Abstract:
This invention provides potassium channel modulators which are compounds of formula I 
                                 
where at least one of W and Z is N;
 
where the moiety
 
                                 
is one of Groups A or B below
 
A
 
                                 
where Ar is a 1,2-fused, six membered ring aromatic group, bearing substituents R 1  and R 2  as defined below, and containing zero or one ring nitrogen atom; and where other substituents are defined herein.
 
     The invention also provides a composition comprising a pharmaceutically acceptable carrier and at least one of the following: i) a pharmaceutically effective amount of a compound of formula I and ii) a pharmaceutically acceptable salt, ester, or prodrug thereof. The invention also provides a method of preventing or treating a disease or disorder which is affected by activities of potassium channels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a salt, ester, or prodrug thereof.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 60/934,396, filed Jun. 13, 2007, which is incorporated by reference herein in its entirety. 
    
    
     FIELD OF THE INVENTION 
     This invention concerns novel compounds that modulate potassium channels. The compounds are useful for the treatment and prevention of diseases and disorders which are affected by activities of potassium ion channels. One such condition is seizure disorders. 
     BACKGROUND OF THE INVENTION 
     Retigabine (N-[2-amino-4-(4-fluorobenzylamino)phenyl]carbamic acid, ethyl ester] (U.S. Pat. No. 5,384,330) has been found to be an effective treatment of seizure disorders in children. Bialer, M. et al.,  Epilepsy Research  1999, 34, 1-41. Retigabine has also been found to be useful in treating pain, including neuropathic pain. Blackburn-Munro and Jensen,  Eur. J. Pharmacol.  2003, 460, 109-116. 
     A form of epilepsy known as “benign familial neonatal convulsions” has been associated with mutations in the KCNQ2/3 channels. Biervert, C. et al.,  Science  1998, 27, 403-06; Singh, N. A. et al.,  Nat. Genet.  1998, 18, 25-29; Charlier, C. et al.,  Nat. Genet.  1998, 18, 53-55, Rogawski,  Trends in Neurosciences  2000, 23, 393-398. Subsequent investigations have established that the primary site of retigabine action is the KCNQ2/3 channel. Wickenden, A. D. et al.,  Mol. Pharmacol.  2000, 58, 591-600; Main, M. J. et al.,  Mol. Pharmcol.  2000, 58, 253-62. Retigabine has been shown to increase the conductance of the channels at the resting membrane potential and to bind the activation gate of the KCNQ 2/3 channel. Wuttke, T. V. et al.,  Mol. Pharmacol.  2005, 67, 1009-1017. 
     The recognition of retigabine as a potassium channel modulator has prompted a search for other potassium channel modulators among compounds related to retigabine. Several such searches have been reported in the patent literature, most notably the following: WO 2004/058739; WO 2004/80950; WO 2004/82677; WO 2004/96767; WO 2005/087754; and WO 2006/029623. 
     BRIEF DESCRIPTION OF THE INVENTION 
     In one embodiment, this invention provides a compound of formula I 
                                
where at least one of W and Z is N;
 
where the moiety
 
                                
hereafter denoted “Amine-Ring” is one of Groups A or B below
 
                                
where Ar is a 1,2-fused, six membered ring aromatic group, bearing substituents R 1  and R 2  as defined below, and containing zero or one ring nitrogen atom;
 
                                
where Ar is a 1,2-fused, six membered ring aromatic group, bearing substituents R 1  and R 2  as defined below, and containing zero or one ring nitrogen atom;
 
where R 1  and R 2 , are, independently, H, CN, halogen, CH 2 CN, OH, NO 2 , CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , C 1 -C 6  alkyl, C(═O)C 1 -C 6  alkyl, NH—C 1 -C 6  alkyl, NHC(═O)C 1 -C 6  alkyl, C(═O)N(CH 3 ) 2 , C(═O)N(Et) 2 , C(═O)NH—C 1 -C 6  alkyl, C(═O)OC 1 -C 6  alkyl, OC(═O)C 1 -C 6  alkyl, OC 1 -C 6  alkyl, SC 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, (CH 2 ) m C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkenyl, (CH 2 ) m C 3 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, Ar 1 , (CH 2 ) m Ar 1 , phenyl, pyridyl, pyrrolyl, (CH 2 ) m imidazolyl, (CH 2 ) m pyrazyl, furyl, thienyl, (CH 2 ) m oxazolyl, (CH 2 ) m isoxazolyl, (CH 2 ) m thiazolyl, (CH 2 ) m isothiazolyl, (CH 2 ) m phenyl, (CH 2 ) m pyrrolyl, (CH 2 ) m pyridyl, or (CH 2 ) m pyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from O, N, and S, and which alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imidazolyl, pyrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyrrolyl, pyridyl, or pyrimidyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methyl, ethyl, or trifluoromethyl, where m is zero, 1, or 2; or R 1  and R 2 , together with the ring carbon atoms to which they are attached, form a 5- or 6-member fused ring, which ring may be saturated, unsaturated, or aromatic, which optionally contains one or two heteroatoms selected independently from O, N, and S, and which is optionally substituted with halogen, CF 3 , or C 1 -C 3  alkyl; R′ is H, halogen, CF 3 , or C 1 -C 3  alkyl; R 3  and R 4  are, independently, H, CN, halogen, CF 3 , OCF 3 , OC 1 -C 3  alkyl, or C 1 -C 6  alkyl, all said C 1 -C 3  alkyl groups and said C 1 -C 6  alkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, C 1 -C 3  alkyl, OC 1 -C 3  alkyl, or trifluoromethyl; X═O or S; Y is O or S; q=1 or 0; R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl, CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where w=0-3, Ar 1  is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 ring heteroatoms selected independently from N, O, and S; R 6  is hydrogen or C 1 -C 3  alkyl; where all cycloalkyl and cycloalkenyl groups optionally contain one or two ring heteroatoms selected independently from N, O, and S; where all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , or Ar 1  are optionally substituted with one or two substituents selected independently from C 1 -C 3  alkyl, halogen, OH, OMe, SMe, CN, CH 2 F, and trifluoromethyl; where, additionally, all cycloalkyl and heterocycloalkyl groups are optionally substituted with either an exocyclic carbon-carbon double bond or a carbonyl group; and where, additionally, the alkenyl and alkynyl groups are also optionally substituted with phenyl or C 3 -C 6  cycloalkyl and all pharmaceutically acceptable salts thereof. Such compounds are potassium channel modulators.
 
     In alternative embodiments, this invention provides a compound of formula I, 
                                
where at least one of W and Z is N;
 
where the moiety
 
                                
hereafter denoted “Amine-Ring” is one of Groups A or B below
 
                                
where Ar is a 1,2-fused, six membered ring aromatic group, bearing substituents R 1  and R 2  as defined below, and containing zero, one, or two ring nitrogen atom;
 
