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US 7,452,906 B2Granted
Pyridine derivatives as Raf kinase inhibitors
AssigneeSmithKline Beecham Corporation
InventorsMark James Bamford, David Kenneth Dean, Antoinette Naylor, Andrew Kenneth Takle, David Matthew Wilson
Life of this patent
Estimating the term…
Abstract
Compounds and their use as pharmaceuticals particularly as Raf kinase inhibitors for the treatment of neurotraumatic diseases, cancer, chronic neurodegeneration, pain, migraine and cardiac hypertrophy.
Claims6
A compound of formula (I):
- wherein:
- X is O, CH2, CO, S or NH, or the moiety X—R1 is hydrogen;
- Y1 and Y2 independently represent CH or N;
- R1 is hydrogen, C1-6alkyl, C3-7cycloalkyl, aryl, arylC1-6alkyl-, heterocyclyl, heterocyclylC1-6alkyl-, heteroaryl, or heteroarylC1-6alkyl-, any of which, except hydrogen, may be optionally substituted;
- R2 is C1-6alkyl, C3-7cycloalkyl, heterocyclyl, heterocyclylC1-6alkyl-, C1-6alkyloxy, C1-6alkylthio, C1-6alkylamino, or C1-6alkylheteroC1-6alkyl- any of which may be optionally substituted;
- Ar is a group of the formula a) or b):
- R3 and R4 are independently selected from hydrogen, halogen, C1-6alkyl, aryl, arylC1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-6alkyl, haloC1-6alkyl, arylC1-6alkoxy, hydroxy, nitro, cyano, azido, amino, mono- and di-N—C1-6alkylamino, acylamino, arylcarbonylamino, acyloxy, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N—C1-6alkylcarbamoyl, C1-6alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, C1-6alkylguanidino, amidino, C1-6alkylamidino, sulphonylamino, aminosulphonyl, C1-6alkylthio, C1-6alkyl sulphinyl or C1-6alkylsulphonyl;
- and
- one of X1 and X2 is selected from O, S or NR11 and the other is CH, wherein R11 is hydrogen, C1-6alkyl, aryl or arylC1-6alkyl;
- or a pharmaceutically acceptable salt thereof.
7 more elements
A compound, wherein the compound is selected from:
- 5-(5-Morpholin-4-ylmethyl-2-pyridin-4-yl-furan-3-yl)-indan-1-one oxime;
- 5-(5-Piperidin-1-ylmethyl-2-pyridin-4-yl-furan-3-yl)-indan-1-one oxime;
- 5-(2-Pyridin-4-yl-5-pyrrolidin-1-ylmethyl-furan-3-yl)-indan-1-one oxime;
- 5-{5-(4-Methyl-piperazin-1-ylmethyl)-2-pyridin-4-yl-furan-3-yl]-indan-1-one oxime;
- 5-[5-(1,1-Dioxo-1-thiomorpholin-4-ylmethyl)-2-pyridin-4-yl-furan-3-yl]-indan-1-one oxime;
- 5-(5-Piperazin-1-ylmethyl-2-pyridin-4-yl-furan-3-yl)-indan-1-one oxime;
- 5-(5-Dimethylaminomethyl-2-pyridin-4-yl-furan-3-yl)-indan-1-one oxime;
- 5-{5-[(2-Methoxyethylamino)-methyl]-2-pyridin-4-yl-furan-3-yl}-indan-1-one oxime;
