Derivatives of isothiazol-3(2h)-one 1,1-dioxides as liver x receptor modulator

Abstract

The present invention relates to certain novel compounds of the formula (I) to processes for preparing such compounds, to their utility in modulation of nuclear hormone receptors Liver X Receptor (LXR) α (NR1H3) and/or β (NR1H2) and in treating and/or preventing clinical conditions including cardiovascular diseases such as atherosclerosis; inflammatory diseases, Alzheimer's disease, lipid disorders (dyslipidemias) whether or not associated with insulin resistance, type 2 diabetes and other manifestations of the metabolic syndrome, to methods for their therapeutic use and to pharmaceutical compositions containing them.

1 . A method of treating and/or preventing lipid disorders (dyslipidemia) whether or not associated with insulin resistance; cardiovascular disease, atherosclerosis, hypercholesterolemia, a condition associated with a need for improving reverse cholesterol transport, a condition associated with a need for decreasing intestinal cholesterol absorption, a condition associated with a need for increasing HDL-cholesterol levels, a condition associated with a need for decreasing LDL-cholesterol levels; an inflammatory condition, Alzheimer's disease, arteriosclerosis, type 2 diabetes, or a condition associated with a need for improving HDL function comprising the administration of a therapeutically effective amount of a compound according to formula (I), 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  represents:
 X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b  or NR a C(O)NR a R a ; 
 cycloalkyl or heterocyclyl each optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a ; 
 phenyl or heteroaryl each optionally substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a ; 
 cycloalkylY or heterocyclylY wherein cycloalkyl or heterocyclyl each optionally is substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a ; 
 phenylY or heteroarylY wherein phenyl or heteroaryl each optionally is substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR c C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a ; 
 
         R 2  represents:
 phenyl which is optionally substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R b , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , S b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R a , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a ; 
 
         R 3  represents:
 aryl or Het 1  wherein aryl or Het 1  each optionally is substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , Q, Het 2 , R, Het 3 , QZ, Het 2 Z, RZ, Het 3 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a ; 
 Het 4  or T wherein Het 4  or T each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , Q, Het 2 , R, Het 3 , QZ, Het 2 Z, RZ, Het 3 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a , and wherein Het 4  or T C(O)R b , C(O)OR a , OC(O)R b , independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , thioxo, Q, Het 2 , R, Het 3 , QZ, Het 2 Z, RZ, Het 3 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a ; 
 
