1. A compound of the formula (I):
wherein
Z is Het2, optionally substituted on a ring carbon atom with one or more substituents selected from the group consisting of halo, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C4)alkyl, (C1-C4)alkyl-S\u2014, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, amino(C1-C4)alkyl, (C1-C4)alkylamino(C1-C4)alkyl, and di(C1-C4)alkylamino(C1-C4)alkyl; andor Het2 is optionally substituted on a ring nitrogen atom with (C1-C4)alkyl, halo(C1-C4)alkyl and (C3-C8)cycloalkyl; with the proviso that Z is not tetrazolyl;
Y1, Y2, Y3 and Y4 are each independently CH, CR1 or N, provided that no more than two of Y1, Y2, Y3 and Y4 are N;
each R1 is independently selected from the group consisting of halo, cyano, amino, hydroxy, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, \u2014C(O)H, \u2014C(O)(C1-C4)alkyl, and \u2014C(O)N(R2)2;
each R2 is independently hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, or (C3-C6)cycloalkyl; or, where a nitrogen is substituted with two R2 groups, each independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, or hydroxy(C1-C4)alkyl, they may be taken together with the N atom to which they are attached to form a 4- to 6-membered ring which, when so formed, may therefore optionally be substituted with hydrogen, alkyl, halo, hydroxy, hydroxyalkyl or haloalkyl;
B is phenyl or Het2, wherein, when B is Het2 it is attached to the oxy linker at a ring carbon atom, and wherein B is optionally further substituted on a ring carbon atom with one or more substituents selected from the group consisting of halo, cyano, hydroxy, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano(C1-C4)alkyl, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, amino(C1-C4)alkyl, (C1-C4)alkylamino(C1-C4)alkyl, di(C1-C4)alkylamino(C1-C4)alkyl, trifluoromethylthio, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, \u2014C(O)R2, \u2014C(O)OR2, \u2014OC(O)R2, \u2014C(O)\u2014N(R2)2, \u2014CH2\u2014C(O)R2, \u2014CH2\u2014C(O)OR2, \u2014CH2\u2014OC(O)R2, \u2014CH2\u2014C(O)\u2014N(R2)2, S(O)2R2, S(O)2N(R2)2, (C3-C8)cycloalkyl, and (C3-C8)cycloalkyl(C1-C4)alkyl; andor
Het2 is optionally substituted on a ring nitrogen atom with a substituent selected from the group consisting of (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, amino(C1-C4)alkyl, (C1-C4)alkylamino(C1-C4)alkyl, di(C1-C4)alkylamino(C1-C4)alkyl, \u2014CH2\u2014C(O)R2, \u2014CH2\u2014C(O)OR2, \u2014CH2\u2014C(O)\u2014N(R2)2, S(O)2R2, and S(O)2N(R2)2;
X is absent, \u2014O\u2014, methylene, ethylene, methylene-O\u2014, or \u2014O-methylene;
C is (C3-C8)cycloalkyl, Het1, phenyl, or Het2, each optionally substituted on a ring carbon atom with one or more substituents selected from the group consisting of halo, cyano, hydroxy, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, N(R2)2, (R2)2N(C1-C4)alkyl, trifluoromethylthio, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, \u2014C(O)R2, \u2014C(O)OR2, \u2014OC(O)R2, \u2014C(O)\u2014N(R2)2, \u2014CH2\u2014C(O)R2, \u2014CH2\u2014C(O)OR2, \u2014CH2\u2014OC(O)R2, \u2014CH2\u2014C(O)\u2014N(R2)2, S(O)2R2, S(O)2N(R2)2, (C3-C8)cycloalkyl(C1-C4)alkyl, (C3-C8)cycloalkoxy, (C3-C8)cycloalkylamino, (C3-C8)cycloalkylamino(C1-C4)alkyl, (C3-C8)cycloalkyl(C1-C4)alkylamino, (C3-C8)cycloalkyl(C1-C4)alkylamino(C1-C4)alkyl, (C3-C8)cycloalkyl(C1-C4)alkoxy and D; andor