                                
where Ar is a 1,2-fused, six membered ring aromatic group, bearing substituents R 1  and R 2  as defined below, and containing zero, one, or two ring nitrogen atom;
 
where R 1  and R 2 , are, independently, H, CN, halogen, CH 2 CN, OH, NO 2 , CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , C 1 -C 6  alkyl, C(═O)C 1 -C 6  alkyl, NH—C 1 -C 6  alkyl, NHC(═O)C 1 -C 6  alkyl, C(═O)N(CH 3 ) 2 , C(═O)N(Et) 2 , C(═O)NH—C 1 -C 6  alkyl, C(═O)OC 1 -C 6  alkyl, OC(═O)C 1 -C 6  alkyl, OC 1 -C 6  alkyl, SC 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, (CH 2 ) m C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkenyl, (CH 2 ) m C 3 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, Ar 1 , (CH 2 ) m Ar 1 , phenyl, pyridyl, pyrrolyl, (CH 2 ) m imidazolyl, (CH 2 ) m pyrazyl, furyl, thienyl, (CH 2 ) m oxazolyl, (CH 2 ) m isoxazolyl, (CH 2 ) m thiazolyl, (CH 2 ) m isothiazolyl, (CH 2 ) m phenyl, (CH 2 ) m pyrrolyl, (CH 2 ) m pyridyl, or (CH 2 ) m pyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from O, N, and S, and which alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imidazolyl, pyrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyrrolyl, pyridyl, or pyrimidyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methyl, ethyl, or trifluoromethyl, where m is zero, 1, or 2; or R 1  and R 2 , together with the ring carbon atoms to which they are attached, form a 5- or 6-member fused ring, which ring may be saturated, unsaturated, or aromatic, which optionally contains one or two heteroatoms selected independently from O, N, and S, and which is optionally substituted with halogen, CF 3 , or C 1 -C 3  alkyl; R′ is H, halogen, CF 3 , or C 1 -C 3  alkyl; R 3  and R 4  are, independently, H, CN, halogen, CF 3 , OCF 3 , OC 1 -C 3  alkyl, or C 1 -C 6  alkyl, all said C 1 -C 3  alkyl groups and said C 1 -C 6  alkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, C 1 -C 3  alkyl, OC 1 -C 3  alkyl, or trifluoromethyl; X═O or S; Y is O or S; q=1 or 0; R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl, CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where w=0-3, Ar 1  is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 ring heteroatoms selected independently from N, O, and S; R 6  is hydrogen or C 1 -C 3  alkyl; where all cycloalkyl and cycloalkenyl groups optionally contain one or two ring heteroatoms selected independently from N, O, and S; where all alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, alkynyl, aryl, and heteroaryl groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , or Ar 1  are optionally substituted with one or two substituents selected independently from C 1 -C 3  alkyl, halogen, OH, OMe, SMe, CN, CH 2 F, and trifluoromethyl; where, additionally, all cycloalkyl and heterocycloalkyl groups are optionally substituted with either an exocyclic carbon-carbon double bond or a carbonyl group; and where, additionally, the alkenyl and alkynyl groups are also optionally substituted with phenyl or C 3 -C 6  cycloalkyl and all pharmaceutically acceptable salts thereof. Such compounds are potassium channel modulators.
 
     In another embodiment, this invention provides a composition comprising a pharmaceutically acceptable carrier and at least one of the following: i) a pharmaceutically effective amount of a compound of formula I and ii) a pharmaceutically acceptable salt, ester, or prodrug thereof. 
     In yet another embodiment, this invention provides a method of preventing or treating a disease or disorder which is affected by modulation of potassium channels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a salt, ester, or prodrug thereof. 
     This invention includes all tautomers and salts, as well as all stereoisomeric forms, of compounds of this invention. This invention also includes all compounds of this invention where one or more atoms are replaced by a radioactive isotope thereof. 
     This invention provides or contemplates compounds of formula I above where NH—C(═X)—(Y) q —R 5  is each of the following: NHC(═O)R 5 , NHC(═O)OR 5 , NHC(═S)R 5 , NHC(═S)SR 5 , NHC(═S)OR 5 , and NHC(═O)SR 5 . 
     Thus, in one embodiment, this invention provides a compound of formula I, where NH—C(═X)—(Y) q —R 5  is NHC(═O)R 5 . 
     In another embodiment, this invention provides a compound of formula I, where NH—C(═X)—(Y) q —R 5  is NHC(═S)R 5 . 
     In another embodiment, this invention provides a compound of formula I, where NH—C(═X)—(Y) q —R 5  is NHC(═S)SR 5 . 
     In another embodiment, this invention provides a compound of formula I, where NH—C(═X)—(Y) q —R 5  is each NHC(═O)OR 5 . 
     In another embodiment, this invention provides a compound of formula I, where NH—C(═X)—(Y) q —R 5  is NHC(═S)OR 5 . 
     In another embodiment, this invention provides a compound of formula I, where NH—C(═X)—(Y) q —R 5  is NHC(═O)SR 5 . 
     In one subgeneric embodiment, this invention provides a compound of formula I, where Amine-Ring is Group A and NH—C(═X)—(Y) q —R 5  is NHC(═O)R 5  or NHC(═S)R 5 . 
     In another subgeneric embodiment, this invention provides a compound of formula I, where Amine-Ring is Group A and NH—C(═X)—(Y) q —R 5  is NHC(═O)SR 5  or NHC(═S)OR 5 . 
     In another subgeneric embodiment, this invention provides a compound of formula I, where Amine-Ring is Group A and NH—C(═X)—(Y) q —R 5  is NHC(═O)OR 5  or NHC(═S)SR 5 . 
     In another subgeneric embodiment, this invention provides a compound of formula I, where Amine-Ring is Group B and NH—C(═X)—(Y) q —R 5  is NHC(═O)R 5  or NHC(═S)R 5 . 
     In another subgeneric embodiment, this invention provides a compound of formula I, where Amine-Ring is Group B and NH—C(═X)—(Y) q —R 5  is NHC(═O)SR 5  or NHC(═S)OR 5 . 
     In another subgeneric embodiment, this invention provides a compound of formula I, where Amine-Ring is Group B and NH—C(═X)—(Y) q —R 5  is NHC(═O)OR 5  or NHC(═S)SR 5 . 
     In another subgeneric embodiment, this invention provides a compound of formula IA1 below. 
     
       
                 
         
             
             
         
      
     
     In another subgeneric embodiment, this invention provides a compound of formula IA2 below. 
     
       
                 
         
             
             
         
      
     
     In another subgeneric embodiment, this invention provides a compound of formula IA3 below. 
     
       
                 
         
             
             
         
      
     
     In another subgeneric embodiment, this invention provides a compound of formula IA4 below. 
     
       
                 
         
             
             
         
      
     
     In another subgeneric embodiment, this invention provides a compound of formula IA5 below. 
     
       
                 
         
             
             
         
      
     
     In another subgeneric embodiment, the invention provides a compound of formula IB1 below. 
     
       
                 
         
             
             
         
      
     
     In another subgeneric embodiment, the invention provides a compound of formula IB2 below. 
     
       
                 
         
             
             
         
      
     
     In another subgeneric embodiment, the invention provides a compound of formula IB3 below. 
     
       
                 
         
             
             
         
      
     
     In another subgeneric embodiment, the invention provides a compound of formula IB4 below. 
     
       
                 
         
             
             
         
      
     
     In another subgeneric embodiment, the invention provides a compound of formula IB5 below. 
     
       
                 
         
             
             
         
      
     
