1. A compound of formula (I):
wherein:
R1 is NR7C(O)R8, NR7S(O)2R8 or NR9R10;
R2 is hydrogen or C1-6 alkyl;
R3 is hydrogen, halogen, C1-4 alkyl or C1-4 alkoxy;
R4 is hydrogen, halogen, cyano, hydroxy, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, C1-4 alkylthio, S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), CO2H or CO2(C1-4 alkyl);
R5 is C1-6 alkyl (substituted by NR11R12 or heterocyclyl), C1-6 alkoxy (substituted by NR11R12 or heterocyclyl), C3-6 cycloalkyl (substituted by NR11R12 or heterocyclyl) or heterocyclyl; provided that if R5 includes a heterocyclyl then said heterocyclyl comprises one or more ring nitrogen atoms; and that if said heterocyclyl is bonded directly via a ring nitrogen either: to the alkyl, alkoxy or cycloalkyl of R5, or to the phenyl ring of formula (I) to which R5 is directly bonded, then said heterocyclyl either has at least two ring heteroatoms, or has an NR46R47 substituent;
R6 is hydrogen, halogen, cyano, hydroxy, SH, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, C(O)H, C1-6 alkylthio, S(O)(C1-6 alkyl), S(O)2(C1-6 alkyl), CO2H, CO2(C1-6 alkyl), NR13R14, C1-6 alkyl (optionally substituted by halogen, OH, CO2H, NR15R16, NHC(O)O(C1-6 alkyl), OS(O)2(C1-6 alkyl) or heterocyclyl), C1-6 alkoxy (optionally substituted by halogen, OH, CO2H, NR15R16 or heterocyclyl), C3-6 cycloalkyl (optionally substituted halogen, OH, CO2H, NR15R16 or heterocyclyl) or heterocyclyl;
R7 is hydrogen or C1-6 alkyl (optionally substituted by NR26R27);
R8 is C1-6 alkyl {optionally substituted by hydroxyl, C1-6 alkoxy, NR21R22, heterocyclyl {optionally substituted by oxo, hydroxy, C1-6 alkyl, CO2(C1-6 alkyl), aryl, heteroaryl, aryl(C1-4 alkyl), heterocyclyl or C(O)(C1-4 alkyl)phenyl}, aryl, heteroaryl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-4 alkyl), CO2H, CO2(C1-6 alkyl), aryl(C1-4 alkoxy), aryl(C1-4 alkylthio), S(O)2(C1-6 alkyl), NHC(O)heteroaryl or NHC(O)R23}, C1-6 alkoxy, C3-6 cycloalkyl {optionally substituted by hydroxyl, NR24R25 or C1-6 alkyl}, heterocyclyl {optionally substituted by oxo, hydroxy, C1-6 alkyl, amino, aryl, heteroaryl, aryl(C1-4 alkyl), heteroaryl(C1-4 alkyl), heterocyclyl or C(O)(C1-4 alkyl)phenyl}, aryl(C1-4 alkyl) {substituted by amino(C1-4 alkyl)}, aryl or heteroaryl;
R9 is hydrogen, C1-6 alkyl (optionally substituted by aryl or heteroaryl), aryl or heteroaryl;
R10 is hydrogen, C1-6 alkyl (optionally substituted by hydroxyl, C1-6 alkoxy, aryl, aryloxy, phenyl(C1-6 alkoxy), heteroaryl, C3-10 cycloalkyl, CO2H, CO2(C1-6 alkyl), NHC(O)O(C1-6 alkyl) or NHC(O)R23), C1-6 alkoxy, C3-6 cycloalkyl (optionally substituted by hydroxy, C1-6 alkyl, phenyl, phenyl(C1-6 alkyl), heteroaryl or heteroaryl(C1-6 alkyl)), heterocyclyl (optionally substituted by C1-6 alkyl, C(O)NH2 or phenyl(C1-6 alkyl)), aryl or heteroaryl;
R21 and R22 are, independently, hydrogen, C1-6 alkyl or phenyl(C1-4 alkyl);
R23 is C1-6 alkyl or phenyl;
the foregoing phenyl, aryl and heteroaryl moieties of R5, R8, R9, R10, R23, R21 and R22 are independently, optionally substituted by: halogen, cyano, nitro, CF3, hydroxy, S(O)qR26, OC(O)NR27R28, NR29R30, NR31C(O)R32, NR33C(O)NR34R35, S(O)2NR36R37, NR38S(O)2R39, C(O)NR40R41, C(O)R42, CO2R43, NR44CO2R45, OC(O)(C1-6 alkyl), C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 alkoxy(C1-6)alkyl, amino(C1-4 alkyl), di(C1-6)alkylamino(C1-6)alkyl, C1-6 alkoxy, C1-6 haloalkoxy, hydroxyl (C1-6 alkoxy), heterocyclyl(C1-6 alkoxy), C1-6 alkoxy(C1-6)alkoxy, amino(C1-4 alkoxy), C1-4 alkylamino(C1-4 alkoxy) (itself optionally substituted by phenyl), di(C1-4 alkyl)amino(C1-4 alkoxy), C1-6 alkylthio, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl (itself optionally substituted by C1-4 alkyl or oxo), methylenedioxy, difluoromethylenedioxy, heterocyclyl, heterocyclyl(C1-4 alkyl), phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkoxy, heteroaryl, heteroaryl(C1-4)alkyl, heteroaryloxy or heteroaryl(C1-4)alkoxy; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, hydroxy, nitro, S(O)r(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NH(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3;
