Author: claimsbot

1. A compound of Formula I
wherein
R1, R2, R3, and R4 are independently H, halo, cyano, hydroxyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, amino, C1-C6 alkylamine, C1-C6 dialkylamine, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkylene(cycloalkyl), C2-C6 alkenyl, C2-C6 alkynyl, aryl, C1-C6 alkylene(aryl), heterocyclyl, or C1-C6 alkylene(heterocyclyl) or R1 and R2 or R3 and R4 can combine with the atom(s) to which they are attached to form a 3- to 6-membered spiro cycloalkyl ring or R3 and R5 or R4 and R5 can combine with the atom(s) to which they are attached to form a 4- to 6-membered heterocyclyl ring,
R5 is H, amino, C1-C6 alkylamine, C1-C6 dialkylamine, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(aryl), C1-C6 alkylene(heterocyclyl), aryl, or heterocyclyl,
R6 is
wherein n is 2,
X is N,
and
Ring A is a 5- or 6-membered aryl, optionally substituted by 1-3 R8 moieties,
R8 is H, halo, nitro, \u2014CHR9S(O)2R10, \u2014NR10R11, \u2014NR9S(O)2R10S or NR9S(O)2NR10R11, wherein R9, R10, and R11 are independently H, C1-C6 alkyl, C3-C8 cycloalkyl, aryl, or heterocyclyl, or R9 and R10 or R10 and R11 combine with the atom(s) to which they are attached to form a 5- or 6-membered heterocyclyl ring,
wherein the above alkyl, alkenyl, alkynyl, aryl, cycloalkyl, or heterocyclyl moieties provided in R1, R2, R3, R4, R5, R9, R10, and R11 are each optionally and independently substituted by 1-3 substituents selected from
alkoxy,
alkylamine,
amino,
aryl, cycloalkyl, heterocyclyl,
C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkylamine, C1-C6 dialkylamine, C2-C6 alkenyl, or C2-C6 alkynyl, wherein each of which may be interrupted by one or more hetero atoms,
carboxyl,
cyano,
halo,
hydroxy,
nitro,
oxo,
\u2014C(O)OH, \u2014C(O)2(C1-C6 alkyl), \u2014C(O)2(C3-C8 cycloalkyl), \u2014C(O)2(aryl), \u2014C(O)2(heterocyclyl), \u2014C(O)2(C1-C6 alkylene)aryl, \u2014C(O)2(C1-C6 alkylene)heterocyclyl, \u2014C(O)2(C1-C6 alkylene)cycloalkyl, \u2014C(O)(C1-C6 alkyl), \u2014C(O)(C3-C8 cycloalkyl), \u2014C(O)(aryl), \u2014C(O)(heterocyclyl), \u2014C(O)(C1-C6 alkylene)aryl, \u2014C(O)(C1-C6 alkylene)heterocyclyl, and \u2014C(O)(C1-C6 alkylene)cycloalkyl,

wherein each of the above optional substituents can be further optionally substituted by 1-5 substituents selected from amino, cyano, halo, hydroxy, nitro, C1-C6 alkylamine, C1-C6 dialkylamine, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, and C1-C6 hydroxyalkyl, wherein each alkyl is optionally substituted by one or more halo substituents, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
2. The compound of claim 1, wherein R1, R2, R3, and R4 are independently H, halo, cyano, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkylene(cycloalkyl), C2-C6 alkenyl, C2-C6 alkynyl, aryl, C1-C6 alkylene(aryl), heterocyclyl, or C1-C6 alkylene(heterocyclyl) or R1 and R2 or R3 and R4 can combine with the atom(s) to which they are attached to form a 3- to 6-membered spiro cycloalkyl ring, or R3 and R5 or R4 and R5 can combine with the atom(s) to which they are attached to form a 4- to 6-membered heterocyclyl ring.
