DK1966214T3 - Triazolpyridaziner som tyrosinkinasemodulatorer - Google Patents

Triazolpyridaziner som tyrosinkinasemodulatorer Download PDF

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DK1966214T3
DK1966214T3 DK06847749.6T DK06847749T DK1966214T3 DK 1966214 T3 DK1966214 T3 DK 1966214T3 DK 06847749 T DK06847749 T DK 06847749T DK 1966214 T3 DK1966214 T3 DK 1966214T3
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alkyl
heteroaryl
compound
mmol
met
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Tianbao Lu
Richard Alexander
Richard W Connors
Maxwell D Cummings
Robert A Galemmo
Dana L Johnson
Ehab Khalil
Kristi A Leonard
Thomas P Markotan
Anna C Maroney
Robert W Tuman
Heather Rae Hufnagel
Jeremy M Travins
Jan L Sechler
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Janssen Pharmaceutica Nv
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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Claims (33)

1. Forbindelse med formel I:
Formel I og N-oxider, farmaceutisk acceptable salte, solvater og stereokemiske isomerer deraf, hvor: R1 er mono- eller bicyklisk heteroaryl eller pyridin-2-onyl, hvor heteroarylen eventuelt er substitueret med en, to eller tre Ra-substituenter; hvor Ra er -NH2, halogen, alkoxy, alkylether, alkylthio, alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, heterocyclylsulfonyl, -SO2NH2, alkylsulfonamid, alkyl, aminoalkyl, alkylamino, phenyl, heteroaryl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, -C02-alkyl, -C (0) -Rb, —C< 1-4) alkyl-morpholinyl, -C < 1-4 > alkylpiperidinyl, —C < 1- 4) alkylpiperazinyl, -C < 1-4) alkyl-N ' -methylpiperazinyl, —C<i- 4>alkyl-Rb, -C (0) NH-C < 1-4) alkyl-Rb eller -C(0)NRcRd; hvor Rb er heterocyclyl, alkylsulfonyl, -SO2NH2, alkylsulfonamid, -OH, -0-alkyl, -NH2, -NH-alkyl eller N(alkyl)2; Rc og Rd er udvalgt uafhængigt blandt: H, phenyl, heteroaryl eller Ci-6alkyl, hvor Ci-6alkyl eventuelt kan være substitueret med én substituent udvalgt blandt: -N(CH3)2, morpholinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, alkylsulfonyl, -SO2NH2, alkylsulfonamid, hydroxyl og alkoxy; eller Rc og Rd sammen kan danne en 5 til 7-leddet heterocyklisk ring, der eventuelt indeholder en anden heterodel udvalgt blandt 0, NH, N (alkyl), SO, S02, eller S; hvor den heterocykliske Rc-Rd-ring eventuelt er substitueret med alkyl, -S02alkyl, eller -C(0)alkyl; A er en ring udvalgt fra gruppen, der består af: phenyl, monoeller bicyklisk heteroaryl, 3-(4-methoxybenzyl)-3H-quinazolin-4-on-6-yl, quinazolin-4-on-6-yl, og benzofusioneret heterocyclyl; hvor phenyl, heteroaryl eller benzofusioneret heterocyclyl eventuelt er substitueret med en til tre substituenter, der er udvalgt uafhængigt fra gruppen, der består af: -OH, alkyl, phenyl, heteroaryl, alkoxy, -CN, halogen, nitro, -NH2, -N(CH3)2, -NHC (0) NHCi-ealkyl og -NHC(0)Ci- 6alkyl; R5 og R6 er F; og R7 og R° er H, halogen eller Ci-6alkyl.
2. Forbindelse ifølge krav 1, hvor R1 er mono- eller bicyklisk heteroaryl eller pyridin-2-on-5-yl, hvor heteroarylen eventuelt er substitueret med en, to eller tre Ra-substituenter; R7 og R8 er H.