     In a more specific subgeneric embodiment, the invention provides a compound of any of formulas IA1-IA5, where W and Z are both N. 
     In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IA1-IA5, where W is N and Z is C. 
     In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IA1-IA5, where W is C and Z is N. 
     In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IA1-IA5, where R′ is H, halogen, CF3, or methyl. 
     In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IA1-IA5, where W and Z are both N and R′ is H, F, or methyl. 
     In another more specific subgeneric embodiment, the invention provides a compound of any of formulas IB1-IB5, where W and Z are both N. 
     In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IB1-IB5, where W is N and Z is C. 
     In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IB1-IB5, where W is C and Z is N. 
     In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IB1-IB5, where R′ is H, halogen, CF3, or methyl. 
     In another more specific subgeneric embodiment, this invention provides a compound of any of formulas IB1-IB5, where W and Z are both N and R′ is H, F, or methyl. 
     In a more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=1, Y is O, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In a still more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O; q=1; Y is O; R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl; and R 1  is H, CF 3 , or halogen. 
     In a still more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O; q=1; Y is O; R 5  is C 1 -C 6  alkyl, substituted with methoxy, methylthio, or halogen; and R 1  is H, CF 3 , or halogen. 
     In another subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=1, Y is O, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=1, Y is O, and R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=1, Y is S, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=1, Y is S, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=1, Y is S, and R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=zero, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O; q=zero; R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl; and R 1  is halogen. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O; q=zero; R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl; R′ is halogen or C 1 -C 3  alkyl; and R 1  is halogen. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=zero, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=zero, and R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=1, Y is O, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=1, Y is O, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=1, Y is O, and R 5  is Ar 1 , (CHR 6 )Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=zero, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=zero, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=zero, and R 5  is Ar 1 , (CHR 6 )Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=1, Y is S, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=1, Y is S, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=1, Y is S, and R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In a more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=1, Y is O, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In a still more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA-1, where X is O; q=1; Y is O; and R 5  is C 1 -C 6  alkyl, substituted with methoxy, methylthio, or halogen. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=1, Y is O, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=1, Y is O, and R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=1, Y is S, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=1, Y is S, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=1, Y is S, and R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=zero, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=zero, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is O, q=zero, and R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is S, q=1, Y is O, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is S, q=1, Y is O, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is S, q=1, Y is O, and R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is S, q=zero, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is S, q=zero, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is S, q=zero, and R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is S, q=1, Y is S, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA-1, where X is S, q=1, Y is S, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is S, q=1, Y is S, and R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=1, Y is O, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=1, Y is O, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=1, Y is O, and R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=1, Y is S, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=1, Y is S, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=1, Y is S, and R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=zero, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=zero, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is O, q=zero, and R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=1, Y is O, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=1, Y is O, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=1, Y is O, and R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=zero, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=zero, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=zero, and R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=1, Y is S, and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=1, Y is S, and R 5  is CR 6 ═CH—C 3 -C 6  cycloalkyl, CH═CR 6 —C 3 -C 6  cycloalkyl, (CHR 6 ) w C 5 -C 6  cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IB, where X is S, q=1, Y is S, and R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 . 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is O, q=1, Y is O, and R 5  is C 1 -C 6  alkyl or (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is S, q=1, Y is S, and R 5  is C 1 -C 6  alkyl or (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is S, q=1, Y is O, and R 5  is C 1 -C 6  alkyl or (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is O, q=1, Y is S, and R 5  is C 1 -C 6  alkyl or (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is O, q zero, and R 5  is C 1 -C 6  alkyl or (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In a still more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is O, q=zero, and R 5  is C 5 -C 6  alkyl, CH 2 —C 5 -C 6  cycloalkyl, CH 2 CH 2 —N-pyrrolidinyl, or CH 2 CH 2 —C 5 -C 6  cycloalkyl. 
     In another still more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is O, q=1, Y is O, and R 5  is C 5 -C 6  alkyl, CH 2 —C 5 -C 6  cycloalkyl, or CH 2 CH 2 —N-pyrrolidinyl, or CH 2 CH 2 —C 5 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R 1  is halogen; R 2  is H, halogen, or C 1 -C 4  alkyl; X is O; and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R 1  is halogen or halomethyl; R 2  is H, halogen, or C 1 -C 4  alkyl; X is O; and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R 1  is halogen or halomethyl; R 2  is H, halogen, or C 1 -C 4  alkyl; R′ is halogen, methyl, or halomethyl; X is O; and R 5  is C 1 -C 6  alkyl, (CHR 6 ) w C 3 -C 6  cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6  cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is O, q zero, and R 5  is C 3 -C 6  alkyl, CH 2 CH 2 -cyclopentyl or one of the groups below: 
     
       
                 
         
             
             
         
      
     