- 5-(5-{[1-(2-Methoxy-ethyl)-piperidin-4-ylamino]-methyl}-3-pyridin-4-yl-furan-2-yl)-indan-1-one oxime;
- 5-(5-Morpholin-4-ylmethyl-3-pyridin-4-yl-furan-2-yl)-indan-1-one oxime;
- 5-(5-Piperidin-1-ylmethyl-3-pyridin-4-yl-furan-2-yl)-indan-1-one oxime;
- 5-[3-Pyridin-4-yl-5-(4-pyrrolidin-1-yl-piperidin-1-ylmethyl)-furan-2-yl]-indan-1-one oxime;
- 5-{5-[(2-Methoxy-ethylamino)-methyl]-3-pyridin-4-yl-furan-2-yl}-indan-1-one oxime;
- 5-(5-Diethylaminomethyl-3-pyridin-4-yl-furan-2-yl)-indan-1-one oxime;
- 5-[5-(4-Ethyl-piperazin-1-ylmethyl)-3-pyridin-4-yl-furan-2-yl]-indan-1-one oxime;
- 5-{5-[4-(2-Methoxy-ethyl)-piperazin-1-ylmethyl]-3-pyridin-4-yl-furan-2-yl}-indan-1-one oxime;
- 5-{5-[(2-Morpholin-4-yl-ethylamino)-methyl]-3-pyridin-4-yl-furan-2-yl}-indan-1-one oxime;
- 5-(5-{[Methyl-(1-methyl-piperidin-4-yl)-amino]-methyl}-3-pyridin-4-yl-furan-2-yl)-indan-1-one oxime;
- 5-[5-(4-Methyl-piperazin-1-ylmethyl)-3-pyridin-4-yl-furan-2-yl]-indan-1-one oxime;
- 5-(3-Pyridin-4-yl-5-pyrrolidin-1-ylmethyl-furan-2-yl)-indan-1-one oxime;
- 5-(5-Dimethylaminomethyl-3-pyridin-4-yl-furan-2-yl)-indan-1-one oxime;
- 5-{5-[4-(2-Hydroxy-ethyl)-piperazin-1-ylmethyl]-3-pyridin-4-yl-furan-2-yl}-indan-1-one oxime;
- 5-(5-{[(2-Methoxy-ethyl)-methyl-amino]-methyl}-3-pyridin-4-yl-furan-2-yl)-indan-1-one oxime;
- 5-(5-{[Isopropyl-(2-methoxy-ethyl)-amino]-methyl}-3-pyridin-4-yl-furan-2-yl)-indan-1-one oxime;
- 5-[5-(1,1-Dioxo-1-thiomorpholin-4-ylmethyl)-3-pyridin-4-yl-furan-2-yl]-indan-1-one oxime;
- 5-(5-Piperazin-1-ylmethyl-3-pyridin-4-yl-furan-2-yl)-indan-1-one oxime;
- 5-(5-Piperidin-1-ylmethyl-2-pyrimidin-4-yl-furan-3-yl)-indan-1-one oxime;
- 5-[2-(2-Amino-pyrimidin-4-yl)-5-piperidin-1-ylmethyl-furan-3-yl]-indan-1-one oxime;
- 5-[5-(4-Hydroxy-piperidin-4-yl)-2-pyridin-4-yl-furan-3-yl]-indan-1-one oxime;
- 5-[2-Pyridin-4-yl-5-(1,2,3,6-tetrahydro-pyridin-4-yl)-furan-3-yl]-indan-1-one oxime;
- 5-(5-Piperidin-4-yl-2-pyridin-4-yl-furan-3-yl)-indan-1-one oxime;
- 5-{5-[1-(2-Methoxyethyl)-piperidin-4-yl]-2-pyridin-4-yl-furan-3-yl}-indan-1-one oxime;
- 5-(5-{1-[2-(4-Chloro-phenoxy)-ethyl]-piperidin-4-yl}-2-pyridin-4-yl-furan-3-yl)-indan-1-one oxime;
- 5-[5-(1-Cyclopentyl-piperidin-4-yl)-2-pyridin-4-yl-furan-3-yl]-indan-1-one oxime;
- 5-[5-(1-Cyclopropylmethyl-piperidin-4-yl)-2-pyridin-4-yl-furan-3-yl]-indan-1-one oxime;
- 5-{5-[1-(2-Morpholin-4-yl-ethyl)-piperidin-4-yl]-2-pyridin-4-yl-furan-3-yl}-indan-1-one oxime;
- 5-[5-(1-Methanesulfonyl-piperidin-4-yl)-2-pyridin-4-yl-furan-3-yl]-indan-1-one oxime;