3. The compound of claim 2, wherein R1, R2, R3, and R4 are independently selected from
or R1 and R2 or R3 and R4 can combine with the atom(s) to which they are attached to form spiro rings from
4. The compound of claim 3, wherein R1, R2, R3, and R4 are independently selected from
or R1 and R2 or R3 and R4 can combine with the atom(s) to which they are attached to form spiro rings selected from
5. The compound of claim 1, wherein R5 is C1-C6 alkylamine, C1-C6 dialkylamine, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(aryl), aryl, or heterocyclyl.
6. The compound of claim 5, wherein R5 is selected from
7. The compound of claim 6, wherein R5 is selected from
8. The compound of claim 1, wherein R3 and R5 or R4 and R5 combine to form a 4- to 6-membered heterocyclyl ring.
9. The compound of claim 1, wherein R6 is
10. The compound of claim 1, wherein Ring A is
wherein R8 is \u2014CHR9S(O)2R10, \u2014NR10R11, \u2014NR9S(O)2R10, or NR9S(O)2NR10R11, wherein R9, R10, and R11 are independently H, C1-C6 alkyl, C3-C8 cycloalkyl, aryl, or heterocyclyl, or R9 and R10 or R10 and R11 combine with the atom(s) to which they are attached to form a 5- or 6-membered heterocyclyl ring.
11. The compound of claim 1, wherein R8 is selected from
12. The compound of claim 11, wherein R8 is
13. A compound selected from
N-{3-1-(4-Fluoro-benzyl)-4-hydroxy-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-4-Hydroxy-5-methyl-1,5-bis-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-5-(4-Fluoro-benzyl)-8-hydroxy-6-oxo-5-aza-spiro2,5oct-7-en-7-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-6-(4-Fluoro-benzyl)-9-hydroxy-7-oxo-6-aza-spiro4,5dec-8-en-8-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-5-Hydroxy-8-methyl-8-(3-methyl-butyl)-7-oxo-1,2,3,7,8,8a-hexahydro-indolizin-6-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-(4-Fluoro-benzyl)-4-hydroxy-6-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-4-Hydroxy-5-methyl-5-(3-methyl-butyl)-2-oxo-1-pyrrolidin-1-yl-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-(4-Fluoro-benzyl)-4-hydroxy-5-methyl-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-(4-Fluoro-benzyl)-4-hydroxy-5-(3-methyl-but-2-enyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-(4-Fluoro-benzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-4-Hydroxy-5,5-dimethyl-1-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-Cyclopentyl-4-hydroxy-5-methyl-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-7-(4-Fluoro-benzyl)-10-hydroxy-8-oxo-7-aza-spiro4,5dec-9-en-9-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-(4-Fluoro-benzyl)-4-hydroxy-5,5-dimethyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1,5-Bis-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-(4-Fluoro-benzyl)-4-hydroxy-5-methyl-2-oxo-5-phenyl-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-Cyclopentyl-5-(4-fluoro-benzyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-3-(1-Cyclopentyl-4-hydroxy-5,5-dimethyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl-methanesulfonamide,
N-{3-1-Cyclohexyl-5-(4-fluoro-benzyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-Cyclopropyl-5-(4-fluoro-benzyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-Cyclopropyl-4-hydroxy-5-methyl-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-Cyclopentyl-4-hydroxy-5-(3-methyl-but-2-enyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-Cyclopentyl-4-hydroxy-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-6-(4-Fluoro-benzyl)-9-hydroxy-7-oxo-6-aza-spiro3,5non-8-en-8-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-5-Cyclopropylmethyl-1-(4-fluoro-benzyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-3-(5-But-2-ynyl-1-cyclopentyl-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl-methanesulfonamide,
N-{3-1-Cyclohexyl-4-hydroxy-5-methyl-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-Cyclobutyl-4-hydroxy-5-methyl-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-4-Hydroxy-5-methyl-5-(3-methyl-butyl)-2-oxo-1-phenyl-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-5-Cyclopentyl-1-(3,3-dimethyl-butyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-Cyclobutyl-5-(3,3-dimethyl-butyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-3-(1-Cyclobutyl-4-hydroxy-5-methyl-2-oxo-5-phenyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl-methanesulfonamide,