         and further wherein:
 X represents a straight or branched, saturated or unsaturated alkyl group having 1 to 6 carbon atoms wherein said alkyl group may optionally be interrupted by one of the following: O, S, SiR b R b , S(O), SO 2 , C(O), NR a , OC(O), C(O)O, NR a C(O), C(O)NR a , SO 2 NR a  or NR a SO 2 ; 
 Y binds to nitrogen in 2-position in the isothiazol-3(2H)-one 1,1-dioxide, and represents a straight or branched, saturated or unsaturated alkylene group having 1 to 3 carbon atoms wherein said alkylene group may optionally be interrupted or ended by one of the following: O, S, SiR b R b , S(O), SO 2 , C(O), OC(O), C(O)O, NR c C(O), C(O)NR c , NR c  and/or Y is optionally substituted by one or more of the following independently selected from: OH, F, CN, NR a R a , C 1 -C 4 alkyl, OR b , SR b , SiR b R b R b , S(O)R b or SO 2 R b ; 
 Z binds to aryl, Het 1 , Het 4  or T and one of the following: Q, Het 2 , R or Het 3 , and represents a straight or branched, saturated or unsaturated alkylene group having 1 to 6 carbon atoms wherein said alkylene group may optionally be interrupted or ended by one of the following: O, S, SiR b R b , S(O), SO 2 , C(O), OC(O), C(O)O, NR a C(O), C(O)NR a , NR a , SO 2 NR a , NR a SO 2 , or is one of the following: O, S, SiR b R b , S(O), SO 2 , C(O), OC(O), C(O)O, NR a C(O), C(O)NR a , NR a , SO 2 NR a , NR a SO 2  and/or Z is optionally substituted by one or more of the following independently selected from: OH, F, CN, NR c R c , C(O)R c , OR b , SR c , SiR b R b R b , S(O)R c , SO 2 R c , phenyl, phenylC 1 -C 3 alkyl, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, NR a R a , SR b , SiR b R b R b , S(O)R b , SO 2 R b , OR b ; 
 Q represents a saturated or unsaturated non-aromatic monocyclic ring composed of 3, 4, 5, 6, 7 or 8 carbon atoms, which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR c (O)NR a R a ; 
 R represents a phenyl group which is optionally substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a ; 
 aryl represents a phenyl group which binds to nitrogen in 4-position on the isothiazol-3(2H)-one 1,1-dioxide; 
 T binds to nitrogen in 4-position on the isothiazol-3(2H)-one 1,1-dioxide, and represents an aromatic or partly aromatic bicarbocyclic ring composed of 8, 9 or 10 carbon atoms, and where it is the aromatic part of the bicarbocyclic ring that binds to nitrogen in 4-position on the isothiazol-3(2H)-one 1,1-dioxide; 
 Het 1  binds to nitrogen in 4-position on the isothiazol-3(2H)-one 1,1-dioxide, and represents an aromatic 5 or 6 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon independently selected from one or more of for example nitrogen, oxygen and sulfur; 
 Het 2  represents a saturated or unsaturated non-aromatic 3, 4, 5, 6, 7, 8, 9 or 10 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon independently selected from one or more of for example nitrogen, oxygen or sulfur, and wherein the ring optionally is substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a ; 
 Het 3  represents an aromatic 5 or 6 membered monocyclic ring in which one or more of the atoms in the ring is an element other than carbon independently selected from one or more of for example nitrogen, oxygen and sulfur, and which is substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a ; 
 Het 4  binds to nitrogen in 4-position on the isothiazol-3(2H)-one 1,1-dioxide, and represents an aromatic or partly aromatic 8, 9 or 10 membered bicyclic ring system in which one or more of the atoms in the ring optionally is an element other than carbon independently selected from one or more of for example nitrogen, oxygen and sulfur, and where it is the aromatic part of the bicyclic ring that binds to nitrogen in 4-position on the isothiazol-3(2H)-one 1,1-dioxide; 
 R a  independently represents H or a straight or branched, saturated or unsaturated C 1 -C 4 alkyl chain optionally substituted by one or more F; 
 R b  independently represents a straight or branched, saturated or unsaturated C 1 -C 4 alkyl chain optionally substituted by one or more F; and 
 R c  independently represents H or a straight or branched, saturated or unsaturated C 1 -C 3 alkyl chain optionally substituted by one or more F; 
 or a suitable pharmaceutically acceptable salt thereof, to a mammal in need thereof. 
 
       
     
     
         2 . A method according to  claim 1 , wherein:
 R 1  represents:
 X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b  or C(O)R b ; 
 cycloalkyl or heterocyclyl each optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b  or C(O)R b ; 
 phenyl or heteroaryl each optionally substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b  or C(O)R b ; 
 cycloalkylY or heterocyclylY wherein cycloalkyl or heterocyclyl each optionally is substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b  or C(O)R b ; 
 phenylY or heteroarylY wherein phenyl or heteroaryl each optionally is substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b  or C(O)R b ; 
   R 2  represents:
 phenyl which is optionally substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b  or C(O)R b . 
   
     
     
         3 . A method according to  claim 2 , wherein R 1  represents X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b  or NR a C(O)NR a R a . 
     
     
         4 . A method according to  claim 3 , wherein R 1  represents X which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b  or C(O)R b . 
     
     
         5 . A method according to  claim 1 , wherein R 3  represents aryl or Het 1  wherein aryl or Het 1  each is substituted by one of the following: Q, Het 2 , R or Het 3  and wherein aryl or Het 1  each is optionally substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a . 
     
     
         6 . A method according to  claim 1 , wherein R 3  represents aryl or Het 1  wherein aryl or Het 1  each optionally is substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , QZ, Het 2 Z, RZ, Het 3 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R a , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a . 
     
     
         7 . A method according to  claim 1 , wherein R 3  represents Het 4  or T wherein Het 4  or T each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O) 2 R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , Q, Het 2 , R, Het 3 , QZ, Het 2 Z, RZ, Het 3 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a , and wherein Het 4  or T each optionally is substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , thioxo, Q, Het 2 , R, Het 3 , QZ, Het 2 Z, RZ, Het 3 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a . 
     