Het2 is optionally substituted on a ring nitrogen atom with a substituent selected from the group consisting of hydroxy, (C1-C4)alkyl, halo(C1-C4)alkyl, amino(C1-C4)alkyl, (C1-C4)alkylamino(C1-C4)alkyl, di(C1-C4)alkylamino(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, \u2014C(O)R2, \u2014C(O)OR2, \u2014CH2\u2014C(O)R2, \u2014CH2\u2014C(O)OR2, \u2014CH2\u2014C(O)\u2014N(R2)2, S(O)2R2, and S(O)2N(R2)2 and D;
with the proviso that C is not 3,5-dioxo-4,5-dihydro-3H-1,2,4triazin-2-yl;
D is phenyl, benzyl, (C3-C8)cycloalkyl, or Het1, each optionally substituted on a carbon atom with one or more substituents independently selected from the group consisting of halo, cyano, hydroxy, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, amino(C1-C4)alkyl, (C1-C4)alkylamino(C1-C4)alkyl, di(C1-C4)alkylamino(C1-C4)alkyl, trifluoromethylthio, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, \u2014C(O)R2, \u2014C(O)OR2, \u2014OC(O)R2, \u2014C(O)\u2014N(R2)2, \u2014CH2\u2014C(O)R2, \u2014CH2\u2014C(O)OR2, \u2014CH2\u2014OC(O)R2, \u2014CH2\u2014C(O)\u2014N(R2)2, S(O)2R2, and S(O)2N(R2)2;
Het1 is a 3- to 8-membered, saturated or partially unsaturated monocyclic heterocyclic group comprising one or two or three ring members selected from \u2014NR3\u2014, \u2014O\u2014, \u2014C(O)\u2014 and \u2014S(O)p\u2014;
R3 is either the point of attachment to X or C to give
or R3 is selected from the group consisting of hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, \u2014C(O)(C1-C4)alkyl, \u2014C(O)O(C1-C4)alkyl, \u2014CH2\u2014C(O)O(C1-C4)alkyl, \u2014CH2\u2014C(O)\u2014N((C1-C4)alkyl)2, S(O)2R2, S(O)2N(R2)2 and (C3-C8)cycloalkyl;
p is 0, 1 or 2; and
Het2 is a 5- or 6-membered aromatic heterocyclic group comprising either (a) 1 to 4 nitrogen atoms, (b) one oxygen or one sulphur atom or (c) 1 oxygen atom or 1 sulphur atom and 1 or 2 nitrogen atoms;
or a tautomer thereof, or a pharmaceutically acceptable salt or solvate of the compound of formula (I), or its tautomer;
with the proviso that the compound of formula (I) is not the following specific compound:
2. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or tautomer thereof, as claimed in claim 1, wherein Z is not isoxazolyl.
3. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or tautomer thereof, as claimed in claim 1, wherein Z is selected from the group consisting of 2-thiazolyl, 4-thiazolyl, 1-thia-3,4-diazolyl, 1-thia-2,4-diazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl.
4. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or tautomer thereof, as claimed in claim 1, wherein Y1 is CR1, and Y2, Y3 and Y4 are each CH; or Y1 and Y3 are CR1 and Y2 and Y4 are CH.
5. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or tautomer thereof, as claimed in claim 4, wherein each R1 is independently selected from halo; cyano; (C1-C4)alkyl; halo(C1-C4)alkyl; (C1-C4)alkoxy; and \u2014C(O)NH2.
6. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or tautomer thereof, as claimed in claim 1, wherein B is phenyl.
7. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or tautomer thereof, as claimed in claim 6, wherein B is unsubstituted, or is substituted on a ring carbon with one or two substituents independently selected from the group consisting of halo; halo(C1-C4)alkyl; or halo(C1-C4)alkoxy.
8. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or tautomer thereof, as claimed in claim 1, wherein C at the atom where it attaches to X, or directly to ring B if X is absent, is not further substituted except that such an atom may be substituted by hydrogen if chemically possible.
9. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or tautomer thereof, as claimed in claim 1, wherein C is selected from the group consisting of pyrazolyl; pyridinyl; pyridazinyl; pyrimidinyl; azetidinyl; piperidinyl; or tetrahydropyranyl.
10. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or tautomer thereof, as claimed in claim 1, wherein X is absent.
11. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or tautomer thereof, as claimed in claim 1, which has the formula (Ib):
12. A compound of formula (I), or a pharmaceutically acceptable salt, solvate or tautomer thereof, as claimed in claim 1, selected from the group consisting of:
4-2-(6-Aminopyridin-3-yl)-4-fluorophenoxy-N-(5-chloro-1,3-thiazol-2-yl)-3-cyanobenzenesulfonamide;
5-chloro-4-(4-chloro-2-piperidin-4-ylphenoxy)-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide;
4-4-Chloro-2-(1H-pyrazol-4-yl)phenoxy-3-cyano-N-1,3-thiazol-2-ylbenzenesulfonamide;
3-cyano-4-2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethoxy)phenoxy-N-1,3-thiazol-2-ylbenzenesulfonamide;
4-(2-azetidin-3-yl-4-chlorophenoxy)-5-chloro-N-(5-chloro-1,3-thiazol-2-yl)-2-fluorobenzenesulfonamide;
N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-4-fluoro-2-(1H-pyrazol-4-yl)phenoxybenzenesulfonamide;
N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-4-chloro-2-(1H-pyrazol-4-yl)phenoxybenzenesulfonamide;
4-2-(2-aminopyridin-4-yl)-4-chlorophenoxy-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
4-2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide;
2,5-difluoro-4-2-(1H-pyrazol-5-yl)-4-(trifluoromethyl)phenoxy-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
2,5-difluoro-4-2-(1H-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
4-(4-chloro-2-(1H-pyrazol-4-yl)phenoxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide;
4-2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
3-cyano-4-2-(1H-pyrazol-5-yl)-4-(trifluoromethoxy)phenoxy-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
4-2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
3-cyano-4-2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethoxy)phenoxy-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
5-chloro-4-(4-chloro-2-piperidin-4-ylphenoxy)-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
3-cyano-4-2-(5-methyl-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
4-{2-2-(aminomethyl)pyridin-4-yl-4-chlorophenoxy}-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
3-Cyano-4-2-(tetrahydro-2H-pyran-4-yl)-4-(trifluoromethyl)phenoxy-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
5-Chloro-2-fluoro-N-(5-fluoropyridin-2-yl)-4-2-piperidin-4-yl-4-(trifluoromethyl)phenoxybenzenesulfonamide;
4-2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
3-cyano-4-2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
4-2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
4-4-chloro-5-fluoro-2-(1H-pyrazol-4-yl)phenoxy-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
2,5-difluoro-4-2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
5-Chloro-2-fluoro-4-{4-fluoro-2-1-(1-methylazetidin-3-yl)-1H-pyrazol-5-ylphenoxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
5-Chloro-2-fluoro-4-{4-fluoro-2-1-(1-methylazetidin-3-yl)-1H-pyrazol-5-ylphenoxy}-N-1,3-thiazol-4-ylbenzenesulfonamide;
4-2-(1-Azetidin-3-yl-1H-pyrazol-5-yl)-4-fluorophenoxy-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide;
4-2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophenoxy-3-cyano-N-1,3-thiazol-4-ylbenzenesulfonamide;
4-2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-fluorophenoxy-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
4-{4-Chloro-2-1-(1-methylazetidin-3-yl)-1H-pyrazol-5-ylphenoxy}-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
4-2-(2-aminopyridin-4-yl)-4-chlorophenoxy-5-chloro-2-fluoro-N-pyrimidin-4-ylbenzenesulfonamide;
5-chloro-4-4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy-2-fluoro-N-pyrimidin-4-ylbenzenesulfonamide;
4-2-(2-aminopyridin-4-yl)-4-chlorophenoxy-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
3-cyano-4-2-pyridazin-4-yl-4-(trifluoromethoxy)phenoxy-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
4-{4-Chloro-2-2-(dimethylamino)pyridin-4-ylphenoxy}-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