N-{3-6-(1-Ethyl-propyl)-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-6-Ethyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-Cyclopentyl-5-ethyl-4-hydroxy-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-(4-Fluoro-benzyl)-4-hydroxy-6(R)-isopropyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-8-(4-Fluoro-benzyl)-5-hydroxy-8-methyl-7-oxo-1,2,3,7,8,8a-hexahydro-indolizin-6-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-Cyclobutyl-5-(2-cyclopropyl-ethyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-Cyclopentyl-5-(2-cyclopropyl-ethyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-(4-Fluoro-benzyl)-4-hydroxy-2-oxo-6-phenyl-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-6(R)-Ethyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-Cyclopentyl-5-(3,3-dimethyl-butyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-Cyclohexyl-5-(3,3-dimethyl-butyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-Cyclopropyl-5-(3,3-dimethyl-butyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-6(R)-tert-Butyl-1-(4-fluoro-benzyl)-4-hydroxy-2-o xo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-(4-Fluoro-benzyl)-6-(4-fluoro-phenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-5-Ethyl-1-(4-fluoro-benzyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-6(S)-Ethyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-4-Hydroxy-1-(3-methyl-butyl)-2-oxo-6(R)-phenyl-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-(4-Fluoro-benzyl)-4-hydroxy-2-oxo-6(R)-phenyl-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-3-(5-Butyl-1-cyclobutyl-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl-methanesulfonamide,
N-3-(1-Cyclobutyl-4-hydroxy-5-methyl-2-oxo-5-propyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl-methanesulfonamide,
N-{3-1-Cyclopentyl-4-hydroxy-6-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-Cyclopentyl-4-hydroxy-5-hydroxymethyl-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-{3-1-(3-Chloro-4-fluoro-benzyl)-4-hydroxy-6(R)-isopropyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide,
N-3-(1-Cyclopentyl-4-hydroxy-6-isobutyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl)-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl-methanesulfonamide, and
N-{3-1-(4-Fluoro-benzyl)-4-hydroxy-6-isobutyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide
N-{3-5-Benzyloxymethyl-1-cyclopentyl-4-hydroxy-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl-1,1-dioxo-1,4-dihydro-1\u03bb6-benzo1,2,4thiadiazin-7-yl}-methanesulfonamide.
14. A pharmaceutically acceptable composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
15. A method for treating hepatitis C virus infection in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.
16. The method of claim 15 wherein the mammal is a human.
17. The method of claim 16 further comprising administering an additional therapeutic agent to the mammal.
18. The method of claim 17 wherein the additional therapeutic agent is selected from the group consisting of an antibiotic, an antiemetic agent, an antidepressant, an antifungal agent, an anti-inflammatory agent, an antiviral agent, an anticancer agent, an immunomodulatory agent, an \u03b1-interferon, a \u03b2-interferon, a ribavirin, an alkylating agent, a hormone, a cytokine and a toll-like receptor modulator.
19. The method of claim 18 wherein the additional therapeutic agent is a toll-like receptor modulator.

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 to control the post sinter dimensions of a multilayer ceramic substrate sintered under load comprising the steps of:
providing at least one first continuous non-densifying structure (40);
providing at least one personalized ceramic greensheet (10) having a local peripheral kerf area (30) and an external peripheral kerf area (20);
placing said at least one first continuous non-densifying structure (40) on the local peripheral kerf area (30) of said at least one personalized ceramic greensheet (10);
placing said at least one personalized ceramic greensheet (10) having said at least one first continuous non-densifying structure (40) in a stack of personalized greensheets;
laminating said stack of personalized ceramic greensheets to form a green ceramic laminate (100) wherein said at least one first continuous non-densifying structure (40) will at least partially control the dimensions of said green ceramic laminate (100) during lamination;
sintering said green ceramic laminate (100) under load to form a multilayer ceramic substrate wherein said at least one first continuous non-densifying structure (40) will at least partially control the dimensions of said multilayer ceramic substrate during sintering.