3. Forbindelse ifølge krav 2, hvor Rc og Rd er udvalgt uafhængigt blandt: H, phenyl, heteroaryl eller Ci-6alkyl, hvor Ci-6alkyl eventuelt kan være substitueret med én substituent udvalgt blandt: -N(CH3)2, morpholinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, alkylsulfonyl, -SO2NH2, alkylsulf onamid, hydroxyl og alkoxy; eller Rc og Rd sammen kan danne en 5 til 7-leddet heterocyklisk ring udvalgt fra gruppen, der består af: piperidinyl, morpholinyl og piperazinyl, hvor piperazinyl eventuelt er substitueret med alkyl, -SCPalkyl eller -C(0)alkyl.
4. Forbindelse ifølge krav 3, hvor A er en ring udvalgt fra gruppen, der består af: phenyl, monoeller bicyklisk heteroaryl, 3-(4-methoxybenzyl)-3H-quinazolin-4-on-6-yl, quinazolin-4-on-6-yl og benzofusioneret heterocyclyl; hvor phenyl, heteroaryl eller benzofusioneret heterocyclyl eventuelt er substitueret med én substituent, der er udvalgt uafhængigt fra gruppen, der består af: -OH, alkyl, phenyl, heteroaryl, alkoxy, -CN, halogen, nitro, -NH2, N(CH3)2, -NHC (0) NHCi-ealkyl og -NHC (0) Ci-6alkyl.
5. Forbindelse ifølge krav 4, hvor A er en ring udvalgt fra gruppen, der består af: 2,3-dihydrobenzofuran-5-yl, quinolin-6-yl, quinolin-6-yl-N-oxid, 2-aminobenzothiazol-6-yl, 4-methoxyphenyl, 3-(4- methoxybenzyl)-3H-quinazolin-4-on-6-yl, quinazolin-4-on-6-yl og 4-hydroxyphenyl.
6. Forbindelse ifølge krav 5, hvor i R1 er mono- eller bicyklisk heteroaryl eller pyridin-2-on-5-yl, hvor heteroarylen eventuelt er substitueret med én Ra-substituent.
7. Forbindelse ifølge krav 6, hvor i R1 er thiophen-2-yl, thiazol-2-yl, pyrazolyl, imidazolyl, pyridin-2-on-5-yl eller pyridyl, hvor thiophen-2-yl, thiazol-2-yl, pyrazolyl, imidazolyl og pyridyl eventuelt kan være substitueret med én Ra-substituent.
8. Forbindelse ifølge krav 1, hvor R1 er mono- eller bicyklisk heteroaryl, hvor heteroarylen eventuelt er substitueret med en, to eller tre Ra- substituenter; hvor Ra er halogen, alkoxy, alkylether, alkylthio, alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, heterocyclylsulfonyl, -SO2NH2, alkylsulfonamid, alkyl, aminoalkyl, alkylamino, phenyl, heteroaryl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, -CCq-alkyl, -C (0) -Rb, —C< 1-4) alkyl-morpholinyl, -C < 1-4> alkylpiperidinyl, —C (1- ) 4) alkylpiperazinyl, -C <i-4) alkyl-N '-methylpiperazinyl, -C<i- 4>alkyl-Rb, -C (0) NH-C <i-4> alkyl-Rb eller -C(0)NRcRci; hvor Rb er heterocyclyl, alkylsulfonyl, -SO2NH2, alkylsulfonamid, -OH, -0-alkyl, -NH2, -NH-alkyl eller N(alkyl)2; Rc og Rd er udvalgt uafhængigt blandt: H, phenyl, heteroaryl eller Ci-6alkyl, hvor Ci-6alkyl eventuelt kan være substitueret med én substituent udvalgt blandt: -N(CH3)2, morpholinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, alkylsulfonyl, -SO2NH2, alkylsulfonamid, hydroxyl og alkoxy; 1 eller Rc og Rd sammen kan danne en 5 til 7-leddet heterocyklisk ring, der eventuelt indeholder en anden heterodel udvalgt blandt 0, NH, N (alkyl), SO, SO2 eller S, hvor den heterocykliske Rn-Rd-ring eventuelt er substitueret med alkyl, -SC>2alkyl eller -C (0)alkyl; A er en ring udvalgt fra gruppen, der består af: phenyl, monoeller bicyklisk heteroaryl og benzofusioneret heterocyclyl; hvor phenyl, heteroaryl eller benzofusioneret heterocyclyl i eventuelt er substitueret med en, to eller tre substituenter, der er udvalgt uafhængigt fra gruppen, der består af: -OH, alkyl, phenyl, heteroaryl, alkoxy, -CN, halogen, nitro, -NH2, -NHC (0) NHCi-salkyl og -NHC (0) Ci-ealkyl; og R7 og R8 er H, halogen eller Ci-6alkyl.
