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US 8,283,383 B2Granted
Biphenyl amides as P2X3 and P2X2/3 antagonists
AssigneeRoche Palo Alto LLC
InventorsChris Allen Broka, Ronald Charles Hawley
Life of this patent
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Abstract
Compounds of the formula I: or a pharmaceutically acceptable salt thereof, wherein, R1 is optionally substituted phenyl or optionally substituted pyridinyl, and R2, R3, R4, R5, R6, R7, R8 and R9 are as defined herein. Also disclosed are methods of using the compounds for treating diseases associated with P2X3 and/or a P2X2/3 receptor antagonists and methods of making the compounds.
Claims16
A compound of formula I
- wherein:
- R1 is:
- phenyl substituted at the 4-position with methyl or halo and which may be substituted at the 2-position with halo;
- R2 is:
- hydrogen;
- or
- C1-6alkyl;
- R3 is:
- C1-6alkyl;
- hydroxy-C1-6alkyl;
- C1-6alkoxy-C1-6alkyl;
- halo-C1-6alkyl;
- C3-7cycloalkyl;
- heteroaryl which may be unsubstituted or substituted once or twice with C1-6alkyl;
- heterocyclyl;
- heterocyclyl-C1-6alkyl;
- or
- C3-7cycloalkyl-C1-6alkyl;
- or R2 and R3 together form a C3-7cycloalkyl;
- R4 is:
- hydrogen;
- C1-6alkyl;
- C3-7cycloalkyl;
- C3-7cycloalkyl-C1-6alkyl;
- or
- pyrimidinyl;
- R5 is:
- C1-6alkyl;
- C1-6alkoxy;
- C3-7cycloalkyl;
- C1-6alkoxy-C1-6alkyl;
- amino-C1-6alkyl;
- oxetanyl which may be unsubstituted or substituted once or twice with C1-6alkyl;
- phenyl which may be unsubstituted or substituted once or twice with a group or groups independently selected from C1-6alkyl, halo, halo-C1-6alkyl and C1-6alkoxy;
- thienyl which may be unsubstituted or substituted once or twice with a group or groups independently selected from C1-6alkyl and C1-6alkoxy;
- furanyl which may be unsubstituted or substituted once or twice with C1-6alkyl;
- thiazolyl which may be unsubstituted or substituted once or twice with C1-6alkyl;
- oxazolyl which may be unsubstituted or substituted once or twice with C1-6alkyl;
- isoxazolyl which may be unsubstituted or substituted once or twice with a group or groups independently selected from C1-6alkyl and phenyl;
- pyrazolyl which may be unsubstituted or substituted once or twice with C1-6alkyl;
- thiadiazolyl which may be unsubstituted or substituted once with C1-6alkyl;
- tetrahydropyranyl;
- morpholinyl;
- piperidinyl which may be unsubstituted or substituted with C1-6alkyl or acetyl;
- pyrimidinyl;
- or
- pyridinyl which may be unsubstituted or substituted once or twice with C1-6alkyl;
- and
- R6, R7 and R8 each independently is:
- hydrogen;
- or
- halo.