2. The method of claim 1 further comprising the step of post sinter sizing said multilayer ceramic substrate thereby separating said at least one first continuous non-densifying structure (40) from said multilayer ceramic substrate.
3. The method of claim 1 further comprising the steps of:
providing at least one second continuous non-densifying structure (60);
placing said at least one second continuous non-densifying structure (60) on the external peripheral kerf area (20) of said at least one personalized ceramic greensheet (10) prior to lamination wherein said at least one second continuous non-densifying structure (60) will at least partially control the dimensions of said green ceramic laminate (100) during lamination, and
pre-sinter sizing said green ceramic laminate (100) thereby separating said at least one second continuous non-densifying structure (60) from said green ceramic laminate (100) prior to sintering.
4. The method of claim 3 wherein said first and second continuous non-densifying structure is metal, ceramic, polymer, or a combination thereof.
5. The method of claim 3 wherein said first and second continuous non-densifying structure is a metal selected from the group consisting of molybdenum, nickel, copper, tungsten, stainless-steel and zirconia.
6. The method of claim 3 wherein said first and second continuous non-densifying structure has a thickness of approximately 0.0003 inch to 0.001 inch and width of greater than 0.5 millimeters.
7. A method to control the post sinter dimensions of a multilayer ceramic substrate which is laminated and sintered under load as a multi-up green ceramic laminate comprising the steps of:
providing at least one first continuous non-densifying structure (40);
providing at least one personalized ceramic greensheet (10) having a plurality of product samples (35) separated by a local kerf area (30) and having peripheral external kerf area (20);
placing said at least one first continuous non-densifying structure (40) on the local kerf area (30) of said at least one personalized ceramic greensheet (10);
placing said at least one personalized ceramic greensheet (10) having said at least one first continuous non-densifying structure (40) in a stack of personalized greensheets;
laminating said stack of personalized ceramic greensheets to form a multi-up green ceramic laminate (100) wherein said at least one first continuous non-densifying structure (40) will at least partially control the dimensions of said multi-up green ceramic laminate (100) during lamination;
sintering said green ceramic laminate (100) under load to form a multi-up multilayer ceramic substrate wherein said at least one first continuous non-densifying structure (40) will at least partially control the dimensions of said multi-up multilayer ceramic substrate during sintering.
8. The method of claim 7 further comprising the step of post sinter sizing said multi-up multilayer ceramic substrate to form individual multilayer ceramic substrates and thereby separating said at least one first continuous non-densifying structure (40) from said individual multilayer ceramic substrates.
9. The method of claim 7 further comprising the steps of:
providing at least one second continuous non-densifying structure (60);
placing said at least one second continuous non-densifying structure (60) on the external peripheral kerf area (20) of said at least one personalized ceramic greensheet (10) prior to lamination wherein said at least one second continuous non-densifying structure (60) will at least partially control the dimensions of said multi-up green ceramic laminate (100) during lamination, and
pre-sinter sizing said multi-up green ceramic laminate (100) thereby separating said at least one second continuous non-densifying structure (60) from said multi-up green ceramic laminate (100) prior to sintering.
10. The method of claim 7 wherein said at least one first continuous non-densifying structure (40) further comprises tailored shapes (51) to control local distortion within said product samples (35).
11. The method of claim 9 wherein said first and second continuous non-densifying structure is metal, ceramic, polymer, or a combination thereof.
12. The method of claim 9 wherein said first and second continuous non-densifying structure is a metal selected from the group consisting of molybdenum, nickel, copper, tungsten, stainless-steel and zirconia.
13. The method of claim 9 wherein said first and second continuous non-densifying structure has a thickness of approximately 0.0003 inch to 0.001 inch and width of greater than 0.5 millimeters.