q and r are, independently, 0, 1 or 2;
unless otherwise stated heterocyclyl is optionally substituted by OH, C1-6 alkyl, C3-7 cycloalkyl, NR46R47, (C1-6 alkyl)OH or (C1-6 alkyl)NR48R49, NR50CO2(C1-6 alkyl), CO2(C1-6 alkyl), C(O)(C1-6 alkyl), C(O)heterocyclyl, heteroaryl, (C1-6 alkyl)C(O)NR51R52, (C1-6 alkyl)C(O)NR53R54, (C1-6 alkyl)C(O)heterocyclyl or heterocyclyl;
R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44 and R45, are, independently, C1-6 alkyl {optionally substituted by halogen, hydroxy or C1-6 alkoxy}, CH2(C2-6 alkenyl), phenyl {itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NH(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3} or heteroaryl {itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NH(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3};
R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R40, R41, R42, R43, R44 and R45 can also be hydrogen;
R12, R14, R15, R25, R47 and R49 are, independently, hydrogen, C1-6 alkyl (optionally substituted by hydroxy, C1-6 alkoxy, C1-6 alkylthio, C3-7 cycloalkyl (optionally substituted by hydroxy) or NR55R56), C3-7 cycloalkyl (optionally substituted by hydroxy(C1-6 alkyl)) or heterocyclyl (optionally substituted by C1-6 alkyl);
R11, R13, R16, R24, R26, R27, R46, R48, R50, R51, R52, R53, R54 R55 and R56 are, independently, hydrogen or C1-6 alkyl;
or a N-oxide thereof or a pharmaceutically acceptable salt thereof.
2. A compound of formula (I) as claimed in claim 1 wherein:
R1 is NR7C(O)R8, NR7S(O)2R8 or NR9R10;
R2 is hydrogen or C1-6 alkyl;
R3 is hydrogen, halogen, C1-4 alkyl or C1-4 alkoxy;
R4 is hydrogen, halogen, cyano, hydroxy, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, C1-4 alkylthio, S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), CO2H or CO2(C1-4 alkyl);
R5 is C1-6 alkyl (substituted by NR11R12 or heterocyclyl), C1-6 alkoxy (substituted by NR11R12 or heterocyclyl), C3-6 cycloalkyl (substituted by NR11R12 or heterocyclyl) or heterocyclyl; provided that if R5 includes a heterocyclyl then said heterocyclyl comprises one or more ring nitrogen atoms; and that if said heterocyclyl is bonded directly via a ring nitrogen either: to the alkyl, alkoxy or cycloalkyl of R5, or to the phenyl ring of formula (I) to which R5 is directly bonded, then said heterocyclyl either has at least two ring heteroatoms, or has an NR46R47 substituent;
R6 is hydrogen, halogen, cyano, hydroxy, SH, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, C(O)H, C1-6 alkylthio, S(O)(C1-6 alkyl), S(O)2(C1-6 alkyl), CO2H, CO2(C1-6 alkyl), NR13R14, C1-6 alkyl (optionally substituted by halogen, OH, CO2H, NR15R16, NHC(O)O(C1-6 alkyl), OS(O)2(C1-6 alkyl) or heterocyclyl), C1-6 alkoxy (optionally substituted by halogen, OH, CO2H, NR15R16 or heterocyclyl), C3-6 cycloalkyl (optionally substituted halogen, OH, CO2H, NR15R16 or heterocyclyl) or heterocyclyl;
R7 is hydrogen or C1-6 alkyl (optionally substituted by NR26R27);
R8 is C1-6 alkyl {optionally substituted by hydroxyl, C1-6 alkoxy, NR21R22, heterocyclyl {optionally substituted by oxo, hydroxy, C1-6 alkyl, CO2(C1-6 alkyl), aryl, heteroaryl, aryl(C1-4alkyl), heterocyclyl or C(O)(C1-4 alkyl)phenyl}, aryl, heteroaryl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-4 alkyl), CO2H, CO2(C1-6 alkyl), aryl(C1-4 alkoxy), aryl(C1-4 alkylthio), S(O)2(C1-6 alkyl), NHC(O)heteroaryl or NHC(O)R23}, C1-6 alkoxy, C3-6 cycloalkyl {optionally substituted by hydroxyl, NR24R25 or C1-6 alkyl}, heterocyclyl {optionally substituted by oxo, hydroxy, C1-6 alkyl, amino, aryl, heteroaryl, aryl(C1-4 alkyl), heteroaryl(C1-4 alkyl), heterocyclyl or C(O)(C1-4 alkyl)phenyl}, aryl(C1-4 alkyl) {substituted by amino(C1-4 alkyl)}, aryl or heteroaryl;