49 more elements
A compound selected from the group consisting of:
- 4-Methyl-thiophene-2-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-amide;
- 5-Methyl-thiophene-2-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-amide;
- Furan-2-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-amide;
- Thiophene-2-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-amide;
- 5-Benzoylamino-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;
- Pyridine-2-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-amide;
- 5-(Cyclohexanecarbonyl-amino)-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;
- 5-(2,4-Dimethyl-benzoylamino)-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;
- 5-(2-Chloro-4-fluoro-benzoylamino)-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;
- 5-(2-Chloro-4-trifluoromethyl-benzoylamino)-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;
- Thiazole-4-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-amide;
- 5-Methyl-3-phenyl-isoxazole-4-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-amide;
- 2,5-Dimethyl-oxazole-4-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-amide;
- 3-Methyl-thiophene-2-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-amide;
- 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-amide;
- 5-Methyl-isoxazole-3-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-amide;
- 4-Methoxy-thiophene-3-carboxylic acid [5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-amide;
- 4′-Methyl-5-(methyl-propionyl-amino)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;
- 4′-Methyl-5-(methyl-propionyl-amino)-biphenyl-3-carboxylic acid ((R)-1-methyl-2-morpholin-4-yl-ethyl)-amide;
- 5-(Acetyl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 5-(Acetyl-ethyl-amino)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 5-[(Methoxy-acetyl)-methyl-amino]-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide
- 5-[Ethyl-(2-methoxy-acetyl)-amino]-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide
- 5-(Acetyl-pyrimidin-4-yl-amino)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 4′-Methyl-5-(propionyl-pyrimidin-4-yl-amino)-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 5-(Isobutyryl-pyrimidin-4-yl-amino)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- Pyrazine-2-carboxylic acid ethyl-[4′-methyl-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-amide;
- N-Ethyl-N-[5-(2-methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-isonicotinamide;
- 5-[Ethyl-(3-methyl-butyryl)-amino]-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 5-[Ethyl-(3-methyl-butyryl)-amino]-4′-methyl-biphenyl-3-carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide;
- N-Ethyl-N-[4′-methyl-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-nicotinamide;
- 5-[(2,2-Dimethyl-propionyl)-methyl-amino]-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 5-(Isobutyryl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 5-(Cyclopropanecarbonyl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- Ethyl-[4′-methyl-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-carbamic acid isobutyl ester;
- 4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid methyl-[4′-methyl-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-amide;
- Ethyl-[4′-methyl-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-carbamic acid isopropyl ester;
- 5-(Ethyl-isobutyryl-amino)-4′-methyl-biphenyl-3 -carboxylic acid (1 -pyrazin-2-yl-ethyl)-amide;
- Ethyl-[4′-methyl-5-(1 -pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-carbamic acid methyl ester;
- 5-(Isobutyryl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;
- Tetrahydro-pyran-4-carboxylic acid ethyl-[4′-methyl-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-amide;
- 5-Isobutyrylamino-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide
- Tetrahydro-pyran-4-carboxylic acid methyl-[4′-methyl-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-amide;
- Morpholine-4-carboxylic acid [4′-chloro-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-methyl-amide;
- 4′-Chloro-5-(3-ethyl-1-methyl-ureido)-biphenyl-3 -carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 4′-Methyl-5-[methyl-(2-methyl-butyryl)-amino]-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 5-[(2-Ethyl-butyryl)-methyl-amino]-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 5-[(2,2-Dimethyl-butyryl)-methyl-amino]-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 5-(Ethyl-isobutyryl-amino)-4′-methyl-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;
- 5-(Cyclopentanecarbonyl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;
- 5-(Cyclopentanecarbonyl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 5-(Cyclohexanecarbonyl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 4′-Methyl-5-[methyl-(2-methyl-butyryl)-amino]-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;
- 2′-Chloro-5-(isobutyryl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 2′-Chloro-5-(isobutyryl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;
- 2′-Chloro-5-(isobutyryl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid (pyrazin-2-ylmethyl)-amide;
- 4′-Chloro-5-(trimethyl-ureido)-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 2′-Fluoro-5-(isobutyryl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 2′-Fluoro-5-(isobutyryl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;
- 2′-Fluoro-5-(isobutyryl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid (pyrazin-2-ylmethyl)-amide;
- 1-Acetyl-piperidine-4-carboxylic acid methyl-[4′-methyl-5-(1-pyrazin-2-yl-ethylcarbamoyl)-biphenyl-3-yl]-amide;
- 5-(Isobutyryl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid (pyrazin-2-ylmethyl)-amide;
- 2′,4′-Dichloro-5-(isobutyryl-methyl-amino)-biphenyl-3-carboxylic acid ((R)-2-methoxy-1-methyl-ethyl)-amide;
- 2′,4′-Dichloro-5-(isobutyryl-methyl-amino)-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;
- 2′,4′-Difluoro-5-(isobutyryl-methyl-amino)-biphenyl-3-carboxylic acid ((R)-2-methoxy-1-methyl-ethyl)-amide;
- and
- 2′,4′-Difluoro-5-(isobutyryl-methyl-amino)-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide.
64 more elements
Dependencies are inferred from the claim text.