2,5-Difluoro-4-{2-1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl-4-(trifluoromethyl)phenoxy}-N-1,3-thiazol-4-ylbenzenesulfonamide;
4-{4-Chloro-2-1-(1-ethylazetidin-3-yl)-1H-pyrazol-5-ylphenoxy}-3-cyano-N-1,3-thiazol-4-ylbenzenesulfonamide;
4-{4-Chloro-2-2-(cyclobutyloxy)pyridin-4-ylphenoxy}-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
4-{4-Chloro-2-2-(dimethylamino)pyridin-4-ylphenoxy}-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
5-chloro-2-fluoro-4-2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
4-2-(3-amino-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
4-2-(3-amino-1H-pyrazol-4-yl)-4-(trifluoromethyl)phenoxy-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide;
4-4-Chloro-2-(2-piperazin-1-ylpyrimidin-4-yl)phenoxy-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
4-2-(2-aminopyridin-4-yl)-4-chlorophenoxy-5-chloro-2-fluoro-N-pyridazin-3-ylbenzenesulfonamide;
4-{2-2-(Azetidin-1-ylmethyl)pyridin-4-yl-4-chlorophenoxy}-2,5-difluoro-N-1,3-thiazol-4-ylbenzenesulfonamide;
3-Cyano-4-{2-1-(1-ethylazetidin-3-yl)-1H-pyrazol-5-yl-4-(trifluoromethyl)phenoxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide;
5-Chloro-2-fluoro-4-5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide;
3-Cyano-4-5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy-N-1,2,4-thiodiazol-5-ylbenzenesulfonamide;
4-2-(3-amino-1H-pyrazol-4-yl)-4-chlorophenoxy-5-chloro-2-fluoro-N-pyrimidin-4-ylbenzenesulfonamide;
2-fluoro-5-methyl-4-2-pyridazin-4-yl-4-(trifluoromethoxy)phenoxy-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide; and
4-2-(3-amino-1H-pyrazol-4-yl)-4-chlorophenoxy-5-chloro-2-fluoro-N-pyridazin-3-ylbenzenesulfonamide.
13. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate or tautomer thereof, as claimed in claim 1, and one or more pharmaceutically acceptable excipients.
14. A pharmaceutical composition as claimed in claim 13 comprising one or more additional therapeutic agents.
15. A method of treating pain in a mammal comprising administering to a mammal requiring such treatment an effective amount of a compound of the formula (I), or a pharmaceutically acceptable salt, solvate or tautomer thereof, according to claim 1.
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 method of making optical elements for an optical disc system, comprising:
providing a glass wafer of a diameter sufficiently large to form a plurality of lens elements side-by-side therein;
selectively etching a lens in each lens element;
selectively etching angled surfaces in each lens element;
depositing a reflective material on the angled surfaces;
selectively etching the outline of each lens element leaving rods connecting the lens elements to the wafer; and
cutting through the rods to separate the lens elements from the wafer.
2. The method of claim 1 wherein the reflective material comprises an oxide, nitride, sulfide, or fluoride of a transition metal.
3. The method of claim 2 wherein the reflective material comprises titanium nitride deposited to a thickness that forms partially reflective mirrors.
4. The method of claim 1 wherein a second large-diameter glass wafer is provided to form a plurality of base elements, and the method includes:
selectively etching an angled surface on each base element;
depositing a second reflective material on the angled surface to provide a fully reflective mirror;
selectively etching the outline of each base element leaving rods connecting the base elements to the second wafer; and
cutting through the rods to separate the base elements from the second wafer.
5. The method of claim 4 wherein the second reflective material comprises aluminum.
6. The method of claim 4 further comprising assembling each lens element with a base element to align optical paths for light passing therethrough.
7. The method of claim 1 wherein the lens is etched part way into a first side of the lens element, and further comprising selectively etching a second lens juxtaposed with the first-recited lens, the second lens being etched part way into the lens element from a side opposite from the first side to provide separate paths for light leaving the lens element and returning into the lens element.