R9 is hydrogen, C1-6 alkyl (optionally substituted by aryl or heteroaryl), aryl or heteroaryl;
R10 is hydrogen, C1-6 alkyl (optionally substituted by hydroxyl, C1-6 alkoxy, aryl, aryloxy, phenyl(C1-6 alkoxy), heteroaryl, C3-10 cycloalkyl, CO2H, CO2(C1-6 alkyl), NHC(O)O(C1-6 alkyl) or NHC(O)R23), C1-6 alkoxy, C3-6 cycloalkyl (optionally substituted by hydroxy, C1-6 alkyl, phenyl, phenyl(C1-6 alkyl), heteroaryl or heteroaryl(C1-6 alkyl)), heterocyclyl (optionally substituted by C1-6 alkyl, C(O)NH2 or phenyl(C1-6 alkyl)), aryl or heteroaryl;
R21 and R22 are, independently, hydrogen, C1-6 alkyl or phenyl(C1-4 alkyl);
R23 is C1-6 alkyl or phenyl;
the foregoing phenyl, aryl and heteroaryl moieties of R8, R9, R10, R23, R21 and R22 are, independently, optionally substituted by: halogen, cyano, nitro, hydroxy, S(O)qR26, OC(O)NR27R28, NR29R30, NR31C(O)R32, NR33C(O)NR34R35, S(O)2NR36R37, NR38S(O)2R39, C(O)NR40R41, C(O)R42, CO2R43, NR44CO2R45, OC(O)(C1-6 alkyl), C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 alkoxy(C1-6)alkyl, amino(C1-4 alkyl), di(C1-6)alkylamino(C1-6)alkyl, C1-6 alkoxy, C1-6 haloalkoxy, hydroxyl (C1-6 alkoxy), heterocyclyl(C1-6 alkoxy), C1-6 alkoxy(C1-6)alkoxy, amino(C1-4 alkoxy), C1-4 alkylamino(C1-4 alkoxy) (itself optionally substituted by phenyl), di(C1-4 alkyl)amino(C1-4 alkoxy), C1-6 alkylthio, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl (itself optionally substituted by C1-4 alkyl or oxo), methylenedioxy, difluoromethylenedioxy, heterocyclyl, heterocyclyl(C1-4 alkyl), phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4 alkoxy, heteroaryl, heteroaryl(C1-4 alkyl, heteroaryloxy or heteroaryl(C1-4)alkoxy; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, hydroxy, nitro, S(O)r(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NH(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3;
q and r are, independently, 0, 1 or 2;
unless otherwise stated heterocyclyl is optionally substituted by OH, C1-6 alkyl, C3-7 cycloalkyl, NR46R47, (C1-6 alkyl)OH or (C1-6 alkyl)NR48R49, NR50CO2(C1-6 alkyl), CO2(C1-6 alkyl), C(O)(C1-6 alkyl), C(O)heterocyclyl, heteroaryl, (C1-6 alkyl)C(O)NR51R52, (C1-6 alkyl)C(O)NR53R54, (C1-6 alkyl)C(O)heterocyclyl or heterocyclyl;
R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44 and R45, are, independently, C1-6 alkyl {optionally substituted by halogen, hydroxy or C1-6 alkoxy}, CH2(C2-6 alkenyl), phenyl {itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NH(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3} or heteroaryl {itself optionally substituted by halogen, hydroxy, nitro, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(O)2(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NH(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3};
R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R40, R41, R42, R43, R44 and R45 can also be hydrogen;
R12, R14, R15, R25, R47 and R49 are, independently, hydrogen, C1-6 alkyl (optionally substituted by hydroxy, C1-6 alkoxy, C1-6 alkylthio, C3-7 cycloalkyl (optionally substituted by hydroxy) or NR55R56), C3-7 cycloalkyl (optionally substituted by hydroxy(C1-6 alkyl)) or heterocyclyl (optionally substituted by C1-6 alkyl);
R11, R13, R16, R24, R26, R27, R46, R48, R50, R51, R52, R53, R54 R55 and R56 are, independently, hydrogen or C1-6 alkyl;
or a N-oxide thereof or a pharmaceutically acceptable salt thereof.