     
         8 . A method according to  claim 2 , wherein R 3  represents aryl or Het 1  wherein aryl or Het 1  each is substituted by one of the following: Q, Het 2 , R or Het 3  and wherein aryl or Het 1  each is optionally substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a . 
     
     
         9 . A method according to  claim 2 , wherein R 3  represents aryl or Het 1  wherein aryl or Het 1  each optionally is substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , QZ, Het 2 Z, RZ, Het 3 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a . 
     
     
         10 . A method according to  claim 2 , wherein R 3  represents Het 4  or T wherein Het 4  or T each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , Q, Het 2 , Het 3 , QZ, Het 2 Z, RZ, Het 3 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a , and wherein Het 4  or T each optionally is substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , thioxo, Q, Het 2 , R, Het 3 , QZ, Het 2 Z, RZ, Het 3 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a . 
     
     
         11 . A method according to  claim 3 , wherein R 3  represents aryl or Het 1  wherein aryl or Het 1  each is substituted by one of the following: Q, Het 2 , R or Het 3  and wherein aryl or Het 1  each is optionally substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a . 
     
     
         12 . A method according to  claim 3 , wherein R 3  represents aryl or Het 1  wherein aryl or Het 1  each optionally is substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , QZ, Het 2 Z, RZ, Het 3 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a . 
     
     
         13 . A method according to  claim 3 , wherein R 3  represents Het 4  or T wherein Het 4  or T each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , Q, Het 2 , R, Het 3 , QZ, Het 2 Z, RZ, Het 3 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a , and wherein Het 4  or T each optionally is substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , thioxo, Q, Het 2 , R, Het 3 , QZ, Het 2 Z, RZ, Het 3 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a . 
     
     
         14 . A method according to  claim 4 , wherein R 3  represents aryl or Het 1  wherein aryl or Het 1  each is substituted by one of the following: Q, Het 2 , R or Het 3  and wherein aryl or Het 1  each is optionally substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a (O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a (O)NR a R a . 
     
     
         15 . A method according to  claim 4 , wherein R 3  represents aryl or Het 1  wherein aryl or Het 1  each optionally is substituted by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , QZ, Het 2 Z, RZ, Het 3 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a . 
     
     
         16 . A method according to  claim 4 , wherein R 3  represents Het 4  or T wherein Het 4  or T each optionally is substituted on the aromatic ring by one or more of the following independently selected from: halogen, OH, CN, NO 2 , NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , OSO 2 R b , NR a C(O)NR a R a , SO 2 NHC(O)R b , Q, Het 2 , R, Het 3 , QZ, Het 2 Z, RZ, Het 3 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR a R a  or NR a C(O)NR a R a , and wherein Het 4  or T each optionally is substituted on the non-aromatic ring by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , phenylC 1 alkyl, C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , SO 2 NR a R a , NR a SO 2 R b , NR a C(O)OR b , OC(O)NR a R a , NR a C(O)NR a R a , thioxo, Q, Het 2 , R, Het 3 , QZ, Het 2 Z, RZ, Het 3 Z, or C 1 -C 4 alkyl which is optionally substituted by one or more of the following independently selected from: F, OH, CN, NR a R a , OR b , SR b , SiR b R b R b , S(O)R b , SO 2 R b , C(O)R b , C(O)NR a R a , NR a C(O)R b , C(O)OR a , OC(O)R b , NR a SO 2 R b , SO 2 NR a R a , NR a C(O)OR b , OC(O)NR b R a  or NR a C(O)NR a R a . 
     