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R 1  is halogen or halomethyl; R 2  is H, halogen, or C 1 -C 4  alkyl; X is O; and R 5  is one of the groups above. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where X is S, q zero, and R 5  is C 1 -C 6  alkyl or (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R 1  is H, CN, halogen, CH 2 CN, OH, NO 2 , CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , C 1 -C 6  alkyl, or C(═O)C 1 -C 6  alkyl. 
     In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R 1  is C(═O)C 1 -C 6  alkyl, NHC(═O)C 1 -C 6  alkyl, C(═O)N(CH 3 ) 2 , C(═O)N(Et) 2 , C(═O)NH—C 1 -C 6  alkyl, C(═O)OC 1 -C 6  alkyl, or OC(═O)C 1 -C 6  alkyl. 
     In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R 1  is OC 1 -C 6  alkyl, SC 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, (CH 2 ) m C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkenyl, (CH 2 ) m C 3 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl. 
     In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R 1  is phenyl, pyridyl, pyrrolyl, (CH 2 ) m pyrazyl, (CH 2 ) m imidazolyl, (CH 2 ) m oxazolyl, (CH 2 ) m isoxazolyl, (CH 2 ) m thiazolyl, (CH 2 ) m pyridyl, (CH 2 ) m isothiazolyl, (CH 2 ) m phenyl, (CH 2 ) m pyrrolyl, or (CH 2 ) m pyrimidyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R 1  is C(═O)C 1 -C 6  alkyl, NHC(═O)C 1 -C 6  alkyl, C(═O)N(CH 3 ) 2 , C(═O)N(Et) 2 , C(═O)NH—C 1 -C 6  alkyl, C(═O)OC 1 -C 6  alkyl, or OC(═O)C 1 -C 6  alkyl, and R 5  is C 5 -C 6  alkyl or CH 2 —C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R 1  is OC 1 -C 6  alkyl, SC 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, (CH 2 ) m C 3 -C 6  cycloalkyl, C 3 -C 6  cycloalkenyl, (CH 2 ) m C 3 -C 6  cycloalkenyl, C 2 -C 6  alkenyl, or C 2 -C 6  alkynyl, and R 5  is C 5 -C 6  alkyl or CH 2 —C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R 1  is phenyl, pyridyl, pyrrolyl, (CH 2 ) m imidazolyl, (CH 2 ) m pyrazyl, (CH 2 ) m oxazolyl, (CH 2 ) m isoxazolyl, (CH 2 ) m thiazolyl, (CH 2 ) m isothiazolyl, (CH 2 ) m phenyl, (CH 2 ) m pyrrolyl, (CH 2 ) m pyridyl, or (CH 2 ) m pyrimidyl, and R 5  is C 5 -C 6  alkyl or CH 2 —C 3 -C 6  cycloalkyl. 
     In a more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=1, Y is O, and R 5  is Ar 1  or CH 2 —Ar 1 , where Ar 1  is unsubstituted phenyl, mono substituted phenyl, unsubstituted pyridyl, or unsubstituted pyrrolyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IA1-IA5, where X is O, q=zero, and R 5  is Ar 1  or CH 2 —Ar 1 , where Ar 1  is unsubstituted phenyl, mono substituted phenyl, unsubstituted pyridyl, or unsubstituted pyrrolyl. 
     In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA or IB, where R 1  and R 2  form a fused phenyl group, X is O, q=1, Y is O, and R 5  is C 1 -C 6  alkyl or (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA or IB, where R 1  and R 2  form a fused pyridyl group, X is O, q=1, Y is O, and R 5  is C 1 -C 6  alkyl or (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R 1  is halogen, C 1 -C 6  alkyl, mono-halo C 1 -C 6  alkyl, CN, di-halo C 1 -C 6  alkyl, CF 3 , CN, or O—C 1 -C 6  alkyl, and R 5  is C 5 -C 6  alkyl or CH 2 —C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R 1  is halogen, cyano, CF 3 , or methoxy, R 2  is H or methyl, R′ is H, halogen, or methyl, and R 5  is C 5 -C 6  alkyl or CH 2 —C 3 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R′ is halogen, CF 3 , or C 1 -C 3  alkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R 1  is halogen; R 2  is H or methyl, R′ is H, halogen, or methyl; and R 5  is C 5 -C 6  alkyl or CH 2 —C 5 -C 6  cycloalkyl. 
     In another more specific subgeneric embodiment, this invention provides or contemplates a compound of formula IA1, IA2, IA3, IA4, IA5, IB1, IB2, IB3, IB4 or IB5, where R 1  is halogen; R 2  is H or methyl, R′ is H, halogen, or methyl; and R 5  is CH 2 —C 4 -alkyl or CH 2 —C 5 — alkyl. 
     In another subgeneric embodiment, this invention provides a compound of formula I, where R 1  or R 5  is CH 2 Ar 1  or CH 2 CH 2 —Ar 1 , where Ar 1  is phenyl, pyridyl, pyrrolyl, imidazolyl, oxazolyl, or thiazolyl. 
     In another subgeneric embodiment, this invention provides a compound of formula I, where R 1  and R 2  form pyrrolo, imidazolo, oxazolo, or thiazolo. 
     In another subgeneric embodiment, this invention provides a compound of formula I, where R 1  or R 5  is CH 2 Ar 1  or CH 2 CH 2 —Ar 1 , where Ar 1  is isoxazolyl or isothiazolyl. 
     In another subgeneric embodiment, this invention provides a compound of formula I, where R 1  or R 5  is CH 2 Ar 1  or CH 2 CH 2 —Ar 1 , where Ar 1  is quinolyl or isoquinolyl. 
     In another subgeneric embodiment, this invention provides a compound of formula I, where R 1  or R 5  is CH 2 Ar 1  or CH 2 CH 2 —Ar 1 , where Ar 1  is pyrimidyl or purinyl. 
     In another subgeneric embodiment, this invention provides a compound of formula I, where R 1  or R 5  is CH 2 Ar 1  or CH 2 CH 2 —Ar 1 , where Ar 1  is indolyl, isoindolyl, or benzimidazolyl. 
     In a more specific embodiment, this invention provides a compound of formula I, where R 1  or R 5  is CH 2 Ar 1  or CH 2 CH 2 —Ar 1 , where Ar 1  is halo phenyl. 
     In another more specific embodiment, this invention provides a compound of formula I, where R 1  or R 5  is CH 2 Ar 1  or CH 2 CH 2 —Ar 1 , where Ar 1  is dihalophenyl or dihalopyridyl. 
     In another more specific embodiment, invention provides or contemplates a compound of formula I, where Ar 1  is mono- or di-halothienyl, mono- or di-halofuryl, mono- or di-halobenzothienyl, or mono- or di-halobenzofuryl. 
     In another more specific embodiment, this invention provides or contemplates a compound of formula I, where R 1  or R 5  is CH 2 Ar 1  or CH 2 CH 2 —Ar 1 , where Ar 1  is o-, m-, or p-xylyl or o-, m-, or p-anisyl. 
     In another more specific embodiment, this invention provides or contemplates a compound of formula I, where R 1  or R 5  is CH 2 Ar 1  or CH 2 CH 2 —Ar 1 , where Ar 1  is m- or p-cyanophenyl or m- or p-cyanomethyl phenyl. 
     In another more specific embodiment, this invention provides a compound of formula I, where R 1  or R 5  is CH 2 Ar 1  or CH 2 CH 2 —Ar 1 , where Ar 1  is C 2 -C 5  alkylphenyl. 
     In another more specific embodiment, this invention provides a compound of formula I, where R 1  or R 5  is CH 2 Ar 1  or CH 2 CH 2 —Ar 1 , where Ar 1  is 3,5-dichlorophenyl or 3,5-difluorophenyl. 
     In a more specific embodiment, this invention provides a compound of formula I, where R 1  or R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where Ar 1  is phenyl or pyridyl, R 3  and R 4  are H or C 1 -C 6  alkyl, unsubstituted or substituted with one or two groups selected from OH, OMe; R 1  is CN, CH 2 CN, or halogen; q is 1; and X and Y are both O. 
     In another subgeneric embodiment, this invention provides a compound of formula I, where R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where Ar 1  is phenyl or pyridyl, R 1  is F, CH 2 F, CHF 2 , CF 3 , or CF 2 CF 3 , q is 1, and X and Y are both O. 
     In a more specific embodiment, this invention provides a compound of formula I, where R 1  or R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where Ar 1  is phenyl or pyridyl, R 1  is OC 1 -C 6  alkyl or C(═O)C 1 -C 6  alkyl, q is 1, and X and Y are both O. 
     In a more specific embodiment, this invention provides a compound of formula I, where R 1  or R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where Ar 1  is phenyl or pyridyl, R 1  is C(═O)OC 1 -C 6  alkyl or OC(═O)C 1 -C 6  alkyl, q is 1, and X and Y are both O. 
     In a more specific embodiment, this invention provides a compound of formula I, where R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where Ar 1  is phenyl or pyridyl, R 1  is C 2 -C 6  alkenyl or C 2 -C 6  alkynyl, q is 1, and X and Y are both O. 
     In a more specific embodiment, this invention provides a compound of formula I, where where R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , Ar 1  is phenyl or pyridyl, R 1  is SC 1 -C 6  alkyl, q is 1, and X and Y are both O. 
     In a more specific embodiment, this invention provides a compound of formula I, where R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where Ar 1  is phenyl or pyridyl, R 3  and R 4  are H or C 1 -C 3  alkyl, R 1  is C 1 -C 6  alkyl, q is zero, and X is O. 
     In a more specific embodiment, this invention provides a compound of formula I, where R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where Ar 1  is phenyl or pyridyl; R 3  and R 4  are H or C 1 -C 3  alkyl; R 1  is C 1 -C 6  alkyl; q is 1; and X is O. 
     In a more specific embodiment, this invention provides a compound of formula I, where R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where Ar 1  is phenyl or pyridyl, R 3  and R 4  are H or C 1 -C 3  alkyl, R 1  is CN, CH 2 CN, or halogen, q is 1, Y is O, and X is O. 
     In another embodiment, this invention provides a compound of formula I, where R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where Ar 1  is thienyl, furyl, benzothienyl, or benzofuryl; R 3  and R 4  are, independently, H, methyl, or ethyl; and R 5  is C 1 -C 6  alkyl or (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another embodiment, this invention provides a compound of formula I, where R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where Ar 1  is pyrrolyl, imidazolyl, oxazolyl, or thiazolyl; R 3  and R 4  are, independently, H, methyl, or ethyl; and R 5  is C 1 -C 6  alkyl or (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another embodiment, this invention provides a compound of formula I, where R 5  is Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where Ar 1  is isoxazolyl or isothiazolyl; R 3  and R 4  are, independently, H, methyl, or ethyl; and R 5  is C 1 -C 6  alkyl or (CHR 6 ) w C 3 -C 6  cycloalkyl. 
     In another embodiment, this invention provides a compound of formula I, in which R 5  is C 1 -C 6  alkyl, where the alkyl group is substituted with one or two groups selected, independently, from OH, OMe, OEt, F, CF 3 , Cl, or CN. 
     In another embodiment, this invention provides a compound of formula I, in which R 5  is (CHR 6 ) w C 3 -C 6  cycloalkyl, where w is 1 or 2 and R 6  is H or methyl, and where the cycloalkyl group is substituted with Me, OH, OMe, OEt, F, CF 3 , Cl, or CN. 
     In a more specific embodiment, this invention provides a compound of formula I, in which R 5  is (CH 2 ) w —C 5 -C 6  cycloalkyl or (CH 2 ) w —C 5 -C 6  heterocycloalkyl. 
     In another embodiment, this invention provides a compound of formula I, in which R 5  is CH═CH—C 3 -C 6  cycloalkyl or heterocycloalkyl, where the carbon-carbon double bond has the E configuration. 
     In another embodiment, this invention provides a compound of formula I, in which R 5  is CH═CH—C 3 -C 6  cycloalkyl or heterocycloalkyl, where the carbon-carbon double bond has the Z configuration. 
     In another embodiment, this invention provides a compound of formula I, in which R 5  is CH 2 —CH═CH—C 3 -C 6  cycloalkyl or heterocycloalkyl, where the carbon-carbon double bond has the E configuration. 
     In another embodiment, this invention provides a compound of formula I, in which R 5  is CH 2 CH═CH—C 3 -C 6  cycloalkyl or heterocycloalkyl, where the carbon-carbon double bond has the Z configuration. 
     In another embodiment, this invention provides a compound of formula I, in which R 5  is CH═CH—CH 2 —C 3 -C 6  cycloalkyl or heterocycloalkyl, where the carbon-carbon double bond has the E configuration. In another embodiment, this invention provides a compound of formula I, in which R 5  is CH═CH—CH 2 —C 3 -C 6  cycloalkyl or heterocycloalkyl, where the carbon-carbon double bond has the Z configuration. 
     In another, more specific embodiment, this invention provides a compound of formula I, in which R 5  is (CHR 6 ) w C 3 -C 6  cycloalkyl or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl group is monosubstituted. 
     In another embodiment, this invention provides a compound of formula I, in which R 5  is CH═CH—CH 2 —C 3 -C 6  cycloalkyl or heterocycloalkyl or CH═CH—C 3 -C 6  cycloalkyl or heterocycloalkyl, where the cycloalkyl or heterocycloalkyl group is monosubstituted. 
     In another embodiment, this invention provides a compound of formula I, in which R 5  is C 5 -C 6  alkyl. 
     In another embodiment, this invention provides a compound of formula I, in which q is zero and R 5  is CH 2 —C 4 -alkyl or CH 2 —C 5 — alkyl. 
     In another embodiment, this invention provides a compound of formula I, in which R 5  is C 2 -C 6  alkynyl. 
     In another embodiment, this invention provides a compound of formula I, in which R 5  is C 2 -C 6  alkenyl. 
     In a more specific embodiment, this invention provides a compound of formula IA1, IA2, IA3, IA4, or IA5, where X is O, R 2 , R′, and R 3  are H, and q=zero. 
     In another embodiment, this invention provides a compound of formula IB1, IB2, IB3, IB4 or IB5, where X is O, R 2 , R′, and R 3  are H, and q=zero. 
     In a more specific embodiment, this invention provides a compound of formula IA1, IA2, IA3, IA4, or IA5, where X is O, R 2 , and R′ are H, R 3  and R 4  are methyl or methoxy, and q=zero. 
     In another embodiment, this invention provides a compound of formula IB1, IB2, IB3, IB4 or IB5, where X is O, R 2 , and R′ are H, R 3  and R 4  are methyl or methoxy, and q=zero. 
     In a more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IB1-IB5, where X is O; q=1; Y is O; and R 5  is C 1 -C 6  alkyl, CH 2 —C 3 -C 6  cycloalkyl, CH═CH—C 3 -C 6  cycloalkyl or CH═CH—CH 2 —C 3 -C 6  cycloalkyl. 
     In a still more specific subgeneric embodiment, this invention provides or contemplates a compound of any of formulas IB1-IB5, where X is O; q=1; Y is O; and R 5  is C 1 -C 6  alkyl, substituted with methoxy, methylthio, or halogen. 
     In a more specific embodiment, this invention provides a compound of formula IA1, IA2, IA3, IA4, or IA5, where X is O, R 2 , and R′ are H, R 3  and R 4  are methyl or methoxy, R 5  is C 5 -C 6  alkyl, and q=zero. 
     In another embodiment, this invention provides a compound of formula IB1, IB2, IB3, IB4 or IB5, where X is O, R 2 , and R′ are H, R 3  and R 4  are methyl or methoxy, R 5  is C 5 -C 6  alkyl, and q=zero. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     As used herein, the term heterocycloalkyl denotes a saturated carbocyclic moiety in which one or more ring carbon atoms is replaced by an atom selected from O, N, and S. As used herein, the term heterocycloalkenyl denotes a mono- or poly-unsaturated carbocyclic moiety in which one or more ring carbon atoms is replaced by an atom selected from O, N, and S. As used herein, the term heteroaryl denotes a mono- or bi-cyclic aromatic ring system with one or more ring atoms equal to O, N, and/or S. 
     Prophetic Examples 
     The examples below are intended to illustrate—but not to limit—the range of compounds contemplated by this invention. 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
     Preparation of Compounds 
     Preparation of Compounds as Potential KCNQ Channel Opener 
     Section I. The preparation of compounds of formula VIII is outlined in Scheme 1. 
     