3. A compound of formula (I) as claimed in claim 1 wherein R1 is NR7C(O)R8.
4. A compound of formula (I) as claimed in claim 1 wherein R8 is aryl or heteroaryl optionally substituted by halogen, cyano, nitro, hydroxy, S(O)qR26, OC(O)NR27R28, NR29R30, NR31C(O)R32, NR33C(O)NR34R35, S(O)2NR36R37, NR38S(O)2R39, C(O)NR40R41, C(O)R42, CO2R43, NR44CO2R45, OC(O)(C1-6 alkyl), C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 haloalkyl, C1-6 alkoxy(C1-6)alkyl, amino(C1-4 alkyl), di(C1-6)alkylamino(C1-6)alkyl, C1-6 alkoxy, C1-6 haloalkoxy, hydroxyl(C1-6 alkoxy), heterocyclyl(C1-6 alkoxy), C1-6 alkoxy(C1-6)alkoxy, amino(C1-4 alkoxy), C1-4 alkylamino(C1-4 alkoxy) (itself optionally substituted by phenyl), di(C1-4 alkyl)amino(C1-4 alkoxy), C1-6 alkylthio, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl (itself optionally substituted by C1-4 alkyl or oxo), methylenedioxy, difluoromethylenedioxy, heterocyclyl, heterocyclyl(C1-4 alkyl), phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkoxy, heteroaryl, heteroaryl(C1-4)alkyl, heteroaryloxy or heteroaryl(C1-4)alkoxy; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halogen, hydroxy, nitro, S(O)r(C1-4 alkyl), S(O)2NH2, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NH(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3, or R8 is C3-6 cycloalkyl substituted by NR24R25.
5. A compound of formula (I) as claimed in claim 1 wherein R5 is methyl, ethyl or propyl substituted by piperidinyl, piperazinyl, morpholinyl, homomorpholinyl or homopiperazinyl.
6. A compound of formula (I) as claimed in claim 1 wherein R6 is hydroxy or C1-6 alkyl optionally substituted by piperidinyl, piperazinyl, morpholinyl, homomorpholinyl or homopiperazinyl.
7. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 6, and a pharmaceutically acceptable adjuvant, diluent or carrier.
8. A pharmaceutical product comprising, in combination, a first active ingredient which is a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, as hereinbefore described, and at least one further active ingredient selected from:\u2014
a \u03b22. adrenoceptor agonist,
a modulator of chemokine receptor function,
an inhibitor of kinase function,
a protease inhibitor,
a steroidal glucocorticoid receptor agonist,
an anticholinergic agent, or
a non-steroidal glucocorticoid receptor agonist.
9. A compound of formula (I) as claimed in claim 1 wherein the compound is 2-(4\u2032-(((3S,5R)-3,5-dimethylpiperazin-1-yl)methyl)-2\u2032-(morpholinomethyl)biphenyl-3-yloxy)-5-fluoro-N-((1s,4s)-4-(2-hydroxy-5-methylbenzamido)cyclohexyl)nicotinamide, which has the formula shown below:
or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition which comprises a compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 9, and a pharmaceutically acceptable adjuvant, diluent or carrier.
11. A pharmaceutical product comprising, in combination, a first active ingredient which is a compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 9, and at least one further active ingredient selected from:\u2014
a \u03b22. adrenoceptor agonist,
a modulator of chemokine receptor function,
an inhibitor of kinase function,
a protease inhibitor,
a steroidal glucocorticoid receptor agonist,
an anticholinergic agent, or
a non-steroidal glucocorticoid receptor agonist.
12. A compound of formula (I) as claimed in claim 1 wherein the compound is N-((1s,4s)-4-(2-(4\u2032-(((3S,5R)-3,5-dimethylpiperazin-1-yl)methyl)-2\u2032-(morpholinomethyl)biphenyl-3-yloxy)-5-fluoronicotinamido)cyclohexyl)-4-methylthiazole-2-carboxamide, which has the formula shown below:
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition which comprises a compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 12, and a pharmaceutically acceptable adjuvant, diluent or carrier.