9. Forbindelse ifølge krav 1, hvor R1 er thiophen-2-yl, thiazol-2-yl, pyrazolyl, imidazolyl, pyridin-2-on-5-yl eller pyridyl, hvor thiophen-2-yl, thiazol-2-yl, pyrazolyl, imidazolyl og pyridyl eventuelt kan være 1 substitueret med én Ra-substituent; hvor Ra er -NH2, halogen, alkoxy, alkylether, alkylthio, alkylsulfonyl, phenylsulfonyl, heteroarylsulfonyl, heterocyclylsulfonyl, -SO2NH2, alkylsulfonamid, alkyl, aminoalkyl, alkylamino, phenyl, heteroaryl, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, -C02-alkyl, -C (0) -Rb, -C(i-4) alkyl-morpholinyl, -C <i-4) alkylpiperidinyl, -C(i- 4) alkylpiperazinyl, -C <i-4) alkyl-N ' -methylpiperazinyl, —C<i- 4>alkyl-Rb, -C (0) NH-C <i-4) alkyl-Rb eller -C(0)NRcRd; hvor Rb er heterocyclyl, alkylsulfonyl, -SO2NH2, 1 alkylsulfonamid, -OH, -0-alkyl, -NH2, -NH-alkyl eller N(alkyl)2; Rc og Rd er udvalgt uafhængigt blandt: H, phenyl, heteroaryl eller Ci-6alkyl, hvor Ci-6alkyl eventuelt kan være substitueret med én substituent udvalgt blandt: -N(CH3)2, morpholinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, alkylsulfonyl, -SO2NH2, alkylsulfonamid, hydroxyl og alkoxy; eller Rc og Rd sammen kan danne en 5 til 7-leddet heterocyklisk ring udvalgt fra gruppen, der består af: piperidinyl, morpholinyl og piperazinyl, hvor piperazinyl eventuelt er 1 substitueret med alkyl, -S02alkyl eller -C(0)alkyl; A er en ring udvalgt fra gruppen, der består af: 2,3-dihydrobenzofuran-5-yl, quinolin-6-yl, quinolin-6-yl-N-oxid, 2-aminobenzothiazol-6-yl, 4-methoxyphenyl, 3-(4- methoxybenzyl)-3H-quinazolin-4-on-6-yl, quinazolin-4-on-6-yl, 2-dimethylaminobenzothiazol-6-yl og 4-hydroxyphenyl; og R7 og R8 er H.
10. Forbindelse ifølge krav 1 udvalgt fra gruppen, der består af:
og N-oxider, farmaceutisk acceptable salte, solvater og stereokemiske isomerer deraf.
11. Forbindelse ifølge krav 1 udvalgt fra gruppen, der består af: F d" N F // N N N N = / \. N og N-oxider, farmaceutisk acceptable salte, solvater og stereokemiske isomerer deraf.
12. Forbindelse ifølge krav 1, som er
og N-oxider, farmaceutisk acceptable salte og solvater deraf.
13. Forbindelse ifølge krav 1, som er
og farmaceutisk acceptable salte deraf.