- 5-{5-[1-(2-Dimethylamino-ethanoyl)-piperidin-4-yl]-2-pyridin-4-yl-furan-3-yl}-indan-1-one oxime;
- 5-{5-[1-(3-Piperidin-1-yl-propanoyl)-piperidin-4-yl]-2-pyridin-4-yl-furan-3-yl}-indan-1-one oxime;
- 5-(5-Piperidin-4-yl-3-pyridin-4-yl-furan-2-yl)-indan-1-one oxime;
- 5-{5-[1-(2-Methoxyethyl)piperidin-4-yl]-3-pyridin-4-ylfuran-2-yl}indan-1-one oxime;
- 5-[5-(1-Cyclopropylmethylpiperidin-4-yl)-3-pyridin-4-ylfuran-2-yl]indan-1-one oxime;
- 5-[5-(1-Cyclopentylpiperidin-4-yl)-3-pyridin-4-ylfuran-2-yl]indan-1-one oxime;
- 5-(5-{1-[2-(4-Chlorophenoxy)ethyl]-piperidin-4-yl}-3-pyridin-4-ylfuran-2-yl)indan-1-one oxime;
- {4-[5-(1-Hydroxyiminoindan-5-yl)-4-pyridin-4-ylfuran-2-yl]piperidin-1-yl}acetonitrile;
- 5-{5-[1-(2-Hydroxyethyl)piperidin-4-yl]-3-pyridin-4-ylfuran-2-yl}indan-1-one oxime;
- 5-{5-[1-(2-Morpholin-4-ylethanoyl)piperidin-4-yl]-3-pyridin-4-ylfuran-2-yl}indan-1-one oxime;
- 5-{5-[1-(2-Piperidin-1-ylethanoyl)piperidin-4-yl]-3-pyridin-4-ylfuran-2-yl}indan-1-one oxime;
- 5-{5-[1-(2-Piperazin-1-ylethanoyl)piperidin-4-yl]-3-pyridin-4-ylfuran-2-yl}indan-1-one oxime;
- 5-(5-Piperidin-3-yl-2-pyridin-4-yl-furan-3-yl)-indan-1-one oxime;
- 5-[5-(1-Methyl-piperidin-3-yl)-2-pyridin-4-yl-furan-3-yl]-indan-1-one oxime;
- N-Hydroxy-2-{3-[4-(1-hydroxyimino-indan-5-yl)-5-pyridin-4-yl-furan-2-yl]-piperidin-1-yl}-acetamidine;
- 5-{5-[1-(2-Methoxy-ethyl)-piperidin-3-yl]-2-pyridin-4-yl-furan-3-yl}-indan-1-one oxime;
- 5-[5-(1-Cyclopropylmethyl-piperidin-3-yl)-2-pyridin-4-yl-furan-3-yl]-indan-1-one oxime;
- 5-{5-[1-(2-Morpholin-4-yl-ethanoyl)-piperidin-3-yl]-2-pyridin-4-yl-furan-3-yl}-indan-1-one oxime;
- 5-{5-[1-(2-Piperidin-1-yl-ethanoyl)-piperidin-3-yl]-2-pyridin-4-yl-furan-3-yl}-indan-1-one oxime;
- 5-{2-Pyridin-4-yl-5-[1-(2-pyrrolidin-1-yl-ethanoyl)-piperidin-3-yl]-furan-3-yl}-indan-1-one oxime;
- 5-(5-{1-[2-(4-Methyl-piperazin-1-yl)-ethanoyl]-piperidin-3-yl}-2-pyridin-4-yl-furan-3-yl)-indan-1-one oxime;
- 5-[5-(1-{2-[4-(2-Methoxy-ethyl)-piperazin-1-yl]-ethanoyl}-piperidin-3-yl)-2-pyridin-4-yl-furan-3-yl]-indan-1-one oxime;
- 5-{5-[4-Hydroxy-1-(2-methoxyethyl)-piperidin-4-yl]-2-pyridin-4-yl-furan-3-yl}-indan-1-one oxime;
- 5-[5-(1-Cyclopropylmethyl-4-hydroxy-piperidin-4-yl)-2-pyridin-4-yl-furan-3-yl]-indan-1-one oxime;
- and
- 5-(5-Hydroxymethyl-2-pyridin-4-yl-furan-3-yl)indan-1-one oxime.
60 more elements
A method for therapeutic treatment of cancer in a human, or other mammal, which comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof;
- wherein the cancer selected from colorectal carcinoma or melanoma.
Dependencies are inferred from the claim text.