14. A pharmaceutical product comprising, in combination, a first active ingredient which is a compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 12, and at least one further active ingredient selected from:\u2014
a \u03b22. adrenoceptor agonist,
a modulator of chemokine receptor function,
an inhibitor of kinase function,
a protease inhibitor,
a steroidal glucocorticoid receptor agonist,
an anticholinergic agent, or
a non-steroidal glucocorticoid receptor agonist.
15. A compound of formula (I) as claimed in claim 1 wherein the compound is N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(4\u2032-((3S,5R)-3,5-dimethylpiperazin-1-yl)methyl)biphenyl-3-yloxy)-5-fluoronicotinamide, which has the formula shown below:
or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition which comprises a compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 15, and a pharmaceutically acceptable adjuvant, diluent or carrier.
17. A pharmaceutical product comprising, in combination, a first active ingredient which is a compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 15, and at least one further active ingredient selected from:\u2014
a \u03b22. adrenoceptor agonist,
a modulator of chemokine receptor function,
an inhibitor of kinase function,
a protease inhibitor,
a steroidal glucocorticoid receptor agonist,
an anticholinergic agent, or
a non-steroidal glucocorticoid receptor agonist.
18. A compound of formula (I) as claimed in claim 1 wherein the compound is N-((1s,4s)-4-(1,5-dimethyl-1H-pyrazole-3-carboxamido)cyclohexyl)-2-(3\u2032-((3S,5R)-3,5-dimethylpiperazin-1-yl)methyl)biphenyl-3-yloxy)-5-fluoronicotinamide, which has the formula shown below:
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition which comprises a compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 18, and a pharmaceutically acceptable adjuvant, diluent or carrier.
20. A pharmaceutical product comprising, in combination, a first active ingredient which is a compound, or a pharmaceutically acceptable salt thereof, as claimed in claim 18, and at least one further active ingredient selected from:\u2014
a \u03b22. adrenoceptor agonist,
a modulator of chemokine receptor function,
an inhibitor of kinase function,
a protease inhibitor,
a steroidal glucocorticoid receptor agonist,
an anticholinergic agent, or
a non-steroidal glucocorticoid receptor agonist.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A pneumatic tire comprising:
a tread portion and a carcass layer, the carcass layer comprising a plurality of carcass cords and a coating rubber covering and extending between the carcass cords;
an innermost, air permeation-preventing liner layer disposed inside of the carcass layer in a tire radial direction, said liner layer composed of either a thermoplastic resin or a thermoplastic elastomer composition consisting of a thermoplastic resin and an elastomer, said liner layer being either directly adjacent to the carcass layer or separated from the carcass layer only by an adhesive layer,
wherein a multiplicity of interlocking elements protruding to the hollow side of the tire are integrally molded on the surface of said inner liner layer, and wherein the liner layer further comprises a multiplicity of anchor elements integrally molded with said inner liner layer and provided in a protruding condition on the surface of said inner liner layer opposite to said interlocking elements, said anchoring elements buried in said coating rubber of the carcass layer and helping to anchor said inner liner layer and said carcass layer together, and
wherein each of the interlocking elements and the anchor elements, respectively, comprises a supporting portion and a widening portion, the supporting portion being erected on a surface of the inner liner layer, and the widening portion being formed at a distal end of the supporting portion.
2. The pneumatic tire according to claim 1, wherein said interlocking element has a height of 0.5 to 5.0 mm.
3. The pneumatic tire according to claim 1, wherein said interlocking elements are arranged in a region corresponding to the tread portion of said pneumatic tire, and these interlocking elements are loaded with an acoustic material consisting of a porous material.
4. The pneumatic tire according to claim 1, wherein the relation of the width Wa of said supporting portion of the anchor element and the greatest width Wb of said widening portion of the anchor element satisfies the formulae (1) and (2) below, while denoting the height of the anchor element by H:
1.6Wa\u2266H\u22663.8Wa\u2003\u2003(1)
2.0Wa\u2266Wb\u22663.5Wa\u2003\u2003(2).
5. The pneumatic tire according to claim 4, wherein the thickness T of said anchor element satisfies the formula (3) below relative to said width Wa:
0.7Wa\u2266T\u22661.3Wa\u2003\u2003(3).
6. The pneumatic tire according to claim 1, wherein each of said anchor elements has a height H in a range of 0.1 to 0.5 mm.