14. A multilayer ceramic laminate structure comprising:
a plurality of laminated ceramic greensheets;
at least one personalized ceramic greensheet (10) having a local peripheral kerf area (30) and an external peripheral kerf area (20);
at least one first continuous non-densifying structure (40) placed on said local peripheral kerf area (30) of said at least one personalized ceramic greensheet (10).
15. The multilayer ceramic laminate structure of claim 14 further comprising:
at least one second continuous non-densifying structure (60) placed on said external peripheral kerf area (20).
16. The multilayer ceramic laminate structure of claim 15 wherein said first and second continuous non-densifying structure is metal, ceramic, polymer, or a combination thereof.
17. The multilayer ceramic laminate structure of claim 15 wherein said first and second continuous non-densifying structure is a metal selected from the group consisting of molybdenum, nickel, copper, tungsten, stainless-steel and zirconia.
18. The multilayer ceramic laminate structure of claim 15 wherein said first and second continuous non-densifying structure has a thickness of approximately 0.0003 inch to 0.001 inch and width of greater than 0.5 millimeters.
19. A multi-up multilayer ceramic laminate structure comprising:
a plurality of laminated ceramic greensheets;
at least one personalized ceramic greensheet (10) having a plurality of product samples (35) separated by a local kerf area (30) and having peripheral external kerf area (20);
at least one first continuous non-densifying structure (40) placed on said local kerf area (30) of said at least one personalized ceramic greensheet (10).
20. The multi-up multilayer ceramic laminate structure of claim 19 further comprising:
at least one second continuous non-densifying structure (60) placed on said external peripheral kerf area (20).
21. The multi-up multilayer ceramic laminate structure of claim 19 wherein said at least one first continuous non-densifying structure (40) further comprises tailored shapes (51) to control local distortion within said product samples (35).
22. The multi-up multilayer ceramic laminate structure of claim 20 wherein said first and second continuous non-densifying structure is metal, ceramic, polymer, or a combination thereof.
23. The multi-up multilayer ceramic laminate structure of claim 20 wherein said first and second continuous non-densifying structure is a metal selected from the group consisting of molybdenum, nickel, copper, tungsten, stainless-steel and zirconia.
24. The multi-up multilayer ceramic laminate structure of claim 20 wherein said first and second continuous non-densifying structure has a thickness of approximately 0.0003 inch to 0.001 inch and width of greater than 0.5 millimeters.
25. The multilayer ceramic laminate structure of claim 14 further comprising:
discrete tailored shapes to control local distortion within the multilayer ceramic laminate.

1. An exterior rearview mirror mechanism for a skid loader comprising:
a support configured to extend from a movable lifting arm of the skid loader, the skid loader including a central axis and first movement means on a first side of the skid loader and second movement means on an opposing second side of the skid loader, the first movement means operable independently of the second movement means in a manner configured to rotate the skid loader about the central axis to define a tail swing path of the skid loader, the movable lifting arm configured to move from a non-elevated position to an elevated position; and
a mirror attached to the support and thus elevated above and opposite the movable lifting arm, the mirror movable with the lifting arm and positioned to enable an operator of the skid loader to visualize substantially an entirety of the tail swing path on either rear side of the skid loader when the movable lifting arm is in the elevated position.
2. The exterior rearview mirror mechanism of claim 1, wherein the support comprises a mirror end that defines a bore and an arm end opposite of the mirror end, the bore configured to accept a bolt extending from the mirror.
3. The exterior rearview mirror mechanism of claim 1, wherein the support comprises a mirror end and an arm end opposite of the mirror end, the arm end including an annular ring configured to couple around a lifting lug of the lifting arm.
4. The exterior rearview mirror mechanism of claim 3, wherein the annular ring defines a gap and includes a closure mechanism extending across the gap, the closure mechanism configured to tighten the annular ring about the lifting lug.