14. Forbindelse ifølge krav 1, som er
15. Forbindelse ifølge krav 1, som er
og N-oxider, farmaceutisk acceptable salte og solvater deraf.
16. Forbindelse ifølge krav 1, som er
og farmaceutisk acceptable salte deraf.
17. Forbindelse ifølge krav 1, som er
18. Forbindelse ifølge krav 1 udvalgt fra gruppen, der består af:
og N-oxider, farmaceutisk acceptable salte, solvater og stereokemiske isomerer deraf.
19. Farmaceutisk sammensætning, der omfatter en forbindelse ifølge et hvilket som helst af kravene 1-18 og et farmaceutisk acceptabelt bæremateriale.
20. Forbindelse ifølge et hvilket som helst af kravene 1-18 til anvendelse som et medikament.
21. Anvendelse af en forbindelse ifølge et hvilket som helst af kravene 1-18 til fremstilling af et medikament til behandling af en celleproliferativ forstyrrelse.
22. Forbindelse ifølge et hvilket som helst af kravene 1-18 til anvendelse til reducering eller hæmning af kinaseaktiviteten af c-Met hos et individ.
23. Forbindelse ifølge et hvilket som helst af kravene 1-18 til anvendelse til modulering ekspressionen af c-Met hos et individ.
24. Farmaceutisk sammensætning ifølge krav 19 til anvendelse til forebyggelse hos et individ af en forstyrrelse, der er forbundet med c-Met.
25. Farmaceutisk sammensætning ifølge krav 19 til anvendelse til behandling hos et individ af en forstyrrelse, der er forbundet med c-Met.
26. Farmaceutisk sammensætning ifølge krav 19 til anvendelse til modulering hos et individ af en forstyrrelse, der er forbundet med c-Met.
27. Farmaceutisk sammensætning til anvendelse ifølge krav 24 eller 25 eller 26, der yderligere omfatter administration af et hvilket som helst af et kemoterapeutisk middel, genterapi, immunterapi og stråleterapi.
28. Forbindelse ifølge et hvilket som helst af kravene 1-18 til anvendelse til behandling af en forstyrrelse, der er forbundet med c-Met, eller en celleproliferativ forstyrrelse, der omfatter kontrolleret fremføring af forbindelsen ved frigivelse fra en intraluminal medicinsk anordning i en i terapeutisk effektiv mængde.
29. Forbindelse til anvendelse ifølge krav 28, hvor den intraluminale medicinske anordning omfatter en stent.
30. Farmaceutisk sammensætning, der omfatter en effektiv mængde af en forbindelse ifølge et hvilket som helst af kravene 1-18, der er konjugeret til et målretningsmiddel, og et farmaceutisk acceptabelt bæremateriale.
31. Forbindelse ifølge et hvilket som helst af kravene 1-18, der er konjugeret til et målretningsmiddel, til anvendelse til behandling en forstyrrelse, der er forbundet med c-Met.
32. Kombination af et kemoterapeutisk middel og en forbindelse ifølge et hvilket som helst af kravene 1-18.
33. Fremgangsmåde til fremstilling af en forbindelse ifølge krav 1, hvilken fremgangsmåde omfatter a) reaktion af en forbindelse med formel IV:
med en forbindelse med formel V:
hvor X er Cl eller I eller Br, og Y er zinkat, boronsyre, boronatester eller stannan, og variabierne er som defineret i krav 1; eller b) reaktion af en forbindelse med formel III: i
med en forbindelse med formel VI:
hvor variabierne er som defineret i krav 1, og hvor X er Cl eller I eller Br.
DK06847749.6T 2005-12-21 2006-12-18 Triazolpyridaziner som tyrosinkinasemodulatorer DK1966214T3 (da)

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US75263405P 2005-12-21 2005-12-21
PCT/US2006/048241 WO2007075567A1 (en) 2005-12-21 2006-12-18 Triazolopyridazines as tyrosine kinase modulators

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