxyl, Ci-6-alkyl, haloCi-6-alkyl, =0, cyano, -C(=0)-Ci-6-alkyl, Ci-6-alkoxy, eller -NR14R15; R14 og R15 hver uafhængigt repræsenterer hydrogen, eller haloCi-4-alkyl, eller Ci-4-alkyl eventuelt substitueret med en substituent udvalgt fra hydroxyl, Ci-4-alkoxy, amino eller monoeller di(Ci-4-alkyl)amino; R16 repræsenterer hydroxyl, halogen, cyano, Ci-4-alkyl, Ci-4-alkoxy, -NR14R15 eller -C(=0)NR14R15; n uafhængigt repræsenterer et heltal svarende til O, 1, 2, 3 eller 4; et 7V-oxid deraf, et farmaceutisk acceptabelt salt deraf eller et solvat deraf.
2. Forbindelse ifølge krav 1, hvor D er (i) eventuelt substitueret pyrazolyl eller (ii) piperidinyl, pyridinyl, phenyl, pyrolyl, imidazolyl, triazolyl, pyrolopyridinyl, 1,3-benzodioxolyl, indolyl, thiazolyl, cyclopentyl, azetidinyl, morpholinyl, tetrazolyl, oxazolyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrolyl, pyrimidinyl, pyrolidinyl, hvor ringene eventuelt er substitueret.
3. Forbindelse ifølge et hvilket som helst af de foregående krav, hvor W er -N(R3)-.
4. Forbindelse ifølge et hvilket som helst af kravene 1 eller 2, hvor W er -C(R3aR3b)-.
5. Forbindelse ifølge et hvilket som helst af de foregående krav, hvor R1 repræsenterer Ci-6-alkyl.
6. Forbindelse ifølge et hvilket som helst af de foregående krav, hvor R2: (i) er uafhængigt udvalgt fra hydroxyl, halogen, cyano, Ci-4-alkyl, C2-4-alkenyl, Ci-4-alkoxy, hydroxyCi-4-alkyl, hydroxyCi-4-alkoxy, haloCi-4-alkoxy, Ci-4-alkoxyCi-4-alkyl, R13, Ci-4-alkoxy substitueret med R13, -C(=0)-R13, Ci-4-alkyl substitueret med NR7R8, Ci-4-alkoxy substitueret med NR7R8, -NR7R8 eller -C(=0)-NR7R8; eller (ii) repræsenterer Ci-4-alkoxy eller (iii) repræsenterer Ci-4-alkoxy eller halogen.
7. Forbindelse ifølge et hvilket som helst af kravene 1 til 3, 5 til 6, hvor R3 repræsenterer (i) Ci-6-alkyl, hydroxyCi-6-alkyl, hydroxyhaloCi-6-alkyl, haloCi-6-alkyl, Ci-6-alkyl substitueret med -C(=0)-Ci-6-alkyl, Ci_6-alkoxyCi-6-alkyl, hvor hver Ci-6-alkyl eventuelt kan være substitueret med én eller to hydroxylgrupper, Ci-6-alkyl substitueret med R9, Ci-6-alkyl substitueret med -NR10Rn, C i -6-alkyl substitueret med hydroxyl og -NR10Rn, Ci-6-alkyl substitueret med ét eller to halogener og -NR10Rn, Ci-6-alkyl substitueret med -C(=0)-0-Ci-6-alkyl, Ci-6-alkyl substitueret med -O-C(=O)-NR10Rn, Ci-6-alkyl substitueret med carboxyl, Ci-6-alkyl substitueret med -NR12-S(=0)2-Ci-6-alkyl, Ci-6-alkyl substitueret med -NR12-S(=0)2-NR14R15, Ci-6-alkyl substitueret med hydroxyl og R9, -Ci-6-alkyl-C(R12)=N-0-R12, Ci-e-alkyl substitueret med -C(=O)-NR10Rn, Ci-e-alkyl substitueret med -C(=0)-R9, C2-6-alkynyl substitueret med R9, hydroxyCi-6-alkoxy, C2-6-alkenyl, C2-6-alkynyl eller R13; eller (ii) hydroxyCi-6-alkyl, hydroxyhaloCi-6-alkyl, Ci-6-alkyl substitueret med R9, Ci-6-alkyl substitueret med -NR10Rn, C2-6-alkynyl substitueret med R9, eller C2-6-alkynyl.
8. Forbindelse ifølge et hvilket som helst af kravene 1, 2, 4 til 6, hvor R3a repræsenterer hydroxyl, Ci-6-alkyl substitueret med -C(=O)-NR10Ru, cyanoCi-6-alkyl, hydroxyCi-6-alkyl, Ci-6-alkyl substitueret med -C(=0)-0-Ci-6-alkyl.