       
                 
         
             
             
         
      
     
     Section II. The preparation of compounds of formula XI is outlined in Scheme 2. 
     
       
                 
         
             
             
         
      
     
     Section III. The preparation of compound of formula XIV is outlined in Scheme 3. 
     
       
                 
         
             
             
         
      
     
     Section IV. The preparation of compound of formula XV is outlined in Scheme 4. 
     
       
                 
         
             
             
         
      
     
     Section V. The preparation of compound of formula XVI is outlined in Scheme 5. 
     
       
                 
         
             
             
         
      
     
     Section VI. The preparation of compound of formula XX is outlined in Scheme 6. 
     
       
                 
         
             
             
         
      
     
     EXAMPLES 
     Example 1 
     N-(6-(3,4-dihydroisoquinolin-2(1H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutanamide 
     
       
                 
         
             
             
         
      
     
     Step 1. Synthesis of 2,4-dimethylnicotinic acid, 1a 
     
       
                 
         
             
             
         
      
     
     A mixture of ethyl 2,4-dimethylnicotinate (3.58 g, 20 mmol) and an aqueous solution of NaOH (10M, 20 ml) in ethanol (20 ml) was stirred at room temperature for 24 hours. The mixture was cooled to 0° C. and methanol (200 ml) was added follow by aqueous HCl (10 M) to adjust pH to 7. The resulting precipitated (NaCl) was filtered off. 
     The filtrated was concentrated to remain approximately 20 ml and methanol (100 ml) was added again to precipitate the remaining sodium chloride. The precipitation (NaCl) was repeated until all NaCl was removed from methanolic solution of the reaction mixture. The mixture was concentrated to dryness to yield 1a (3.01 g, 19.9 mmol, 99%). 
     Step 2. Synthesis of 2,4-dimethyl-3-aminopyridine, 1b 
     
       
                 
         
             
             
         
      
     
     A mixture of 1a (0.98 g, 6.5 mmol) and thionyl chloride (5 ml) was heated to 60° C. for 1 hour. The mixture was concentrated to dryness. The mixture was then dissolved in acetone (10 ml) prior to the addition of NaN 3  (0.65 g, 10 mmol) and water (5 ml). The solution was heated to 70° C. for 1 hour. Acetone was evaporated from the reaction mixture which was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO 4 , concentrated and chromatographed to yield 1b (0.585 g, 4.79 mmol, 74%). 
     Step 3. Synthesis of 6-bromo-2,4-dimethyl-3-aminopyridine, 1c 
     
       
                 
         
             
             
         
      
     
     A solution of bromine in dichloromethane (0.96 g in 5 ml) was added to a solution of 1b (0.585, 4.79 mmol) in dichloromethane (25 ml) at 0° C. over 5 minutes. The mixture was warmed to room temperature and stirred for 2 hours. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to yield 3c (0.364 g, 1.81 mmol, 38%). 
     Step 4. Synthesis of N-(6-bromo-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutanamide, 1d 
     
       
                 
         
             
             
         
      
     
     To a mixture of 1c (0.364 g, 1.81 mmol) and pyridine (0.158 ml, 2 mmol) in dichloromethane (5 ml) was added tert-butylacetyl chloride (0.242 g, 1.8 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO 4 , concentrated and chromatographed to yield 1d (0.361 g, 1.64 mmol, 91%). 
     Step 5. Synthesis of N-(6-(3,4-dihydroisoquinolin-2(1H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutanamide 
     