     
         17 . A method according to  claim 1  in which:
 R 1  is selected from methyl, ethyl, isopropyl, n-butyl, tert-butyl, 2-methoxyethyl, 6-aminopyridin-3-ylmethyl, 6-difluoromethoxyphenyl or 6-difluoromethoxybenzyl;   R 2  is selected from phenyl, 3-chlorophenyl, 4-chlorophenyl or 4-trifluoromethylphenyl; and   R 3  is selected from 4-methoxyphenyl, 4-hydroxyphenyl, 4-isopropoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4-fluorophenyl, 4-hydroxymethylphenyl, 1-benzyloxyphenyl, 4-cyclohexylphenyl, 4-morpholin-4-ylphenyl, 4-piperidin-1-ylphenyl, 4-pyrrolidin-1-ylphenyl, 4-azepan-1-ylphenyl, 4-benzylpiperazin-1-ylphenyl, 4-(tertbutoxycarbonylamino)phenyl, 4-(N-acetylsulfonamide)phenyl, 2-dimethylaminocarbonyl-1-benzofuran-5-yl, 2-acetyl-1-benzofuran-5-yl, 2-tertbutoxycarbonyl-1-benzofuran-5-yl, 2-carboxy-1-benzofuran-5-yl, 1-benzofuran-5-yl, 2-ethoxycarbonyl-3-methyl-1-benzothiophene-5-yl, 1H-indol-5-yl, 6-morpholin-4-ylpyridin-3-yl, 6-methoxypyridin-3-yl, 5-cyclohexyl-2-methoxyphenyl, 3-chloro-4-morpholin-4-ylphenyl, 2,5-diethoxy-4-morpholin-4-ylphenyl, 2-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl, 2-methylaminocarbonyl-3,4-dihydroisoquinoline-2(1H)-6-yl, 1,2,3,4-tetrahydroisoquinolin-6-yl, 2-tertbutoxycarbonyl-3,4-dihydroisoquinoline-2(1H)-6-yl, 5,6,7,8-tetrahydronaphtalen-1-yl, 2-thioxo-2,3-dihydro-1,3-benzothiazol-6-1H-isoindole-1,3(2H)-dione-5-yl, 1H-benzimidazol-2-yl, 1H-1,2,4-triazol-3-yl, 3-morpholin-4-yl-1H-1,2,4-triazol-5-yl or 5-methyl-1-phenyl-pyrazol-3-yl.   
     