5. The exterior rearview mirror mechanism of claim 1, wherein the movable lifting arm defines a width and the support comprises:
a U-shaped brace defining a base and an open end;
a mirror stand extending from the base; and
a bracket configured to removably couple to the open end of the U-shaped brace;
wherein when the support is attached to the skid loader, the open end of the U-shaped brace straddles the width of the movable lifting arm and the bracket extends across at least the width of the movable lifting arm to secure the brace to the movable lifting arm.
6. The exterior rearview mirror mechanism of claim 1, wherein the support comprises a vibration dampener.
7. The exterior rearview mirror mechanism of claim 6, wherein the vibration dampener comprises a separate mass attached to the support.
8. The exterior rearview mirror mechanism of claim 6, wherein the vibration dampener comprises a spring.
9. The exterior rearview mirror mechanism of claim 1, wherein the support is magnetically coupled to and extends from the movable lifting arm of the skid loader.
10. The exterior rearview mirror mechanism of claim 1, wherein the mirror defines a back side and a convex mirrored surface opposite the back side.
11. An exterior rearview mirror mechanism for a skid loader comprising:
a support configured to extend from a lifting arm assembly of the skid loader, the support defining a support length and the skid loader including a central axis and first movement means on a first side of the skid loader and second movement means on an opposing second side of the skid loader, the first movement means operable independently of the second movement means in a manner configured to rotate the skid loader about the central axis to define a tail swing path of the skid loader, the lifting arm assembly configured to move to an elevated position; and
a mirror attachable to an end of the support opposite the lifting arm assembly such that the attached mirror extends by about the support length away from the lifting arm assembly and is positioned to enable an operator of the skid loader to visualize substantially an entirety of the tail swing path on either rear side of the skid loader when the lifting arm assembly is in the elevated position.
12. The exterior rearview mirror mechanism of claim 11, wherein the support is configured to extend from a movable lifting arm of the lifting arm assembly.
13. The exterior rearview mirror mechanism of claim 11, wherein the support is configured to extend from a substantially fixed portion of a support structure of the lifting arm assembly.
14. The exterior rearview mirror mechanism of claim 11, wherein the lifting arm assembly includes a lifting arm that defines a width and the support comprises:
a U-shaped brace defining a base and an open end; and
a bracket;
wherein the open end of the U-shaped brace is configured to straddle the width of the lifting arm of the lifting arm assembly and the bracket is configured to extend across at least the width of the lifting arm and attach to the open end of the U-shaped brace in securing the support to the lifting arm.
15. The exterior rearview mirror mechanism of claim 11, wherein the support comprises an annular ring configured to encompass a lifting lug of the lifting arm assembly.
16. The exterior rearview mirror mechanism of claim 15, wherein the annular ring defines a gap and includes a closure mechanism extending across the gap, the closure mechanism configured to close the gap and tighten the annular ring about the lifting lug.
17. A method of equipping a skid loader for improved rearward viewing, the method comprising:
providing an exterior rearview mirror mechanism;
providing the skid loader including a central axis and first movement means on a first side of the skid loader and second movement means on an opposing second side of the skid loader, the first movement means operable independently of the second movement means in a manner configured to rotate the skid loader about the central axis to define a tail swing path of the skid loader,
attaching the exterior rearview mirror mechanism to a lifting arm assembly of the skid loader; and
providing, with the exterior rearview mirror mechanism, a seated operator of the skid loader with a view of substantially an entirety of the tail swing path on either rear side of the skid loader with the lifting arm assembly elevated.
18. The method of claim 17, wherein the exterior rearview mirror mechanism includes a support configured to extend from the lifting arm assembly of the skid loader and a mirror attached to the support opposite the lifting arm assembly.
19. The method of claim 18, wherein the support is configured to extend from a movable lifting arm of the lifting arm assembly.
20. The method of claim 17, wherein providing an exterior rearview mirror mechanism comprises providing a first of a pair of exterior rearview mirror mechanisms, and the method further comprises providing a second of a pair of exterior rearview mirror mechanisms, each of the pair of exterior rearview mirror mechanisms being removably attachable to an opposing lifting arm assembly of the skid loader.