       
                 
         
             
             
         
      
     
     In a tube, a mixture of 1d (0.299 g, 1.0 mmol), 1,2,3,4-tetrahydroisoquinoline (0.20 g, 1.5 mmol) in toluene (10 ml) was degassed by nitrogen flow for 15 minutes. To this mixture was added tris(dichlorobenzylidenacetone)palladium (0) (0.046 g, 0.05 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.06 g, 0.15 mmol) and potassium tert-butoxide (0.168 g, 1.5 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 2 hour at 100° C. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 , concentrated and chromatographed to yield the title product (0.278 g, 0.79 mmol, 79%).  1 H NMR (CDCl 3 , 400 MHz) δ 1.14 (s, 9H), 2.19 (s, 3H), 2.27 (s, 2H), 2.35 (s, 3H), 2.93 (t, J=6.2 Hz, 2H), 3.84 (t, J=6.2 Hz, 2H), 4.66 (s, 2H), 6.39 (s, 1H), 6.49 (bs, 1H), 7.15-7.19 (m, 4H). 
     Example 2 
     N-(6-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutanamide 
     
       
                 
         
             
             
         
      
     
     In a tube, a mixture of 1d (0.65 g, 2.15 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline (0.348 g, 2.6 mmol) in toluene (15 ml) was degassed by nitrogen flow for 15 minutes. To this mixture was added tris(dichlorobenzylidenacetone)palladium (0) (0.052 g, 0.055 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.08 g, 0.2 mmol) and potassium tert-butoxide (0.437 g, 3.9 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 6 hour at 100° C. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 , concentrated and chromatographed to yield the title compound (0.584 g, 1.58 mmol, 73%).  1 H NMR (CDCl 3 , 400 MHz) δ 1.14 (s, 9H), 2.19 (s, 3H), 2.27 (s, 2H), 2.35 (s, 3H), 2.91 (t, J=6.2 Hz, 2H), 3.82 (t, J=6.2 Hz, 2H), 4.62 (s, 2H), 6.38 (s, 1H), 6.50 (bs, 1H), 6.85-6.92 (m, 2H), 7.09-7.16 (m, 1H). 
     Example 3 
     N-(2,4-dimethyl-6-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)pyridin-3-yl)-3,3-dimethylbutanamide 
     
       
                 
         
             
             
         
      
     
     In a tube, a mixture of 1d (0.374 g, 1.25 mmol), 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline (0.301 g, 1.5 mmol) in toluene (15 ml) was degassed by nitrogen flow for 15 minutes. To this mixture was added tris(dichlorobenzylidenacetone)palladium (0) (0.037 g, 0.04 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.06 g, 0.15 mmol) and potassium tert-butoxide (0.336 g, 3.0 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 6 hour at 100° C. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 , concentrated and chromatographed to yield the title compound (0.326 g, 0.78 mmol, 63%).  1 H NMR (CDCl 3 , 400 MHz) δ 1.14 (s, 9H), 2.19 (s, 3H), 2.27 (s, 2H), 2.35 (s, 3H), 2.91 (t, J=6.2 Hz, 2H), 3.82 (t, J=6.2 Hz, 2H), 4.62 (s, 2H), 6.39 (s, 1H), 6.55 (bs, 1H), 6.98 (d, J=7.2 Hz, 2H), 7.24 (s, 1H). 
     Example 4 
     N-(2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethoxypyrimidin-5-yl)-3,3-dimethylbutanamide 
     
       
                 
         
             
             
         
      
     
     Step 1. Synthesis of 2-chloro-4,6-dimethoxy-5-nitropyrimidine, 4a 
     
       
                 
         
             
             
         
      
     
     Triflic anhydride (4.25 g, 15 mmol) was added to a suspension of tetramethylammonium nitrate (2.04 g, 15 mmol) in dichloromethane (40 ml) at 0° C. over 15 minutes. The mixture was warmed to room temperature and stirred for 2 hours and then a solution of 2-chloro-4,6-dimethoxypyrimidine (1.75 g in 10 ml, 10 mmol) was added to the mixture over 30 minutes. The mixture was stirred for 2 days. The reaction mixture was poured into ice bath, washed with an aqueous solution of NaHCO 3  and extracted with dichloromethane. The organic layer was washed with brine, concentrated to dryness to yield 4a (2.13 g, 9.73 mmol, 97%). 
     Step 2. Synthesis of 2-(4,6-dimethoxy-5-nitropyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline, 4b 
     
       
                 
         
             
             
         
      
     
     1,8-diazabicyclo[5.4.0]undec-7-ene (0.304 g, 2 mmol) was added to a mixture of 4a (0.438 g, 2 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.293 g, 2.2 mmol) in DMF (3 ml) at 0° C. over 5 minutes. The mixture was stirred for an additional 5 minutes at room temperature. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to yield 4b (0.592 g, 1.87 mmol, 94%). 
     Step 3. Synthesis of 2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethoxypyrimidin-5-amine, 4c 
     
       
                 
         
             
             
         
      
     
     A suspension of Raney®-Nickel in a methanolic solution of 4b (0.57 g in 50 ml, 1.8 mmol) was shaken under 50 psi of hydrogen atmosphere for 12 hours. The mixture was filtered and the filtrate was concentrated and used for the next step without further purification (0.51 g, 1.78 mmol, 99%). 
     Step 4. Synthesis of N-(2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethoxypyrimidin-5-yl)-3,3-dimethylbutanamide. 4d 
     
       
                 
         
             
             
         
      
     
     To a mixture of 4c (0.219 g, 0.76 mmol) and pyridine (0.06 g, 0.76 mmol) in dichloromethane (5 ml) was added tert-butylacetyl chloride (0.102 g, 0.76 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO 4 , concentrated and chromatographed to yield the title compound (0.262 g, 0.73 mmol, 96%).  1 H NMR (CDCl 3 , 400 MHz) δ 1.10 (s, 9H), 2.20 (s, 2H), 2.90 (t, J=5.8 Hz, 2H), 3.92 (s, 6H), 4.01 (t, J=5.8 Hz, 2H), 4.87 (s, 2H), 6.14 (s, 1H), 7.15-7.19 (m, 4H). 
     Example 5 
     N-(4,6-dimethoxy-2-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-5-yl)-3,3-dimethylbutanamide 
     
       
                 
         
             
             
         
      
     
     Step 1. Refer to example 4 
     Step 2. Synthesis of 2-(4,6-dimethoxy-5-nitropyrimidin-2-yl)-6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline, 5b 
     
       
                 
         
             
             
         
      
     
     1,8-diazabicyclo[5.4.0]undec-7-ene (0.669 g, 4.4 mmol) was added to a mixture of 4a (0.438 g, 2 mmol) and 6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.487 g, 2.05 mmol) in DMF (5 ml) at 0° C. over 5 minutes. The mixture was stirred for an additional 5 minutes at room temperature. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to yield 5b (0.76 g, 1.98 mmol, 99%). 
     Step 3. Synthesis of 4,6-dimethoxy-2-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-5-amine, 5c 
     
       
                 
         
             
             
         
      
     