     
         18 . A method of  claim 1  wherein the compound is selected from one or more of the following:
 2-tert-butyl-4-[(4-morpholin-4-ylphenyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-tert-butyl-4-[(4-methoxyphenyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-tert-butyl-5-phenyl-4-[(4-piperidin-1-ylphenyl)amino]isothiazol-3(2H)-one 1,1-dioxide   2-tert-butyl-4-[(4-isopropoxyphenyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-tert-butyl-5-phenyl-4-[(4-pyrrolidin-1-ylphenyl)amino]isothiazol-3(2H)-one 1,1-dioxide   tert-butyl {4-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]phenyl}carbamate   4-[(4-isopropoxyphenyl)amino]-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-isopropyl-5-phenyl-4-[(4-piperidin-1-ylphenyl)amino]isothiazol-3(2H)-one 1,1-dioxide   4-[(4-azepan-1-ylphenyl)amino]-2-tert-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-isopropyl-4-[(4-morpholin-4-ylphenyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-butyl-4-[(4-methoxyphenyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   4-[(2-acetyl-1-benzofuran-5-yl)amino]-2-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-tert-butyl-4-[(6-morpholin-4-ylpyridin-3-yl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-butyl-4-{[4-(difluoromethoxy)phenyl]amino}-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-butyl-4-[(4-morpholin-4-ylphenyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   tert-butyl 6-[(2-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]-3,4-dihydroisoquinoline-2(1H)-carboxylate   2-butyl-4-[(3-chloro-4-morpholin-4-ylphenyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-butyl-5-(3-chlorophenyl)-4-[(4-morpholin-4-ylphenyl)amino]isothiazol-3(2H)-one 1,1-dioxide   2-ethyl-4-[(4-morpholin-4-ylphenyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   4-[(2-acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino]-2-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-butyl-4-[(4-hydroxyphenyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-butyl-4-(1H-indol-5-ylamino)-5-phenylisothiazol-3(2H)-one 1,1-dioxide   5-[(2-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]-N,N-dimethyl-1-benzofuran-2-carboxamide   2-[4-(difluoromethoxy)benzyl]-4-[(4-morpholin-4-ylphenyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-butyl-5-(3-chlorophenyl)-4-{[4-(difluoromethoxy)phenyl]amino}isothiazol-3(2H)-one 1,1-dioxide   2-butyl-5-phenyl-4-{[4-(trifluoromethoxy)phenyl]amino}isothiazol-3(2H)-one 1,1-dioxide   2-butyl-4-{[4-(hydroxymethyl)phenyl]amino}-5-phenylisothiazol-3(2H)-one 1,1-dioxide   4-{[4-(benzyloxy)phenyl]amino}-2-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide   4-{[4-(4-benzylpiperazin-1-yl)phenyl]amino}-2-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-[4-(difluoromethoxy)benzyl]-4-[(4-methoxyphenyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   4-(1-benzofuran-5-ylamino)-2-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-butyl-5-(4-chlorophenyl)-4-{[4-(difluoromethoxy)phenyl]amino}isothiazol-3(2H)-one 1,1-dioxide   2-butyl-5-phenyl-4-(1H-1,2,4-triazol-3-ylamino)isothiazol-3(2H)-one 1,1-dioxide   2-butyl-4-[(5-methyl-1-phenyl-1H-pyrazol-3-yl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-butyl-4-[(6-methoxypyridin-3-yl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   4-[(2-acetyl-1-benzofuran-5-yl)amino]-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-[4-(difluoromethoxy)benzyl]-4-{[4-(difluoromethoxy)phenyl]amino}-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-butyl-5-phenyl-4-[(2-thioxo-2,3-dihydro-1,3-benzothiazol-6-yl)amino]isothiazol-3(2H)-one 1,1-dioxide   2-methyl-4-[(4-morpholin-4-ylphenyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   4-[(4-methoxyphenyl)amino]-2-methyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide   4-[(4-cyclohexylphenyl)amino]-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide   4-[(2-acetyl-1-benzofuran-5-yl)amino]-2-methyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-(2-methoxyethyl)-5-phenyl-4-(5,6,7,8-tetrahydronaphthalen-1-ylamino)isothiazol-3(2H)-one 1,1-dioxide   4-(1H-indol-5-ylamino)-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide   4-[(4-fluorophenyl)amino]-2-methyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-[(6-aminopyridin-3-yl)methyl]-4-[(4-morpholin-4-ylphenyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   N-({4-[(2-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]phenyl}sulfonyl)acetamide   ethyl 5-[(2-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]-3-methyl-1-benzothiophene-2-carboxylate   5-[(2-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]-1-benzofuran-2-carboxylic acid   tert-butyl 5-[(2-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]-1-benzofuran-2-carboxylate   4-[(2-acetyl-1-benzofuran-5-yl)amino]-2-ethyl-5-[4-(trifluoromethyl)phenyl]isothiazol-3(2H)-one 1,1-dioxide   2-(2-methoxyethyl)-4-[(3-morpholin-4-yl-1H-1,2,4-triazol-5-yl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   ethyl 5-{[2-(2-methoxyethyl)-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl]amino}-3-methyl-1-benzothiophene-2-carboxylate   4-[(5-cyclohexyl-2-methoxyphenyl)amino]-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide   4-[(4-hydroxyphenyl)amino]-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide   4-(1H-benzimidazol-2-ylamino)-2-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-[(6-aminopyridin-3-yl)methyl]-4-{[4-(difluoromethoxy)phenyl]amino}-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-methyl-4-[(6-morpholin-4-ylpyridin-3-yl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-butyl-5-phenyl-4-(1,2,3,4-tetrahydroisoquinolin-6-ylamino)isothiazol-3(2H)-one 1,1-dioxide   5-[(2-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]-1H-isoindole-1,3(2H)-dione   2-butyl-4-[(2,5-diethoxy-4-morpholin-4-ylphenyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-(2-methoxyethyl)-4-[(4-morpholin-4-ylphenyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide   4-{[4-(difluoromethoxy)phenyl]amino}-2-(2-methoxyethyl)-5-phenylisothiazol-3(2H)-one 1,1-dioxide   2-ethyl-4-[(4-morpholin-4-ylphenyl)amino]-5-[4-(trifluoromethyl)phenyl]isothiazol-3(2H)-one 1,1-dioxide   6-[(2-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]-N-methyl-3,4-dihydroisoquinoline-2(1H)-carboxamide   4-{[4-(difluoromethoxy)phenyl]amino}-2-methyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide   4-[(2-acetyl-1-benzofuran-5-yl)amino]-2-ethyl-5-[4-(trifluoromethyl)phenyl]isothiazol-3(2H)-one 1,1-dioxide   or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.   
     
     
         19 - 25 . (canceled)