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 medical device system including an electrode configured to be subcutaneously placed at a target site in a patient using a lead that is adapted to extend within a subcutaneous tunnel wall of a patient’s body tissue formed outside a patient’s vascular system, comprising:
the lead having a lead body extending from a proximal end to a distal end, the electrode configured to be positioned along the distal end of the lead; and
a fixation mechanism configured to be positioned along the lead body proximal to the electrode, the fixation mechanism including a locking sleeve and a mating portion, the mating portion configured to be part of the lead body, the locking sleeve capable of being advanced distally along the lead body and over the mating portion, the locking sleeve having an inner surface facing the lead body and a flange extending from the inner surface of the locking sleeve toward the lead body, and the mating portion having a proximal section, a distal section and an intermediate section between the proximal section and the distal section, the intermediate section configured to form a channel for receiving the flange, wherein the proximal portion is sloped such that a diameter of the proximal section of the mating portion increases along a sloped surface from a proximal end of the proximal section to a distal end of the proximal section, wherein a diameter of the locking sleeve is increased as the locking sleeve is advanced over the proximal section of the mating portion, and wherein the flange has an inner diameter smaller than the inner diameter defined by the inner surface of the locking sleeve when the flange is located in the channel
2. The medical device system of claim 1, wherein a diameter of the distal section of the mating portion is greater than a diameter of the proximal section of the mating portion.
3. The medical device system of claim 1, further comprising an elongated member configured to receive the lead therein.
4. The medical device system of claim 3, wherein a distal end of the elongated member is configured to engage against a proximal end of the locking sleeve to advance the locking sleeve distally along the lead body and over the mating portion.
5. The medical device system of claim 1, wherein the flange is configured to fixedly engage within the channel when the locking sleeve is advanced over the mating portion.
6. The medical device system of claim 1, further comprising a suture ring configured to be positioned along the locking sleeve, wherein the suture ring comprises an opening.
7. A medical device system including an electrode configured to be subcutaneously placed at a target site in a patient using a lead that is adapted to extend within a subcutaneous tunnel wall of a patient’s body tissue formed outside a patient’s vascular system, comprising:
the lead having a lead body extending from a proximal end to a distal end, the electrode configured to be positioned along the distal end of the lead; and
a fixation mechanism including a locking sleeve and a mating portion, the mating portion configured to be part of the lead body, the fixation mechanism configured to be positioned along the lead body proximal to the electrode, the mating portion having an outer diameter at a distal end section that is greater than a diameter of the lead body and having a sloped proximal section, wherein the outer diameter of the mating portion is progressively reduced when moving proximally along the sloped proximal section from a distal end of the proximal section to a proximal end of the proximal section,
the locking sleeve configured to define a closed lumen with an inner diameter capable of being inserted over and encircling the lead body, the locking sleeve further capable of being advanced longitudinally along the lead body and over the mating portion, the locking sleeve being made of a compliant material wherein the inner diameter expands from a first state corresponding to a first inner diameter of the locking sleeve to a second state as the locking sleeve is advanced over the sloped proximal section of the mating portion and corresponding to a second inner diameter of the locking sleeve, the second inner diameter being greater than the first inner diameter, the second inner diameter of the locking sleeve being approximately equal to the outer diameter of the distal end section of the mating portion that is greater than the diameter of the lead body,
the locking sleeve configured to have an inner surface facing the closed lumen and a flange extending from the inner surface of the locking sleeve toward the closed lumen, wherein the flange has an inner diameter smaller than the inner diameter defined by the inner surface of the locking sleeve when the flange is received in the channel.
8. The medical device system of claim 7, wherein the mating portion includes an intermediate section between the proximal section and the distal end section, wherein the channel is formed in the intermediate section.
9. The medical device system of claim 7, wherein a diameter of the distal end section of the mating portion is greater than a diameter of a proximal end of the proximal section of the mating portion.