     A suspension of Raney®-Nickel in a methanolic solution of 5b (0.76 g in 50 ml, 1.98 mmol) was shaken under 50 psi of hydrogen atmosphere for 12 hours. The mixture was filtered and the filtrate was concentrated and used for the next step without further purification (0.69 g, 1.96 mmol, 99%). 
     Step 4. Synthesis of N-(4,6-dimethoxy-2-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-5-yl)-3,3-dimethylbutanamide 
     To a mixture of 5c (0.69 g, 1.96 mmol) and pyridine (0.156 g, 2.0 mmol) in dichloromethane (20 ml) was added tert-butylacetyl chloride (0.269 g, 2.0 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO 4 , concentrated and chromatographed to yield the title compound (0.657 g, 1.45 mmol, 72%).  1 H NMR (CDCl 3 , 400 MHz) δ 1.10 (s, 9H), 2.20 (s, 2H), 2.95 (t, J=5.8 Hz, 2H), 3.92 (s, 6H), 4.04 (t, J=5.8 Hz, 2H), 4.92 (s, 2H), 6.18 (s, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.44 (d, J=7.8 Hz, 1H). 
     Example 6 
     N-(2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethylpyrimidin-5-yl)-3,3- 
     
       
                 
         
             
             
         
      
     
     Step 1. Synthesis of ethyl 2-hydroxy-4,6-dimethylpyrimidine-5-carboxylate. 6a 
     
       
                 
         
             
             
         
      
     
     A mixture of ethyl diacetoacetate (17.22 g, 100 mmol), urea (9.61 g, 160 mmol) and HCl (10 M, 4 ml) in ethanol (400 ml) was heated to 90° C. for 12 hours. The mixture was concentrated to remain 200 ml and then was cooled to −20° C. to allow precipitation. The mixture was filtered at room temperature to obtained 6a as solid granulate (5.32 g, 2.71 mmol, 27%). 
     Step 2. Synthesis of ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate, 6b 
     
       
                 
         
             
             
         
      
     
     Phosphorus oxychloride (2.8 ml, 30 mmol) was added to a mixture of 6a (1.47 g, 7.5 mmol), benzyltriethylammonium chloride (1.71 g, 7.5 mmol) and N,N-dimethylaniline (1.82 g, 15 mmol) in acetonitrile (30 ml). The mixture was reflux for 5 hours. The mixture was poured into ice water and neutralized with NaHCO 3 . The solution was extracted with ethyl acetate. The organic layer washed with brine, dried over MgSO 4 , concentrated and chromatographed to obtain 6b, (1.02 g, 4.75 mmol, 63%). 
     Step 3. Synthesis of ethyl 2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethylpyrimidine-5-carboxylate, 6c 
     
       
                 
         
             
             
         
      
     
     1,8-diazabicyclo[5.4.0]undec-7-ene (1.086 g, 7.15 mmol) was added to a mixture of 6b (1.02 g, 4.75 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.95 g, 7.13 mmol) in DMSO (5 ml) at 0° C. over 5 minutes. The mixture was stirred for an additional 5 minutes at room temperature. The mixture was washed with brine, extracted with ethyl acetate and chromatographed to yield 6c (1.43 g, 4.5 mmol, 95%). 
     Step 4. Synthesis of 2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethylpyrimidine-5-carboxylic acid, 6d 
     
       
                 
         
             
             
         
      
     
     A mixture of 6c (1.43 g, 4.5 mmol) and an aqueous solution of NaOH (10M, 20 ml) in ethanol (20 ml) was refluxed for 6 hours. To the mixture was added 100 ml of water and then the mixture was washed with dichloromethane (100 ml). The aqueous phase was neutralized with hydrochloric acid to pH=6. Product was precipitated at pH=6. After filtration, 6d was obtained as white powder (1.10 g, 3.88 mmol, 86%). 
     Step 5. Synthesis of 2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethylpyrimidin-5-amine, 6e 
     
       
                 
         
             
             
         
      
     
     To a cold (−20° C.) thionyl chloride (5 ml) was added 9d (0.8 g, 2.82 mmol). The mixture was heated to 70° C. for 1 hour. Excess thionyl chloride was evaporated. The residue was dissolved in THF (3 ml) and acetone (3 ml) and then trimethylsilyl azide (0.55 ml, 4.25 mmol) was added into the mixture. The mixture was heated to 70° C. for 2 hours. The reaction media was washed with brine, extracted with ethyl acetate. Organic layer was dried over MgSO 4 , concentrated and chromatographed to yield 6e (0.028 g, 0.11 mmol, 4%). 
     Step 6. Synthesis of N-(2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethylpyrimidin-5-yl)-N-(3,3-dimethylbutanoyl)-3,3-dimethylbutanamide, 6f 
     
       
                 
         
             
             
         
      
     
     To a mixture of 6e (0.028 g, 0.11 mmol) and pyridine (0.03 g, 0.4 mmol) in dichloromethane (2 ml) was added tert-butylacetyl chloride (0.053 g, 0.4 mmol). The mixture was stirred at room temperature for 5 hour. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO 4 , concentrated and chromatographed to yield 6f (0.031 g, 0.07 mmol, 63%). 
     Step 7. Synthesis of N-(2-(3,4-dihydroisoquinolin-2(1H)-yl)-4,6-dimethylpyrimidin-5-yl)-3,3-dimethylbutanamide 
     
       
                 
         
             
             
         
      
     
     An aqueous solution of ammonium hydroxide (30%, 1 ml) was added to a solution of 6f (0.031 g, 0.07 mmol) in methanol (1 ml) and stirred for 20 hours. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO 4 , concentrated and chromatographed to yield the title compound (0.019 g, 0.054 mmol, 77%).  1 H NMR (CDCl 3 , 400 MHz) δ 1.11 (s, 9H), 2.23 (s, 2H), 2.30 (s, 6H), 2.91 (t, J=6.0 Hz, 2H), 4.04 (t, J=6.0 Hz, 2H), 4.89 (s, 2H), 6.68 (s, 1H), 7.17 (dd, J=7.8, 3.4 Hz, 4H). 
     Example 7 
     N-(6-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,4-dimethylpyridin-3-yl)-2-(2-methoxyethoxy)acetamide 
     Step 1. Synthesis of N-(6-bromo-2,4-dimethylpyridin-3-yl)-2-(2-methoxyethoxy)acetamide 
     
       
                 
         
             
             
         
      
     
     To a mixture of 1c (0.5114 g, 2.54 mmol) and pyridine (0.22 ml, 2.78 mmol) in dichloromethane (5 ml) was added 2-(2-methoxyethoxy)acetyl chloride (0.425 g, 2.78 mmol). The mixture was stirred at room temperature overnight. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO 4 , concentrated and chromatographed to yield 7d (0.72 g, 2.27 mmol, 90%). 
     Step 2. N-(6-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,4-dimethylpyridin-3-yl)-2-(2-methoxyethoxy)acetamide 
     
       
                 
         
             
             
         
      
     
     In a tube, a mixture of 7d (0.245 g, 0.77 mmol), 6-fluoro-1,2,3,4-tetrahydroisoquinoline (0.1876 g, 1.0 mmol) in toluene (5 ml) was degassed by nitrogen flow for 15 minutes. To this mixture was added tris(dichlorobenzylidenacetone)palladium (0) (0.025 g, 0.027 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.04 g, 0.1 mmol) and potassium tert-butoxide (0.336 g, 3.0 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 6 hour at 100° C. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 , concentrated and chromatographed to yield the title compound (0.259 g, 0.668 mmol, 87%).  1 H NMR (CDCl 3 , 400 MHz) δ 2.19 (s, 3H), 2.36 (s, 3H), 2.92 (t, J=5.7 Hz, 2H), 3.40 (s, 3H), 3.62 (dd, J=4.3, 2.2 Hz, 2H), 3.80-3.84 (m, 4H), 4.19 (s, 2H), 4.64 (s, 2H), 6.40 (s, 1H), 6.85-6.91 (m, 2H), 7.14 (dd, J=7.9, 7.9 Hz, 1H), 8.21 (bs, 1H). 
     Example 8 
     N-(2,4-dimethyl-6-(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)pyridin-3-yl)-2-(2-methoxyethoxy)acetamide 
     
       
                 
         
             
             
         
      
     