9. Forbindelse ifølge et hvilket som helst af kravene 1, 2, 4 til 6 og 8, hvor R3b repræsenterer hydrogen.
10. Forbindelse ifølge krav 1, hvor: (i) n repræsenterer et heltal svarende til 2,3 eller 4; R2 repræsenterer Ci-4-alkoxy eller halo, for eksempel CH3O- eller fluor; R3 repræsenterer hydroxyCi-6-alkyl, hydroxyhaloCi-6-alkyl, Ci-6-alkyl substitueret med R9, Ci-6-alkyl substitueret med -NR10Rn, C2-6-alkynyl substitueret med R9, eller C2-6-alkynyl; D repræsenterer pyrazolyl, navnlig pyrazol-4-yl, eventuelt substitueret med Ci-6-alkyl, hydroxyCi-6-alkyl eller R6; W er -N(R3)- eller -C(R3aR3b)-, hvor R3a er hydroxyl, R3b er hydrogen; eller (ii) n repræsenterer et heltal svarende til 2, 3 eller 4; R2 repræsenterer Ci-4-alkoxy eller halogen, for eksempel CH3O- eller fluor eller chlor; R3 repræsenterer hydroxyCi-6-alkyl, hydroxyhaloCi-6-alkyl, Ci-6-alkyl substitueret med R9, Ci-6-alkyl substitueret med -NR10Rn, C2-6-alkynyl substitueret med R9 eller C2-6-alkynyl; R3a repræsenterer hydroxyl, Ci-6-alkyl substitueret med -C(=O)-NR10Rn, cyanoCi-6-alkyl, hydroxyCi-6-alkyl, Ci-6-alkyl substitueret med -C(=0)-0-Ci-6-alkyl; R3b repræsenterer hydrogen; eller R3a og R3b tages sammen for at danne =0 eller for at danne =CH-Co-4-alkyl substitueret med R3c; D repræsenterer en eventuelt substitueret 5-leddet heterocyklus, en eventuelt substitueret 6-leddet heterocyklus eller phenyl, navnlig en eventuelt substitueret aromatisk 5-leddet heterocyklus, en eventuelt substitueret mættet, delvis mættet eller aromatisk 6-leddet heterocyklus eller phenyl, navnlig pyrazol-4-yl, eventuelt substitueret med Ci-6-alkyl. hydroxyCi-6-alkyl, Ci-6-alkyl substitueret med -S(=0)2-Ci-6-alkyl eller R6, eller phenyl, eller pyridyl eller morpholinyl eller 1, 2, 3, 6-tetrahydropyridyl eller pyrrolyl eventuelt substitueret med Ci-6-alkyl.
11. Forbindelse ifølge et hvilket som helst af kravene 1 til 10 eller et farmaceutisk acceptabelt salt eller solvat deraf.
12. Farmaceutisk sammensætning, der omfatter en forbindelse med formlen (I) ifølge et hvilket som helst af kravene 1 til 11.
13. Forbindelse ifølge et hvilket som helst af kravene 1 til 11 til (i) anvendelse i terapi; eller (ii) anvendelse i profylakse eller behandling af en sygdomstilstand eller tilstand medieret af en FGFR-kinase; eller (iii) anvendelse i profylakse eller behandling af cancer; eller (iv) anvendelse i behandling af cancer, hvor canceren er udvalgt fra prostatacancer, blærecancer, lungecancer, såsom NSCLC, brystcancer, gastrisk cancer og levercancer; eller (v) anvendelse i behandling af cancer, hvor canceren er udvalgt fra multipelt myelom, myeloproliferative forstyrrelser, endometriecancer, prostatacancer, blærecancer, lungecancer, ovariecancer, brystcancer, gastrisk cancer, colorektalcancer og oralt pladeepitelkarcinom; eller (vi) anvendelse i behandling af cancer, hvor canceren er udvalgt ffa lungecancer, navnlig NSCLC, pladeepitelkarcinom, levercancer, nyrecancer, brystcancer, coloncancer, colorektalcancer, prostatacancer; eller (vii) anvendelse i behandling af cancer, hvor canceren er multipelt myelom; eller (viii) anvendelse i behandling af cancer, hvor canceren er t(4; 14) translokations-positivt multipelt myelom; eller (ix) anvendelse i behandling af cancer, hvor canceren er blærecancer; eller (x) anvendelse i behandling af cancer, hvor canceren er blærecancer med en kromosomal FGFR3-translokation; eller (xi) anvendelse i behandling af cancer, hvor canceren er blærecancer med en FGFR3 punktmutation; eller (xii) anvendelse i behandling af cancer, hvor canceren er en tumor med en mutant af FGFR1, FGFR2, FGFR3 eller FGFR4; eller (xiii) anvendelse i behandling af cancer, hvor canceren er en tumor med en mutant af FGFR2 eller FGFR3 med forstærket funktion; eller (xiv) anvendelse i behandling af cancer, hvor canceren er en tumor med overekspression af FGFR1.
14. Forbindelse ifølge et hvilket som helst af kravene 1 til 11 til anvendelse i behandling af cancer, hvor forbindelsen anvendes i kombination med ét eller flere anticancermidler.
15. Produkt, der som den første aktive ingrediens indeholder en forbindelse ifølge et hvilket som helst af kravene 1 til 11 og som yderlige aktiv ingrediens ét eller flere anticancermidler, som et kombineret præparat til simultan, separat eller sekventiel anvendelse i behandling af cancerpatienter.
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