10. The medical device system of claim 7, further comprising an elongated member configured to receive the lead therein.
11. The medical device system of claim 10, wherein a distal end of the elongated member is configured to engage against a proximal end of the locking sleeve to advance the locking sleeve distally along the lead body and over the mating portion.
12. The medical device system of claim 7, wherein the flange is configured to fixedly engage within the channel when the locking sleeve is advanced over the mating portion.
13. The medical device system of claim 7, further comprising a suture ring configured to be positioned along the locking sleeve, wherein the suture ring comprises an opening.
14. The medical device system of claim 7, wherein the first inner diameter is approximately equal to a diameter of the lead body.
15. A medical device system including an electrode configured to be subcutaneously placed at a target site in a patient using a lead that is adapted to extend within a subcutaneous tunnel wall of a patient’s body tissue formed outside a patient’s vascular system, comprising:
the lead having a lead body extending from a proximal end to a distal end, the electrode configured to be positioned along the distal end of the lead;
a fixation mechanism including a locking sleeve and a mating portion configured to be positioned along the lead body proximal to the electrode, the mating portion configured to be part of the lead body and comprising a sloped proximal section and a distal section, wherein a diameter of the distal section of the mating portion is greater than a diameter of a proximal end of the proximal section, wherein the diameter of the proximal section of the mating portion progressively increases from the proximal end of the proximal section to a distal end of the proximal section, the locking sleeve comprising an inner surface facing the lead body, the locking sleeve capable of being advanced distally along the lead body and over the proximal section of the mating portion from a first state along the lead body corresponding to a first inner diameter of the locking sleeve to a second state over the mating portion corresponding to a second inner diameter of the locking sleeve, the second inner diameter being greater than the first inner diameter;
a flange extending from the inner surface of the locking sleeve toward the lead body, the flange capable of being received within a channel formed by the mating portion of the fixation mechanism, wherein the flange has an inner diameter smaller than the inner diameter defined by the inner surface of the locking sleeve when the flange is located in the channel; and
an elongated member configured to receive the lead therein, wherein a distal end of the elongated member engages against a proximal end of the locking sleeve to advance the locking sleeve distally along the lead body to the second state over the mating portion.
16. The medical device system of claim 15, wherein the mating portion includes an intermediate section between the proximal section and the distal section, wherein the channel is formed in the intermediate section.
17. The medical device system of claim 15, wherein the locking sleeve is capable of being advanced over the mating portion to have an inner diameter approximately equal to the diameter of the mating portion distal section, the increased diameter of the locking sleeve causing the locking sleeve to push against a tunneled subcutaneous wall to improve fixation of the lead.
18. A medical device system comprising:
a lead comprising:
a lead body extending from a proximal end to a distal end,
an electrode located proximate the distal end of the lead body, and
a mating portion located between the proximal end and the electrode, wherein the mating portion comprises a proximal section, a distal section and an intermediate section between the proximal section and the distal section, wherein the intermediate section defines a channel, wherein a diameter of the distal section of the mating portion is greater than a diameter of the lead body, and wherein the proximal section of the mating portion is sloped such that a diameter of the proximal section of the mating portion increases from a proximal end of the proximal section to a distal end of the proximal section; and

a locking sleeve formed of compliant material, wherein the locking sleeve defines a closed lumen configured to receive the lead body such that that locking sleeve is capable of being advanced distally along the lead body and over the mating portion, wherein the locking sleeve comprises an inner surface facing the closed lumen and a flange extending from the inner surface of the locking sleeve toward the closed lumen, wherein the flange is configured to be received within the channel of the mating portion of the lead, wherein an inner diameter of the locking sleeve is increased when the locking sleeve is advanced over the proximal section of the mating portion, and wherein the flange has an inner diameter smaller than the inner diameter defined by the inner surface of the locking sleeve when the flange is located in the channel.
19. The medical device system of claim 18, wherein a diameter of the distal section of the mating portion is greater than a diameter of the proximal section of the mating portion.