     In a tube, a mixture of 7d (0.2 g, 0.6 mmol), 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline (0.209 g, 0.88 mmol) in toluene (5 ml) was degassed by nitrogen flow for 15 minutes. To this mixture was added tris(dichlorobenzylidenacetone)palladium (0) (0.025 g, 0.027 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.04 g, 0.1 mmol) and potassium tert-butoxide (0.224 g, 2.0 mmol). The tube was heated under microwave irradiation (Biotage Initiator®) for 6 hour at 100° C. The reaction mixture was cooled to room temperature, washed with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO 4 , concentrated and chromatographed to yield the title compound (0.262 g, 0.6 mmol, 95%).  1 H NMR (CDCl 3 , 400 MHz) δ 2.18 (s, 3H), 2.35 (s, 3H), 2.96 (t, J=5.5 Hz, 2H), 3.37 (s, 3H), 3.62 (dd, J=3.8, 1.6 Hz, 2H), 3.78-3.84 (m, 4H), 4.17 (s, 2H), 4.71 (s, 2H), 6.41 (s, 1H), 7.27 (d, J=7.7, 1H), 7.40 (s, 1H) 7.41 (d, J=8.4 Hz, 1H), 8.25 (bs, 1H). 
     Example 9 
     N-(2,4-dimethyl-6-(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl)pyridin-3-yl)-3,3-dimethylbutanamide 
     
       
                 
         
             
             
         
      
     
     Bis(dibenzylidineacetone)palladium (4 mg, 0.069 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (6.5 mg, 0.014 mmol) were added to dry toluene (1 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (34 mg, 0.3 mmol), 1d (50 mg, 0.17 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (28 mg, 0.14 mmol) were then added and the reaction mixture was stirred at 80° C. over night. The reaction mixture was then cooled to room temperature, concentrated and purified by biotage (75% ethyl acetate:hexanes) to afford the tittle compound as a solid.  1 H NMR (DMSO-d 6 , 400 MHz) δ 1.03 (s, 9H), 2.09 (s, 3H), 2.15 (s, 2H), 2.21 (s, 3H), 3.03 (t, J=4 Hz, 2H), 3.92 (t, J=4 Hz, 2H), 4.79 (s, 2H), 6.68 (s, 1H), 8.12 (s, 1H), 8.75 (s, 1H), 9.02 (s, 1H). 
     Example 10 
     N-(6-(7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-2,4-dimethylpyridin-3-yl)-3,3-dimethylbutanamide 
     
       
                 
         
             
             
         
      
     
     Bis(dibenzylidineacetone)palladium (5 mg, 0.009 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (9 mg, 0.018 mmol) were added to dry toluene (1 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (46 mg, 0.41 mmol), 1d (66 mg, 0.22 mmol) and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (25 mg, 0.19 mmol) were then added and the reaction mixture was stirred at 80° C. over night. The reaction mixture was then cooled to room temperature, concentrated and purified by biotage (75% Ethyl acetate:Hexanes) to afford the tittle compound as a solid.  1 H NMR (CDCl 3 , 400 MHz) δ 1.15 (s, 9H), 2.21 (s, 3H), 2.28 (s, 2H), 2.36 (s, 3H), 3.06 (t, J=4 Hz, 2H), 3.92 (t, J=4 Hz, 2H), 4.73 (s, 2H), 6.48 (s, 1H), 6.55 (s, 1H), 8.55 (s, 1H), 9.01 (s, 1H). 
     Example 11 
     N-(2,4-dimethyl-6-(2-(trifluoromethyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)pyridin-3-yl)-3,3-dimethylbutanamide 
     
       
                 
         
             
             
         
      
     
     Bis(dibenzylidineacetone)palladium (4 mg, 0.07 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethylamine (6.5 mg, 0.014 mmol) were added to dry toluene (1 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (34 mg, 0.31 mmol), 1d (50 mg, 0.18 mmol) and 2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (28 mg, 0.14 mmol) were then added and the reaction mixture was stirred at 80° C. over night. The reaction mixture was then cooled to room temperature, concentrated and purified by biotage (75% Ethyl acetate:Hexanes) to afford compound 9 as a solid.  1 H NMR (CDCl 3 , 400 MHz) δ 1.14 (s, 9H), 2.21 (s, 3H), 2.28 (s, 2H), 2.36 (s, 3H), 3.17 (t, J=4 Hz, 2H), 3.92 (t, J=4 Hz, 2H), 4.83 (s, 2H), 6.51 (s, 1H), 8.70 (s, 1H). 
     Biological Results 
     Compounds of this invention formula were evaluated as potassium channel modulators by measuring rhubidium release in the following assay. 
     Methods: PC-12 cells were grown at 37° C. and 5% CO 2  in DMEM/F12 Medium supplemented with 10% horse serum, 5% fetal bovine serum, 2 mM glutamine, 100 U/ml penicillin, 100 U/ml streptomycin. They were plated in poly-D-lysine-coated 96-well cell culture microplates at a density of 40,000 cells/well and differentiated with 100 ng/ml NGF-7s for 2-5 days. For the assay, the medium was aspirated and the cells were washed once with 0.2 ml in wash buffer (25 mM Hepes, pH 7.4, 150 mM NaCl, 1 mM MgCl 2 , 0.8 mM NaH 2 PO 4 , 2 mM CaCl 2 ). The cells were then loaded with 0.2 ml Rb +  loading buffer (wash buffer plus 5.4 mM RbCl 2 , 5 mM glucose) and incubated at 37° C. for 2 h. Attached cells were quickly washed three times with buffer (same as Rb +  loading buffer, but containing 5.4 mM KCl instead of RbCl) to remove extracellular Rb + . Immediately following the wash, 0.2 ml of depolarization buffer (wash buffer plus 15 mM KCl) with or without compounds was added to the cells to activate efflux of potassium ion channels. After incubation for 10 min at room temperature, the supernatant was carefully removed and collected. Cells were lysed by the addition of 0.2 ml of lysis buffer (depolarization buffer plus 0.1% Triton X-100) and the cell lysates were also collected. If collected samples were not immediately analyzed for Rb +  contents by atomic absorption spectroscopy (see below), they were stored at 4° C. without any negative effects on subsequent Rb +  analysis. 
     The concentration of Rb +  in the supernatants (Rb +   Sup ) and cell lysates (Rb +   Lys ) was quantified using an ICR8000 flame atomic absorption spectrometer (Aurora Biomed Inc., Vancouver, B.C.) under conditions defined by the manufacturer. One 0.05 ml samples were processed automatically from microtiter plates by dilution with an equal volume of Rb +  sample analysis buffer and injection into an air-acetylene flame. The amount of Rb +  in the sample was measured by absorption at 780 nm using a hollow cathode lamp as light source and a PMT detector. A calibration curve covering the range 0-5 mg/L Rb +  in sample analysis buffer was generated with each set of plates. The percent Rb +  efflux (F) was defined by F=[Rb +   sup /(Rb +   sup +Rb +   Lys )]×100%. 
     The effect (E) of a compound was defined by: E=[(F c −F b )/(F s −F b )]×100% where the F c  is the efflux in the presence of compound in depolarization buffer, F b  is the efflux in basal buffer, and F s  is the efflux in depolarization buffer, and F c  is the efflux in the presence of compound in depolarization buffer. The effect (E) and compound concentration relationship was plotted to calculate an EC 50  value, a compound&#39;s concentration for 50% of maximal Rb +  efflux. The results are shown below. Legend: A: EC50=1 nM-50 nM; B: EC50=50 nM-100 nM; C: EC50=100-200 nM. 
     
       
         
               
             
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 ACTIVITIES OF EXEMPLARY COMPOUNDS 
               
             
          
           
               
                 COMPOUND 
                 ACTIVITY 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A 
               
               
                   
               
               
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B